Organic Chemistry in Single- and Multiphase Continuous ... - unipub

DISSERTATION

ZUR ERLANGUNG DES DOKTORGRADES DER

NATURWISSENSCHAFTLICHEN FAKULTÄT DER

KARL-FRANZENS-UNIVERSITÄT GRAZ

ZUM THEMA

Organic Chemistry in Single- and

Multiphase Continuous Flow Regimes

VORGELEGT VON

BARTHOLOMÄUS PIEBER, MSc

am Institut für Chemie

Erstbegutachter: Prof. Dr. C. Oliver Kappe

Zweitbegutachter: Prof. Dr. Frank Uhlig

2015

Obstacles are those frightful things you see

when you take your eyes off your goal.

-Henry Ford

Acknowledgements

The present thesis was accomplished at the Christian Doppler Laboratory for Flow Chemistry

(CDLMC), Institute of Chemistry, Karl-Franzens-University Graz, Austria between

November 2011 and July 2015 under the supervision of Prof. Dr. C. Oliver Kappe. The work

was supported by a grant from the Christian Doppler Research Association (CDG) and

ThalesNano (Budapest, Hungary).

First, I would like to thank my supervisor Prof. C. Oliver Kappe for his guidance,

encouragement and support during this thesis and for giving me the opportunity to work in an

exciting and growing scientific field. I am extremely thankful for his continuous motivation

and especially his trust in me and my ideas.

Special thanks to all former and present colleagues in the group: I am very happy that I had

the ability to work in such an enthusiastic lab. I would especially like to thank Bernhard and

David for their ongoing scientific support. Without you this thesis would lack a lot of quality

and the last years would have never been as funny as they were!

Many thanks to my colleagues Dr. Sigurd Schober, and Dr. Harald Hofbauer for their

scientific support, their motivating words and the possibility to talk about other topics besides

chemistry while drinking a (few) beer(s) during the last couple of years.

I want to express my gratitude to my better half, Cathrin: You are the most important part of

my life and I am very thankful and thoroughly lucky that I found you. You make me happy

like no one else can on every single day.

Thanks to all of my friends who supported me during the last years! Everything is easier when

you are surrounded by so many amazing people.

Last but not least, I am greatly indebted to my family for their financial and moral support

during my whole life.

List of Publications

1 G. S. Kumar, B. Pieber, K. R. Reddy, C. O. Kappe, “Copper-Catalyzed Formation of C-

O Bonds by Direct α-C-H Bond Activation of Ethers Using Stoichiometric Amounts of

Peroxide in Batch and Continuous-Flow Formats”, Chemistry a European Journal,

2012, 18, 6124.

2 B. Pieber, C. O. Kappe, “Direct Aerobic Oxidation of 2-Benzylpyridines in a Gas-

Liquid Continuous-Flow Regime using Propylene Carbonate as Solvent”, Green

Chemistry, 2013, 15, 320.

3 B. Pieber, S. Teixeira Martinez, D. Cantillo and C. O. Kappe, “In situ Generation of

Diimide from Hydrazine and Oxygen - Transfer Hydrogenation of Olefins in

Continuous Flow”, Angewandte Chemie International Edition, 2013, 52, 10241.

4 B. Pieber, T. Glasnov, C. O. Kappe, ”Flash Carboxylation: Fast Lithiation

Carboxylation Sequence at Room Temperature in Continuous Flow” RSC Advances,

2014, 4, 13430.

5 M. M. Moghaddam, B. Pieber, T. Glasnov, C. O. Kappe, “Immobilized Iron Oxide

Nanoparticles as Stable and Reusable Catalysts for Hydrazine-mediated Nitro

Reductions in Continuous Flow”, ChemSusChem, 2014, 7, 3122.

6 B. Pieber, T. Glasnov, C. O. Kappe, “Continuous Flow Reduction of Artemisinic Acid

Utilizing Multi-Injection Strategies – Closing the Gap Toward a Fully Continuous

Synthesis of Antimalaria Drugs”, Chemistry a European Journal, 2015, 21, 4368.

7 C. E. M. Salvador, B. Pieber, P. M. Neu, A. Torvisco, C. K. Z. Andrade, C. O. Kappe,

“A Sequential Ugi Multicomponent/Cu-Catalyzed Azide-Alkyne Cycloaddition

Approach for the Continuous Flow Generation of Cyclic Peptoids”, Journal of Organic

Chemistry, 2015, 80, 4590.

8 B. Pieber, C. O. Kappe, “Aerobic Oxidations in Continuous Flow”, Topics in

Organometallic Chemistry, 2015, in press.

9 J. L. Monteiro, B. Pieber, A. G. Corrêa, C. O. Kappe, “Continuous Synthesis of

Hydantoins: Intensifying the Bucherer-Bergs Reaction”, 2015, submitted.

Table of Contents

i

Table of Contents

Introduction 1

Part 1: Gas/Liquid Reactions in Continuous Flow 11

A. Aerobic Oxidations in Continuous Flow 13

1. Introduction 15

2. Technological Aspects 16

3. Oxidation of Hydrocarbons 18

4. Oxidation of Alcohols 24

4.1 Heterogeneous Catalysis in Common Solvents 24

4.2 Heterogeneous Catalysis in Supercritical CO2 30

4.3 Homogeneous Catalysis 34

5. Oxidation of Aldehydes 37

6. Oxidative Carbon-Carbon Coupling Reactions 39

7. Miscellaneous 43

8. Photochemical Reactions Involving Molecular Oxygen 45

9. Concluding Remarks 50

10. References 51

B. Direct Aerobic Oxidation of 2-Benzylpyridines in a Gas-Liquid

Continuous-Flow Regime using Propylene Carbonate as Solvent 59

1. Introduction 61

2. Results and Discussion 63

3. Conclusion 67

4. References 67

5. Supporting Information 70

Table of Contents

ii

C. In situ Generation of Diimide from Hydrazine and Oxygen - Transfer

Hydrogenation of Olefins in Continuous Flow 77

1. Introduction 79


3. Conclusion 85

4. References 86


D. Continuous Flow Reduction of Artemisinic Acid Utilizing Multi-

Injection Strategies – Closing the Gap Toward a Fully Continuous

Synthesis of Antimalaria Drugs 111

1. Introduction 113


2.1 Continuous Flow Concept 115

2.2 Process Intensification, Scope and Limitations 116

2.3 Efficiency of Hydrazine Oxidation 120

2.4 Reduction of Artemisinic Acid 122

3. Conclusion 127

4. References 128


E. Flash Carboxylation: Fast Lithiation Carboxylation Sequence at

Room Temperature in Continuous Flow 139

1. Introduction 141


3. Conclusion 145

4. References 146


Table of Contents

iii

F. Continuous Synthesis of Hydantoins: Intensifying the Bucherer-Bergs

Reaction 157

1. Introduction 159


3. Conclusion 165

4. References 165


Part 2: Homogeneous and Solid/Liquid Reactions in Continuous Flow 179

G. Copper-Catalyzed Formation of C-O Bonds by Direct α-C-H Bond

Activation of Ethers Using Stoichiometric Amounts of Peroxide in Batch

and Continuous-Flow Formats 181

1. Introduction 183


3. Conclusion 190

4. References 190


H. Immobilized Iron Oxide Nanoparticles as Stable and Reusable Catalysts

for Hydrazine-mediated Nitro Reductions in Continuous Flow 209

1. Introduction 211


2.1 Synthesis, Evaluation, and Characterization of Supported Fe3O4 Nanoparticles 214

2.2 Bench Stability of nano-Fe3O4@Al2O3 217

2.3 Scope and Limitations in Batch 218

2.4 Continuous Flow Reactor 219

2.5 Process Intensification in Continuous Flow 220

2.6 Scope and Limitations in Continuous Flow 222

2.7 Catalyst Stability in Continuous Flow 223

3. Conclusion 225

4. Experimental Section 226

5. References 230

Table of Contents

iv

I. A Sequential Ugi Multicomponent/Cu-Catalyzed Azide-Alkyne

Cycloaddition Approach for the Continuous Flow Generation of Cyclic

Peptoids 235

1. Introduction 237


2.1 Peptoid Synthesis 241

2.2 Isocyanide Preparation 244

2.3 Azide Formation 246

2.4 Multistep Synthesis of Linear Peptoids in Continuous Flow 247

2.5 CuAAC in Continuous Flow 249

3. Conclusion 252

4. Experimental Section 253

5. References 261


Summary & Concluding Remarks 273

Introduction

1

Introduction

Within the last decades continuous flow chemistry emerged from an exotic curiosity in

research laboratories to a well-recognized technique for performing organic synthesis.[1,2]

In

stark contrast to traditional batch procedures, a flow reaction is carried out by introducing a

continuous stream of reactants, reagents and, if necessary, catalysts into a reactor unit

(Scheme 1). After a well-defined amount of time (residence time) the reaction mixture is

continuously leaving the reactor and either collected or subsequently used in another

continuous transformation or purification step. The residence time is determined by the

volume of the reaction zone and the flow rate of the solution which is typically controlled by

standard HPLC, syringe or peristaltic pumps. If more than one stream is used, an active or

passive mixing element combines the different feeds before entering the reaction zone.

Various reactor types can be utilized for carrying out a continuous flow reaction depending on

the processing conditions and the respective chemical transformation. Homogeneous reactions

and biphasic gas/liquid or liquid/liquid reactions are typically performed in chip or coil

reactors made of glass, simple polymeric materials, ceramics or metals/alloys.[1,2]

Reactions

involving heterogeneous catalysts or reagents are generally carried out in packed bed reactors

where the insoluble material is physically trapped inside a cartridge or immobilized on the

channel wall.[1-3]

A further important feature is the use of a pressure regulating unit which

allows straightforward access to elevated pressure regimes. Thus, reactions can be

conveniently performed far above the boiling point of the respective solvent often resulting in

highly intensified processes.

Scheme 1. Schematic description of a simple continuous flow reactor

Introduction

2

Most continuous flow reactors which are utilized in the synthesis of fine chemicals or

pharmaceuticals are characterized by channel sizes below 1000 µm and are often referred as

microreactors.[1-2]

These small dimensions offer unique advantages compared to conventional

“flask chemistry” and opens new horizons for synthetic chemists.

By utilizing microreactor technology a highly efficient mixing of two or more reagent

streams can be easily achieved as diffusion paths are reduced by the order of magnitudes

compared to conventional batch reactors.[1,2]

Thus, continuous flow processing enables a very

accurate control of the reaction time (= residence time, tRes) for extremely fast reactions where

the overall rate is controlled by mass transfer/mixing phenomena. When the substrate and

reagent feeds are merged, the chemical transformation starts and by addition of a quenching

reagent it is immediately stopped (Scheme 2). Residence time control is therefore achieved by

either varying the length/volume of the reaction zone or the flow rate of one or both feeds.

Scheme 2. Residence time control in continuous flow

Another important characteristic is the exceptional heat transfer in a microstructured flow

reactor resulting from the high surface-to-volume ratio.[1,2]

This is extremely important for

controlling highly exothermic reactions where heat has to dissipate from the reaction mixture.

Moreover, precise heating (or cooling) of a reaction mixture happens almost instantaneously.

In general, flow chemistry often provides a safe alternative to hazardous batch

processes due to the small channel dimensions and reactor volumes.[1,2]

Toxic, unstable and

explosive intermediates can be generated in-situ and subsequently used in continuous multi-

step sequences thus avoiding exposure, handling, storage and transport of such substances.

The high pressure resistance of small coil, chip and packed-bed reactors enables processing of

usually slow transformations at high temperature/pressure conditions (“novel process

windows”) in a safe and controllable manner allowing to increase reaction rates - even for

reaction under explosive regimes - on a routine basis.[4]

Introduction

3

An important point for every chemical process is undoubtedly its scalability. In general,

scaling of processes established in continuous flow mode are considerably easier than for

protocols developed in a batch reactor.[1-2]

In many cases, the flow conditions developed in a

research laboratory can be directly translated to larger flow reactors or require just a minimal

re-optimization (scale-up). Alternatively, microreactors can be simply operated for extended

time periods in order to produce sufficient quantities of the desired product (scale-out).

Another promising strategy, especially for the fine chemical industry, is the parallel operation

of several identical continuous flow reactors for production scale (numbering-up).

Especially biphasic reactions (gas/liquid, liquid/liquid, solid/liquid) often dramatically

benefit from microreactor technology due to a significantly enlarged interfacial and an

improved mass transfer. Since the solubility of most gases in organic chemistry is usually

rather low under standard conditions, high pressure operation is often essential for sufficient

reaction rates. Moreover, the utilization of many gaseous reagents suitable for synthetic

applications such as O2, O3, H2 or even CH2N2 is accompanied by severe safety hazards

which are naturally addressed by continuous flow chemistry.[1,2]

Importantly, the flow pattern of a biphasic gas/liquid or liquid/liquid reaction is a

controllable parameter and has a significant impact on the interfacial area and the overall flow

rate (Scheme 3).[1,2]

Depending on the temperature, back pressure, the the flow rate of the

immiscible phases, their partial solubility and physical properties such as surface tension as

well as viscosity different regimes can be observed. In most applications segmented flow

patterns (sometimes also referred to as slug-, plug-, or Taylor flow) are utilized for biphasic

reactions in continuous flow mode. It is worth noting that once these segments are formed, an

internal fluid vortex is generated which causes internal mixing in each segment. Thus, the

interfacial area is continuously refreshed which also contributes to rate acceleration in

biphasic reactions utilizing this enabling technology.

Scheme 3. Flow patterns in biphasic continuous flow applications

Introduction

4

The first part of this thesis focuses on gas/liquid reactions in continuous flow mode for the

production of fine chemicals. The first chapter embodies a comprehensive overview on recent

developments for aerobic oxidations in continuous flow. This critical review includes a

general part on gas/liquid processing as well as current state of the art examples for the

continuous oxidation of hydrocarbons, alcohols, aldehydes and other small organic molecules

utilizing molecular oxygen. Furthermore, oxidative carbon-carbon couplings and

photochemical reactions involving O2 are discussed. Many of these transformations are

usually carried out at elevated temperatures and pressures in organic solvents posing severe

explosion risks. Importantly, the possibility for flame propagation is minimized in the small

channel dimensions of a continuous flow microreactor making it an ideal tool for intensifying

such oxidation reactions even under traditionally “forbidden” conditions.

In that respect, the continuous aerobic oxidation of 2-benzylpyridines to the respective

ketones in an iron-catalyzed protocol is presented in chapter B (Scheme 4). In this example,

the reaction rate is highly increased by working at elevated temperatures (200°C) in an

annular flow regime resulting in a reduction of the reaction time from hours in batch to

several minutes in flow mode.

Scheme 4. Aerobic oxidation of 2-benzylpyridines in continuous flow formats (Chapter B)

Moreover, a segmented flow pattern for the in situ generation of diimide (N2H2) from

molecular oxygen and hydrazine hydrate and its subsequent utilizations for the highly

selective reduction of olefins is discussed in chapter C (Scheme 5). This approach exemplifies

how a combination of the increased mass transfer for biphasic gas/liquid reactions in

continuous flow and high temperature/pressure processing enables chemical transformations

which cannot be (safely) reproduced in batch environments. The initial oxidation of hydrazine

hydrate is rather slow under conventional conditions and usually requires the utilization of a

catalytic species. On the contrary, continuous flow processing allows a catalyst-free olefin

reduction within just several minutes under intensified conditions. As water and nitrogen gas

Introduction

5

are produced as only byproducts this straightforward and selective transformation is

essentially work-up free.

In addition, a detailed study of the hydrazine oxidation with special emphasis on side-

reactions of the reactive intermediate (N2H2) under continuous flow conditions leading to an

advanced methodology for less reactive olefins is described in chapter D. The effective

residence time could be increased by expanding the continuous system by multiple addition of

hydrazine hydrate to circumvent over-oxidation of diimide and reduce its disproportionation.

This strategy enables a highly selective reduction of artemisinic acid resulting in the direct

precursor of the important antimalarial drug artemisinin.

Scheme 5. Olefin reduction via in situ generation of diimide (Chapter C and D)

In chapter E, the accurate residence time control gained by the exceptional mixing capability

in flow devices is utilized for the development of a continuous lithiation-carboxylation

sequence at room temperature (Scheme 6). Initially, a terminal alkyne or a heterocyclic

starting material is directly lithiated upon mixing with a suitable organolithium compound.

After less than 5 seconds the reaction mixture is quenched with gaseous carbon dioxide as

electrophile. Moreover, the extremely fast carboxylation step (~0.5 s) is precisely controlled

by an additional feed for quenching the reaction mixture with water.

Scheme 6. Lithiation-carboxylation sequence in continuous flow (Chapter E)

Introduction

6

Mixing and mass transfer characteristics are also important attributes for the intensified

Bucherer-Bergs reaction in continuous flow (Chapter F). This multicomponent reaction for

the synthesis of hydantoins from simple ketones or aldehydes using potassium cyanide and

ammonium carbonate represents a combination of biphasic liquid/liquid and gas/liquid

continuous flow processing (Scheme 7). Initially, an organic stream containing the precursor

molecule is mixed with an aqueous reagent stream resulting in segmented flow pattern for an

accurate stoichiometry control. Upon heating in the reaction zone (NH4)2CO3 decomposes to

generate ammonia and carbon dioxide as the final reagents. The main benefit of the

continuous route is the lack of gaseous headspace due to the high pressure protocol. Thus, the

gaseous reagents cannot disappear by volatilization or sublimation as in standard reflux or

autoclave protocols allowing reaction times which are unattainable in by conventional flask

chemistry.

Scheme 7. Continuous Bucherer-Bergs hydantoin synthesis (Chapter F)

The main focus of the second part of this thesis lies on homogeneous and solid/liquid

reactions in continuous flow mode. In the latter case, immobilized or heterogeneous catalysts

are utilized for carrying out synthetic transformations.[1-3]

A main advantage is the fact that

catalyst separation occurs simultaneously to the desired reaction. Consequently, the catalytic

material remains in the flow systems allowing its subsequent reutilization (recycling). It has to

be stressed that this strategy may result in catalyst leaching in certain cases.[1-3,5]

Thus, careful

analysis of the liquid phase by e.g. ICPMS is of crucial importance during the development of

such continuous protocols. Nevertheless, the large interfacial areas and the short path required

for molecular diffusion in the narrow microchannel space provides very efficient liquid/solid

interaction which is not attainable in normal batch systems.

Chapter G describes the totally homogeneous copper-catalyzed formation of carbon-

oxygen bonds by the cross dehydrogenative coupling of ethers and carbonyl compounds in

both, batch and continuous flow formats (Scheme 8). This reaction requires a high excess of

Introduction

7

the respective ether (solvent), stoichiometric amounts of tert-butyl hydroperoxide (TBHP) as

oxidant and relatively high temperatures in order to provide the desired, unsymmetrical acetal

scaffolds. As mixtures of ethers and organic peroxides pose severe explosion hazards,

translation to a microreactor protocol offers the opportunity to safely scale this process to

synthetically useful quantities of acetal products. In addition, low boiling ethers, such as Et2O

are unreactive under reflux conditions as the desired reaction temperature cannot be reached.

This limitation can be elegantly circumvented by using high pressure flow protocols for

heating the reaction mixture far above the boiling point of such solvents in a safe and

controllable manner.

Scheme 8. Copper-catalyzed oxidative cross-dehydrogenative-coupling in flow (Chapter G)

In chapter H, the hydrazine mediated nitro reduction utilizing a supported iron oxide

nanocatalyst is described (Scheme 9). The catalytic active material (nano-Fe3O4@Al2O3) can

be easily prepared by a simple impregnation method on basic Al2O3 using Fe(acac)3 as iron

precursor and hydrazine hydrate in batch. By packing the totally heterogeneous material in a

dedicated cartridge system, reductions of nitroarenes can be perfomed in a virtually work-up

free method in continuous flow mode in the range of minutes (Scheme 9). Importantly, no

iron leaching is observed and stable reactions can be carried out for several hours with high

productivity.

Scheme 9. Reduction of nitroarenes catalyzed by nano-Fe3O4@Al2O3 in flow (Chapter H)

Introduction

8

Finally, the multistep synthesis of linear peptoids is demonstrated in chapter I. These

peptidomimetic compounds can be easily synthesized by an Ugi four component reaction. In

order to avoid exposure to the often toxic and malodorous isocyanides the dehydration of the

corresponding amides can be installed providing a telescoped process. Moreover, an azide

functionality can be installed by a nucleophilic substitution in a telescoped process which

allows the possibility for subsequent modifications of the linear reaction products (Scheme

10). This example demonstrates how continuous flow synthesis enables the multistep

synthesis of rather complex molecules without the need of tedious and often unnecessary

isolation procedures which is of particular interest when hazardous reagents or unstable

intermediates are part of the synthetic route.[6]

The functionalized linear peptoid can be further cyclized in a copper-catalyzed azide

alkyne cycloadditions (CuAAC) by utilizing a copper coil reactor without the need of any

additive.[7]

Such reactors represent a special example of heterogeneous flow devices as the

nature of the coil itself avoids the necessity of any catalytically active species. However,

depending on the nature of the linear precursor and the resulting ring strain, either a dimeric

or a monomeric form of the cyclic product can be obtained within less than half an hour under

intensified continuous flow conditions.

Scheme 10. Continuous multi-step synthesis of functionalized, linear peptoids and their

subsequent cyclization in a copper coil reactor (Chapter I)

Introduction

9

References

[1] For reviews on flow chemistry, see: (a) B. Gutmann, D. Cantillo, C. O. Kappe, Angew.

Chem. Int. Ed. 2015, 54, 6688; (b) K. F. Jensen, B. J. Reizmana, S. G. Newman, Lab

Chip 2014, 14, 3206; (c) C. Wiles, P. Watts, Green Chem. 2014, 16, 55; (d) S. G.

Newman, K. F. Jensen, Green Chem. 2013, 15, 1456; (e) I. R. Baxendale, L. Brocken,

C. J. Mallia, Green Proc. Synth. 2013, 2, 211.

[2] For extensive treatises on microreactor and continuous flow technology, see: (a) Flow

Chemistry, (Eds.: F. Darvas, V. Hessel, G. Dorman), De Gruyter, Berlin, 2014; (b)

Microreactors in Preparative Chemistry, (Ed.: W. Reschetilowski), Wiley-VCH,

Weinheim, 2013; (c) Microreactors in Organic Synthesis and Catalysis, 2n Ed. (Ed.:

T. Wirth), Wiley-VCH, Weinheim, 2013; (d) Handbook of Micro Reactors (Eds.: V.

Hessel, J. C. Schouten, A. Renken, Y. Wang, J.-i. Yoshida), Wiley-VCH, Weinheim,

2009; (e) Chemical Reactions and Processes under Flow Conditions (Ed.: S. V. Luis,

E. Garcia-Verdugo), RSC Green Chemistry, 2010.

[3] R. Munirathinam, J. Huskens, W. Verboom, Adv. Synth. Catal. 2015, 357, 1093.

[4] V. Hessel, D. Kralisch, N. Kockmann, T. Noel, Q. Wang, ChemSusChem 2013, 6, 746.

[5] D. Cantillo, C. O. Kappe, ChemCatChem 2014, 6, 3286.

[6] For reviews on continuous flow multi-step synthesis, see: (a) J. Wegner, S. Ceylan, A.

Kirschning, Adv. Synth. Catal. 2012, 354, 17; (b) D. Webb, T. F. Jamison, Chem. Sci.

2010, 1, 675; (c) D. T. McQuade, P. H. Seeberger, J. Org. Chem. 2013, 78, 6384; (d)

J. C. Pastre, D. L. Browne, S. V. Ley, Chem. Soc. Rev. 2013, 42, 8849.

[7] For a recent review about the utilization of copper flow reactors, see: (a) J. Bao, G. K.

Tranmer, Chem. Commun. 2015, 51, 3037.

Part 1

11

Part 1

Gas/Liquid Reactions in

Continuous Flow

Chapter A

13

A. Aerobic Oxidations in Continuous Flow

Graphical Abstract

Abstract

In recent years, the high demand for sustainable processes resulted in the development of

highly attractive oxidation protocols utilizing molecular oxygen or even air instead of more

uneconomic and often toxic reagents. The application of these sustainable, gaseous oxidants

in conventional batch reactors is often associated with severe safety risks and process

challenges especially on larger scales. Continuous flow technology offers the possibility to

minimize these safety hazards and concurrently allows working in high temperature/pressure

regimes to access highly efficient oxidation protocols. This review article critically discusses

recent literature examples of flow methodologies for selective aerobic oxidations of organic

compounds. Several technologies and reactor designs for biphasic gas/liquid- as well as

supercritical reaction media are presented in detail.

Chapter A

15

1. Introduction

The high demand for more sustainable oxidation processes in the synthesis of commodity and

fine chemicals necessitates the development of safe and efficient methodologies employing

virtually ideal oxidants such as O2 or even air. The economic and environmental advantages

using these cheap and readily available oxidation reagents are apparent. However,

applications are often restricted to substrates capable of undergoing selective autoxidation

reactions. For a more widespread use of this sustainable oxidant a plethora of versatile

catalytic methods for aerobic oxidations of complex organic molecules −such as the oxidation

of alcohols, oxidative cross-coupling reactions and selective C−H bond oxidations− have been

developed in recent years.[1-5]

Oxidations using molecular oxygen or air are often associated with severe safety risks

and process challenges. Such transformations are generally exothermic and the heat of the

reaction can be difficult to dissipate. The consequential non-isothermal conditions potentially

reduce reaction selectivity and product quality. Furthermore, aerobic oxidations suitable for

fine chemical manufacturing are usually carried out at elevated temperatures and pressures in

organic solvents posing severe explosion hazards. To avoid spontaneous ignition of such

reactions mixtures, large scale applications in conventional batch reactors have to be carried

out below the limiting oxygen concentration (LOC).[6]

This is typically achieved by mixing

the gaseous oxidant with an inert gas as, e.g. N2 to dilute the oxygen/solvent vapor. Moreover,

non-optimal temperature and pressure ranges are applied resulting in relatively slow and

inefficient processes.

Continuous flow (micro)reactor technology offers the unique possibility to address the

above mentioned safety hazards, concurrently working at high temperature/pressure regimes

(“novel process windows”) feasible for efficient oxidation protocols.[7-13]

Exothermic

reactions are easily controlled by the excellent mass and heat transfer making this technology

an ideal tool to harness hazardous chemical processes.[14]

Importantly, the small volumes and

channel dimensions minimize the possibility of propagation of an explosion inside the reactor

thereby tremendously broadening the possible operation range.[15, 16]

Especially biphasic

gas/liquid reactions such as aerobic oxidations can benefit from this enabling technology due

to fast mixing characteristics and a dramatically enlarged interfacial area between the liquid

and the gaseous phase.[17]

Moreover, continuous flow devices allow for rapid screening of

process conditions in biphasic gas/liquid reactions compared to pressurized autoclave

systems.

Chapter A

16

A crucial issue for many chemical reactions developed in research laboratories, but especially

hazardous reactions involving O2, is related to a possible large-scale application. Scaling is

generally considerably easier for a continuous process than for a batch process and flow

routes developed and optimized in the laboratory can often be scaled to production quantities

with minimal re-optimization and/or without major changes in the synthetic path [14]

.

Numbering-up of flow devices or scaling-up of the reactor volume increases the throughput,

while the performance of the reactor can be largely conserved by keeping certain

characteristics of the system constant (“smart dimensioning”). Alternatively, simply running a

reactor for extended periods of time to generate the desired quantities of pharmaceutical

intermediates or final products is often an acceptable strategy.

In this review we aim to provide a comprehensive overview on recent developments in

aerobic oxidation reactions in gas/liquid continuous flow mode. In the first chapter, reactor

designs and technologies suitable for such biphasic transformations are introduced.

Thereafter, continuous oxidation protocols of small organic molecules and other reactions

involving O2 as sole oxidant are critically discussed. Finally, the photochemical utilization of

molecular oxygen for e.g. the generation of singlet oxygen (1O2) in organic synthesis will be

outlined briefly for selected examples. For reactions involving ozonolysis and gas-phase

oxidations, the authors refer to the following references.[15, 18-21]

2. Technological Aspects

In general, the majority of gas/liquid reactions in continuous flow such as aerobic oxidations

are carried using a gaseous feed and one or more liquid feeds containing the substrate and, if

necessary a homogeneous catalyst or other additives (Scheme 1, A). The liquid solution is

usually pumped using standard HPLC, syringe or peristaltic pumps, whereas the gaseous

phase can be accurately fed using e.g. a mass flow controller (MFC). This dedicated tool

enables an easy control of the stoichiometry of the gaseous reagent which can be hardly done

in conventional batch processes. Mixing of the streams is carried out in either static or active

mixing units before entering the reaction zone where the chemical transformations occurs. A

further important feature –in particular for biphasic gas/liquid flow chemistry– is the use of

backpressure regulators (BPR) which allow a precise control of the residence time and

straightforward access to elevated pressure regimes. Therefore, a higher solubility of the

gaseous oxidant can be conveniently achieved in a safe manner often resulting in intensified

protocols.

Chapter A

17

An alternative approach to feed gaseous reagents in the liquid reaction mixture is the use of

membrane reactors (Scheme 1, B).[17]

Among those, the so called tube-in-tube reactor

developed by Ley and coworkers has gained significant attention since its first application in

2010.[22]

In principal, this device consists of a gas permeable Teflon AF-2400 membrane

tubing (inner tube) that is fixed within larger impermeable tubing (outer tube). These tubes

are separated by T-pieces allowing for an independent feed of both channels. Only gaseous

reagents can pass the membrane and react with substrates in the liquid phase or simply

saturate the solvent for subsequent use. In that respect, Jensen and coworkers recently

communicated a quantitative model for predicting gas and substrate concentration profiles in

the tube-in-tube reactor unit.[23]

The authors concluded that the low gas loading, insufficient

radial mixing and heating characteristics limits the general applicability of this device. It

should be further noted that on the one hand an accurate control of the stoichiometry is hardly

possible and on the other hand membrane materials are often restricted to relatively low

temperature and pressure ranges to avoid damage. Nevertheless, the reactor unit remains a

convenient gas-loading tool on laboratory-scale for certain applications.

Scheme 1. Typical set ups for aerobic oxidations in continuous flow (A,B), reactor types (C)

and common gas/liquid flow regimes (D).

Chapter A

18

Depending on the application, three different common reactor types (reaction zone) are

predominantly used in aerobic oxidations of small molecules (Scheme 1, C). Homogeneously

catalyzed and catalyst-free oxidations are typically carried out in chip or coil reactors made of

glass, simple polymeric materials, ceramics or metals/alloys. Additionally, the gas loading

unit itself can be simultaneously used as reaction zone by using membrane reactor

applications.[22]

If a heterogeneous species is used to enhance an oxidation process packed-

bed reactors loaded with a heterogeneous (supported) catalyst are typically employed [24]

.

The flow pattern of the biphasic mixture represents a very important and controllable

parameter in gas/liquid flow reactions which has a significant influence on the interfacial area

and the overall flow rate (Scheme 1, D). Various flow regimes can be achieved depending on

the solubility of the gaseous oxidant in the reaction medium, the reaction temperature, the

back pressure and the flow rates of the liquid as well as the gaseous stream. If the gas is fully

dissolved, a homogeneous liquid flow appears which is often the case using membrane reactor

applications. Among the biphasic flow patterns, segmented flow (sometimes also referred to

as slug-, plug-, or Taylor flow) and annular flow are most commonly applied in continuous

organic synthesis. Single phase oxidations can be observed in certain cases when supercritical

solvents (sc) like e.g. scH2O are used, since both, the substrate and the oxidant are totally

dissolved in the reaction medium.[25]

In the latter case, extremely high pressures are usually

required which also necessitates special dosing techniques to deliver the gaseous oxidant.

However, an accurate control of gas/liquid reactions such as aerobic oxidations is by

no means trivial as a large number of parameters have to be taken into account during the

reactor development and design of experiments.

3. Oxidation of Hydrocarbons

Highly efficient methods for the preparation of bulk chemicals by liquid phase oxidation with

O2 have been developed, and several commodity chemicals, such as

cyclohexanol/cyclohexanone (KA oil), cumene hydroperoxide, tert-butyl hydroperoxide/tert-

butyl alcohol, or terephthalic acid are produced on an enormous scale by aerobic oxidation of

petroleum-based compounds. The latter material is an important intermediate in the

production of polyester materials. The industrial synthesis (AMOCO Process) is realized by

an oxidation of p-xylene (1) using O2 in acetic acid catalyzed by cobalt and/or manganese

salts in presence of a bromide source.[26]

In 2002, Poliakoff and coworkers presented an

alternative, sustainable methodology for the synthesis of terephthalic acid (2) replacing the

organic solvent by supercritical water in a continuous process (Scheme 2).[27]

A standard

Chapter A

19

reactor design using compressed air was not feasible since the required amount of oxygen for

these experiments was extremely small. Therefore, an aqueous solution of H2O2 was heated at

400 °C to in situ generate O2 in the first coil reactor. The oxygen/water mixture was

subsequently mixed with a solution of MnBr2 and 1 to initiate the supercritical oxidation

process in a Hastelloy C276 coil at 400 °C and 280 bar. Afterwards, a NaOH solution was fed

to prevent the product mixture from precipitation and the solution was subsequently cooled in

an additional coil reactor before passing a backpressure regulator.

Scheme 2. Continuous synthesis of terephthalic acid (2) via aerobic oxidation of p-xylene (1)

in scH2O.

Importantly, due to the extreme reaction conditions, a residence time of only 9 s was

sufficient to generate 2 in good yields (>79 %) and high selectivity (>92 %). Problematic

impurities such as 4-carboxybenzaldehyde were not observed under optimized conditions,

thus offering a potential alternative to common industrial processes. The system could further

be applied to other methylaromatic compounds like o- and m-xylene, mesitylene, toluene,

ethylbenzene and even heteroaromatic picolines.[28, 29]

Despite significant differences in their

reactivity, mixed xylenes can be simultaneously oxidized in reasonable yields and good

selectivity by carefully tuning the experimental conditions.[30]

A main drawback in both, the

scH2O and the conventional acetic acid process is the hydrolysis of the homogeneous

manganese catalyst resulting in insoluble metal oxides.[31]

This not only results in a reduced

activity and recyclability of the active species, but can also lead to reactor clogging in the

continuous route. Hence, Poliakoff and coworkers found out that manganese recovery can be

significantly improved by the addition of Brønsted acids and by increasing the Br:Mn ratio for

the oxidation of o-xylene in scH2O.[31]

Hydrobromic acid was shown to be the most efficient

additive since it provides the required acidity and simultaneously acts as a bromide source.

Detailed mechanistic studies on the continuous oxidation of o- and p-xylene led to the

discovery of another catalytic system using CuBr2 in a selective oxidation process utilizing a

Chapter A

20

similar flow setup.[32, 33]

A synergistic effect between copper and other metals, such as cobalt

was found to enhance this reaction as exemplified by utilizing a four component catalyst

system (Cu/Co/NH4/Br). In this case sub-critical water gave significantly better results than

scH2O which was rationalized by a temperature dependent equilibrium shift in the ammonium

bromide decomposition.[33]

In contrast to the synthesis of carboxylic acids discussed above, Kappe and coworkers

realized a partial aerobic oxidation of ethylbenzene (3) yielding acetophenone (4) in a

gas/liquid coil reactor (Scheme 3, A).[34]

Complete conversion of 3 was obtained within 6 min

at 120 °C in a PFA coil using catalytic amounts of CoBr2 and Mn(OAc)2 and compressed air

as oxygen source. The desired ketone (4) was formed in high selectivity (80 %) and isolated

in 66 % yield. Due to the tight control of reaction parameters, over-oxidation to benzoic acid

was minimized to a relatively small amount (~10 %). This was further demonstrated by

processing the same reaction mixture at higher temperatures (150 °C) in combination with a

longer residence time (16 min) yielding benzoic acid (71 %) as a main product.

A similar set up was used for the oxidation of 2-benzylpyridines to the respective

ketones in an iron-catalyzed protocol.[35]

In this case, standard polar, aprotic solvents like

NMP or DMSO as reaction media were prone to decomposition under the harsh reaction

conditions (200 °C). To overcome these issues, the authors used propylene carbonate, a

sustainable, high boiling solvent with excellent oxidation stability. Good to excellent isolated

yields for potential drug precursor molecules were obtained at 200 °C within 13 min in a

stainless steel coil significantly enhancing the original batch protocol.[36]

Scheme 3. Aerobic oxidation of ethylbenzene (A) and picolines (B) in continuous flow.

Chapter A

21

A silicon nitride coated halo-etched chip reactor was used by Jensen and coworkers for the

metal-free oxidation of picolines (Scheme 3, B).[37]

The reaction is suggested to proceed via

deprotonation of the methyl group in presence of a strong base such as potassium tert-amylate

(t-AmOK) followed by an anionic oxidation step. Notably, different solvent mixtures were

necessary for each picoline derivative in order to obtain high conversions. Moreover, the

same group recently described the application of a surface-passivated silicon microchip in the

solvent-free autoxidation of β-pinene and (+)-valencene gaining insights into reaction kinetics

by visual determination of O2 consumption during the reaction.[38]

KA oil, an unrefined mixture of cyclohexanone and cyclohexanol, is an important

precursor for the production of -caprolactam and adipic acid which are further converted to

nylon polymers. Industrial production of KA oil is mainly carried out via the aerobic

oxidation of cyclohexane in bubble column reactors within 15-60 min. Typical conversions in

these processes are below 6 % for obtaining a sufficient selectivity.[39]

The group of de

Bellefon reported on a segmented flow pattern in a chip-based microreactor by mixing

cyclohexanone and O2 to study this transformation on laboratory scale.[40]

At 200 °C and 25

bar, 4.3 % conversion were obtained maintaining a high selectivity (88 %). Under almost

identical conditions a significantly lower conversion (1.6 %) was observed when oxygen was

replaced by compressed air. However, the higher throughput compared to industrial routes

applying bubble column reactors or continuous stirred tank reactors (CSTR) was explained by

the intensified conditions and the excellent residence time control.

An intensification study for this industrially relevant oxidation in capillary reactors

with inner diameters between 0.5 and 2.15 mm further showed that elevated temperatures

(260 °C) enable a significant reduction of the reactor volume and thus resulting in a reduction

of the power of a potential explosion.[41]

The study was conducted by applying a neat

cyclohexane stream and air in a segmented flow pattern (Fig. 1). However, it has to be

stressed that the improvement of the gas/liquid mass transfer in the microreactor was shown

to be very low compared to standard bubble column reactors.

Figure 1. Gas/liquid segmented flow pattern for the oxidation of cyclohexane with air.

Reproduced with permissions from [41]

Chapter A

22

A more versatile protocol employing homogeneous palladium catalysis was utilized to realize

a continuous anti-Markovnikov Wacker oxidation of functionalized styrenes (Scheme 4,

A).[42]

Initially, an aqueous solution of bis(acetonitrile)dichloropalladium(II) and CuCl2 was

mixed with an organic stream containing a styrene derivative. To avoid solvent freezing of t-

BuOH −which is necessary to obtain the desired selectivity− toluene was added as a co-

solvent. The liquid mixture was subsequently loaded with oxygen as gaseous oxidant in a

tube-in-tube membrane reactor. Afterwards, the final reaction mixture was fed in a stainless

steel coil heated at 60 °C to carry out the desired transformation. It could be shown that an

accurate control of the oxygen pressure is of crucial importance to obtain on the one hand

complete conversion and on the other hand to avoid over-oxidation which would generate

undesired carboxylic acids. Importantly, a modified system using a second gas addition

allowed for higher concentrations and thus an improved throughput, thus accessing a multi-

gram scale protocol.

Scheme 4. (A) Anti-Markovnikov Wacker oxidation of styrenes using a membrane reactor.

(B) Biocatalytic catechol synthesis in a tube-in-tube reactor.

The tube-in tube reactor was also used in the biocatalytic production of 3-phenylcatechol (6)

from 2-hydroxybiphenyl (5) catalyzed by 2-hydroxybiphenyl 3-monooxygenase (HbpA)

Chapter A

23

(Scheme 4, B).[43, 44]

Formate dehydrogenase (FDH) was added for cofactor recycling which

converts sodium formate to carbon dioxide. However, high substrate loadings were achieved

by using an organic liquid feed containing the substrate and an aqueous stream consisting of

both enzymes, the co-factor and sodium formate. Under optimized conditions a productivity

of ~18 g L-1

h-1

of the desired catechol was achieved which is 38 times higher than in

conventional batch reactions.[43]

Chemists from Bristol-Myers Squibb applied continuous flow technology to develop a

scalable, high yielding route for the hydroxylation of buspirone (7) by an enolization/

oxidation sequence (Scheme 5).[45]

In the first step, the substrate feed was mixed with the base

by slowly reducing the temperature in two sequential static mixing units (SMU) to avoid

precipitation of the inorganic base. After complete enolization in a coil-based heat exchanger,

the reaction mixture entered a trickle bed reactor (TBR) packed with Pro-Pak® distillation

packing material. The optimized oxidation process was carried out at a reactor temperature of

-36 °C at atmospheric pressure using a counter-current O2 stream and a residence time of 3-4

min. Afterwards, the reaction was quenched with 2.5 M HCl in a continuous stirred tank

reactor. Upscaling by a larger reactor volume was not feasible due to a lower cooling

efficiency (heat transfer) causing the researchers to use a numbering-up approach. Therefore,

the reaction mixture was spilt into four different streams after enolization and fed into a 4-

channel oxidation reactor (Quad reactor), to finally result in the potential anxiolytic agent 6-

hydroxybuspirone (8, Scheme 5). The whole sequence was operated for 72 h using process

analytical techniques for in situ control of its performance. Notably, a constant purity profile

was monitored (90 %) over time at a high production rate (15 kg d-1

).

Scheme 5. Continuous enolization, oxidation sequence of Buspirone (7). A numbering-up

technique is used for the oxidation step (Quad reactor). Adapted with permission from [45]

Chapter A

24

The last examples clearly demonstrate that aerobic oxidation reactions of hydrocarbons in a

continuous manner are not only limited to bulk chemical synthesis. However, applications in

fine chemical manufacturing are extremely rare since selective C-H oxidations of more

complex organic molecules are by no means trivial due to the lack of selective autoxidation

processes. In contrast, oxidations of functional groups, such as alcohols or catalytic reactions

involving an aerobic oxidation of the catalyst potentially allow for a significantly broader

scope.

4. Oxidation of Alcohols

The oxidation of primary and secondary alcohols to the corresponding carbonyl compounds is

among the most fundamental transformations in organic synthesis. Common strategies

involve stoichiometric amounts of special oxidants such as NMO in the presence of TPAP,

bleach in combination with TEMPO, permanganates, activated DMSO, toxic chromium(VI)

complexes (Collins reagent, PDC, PCC) or hypervalent iodine reagents such as Dess-Martin

periodinane and IBX. These relatively expensive reagents generate considerable amounts of

often toxic waste and suffer from poor atom economies. In stark contrast, oxidations using air

or molecular oxygen theoretically produce water as the only by-product. Therefore,

considerable effort has been invested in the development of catalytic protocols to explore the

applicability of these environmentally benign alternatives.[46-49]

4.1 Heterogeneous Catalysis in Common Solvents

It is not surprising that aerobic alcohol oxidations, especially examples involving

heterogeneous catalysis, are often studied in continuous flow reactors since the many

advantages of triphasic gas/liquid/solid reactions are quite evident. Early examples applying

continuous packed bed reactors were published already in the late 1980s and early 1990s,

marking the beginning of continuous aerobic oxidation studies in research laboratories.[50-52]

.

Various heterogeneous catalysts, especially supported noble metals, are well known to

facilitate the aerobic oxidation of primary and secondary alcohols.[46, 48]

Among those,

ruthenium is probably the most promising and extensively studied material. The pioneering

work by Plucinski and coworkers showed the applicability of supported ruthenium catalysts in

a multichannel compact reactor for the selective oxidation of benzyl alcohol (9) with

molecular oxygen (Scheme 6).[53-56]

The reactor elements were fabricated by etching of thin

stainless steel plates followed by their assembly applying a diffusion bonding technique. The

Chapter A

25

liquid and gaseous feeds are combined in a static mixing unit and the resulting stream is

guided into a packed-bed channel. Since the reactor contains five of those units, the length of

the catalyst bed can be conveniently varied by connecting two or more channels. This

approach also allows for multiple addition of e.g. O2 by installing another gas feed between

two consecutive packed bed units.

Scheme 6. Aerobic oxidation of benzyl alcohol (9) using a multichannel compact reactor.

Adapted with permission from [53]

In addition, temperature control can be ensured using glycerol as heat transfer fluid which is

circulated towards heat exchange channels. For testing the multichannel reactor, the aerobic

oxidation of benzyl alcohol (9) to benzaldehyde (10) in toluene catalyzed by Ru/Al2O3 was

chosen as model reaction. Careful optimization of all reaction parameters resulted in 25 %

and 39 % conversion at 115 °C by using one or two channels, respectively. In addition,

splitting of the oxygen stream by installing a second gas feed after the first packed bed

channel slightly increased the consumption of 9 resulting in 46 % of the corresponding

aldehyde 10. Noteworthy, the catalyst activity decreased very slowly during a stability study

which is most likely a result of poisoning by over-oxidized benzoic acid. Subsequently, the

same reactor design was used to test a ruthenium(III) hydrated oxide catalyst supported on

TiO2 nanotubes for its catalytic activity in the aerobic oxidation of aromatic primary alcohols

[54]. The application of this more active ruthenium species improved the single pass

conversions dramatically (75 %) maintaining an excellent selectivity for the corresponding

aldehyde at similar conditions to the Ru/Al2O3 system discussed above.

The versatility of the easily accessible Ru/Al2O3 catalyst was further explored on a

broader scope by the group of Hii in collaboration with Pfizer using a commercially available

reactor system (Scheme 7, A).[57]

The oxygen flow was controlled by a pressure valve and the

gas/liquid ratio was monitored by a bubble detector unit prior to the packed bed reactor.

Chapter A

26

Relatively low single-pass conversions for various alcohols at 115 °C and 5 bar caused the

authors to recirculate the reaction mixture for 45 min to 7 h depending on the reactivity of the

respective primary or secondary alcohol. High conversions and selectivities were achieved for

a range of allylic and benzylic primary alcohols including pyridyl and thienyl systems. Even

the more challenging aliphatic secondary and primary alcohols could be selectively oxidized

in moderate to good conversions under those conditions. It could be shown that catalyst

deactivation over time can be circumvented by installing an additional cartridge filled with

MgSO4 as desiccant to remove accumulated water. This scavenging technique resulted in

improved conversions of 2-hexanol (91 % instead of 75 %) within a 7 h recirculation

experiment. ICP analysis revealed no leaching of the catalytically active material allowing for

an almost work-up free procedure. Given the fact that the reaction mixture exclusively

consists of the desired product, the researchers designed a telescoped process by combining

the continuous aerobic oxidation with a subsequent Wittig olefination in batch.

Scheme 7. (A) Ru-catalyzed aerobic oxidation of alcohols using a recirculation technique.

(B) Continuous tow-step amide synthesis towards alcohol oxidation and subsequent

amidation.

More recently, an almost identical experimental set up was utilized to demonstrate the

potential of immobilized iron oxide nanoparticles as catalyst for the aerobic oxidation of

benzyl alcohol (9).[58]

The catalytic material was generated and immobilized by heating FeCl2

together with dispersed aluminum doped mesoporous silica (Al-SBA15) in ethanol at 150 °C

Chapter A

27

for several minutes. The supported catalyst showed promising activities in the presence of

TEMPO as a co-catalyst resulting in single pass conversions of 42 % using a n-heptane-

dioxane mixture as liquid phase. Again recirculation over 1 h was necessary to obtain a

selective, almost quantitative oxidation without detectable amounts of iron leaching.

These semi-continuous recirculation protocols are utilized to simulate an extension of

the small packed bed reactors usually applied on laboratory scale. It has to be stressed that

after each single-pass a separation of the oxidation agent occurs and fresh oxygen is added for

the next cycle. Overall, an enormous excess of the gaseous reagent is necessary and a

continuous monitoring of the conversion over a long time period is required. These

circumstances may limit the practical application in the context of an industrial protocol but

undoubtedly show the potential of such gas/liquid/solid oxidation procedures in continuous

flow.

In contrast to these relatively inconvenient recirculation procedures, Jensen and

coworkers could show that high conversions (95 %) for aerobic benzyl alcohol oxidations can

be achieved in a residence time as low as 19 s at 80 °C using the Ru/Al2O3 catalyst.[59]

A high

excess of oxygen (200 µL min-1

) was mixed with the aldehyde precursor in acetonitrile (0.1

M, 5 µL min-1

) and the combined mixture entered a silicon-Pyrex microreactor filled with the

supported catalyst. Notably, a stable conversion was observed over a period of 24 h. The

oxidation procedure was further utilized for a continuous two-step synthesis of amides from

various benzylic alcohols and secondary amines (Scheme 7, B). Therefore, a membrane

separator was installed after the heterogeneously catalyzed oxidation, in order remove

unreacted O2 enabling a better residence time control for the subsequent oxidative amidation

using urea hydrogen peroxide (UHP), based on a previous protocol from the same group.[60]

More recently, Ru(OH)x/Al2O3 was introduced as an efficient alternative to the

classical Ru/Al2O3 catalyst for continuous aerobic oxidations circumventing the necessity for

tedious recirculation procedures or high excess of O2.[61]

Careful analysis of the standard

benzyl alcohol model oxidation provided insights into the deactivation caused by over-

oxidized benzoic acid. Initially, a significant drop in the catalytic activity was observed

followed by an almost stable conversion. The resulting catalyst activity profile was the basis

for the development of high steady state single-pass conversions (up to 99 %) using the

partially deactivated catalyst. The final protocol is characterized by an O2/substrate molar

ratio of 2:1, a single pass residence time of 1 h at 80 °C and a back pressure of 11 bar.

Noteworthy, the authors used diluted O2 (8 % in N2) to work below the LOC of toluene in all

Chapter A

28

experiments, thus showcasing the superior activity of supported Ru(OH)x compared to

metallic ruthenium.

Despite these common heterogeneous catalysts for aerobic oxidation, also TPAP was

reported to show activity in the transformation of benzyl alcohol to the corresponding

aldehyde.[62]

Other common noble metal catalysts such as metallic silver, palladium or

platinum were also mentioned in combination with various supports for the oxidation of

alcohols in continuous flow mode.[63-68]

Gold catalyzed oxidation procedures are currently gaining a considerable amount of

interest in the continuous flow community.[69-78]

Among those, an extremely efficient protocol

was communicated by Kobayashi and coworkers (Scheme 8, A).[69]

Their reactor unit was

fabricated by immobilization of microencapsulated gold on a polysiloxane-coated capillary

via cross-linking. Initially, an organic substrate feed was mixed with an aqueous solution

containing potassium carbonate and the combined liquid stream was merged with O2

accurately added by a mass flow controller. The multiphasic mixture passed the

functionalized heated capillary (50 – 70 °C). Notably, no back pressure is required to convert

various secondary alcohols to the corresponding ketones in almost perfect isolated yields at

temperatures below the boiling point of the solvent mixture. It could be shown that the

catalytic activity is completely stable over 4 d and no catalyst leaching could be detected.

Unfortunately, low yields were obtained for benzylic and allylic primary alcohols using the

Au functionalized capillary. However, this problem could be solved by using a bimetallic

Au/Pd immobilized reactor column instead, resulting in almost quantitative amounts for these

less reactive starting materials.

Another strategy was communicated by Kirschning and coworkers in 2014 using an

unconventional heating methodology (Scheme 8, B).[78]

Catalytically active gold(0)

nanocrystals were immobilized on nanostructured particles with a superparamagnetic iron

oxide core and a silica shell (MAGSILICA®). The resulting material was filled into a PEEK

reactor in order to perform the oxidation of primary and secondary alcohols under continuous

flow conditions. By applying an external oscillating electromagnetic field the particles can be

heated inductively. Therefore, the material was not only serving as catalyst but also as heating

tool. The starting materials were dissolved in benzene and the organic solution was mixed

with oxygen using a tube-in-tube membrane reactor. Inductive heating at 150 °C was reported

to be necessary to obtain single pass conversions with residence times of approximately 30

min for simple primary and secondary alcohols. Replacement of benzene by less toxic

solvents was not feasible since solvent oxidation or comparably low conversions were

Chapter A

29

observed. Nevertheless, the authors could replace O2 by compressed air due to the high

activity of the nano-catalyst.

Scheme 8. Gold catalyzed aerobic oxidation of alcohols using (A) microencapsulated Au

immobilized on a capillary or (B) gold-doped superparamagnetic nanoparticles.

Inspired by HNO3 based oxidations, Hermans and coworkers recently developed a metal-free

batch oxidation protocol using catalytic amounts of HNO3 as oxygen shuttle in combination

with Amberlyst-15. This combination led to an NOx propagated chain oxidation using O2 as

terminal oxidant.[79]

Subsequently, the group developed an intensified process using

continuous flow technology (Scheme 9).[80]

The ion exchange resin was placed into a packed

bed reactor as heterogeneous catalyst. Oxygen was mixed with a liquid feed containing the

alcohol and 10 mol% HNO3. At a reaction temperature of 100 °C 4-25 s were sufficient to

synthesize several aldehydes and ketones in excellent yields and selectivity. On-line

monitoring of gas phase N2O and of the oxidation efficiency was realized by using a

gas/liquid separator in combination with different infrared spectroscopic techniques. In

addition, a milder protocol (55 °C) using TEMPO on silica instead of Amberlyst 15 was

developed.[81]

Scheme 9. Metal free aerobic oxidation of alcohols using a packed bed reactor.

Chapter A

30

4.2 Heterogeneous Catalysis in Supercritical CO2

Supercritical CO2 (scCO2) is an extremely attractive medium for reactions involving

molecular oxygen due to its inert environment which minimizes safety concerns compared to

common organic solvents.[82-84]

Although the advantages connected with this green solvent

are quite obvious, the necessity of high pressure equipment such as autoclaves has limited its

application in organic synthesis. Continuous flow processing offers a comparably convenient

access to such process windows especially in academic research laboratories. As already

discussed in the oxidation of xylenes in scH2O, the reactor design usually differs from

common gas/liquid phase flow setups. The relatively harsh temperature and pressure

conditions often necessitate special materials compared to liquid phase oxidations for safety

reasons. In case of scCO2, the substrate is usually fed into the flow system in a separate

stream and mixed with the supercritical solvent in the reactor system.

At the turn of the millennium, Baiker and colleagues started an intensive research

period on heterogeneous noble metal-catalyzed aerobic oxidations using this nonexplosive

and nonflammable “solvent” under continuous flow conditions (Scheme 10).[85-97]

In general,

their setup consisted of a liquid CO2 feed controlled by a compressor unit which was in a first

step mixed with O2. Control of the gaseous oxidant supply was carried out using a 6-way-

valve, dosing 50 µL pulses at high pressure and constant frequency. Afterwards, the CO2/O2

stream was combined with a liquid stream of the substrate (neat or with butanone as co-

solvent) and the mixture was heated in a fixed bed reactor filled with a precious metal catalyst

(e.g., 4 % Pd – 1 % Pt – 5 % Bi/C) at a back pressure of 95 – 120 bar. Several secondary

alcohols could be oxidized to the corresponding ketones in good yields and selectivities

within less than 30 s. The oxidation of primary alcohols required an internal stabilization by

an aromatic system or unsaturated carbon−carbon bonds in order to give satisfactory results.

Furthermore, accurate control of the oxygen concentration was crucial to avoid over-oxidation

of the catalyst which could cause a dramatic reduction in activity. Under optimized

conditions, neither catalyst deactivation, nor metal leaching was observed.

A detailed investigation of all reaction parameters using 1- and 2-octanol as model

substrates in the presence of Pd/Al2O3 using the same reactor showed that the oxidation of

unstabilized primary alcohols is generally troublesome whilst ketone synthesis from the

corresponding secondary alcohols is straightforward and conversions up to 46 % can be

obtained at 140°C.[86]

Good selectivity values for 1-octanol could be achieved at low

conversion rates avoiding a subsequent hydration of the aldehyde which would result in a

Chapter A

31

geminal diol which itself is prone to oxidative dehydration resulting in the corresponding

carboxylic acid.

Scheme 10. Aerobic oxidation of alcohols in scCO2.

More recently, the group of Poliakoff reported an improved protocol using a supported

platinum and bismuth catalyst.[98]

Initial problems of catalyst over-oxidation due to

inhomogeneous O2 concentrations and formation of “hot-spots” in the exothermic reaction

were solved by dosing smaller volumes of O2 via the 6-port-valve and improving the CO2/O2

mixing prior to addition of the substrate. This strategy resulted in 75 % conversion of 2-

octanol without evidence for catalyst deactivation over 5 h at 150 °C. A higher mass balance

could be obtained using a catalyst-filled T-piece instead of a standard packed bed reactor unit.

Utilizing the final experimental design, several simple secondary alcohols were converted to

the corresponding ketones in reasonable yields. Furthermore, the challenging oxidation of 1-

octanol leading to the corresponding aldehyde in >70 % yield could be realized by carefully

optimizing temperature and equivalents of O2.[98]

Notably, supported Palladium was shown to be far more active than Pt or Ru in the

selective oxidation of benzyl alcohol (9).[87]

In order to obtain operando structural analysis by

X-ray absorption spectroscopy (XAS) the standard reactor design of the Baiker group

(Scheme 10) was adapted for analytical applications (Fig. 2, A).[88, 89, 96]

Miniaturization of the

fixed bed reactor and installation of two X-ray transparent beryllium windows on both sites of

the catalyst compartment facilitated in situ measurements of the solid catalyst during aerobic

oxidation of 9 in scCO2. The continuous experiments indicated that palladium was mainly

present in the metallic state during the overall process. As anticipated, the catalytic activity

increased with the O2 concentration since removal of adsorbed hydrogen (Had) originating

from alcohol dehydration is accelerated (Fig. 2, B). The reaction rate reaches a maximum and

Chapter A

32

subsequently drops at higher oxygen concentrations. This was rationalized by the inhibiting

effect of surface PdOx species resulting from catalyst over-oxidation as analyzed by XAS.

Figure 2. (A) Packed bed reactor for in situ XAS measurements of aerobic oxidation in

scCO2. (B) Simplified model for structure-activity relationship in Pd catalyzed oxidation of

benzyl alcohol (9).

A similar analytical reactor was further used for in situ EXAFS studies of aerobic benzyl

alcohol and cinnamyl alcohol oxidations in O2-saturated organic solvents, demonstrating that

metallic palladium exhibits a higher activity for alcohol oxidation than the palladium oxide

species.[99-101]

In 2005, Leitner and colleagues realized that the palladium cluster

[Pd561phen60(OAc)180] displays an active catalyst in the aerobic oxidation of alcohols in scCO2

when embedded in a PEG-1000 matrix.[102]

The active material was identified as highly

dispersed Pd nanoparticles stabilized by the organic matrix. A similar catalyst could be also

obtained by simply heating Pd(acac)2 in PEG-1000 in the presence of a commercial

surfactant. Benzyl alcohol (9) was chosen as model substrate for the development of a

continuous process in a CSTR. It was shown that the aldehyde precursor and O2 can be

transported through the catalytic PEG phase without extrusion of the nanoparticles or the

matrix material using scCO2. With both Pd nanoparticle precursors ~15 % single pass

conversion with excellent selectivity was obtained at 80 °C and 155 bar backpressure after

isolating the product mixture in a cold trap. Notably, a steady increase in activity was

observed during continuous operation over 40 h. Transmission electron microscopy (TEM)

studies of the catalytic material formed from the Pd cluster indicated that the dispersion of the

nanoparticles is significantly improved after a batch oxidation process explaining the

increasing activity in the continuous long run experiment (Fig. 3). However, reduction of the

system pressure to 132 bar resulted in a 2-fold higher activity due to a shift of the partition

Chapter A

33

coefficient of the substrate in the biphasic medium. This rationalization could be supported by

the fact that the solubility of 9 became insufficient in scCO2 when the back pressure is further

decreased to 110 bar.[102]

Figure 3. TEM images of the catalytically active material formed from [Pd531phen60(OAc)180]

and PEG-1000 before (a) and after (b) the aerobic oxidation. Reproduced with permission

from [102]

Based on these results the authors developed a well-defined Pd nanoparticle catalyst on a

solid, inorganic matrix using PEG-modified silica surfaces for the application in a continuous

packed bed reactor.[103]

Initially, a covalently anchored PEG-phase (12) was synthesized by

reacting 3-chloropropyltriethoxysilane (11) with polyethylene glycol 750 monomethyl ether

in the presence of NaH (Scheme 11, A). Copolymerization with tetraethoxysilane (TEOS)

afforded the PEG-modified silica support 13 which was subsequently impregnated with a

solution of [Pd561phen60(OAc)180] yielding the final catalytic material 14. The supported

nanoparticles were shown to efficiently catalyze the aerobic oxidation of several secondary

alcohols as well as benzylic and allylic primary alcohols to the corresponding ketones and

aldehydes using scCO2 in batch mode. A stainless steel packed bed reactor was used for the

translation to a continuous process and good single pass conversions (50-60 % with a

selectivity of >98 %) were obtained for the benzyl alcohol oxidation within an estimated

residence time of 1.2 h at 80 °C and 150 bar. Importantly, a stable catalytic activity was

observed during a 30 h experiment with a total turnover number of 1750. TEM analysis

confirmed that the particles were effectively prevented from agglomeration by the covalently

bound PEG chains.

In an alternative approach, 2,2’-dipyridylamine (16) was installed as a linker unit

instead of PEG to immobilize and simultaneously stabilize the Pd nanoparticles on

mesoporous silica for a catalytic aerobic oxidation in scCO2.[104]

Similar to the immobilization

technique discussed above, coupling of a trialkoxysilyl derivative (15) with 16 followed by

Chapter A

34

addition of TEOS led to a functionalized mesoporous material (18) (Scheme 11, B).

Treatment with palladium acetate and subsequent reduction with benzyl alcohol under reflux

yields the catalytically active supported nanoparticles 19. It has to be noted that significant

amounts of unreduced Pd(II) were still present on the surface. An alternative reduction using

molecular hydrogen on the one hand provided a higher degree of Pd(II) reduction but on the

other hand resulted in a significantly decreased catalytic activity for the aerobic oxidation of

benzyl alcohol in scCO2. This could be explained by generation of small primary crystallites

in case of the benzyl alcohol reduction leading to a large number of high indexed planes in

small volume units. However, catalyst 19 showed good single pass conversions (41 % at a

selectivity >98 %) at temperatures as low as 60 °C and remained constant over >28 h.

Although at higher temperatures an increased activity was achieved, a significantly lower

selectivity (90 %) and leaching of catalytic material did not allow for further intensification.

Scheme 11. Catalyst preparation using a PEG (A) and a 2,2’dipyridylamine (B) unit for

immobilization of Pd nanoparticles.

4.3 Homogeneous Catalysis

Homogeneous catalysts are often superior compared to heterogeneous materials regarding

their activity and selectivity. Furthermore, the possibility for fine-tuning of the active material

by e.g., ligands often accesses a broader scope compared to metallic species or salts used in

heterogeneous catalysis. Over the past years a plethora of effective aerobic oxidation

Chapter A

35

protocols utilizing homogeneous palladium or copper catalysis have been developed.[49, 105, 106]

These contributions are almost exclusively small scale laboratory reactions predominantly

carried out in a flask equipped with an O2-filled balloon. Apparently, the oxygen

concentration in the liquid solution is relatively low and mixing of the different phases is

rather poor. This is especially problematic for homogeneous palladium catalysis as the

catalyst stability is highly sensitive to the dissolved oxygen concentration. Even temporary

periods of poor gas/liquid mixing can lead to catalyst decomposition via agglomeration of

homogeneous Pd(0) complexes forming metallic palladium.[107]

In order to tackle these mechanistic challenges and simultaneously providing a

scalable aerobic oxidation protocol, a continuous approach was developed by the Stahl group

together with chemists from Eli Lilly (Scheme 12).[108]

Translation of the batch protocol using

catalytic amounts of Pd(OAc)2 and pyridine was realized towards a three feed methodology.

To avoid the above mentioned reduction or decomposition of the catalyst, a solution of

Pd(OAc)2 was initially mixed with oxygen. Subsequently, the substrate as well as pyridine

enter the flow system via a second mixing unit before the central coil reactor. A residence

time of 2.5 h was necessary to oxidize several secondary and benzylic primary alcohols to the

corresponding carbonyl compounds on a multi-gram scale using diluted oxygen (8 % in N2).

Furthermore, the synthesis of benzaldehyde (6) was carried out on a kilogram scale using a 7

L stainless steel coil as residence time unit highlighting the reliability of the flow reactor for

large scale applications.

Scheme 12. Aerobic oxidation of alcohols using homogeneous Pd catalysis in flow:

However, all alcohol oxidations discussed so far were limited to secondary alcohols or

stabilized primary alcohols due to over-oxidation of unstabilized derivatives to the

corresponding carboxylic acid. This limitation can be elegantly circumvented by the well-

established homogeneous copper-catalyzed aerobic oxidation protocol developed by Stahl

using a catalytic mixture of Cu(OTf)2, 2,2’-bipyridine, TEMPO and NMI.[49]

Similar reactor

Chapter A

36

concepts as for the Pd catalyzed protocol were used in order to test the feasibility of the

copper-based system for continuous purposes.[109, 110]

Importantly, a stainless steel syringe

pump and storage unit for the catalyst mixture caused severe problems since a significant drop

in catalytic activity was observed.[109]

This was attributed to a reaction of the catalyst material

with stainless steel. Thus, the authors modified the experimental setup by replacing steel units

by e.g., PTFE based equipment. A range of aliphatic alcohols could be almost quantitatively

converted into the corresponding aldehydes at 60 °C within 30-45 min (Table 1). Moreover,

stabilized alcohols were selectively oxidized within only 5 min at 100 °C showing the

tremendous activity of the Cu(I)/TEMPO strategy compared to palladium catalysis.

Table 1. Scope of the Cu(I)/TEMPO Catalyzed Aerobic Oxidation in Flow

Root and colleagues used this copper catalyzed protocol to test an inexpensive variant of the

tube-in-tube reactor by utilizing simple PTFE instead of the costly Teflon-AF 2400 as gas

permeable membrane material.[111]

Their reactor design consisted of a PTFE tubing coiled

into a stainless steel shell (tube-in-shell, Scheme 13). An oxygen bottle was connected to the

“shell” and the whole reactor unit was heated. Under elevated conditions (100 °C) the oxygen

permeability of the PTFE tubing was high enough to convert a 0.2 M solution of primary or

secondary alcohols within only 1 min residence time. The scalability was also demonstrated

in a multi-tube membrane reactor by mounting 13 PTFE tubes in a pressure vessel. This

numbering-up approach could be used to oxidize 10 g of benzyl alcohol within a total

processing time of 45 min instead of 21 h in the single tube reactor. Furthermore, the authors

Chapter A

37

used the prototype tube-in-shell reactor as gas loading unit prior to a packed bed reactor filled

with RuOHx/Al2O3 in a heterogeneously catalyzed oxidation of benzyl alcohol to highlight its

versatility for multiple applications.

Albeit this method exemplifies a potential alternative to expensive gas-permeable

membrane materials such as Teflon-AF2400, the utilization of PTFE, PFA or other common

tubing materials is presumably limited to applications at relatively harsh conditions since the

gas permeability of these material strongly depends on the temperature. Thus, reactions at

room temperature or below might not be feasible or would require extremely diluted

conditions to maintain a proper stoichiometry.

Scheme 13. Cu(I)/TEMPO catalyzed aerobic oxidation of alcohols using in a tube-in-shell

reactor.

5. Oxidation of Aldehydes

Aldehydes are produced on an enormous scale typically from olefins and syngas (CO/H2) via

hydroformylation (oxo-process).[112]

These valuable compounds are further used in the

synthesis of several bulk chemicals such as alcohols, amines, or carboxylic acids (and their

corresponding esters). The latter are usually obtained via liquid-phase aerobic oxidation

processes either in presence of a metal catalyst or following catalyst-free strategies.[113]

Catalytic oxidations of aldehydes are interesting model reactions for gas/liquid microreactors

since the transformations generally are quite fast and selective.[114, 115]

As an example, Hessel

and coworkers used the oxidation of butyraldehyde to test the reliability of a mathematical

reactor model for predicting conversions in a micro-bubble column based on hydrodynamic

information and transport modeling.[114]

A heterogeneously catalyzed oxidation of 4-isopropoxybenzaldehyde using Pt/Al2O3

in a single-channel silicon-Pyrex reactor was carried out by Jensen and colleagues (Fig.

4).[115]

An initial temperature screening showed an optimum temperature of 90 °C. The molar

ratio of O2 to the substrate was optimized by varying the liquid flow at constant flow rate of

Chapter A

38

the gaseous oxidant. An O2/substrate ratio of 1.5 was sufficient to obtain 95 % conversion to

the corresponding carboxylic acid within less than 6 s. Replacement of O2 by compressed air

at the same O2/substrate ratio gave a conversion of only 76 % since the gas flow had to be

increased resulting in a shorter contact time (~1 s). In order to obtain a higher residence time

and a better conversion, the liquid flow had to be decreased. This increased the amount of O2

by a factor of ~5 compared to the substrate.

Figure 4. (A) Single-channel packed bed reactor for heterogeneously catalyzed aldehyde

oxidations (B) Front view showing the catalyst bed. Reproduced with permission from [115]

The group of Favre-Réguillon could show that the aerobic oxidation of reactive aliphatic

aldehydes can be carried out in a segmented flow pattern without the need of adding any

catalytically active material at room temperature (Scheme 14).[116]

To maintain mild

conditions catalytic amounts of a Mn(II) salt (100 ppm) were added in the oxidation of less

reactive substrates. More recently, these authors established a synergistic effect of Mn(II)

catalyst and a large range of salts as additives improving both the reaction rate and selectivity

for the oxidation of aldehydes.[117]

Scheme 14. Catalyst-free aerobic oxidation of aldehydes at room temperature.

Chapter A

39

6. Oxidative Carbon−Carbon Coupling Reactions

Metal catalyzed coupling reactions are undoubtedly among the most widely used reactions to

construct carbon−carbon or carbon−heteroatom bond. Among those, palladium-catalyzed

cross-coupling reactions have a significant impact on the synthesis of pharmaceuticals,

agrochemicals and natural products due to their high selectivity and functional group

tolerance.[118]

Over the past years, a plethora of examples were translated from conventional

batch regimes into flow approaches allowing for continuous manufacturing.[119, 120]

The oxidative Heck reaction (Fujiwara-Moritana reaction) is of special interest since it

does not require an electrophilic (pseudo)halide. This avoids the formation of stoichiometric

amounts of the corresponding salts which typically cause extensive environmental

pollution.[121, 122]

From a mechanistic point of view, these transformations involve catalytic

amounts of a Pd(II) species which initially undergoes an oxidative addition of the nucleophile

followed by coordination of an alkene, β-hydride elimination and reductive elimination of the

desired product. To close the catalytic cycle, the resulting Pd(0) species has to be re-oxidized

by e.g., molecular oxygen.[121, 122]

It is therefore not surprising that several researchers have

recognized the potential of continuous gas/liquid processing for this versatile coupling

strategy.

In their seminal contribution, Park and Kim established a membrane based dual-

channel microreactor for the oxidative Heck reaction of arylboronic acids and alkenes under

continuous flow conditions (Scheme 15, A).[123]

In a typical dual-channel setup, one of the

channels carries the liquid feed containing the substrates and the catalyst, while the other

channel is fed with O2. The oxidant diffuses through a permeable poly(dimethylsiloxane)

(PDMS) membrane separating the two channels thus providing a continuous supply of the

gaseous reagent. PDMS is reasonably stable in polar organic solvents such as DMF, DMSO

or acetonitrile, but many common nonpolar solvents diffuse into the PDMS polymer and

cause the material to swell. However, the authors demonstrated that good conversions can be

obtained within 30 min at room temperature using their experimental setup. A comparison of

the results of oxidative couplings in the dual channel reactor with a simple single-channel

reactor using a segmented flow showed slightly better conversions as well as higher

selectivity for the desired product using the membrane concept.

In a related approach Park and coworkers applied the tube-in-tube reactor for an

oxidative Heck coupling of arylboronic acids with cyclohex-2-enone and its subsequent

oxidative dehydrogenation to the corresponding phenol.[124]

Excellent yields were observed at

70 °C for various arylboronic acids at residence times of just 20 min. A comparison of the

Chapter A

40

oxidative coupling of 4-methxyphenylboronic acid and cyclohex-2-enone under identical

conditions (20 min, 70 °C) gave excellent isolated yields for the continuous approach (92 %)

in contrast to a classical batch reaction (20 %) clearly showing the benefits of continuous

gas/liquid processing. The authors put great efforts into the development of an oxidative

dehydrogenation protocol for the transformation of the coupling product to the corresponding

phenol. Long reaction times (120 min) were required in order to obtain sufficient conversions

at 120° and a back pressure of 5 bar in presence of TFA. Gratifyingly, after further

optimization studies a combination of both steps using a sequence of tube-in-tube reactors

was applicable resulting in a single continuous process at 120 °C with two consecutive

reactions involving O2 (Scheme 15, B).

Scheme 15. (A) Dual-channel reactor for oxidative Heck reactions in continuous flow. (B)

Oxidative Heck reaction followed by oxidative dehydrogenation in a sequence of tube-in-tube

reactors.

It is worth noting that the oxidative Heck coupling is not only limited to arylboronic acids as

nucleophilic reagent. As an alternative strategy, Leadbeater et al. optimized the reaction

conditions for the decarboxylative Heck reaction of 2,6-dimethoxycinnamic acid (20) and

methyl acrylate (21) utilizing microwave irradiation in batch.[125]

A direct translation of the

optimized protocol (140 °C, 30 min) was not feasible using the tube-in-tube technique. After a

re-evaluation in flow a residence time of 2 h at 140 °C was found to be necessary to obtain

Chapter A

41

satisfying yields of the coupling product 22 (Scheme 16, A). However, the process suffers

from some limitations as other alkenes such as styrene or acrylonitrile were prone to

decomposition. This resulted in the formation of large amounts of undesired byproducts under

the relatively harsh reaction conditions.

The continuous cross-dehydrogenative Heck reaction of olefins and indoles has

recently been described by Noel and coworkers using a coil reactor setup (Scheme 16, B).[126]

A solution of the indole and TFA was first mixed with the alkene in a mixing unit.

Afterwards, oxygen was added using a mass flow controller and another static T-mixer. The

utilization of high boiling DMSO allowed for a continuous process without the need of a back

pressure controlling unit. A short residence time of 10-20 min was demonstrated to be

sufficient to generate a broad range of coupling products at 110 °C using a segmented flow

pattern whilst higher temperatures caused decomposition of the catalytically active material.

Importantly, control experiments in batch showed that very long reaction times (4 h) were

necessary to obtain full conversion of the starting materials. Moreover, significantly lower

yields were obtained in batch mode presumably due to indole decomposition as a result of the

long reaction times.

Scheme 16. (A) Decarboxylative oxidative Heck-type coupling in a tube-in-tube-reactor. (B)

Cross-dehydrogenative coupling of indoles and olefins using molecular oxygen.

Chapter A

42

In addition to the Pd catalyzed cross-coupling protocols discussed above, the Ley group

demonstrated the applicability of their tube-in-tube membrane reactor for copper catalyzed

Glaser-Hay acetylene homocouplings (Scheme 17, A).[127]

An oxygenated solvent stream was

merged with a pre-combined solution of the terminal alkyne and catalytic amounts of

CuOTf(MeCN)4 and TMEDA. The combined mixture then entered a coil reactor heated at

100 °C. Several aromatic alkynes resulted in good to excellent yields after 17 min reaction

time. In case of aliphatic derivatives 25 mol% of DBU had to be added in order to obtain

satisfying results. Scavenger cartridges were used for in-line purification of the generated 1,3-

butadienes. Immobilized thiourea was packed into a cartridge to remove the copper catalyst

and polymer-supported sulfonic acid neutralized remaining TMEDA to avoid purification by

column chromatography.

In 2015, a combination of a tube-in-tube membrane reactor followed by a residence

time coil was utilized in an iron-catalyzed aerobic nitro-Mannich reaction via a radical

pathway by the group of Polyzos (Scheme 17, B).[128]

A process intensification study resulted

in a 2 h protocol using 10 mol% of FeCl2 as catalyst whilst the original batch protocol

required 5-7 d for similar results.[129]

Scheme 17. Tube-in-tube based continuous flow setups for (A) a Glaser-Hay coupling for the

synthesis of symmetric 1,3-butadiynes and (B) the iron-catalyzed aerobic nitro-Mannich

reaction.

Chapter A

43

7. Miscellaneous

The fact that alkyl Grignard reagents can be oxidized by O2 to produce the corresponding

alcohols has been known for more than hundred years.[130]

Aerobic oxidation of the analogous

aryl Grignard compounds often results in complex reaction mixtures resulting from poor

selectivity for the desired phenols due to the low reactivity of the aryl radicals intermediates

towards O2.[131, 132]

Scheme 18. Aerobic oxidation of aryl Grignard reagents in single step flow procedure (A)

and in a telescoped three step process (B).

In 2014, Jamison and coworkers hypothesized that the high surface-to-volume ratio of a

continuous flow reaction in combination with the faster heat and mass transfer may enhance

the reactivity and thus providing a general strategy for the synthesis of valuable phenols.[133]

A simple two-feed flow reactor was assembled to evaluate this theory (Scheme 18, A). Under

optimized conditions (-25 °C, 17 bar, 3.4 min) several electron-rich or electron-deficient aryl

magnesium bromides and even heteroaryl magnesium reagents could be successfully

converted into the corresponding phenols in good yields using pressurized air as oxygen

source. Noteworthy, oxidation-sensitive functional groups such as alkenes, anilines, tertiary

Chapter A

44

amines and thiol ethers were tolerated illustrating the broad applicability of this methodology.

Furthermore, the authors were able to expand their continuous system by generating ortho-

substituted aryl magnesium compounds prior to the oxidation (Scheme 18, B).

The aromatic hydroxyl group synthesized via this oxidation strategy is undoubtedly an

important structural motif in several relevant compounds. Among them, the simplest

molecule, phenol, is produced on an enormous scale via several industrial routes starting from

cumene, chlorobenzene, benzene or toluene.[134]

In case of the latter raw material, aerobic

oxidation generates benzoic acid which is further oxidized to phenol (Dow phenol process).

The second step was studied by Poliakoff using heterogeneous catalysis in water under high

temperature/high pressure continuous flow conditions.[135]

The general setup involving

hydrogen peroxide decomposition to in situ generate oxygen was already thoroughly

discussed in Chapter 3 (Scheme 2). The main difference to their earlier contributions is that

the heated coil was replaced by a packed bed reactor to evaluate various heterogeneous

materials for their applicability in this industrially relevant process. Among the tested

catalysts, Carulite®

showed promising activity and high robustness at 350 °C and 200 bar for

the selective formation of phenol in this proof-of-concept study.

The researchers additionally used this setup in studies on the oxidative

dehydrogenation of 4-vinylcyclohexene to yield ethylbenzene catalyzed by Pd/Al2O3.[136]

Unfortunately, total oxidation to CO2 was to a large extend observed at 420 °C and 90 bar.

This could be rationalized by periodic temperature spikes at the catalyst bed indicating flame

propagation due to the extremely harsh conditions.

Oxygen is not exclusively applied for the oxidation of hydrocarbons, specific

functionalities or to re-oxidize a catalyst but also in the generation of the highly reactive

species diimide (N2H2) from hydrazine, which subsequently acts as selective reducing agent

for unpolarized carbon-carbon double bonds.[137, 138]

Since the initial oxidation step is rather

slow under laboratory batch conditions, catalysts are usually added in order to provide a

feasible experimental protocol. Kappe and coworkers could show that a continuous flow

protocol in a high-temperature/high-pressure regime significantly enhances this process and

thus eliminates the need for a catalyst.[139, 140]

In the original procedure, an organic stream

consisting of an olefin and hydrazine hydrate in n-propanol was mixed with oxygen resulting

in a segmented flow pattern which is heated in a residence time unit to 100-120 °C at a back

pressure of 20 bar.[139]

Reaction times of 10-30 min were sufficient to selectively reduce

various terminal and internal carbon−carbon double bonds. Since nitrogen gas and water were

Chapter A

45

the only byproducts most saturated compounds could be isolated simply by evaporation of the

solvent.

By studying the hydrazine oxidation in more detail the authors developed a strategy

for more challenging substrates such as artemisinic acid (23) to obtain the direct precursor

molecule (24) of the antimalaria drug artemisinin (Scheme 19).[140]

Scheme 19. Selective reduction of artemisinic acid (23) by in situ generated diimide.

Key to the success was the multiple addition of small portions of hydrazine hydrate to reduce

the disproportionation of the reactive intermediated diimide and circumvent its complete

over-oxidation in a single coil. In addition, the temperature could be reduced to 60 °C in order

to obtain high selectivity and diastereomeric ratio. Notably, a comparison with the catalyst-

free batch reduction of the same compound at 40 °C demonstrated significantly longer

reaction times (11 h) in order to obtain similar values for isolated yield and product purity.[141]

8. Photochemical Reactions Involving Molecular Oxygen

A serious issue coming along with photochemical transformations –especially on larger

scales– is arising from the logarithmic decrease with path length of the transmission of light

through a liquid medium (Lambert−Beer law) resulting in inefficient irradiation of the entire

reaction mixture. This severe limitation in conventional batch processes can be addressed

using continuous flow processing.[142, 143]

The large surface-to-volume ratio which is typically

present using this enabling technology ensures a highly increased irradiation efficiency of the

entire solution often resulting in significantly intensified protocols. Apparently, such a

process using oxygen as reagent is well suited for continuous flow processing since it offers

advantages in both gas/liquid processing and photochemistry.

Chapter A

46

Noël and coworkers used oxygen in a photocatalytic oxidation of thiols to generate the

corresponding symmetric disulfides.[144, 145]

Initial batch experiments revealed that a

combination of Eosin Y as catalyst and stoichiometric amounts of TMEDA can facilitate this

oxidation in the presence of oxygen.[144]

Mechanistically, the photosensitizer is excited by

visible light and subsequently activates the thiol by generating a thiyl radical. This key step is

proposed to be facilitated by the base as demonstrated in kinetic experiments. Oxygen is used

to re-oxidize [Eosin Y]- via single electron transfer (SET) in order to close the catalytic cycle.

The continuous strategy is based on a simple two feed setup using a mass flow controller to

control the O2 stream. The resulting segmented flow pattern entered a PFA capillary which

was irradiated by white LED light for 20 min to convert various simple thiols to the

corresponding disulfide in excellent yield (87-99 %). Furthermore, the authors put great effort

in demonstrating the versatility of their strategy in an intramolecular peptide coupling

affording the hormone oxytocin in a short residence time of 200 s (Scheme 20).

Scheme 20. Continuous photochemical disulfide formation to produce Oxytocin.

The single electron transfer from a reduced photocatalyst and oxygen is not only interesting

for the re-oxidation of the catalytic species but also for generating a superoxide radical (O2∙-).

This reactive oxygen species is able to react with aryl boronic acids selectively generating the

corresponding phenols.[146]

Safety concerns and long reaction times in batch forced George

and coworkers to intensify this process under flow conditions using air as oxygen source.[147]

The gaseous oxidant was mixed with the liquid feed and irradiated with white LEDs in a

tubular sapphire photoreactor filled with glass beads to promote gas/liquid mixing. With the

aid of continuous processing under high pressure regimes, the original catalyst

[Ru(bpy)3Cl2]∙6H2O could be replaced by the inexpensive organic dye Rose Bengal and the

Chapter A

47

solvent (DMF) was substituted by a more sustainable ethanol-water mixture. Notably, a

continuous reaction at 20 bar gave a quantitative reaction with a 90-fold higher productivity

than the batch control experiment.

Another versatile reactive dioxygen species is singlet oxygen (1O2) which can be

generated either through chemical processes or, more commonly, by photoexcitation of

molecular oxygen in the presence of a photosensitizer.[148]

Even though singlet oxygen is

rather widely used in contemporary organic synthesis, its application in the pharmaceutical

industry on a large scale has not yet proven to be feasible. In 2002, de Mellow and coworkers

demonstrated that microreactor technology is a promising tool to tackle this limitation.[149]

In

their pioneering work, a solution of Rose Bengal and terpinene (25) in methanol was mixed

with oxygen in a glass chip reactor irradiated by a tungsten lamp (Scheme 21). Both, the

gaseous and the liquid stream were controlled by using gas tight syringe pumps resulting in

residence times of approximately 5 s. Within this short residence time 85 % conversion to

ascaridole (26) was observed.

Scheme 21. Generation of singlet oxygen for the synthesis of ascaridole (26) from α-terpinene

(25).

Prompted by these encouraging results, a multitude of reactor designs –including microfluidic

chip reactors,[150]

falling-film reactors,[151]

dual- and triple-channel microreactors,[152, 153]

coil

based devices,[154, 155]

gas permeable microcapillary films,[156]

tube-in-tube membrane devices

[157]– were subsequently applied for the generation and subsequent utilization of

1O2 in

gas/liquid continuous flow regimes using well-known photosensitizers such as Rose Bengal,

methylene blue and porphyrins. Furthermore, it was shown that porphyrins can be

immobilized on the channel wall of a glass microreactor to heterogeneously catalyze the

formation of the reactive oxygen species.[158]

In this context Seeberger and coworkers developed a procedure for the oxidation of

primary and secondary amines to the corresponding imines in continuous flow using singlet

oxygen which was generated using low amounts of meso-tetraphenylporphyrin (TPP).[159-162]

Chapter A

48

The imines generated from secondary amines immediately resulted in the corresponding α-

aminonitriles in good to excellent isolated yields at room temperature using CH2Cl2 as solvent

in the presence of trimethylsilyl cyanide as trapping agent (Scheme 22).[159]

Scheme 22. Oxidation of amines to imines with singlet oxygen in continuous flow and

subsequent trapping to yield α-aminonitriles.

When primary amines were subjected to these conditions an oxidative homo-coupling

resulting in the corresponding N-substituted imines was observed. The authors found that

primary amines could be converted to α-aminonitriles in a selective manner by switching

from CH2Cl2 to THF as solvent at significantly lower temperatures (-50 °C) adding sub-

stoichiometric amounts of TBAF to activate the TMSCN. The concept was further expanded

for the synthesis of α-cyanoepoxides and fluorinated α-amino acids.[160, 162]

Oxygen, and especially singlet oxygen plays an important role in the (semi-)synthesis

of the antimalaria drug artemisinin. In the previous chapter, the reduction of artemisinic acid

(23) to dihydroartemisinic acid (24) utilizing O2 and hydrazine was already discussed.[140]

The

reduced compound 24 forms an allylic hydroperoxide in the presence of 1O2 which

subsequently undergoes an acid-promoted Hock cleavage, and oxidation by O2. This triggers

a spontaneous cascade of condensation reactions generating artemisinin (27). Seeberger and

coworkers performed the whole reaction sequence as a single, fully continuous process using

a sequence of coil reactors (Scheme 23).[163, 164]

Under optimized conditions, a mixture of 24,

TFA and catalytic amounts of 9,10-dicyanoanthracene in toluene were mixed with pure O2

and passed through the photoreactor at -20 °C.[164]

The reactor unit consisted of FEP tubing

wrapped around a glass plate which was immersed in a cooling bath. A LED module was

mounted at a fixed distance in front of the reactor to efficiently irradiate the solution.

Afterwards, the mixture was slowly heated in to consecutive coils to accomplish the acid-

catalyzed Hock-cleavage, the oxidation and the condensation cascade resulting in 27 in good

selectivity. Extraction and recrystallization gave 46 % of the final antimalarial drug. The

Chapter A

49

continuous protocol was subsequently expanded to a modular multi-step approach to access

various pharmaceutically active derivatives of 27.[165]

Scheme 23. Synthesis of artemisinin (27) from dihydroartemisinic acid (24) in continuous

flow.

George and coworkers thoroughly studied the applicability of scCO2 as solvent for the

continuous generation and utilization of 1O2 in a tubular sapphire reactor using homogeneous

and immobilized photosensitizers.[166-171]

Their findings recently led to a more sustainable

strategy for the continuous synthesis of artemisinin (27) using liquid CO2 and a solid catalyst

(Scheme 24).[172]

Thus, meso-tetraphenylporphyrin was anchored onto the ion-exchange resin

Amberlyst-15 resulting in [TPP-Amb]. This elegant dual catalyst system combines the ability

to facilitate the generation of singlet oxygen as well as the Brønsted-acid mediated Hock

cleavage to generate 27. In the final continuous protocol, O2 was mixed with CO2 using a

dosing technique (see Chapter 4.2). Afterwards a solution of 24 in toluene was added via a

second mixing unit at a back pressure of 180 bar. The final reaction mixture was passed

through the tubular sapphire tube reactor containing the dual-function solid catalyst at 5 °C.

The whole reactor unit is subjected to irradiation by light in the visible region using an array

of LEDs. A residence time of 20 min was sufficient to fully convert dihydroartemisinic acid

(24) and obtain similar yields to the homogeneously catalyzed process discussed above.

In addition, the authors presented a second sustainable continuous strategy utilizing

aqueous solvent mixtures to obtain up to 66 % of artemisinin (27) by using [Ru(bpy)3]Cl2 as

catalyst in the presence of TFA in THF:H2O (6:4).[172]

Chapter A

50

Scheme 24. Synthesis of artemisinin (27) in liquid CO2 using a dual-function solid catalyst.

Adapted with permission from [172].

9. Concluding Remarks

The utilization of oxygen in continuous flow environments offers several advantages

compared to conventional batch techniques and a broad range of oxidation reactions have

been studied using this enabling technology. The main drivers are on the one hand that safety

concerns can be significantly reduced when working with a continuous flow (micro-) reactor.

Exothermic reactions are easily controlled by the excellent mass and heat transfer and the

small volumes and channel dimensions minimize the possibility for propagation of an

explosion inside the reactor even under extreme conditions. On the other hand, working at

elevated temperatures and, more importantly, at high pressures can be easily achieved often

resulting in improved and highly intensified oxidation protocols. Thus, especially aerobic

oxidation protocols using supercritical solvents are predominantly studied in continuous

environments.

Several technologies and reactor designs have been developed in the past to perform

reactions involving oxygen in order to meet these demands. Liquid phase oxidations are

typically carried out by using a mass flow controlling unit or membrane reactors to deliver the

gaseous reagent. In case of supercritical solvents dosing techniques are often applied due to

the high system pressures. However, a universal reactor design does not exist and all reaction

parameters have to be taken into account for developing a suitable continuous flow reactor.

Thus, strong collaborations between chemists and process engineers are of utmost importance

for this rapidly growing area.

Chapter A

51

The application of continuous flow has already reached widespread use for the aerobic

oxidation of specific functional groups such as alcohols in order to replace expensive and

often toxic reagents thus providing more sustainable alternatives. Furthermore, in recent years

a clear trend to other applications such as oxidative coupling reactions or photochemical

applications can be observed. Since continuous processing is gaining increasing attention by

synthetic chemists it is apparent that entirely new synthetic routes will be developed on a

more routine basis by using this enabling technology. Therefore, flow chemistry can

potentially help to access more selective strategies and better (catalytic) systems which are

hardly feasible in traditional batch equipment. Flow chemistry on laboratory scale is not only

used to enhance aerobic oxidations developed in batch, but also to get deeper insights into

industrial processes and reaction mechanisms of well-known transformations.

10. References

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113, 6234.

[2] A. N. Campbell, S. S. Stahl, Acc. Chem. Res. 2012, 45, 851.

[3] Q. Cao, L. M. Dornan, L. Rogan, N. L. Hughes, M. J. Muldoon, Chem. Commun.

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Chapter B

59

B. Direct Aerobic Oxidation of 2-Benzylpyridines in a Gas-Liquid

Continuous-Flow Regime using Propylene Carbonate as Solvent

Graphical Abstract

Abstract

The use of high-temperature/pressure gas-liquid continuous flow conditions dramatically

enhances the iron-catalyzed aerobic oxidation of 2-benzylpyridines to their corresponding

ketones. Pressurized air serves as readily available oxygen source and propylene carbonate

as green solvent in this radically intensified preparation of synthetically valuable 2-

aroylpyridines.

Chapter B

61

1. Introduction

The direct oxidation of CH bonds for atom- and step-economical synthesis of functionalized

molecules is a rapidly growing field in the organic chemistry community.[1]

The oxidation of

2-benzylpyridines to the corresponding benzoyl derivatives, for example, was developed in

1930 using potassium permanganate as oxidant in large excess.[2]

In the last few years

catalytic methods for such transformations were developed using stoichiometric amounts of

strong oxidants such as potassium bromate or tert-butylhydroperoxide.[3-5]

Very recently

substantial progress in this reaction was reported by Maes and coworkers, who discovered

that this oxidation can be carried out using molecular oxygen in the presence of catalytic

amounts of iron or copper salts in combination with acetic acid as additive (Scheme 1).[6]

The

ketones resulting from this transformation are key intermediates for the synthesis of several

active pharmaceutical ingredients (APIs) including antihistamines (e.g. Pheniramine,

Triprolidine, Doxylamine, Carbinoxamine, Arpromidine),[7]

antiarrhytmic agents

(Disopyramide),[8]

and of promising candidates for cancer treatment such as 2-

benzoylpyridine 2´-pyridylhydrazones and 2-benzoylpyridine thiosemicarbazone derivatives

(Scheme 1).[9,10]

In recent years, the use of microreactors and continuous flow technology in general

has become increasingly popular in synthetic organic chemistry.[11,12]

One of the main

advantages of continuous flow processing is the ease with which reactions can be

scaledwithout the need for reoptimizationthrough the operation of multiple systems in

parallel (numbering-up, scaling-out) or related strategies, thereby readily achieving

production scale quantities.[11,12]

Enhanced heat- and mass transfer characteristics and the

ability to efficiently optimize reaction conditions by control of residence time add value to the

technology. Notably, biphasic reactions can often be dramatically improved using

microreactor technology owing to an enhanced mass transfer of e.g., gaseous reactants into a

liquid phase.[13]

Examples of such continuous gasliquid reactions including

hydrogenations,[14]

hydroformylations,[15]

carbonylations,[16]

halogenations,[17]

ethylene

cycloadditions,[18]

ozonoloysis reactions,[19]

and oxidations[20]

have been carried out in a

variety of biphasic flow patterns and formats.

A very important factor in the reaction design is undoubtedly the correct choice of

solvents. A proper solvent can affect a chemical transformation not just by dissolving reaction

partners, it is also able to stabilize transition states, shift the reaction equilibrium by

precipitating a (by)product, or allows an accurate setting of the reaction temperature (e.g.

Chapter B

62

reflux conditions). Nowadays sustainability is a major concern in the development of any

chemical process.

N

10 mol% Fe or Cu1 equiv. AcOH1 atm O2

DMSO, 24 h, 100°C

N

O

R

R

N

N

R

HN

N

N

NHN

SRHN

N

NH2

O

NiPr

iPr

N

O

Cl

N

N

O

N

N

N

N

R

N

N

F

HN

NH2N

N

HN

Arpromidine

R=H PheniramineR=Cl Chloropheni ramine

Triprolidine Doxylamine Carbinoxamine Disopyramide

2-benzoylpyridine 2´-pyridylhydrazones

2-benzoylpyridine th iosemicarbazones

Maes and coworkers(ref. 6)

Scheme 1 Cu or Fe catalyzed direct oxidation of 2-benzylpyridines using molecular oxygen

as sole oxidant provides important intermediates for API synthesis.

The replacement of traditional organic solvents by “greener alternatives” represents a

fundamental challenge in academic as well as industrial research.[21]

In this context, propylene

carbonate (PC), a nontoxic and biodegradable cyclic carbonate which can be prepared from

CO2 and propylene oxide in an highly atom-efficient process,[22]

has been introduced as

greener alternative to more traditional solvents for intermolecular alkyne

hydroacetylations,[23]

proline-catalyzed aldol reactions,[24]

asymmetric hydrogenations,[25,26]

proline-catalyzed aminations,[27]

and in asymmetric cyanohydrin syntheses.[28]

In particular,

there is need to substitute common aprotic, dipolar solvents owing to their poor performances

in waste (MeCN), health (DMF, NMF, NMP, DMA) or reactivity (DMSO) rankings in e.g.

the GSK solvent selection guide.[29]

Therefore, PC presents an promising alternative as it is

nontoxic and stable while its polarity is even higher than compared to MeCN.[21,29]

Chapter B

63

Herein, we describe a gasliquid continuous flow protocol for the direct oxidation of 2-

benzylpyridines using propylene carbonate as solvent, which exhibits several advantages

compared to the previously described process in DMSO.[25,29]

In addition inexpensive iron(III)

chloride was used as catalyst underlining the sustainability of this transformation.[30]

The

utilization of a high- temperature/high-pressure (high-T/p) process window,[31]

results in an

intensified process which requires lower amounts of the catalytically active species and

allows a high productivity of the desired ketones in an efficient, continuous manner.

2. Results and Discussion

The microreactor concept used in this study followed a standard two feed approach. The

gaseous oxygen source, synthetic air, was mixed with the liquid phase in a T-shaped mixing

device (Figure 1). The liquid phase containing iron(III) chloride and 2-benzylpyridine

dissolved in the respective solvent was pumped by an HPLC pump. The biphasic reaction

stream passed through a 120 m stainless steel coil (inner diameter of 0.8 mm) heated to the

respective reaction temperature with a standard GC oven. To obtain detailed information

about the temperature homogeneity along the coil temperature sensors were installed at

different positions: at the beginning of the heated reaction zone, one after approximately 1 m,

and at the outlet of the oven. It has to be emphasized that no back pressure regulator was used

at the end of the residence time unit as this was not necessary when a liquid flow rate of 0.6

mL min-1

and gaseous inputs of 1.2 – 1.7 NL min-1

were applied.

Figure 1. Schematic diagram of the gasliquid continuous flow reactor used in this study:

The flow rate of the liquid phase is controlled by an HPLC pump. The gas flow was measured

using a mass flow controller (MFC). The two phases are mixed in a T-shaped mixing unit

before entering the residence time unit (stainless steel coil, inner diameter 0.8 mm, length 120

m) heated in a GC oven. The reaction temperature was additionally monitored using thermo

couples (TC 1-3; for illustrations of the reactor and detailed descriptions of all parts, see the

ESI).

Chapter B

64

The oxidation of 2-benzylpyridine (1a) served as model reaction for an initial optimization

study (Table 1). First attempts to reproduce the conditions reported in the original work in

DMSO at higher temperatures (100-170 °C) resulted in a repulsive odor presumably from side

reactions of the solvent.[6]

Thus, for a continuous application we decided to use a more stable

solvent under the high-temperature conditions such as N-methyl-pyrrolidone (NMP). Reaction

at 150 °C with a catalyst loading of 10 mol% (FeCl3) resulted in 75 % conversion when a

liquid flow rate of 0.6 ml min-1

and an air stream of 1.7 NL min-1

was applied (Table 1, entry

1). Notably, under these intensified conditions the use of an additive such as acetic acid as

described by Maes and coworkers was not necessary for a successful oxidation.[6]

A further

increase of the reaction temperature to 170 °C enabled an almost full conversion of the

starting material 1a (Table, entry 2 and 3). Unfortunately, it was not possible to further raise

the temperature as decomposition of NMP was observed resulting in a characteristic odor and

a dark brown to black discoloration of the solvent.

Since acetic acid showed the ability to significantly enhance the reaction rate in the

batch protocol[6]

this solvent was also evaluated under continuous flow conditions. When the

oxidation was performed at 100 °C no product was identified by GC-FID analysis (Table 1,

entry 4). At 120 °C the reaction solvent was essentially “distilled” off in the microreactor

leaving the catalyst/substrate/product mixture inside the heated reaction zone (Table 1, entry

5). To avoid this effect we reduced the gaseous flow rate to 1.2 NL min-1

, resulting however in

only 15 % conversion (Table 1, entry 6).

The problems described above with DMSO, NMP and AcOH indicate that a

successful reaction under high-temperature conditions requires a solvent which is extremely

stable against oxidation and also has a high boiling point. The excellent properties of PC,

including its high boiling point (242 °C), good chemical stability and low viscosity, make this

solvent a very attractive alternative to traditional aprotic polar solvents such as NMP, DMSO,

etc.0,[25,29]

in particular for continuous flow applications in a high-T/p process window. An

initial experiment at 180 °C provided a somewhat lower conversion compared to NMP at 170

°C but, satisfyingly, no decomposition or other undesired effects occurred (Table 1, entry 7).

Thus, the temperature was increased to 200 °C resulting in total consumption of substrate 1a

(Table 1, entry 8). A subsequent reduction of the catalyst loading to 5 mol% with concomitant

increase of the starting material concentration still led to full conversion (Table 1, entry 9).

Product isolation by simple filtration over a plug of silica with hexanes provided 81 % of the

desired ketone 2a which is in good agreement with the results described for the batch protocol

(80%).[6,32]

Lower amounts of catalyst resulted in high conversions as well but small amounts

Chapter B

65

of the substrate 1a were still present (Table 1, entry 10). Notably, a control experiment in the

absence of the catalyst revealed that a homogeneous iron source is clearly required for this

oxidation reaction to proceed and that the stainless steel coil itself cannot enhance this

reaction in any significant way (Table 1, entry 11). Additional temperature monitoring

demonstrated that the target temperature (200 °C) was reached after 1 m of the stainless steel

coil. As expected, the temperature at the reactor entrance is significantly lower (165 °C, for

detailed information about the temperature monitoring see the ESI).

Table 1. Optimization of the direct aerobic oxidation of 2-benzylpyridinea

N NFeCl3

O2 (synthetic air)

solvent, conditions(continuous flow)

O

1a 2a

Entry FeCl3 (mol%) 2-Benzylpyridine (M) Solvent T (°C) Conv. b

(%)

1 10 0.6 NMP

150 75

2 10 0.6 NMP 160 93

3 10 0.6 NMP 170 98

4 10 0.6 AcOH 100 0

5

10 0.6 AcOH 120 n.d.c

6d

10 0.6 AcOH 120 15

7 10 0.6 PCe

180 97

8 10 0.6 PC 200 >99

9 5.0 1.2 PC 200 >99(81%)f

10 2.5 1.2 PC 200 97

11 -- 1.2 PC 200 3

a Reaction conditions for optimized conditions (entry 9): 2.3 mmol 2-benzylpyridine (1a), 0.12 mmol FeCl3, 2

mL propylene carbonate; flow rate liquid phase 0.6 mL min-1

; flow rate synthetic air: 1.7 NL min-1

.b

GC-FID

peak area percent of 2-benzoylpyridine (2a). c

not determined, solvent distillation. d Flow rate of synthetic air

was 1.2 NL min-1

.e Propylene carbonate.

f Isolated yield in parentheses.

The overall processing time for the optimized reaction conditions from the HPLC pump to the

point where the reaction mixture leaves the residence time unit was exactly 13 min. This

constitutes a major advantage in comparison to the originally published batch protocol where

24 h were required for full conversion of the starting material.[6]

Furthermore, our intensified

Chapter B

66

process did not require any additive (AcOH) while working at higher concentrations (1.2 M

vs. 0.5 M) and significantly lower catalyst loadings (5 mol% vs. 10 mol%).[6]

Importantly,

pure oxygen could be replaced by pressurized air, apparently due to the high mass transfer

between the gaseous and the liquid phase.[33]

With the optimized conditions in hand we moved on to synthesize some of the other

desired 2-aroylpyridine target intermediates shown in Scheme 1 (Table 2). The oxidation of 2-

(4-methylbenzyl)pyridine (1b) furnished the precursor for Triprolidine in 69 % isolated yield

(Table 2, entry 1). For the chloro-substituted derivative (1c) 81 % of the pure ketone

compound could be obtained (Table 2, entry 2). A Wittig reaction of this ketone with

subsequent reduction of the double bond can result in Chloropheniramine, while a reduction

of the keto-group with subsequent etherification will lead to the H1-antagonist

Carbinoxamine.[7]

The intermediate for Arpromidine, containing a fluorine atom at the benzyl

moiety was obtained in 83 % (Table 2, entry 3).

Table 2. Direct aerobic oxidation of 2-benzylpyridine derivativesa

Entry Substrate Product Yield (%)

1

69

2

81

3

83

a Reaction conditions see Table 1, footnote a

Chapter B

67

3. Conclusion

In summary, we have demonstrated that the direct aerobic oxidation of 2-benzylpyridine

derivatives can be dramatically enhanced using continuous flow methodology in a high-T/p

process window in combination with propylene carbonate as green solvent. The reaction time

could be significantly reduced from hours to minutes and molecular oxygen could be replaced

by synthetic air as sole oxygen source. Thus, several key intermediates for API synthesis can

be synthesized in a continuous and environmentally benign manner.

4. References

[1] For a review on CH functionalization in total synthesis including several examples of

direct oxidation, see: W. R. Gutekunst, P. S. Baran, Chem. Soc. Rev. 2011, 40, 1976.

[2] K. E. Crook, S. M. McElvain, J. Am. Chem. Soc. 1930, 52, 4006.

[3] B. Akhlaghinia, H. Ebrahimabadi, E. K. Goharshadi, S. Samiee, S. Rezazadeh, J. Mol.

Catal. A-Chem., 2012, 357, 67-72.

[4] J. Zhang, Z. Whang, Y, Wang, C. Wan, X. Zheng, Z. Wang, Green Chem. 2009, 11,

1973.

[5] M. Nakanishi, C. Bolm, Adv. Synth. Catal. 2007, 349, 861.

[6] J. de Houwer, K. A. Tehrani, B. U. W. Maes, Angew. Chem. Int. Ed. 2012, 51, 2745.

[7] A. Kleemann, J. Engel, B. Kutscher, D. Reichert, Pharmaceutical Substances, Georg

Thieme, 4th ed., Stuttgart,

[8] A. C. Guyton, J. E. Hall, Textbook of Medical Physiology, Elsevier Saunders, 11th

ed.,

Philadelphia.

[9] J. Easmon, G. Heinisch, G. Pürstinger, T. Langer, J. K. Österreicher, J. Med. Chem.

1997, 40, 4420.

[10] D. C. Reis, M. C. X. Pinto, E. M. Souza-Fagundes, S. M. S. V. Wardell, J. L. Wardell,

H. Beraldo, Eur. J. Med. Chem. 2010, 45, 3904.

[11] For recent reviews on continuous flow/microreactor chemistry, see: (a) J. Wegner, S.

Ceylan, A. Kirschning, Adv. Synth. Catal. 2012, 354, 17; (b) C. Wiles, P. Watts, Green

Chem. 2012, 14, 38; (c) R. L. Hartman, J. P. McMullen, K. F. Jensen, Angew. Chem.

Int. Ed. 2011, 50, 7502.

[12] (a) Microreactors in Organic Synthesis and Catalysis, ed. T. Wirth, Wiley-VCH,

Weinheim, 2008; (b) Handbook of Micro Reactors, ed. V. Hessel, J. C. Schouten, A.

Chapter B

68

Renken, Y. Wang, J.-i. Yoshida, Wiley-VCH, Weinheim, 2009; (c) J.-i. Yoshida,

Flash Chemistry—Fast Organic Synthesis in Microsystems, Wiley-VCH, Weinheim,

2008.

[13] P. Sobieszuk, J. Aubin, R. Pohorecki, Chem. Eng. Technol. 2012, 35, 1346.

[14] J. Kobayashi, Y. Mori, K. Okamoto, R. Akiyama, M. Ueno, T. Kitamori, S.

Kobayashi, Science 2004, 304, 1305.

[15] P. B. Webb, M. F. Sellin, T. E. Kunene, S. Williamson, A. M. Z. Slawin, D. J. Cole-

Hamilton, J. Am. Chem. Soc. 2003, 125, 15577.

[16] (a) P. W. Miller, N. J. Long, A. J. de Mello, R. Vilar, J. Passchier, A. Gee, Chem.

Commun. 2006, 546; (b) P. W. Miller, N. J. Long, A. J. de Mello, R. Vilar, H.

Audrain, D. Bender, J. Passchier, A. Gee, Angew. Chem. Int. Ed. 2007, 46, 2875; (c)

X. Gong, P. W. Miller, A. D. Gee, N. J. Long, A. J. de Mello, R. Vilar, Chem. Eur. J.

2012, 18, 2768. (d) C. G. Kelly, C. Lee, M. A. Mercadante, N. E. Leadbeater, Org.

Process. Res. Dev. 2011, 15, 717.

[17] (a) N. de Mas, A. Günther, M. A. Schmidt, K. F. Jensen, Ind. Eng. Chem. Res. 2002,

42, 698; (b) P. Tundo, M. Selva, Green Chem. 2005, 7, 464.

[18] K. Terao, Y. Nishiyama, H. Tanimoto, T. Morimoto, M. Oelgemöller, K. Kakiuchi, J.

Flow. Chem. 2012, 2, 73.

[19] M. O’Brien, I. R. Baxendale, S. V. Ley, Org. Lett. 2010, 12, 1596.

[20] Z. Hou, N. Theyssen, A. Brinkmann, W. Leitner, Angew. Chem. Int. Ed. 2005, 44,

1346.

[21] For an excellent perspective article about green solvents, see: P. G. Jessop, Green

Chem. 2011, 13, 1391.

[22] (a) M. North, R. Pasquale, C. Young, Green Chem. 2010, 12, 1514; (b) J. E. Dengler,

M. W. Lehenmeier, S. Klaus, C. E. Anderson, E. Herdtweck, B. Rieger, Eur. J. Inorg.

Chem. 2011, 336.

[23] P. Lenden, P. M. Ylioja, C. González-Rodríguez, D. A. Entwistle, M. C. Willis, Green

Chem. 2011, 13, 1980.

[24] W. Clegg, R. W. Harrington, M. North, F. Pizzato, P. Villuendas, Tetrahedron:

Asymmetry 2010, 21, 1262.

[25] J. Bayardon, J. Holz, B. Schäffner, V. Andrushko, S. Verevkin, A. Preetz, A. Börner,

Angew. Chem. Int. Ed. 2007, 46, 5971.

[26] B. Schäffner, V. Andrushko, J. Holz, S. P. Verevkinand, A. Börner, ChemSusChem

2008, 1, 934.

Chapter B

69

[27] C. Beattie, M. North, P. Villuendas, Molecules 2011, 16, 3420.

[28] M. North, M. Omedes-Pujol, Beilstein J. Org. Chem. 2010, 6, 1043.

[29] A comparison of solvents can be found in the extended GSK solvent selection guide:

R. K. Henderson, C. Jiménez-González, D. J. C. Constable, S. R. Alston, G. G. A.

Inglis, G. Fisher, J. Sherwood, S. P. Binks, A. D. Curzons, Green Chem. 2011, 13,

854.

[30] S. Enthaler, K. Junge, M. Beller, Angew. Chem. Int. Ed. 2008, 47, 3317.

[31] For a general discussion on novel process windows and process intensification

technologies based on high-T/p conditions, see: (a) V. Hessel, Chem. Eng. Technol.

2009, 32, 1655; (b) V. Hessel, B. Cortese, M. H. J. M. de Croon, Chem. Eng. Sci.

2011, 66, 1426; (c) T. Van Gerven, A. Stankiewicz, Ind. Eng. Chem. Res. 2009, 48,

2465; (d) T. Razzaq, C. O. Kappe, Chem. Asian J. 2010, 5, 1274.

[32] The yield of 2-benzylpyridine 2a was also calculated by GC-FID analysis using

methyl phenylacetate as internal standard and is consistent with the isolated yield.

[33] It is worth mentioning that the high-T/p gas-liquid continuous flow approach

described herein cannot be carried out using the “tube-in-tube” concept developed by

the Ley group (e.g., ref. 19). Commercially available instruments using this

technology are either used to saturate the liquid phase with the gaseous reactant before

entering a heated residence time unit, or are limited to temperatures below 150 °C. For

representative examples, see: (a) P.B. Cranwell, M. O’Brien, D. Browne, P. Koos, A.

Polyzos, M. Pêna López, S.V. Ley, Org. Biomol. Chem. 2012, 10, 5774; (b) S.

Newton, S.V. Ley, E.C. Arce, D. Grainger, Adv. Synth. Catal. 2012, 354, 1805; (c)

T.P. Peterson, A. Polyzos, M. O’Brien, T. Ulven, I.R. Baxendale, S.V. Ley,

ChemSusChem 2012, 5, 274; (d) M. A. Mercandate, N. E. Leadbeater, Org. Biomol.

Chem. 2011, 9, 6575.

Chapter B

70

5. Supporting Information

General Remarks. All chemicals were purchased from Sigma-Aldrich, or Alfa Aesar and

were used without further purification. Reagents were weighed and handled in air at room

temperature. 1H-NMR and

13C spectra were recorded on a Bruker 300 MHz instrument using

CDCl3 as solvent. Chemical shifts (δ) are expressed in ppm downfield from TMS as internal

standard. The letters s, d, t, q, and m are used to indicate a singlet, doublet, triplet, quadruplet,

and multiplet. Melting points were determined on a Stuart™ SMP3 melting point apparatus.

GC-FID analysis was performed on a Trace-GC (ThermoFisher) with a flame ionization

detector using a HP5 column (30 m×0.250 mm×0.025 μm). After 1 min at 50°C the

temperature was increased in 25°C min−1

steps up to 300°C and kept at 300°C for 4 min. The

detector gas for the flame ionization is H2 and compressed air (5.0 quality).GC-MS analysis

was performed on a Trace-GC Ultra – DSQ II-MS system (ThermoElectron, Waltham, MA,

USA). The GC conditions were as follows: HP-5 MS column (30 m × 0.25 mm ID, 0.25 μm

film, Agilent, Waldbronn, Germany); carrier gas helium 5.0, flow 1 mL min-1

, temperature

gradient identical to GC-FID. The MS conditions were as follows: positive EI ionization,

ionization energy 70 eV, ionization source temperature 280 °C, emission current 100 μA; full-

scan-mode. Silica gel flash chromatography separations were performed on a Biotage SP1

instrument using petroleum ether/ethyl acetate mixtures as eluent.

Chapter B

71

Gas-Liquid continuous flow reactor

Figure S1: Gas-liquid continuous flow reactor. The main parts of this custom-built device

are a gas bottle (synthetic air, 5.0 quality) with a 50 bar pressure regulating valve (A), a

mass flow controller (B),[S1]

a binary pumping module (C),[S2]

a GC oven (D) to heat the

residence time unit (E) and a digital 4-channel-thermometer equipped with three

thermocouples (F) to monitor the reaction temperature at different positions of the reaction

coil.[S3]

Figure S2: Mass Flow controller (MFC, EL-FLOW Select F-201CV-5K0)[S1]

and the

Uniqsis Binary Pumping Module.[S2]

The gaseous reagent (synthetic air) is controlled by the

MFC and mixed with the liquid phase in a T-mixer (M) containing a pressure transducer

after passing a 7 bar backpressure regulator (BPR). The liquid stream enters the binary

pumping module through an inlet selection valve (ISV) which is used to control the liquid

feed (e.g. either solvent or reagent). The flow rate is controlled by a HPLC pump (P) allowing

flow rates from 0.01 to 10 mL min-1

. The priming valve (PV) equipped with another pressure

transducer enables priming with solvent before performing a reaction. The system constantly

monitors the pressure and will stop if the pressure either rises above or falls below the global

limits. The maximum allowed pressure of this device is 100 bar.

Chapter B

72

Figure S3: Residence time unit (120 m stainless steel coil with an inner diameter of 0.8 mm)

inside a GC-oven. To monitor the temperature at different positions thermocouples were

installed at the entrance of the heated reaction zone (TC 1), after approximately 1 m of the

coil (TC 2) and at the outlet of the oven (TC 3).

Figure S4: Temperature profile of the temperature at the entrance of the heated reaction zone

(TC 1), after approximately 1 m of the coil (TC 2) and at the outlet of the oven (TC 3) over 30

minutes using the optimized reaction conditions (liquid flow rate: 0.6 mL min-1

; air flow rate:

1.7 NL min-1

. At the beginning of the heated zone (TC 1) the temperature is significantly lower

than the desired temperature (~ 165 °C), after 1 m of the stainless steel coil (TC 2, 198 °C)

the temperature raised almost to the target temperature. The thermocouple at the end of the

residence time unit (TC 3, 200 °C) shows exactly the reaction temperature.

Chapter B

73

Synthesis of 2,4-Dimethyl-3-(2-pyridinylmethyl)pentan-3-ol.[S4]

To a stirred solution of 2-methylpyridine (2 mL, 20.3 mmol) in dry THF (30 mL), under Ar-

atmosphere was added BuLi (8.5 mL, 2.5 M in hexanes, 21.3 mmol) dropwise at -84 °C. After

30 min stirring at -84 °C the mixture was stirred for 30 min at 50 °C. Then diisopropylketone

(3.3 mL, 22.9 mmol) was added and the mixture was stirred further at -50 °C for 2 h. The

reaction was then quenched with water (25 mL) and extracted three times with ethyl acetate

(25 mL). The combined organic fractions were washed with brine (25 mL), dried over

MgSO4, filtered over a pad of Celite and concentrated. Column chromatography with an

automated chromatography system using silica flash cartridges applying a heptane-ethyl

acetate gradient resulted in 2,4-dimethyl-3-(2-pyridinylmethyl)pentan-3-ol (3.6 g, 86 %) as a

yellow oil. 1H NMR (300 MHz, CDCl3) δ 8.44 (d, J = 4.1 Hz, 1H), 7.60 (td, J = 7.7, 1.8 Hz,

1H), 7.23 – 7.07 (m, 2H), 6.33 (s, 1H), 2.91 (s, 2H), 2.01 – 1.82 (m, 2H), 0.89 (dd, J = 6.9, 4.8

Hz, 13H).13

C NMR (75 MHz, CDCl3) δ 161.78, 147.83, 136.80, 124.55, 121.02, 78.11, 38.07,

35.18, 18.17, 17.92.

General procedure for the synthesis of 2-Benzylpyridines.[S4]

Palladium(II) trifluoroacetate (83 mg, 0.25 mmol), the aryl halide (5.0 mmol), 2,4-dimethyl-

3-(2-pyridylmethyl)pentan-3-ol (1.25 g, 6.0 mmol), Cs2CO3 (2.45 g, 7.5 mmol), xylene (10

mL) and tricyclohexylphosphine (0.50 mmol) were subsequently transferred in an round

bottomed flask. The resulting mixture was flushed with argon for 5 min and stirred at reflux

under an argon-atmosphere for 6 h. After cooling to room temperature, the mixture was

filtered over a pad of Celite (dichloromethane, 50 mL). The solvent was removed under

reduced pressure and the crude residue was finally purified via column chromatography with

an automated chromatography system using silica flash cartridges applying a heptane-ethyl

acetate gradients.

Chapter B

74

2-(4-Methylbenzyl)pyridine (1b).

From 1-chloro-4-methylbenzene.Yield: 1.07 g (97 %). Isolated as yellow oil.1H NMR (300

MHz, CDCl3) δ 8.56 (d, J = 3.7 Hz, 1H), 7.58 (td, J = 7.7, 1.8 Hz, 1H), 7.15 (dt, J = 7.7, 5.7

Hz, 6H), 4.14 (s, 2H), 2.34 (s, 3H).13

C NMR (75 MHz, CDCl3) δ 161.29, 149.31, 136.49,

136.44, 135.88, 129.28, 128.99, 123.02, 121.15, 44.35, 21.03.

2-(4-Fluorobenzyl)pyridine (1d).

From 1-bromo-4-fluorobenzene. Yield: 843 mg (75 %). Isolated as yellow oil.1H NMR (300

MHz, CDCl3) δ 8.57 (d, J = 4.2 Hz, 1H), 7.60 (td, J = 7.7, 1.8 Hz, 1H), 7.24 (dd, J = 8.6, 5.5

Hz, 2H), 7.13 (dd, J = 10.1, 6.9 Hz, 2H), 7.00 (t, J = 8.7 Hz, 2H), 4.14 (s, 2H).13

C NMR (75

MHz, CDCl3) δ 163.21, 160.72, 159.97, 149.45, 136.60, 135.18 (d, J = 3.2 Hz) , 130.48 (d, J

= 7.9 Hz), 123.00, 121.34, 115.34 (d, J = 21.2 Hz), 43.83.

General procedure for the direct aerobic oxidation of 2-benzylpyridines (1a-d) in

continuous flow.

Feed A consisted of the respective 2-benzylpyridine 1 (2.3 mmol), FeCl3 (19 mg; 0.12 mmol)

dissolved in propylene carbonate (2 mL), whereas feed B was synthetic air (purity 5.0). The

liquid stream (0.6 mL min-1

) and the gaseous stream (1.7 NL min-1

) were mixed together in a

T-shaped mixing device. The resulting biphasic stream was passed through a stainless steel

reactor coil (0.8 mm inner diameter, 120 m length) at 200°C. The reaction mixture was

collected at the outlet of the coil and isolated by filtration over a plug of silica (20 g) using

copious amounts of petroleum ether/ ethyl acetate/ triethylamine (9:1:0.02).

Chapter B

75

Phenyl(pyridine-2-yl)methanone (2a).

Compound 2a was isolated in 81 % (338.3 mg) as yellow oil. 1H NMR (300 MHz, CDCl3) δ

8.74 (ddd, J = 4.7, 1.6, 0.9 Hz, 1H), 8.12 – 8.02 (m, 3H), 7.91 (td, J = 7.7, 1.7 Hz, 1H), 7.65 –

7.56 (m, 1H), 7.54 – 7.46 (m, 3H).13

C NMR (75 MHz, CDCl3) δ 193.91, 155.10, 148.57,

137.07, 136.27, 132.94, 130.99, 128.17, 126.17, 124.63.

(4-Methylphenyl)(pyridine-2-yl)methanone (2b).

Compound 2b was isolated in 69 % (321.6 mg) as yellow oil. 1H NMR (300 MHz, CDCl3) δ

8.74 (ddd, J = 4.7, 1.5, 0.8 Hz, 1H), 8.07 – 7.96 (m, 3H), 7.91 (td, J = 7.7, 1.7 Hz, 1H), 7.49

(ddd, J = 7.5, 4.8, 1.2 Hz, 1H), 7.31 (d, J = 8.0 Hz, 2H), 2.45 (s, 3H). 13

C NMR (75 MHz,

CDCl3) δ 193.60, 155.41, 148.50, 143.80, 136.98, 133.63, 131.13, 128.90, 125.98, 124.53,

21.73.

(4-Chlorophenyl)(pyridine-2-yl)methanone (2c).

Compound 2c was isolated in 81 % (411.4 mg) as white solid. m.p. 62-64 °C. 1H NMR (300

MHz, CDCl3) δ 8.73 (d, J = 4.8 Hz, 1H), 8.08 (d, J = 8.6 Hz, 3H), 7.93 (td, J = 7.7, 1.7 Hz,

1H), 7.56 – 7.42 (m, 3H).13

C NMR (75 MHz, CDCl3) δ 192.43, 154.68, 148.52, 139.41,

137.21, 134.58, 132.50, 128.47, 126.43, 124.69.

Chapter B

76

(4-Fluorophenyl)(pyridine-2-yl)methanone (2d).

Compound 2d was isolated in 83 % (391,3 mg) as white solid. m. p. 83-85 °C; 1H NMR (300

MHz, CDCl3) δ 8.74 (d, J = 4.7 Hz, 1H), 8.24 – 8.14 (m, 2H), 8.08 (d, J = 7.8 Hz, 1H), 7.93

(td, J = 7.7, 1.7 Hz, 1H), 7.52 (ddd, J = 7.6, 4.8, 1.2 Hz, 1H), 7.23 – 7.14 (m, 2H). 13

C NMR

(75 MHz, CDCl3) δ 192.06, 165.70 (dCF, J = 254.9 Hz), 154.90, 148.44, 137.18, 133.80 (dCF,

J = 9.3 Hz), 132.50 (dCF, J = 3.0 Hz), 132.48, 126.29, 124.68, 115.45, 115.31 (dCF, J = 21.8

Hz).

References

[S1] www.bronkhorst.com

[S2] www.uniqsis.com

[S3] www.voltcraft.ch

[S4] T. Niwa, H. Yorimutsu, K. Oshima, Angew. Chem. Int. Ed. 2007, 46, 2643.

Chapter C

77

C. In situ Generation of Diimide from Hydrazine and Oxygen - Transfer

Hydrogenation of Olefins in Continuous Flow

Graphical Abstract

Abstract

A highly efficient, catalyst-free process to generate diimide in situ from hydrazine

monohydrate and molecular oxygen for the selective reduction of alkenes is presented. The

use of a gas-liquid segmented flow regime allowed safe operating conditions and

dramatically enhanced this atom economic reaction resulting in short processing times.

Mixing

Heating

Chapter C

79

1. Introduction

In situ generated diimide (N2H2)[1]

has been used as transfer hydrogenation agent in synthetic

organic chemistry for more than a century,[2]

and its ability to selectively reduce unsaturated

carboncarbon bonds has been established already in the early 1960s.[2]

Investigations on the

thermal stability demonstrated that diimide readily undergoes disproportionation to N2 and

hydrazine at temperatures around -180°C.[2]

In solution phase the first direct evidence for the

existence of diimide was obtained by Sellmann and Hennige who were able to trap the trans

isomer as a diazene complex.[3]

The most straightforward and atom economic pathway for the

generation of diimide is the oxidation of hydrazine using, e.g., H2O2, NaIO4, K3[(FeCN)6], or

molecular oxygen as oxidants.[2]

The generated diimide is then typically utilized as transfer

hydrogenation agent for the highly selective reduction of unsaturated carboncarbon bonds.[2]

Compared to classical, transition-metal catalyzed reduction processes involving hydrogen gas,

this method often provides a useful alternative owing to its extremely high selectivity.[4]

Synthetically useful protocols for the oxidation of hydrazine with molecular oxygen in

general require catalysts to enhance this transformation. Traditionally, copper salts were used

in order to obtain high reaction rates,[2]

whereas today iron salts[5,6]

and organocatalysts such

as guanidine salts,[7]

or flavin derivatives are well studied alternatives.[8]

The generation of

diimide by oxidation of hydrazine with oxygen gas in the absence of a catalyst is also

possible, even though significantly longer reaction times in combination with a high excess of

hydrazine are often required, as the oxidation proceeds relatively slow and the reactive

intermediate is prone to disproportionation (re-formation of hydrazine) and over-oxidation

(Scheme 1).[2]

In fact, Burgard and co-workers recently described the selective reduction of a

terminal olefin (artemisinic acid) employing 3 equivalents of hydrazine hydrate in

combination with synthetic air (5% v/v oxygen for safety reasons) on pilot plant scale.[9]

A

continuous process employing microreactors could potentially overcome these limitations by

allowing intensified process conditions (i.e., high temperature/pressure) in a safe and

controllable manner.[10]

Importantly, biphasic gas-liquid continuous flow processing in

microreactors leads to extremely large and well-defined interfacial areas (e.g., in segmented

flow regimes) compared to the situation in conventional batch environments, and thus to a

significantly enhanced mass transfer.[11]

In this communication we present a highly intensified and catalyst-free protocol for

the in situ generation of diimide from hydrazine monohydrate (N2H4·H2O) and molecular

oxygen in continuous flow mode. The diimide generated via this novel gas-liquid flow

protocol is applied to the selective reduction of a variety of alkenes to provide the

Chapter C

80

corresponding alkanes in excellent yields and high selectivity.[12]

Notably, the high surface-to-

volume area in combination with high-temperature/high-pressure conditions (Novel Process

Windows)[13]

results in remarkably short reaction times (10-30 min) employing only 4-5

equivalents of the hydrazine precursor.

Scheme 2. Aerobic oxidation of hydrazine to diimide and subsequent transfer hydrogenation,

disproportionation and over-oxidation.

In this communication we present a highly intensified and catalyst-free protocol for the in situ

generation of diimide from hydrazine monohydrate (N2H4·H2O) and molecular oxygen in

continuous flow mode. The diimide generated via this novel gas-liquid flow protocol is

applied to the selective reduction of a variety of alkenes to provide the corresponding alkanes

in excellent yields and high selectivity.[12]

Notably, the high surface-to-volume area in

combination with high-temperature/high-pressure conditions (Novel Process Windows)[13]

results in remarkably short reaction times (10-30 min) employing only 4-5 equivalents of the

hydrazine precursor.


The continuous flow setup (Figure 1) consists of a pump (P), a mass flow controller (MFC), a

glass static mixer (GSM) to generate segments of the liquid phase and O2, a residence time

unit (RT) made of perfluoroalkoxy (PFA), a heat exchanger (HE) and a static (BPR1) as well

as an adjustable back pressure regulator (BPR2).[14]

Preliminary experiments using ethanol as

solvent revealed that at a backpressure of 20 bar, a liquid flow rate of 0.4 mL min-1

and a

gaseous stream of 2 mL min-1

are necessary to maintain both a suitable segment pattern and a

proper residence time (10 min).

Chapter C

81

Figure 1. Continuous flow set up for the in situ generation of diimide and subsequent olefin

reductions. (for further details, see the Supporting Information).

The reduction of allylbenzene to propylbenzene was chosen as model transformation for a

detailed optimization study of the continuous process. Initially, a solvent screening was

performed using a variety of alkyl alcohols and 5 equivalents of hydrazine monohydrate at

different temperatures (see Table S1 and Figure S4 in the Supporting Information). At 80 °C a

clear trend with respect to reaction rate (MeOH<EtOH<i-PrOH<n-PrOH<n-butanol<n-

pentanol) was observed. The most reasonable explanation for this phenomenon is related to

the increasing solubility of oxygen gas in this series of alcohols.[15]

We therefore decided to

utilize n-PrOH for all further optimization experiments as the conversions in this solvent were

significantly higher than in MeOH, EtOH or i-PrOH, and the boiling point of n-PrOH,

compared to the higher homologues, is still low enough to allow for a convenient work up.

The allylbenzene model reaction was further tested at higher temperatures resulting in

a conversion of 94 % at 100 °C by using 5 equivalents of N2H4·H2O (see Table S2 in the

Supporting Information). To drive the reaction to completion and simultaneously increase the

throughput, the substrate concentration was increased from 0.1 to 0.5 M. This intensified

process allowed us to reduce the amount of hydrazine hydrate to 4 equivalents while still

maintaining quantitative conversion with perfect selectivity in only 10 min reaction time,[16,17]

whereas lower amounts resulted in incomplete reactions, even at elevated temperatures. It has

to be stressed that mixtures of oxygen and organic solvents have a rather high potential for

explosions and therefore the small volumes and channel dimensions of a continuous flow

(micro-)reactor minimizes a possible flame propagation.[18]

The installed heat exchanger cools

the reaction mixture to ambient temperatures before depressurization. As anticipated, the use

of synthetic air instead of O2 resulted in dramatically reduced substrate consumption (53 %).

Chapter C

82

Control experiments without hydrazine (<1 % conversion) or nitrogen instead of oxygen (8 %

conversion) were additionally carried out.

Table 1. Reduction of olefins via in situ generated diimide form N2H4·H2O and O2 (Scheme

1).[a]

Entry Substrate Coil

[mL]

N2H4· H2O

[equiv] T [°C]

Conversion

[%][b]

Selectivity

[%][b]

Yield

[%][c]

1

10 4 100 >99 >99 99

2 10 4 100 >99 >99 98

3

10 4 100 >99 >99 92

4

10 4 100 >99 >99 95

5

10 4 100 >99 >99 92

6 10 5 100 >99 >99 88

7[d]

10 4 100 >99

[e] >99

[e] 87

8[f]

10 5 100 >99

[e] >99

[e] 97

9

10 4 100 >99 >99 93

10

10 5 100 >99 66[g]

58

11 16 5 120 >99 >99 94

12

26 5 120 >99 >99 91

[a] Conditions: 0.5 M (0.5 or 1 mmol) alkene in n-PrOH, 0.4 mL min-1

liquid flow rate, 2 mL min-1

gas flow

rate, 20 bar backpressure, residence time 10 min (10 mL coil), 20 min (16 mL coil), 30 min (26 mL coil);[b]

Determined as GC-FID peak area percent. [c] Isolated yield. [d] Concentration was 0.33 M. [e] Determined

by 1H NMR analysis. [f] n-PrOH:H2O (1:1) as solvent. [g] Determined as HPLC peak area percent at 215

nm.

Chapter C

83

With the optimized conditions for allylbenzene in hand, we next evaluated the continuous

flow transfer hydrogenation system for a variety of functionalized alkenes. The suitability of

the substrates for the reaction was pre-evaluated through calculations at the M06-2X level[19]

for the hydrogen transfer from cis-diimide to the corresponding olefin. Notably, the

computational results provided valuable guidance prior to the experimental assessment of the

reactivity (Table 1 and Table S4 in the Supporting Information). Most of the chosen

substrates (1-5,7,9) underwent total consumption without any need for re-optimization

compared to conditions used for allylbenzene, whilst some other olefins required a higher

excess of the hydrazine (6, 8, 10), or a combination of higher amounts of hydrazine, longer

reaction times and slightly increased temperatures (11, 12). In terms of selectivity it is worth

noting that olefins containing nitro groups (1, 3) resulted in the desired products in near

quantitative yields.[20]

Silyl ether protecting groups (5) and halogen atoms (9) easily resisted

the applied conditions. In addition, Cbz-protected amines (7), which are prone to deprotection

in transition metal catalyzed hydrogenations were reduced in almost quantitative yields.[21]

Notably, carbonyl functionalities are somewhat critical when hydrazine is used as a reagent.

Somewhat surprisingly, the reduction of ethyl cinnamate (11) however afforded the desired

product in almost quantitative yield without any detectable amount of the corresponding

hydrazide.

A comparison study for the reduction of cinnamate 11 using standard batch balloon

methodology was carried out in n-pentanol to mimic the experimental conditions (120°C) of

the continuous experiment (Scheme 2). Analysis of the reaction mixture revealed that in the

batch experiment the majority of the cinnamate (11) reacted with N2H4, resulting in hydrazide

11c, whilst only very small amounts of the saturated ester (11a) resulting from diimide

reduction were obtained. With prolonged reaction time hydrazide 11c is reduced by diimide

resulting in 3-phenylpropanehydrazide (11b). This example impressively highlights that the

generation of diimide in the gas-liquid segmented flow reactor is dramatically enhanced and

significantly faster than, e.g., hydrazide formation. The same reaction was also carried out in a

small scale quartz autoclave using n-propanol at 120°C and 10 bar O2 pressure.[17]

Under

these conditions, a quantitative reaction was obtained within 20 min resulting in the desired

ester (11a) in good selectivity (97%, see also Scheme 2 and Figure S8 in the Supporting

Information). However, an autoclave experiment of this nature involving pure oxygen and a

mixture of flammable organic solvent and hydrazine is of very limited practical usability

owing to the high potential for explosions which is minimized in the continuous approach.

Chapter C

84

Scheme 2. Comparison of continuous flow, pressurized and atmospheric batch reductions of

ethyl cinnamate 11 (conversions for batch experiments were determined by GC-MS peak area

integration).

In order to estimate the rate of oxidation of hydrazine and the stability of diimide under the

gas-liquid reaction conditions a set of additional experiments was designed. Using a modified

continuous flow set-up with two separate residence time units incorporating an additional

liquid feed in between the two units (Figure 2, see also Figure S9 in the Supporting

Information), the consumption of hydrazine in the oxidation process was investigated. For this

purpose a 5.5 mL residence time unit was installed in which hydrazine monohydrate in n-

PrOH was allowed to react with oxygen at 100 °C in the absence of the olefin substrate. After

the first residence time unit a stream of benzaldehyde dissolved in n-PrOH was introduced via

a T-mixer and the mixture was passed through and collected after an additional residence time

unit (6.5 mL, 100 °C). Notably, only very small amounts of the benzaldehyde trapping

reagent were consumed, demonstrating that under these intensified conditions hydrazine has

been almost completely oxidized within the residence time of ~5 min in coil 1. Changing the

first residence time unit to smaller volumes (2.5 mL, residence time ~2 min) resulted in a

significantly higher conversion of benzaldehyde, indicating residual amounts of hydrazine in

the reaction mixture.

Chapter C

85

Figure 2. Continuous flow set up for hydrazine trapping experiments with benzaldehyde or 3-

nitrostyrene.

When the same trapping experiments were repeated with 3-nitrostyrene (3) instead of

benzaldehyde (in order to estimate the lifetime of diimide), 12% of the reduced olefin were

obtained utilizing the 2.5 mL coil. Only trace amounts of the transfer hydrogenation product

were observed when the longer 5.5 mL coil was used, indicating that hydrazine was almost

completely over-oxidized to nitrogen and water in the absence of an olefin substrate. This

clearly demonstrates the extremely short lifetime of the diimide intermediate in solution phase

as well as the efficiency of the gas-liquid flow procedure.

3. Conclusion

In summary, we have developed a highly efficient and catalyst-free process for the in situ

generation of diimide from hydrazine hydrate and molecular oxygen and its application for

the selective reduction of unsaturated carboncarbon bonds. Key to the success was the use of

a gas-liquid continuous flow methodology which enabled a catalyst-free protocol at high

oxygen pressure in a safe and scalable way. The protocol described herein was shown to

enable olefin reductions which cannot be reproduced using batch techniques at atmospheric

pressure.

Chapter C

86

4. References

[1] Alternative names for diimide reported in the literature are diazene and diimine.

[2] a) S. Hünig, H. R. Müller, W. Thier, Angew. Chem. 1965, 77, 386; Angew. Chem., Int.

Ed. 1965, 4, 271; b) D. J. Pasto, R. T. Taylor, Org. React. 1991, 40, 91.

[3] D. Sellmann, A. Hennige, Angew. Chem. 1997, 109, 270; Angew. Chem., Int. Ed.

1997, 36, 276.

[4] a) P. A. Chaloner, M. A. Esteruleas, F. Joó, L. A. Oro, Homogeneous Hydrogenation,

Kluwer, Dodrecht, 1994; b) Handbook of Homogeneous Hydrogenation, Vols. 1-3,

(Eds. J. G. de Vries, C. J. Elsevier), Wiley-VCH, Weinheim, 2007.

[5] M. Lamani, G. S. Ravikumara, K. R. Prabhu, Adv. Synth. Catal. 2012, 354, 1437.

[6] For reports on olefin reductions under argon atmosphere employing N2H4 in the

presence of Fe3O4 nanoparticles or Rh-Fe3O4 heterodimer nanocrystals without

further oxidizing agents, see: a) E. Kim, S. Kim, B. M. Kim, Bull. Korean Chem.

Soc. 2011, 32, 3183; b) Y. Jang, S. Kim, S. W. Jun, B. H. Kim, S. Hwang, I. K.

Song, B. M. Kim, T. Hyeon, Chem. Commun. 2011, 47, 3601.

[7] M. Lamani, R. S. Guralamata, K. R. Prabhu, Chem. Commun. 2012, 48, 6583.

[8] a)Y. Imada, H. Iida, T. Naota, J. Am. Chem. Soc. 2005, 127, 14544; b) C. Smit, M. W,

Fraaije, A. J. Minnaard, J. Org. Chem. 2008, 73, 9482; c) B. J. Marsh, E. L. Heath, D.

R. Carbery, Chem. Commun. 2011, 47, 280; d) J. F. Teichert, T. den Hartog, M.

Hanstein, C. Smit, B. ter Horst, V. Hernandez-Olmos, B. L. Feringa, A. J. Minnaard,

ACS Catal. 2011, 1, 309, e) Y. Imada, H. Iida, T. Kitagawa, T. Naota, Chem. Eur. J.

2011, 17, 5908.

[9] M. P. Feth, K. Rossen, A. Burgard, Org. Process. Res. Dev. 2013, 17, 282

[10] Micro Process Engineering (Eds.: V. Hessel, A. Renken, J. C. Schouten, J. Yoshida),

Wiley-Blackwell, Oxford, 2009.

[11] For a recent summary and further information about gas-liquid flow chemistry, see: T.

Noël, V. Hessel, ChemSusChem 2013, 6, 405; and references therein.

[12] For a recent publication describing olefin reductions in continuous flow mode using

diimide generated via a different pathway from hydroxylamine and N,O-

bistrifluoroacetyl hydroxylamine, see: A. S. Kleinke, T. F. Jamison, Org. Lett. 2013,

15, 710.

[13] For a recent review on Novel Process Windows and process intensification

technologies based on high-T/p conditions, see: V. Hessel, D. Kralisch, N. Kockmann,

T. Noël, Q. Wang, ChemSusChem 2013, 6, 746.

Chapter C

87

[14] A detailed description of the continuous flow set up is given in the Supporting

Information. See also, B. Gutmann, D. Obermayer, J.-P. Roduit, D. M. Roberge, C. O.

Kappe, J. Flow. Chem. 2012, 1, 8.

[15] R. Battino, T. R. Rettich, T. Tominaga, J. Phys. Chem. Ref. Data. 1983, 12, 163.

[16] The only byproduct observed in these experiments according to GC-MS analysis was

a small amount of 1,2-dipropylidenehydrazine resulting from solvent oxidation and

subsequent reaction with hydrazine (see Figure S5 in the Supporting Information).

[17] Caution: Reactions/reagents described herein have the potential to release large

amounts of energy in an uncontrolled way. These oxidations should not be undertaken

without stringent hazard assessment and proper safety precautions put in place.

[18] M. Hamano, K. D. Nagy, K. F. Jensen, Chem. Commun. 2012, 48, 2086.

[19] For further details on the calculations and references see Supporting Information.

[20] This remarkable selectivity is the result of performing the reaction in the absence of a

metal catalyst. For an Fe-catalyzed, hydrazine mediated protocol for nitro group

reductions, see: D. Cantillo, M. Baghbanzadeh, C. O. Kappe, Angew. Chem. 2012,

124, 10337; Angew. Chem., Int. Ed. 2012, 51, 10190.

[21] H. Sajiki, Tetrahedron Lett. 1995, 36, 3465.

Chapter C

88


General Remarks. All chemicals were purchased from Sigma-Aldrich or Alfa Aesar and

were used without further purification. Reagents were weighed and handled in air at room

temperature. 1H-NMR and


CDCl3 as solvent. Chemical shifts (δ) are expressed in ppm downfield from TMS as internal

standard. The letters s, d, t, q, and m are used to indicate a singlet, doublet, triplet, quadruplet,

and multiplet. Melting points were determined on a Stuart™ SMP3 melting point apparatus.

GC-FID analysis was performed on a Trace-GC (ThermoFisher) with a flame ionization

detector using a HP5 column (30 m×0.250 mm×0.025 μm). After 1 min at 50°C the

temperature was increased in 25°C min−1

steps up to 300°C and kept at 300°C for 4 min. The

detector gas for the flame ionization is H2 and compressed air (5.0 quality).GC-MS analysis

was performed on a Trace-GC Ultra – DSQ II-MS system (ThermoElectron, Waltham, MA,

USA). The GC conditions were as follows: HP-5 MS column (30 m × 0.25 mm ID, 0.25 μm

film, Agilent, Waldbronn, Germany); carrier gas helium 5.0, flow 1 mL min-1

, temperature

gradient identical to GC-FID. The MS conditions were as follows: positive EI ionization,

ionization energy 70 eV, ionization source temperature 280 °C, emission current 100 μA; full-

scan-mode. Analytical HPLC (Shimadzu LC20) analysis was carried out on a C18 reversed-

phase (RP) analytical column (150 × 4.6 mm, particle size 5 μm) at 25 °C using a mobile

phase A (water/acetonitrile 90:10 (v/v) + 0.1 % TFA) and B (MeCN + 0.1 % TFA) at a flow

rate of 1.0 mL/min. The following gradient was applied: linear increase from solution 30% B

to 100 % B in 8 min, hold at 100% solution B for 2 min. Pressurized batch experiments were

carried out in a Multiwave Pro multimode microwave reactor (Anton Paar GmbH, Austria)

using 80 mL quartz reaction vessels in combination with a dedicated gas loading tool.[S1]

Silica gel flash chromatography separations were performed on a Biotage SP1 instrument

using petroleum ether/ethyl acetate mixtures as eluent. ICPMS analyses were performed in

an Agilent 7500ce inductively coupled plasma mass spectrometer. Substrates were

synthesized according to literature procedures. All synthesized substrates and reduced olefins

have been characterized by 1H and

13C NMR analysis and identified by data reported in

literature.

Chapter C

89

Continuous Flow Setup

Figure S1. Oxygen is controlled by the mass flow controller (MFC)[S2]

and mixed with the

liquid phase in a glass static mixer (GSM) after passing a static back pressure regulator (11

bar, BPR1) which was installed for safety reasons. The liquid stream enters the system via a

HPLC pump (P) allowing flow rates from 0.01 to 10 mL min-1

. The biphasic reaction mixture

was heated in a polyfluoroalkoxy coil (PFA, inner diameter: 0.8 mm, volume 10 – 26 mL)

before cooling in a water-cooled heat exchanger (HE, located behind the GSM). Finally, an

adjustable back pressure regulator (BPR2, Swagelok, 0-26 bar) was installed to maintain a

pressure of 20 bar. The main part of this continuous flow reactor (GSM, RT, P, HE) is part of

the Uniqsis FlowSyn.[S3]

Chapter C

90

Segmented Flow Pattern

Figure S2. Segmented flow generation in the glass static mixer. Fluorescein was added to a

3:1 mixture of n-propanol and 1% NaOH to visualize the segment generation under black

light.

Figure S3. Gas-liquid segments in the 10 mL residence time unit. The liquid phase (n-

propanol) was colored with a purple dye for better visualization.

Chapter C

91

Solvent Screening in Continuous Flow

Table S1. Solvent screening for the reduction of allylbenzene using in situ generated

diimide[a]

Entry Solvent Conversion at 60 °C [%][b]

Conversion at 80 °C

[%][b]

1 Methanol 10 18

2 Ethanol 10 27

3 i-Propanol 41 50

4 n-Propanol 32 60

5 n-Butanol 41 66

6 n-Pentanol 39 72

[a] Conditions: 0.2 mmol allylbenzene, 1 mmol N2H

4*H

2O, 2 mL ROH, 0.4 mL min

-1

liquid flow

rate, 2 mL min-1

O2 flow rate, 20 bar back pressure; [b] Conversion was determined as HPLC peak

area percent at 254nm.

Figure S4. Conversions for the reduction of allylbenzene in different alcohols using 5

equivalents hydrazine hydrate and oxygen in continuous flow at 60 and 80 °C (Table S1).

Chapter C

92

Optimization in Continuous Flow

Table S2.Optimization of the reduction of allylbenzene using in situ generated diimide[a]

Entry Substrate [M] N2H

4 * H

2O [equiv.] Oxidant T [°C]

Conversion

[%][b]

1 0.1 5 O2 100 94

2 0.2 5 O2 100 98

3 0.4 5 O2 100 >99

4 0.5 5 O2 100 >99

5 0.5 5 Air 100 53

6 0.5 4 O2 100 >99

7 0.5 3.5 O2 100 98

8 0.5 3 O2 100 97

9 0.5 3 O2 120 98

11 0.5 0 O2 100 <1

12 0.5 4 N2 100 8

[a] Conditions: allylbenzene and hydrazine hydrate in 2 mL n-PrOH, 0.4 mL min-1 liquid flow rate, 2 mL min-1

gas flow rate, 20 bar back pressure; [b] Conversion was determined as GC peak area percent.

Figure S5. GC-MS chromatogram of the reaction mixture after a continuous flow reaction at

optimized conditions (Table S2, entry 6).

RT: 0.00 - 14.03

0 2 4 6 8 10 12 14

Time (min)

0

50000000

100000000

150000000

200000000

250000000

300000000

350000000

400000000

450000000

Rel

ativ

e A

bund

ance

3.79

3.203.98 4.41 6.71 7.23 10.38 11.36 12.269.48

NL:4.97E8

TIC MS olred_45

Chapter C

93

Table S3: ICPMS data from the reduction of allybenzene under optimized conditions (Table

S2, Entry 6)

Element Concentration [mg/L] Element Concentration [mg/L]

Li < 0.01 Sn < 0.01

Be < 0.01 Sb < 0.01

B < 0.1 Te < 0.01

Na < 1 Cs < 0.01

Mg < 0.1 Ba < 0.01

Al < 0.1 La < 0.01

K < 0.01 Ce < 0.01

Ca < 1 Pr < 0.01

Sc < 0.01 Nd < 0.01

Ti < 0.01 Sm < 0.01

V < 0.01 Eu < 0.01

Cr < 0.01 Gd < 0.01

Mn < 0.01 Tb < 0.01

Fe < 0.01 Dy < 0.01

Co < 0.01 Ho < 0.01

Ni < 0.01 Er < 0.01

Cu < 0.01 Tm < 0.01

Zn < 0.01 Yb < 0.01

Ga < 0.01 Lu < 0.01

Ge < 0.01 Hf < 0.01

As < 0.01 Ta < 0.01

Se < 0.01 W ~0.02

Rb < 0.01 Re < 0.01

Sr < 0.01 Os < 0.01

Y < 0.01 Ir < 0.01

Zr < 0.01 Pt < 0.01

Nb < 0.01 Au < 0.01

Mo ~0.02 Hg < 0.01

Ru < 0.01 Tl < 0.01

Rh < 0.01 Pb < 0.01

Pd < 0.01 Bi < 0.01

Ag < 0.01 Th < 0.01

Cd < 0.01 U < 0.01

In < 0.01

Chapter C

94

Substrate Screening and in silico Data

Computational Details. All of the calculations were carried out using the Gaussian 09

package.[S4]

The M06-2X[S5]

density-functional method in conjunction with the 6-31G(d,p)

basis set was selected for all the geometry optimizations and frequency analysis. The

geometries were optimized including solvation effects. For this purpose, the SMD[S6]

solvation method was employed and n-propanol was selected as solvent. Frequency

calculations at 298.15 K on all the stationary points were carried out at the same level of

theory as the geometry optimizations to ascertain the nature of the stationary points. Ground

and transition states were characterized by none and one imaginary frequency, respectively.

Reported values for exp(-ΔG/RT) (Table S4) correspond to the calculated barriers for the

hydrogen transfer from cis-diimide to the olefin double bond.

Table S4. In silico and experimental data of the olefin reduction via the in situ synthesis of

diimide form hydrazine hydrate and O2.[a]

Conversion

10 mL [%][b] Conversion


26 mL [%][b]

Entry Substrate e-ΔG/RT

(calc.)

100°C

4 eq.

100°C

5 eq.

100°C

5 eq.

120°C

4 eq.

120°C

5 eq.

120°C

5 eq.

140°C

5 eq.

1 14.1 >99 -- -- -- -- -- --

2

17.6 >99 -- -- -- -- -- --

3

50.8 >99 -- -- -- -- -- --

4

26.5 >99 -- -- -- -- -- --

5

225 >99 -- -- -- -- -- --

6

18.1 92 >99 -- -- -- -- --

7[c]

28.3 >99[d] -- -- -- -- -- --

8[e]

18.1 93[d] >99[d] -- -- -- -- --

Chapter C

95

Conversion



26 mL [%][b]

Entry Substrate e-ΔG/RT

(calc.)

100°C

4 eq.

100°C

5 eq.

100°C

5 eq.

120°C

4 eq.

120°C

5 eq.

120°C

5 eq.

140°C

5 eq.

9

86.4 >99 -- -- -- -- -- --

10

3.37 97 >99 -- -- -- -- --

11 0.435 80 91 97 98 >99 -- --

12

0.614 70 -- 85 88 91 >99 --

14

0.383 51 -- -- -- -- 70 84

13[f]

0.328 53 -- -- -- -- -- --

15

0.043

0.564 40 -- -- -- -- -- --

16[g]

0.364 30 -- -- -- -- -- --

17[h]

0.326 <1 -- -- -- -- -- --

18[i]

0.0037

0.0002 <1[d] -- -- -- -- -- --

[a] Conditions: 0.5 M alkene in n-propanol, 0.4 mL min-1 liquid flow rate, 2 mL min-1 gas flow rate, 20 bar back

pressure; [b] Determined as GC-FID peak area percent. [c] Concentration was 0.33 M. [d] Determined by 1H NMR

analysis. [e] Dissolved in n-PrOH: H2O (1:1).[f] Toluene:n-PrOH (3:7) was used as solvent. [g] 0.1 Min toluene:n-

PrOH (3:2). [h] 0.25 M in toluene:n-PrOH (1:1). [i] Concentration was 0.25M

Chapter C

96

Olefin Reduction

General Experimental Procedure for the Reduction of Olefins.Feed A consisted of the

respective olefin and hydrazine monohydrate dissolved in n-propanol, whereas feed B was

oxygen (purity 5.0). The liquid stream (0.4 mL min-1

) and the gaseous stream (the flow was

set at 40 mL min-1

(standard conditions) at the instrument, resulting in a calculated flow of 2

mL min-1

at a back pressure of 20 bar) were mixed together in a glass static mixer. The

resulting segmented flow stream was passed through a PFA reactor coil (0.8 mm inner

diameter, 10, 16 or 26 mL reactor volume) at the desired temperature. Subsequently, the

mixture was cooled in a heat exchanger with water as cooling agent. After passing a back

pressure regulator (20 bar) the solution was collected.

Work up procedure A. The solvent was evaporated under reduced pressure. Afterwards the

product was dried overnight using a desiccator with CaCl2.

Work up procedure B. The reaction mixture was concentrated under reduced pressure; the

residue was filtered through a plug of silica and eluted with copious amounts of CHCl3. The

solvent was evaporated under reduced pressure and the product was dried overnight using a

desiccator with CaCl2.

Work up procedure C. The reaction mixture was concentrated under reduced pressure and

the residue was purified by preparative flash chromatography using petroleum ether – ethyl

acetate gradient as eluent.

1-Nitro-4-propoxybenzene (Table 1 & S4, Entry 1). From 1-nitro-4-allyloxybenzene (179.2

mg, 1 mmol) with 4 equivalents of hydrazine monohydrate (200.2 mg, 4 mmol) dissolved in

n-propanol (2 mL).

Residence time unit: 10 mL Temperature: 100 °C Work up procedure: A

Yield: 99% of the title compound as orange liquid (180.1 mg, 0.99 mmol).

1H NMR (300 MHz, CDCl3) δ 8.21 (d, J = 9.3 Hz, 1H), 6.96 (d, J = 9.3 Hz, 1H), 4.03 (t, J =

6.5 Hz, 1H), 1.94 – 1.80 (m, 1H), 1.07 (t, J = 7.4 Hz, 2H). 13

C NMR (75 MHz, CDCl3) δ

164.24, 141.28, 125.90, 114.38, 70.32, 22.34, 10.40.

Chapter C

97

2-Propylphenol (Table 1 & S4, Entry 2). From 2-allylphenol (136.9 mg, 1 mmol) with 4

equivalents of hydrazine monohydrate (200.2 mg, 4 mmol) dissolved in n-propanol (2 mL).


Yield: 98% of the title compound as yellowish liquid (133.0 mg, 0.98 mmol).

1H NMR (300 MHz, CDCl3) δ 7.11 (dd, J = 14.8, 7.5 Hz, 1H), 6.89 (t, J = 7.4 Hz, 1H), 6.79

(d, J = 7.9 Hz, 1H), 2.67 – 2.55 (m, 1H), 1.75 – 1.59 (m, 1H), 1.00 (t, J = 7.3 Hz, 1H).13

C

NMR (75 MHz, CDCl3) δ 153.50, 130.24, 128.39, 127.01, 120.65, 115.16, 32.00, 22.90,

14.03.

1-Ethyl-3-nitrobenzene (Table 1 & S4, Entry 3). From 3-nitrostyrene (149.1 mg, 1 mmol)

with 4 equivalents of hydrazine monohydrate (200.2 mg, 4 mmol) dissolved in n-propanol (2

mL).


Yield: 92% of the title compound as yellow liquid (180.1 mg, 0.92 mmol).


7.7 Hz, 1H), 2.78 (q, J = 7.6 Hz, 1H), 1.31 (t, J = 7.6 Hz, 1H).13


148.35, 146.05, 134.24, 129.14, 122.69, 120.86, 28.56, 15.18.

4-Ethylaniline (Table 1& S4, Entry 4). From 4-aminostyrene (122.9 mg, 1 mmol) with 4

equivalents of hydrazine monohydrate (200.2 mg, 4 mmol) dissolved in n-propanol (2 mL).


Yield: 95% of the title compound as orange liquid (115.6 mg, 0.95 mmol).

1H NMR (300 MHz, CDCl3) δ 7.02 (d, J = 8.3 Hz, 1H), 6.66 (d, J = 8.3 Hz, 1H), 3.44 (s, 1H),

2.57 (q, J = 7.6 Hz, 1H), 1.22 (t, J = 7.6 Hz, 2H).13

C NMR (75 MHz, CDCl3) δ 144.01,

134.49, 128.59, 115.29, 27.99, 15.97.

Tert-butyldimethyl-(2-propylphenoxy)silane (Table 1 & S4, Entry 5). From (2-

allylphenoxy)(tert-butyl)dimethylsilane (124.2 mg, 0.5 mmol) with 4 equivalents of hydrazine

monohydrate (100.1 mg, 2 mmol) dissolved in n-propanol (1 mL).

Residence time unit: 10 mL Temperature: 100 °C Work up procedure: B

Yield: 92% of the title compound as colorless liquid (114.7 mg, 0.92 mmol).

1H NMR (300 MHz, CDCl3) δ 7.16 (dd, J = 7.4, 1.6 Hz, 1H), 7.09 (td, J = 7.7, 1.8 Hz, 1H),

6.90 (td, J = 7.4, 1.1 Hz, 1H), 6.81 (dd, J = 8.0, 0.9 Hz, 1H), 2.68 – 2.50 (m, 1H), 1.73 – 1.53

Chapter C

98

(m, 1H), 1.05 (s, 2H), 0.98 (t, J = 7.3 Hz, 1H), 0.26 (s, 1H).13


153.55, 133.32, 130.21, 126.57, 120.87, 118.34, 32.74, 25.78, 23.32, 18.25, 14.12, -4.15.

N-Ethyl-N-o-tolylbutyramide (Table 1 & S4, Entry 6). From (E)-N-ethyl-N-o-tolylbut-2-

enamide (180.6 mg, 1 mmol) with 5 equivalents of hydrazine monohydrate (250.3 mg,

5mmol) dissolved in n-propanol (2 mL).



1H NMR (300 MHz, CDCl3) δ 7.35 – 7.21 (m, 1H), 7.11 – 7.04 (m, 1H), 4.13 (dq, J = 14.2,

7.2 Hz, 1H), 3.22 (dt, J = 14.0, 7.1 Hz, 1H), 2.23 (s, J = 6.5 Hz, 1H), 1.89 (dtd, J = 22.5, 15.1,

7.2 Hz, 1H), 1.67 – 1.50 (m, 1H), 1.13 (t, J = 7.2 Hz, 1H), 0.82 (t, J = 7.4 Hz, 1H).13

C NMR

(75 MHz, CDCl3) δ 172.64, 141.08, 135.87, 131.40, 129.34, 128.11, 126.95, 42.88, 36.01,

18.61, 17.57, 13.89, 12.93.

Benzyl 4-Ethylphenylcarbamate (Table 1 & S4, Entry 7). From benzyl 4-

vinylphenylcarbamate (126.7 mg, 0.5 mmol) with 4 equivalents of hydrazine monohydrate

(100.1 mg, 2 mmol) dissolved in n-propanol (1.5 mL).


Yield: 87% of the title compound as white solid (110.9mg, 0.434 mmol).

m.p. 67-69 °C1H NMR (300 MHz, CDCl3) δ 7.51 – 7.25 (m, 1H), 7.16 (d, J = 8.5 Hz, 1H),

6.63 (s, 1H), 5.22 (s, 1H), 2.63 (q, J = 7.6 Hz, 1H), 1.23 (t, J = 7.6 Hz, 1H). 13

C NMR (75

MHz, CDCl3) δ 153.46, 139.62, 136.14, 135.33, 128.62, 128.41, 128.32, 118.92, 66.96, 28.21,

15.70.

N-Propylurea (Table 1 & S4, Entry 8). From N-allylurea (100.1 mg, 1 mmol) with 5

equivalents of hydrazine monohydrate (250.3 mg, 5 mmol) dissolved in n-propanol:H2O (1:1,

2 mL).


Yield: 97% of the title compound as pale yellow solid (98.6 mg, 0.97 mmol).

m.p. 106-110 °C1H NMR (300 MHz, DMSO) δ 5.90 (s, 1H), 5.35 (s, 2H), 2.90 (dd, J = 12.8,

6.9 Hz, 2H), 1.45 – 1.24 (m, 2H), 0.82 (t, J = 7.4 Hz, 3H). 13

C NMR (75 MHz, DMSO) δ

159.17, 41.44, 23.65, 11.80.

Chapter C

99

1-Bromo-4-propoxybenzene (Table 1 & S4, Entry 9). From 1-(allyloxy)-4-bromobenzene

(213.07 mg, 1 mmol) with 4 equivalents of hydrazine monohydrate (200.2 mg, 4 mmol)

dissolved in n-propanol (2.0 mL).




6.6 Hz, 1H), 1.90 – 1.72 (m, 1H), 1.05 (t, J = 7.4 Hz, 1H).13


158.24, 132.19, 116.29, 112.56, 77.45, 77.03, 76.61, 69.74, 22.50, 10.49.

Phenyl(propyl)sulfane (Table 1 & S4, Entry 10). From allyl(phenyl)sulfane (150.24 mg,

1mmol) with 5 equivalents of hydrazine monohydrate (250.3 mg, 5mmol) dissolved in n-

propanol (2.0 mL).

Residence time unit: 10 mL Temperature: 100 °C Work up procedure: C

Yield: 58 % of the title compound as colorless liquid (88.3 mg, 0.579 mmol).

1H NMR (300 MHz, CDCl3) δ 7.39 – 7.26 (m, 1H), 7.23 – 7.14 (m, 1H), 2.97 – 2.86 (m, 1H),

1.78 – 1.61 (m, 1H), 1.05 (t, J = 7.3 Hz, 1H).13

C NMR (75 MHz, CDCl3) δ 136.93, 128.95,

128.82, 125.67, 35.60, 22.52, 13.46.

Ethyl 3-Phenylpropanoate (Table 1 & S4, Entry 11). From ethyl cinnamate (176.21 mg, 1

mmol) with 5 equivalents of hydrazine monohydrate (250.3 mg, 5 mmol) dissolved in n-

propanol (2.0 mL).


Yield: 94 % of the title compound as pale yellow liquid (168.1 mg, 0.943 mmol).

1H NMR (300 MHz, CDCl3) δ 7.35 – 7.28 (m, 2H), 7.26 – 7.17 (m, 3H), 4.15 (q, J = 7.1 Hz,

2H), 3.02 – 2.92 (m, 2H), 2.64 (t, J = 7.8 Hz, 2H), 1.25 (t, J = 7.1 Hz, 3H).13

C NMR (75

MHz, CDCl3) δ 172.98, 140.47, 128.47, 128.29, 126.22, 60.44, 35.96, 30.97, 14.20.

1-Methoxy-4-propylbenzene (Table 1 & S4, Entry 2). From trans-anethole (148.2 mg, 1

mmol) with 5 equivalents of hydrazine monohydrate (250.3 mg, 5 mmol) dissolved in n-

propanol (2.0 mL).


Yield: 91 % of the title compound as colorless liquid (136.0 mg, 0.905 mmol).

1H NMR (300 MHz, CDCl3) δ 7.11 (d, J = 8.6 Hz, 2H), 6.84 (d, J = 8.6 Hz, 2H), 3.81 (s, 3H),

2.65 – 2.44 (m, 2H), 0.95 (t, J = 7.3 Hz, 3H).13

C NMR (126 MHz, CDCl3) δ 157.65, 134.83,

129.31, 113.65, 55.25, 37.15, 24.79, 13.78.

Chapter C

100

Case Study: Ethyl Cinnamate (Scheme 2)

Reduction of Ethyl cinnamate in batch mode at atmospheric pressure. Ethyl cinnamate

(176.21 mg, 1 mmol) and hydrazine monohydrate (250.3 mg, 5 mmol) were dissolved in n-

pentanol (2 mL) in a microwave vial. The vial was crimped and flushed with oxygen for 5

minutes. Afterwards, a balloon filled with oxygen was added via a syringe needle through the

septum. After 1 and 2h samples (100µL) were taken, diluted with n-PrOH and analyzed by

GC-MS.

Reduction of Ethyl cinnamate in batch mode at 10 bar in a microwave autoclave. Ethyl

cinnamate (1.32 g, 7.5 mmol) and hydrazine monohydrate (1.88 g, 37.5 mmol) were dissolved

in n-propanol (15 mL) in a 80 mL XQ80 quartz vessel. The vessel was placed in a 8SXQ80

rotor and pre-pressurized with 10 bar O2 using the dedicated gas loading tool before heating at

120 °C for 20 minutes using microwave irradiation (Multiwave Pro, Anton Paar GmbH).

After cooling, 100 µL of the reaction mixture were diluted with n-PrOH and analyzed by GC-

MS.

Chapter C

101

Figure S6. GC-MS chromatogram from the reduction of ethyl cinnamate in batch at

atmospheric pressure after 1h.

Chapter C

102

Figure S7. GC-MS chromatogram from the reduction of ethyl cinnamate in batch at

atmospheric pressure after 2h.

Chapter C

103

Figure S8. GC-MS chromatogram from the reduction of ethyl cinnamate in batch at 10 bar

after 20min.

Chapter C

104

Stability Studies in Continuous Flow

General Experimental Conditions for Hydrazine Trapping Experiments. Feed A

consisted hydrazine monohydrate dissolved in n-propanol (0.5 M) , whereas feed B was

oxygen (purity 5.0). The liquid stream (0.4 mL min-1

) and the gaseous stream (2.3 mL min-1

)

were mixed together in a glass static mixer. The resulting segmented flow stream was passed

through a PFA reactor coil (0.8 mm inner diameter, 2.5 or 5.5 mL reactor volume) at 100°C.

Afterwards a third feed (C) was introduced towards a T-shaped mixing unit, consisting of

benzaldehyde or 3-nitrostyrene (1 M, respectively) at 0.2 mL min-1

. The biphasic reaction

mixture enters a second residence time unit (6.5 mL), set at 100°C. Subsequently, the mixture

was cooled in a heat exchanger with water as cooling agent. After passing a back pressure

regulator (set at 20 bar) the solution was collected

Figure S9. Three-feed set up for continuous flow trapping studies to study the formation and

stability of diimide. The continuous flow setup basically consists of two HPLC pumps (P), a

mass flow controller (MFC), a glass static mixer (GSM) to generate segments of the liquid

phase and O2, two different residence time units (RT1 & 2) made of perfluoroalkoxy, a T-

piece (T), a heat exchanger (HE) and a static (BPR1) as well as an adjustable back pressure

regulator (BPR2)

Chapter C

105

Figure S10. GC-FID chromatogram from the trapping experiment of hydrazine with

benzaldehyde after oxidation in a 2.5 mL coil.

Chapter C

106

Figure S11. GC-FID chromatogram from the trapping experiment of hydrazine with

benzaldehyde after oxidation in a 5.5 mL coil.

Chapter C

107

Figure S12. GC-FID chromatogram from the trapping experiment of hydrazine with 3-

nitrostyrene after oxidation in a 2.5 mL coil.

Chapter C

108

Figure S13. GC-MS chromatogram from the trapping experiment of hydrazine with 3-

nitrostyrene after oxidation in a 5.5 mL coil.

Chapter C

109

References

[S1] http://www.anton-paar.com/

[S2] The ThalesNano Gas module was used as mass flow controller;

http://www.thalesnano.com

[S3] http://www.uniqsis.com

[S4] Gaussian 09, Revision A.02, M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E.

Scuseria, M. A. Robb, J. R. Cheeseman, G. Scalmani, V. Barone, B. Mennucci, G. A.

Petersson, H. Nakatsuji, M. Caricato, X. Li, H. P. Hratchian, A. F. Izmaylov, J.

Bloino, G. Zheng, J. L. Sonnenberg, M. Hada, M. Ehara, K. Toyota, R. Fukuda, J.

Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai, T. Vreven, J. A.

Montgomery, Jr., J. E. Peralta, F. Ogliaro, M. Bearpark, J. J. Heyd, E. Brothers, K. N.

Kudin, V. N. Staroverov, R. Kobayashi, J. Normand, K. Raghavachari, A. Rendell, J.

C. Burant, S. S. Iyengar, J. Tomasi, M. Cossi, N. Rega, J. M. Millam, M. Klene, J. E.

Knox, J. B. Cross, V. Bakken, C. Adamo, J. Jaramillo, R. Gomperts, R. E. Stratmann,

O. Yazyev, A. J. Austin, R. Cammi, C. Pomelli, J. W. Ochterski, R. L. Martin, K.

Morokuma, V. G. Zakrzewski, G. A. Voth, P. Salvador, J. J. Dannenberg, S. Dapprich,

A. D. Daniels, Ö. Farkas, J. B. Foresman, J. V. Ortiz, J. Cioslowski, and D. J. Fox,

Gaussian, Inc., Wallingford CT, 2009.

[S5] Y. Zhao, D. G. Truhlar, Theor. Chem. Acc. 2008, 120, 215.

[S6] A. V. Marenich, C. J. Cramer, D. G. Truhlar, J. Phys. Chem. B 2009, 113, 6378.

Chapter D

111

D. Continuous Flow Reduction of Artemisinic Acid Utilizing Multi-

Injection Strategies – Closing the Gap Toward a Fully Continuous

Synthesis of Antimalaria Drugs

Graphical Abstract

Abstract

One of the rare alternative reagents for the reduction of carboncarbon double bonds is

diimide (HN=NH) which can be generated in situ from hydrazine hydrate (N2H4 ∙ H2O) and

O2. Albeit this selective method is extremely clean and powerful it is rarely used as the rate-

determining oxidation of hydrazine in the absence of a catalyst is relatively slow using

conventional batch protocols. A continuous high-temperature/high-pressure methodology

dramatically enhances the initial oxidation step, at the same time allowing for a safe and

scalable processing of the hazardous reaction mixture. Simple alkenes can be selectively

reduced within 10-20 minutes at 100-120 °C and 20 bar O2 pressure. The development of a

multi-injection reactor platform for the periodic addition of N2H4 ∙ H2O enables the reduction

of less reactive olefins even at lower reaction temperatures. This concept was utilized for the

highly selective reduction of artemisinic acid to dihydroartemisinic acid, the precursor

molecule for the semi-synthesis of the antimalarial drug artemisinin. The industrially relevant

reduction was achieved by using four consecutive liquid feeds (of N2H4 ∙ H2O) and residence

time units resulting in an highly selective reduction within ~40 min at 60 °C and 20 bar O2

pressure providing dihydroartemisinic acid in ≥93% yield and ≥95% selectivity.

Chapter D

113

1. Introduction

The advantages of continuous flow processing are increasingly appreciated by a growing

number of scientists, from research chemists in academia to process chemists and chemical

engineers in pharmaceutical companies. Thus, continuous flow technologies are nowadays

more and more used on a routine basis on laboratory as well as industrial scales for fine

chemical production.[1-3]

An intriguing recent example of industrial importance is the

development of a continuous photochemical reactor for the synthesis of artemisinin from

dihydroartemisinic acid.[4]

Artemisinin, a sesquiterpene endoperoxide, is the key component of so called

artemisinin-based combination therapies (ACTs) which are currently the standard treatment

for malaria.[5]

The pharmaceutically active ingredient can be extracted in low amounts

(typically ≤1 wt%) from Artemisia annua (sweet wormwood) but unfortunately,

environmental and economic factors render the amount of artemisinin obtained to be

unpredictable causing a steadily fluctuating price situation.[6]

These issues can be tackled by

semi-synthetic approaches starting from potential precursor molecules like artemisinic acid

(AA) or dihydroartemisinic acid (DHAA), which can be also found in the plant extract

(Scheme 1).[7]

Furthermore, recent breakthroughs in synthetic biology have shown that

glucose can be used to generate amorphadiene or even AA in genetically modified yeast

offering a plant–independent production strategy.[8,9]

Scheme 1. Production routes to Artemisinin and its derivatives

The semi-synthetic route to artemisinin is based on a biomimetic, photochemical reaction of

DHAA which was discovered in the late 1980s.[10]

Central in this chemical transformation is

an ene reaction of dihydroartemisinic acid with singlet oxygen (1O2). The photooxidation is

Chapter D

114

subsequently followed by a Hock cleavage, addition of triplet oxygen and a series of

spontaneous condensation reactions. Unfortunately, the photochemical generation of singlet

oxygen proved to be extremely challenging to scale. In fact, it took industrial scientists more

than two decades to overcome these limitation and recently researchers from Sanofi-Aventis

were able to adapt this chemical route for industrial artemisinin production.[11]

Simultaneously, Seeberger and coworkers showed that the complete reaction sequence can be

ultimately performed as a single, fully continuous chemical process.[4]

In addition, the same

group recently communicated a module based continuous flow strategy for the synthesis of

dihydroartemisinin, β-arthemeter, β-artemotil and artesunate from AA, all ingredients of ACT

antimalarials.[12]

Since both, plant extraction as well as synthetic biology provides AA, a simple and

efficient strategy for the diastereoselective reduction to DHAA is essential for a productive

process. Batch hydrogenation in the presence of Wilkinson’s catalyst results in quantitative

conversion and good diastereoselectivity (94:6) after 19 h at 80°C at 47 bar hydrogen

pressure.[9b]

The improved protocol by Sanofi-Aventis provides similar results within 6 h at

room temperature and 22 bar using a ruthenium catalyst in presence of triethylamine.[11]

Importantly, the same group recently presented a catalyst free protocol using diimide (N2H2),

generated in situ from hydrazine hydrate and O2.[13]

Due to safety reasons, the highest

admissible oxygen concentration allowed in the presence of a flammable solvent (i-PrOH)

was 5% O2 in N2 (v/v). At 40°C full conversion was achieved after 11 h using only 3

equivalents of N2H4 ∙ H2O. The surprisingly high diastereomeric ratio (≥97:3) achieved in this

reduction process can be explained mechanistically.[14]

In situ generated diimide has been used as transfer hydrogenation agent for more than

one century.[15]

Several methods for its generation such as decarboxylation of dipotassium

azodicarboxylate or the thermal decomposition of sulfonylhydrazides are known.[15]

However,

from an (atom-)economic point of view the aerobic oxidation of N2H4 is the most attractive

source. Since this oxidation is generally very slow, several catalysts such as Cu-,[15]

or Fe

salts,[16,17]

guanidine derivatives,[18]

flavin-based catalysts,[19]

or even visible light[20]

were

studied. The generation of diimide in batch by oxidation of hydrazine with O2 in the absence

of a catalyst is also possible, even though significantly longer reaction times in combination

with a high excess of hydrazine are required to reduce simple olefins.[21]

Recently, our group has communicated a catalyst-free continuous flow protocol for the

selective reduction of olefins to alkanes based on the highly efficient in situ generation of

N2H2 from N2H4 ∙ H2O and O2.[22]

Herein, we present the application of this methodology

Chapter D

115

towards the stereoselective reduction of artemisinic acid to dihydroartemisinic acid under

relatively mild conditions applying a multi-injection continuous flow platform.


2.1 Continuous Flow Concept

The reduction of olefins is traditionally carried out by metal-catalyzed processes involving

hydrogen gas, typically at elevated pressures in dedicated hydrogenation devices. However, in

certain cases this strategy is accompanied by severe selectivity problems as several undesired

side-reactions such as hydrogenolysis of protecting groups, reduction of other functionalities,

alkene migration or racemization can occur.[19b]

In contrast, in situ generated diimide is an

extremely selective reagent for the reduction of unsaturated carboncarbon bonds.[15]

The

generation of this highly unstable and reactive azo compound from simple hydrazine hydrate

and oxygen/air is of particular interest as both reagents are readily available and of low cost.

In addition, a catalyst free protocol ultimately results in a virtually work-up free methodology

as only water and nitrogen gas are generated as benign chemical byproducts. However, since

this reaction is predominantly carried out in presence of a catalyst,[15-19]

the oxidation of

hydrazine is a rather slow and inefficient process under standard batch conditions.[21]

Noteworthy, diimide generation using this oxidation protocol not only results in the reduction

of olefins. An over-oxidation process of the unstable N2H2 intermediate results in the

formation of nitrogen and water. Furthermore, a disproportionation can cause the formation of

hydrazine and nitrogen. Thus, the diimide precursor has to be usually added in (high) excess

to guarantee a quantitative consumption of the unsaturated starting material.

Based on this knowledge we started to design a continuous flow reactor for the

reduction of olefins using this methodology. Our initial hypothesis was that the typical high

surface-to-volume areas in a biphasic reaction mixture in continuous flow should dramatically

enhance the oxidation rate of hydrazine hydrate.[2]

Furthermore, we assumed that the

additional use of a high-temperature/high-pressure protocol (Novel Process Windows)[23]

would push the diimide generation to its limits. We thus assembled a two feed continuous

flow reactor as shown in Figure 1.

Chapter D

116

Figure 1. Two feed continuous flow set-up for the reduction of olefins with diimide.

A HPLC pump (P) was used to continuously pump the olefin and hydrazine hydrate dissolved

in a proper solvent. Oxygen was delivered from by a standard compressed gas cylinder and

the flow controlled by a mass flow controller (MFC). The two reagent streams were combined

in a glass static mixer (GSM) resulting in a segmented flow pattern which was then allowed to

pass a heated residence time unit (RTU). For that purpose, a perfluoroalkoxy tubing (PFA, i.

d. 0.8 mm, o. d. 1.6 mm) was used which has lower gas permeability than e.g. PTFE.

Concerning gas permeability, stainless steel would be a more suitable option but from a

chemical point of view we were concerned that over time iron oxide could be generated in

such a corrosive regime. This material was recently shown to catalyze the reduction of nitro

and azide groups in the presence of hydrazine and could therefore cause selectivity problems

in certain cases.[17b,24]

The reaction mixture was finally cooled in a heat exchanger and

depressurized by passing a backpressure regulating unit (BPR).

2.2 Process Intensification, Scope and Limitations

Initially, the reduction of allylbenzene was studied using the above described continuous flow

setup. Since most protocols involving the generation of diimide from hydrazine and oxygen

are using polar, protic solvents, such as e.g., ethanol we decided to start the process

intensification by a screening of various alcohols as reaction media. For that purpose, the

model substrate (0.1 M) and 5 equivalents of hydrazine hydrate where dissolved in different

alcohols (methanol, ethanol, i-propanol, n-propanol, n-butanol or n-pentanol) and pumped at a

flow rate of 0.4 mL min-1

. The oxygen stream was set at 40 mLN min-1

resulting in a suitable

segmented flow pattern at a back pressure of 20 bar. By using a 10 mL PFA coil a residence

time of 10 minutes was observed which appeared to be adequate for comparing different

solvents for the chosen model reaction. The assessment of the different alcohols at 80°C

showed a nearly linear trend with respect to the reaction rate (Figure 2).

Chapter D

117

Figure 2. Solvent screening for the continuous reduction of allylbenzene using 5 equivalents

of hydrazine hydrate in presence of oxygen.

This observation seems to directly relate to the oxygen solubility in this series of alcohols.[25]

However, when the same experiments were carried out at a somewhat lower temperature

(60°C) a significant reduction of this phenomenon was observed. Whilst methanol and

ethanol resulted in ~10% conversion of allylbenzene to propylbenzene, reactions using the

higher boiling homologs showed starting material consumptions between 30% and 40%.

Therefore, we assume that in particular at elevated temperatures the solvent choice is of

crucial importance for enhancing the rate determining oxidation step.

Since this catalyst-free methodology generates only water and nitrogen as byproducts

finding a convenient work up protocol was one of the ultimate goals of this study. Given the

low boiling nature of some potential target molecules n-PrOH (b.p. 97 °C) was the solvent of

choice being a compromise between reaction rate at higher temperatures and the ability for

smooth solvent evaporation. The model reaction was further optimized aiming for quantitative

consumption of the starting material (Table 1). When the reaction temperature was increased

to 100°C a significantly higher conversion was obtained (entry 2). We further noticed that

better conversions could be achieved by using a higher olefin concentration (entry 3-5). The

use of a 0.5 M solution resulted in an oxygen stoichiometry of ~8 equivalents. Changing the

oxidizing agent to synthetic air (~1.6 equivalents O2), caused a dramatic reduction in

conversion (entry 6). Nevertheless, it was possible to reduce the amount of hydrazine hydrate

to 4 equivalents resulting in a selective and quantitative reduction of allylbenzene within just

10 minutes (entry 7). Further attempts to reduce the amount of the diimide precursor gave

incomplete reactions even at higher temperatures corroborating the need of a relatively high

excess of hydrazine owing to over-oxidation and disproportionation of hydrazine (entry 8-10).

Chapter D

118

In the absence of hydrazine hydrate no conversion was observed at all (entry 11). Since a

catalytic hydrazine mediated reduction of double bonds was also reported to proceed under

inert conditions,[17]

a control experiment using N2 instead of O2 was carried out resulting in a

conversion of only 8 %. This can be rationalized by small amounts of oxygen dissolved in n-

PrOH.

Table 1. Optimization of the reduction of allylbenzene using in situ generated diimide[a]

Entry Concentration

[M]

N2H

4 · H

2O

[eq.] Oxidant

T

[°C] Conversion

[%][b]

1 0.1 5 O2 80 60

2 0.1 5 O2 100 94

3 0.2 5 O2 100 98

4 0.4 5 O2 100 >99

5 0.5 5 O2 100 >99

6 0.5 5 Air 100 53

7 0.5 4 O2 100 >99

8 0.5 3.5 O2 100 98

9 0.5 3 O2 100 97

10 0.5 3 O2 120 98

11 0.5 0 O2 100 <1

12 0.5 4 N2 100 8

[a] Conditions: allylbenzene and hydrazine hydrate in 2 mL n-PrOH, 0.4 mL min-1 liquid flow rate, 40 mLN

min-1 gas flow rate, 20 bar back pressure; [b] Conversion was determined as GC peak area percent.

The optimized conditions were further tested for a range of simple olefins to evaluate the

scope and robustness of the continuous methodology (Table 2). The majority of the chosen

simple olefins resulted in quantitative conversion under the optimized reaction conditions (2a-

e, 2g, 2i-j). However, in some cases it was necessary to increase the amount of hydrazine

hydrate to drive the reaction to completion (2f, 2h). For some less reactive examples an

increased reaction temperature in combination with a somewhat longer reaction time

successfully led to the saturated derivatives (2k-l). Noteworthy, neither a nitro-reduction (2c)

nor a deprotection (2e, 2g) as side reaction was observed. The only example where a non-

selective transfer hydrogenation occurred was by using sulfide 2j. In this case, oxidation

products (sulfoxides and sulfones) of both, the olefin and its saturated derivative were

Chapter D

119

observed. We argue that this is not a result of an aerobic oxidation, but more likely due to the

formation of hydrogen peroxide during the hydrazine oxidation process. A similar finding

was made by Imada and coworkers reporting that the hydrazine/O2 system can oxidize

sulfides and amines under ambient conditions in the presence of a flavin catalyst.[26]

Table 2. Reduction of olefins in continuous flow using hydrazine hydrate and oxygen.[a]

[a] Conditions: olefin (0.5M) and hydrazine hydrate (4 equiv) in n-PrOH, 0.4 mL min-1 liquid flow

rate, 40 mLN min-1 O2 flow rate, 20 bar back pressure, 10 mL PFA coil. [b] 5 equiv of hydrazine

hydrate were used. [c] conc.=0.33 M. [d] n-PrOH/H2O (1:1) as solvent. [e] Reaction was carried out at

120°C in a 16 mL coil. [f] Reaction was carried out at 120°C in a 26 mL coil.

The main limitation of this protocol is the use of aldehydes or ketones as starting materials as

these functionalities immediately undergo hydrazine and azine formation in the presence of

hydrazine. It is somewhat surprising that ethyl cinnamate (2k) could be selectively reduced

albeit the ester moiety is prone to hydrazide formation. In fact, the same reaction in batch

under atmospheric conditions (O2 balloon) resulted mainly in the unreduced hydrazide after 1-

2 h at 120°C. An autoclave experiment resulted in selectivity similar to the continuous

experiment under more or less identical conditions (120°C, 20min, 10 bar). We can therefore

conclude that the oxidation efficiency in the continuous protocol is clearly more a result of the

high-temperature/high-pressure concept than of the high surface-to-volume area obtained by

the segmented flow pattern.

Chapter D

120

2.3 Efficiency of Hydrazine Oxidation

The above described method is limited to olefins of relatively high reactivity. When less

reactive substrates such as e.g., menthol (2m) were passed through the continuous flow

reactor under optimized conditions only moderate conversions were obtained (Table 3). Even

at higher temperatures (120°C) and a longer residence time (~30 min, 26 mL coil volume)

only 70% of the starting material was consumed. Similar reactivates could be observed for the

carbazole derivative 2n, camphene (2o) and a stilbene analog (2o).

It appears that the competitive over-oxidation and disproportionation of diimide

consumes comparably high amounts of the reactive intermediate resulting in insufficient

reduction rates. This would imply that a total reduction of such compounds would

theoretically need an enormous excess of hydrazine and therefore also the amount of oxygen

gas would have to be increased dramatically. To overcome this severe limitation, a deeper

understanding of the initial oxidation step is clearly of great importance.

Table 3. Conversion of olefins of lower reactivity in continuous flow using hydrazine hydrate

and oxygen.[a]

[a] Conditions: olefin (0.5 M) and hydrazine hydrate (4 equiv) in n-PrOH,

0.4 mL min-1 liquid flow rate, 40 mLN min-1 O2flow rate, 20 bar back

pressure, 10 mL PFA coil. Conversions determined as GC-FID peak area

percent. [b] Reaction was carried out at 120°C in a 26 mL coil. [c]

Toluene:n-PrOH (3:7) was used as solvent. [d] 0.1 M in toluene:n-PrOH

(3:2).

To get a general idea of the efficiency of the initial hydrazine oxidation and the unwanted

(side-) reactions of the highly reactive diimide species we decided to carry out a range of

trapping experiments. The underlying idea was that in a first coil O2 and N2H4 ∙ H2O are

allowed to react and remaining hydrazine can be subsequently trapped by the addition of

benzaldehyde. If unreacted N2H4 ∙ H2O is still in solution after a defined residence time this

will ultimately lead to the formation of the corresponding hydrazone which subsequently

undergoes a condensation forming benzaldehyde azine. Therefore, we modified the original

Chapter D

121

flow set up by installing a second liquid feed and an additional residence time unit (RTU 2)

connected by a T-mixer (T, Figure 3).

Figure 1. Continuous flow setup for the hydrazine trapping experiments using benzaldehyde

Initially, we mounted a 2.5 mL coil for the oxidation step at 100°C using a hydrazine hydrate

concentration of 0.5 M. The liquid flow rate was set at 0.4 mL min-1

and the oxygen stream at

40 mL min-1

. After passing the heated reaction zone a 1 M solution of benzaldehyde was

added via the mixing unit at a flow rate of 0.2 mL min-1

and the mixture passed the second

heated zone (100 °C, 6.5 mL PFA coil) before cooling and depressurization. GC-MS analysis

of the resulting reaction mixture showed 38% benzaldehyde and the desired benzaldehyde

azine in 52 %. In addition, we could identify an azine formed of benzaldehyde and propanal

(10 %) which likely resulted from solvent oxidation (Figure 4A). When the same experiment

was carried out with a 5.5 mL coil (RTU 1), the majority of hydrazine was consumed as GC

analysis showed benzaldehyde as main analyte (>80 %) (Figure 4B). In addition, the same

experimental approach was carried out with 3-nitrostyrene instead of benzaldehyde to

estimate how much of the remaining hydrazine initializes the reduction of the alkene moiety.

The experiment using a 2.5 mL coil resulted in a consumption of just ~10 % of the olefin.

Since the corresponding benzaldehyde experiment indicated significant amounts of residual

hydrazine it can be concluded that the majority of hydrazine entering the second coil is not

contributing to the olefin reduction. This observation could be confirmed in the second

example (RTU 1: 5.5 mL) where just trace amounts (~1%) of the reduction product could be

detected albeit the aldehyde trapping experiments indicated remaining hydrazine. However,

the values have to be taken with caution as all experiments contained small amounts of

propanal azine which was most likely formed in the first coil. In addition, the aldehyde

Chapter D

122

experiments also showed significant amounts of benzaldehyde propanal azine which is

probably a result of propanal hydrazone formed in RTU 1.

Figure 4. GC-MS chromatograms from the benzaldehyde trapping experiments using a 2.5

(A) or a 5.5 mL coil (B) for the oxidation of hydrazine and diimide

oxidation/disproportionation.

2.4 Reduction of Artemisinic Acid

The ultimate target of our studies on the in situ generation of diimide in continuous flow was

to establish an efficient protocol for the reduction of artemisinic acid to the artemisinin

precursor DHAA. Since the conversion of DHAA to artemisinin as well as the subsequent

transformation to its pharmaceutically active derivatives was already reported in a continuous

protocol,[4,12]

the selective AA to DHAA reduction can be regarded as the “missing link”

towards a fully continuous strategy for the synthesis of such antimalarial drugs. Inspired by

the previous work by Sanofi-Aventis,[13]

we hypothesized that diimide reduction of AA to

DHAA could be dramatically enhanced by our continuous strategy. Safety concerns in batch

Chapter D

123

prompted the Sanofi-Aventis team to use 5% O2 in N2 at atmospheric pressure which is most

likely the reason for the comparably long reaction time (11 h at 40 °C). The small volumes

and channel dimensions in a continuous flow (micro)reactor minimize possible flame

propagation leading to an inherently safer processing of such explosive mixtures even under

relatively harsh reaction conditions.[27]

We started our optimization study using a slightly modified protocol (Table 4). The

glass static mixer described above was replaced by a simple T-mixer since we realized that a)

the flow pattern is similar without the active mixing unit, and b) that the efficiency of the

hydrazine oxidation is essentially a result of the elevated temperature/pressure combination

and not of the mixing or flow pattern achieved.

By applying similar conditions as in the previous study 82 % conversion of AA were

obtained as analyzed by HPLC-UV/VIS (entry 1).[28]

However, decreasing the oxygen flow to

20 mL min-1

resulted in a longer residence time maintaining an excess of the oxidizing agent.

Unfortunately, neither an increased residence time nor the use of a higher reaction

temperature gave a quantitative formation of DHAA (entry 2-4).

Table 4. Reduction of artemisinic acid in continuous flow.[a]

Entry N2H4

[equiv] O2 [mL/min] T [°C] RTU [mL] t [min] Conversion [%]

[b]

1 4 40 (4 equiv) 100 10 7 82

2 4 20 (2 equiv) 100 10 11 91

3 4 20 (2 equiv) 120 10 11 90

4 4 20 (2 equiv) 100 20 25 92

[a] Conditions: artemisinic acid (1 mmol) and hydrazine hydrate dissolved in n-PrOH (1 mL), liquid flow rate

0.4 mL min-1

. [b] Determined as HPLC peak area percent at 215 nm; relative response factor of AA:DHAA

(4.6:1)

Taking the previous experiments on oxidation efficiency into consideration we concluded that

a multiple injection, mimicking a traditional dropping funnel in batch experiments, could

drive the reaction to completion by continuously adding fresh hydrazine hydrate. This

strategy was originally used in continuous processes involving highly exothermic reactions to

Chapter D

124

improve thermal control.[29,30]

We argued that a multiple injection of hydrazine hydrate would

possibly reduce the amount of disproportionation due to a reduced hydrazine/diimide

concentration along the reactor. In addition, this methodology enables the possibility to

increase the effective reaction time since we have already shown that under the continuous

high-temperature/high-pressure conditions most of the N2H4 ∙ H2O is consumed within less

than 10 min. However, from a technical point of view this setup is similar to the trapping

experiment described above (Figure 3). Since low flow rates for the additional hydrazine

feeds were required syringe pumps were used instead of standard HPLC pumps. The pressure

limit of these devices necessitates a maximum backpressure of 20 bar. In addition all further

optimization experiments were carried out with a liquid flow rate of 0.4 mL min-1

at an AA

concentration of ~0.8 M and a gas flow rate of 20 mL min-1

corresponding to 2 equivalents of

O2 (Table 5).

Table 5. Reduction of artemisinic acid in flow using multi injection of hydrazine hydrate.[a]

Entry N2H4 [eq.] T [°C] RTU [mL] t [min] Conversion [%][b]

1 2+2 100 2 x 10 18 >99(78)[c]

2 2+2 80 2 x 10 18 >99(79)[c]

3 2+2 60 2 x 10 18 89

4 3+3 60 2 x 10 18 95(89)[c]

5 2+2+2 60 3 x 10 27 96(91)[c]

6 2+1+1 60 3 x 10 27 97(91)[c]

7 2+1+1 40 3 x 10 27 80

8 2+1+1 25 3 x 10 27 67

9 4+0+0 60 3 x 10 27 83

10 2+1+1+1 60 4 x 10 37 >99(80)[d]

[a] Conditions: artemisinic acid (1 mmol) and hydrazine hydrate dissolved in n-PrOH (1

mL), liquid flow rate 0.4 mL min-1

. [b] Determined as HPLC peak area percent at 215 nm;

relative response factor of AA:DHAA (4.6:1). [c] Determined by 1H-NMR analysis using

pyridine as internal standard. [d] Isolated yield.

Chapter D

125

The first multi-injection experiment was carried out using two times two equivalents of

hydrazine hydrate and two identical residence time units (2 x 10 mL) at 100°C resulting in an

overall reaction time of ~18 min (entry 1). Interestingly, we ultimately observed full

consumption of the starting material whilst a similar experiment with 4 equivalents of N2H4 ∙

H2O and a 20 mL residence time showed an incomplete reaction (Table 4, entry 4). This result

already strongly supports our initial hypotheses on the benefits of the multi-injection

approach. However, NMR analysis revealed that the DHAA yield was only 78%. GC-MS

analysis after silylation revealed that the reaction was not as selective as the batch protocol,[13]

showing a purity of 85% with 7 % of the undesired diastereomer (DHAA 2) and 8 % of the

over-reduced tetrahydroartemisinic acid (THAA). We assumed that this selectivity problem is

a result of the comparably high reaction temperature. Therefore, a similar experiment at 80°C

was carried out which unfortunately led to similar values (entry 2). A further reduction of the

temperature to 60°C decreased the reaction rate and an even higher excess of hydrazine was

not enough to fully consume the substrate (entry 3-4). However, at this temperature a higher

selectivity was obtained according to 1H-NMR analysis. Encouraged by this promising result

a third hydrazine feed was added and almost quantitative conversion was observed (entry 5).

In addition, the amount of hydrazine could be decreased to an overall value of 4 equivalents

(entry 6). A further reduction of the reaction temperature caused a significant reduction of the

reaction rate (entry 7-8) indicating that the optimal temperature for high conversions and

sufficient selectivity is 60°C. Importantly, a control experiment also demonstrated that a

single hydrazine addition at the beginning results in comparably low conversion (entry 9).

Finally, by adding a fourth liquid feed AA could be quantitatively reduced within 37 minutes

at 60 °C using an overall hydrazine stoichiometry of 5 equivalents (2+1+1+1) and just two

equivalents of O2 (entry 10, Figure 5).

Figure 5. Optimized multi-injection setup for the reduction of artemisinic acid towards in situ

generation of diimide from hydrazine hydrate and oxygen

Chapter D

126

Isolation by crystallization afforded DHAA in 80 %. GC-MS analysis confirms a highly

selective reduction with low amounts of THAA (~2 %) and DHAA 2 (~1 %) as only

byproducts.

Scale-out experiments using 8.5 mmol of artemisinic acid resulted in an identical

selectivity with slightly lower conversion (~97% according to HPLC). However, on this scale

crystallization afforded the desired artemisinin precursor in significantly higher yield (≥ 93

%) with only 2 % of THAA present and a diastereomeric ratio of ≥97:3.

A comparison of the continuous methodology with other published batch strategies for

the reduction of artemisinic acid demonstrates that the major advantage of this novel protocol

is the relatively short reaction time of less than 40 minutes (Table 6). A more detailed

inspection reveals that the diastereomeric ratio in the diimide protocols is slightly higher

compared to transition metal-catalyzed hydrogenation procedures. From an economic point of

view, it is noteworthy that no precious metal catalyst has to be used when N2H2 is used as

reducing agent. Due to the lack of values for isolated yields from the literature protocols we

calculated the space-time-yield based on quantitative reactions for the ruthenium-catalyzed

hydrogenation protocol. A comparison of this value shows that the continuous methodology

described herein is clearly superior over the batch protocols for the reduction of artemisinic

acid.

Table 6. Comparison of different strategies for the reduction of artemisinic acid.

Amyris[a]

Sanofi-

Aventis[b]

Sanofi-

Aventis[c]

This work

Technology Batch Batch Batch Continuous

Flow

Reducing agent H2 H2 N2H2 N2H2

Catalyst RhCl(PPh3)3

[0.05mol%]

RuCl2[(R)-dtbm-

Segphos](DMF)2

[~0.01mol%]

-- --

T [°C] 80 25 40 60

p [bar] 47 22 atm. 20

t [h] 19 6 11 ~0.6

Yield [%] quant.

(not isolated)

quant.

(not isolated) >90 ≥93

d.r. 94:6 95:5 ≥97:3 ≥97:3

Space-time-yield

[mmol L-1

h-1

] 0.023 --

[d] 0.023 0.56

[a] Data taken from ref [9b]. [b] Data taken from ref [10]. [c] Data taken from ref [13]. [d] Space-time-yield

cannot be calculated as no reactor volume was reported.

Chapter D

127

Due to the relatively clean reaction and the inert nature of the main byproducts (H2O, N2), we

assume that the crude reaction mixture can be directly converted to the antimalarial

artemisinin since also a crude plant extract from Artemisia annua could be processed in the

continuous drug synthesis.[4a]

In an ideal case the reduction process could be directly coupled

with the photochemical methodology as both transformations require the same gaseous

reagent.[4]

3. Conclusion

The in situ generation of diimide for the transfer hydrogenation of olefins from hydrazine and

oxygen can be efficiently carried out in a catalyst-free procedure using a gas-liquid

continuous flow approach. Simple alkenes can be selectively reduced within 10 minutes in a

virtually work-up free procedure.

It could be shown that the oxidation of hydrazine hydrate, a time consuming step

under conventional batch conditions, can be dramatically enhanced using this enabling

technology. The obtained kinetic information led to the development of a multi-injection

principle applying periodic additions of fresh hydrazine hydrate. This methodology enables

the possibility for increased effective residence times and can be applied in cases where less

reactive olefins need to be reduced.

As illustrative example, the selective reduction of artemisinic acid yielding the direct

precursor molecule for the antimalarial drug artemisinin could be successfully accomplished.

This industrially relevant reduction was achieved by using four consecutive liquid feeds and

residence time units with 2 equivalents of O2, a total amount of 5 equivalents N2H4 ∙ H2O and

an overall reaction time of ~40 min. A comparison with other published procedures for this

reduction shows a >20 fold higher space-time-yield for the continuous process described

herein.

Chapter D

128

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W, Fraaije, A. J. Minnaard, J. Org. Chem. 2008, 73, 9482; (c) B. J. Marsh, E. L. Heath,

Chapter D

130

D. R. Carbery, Chem. Commun. 2011, 47, 280; (d) J. F. Teichert, T. den Hartog, M.

Hanstein, C. Smit, B. ter Horst, V. Hernandez-Olmos, B. L. Feringa, A. J. Minnaard,

ACS Catal. 2011, 1, 309; (e) Y. Imada, H. Iida, T. Kitagawa, T. Naota, Chem. Eur. J.

2011, 17, 5908.

[20] D. Leow; Y.-H. Chen, Y. Su, Y.-Z. Lin, Eur. J. Org. Chem. 2014, 7347.

[21] (a) N. Menges, M. Balci, Synlett 2014, 25, 671; (b) H. Chen. J. Wang, X. Hong, H.-B.

Zhou, C. Dong, Can. J. Chem. 2012, 90, 758

[22] B. Pieber, S. T. Martinez, D. Cantillo, C. O. Kappe, Angew. Chem. Int. Ed. 2013, 52,

10241; Angew. Chem. 2013, 125, 10431.

[23] V. Hessel, D. Kralisch, N. Kockmann, T. Noel, Q. Wang, ChemSusChem 2013, 6, 746.

[24] For the continuous reduction of nitro groups by iron oxide and hydrazine, see (a) D.

Cantillo, M. Baghbanzadeh, C. O. Kappe, Angew. Chem. 2012, 124, 10337; Angew.

Chem. Int. Ed. 2012, 51, 10190; (b) D. Cantillo, M. M. Moghaddam, C. O. Kappe, J.

Org. Chem. 2013, 78, 4530; (c) M. M. Moghaddam, B. Pieber, T. Glasnov, C. O.

Kappe, ChemSusChem 2014, 7, 3122.

[25] R. Battino, T. R. Retich, T. Tominaga, J. Phys. Chem. Ref. Data, 1983, 12, 163.

[26] Y. Imada, H. Iida, S. Ono, S.-I. Murahashi, J. Am. Chem. Soc. 2003, 125, 2868.

[27] M. Hamano, K. D. Nagy, K. F. Jensen, Chem. Commun, 2012, 48, 2086.

[28] It has to be noted that HPLC analysis just shows DHAA and AA, we could neither

seperate DHAA from its diastereomer (DHAA 2), nor detect the over-reduced

tetrahydroartemisinic acid (THAA).

[29] J. Haber, M. N. Kashid, A. Renken, L. Kiwi-Minsker, Ind. Eng. Chem. Res. 2012, 51,

1474.

[30] a) P. Barthe, C. Guermeur, O. Lobet, M. Moreno, P. Woehl, D. M. Roberge, N. Bieler,

B. Zimmermann, Chem. Eng. Technol. 2008, 31, 1146; b) D. M. Roberge, N. Bieler, M.

Mathier, M. Eyholzer, B. Zimmermann, P. Barthe, C. Guermeur, O. Lobet, M. Moreno,

P. Woehl, Chem. Eng. Technol. 2008, 31, 1155.

Chapter D

131


General Remarks. All standard chemicals were purchased from Sigma-Aldrich and used

without further purification. Reagents were weighed and handled in air at room temperature.

1H-NMR and

13C spectra were recorded on a Bruker 300 MHz instrument using CDCl3 or

DMSO-d6 as solvent. Chemical shifts (δ) are expressed in ppm downfield from TMS as

internal standard. The letters s, d, t, q, and m are used to indicate a singlet, doublet, triplet,

quadruplet, and multiplet. Melting points were determined on a Stuart™ SMP3 melting point

apparatus. Analytical HPLC (Shimadzu LC20) analysis was carried out on a C18 reversed-

phase (RP) analytical column (150 × 4.6 mm, particle size 5 μm) at 25 °C using a mobile

phase A (water/acetonitrile 90:10 (v/v) + 0.1 % TFA) and B (MeCN + 0.1 % TFA) at a flow

rate of 1.0 mL/min. The following gradient was applied: linear increase from solution 30% B

to 100 % B in 8 min, hold at 100% solution B for 2 min. GC-FID analysis was performed on a

Trace-GC (ThermoFisher) with a flame ionization detector using a HP5 column (30 m×0.250

mm×0.025 μm). After 1 min at 50°C the temperature was increased in 25°C min−1

steps up to

300°C and kept at 300°C for 4 min. The detector gas for the flame ionization is H2 and

compressed air (5.0 quality).GC-MS analysis was performed on a Trace-GC Ultra – DSQ II-

MS system (ThermoElectron, Waltham, MA, USA). The GC conditions were as follows: HP-

5 MS column (30 m × 0.25 mm ID, 0.25 μm film, Agilent, Waldbronn, Germany); carrier gas

helium 5.0, flow 1 mL min-1

, temperature gradient identical to GC-FID for the simple olefins.

For the reduction of Artemisinic acid the following temperature gradient was used: After 1

min at 100°C the temperature was increased in 5°C min−1

steps up to 300°C and kept at

300°C for 4 min. The MS conditions were as follows: positive EI ionization, ionization

energy 70 eV, ionization source temperature 280 °C, emission current 100 μA; full-scan-

mode. Silica gel flash chromatography separations were performed on a Biotage SP1

instrument using petroleum ether/ethyl acetate mixtures as eluent. All synthesized compounds

have been characterized by 1H and

13C NMR analysis and identified by data reported in

literature.

Chapter D

132

General Experimental Procedure for the Reduction of Simple Olefins in a Single Liquid

Injection Reactor (Table 2). Feed A consisted of the respective olefin and hydrazine

monohydrate dissolved in n-propanol, whereas feed B was oxygen (purity 5.0). The liquid

stream (0.4 mL min-1

) and the gaseous stream (the flow was set at 40 mL min-1

(standard

conditions) at the instrument, resulting in a calculated flow of 2 mL min-1

at a back pressure

of 20 bar) were mixed together in a glass static mixer. The resulting segmented flow stream

was passed through a PFA reactor coil (0.8 mm inner diameter, 10 mL reactor volume if not

stated otherwise) at 100°C (if not stated otherwise). Subsequently, the mixture was cooled in a

heat exchanger with water as cooling agent. After passing a back pressure regulator (20 bar)

the solution was collected. For isolating the title compounds the solvent was evaporated under

reduced pressure and the product was dried overnight (work up A). In certain cases the

reaction mixture was concentrated, filtered through a plug of silica and eluted with copious

amounts of CHCl3. The solvent was evaporated under reduced pressure and the product was

dried overnight using a desiccator with CaCl2 (work up B).

1-Nitro-4-propoxybenzene (Table 2, 2a). From 1-nitro-4-allyloxybenzene (179.2 mg, 1

mmol) with 4 equivalents of hydrazine monohydrate (200.2 mg, 4 mmol). Yield (work up A):

99% as orange liquid (180.1 mg, 0.99 mmol). 1H NMR (300 MHz, CDCl3) δ 8.21 (d, J = 9.3

Hz, 1H), 6.96 (d, J = 9.3 Hz, 1H), 4.03 (t, J = 6.5 Hz, 1H), 1.94 – 1.80 (m, 1H), 1.07 (t, J =

7.4 Hz, 2H). 13

C NMR (75 MHz, CDCl3) δ 164.24, 141.28, 125.90, 114.38, 70.32, 22.34,

10.40.

2-Propylphenol (Table 2, 2b). From 2-allylphenol (136.9 mg, 1 mmol) with 4 equivalents of

hydrazine monohydrate (200.2 mg, 4 mmol). Yield (work up A): 98% as yellowish liquid

(133.0 mg, 0.98 mmol). 1H NMR (300 MHz, CDCl3) δ 7.11 (dd, J = 14.8, 7.5 Hz, 1H), 6.89

(t, J = 7.4 Hz, 1H), 6.79 (d, J = 7.9 Hz, 1H), 2.67 – 2.55 (m, 1H), 1.75 – 1.59 (m, 1H), 1.00 (t,

J = 7.3 Hz, 1H).13

C NMR (75 MHz, CDCl3) δ 153.50, 130.24, 128.39, 127.01, 120.65,

115.16, 32.00, 22.90, 14.03.

1-Ethyl-3-nitrobenzene (Table 2, 2c). From 3-nitrostyrene (149.1 mg, 1 mmol) with 4

equivalents of hydrazine monohydrate (200.2 mg, 4 mmol). Yield (work up A): 92% of the

title compound as yellow liquid (180.1 mg, 0.92 mmol).1H NMR (300 MHz, CDCl3) δ 8.06

(d, J = 9.3 Hz, 1H), 7.54 (d, J = 7.6 Hz, 1H), 7.46 (t, J = 7.7 Hz, 1H), 2.78 (q, J = 7.6 Hz, 1H),

1.31 (t, J = 7.6 Hz, 1H).13

C NMR (75 MHz, CDCl3) δ 148.35, 146.05, 134.24, 129.14,

122.69, 120.86, 28.56, 15.18.

Chapter D

133

4-Ethylaniline (Table 2, 2d). From 4-aminostyrene (122.9 mg, 1 mmol) with 4 equivalents

of hydrazine monohydrate (200.2 mg, 4 mmol). Yield (work up A): 95% of the title

compound as orange liquid (115.6 mg, 0.95 mmol). 1

H NMR (300 MHz, CDCl3) δ 7.02 (d, J

= 8.3 Hz, 1H), 6.66 (d, J = 8.3 Hz, 1H), 3.44 (s, 1H), 2.57 (q, J = 7.6 Hz, 1H), 1.22 (t, J = 7.6

Hz, 2H).13

C NMR (75 MHz, CDCl3) δ 144.01, 134.49, 128.59, 115.29, 27.99, 15.97.

Tert-butyldimethyl-(2-propylphenoxy)silane (Table 2, 2e). From (2-allylphenoxy)(tert-

butyl)dimethylsilane (124.2 mg, 0.5 mmol) with 4 equivalents of hydrazine monohydrate

(100.1 mg, 2 mmol). Yield (work up B): 92% of the title compound as colorless liquid (114.7

mg, 0.92 mmol). 1H NMR (300 MHz, CDCl3) δ 7.16 (dd, J = 7.4, 1.6 Hz, 1H), 7.09 (td, J =

7.7, 1.8 Hz, 1H), 6.90 (td, J = 7.4, 1.1 Hz, 1H), 6.81 (dd, J = 8.0, 0.9 Hz, 1H), 2.68 – 2.50 (m,

1H), 1.73 – 1.53 (m, 1H), 1.05 (s, 2H), 0.98 (t, J = 7.3 Hz, 1H), 0.26 (s, 1H).13

C NMR (75

MHz, CDCl3) δ 153.55, 133.32, 130.21, 126.57, 120.87, 118.34, 32.74, 25.78, 23.32, 18.25,

14.12, -4.15.

N-Ethyl-N-o-tolylbutyramide (Table 2, 2f). From (E)-N-ethyl-N-o-tolylbut-2-enamide

(180.6 mg, 1 mmol) with 5 equivalents of hydrazine monohydrate (250.3 mg, 5mmol). Yield

(work up B): 88% of the title compound as yellow liquid (180.6 mg, 0.88 mmol). 1H NMR

(300 MHz, CDCl3) δ 7.35 – 7.21 (m, 1H), 7.11 – 7.04 (m, 1H), 4.13 (dq, J = 14.2, 7.2 Hz,

1H), 3.22 (dt, J = 14.0, 7.1 Hz, 1H), 2.23 (s, J = 6.5 Hz, 1H), 1.89 (dtd, J = 22.5, 15.1, 7.2 Hz,

1H), 1.67 – 1.50 (m, 1H), 1.13 (t, J = 7.2 Hz, 1H), 0.82 (t, J = 7.4 Hz, 1H).13

C NMR (75

MHz, CDCl3) δ 172.64, 141.08, 135.87, 131.40, 129.34, 128.11, 126.95, 42.88, 36.01, 18.61,

17.57, 13.89, 12.93.

Benzyl 4-Ethylphenylcarbamate (Table 2, 2g). From benzyl 4-vinylphenylcarbamate (126.7

mg, 0.5 mmol) with 4 equivalents of hydrazine monohydrate (100.1 mg, 2 mmol) in 1.5 mL

n-PrOH (0.33 M). Yield (work up B): 87% of the title compound as white solid (110.9mg,

0.434 mmol). m.p. 67-69 °C1H NMR (300 MHz, CDCl3) δ 7.51 – 7.25 (m, 1H), 7.16 (d, J =

8.5 Hz, 1H), 6.63 (s, 1H), 5.22 (s, 1H), 2.63 (q, J = 7.6 Hz, 1H), 1.23 (t, J = 7.6 Hz, 1H). 13

C

NMR (75 MHz, CDCl3) δ 153.46, 139.62, 136.14, 135.33, 128.62, 128.41, 128.32, 118.92,

66.96, 28.21, 15.70.

Chapter D

134

N-Propylurea (Table 2, 2h). From N-allylurea (100.1 mg, 1 mmol) with 5 equivalents of

hydrazine monohydrate (250.3 mg, 5 mmol) dissolved in n-propanol:H2O (1:1, 2 mL). Yield

(work up A): 97% of the title compound as pale yellow solid (98.6 mg, 0.97 mmol).m.p. 106-

110 °C1H NMR (300 MHz, DMSO) δ 5.90 (s, 1H), 5.35 (s, 2H), 2.90 (dd, J = 12.8, 6.9 Hz,

2H), 1.45 – 1.24 (m, 2H), 0.82 (t, J = 7.4 Hz, 3H). 13

C NMR (75 MHz, DMSO) δ 159.17,

41.44, 23.65, 11.80.

1-Bromo-4-propoxybenzene (Table 2, 2i). From 1-(allyloxy)-4-bromobenzene (213.07 mg,

1 mmol) with 4 equivalents of hydrazine monohydrate (200.2 mg, 4 mmol). Yield (work up

A): 93% of the title compound as yellow liquid (199.0 mg, 0.925 mmol). 1H NMR (300 MHz,

CDCl3) δ 7.38 (d, J = 9.0 Hz, 1H), 6.79 (d, J = 9.0 Hz, 1H), 3.90 (t, J = 6.6 Hz, 1H), 1.90 –

1.72 (m, 1H), 1.05 (t, J = 7.4 Hz, 1H).13

C NMR (75 MHz, CDCl3) δ 158.24, 132.19, 116.29,

112.56, 77.45, 77.03, 76.61, 69.74, 22.50, 10.49.

Phenyl(propyl)sulfane (Table 2, 2j). From allyl(phenyl)sulfane (150.24 mg, 1mmol) with 5

equivalents of hydrazine monohydrate (250.3 mg, 5mmol). Yield after column

chromatography using petroleum ether/ethyl acetate: 58 % of the title compound as colorless

liquid (88.3 mg, 0.579 mmol). 1H NMR (300 MHz, CDCl3) δ 7.39 – 7.26 (m, 1H), 7.23 – 7.14

(m, 1H), 2.97 – 2.86 (m, 1H), 1.78 – 1.61 (m, 1H), 1.05 (t, J = 7.3 Hz, 1H).13

C NMR (75

MHz, CDCl3) δ 136.93, 128.95, 128.82, 125.67, 35.60, 22.52, 13.46.

Ethyl 3-Phenylpropanoate (Table 2, 2k). From ethyl cinnamate (176.21 mg, 1 mmol) with 5

equivalents of hydrazine monohydrate (250.3 mg, 5 mmol) using a 16 mL residence time unit

and a reaction temperature of 120°C. Yield (work up B): 94 % of the title compound as pale

yellow liquid (168.1 mg, 0.943 mmol). 1H NMR (300 MHz, CDCl3) δ 7.35 – 7.28 (m, 2H),

7.26 – 7.17 (m, 3H), 4.15 (q, J = 7.1 Hz, 2H), 3.02 – 2.92 (m, 2H), 2.64 (t, J = 7.8 Hz, 2H),

1.25 (t, J = 7.1 Hz, 3H).13

C NMR (75 MHz, CDCl3) δ 172.98, 140.47, 128.47, 128.29,

126.22, 60.44, 35.96, 30.97, 14.20.

1-Methoxy-4-propylbenzene (Table 2, 2l). From trans-anethole (148.2 mg, 1 mmol) with 5

equivalents of hydrazine monohydrate (250.3 mg, 5 mmol) using a 26 mL residence time unit

and a reaction temperature of 120°C. Yield (work up B): 91 % of the title compound as

colorless liquid (136.0 mg, 0.905 mmol). 1H NMR (300 MHz, CDCl3) δ 7.11 (d, J = 8.6 Hz,

2H), 6.84 (d, J = 8.6 Hz, 2H), 3.81 (s, 3H), 2.65 – 2.44 (m, 2H), 0.95 (t, J = 7.3 Hz, 3H).13

C

NMR (126 MHz, CDCl3) δ 157.65, 134.83, 129.31, 113.65, 55.25, 37.15, 24.79, 13.78.

Chapter D

135

General Procedure for the Reduction of Artemisinic Acid in a Multi-Injection Flow

Reactor. Feed A consisted of n-propanol, whereas feed B was oxygen (purity 5.0).

Artemisinic acid (1 or 8.5 mmol) and hydrazine hydrate (2 equivalents) were dissolved in n-

PrOH (1 or 8.5 mL) and injected in a sample loop which was connected to Feed A via a 6-

way valve. The liquid stream (400 µL min-1

) and the gaseous stream (40 mLN min-1

) were

mixed together in a T-mixer. The resulting segmented flow stream was passed through a PFA

reactor coil (0.8 mm inner diameter, 10 mL reactor volume) at 60°C. After coil 1, a T-mixer

connected another Feed C adding hydrazine hydrate Feed in n-PrOH (3.33 M in n-PrOH) at a

flow rate of 100µL min-1

. The combined stream passes another 10 mL PFA tubing at 60°C

(coil 2). This addition principle is repeated two times (Feed D, coil 3, Feed E, coil 4) resulting

in three additional hydrazine hydrate feeds and an overall reactor volume of 40 mL.

Subsequently, the mixture was cooled in a heat exchanger with water as cooling agent. After

passing a back pressure regulator (20 bar) the solution was collected. For isolating the title

compound, the solvent was evaporated under reduced pressure and the product was

precipitated by adding water (3-5 mL) and concentrated H3PO4 until pH <2. The solids were

filtered and dried overnight. Yields and purities are summarized in Table S1.

Derivatization Procedure for the Determination of Purity and Diastereomeric Ratio by

GC-MS. A representative, small amount of the solid material was dissolved in MeCN (200

µL) in an GC vial and 100 µL N-Methyl-N-(trimethylsilyl) trifluoroacetamide (MSTFA) were

added. The vial was capped and put in a drying oven set at 50°C for 30 min. After cooling to

room temperature the mixture was diluted with MeCN and subjected to analysis.

Table S1. Results of the reduction of artemisinic acid using the optimized multi-injection

protocol.

GC-MS

Entry AA

[g]

AA

[mmol]

Yield

[g]

Yield

[%] Appearance

DHAA

[%]

DHAA 2

[%]

THAA

[%]

AA

[%]

1 0.243 1 0.189 80 pale-yellow solid 97 1 2 <1

2 1.989 8.5 1.883 94 yellow solid 95 2 2 1

3 1.996 8.5 1.8714 93 yellow solid 95 2 2 1

Chapter D

136

Figure S1. GC-MS-TIC chromatogram of the reduction of 1 mmol artemisinic acid (Table S1,

Entry 1).

Figure S2. GC-MS-TIC chromatogram (detail) of the reduction of 1 mmol artemisinic acid

(Table S1, Entry 1).

Chapter D

137

Figure S3. GC-MS-TIC chromatogram (detail) of the reduction of 8.5 mmol artemisinic acid

(Table S1, Entry 2&3).

Figure S4. 1H-NMR spectrum of the isolated product from the reduction of 8.5 mmol

artemisinic acid. Small amounts of the substrate and the undesired stereoisomer are indicated

in the enlarged area. All other peaks are identical to literature data.

Chapter D

138

Figure S5. 13

C-NMR spectrum of the isolated product from the reduction of artemisinic acid.

Chapter E

139

E. Flash Carboxylation: Fast Lithiation Carboxylation Sequence at

Room Temperature in Continuous Flow

Graphical Abstract

Abstract

A method for the direct lithiation of terminal alkynes and heterocycles with subsequent

carboxylation in a continuous flow format was developed. This method provides

carboxylic acids at ambient conditions within less than five seconds with only little excess

of the organometallic base and CO2.

Chapter E

141

1. Introduction

Carbon dioxide (CO2) is a highly attractive building block for organic synthesis as it is readily

available, extremely cheap, abundant, non-toxic, nonflammable, and is classified as an ideal

renewable carbon source.[1]

Due to its low reactivity a large energy input is required to use the

greenhouse gas as reagent for synthetic transformations. Several methods for the utilization of

CO2 are well studied and used on laboratory as well as on industrial scales.

The most straightforward strategy to tackle the low reactivity of CO2 is the use of

high-energy starting materials such as Grignard or organolithium compounds.[1]

The latter

carbanion equivalents are often highly unstable and are usually prepared at very low

temperatures. Furthermore, reactions of these intermediates with electrophiles are difficult to

control as a result of their exothermic nature resulting in severe limitations for industrial

applications.

Pioneering work by Yoshida on halogenlithium exchange reactions demonstrated

that the generation as well as the use of various organolithium species can be performed at

much higher temperatures when a continuous microreactor is used instead of traditional batch

macroreactors.[2,3]

Such “flash chemistry” transformations are typically carried out in the

range of (milli-)seconds offering several advantages compared to traditional approaches.[4]

The use of microreactors in general has become increasingly popular in synthetic organic

chemistry.[5,6]

Both, heat and mass transfer is superior compared to traditional techniques and

multiphasic reactions (e.g. gas/liquid,[7]

gas/liquid/solid,[8]

liquid/liquid[9]

) can therefore be

often dramatically improved. In addition, combustion and explosion hazards are reduced and,

consequently, reactions in the explosive or thermal runaway regime can be exploited in a safe

and controllable manner.

Carbon dioxide was recently intensively studied in its supercritical form (scCO2) as

reaction medium during continuous processes.[10]

The use as gaseous reagent is comparably

less studied, albeit several case studies show its potential in continuous manufacturing. One of

the first examples was carried out using immobilized decarboxylase for the synthesis of

pyrrole-2-carboxylates.[11]

The carboxylation of Grignard reagents using the tube-in-tube

methodology has been studied with different continuous flow setups.[12,13]

Very recently, a

lithiumhalogen exchange reaction was combined with a subsequent carboxylation using the

tube-in-tube gas addition concept in the continuous synthesis of Amitryptiline.[3]

Leitner and

coworkers were able to show that scCO2 can be continuously hydrogenated to pure formic

acid using an immobilized catalyst.[14]

A novel synthesis of cyclic carbonates from epoxides

and CO2 was recently presented by the Jamison laboratories.[15]

Interestingly, the only

Chapter E

142

lithiationcarboxylation sequence of heterocycles reported so far was carried out for the

conversion of furan and 2-chlorothiophene with n-BuLi and carbon dioxide at -30°C (in case

of the latter at 0°C) resulting in the corresponding acids after 2 - 3.5 minutes.[16]

The present study was designed in order to develop a facile and efficient flash

synthesis of carboxylic acids from terminal alkynes and heterocycles (Fig 1) in a multistep

continuous process. Therefore, the substrates were initially lithiated using suitable metalation

agents. The organometallic intermediate was then treated with a well-defined amount of CO2

and subsequently quenched yielding the desired target molecules within a few seconds.

Figure 1. Carboxylation of alkynes and heterocycles using organolithium bases and CO2.


Phenylacetylene (1a) was chosen as model substrate to establish a setup for the

metalationcarboxylation sequence with lithium bis(trimethylsilyl)amide (LiHMDS) and CO2

in a gas/liquid continuous flow regime. We initially optimized the parameters required for the

carboxylation step by mixing a solution of LiHMDS and 1a in THF with the gaseous reagent

in a T-mixing unit.[17]

After an intensive evaluation of various reaction parameters, including

gas and liquid flow rates, residence time, temperature as well as back pressure regulation it

was established that the carboxylate is formed in sufficient amounts within ~0.5 seconds at

room temperature. The next logical step was to combine the gas/liquid carbon dioxide fixation

with an on-demand continuous flow generation of the reactive intermediate.[17]

Importantly,

this could be easily implemented using an additional mixer in combination with a 0.1 mL

residence time, resulting in the 4-feed approach shown in Fig. 2.[18]

In the final setup, a liquid stream of a commercially available 1M solution of LiHMDS

in THF was mixed with the alkyne dissolved in THF via a T-mixer. The flow rates and

substrate concentration were set in order to obtain a slight excess of the lithium amide (1.1

equiv). After a residence time of ~3 seconds the lithium alkynate was mixed with the gaseous

reagent in a second T-mixer resulting in a completely homogenous gas/liquid mixture at a

Chapter E

143

back pressure of 10 bar. It has to be pointed out that the CO2 flow rate of 19 mLN min-1

corresponds to a comparably low excess (1.2 equiv) and therefore constitutes an almost

quantitative consumption of the greenhouse gas. However, we additionally realized that the

performance of the CO2 mass flow controller had to be stabilized by preheating the gas to

65°C in a stainless steel coil.[19]

High conversions of the organolithium intermediate to the

corresponding carboxylate could be achieved within a short residence time of only ~0.5

seconds. It is worth noting, that the residence time can be accurately controlled using a water

quench before depressurization and collection of the reaction mixture. As small amounts of

precipitates were formed either during the carboxylation, or after adding H2O a 1 mL coil was

installed directly after the quench. During the time in which the reaction mixture passes this

residence unit all solids dissolved, allowing the reaction mixture to smoothly pass the

pressure-regulating unit.

Figure 2. Continuous flow set up for the synthesis of carboxylic acids with CO2.

With the optimized conditions in hand, we next evaluated our setup using several terminal

alkynes (Table 1). It has to be noted that in all examples, small amounts of the substrate were

still present in the reaction mixture as analyzed by HPLC-UV.[20]

Furthermore, we realized

that 1-10% of a byproduct was formed during the reaction which could be identified as a

trimethylsilane derivative apparently from a reaction of the base and the alkyne moiety.

Chapter E

144

Electron-rich (1a, 1b) and electron poor (1c, 1d, 1f) aromatic alkynes were transformed into

their corresponding carboxylic acids resulting in good yields after extraction of the

byproducts followed by acidification and crystallization. Unfortunately, it was not possible to

convert the phenol derivative 1e and 3-ethynylpyridine (1h) due to precipitation of either the

organometallic intermediate or, in case of 1h, the carboxylate, resulting in a clogged reactor.

However, we could expand the synthetic scope of our methodology by heterocyclic (1g) and

aliphatic (1i, 1j) substrates without further modifications.

The propiolic acids obtained are valuable synthetic intermediates for a range of

pharmaceutically or industrially relevant molecules, including polymers, coumarins, flavones,

spirobenzofuranes, spiroindoles or vinyl sulfides.[21]

Table 2 Preparation of propionic acids in continuous flowa

Substrate

Conversionb

(Selectivity)

(%)

Yieldc

(%) Substrate

Conversionb

(Selectivity)

(%)

Yieldc

(%)

93(99) 85

93(98) 89

94(92) 81

91(89) 81

91(98) 78

clogging --

97(95) 84

n.d.(n.d.)d 90

clogging --

n.d.(n.d.) 66

a Reactions were carried out using 1.42 mmol alkyne, for general conditions see Figure 2.

b Determined as

HPLC-UV peak area percent at 215 nm. c Isolated yield.

d Not determined.

In order to broaden the synthetic horizon of the lithiationcarboxylation flow reactor concept,

we decided to test the same methodology for its suitabilityto convert heterocycles into their

corresponding carboxylic acids. Initially we decided to use the lithiation of thiophene (3a) by

Chapter E

145

lithium diisopropylamide (LDA) with subsequent carboxylation for a feasibility study. In an

initial experiment the reactor clogged immediately after the water quench which prompted us

to change to a mixture of water and acetic acid (10:1) to overcome this hurdle. Gratifyingly,

thiophene-2-carboxylic acid (4a) could be isolated by extraction after this minor modification

in satisfying yields without any further re-optimization of the continuous method (Fig. 3). An

additional experiment using significantly higher amounts of CO2 (1.9 equiv) resulted in only

slightly higher amounts of the desired target molecule. Methyl substituted thiophenes (3b, 3c)

as well as benzofuran (3f) provided moderate yields. Further optimization studies using 3b

and either a higher excess of LDA (2M, 2.2 equiv) or larger amounts of carbon dioxide (30

mLN min-1

, 1.9 equiv) did not result in a significant improvement. In case of 1-phenylpyrazole

the reactor immediately clogged after mixing with the organometallic base as the intermediate

is apparently completely insoluble in THF. However, the use of electron poor thiophenes (4d,

4e) expanded the synthetic potential of the presented continuous flow methodology.

Fig. 3 LDA mediated carboxylation of heterocycles in flowa

a

Reactions were carried out using 1.42 mmol alkyne, for

all general conditions see Figure 2. b

Reaction was carried

out using 1.9 equiv CO2 (30 mLN min-1

).

3. Conclusion

In summary, we have developed a fast and efficient process for the continuous lithiation and

subsequent carboxylation with carbon dioxide of terminal alkynes and heterocycles. The

presented method provides valuable carboxylic acids within ~3.5 seconds reaction time using

low excess of the organometallic base and the gaseous reagent in moderate to good isolated

yields.

Chapter E

146

4. References

[1] (a) T. Sakaura, J.-C. Choi, H. Yasuda, Chem. Rev. 2007, 107, 2365; (b) M. Aresta,

A. Dibeneedetto, Dalton Trans. 2007, 2975; (c) I. Omae, Coord. Chem. Rev. 2012,

256, 1384; (d) X. Cai, B. Xie, Synthesis, 2013, 45, 3305.

[2] (a) A. Nagaki, D. Ichinari, J.Yoshida, Chem. Commun. 2013, 49, 3242; (b) A.

Nagaki, Y. Uesugi, H. Kim, J. Yoshida, Chem. Asian J. 2013, 8, 705; (c) A.

Nagaki, Y. Takahashi, S. Yamada, C. Matsuo, S. Haraki, Y. Moriwaki, S. Kim, J.

Yoshida, J. Flow. Chem. 2012, 2, 70; (d) A. Nagaki, Y. Moriwaki, S. Haraki, A.

Kenmoku, A. Hayashi, J. Yoshida, Chem. Asian J. 2012, 7, 1061.

[3] L. Kupracz , A. Kirschning, Adv. Synth. Catal. 2013, 355, 3375.

[4] (a) J. Yoshida, Y. Takahashi, A. Nagaki, Chem. Commun. 2013, 49, 9896; (b) J.

Yoshida, Chem. Rec. 2010, 10, 323; (c) J. Yoshida, Flash Chemistry: Fast

Organic Synthesis in Microsystems, Wiley-Blackwell, Oxford, U.K. 2008.

[5] For selected books see: (a) W. Ehrfeld, V. Hessel, H. Lowe, Microreactors,

Wiley-VCH, Weinheim, Germany, 2000; (b) V. Hessel, S. Hardt, H. Lowe,

Chemical Micro Process Engineering, Wiley-VCH, Weinheim, Germany, 2004;

(c) V. Hessel, A. Renken, J. C. Schouten, J. Yoshida, Micro Process Engineering,

Wiley-Blackwell, Oxford, U.K., 2009; (d) T. Wirth, Microreactors in Organic

Synthesis and Catalysis, Wiley-VCH, Weinheim, Germany, 2nd edn., 2013.

[6] For recent reviews see: (a) R. L. Hartman, J. P. McMullen, K. F. Jensen, Angew.

Chem. Int. Ed. 2011, 50, 7502; (b) J. Wegner, S. Ceylan , A. Kirschning, Adv.

Synth. Catal. 2012, 354, 17; (c) C. Wiles, P. Watts, Green Chem. 2012, 14, 38; (d)

S. G. Newman, K. F. Jensen, Green Chem. 2013, 15, 1456; (e) S. C. Stouten, T.

Noel, Q. Wang, V. Hessel, Aust. J. Chem., 2013, 66, 121.

[7] For recent publications on continuous gas/liquid chemistry from our laboratories,

see: (a) B. Gutmann, P. Elsner, D. Roberge, C. O. Kappe, ACS Catal. 2013, 3,

2669; (b) F. Mastronardi, B. Gutmann, C. O. Kappe, Org. Lett. 2013, 16, 5590; (c)

B. Pieber, S. T. Martinez, D. Cantillo, C. O. Kappe, Angew. Chem. Int. Ed. 2013,

52, 10241; (d) B. Pieber, C. O. Kappe, Green Chem. 2013, 15, 320.

[8] For a recent publications on continuous gas/liquid/solid chemistry from our

laboratories, see: D. Obermayer, A. M. Balu, A. A. Romero, W. Goessler, R.

Luque, C. O. Kappe, Green Chem. 2013, 15, 1530.

Chapter E

147

[9] For recent publications on continuous liquid/liquid chemistry from our

laboratories, see: (a) B. Reichart, T. N. Glasnov, C. O. Kappe, Synlett 2013, 24,

239; (b) M. Damm, B. Gutmann, C. O. Kappe, ChemSusChem 2013, 6, 978.

[10] (a) U. Hintermair, G. Francio, W. Leitner, Chem. Eur. J. 2013, 19, 4538; (b) J.

Theuerkauf, G. Francio, W. Leitner, Adv. Synth. Catal. 2013, 355, 209; (c) M. J.

Casciato, G. Vevitin, D. W. Hess, M. A. Grover, ChemSusChem, 2012, 5, 1186;

(d) M. Selva, S. Guidi, A. Perosa, M. Signoretto, P. License, T. Maschmeyer,

Green Chem. 2012, 14, 2727.

[11] T. Matsuda, R. Marukado, S. Koguchi, T. Nagasawa, M. Mukouyama, T. Harada,

K. Nakamura, Terahedron Lett. 2008, 49, 6019.

[12] A. Polyzos, M. O’Brien, T. P. Petersen, I. R. Baxendale, S. V. Ley, Angew. Chem.

Int. Ed. 2011, 50, 1190.

[13] J. J. F. van Gool, S. A. M. W. van den Broek, R. M. Ripken, P. J. Nieuwland, K.

Koch, F. P. J. T. Rutjes, Chem. Eng. Technol. 2013, 36, 1042.

[14] S. Wesselbaum, U. Hintermair, W. Leitner, Angew. Chem. Int. Ed. 2012, 51, 8585.

[15] J. A. Kozak, J. Wu, F. Simeon, T. A. Hatton, T. F. Jamison, J. Am. Chem. Soc.,

2013, 153, 18497.

[16] S. Buchholz, C. Severins, K. Tellmann, K. Weidemann, J. Wieschemeyer, Ger.

Pat., DE102009060033, 2011.

[17] A detailed summary of the optimization see Table S1& S2 in the ESI.

[18] For a detailed description including images of the continuous flow set up, see ESI.

[19] The mass flow controller was not able to control the gaseous reagent in a stable

fashion, presumably due to condensation.

[20] A representative HPLC chromatogram is given in the ESI (Figure S3).

[21] F. Manjolinho, M. Arndt, K. Gooßen , L. J. Gooßen, ACS Catal. 2012, 2, 2014.

Chapter E

148


General Remarks. All substrates and reagents were purchased from Sigma-Aldrich and were

used without further purification. THF (HPLC grade) was dried using molecular sieves (3Å)

prior to use. 1H-NMR and


DMSOd6 or CDCl3 as solvent. Chemical shifts (δ) are expressed in ppm downfield from TMS

as internal standard. The letters s, d, t, q, and m are used to indicate a singlet, doublet, triplet,

quadruplet, and multiplet respectively. Melting points were determined on a Stuart™ SMP3

melting point apparatus. Analytical HPLC (Shimadzu LC20) analysis was carried out on a

C18 reversed-phase (RP) analytical column (150 × 4.6 mm, particle size 5 μm) at 25 °C using

a mobile phase A (water/acetonitrile 90:10 (v/v) + 0.1 % TFA) and B (MeCN + 0.1 % TFA)

at a flow rate of 1.0 mL/min. The following gradient was applied: linear increase from

solution 30% B to 100 % B in 8 min, hold at 100% solution B for 2 min. All synthesized

compounds have been characterized by 1H and

13C NMR analysis as well as their melting

points and identified by data reported in literature.

Continuous Flow Set up

Figure S1. 4-Feed gas/liquid continuous flow reactor for carboxylation using CO2. Carbon

dioxide is preheated using a stainless steel coil (~10 mL) in an oil bath (OB) set at 65°C

before entering the mass flow controller (MFC).[S1]

The liquid flow rate of the organometallic

base and the substrate in dry THF is controlled using HPLC pumps (P1,P2). The reagents are

loaded in either a 4 mL (substrate, SL1) or a 3 mL (base, SL2) sample loop and can be

introduced in the flow system by 6 way valves (6W1, 6W2).[S2]

The reaction zone (RZ) is

explained in more detailed below (Figure S2). For adding the water quench a third HPLC

pump (P3) is used. The reaction mixture and the quench solution pass a 1 mL coil (Coil) for

dissolving any precipitates. Pressure regulation occurs in a static 10 bar back pressure

regulator (BPR).

Chapter E

149

Figure S2. Reaction Zone. The substrate solution is mixed with the organometallic base in a

T-mixing unit (T1, i.d. 0.5 mm). Metalation is carried out in a residence time unit made of

PTFE (R1, i.d. 0.8 mm, 0.1 mL). The organometallic intermediate is mixed with CO2 in a

second T-mixer (T2, i.d. 0.5 mm) entering a second residence coil (R2, PTFE, i.d. 0.8 mm,

0.02 mL). The reaction is then quenched in a third mixing unit (T3, i.d. 0.5 mm) before

reaching the back pressure regulator.

General Conditions for Using the Mass Flow Controller[S1]

with CO2. The pressure

regulator of the gas cylinder was set at 30-40 bar and the system was first flushed with the

maximum CO2 flow rate (74 ml min-1

). As soon as the system pressure was reached (~10 bar)

the liquid streams were activated. After 2-5 minutes additional flushing at the maximum gas

the desired gas flow rate was chosen and experiments were started after the gas flow rate got

stable.

Cleaning Procedure. In order to avoid clogging or other serious problems during the course

of this research study the reactor was flushed with a cleaning solvent after use. The solvent

mixture of choice for such efforts is AcOH:THF:H2O (1:1:1) which removes all impurities

caused by the organometallic reagent/intermediate and traces of water within the reaction

solvents. After washing, the reactor was additionally flushed/stored in iPrOH.

Chapter E

150

Optimization

Table S1. Optimization of the carboxylation parameters.a

Entry T (RTU)

[°C]

RTU

[V]

Liquid Flow

(P1)

[mL min-1

]

Gas Flow

[mL min-1

]

BPR

[bar]

A

[%]c

B

[%]c

C

[%]c

1 100 10 0.8 45(9.0)b

17 93 7 <1

2 80 10 0.8 45(9.0) 17 96 4 <1

3 60 10 0.8 45(9.0) 17 95 5 <1

4 r.t. 10 0.8 45(9.0) 17 97 3 <1

5 r.t. 10 0.8 45(9.0) 10 97 3 <1

6 r.t. 10 1.5 45(4.8) 10 96 4 <1

7 r.t. 4.0 2 15(1.2) 10 90 5 4

8 r.t. 4.0 2.5 19(1.2) 10 94 5 1

9 r.t. 2.0 3 23(1.2) 10 88 6 6

10 r.t. 1.0 2.5 19(1.2) 10 91 7 1

11 r.t. 1.0 3 23(1.2) 10 93 4 3

12 r.t. 0.1 2.5 19(1.2) 10 92 3 5

13 r.t. 0.02 2.5 19(1.2) 10 92 5 3 a Conditions: 1 mmol phenylacetylene and 1.1 mmol LiHMDS (1M in THF) were dissolved in 2 mL dry

THF and injected via a sample loop. b

CO2 equivalents in parentheses. c

Determined as HPLC-UV/VIS

peak area percent at 215 nm.

Chapter E

151

Table S2. Implementation of the metalation step.a

Entry Coil 1

[V]

Liquid Flow

(P1)

[mL min-1

]

Liquid Flow

(P2)

[mL min-1

]

A

[%]b

B

[%]b

C

[%]b

1 1 0.7 1.8 87 5 8

2 0.1 0.7 1.8 88 5 7

3 0.02 0.7 1.8 74 14 12 a

The reaction was carried out using 1.42 mmol phenylacetylene. c

Determined as HPLC-

UV/VIS peak area percent at 215 nm.

Figure S3. Representative HPLC-UV/VIS chromatogram (215 nm) for the carboxylation of

phenylacetylene under the optimized conditions (Table S2, Entry 2)

Chapter E

152

General experimental procedure for the synthesis of carboxylic acids from alkynes and

heterocycles (Table 1, Figure 3). The respective alkyne or heterocycle (1.42 mmol) in dry

THF (4 mL) and 3 mL of either an1 M solution of LiHMDS in THF (commercially available)

or an 1M solution of LDA in THF/hexanes (commercially available) were loaded into

individual sample loops. Pump 1 was set at 1.8 mL min-1

and pump 2 at 0.7 mL min-1

. Sample

loop 2 containing the base was switched 45 seconds prior to sample loop 1 to injecting mode

in order to avoid diffusion phenomena and guarantee a proper stoichiometry. The 2 streams

were combined in a T-mixing unit before passing a 0.1 mL residence time unit. Afterwards,

the mixture entered a second T-mixer where CO2 was introduced at 19 mLN min-1

.

Carboxylation occurs in a second residence time unit (0.02 mL) prior to a third mixer where,

in case of LiHMDs a water quench (1 mL min-1

), or in case of LDA a water:AcOH quench

(10:1, 1 mL min-1

) was added. The mixture was finally collected after passing a 10 bar static

back pressure regulator.

Work up A. THF was removed under reduced pressure and the aqueous residue was

extracted twice using Et2O (15 mL). The organic layer was discarded and the aqueous phase

was acidified using concentrated HCl until precipitation (pH ~1). The mixture was cooled in

an ice bath, the solid collected by filtration and carefully washed with cold, aqueous HCl

(1M) to furnish analytically pure carboxylic acids after drying in a desiccator under reduced

pressure.

Work up B. THF was removed under reduced pressure and the aqueous residue was

extracted twice using Et2O (15 mL). The organic layer was discarded and the aqueous phase

was acidified using HCl (pH ~1). Afterwards, Et2O (20 mL) was added to extract the

carboxylic acid. The organic phase was washed with brine and dried over Na2SO4.

Evaporation of the organic solvent afforded the respective carboxylic acids which were finally

dried in a desiccator under reduced pressure.

3-Phenylpropiolic acid (Table 1, 2a). From phenylacetylene (145.1 mg, 1.42mmol) and

LiHMDS. Work up A resulted in the title compound as white solid in 85% (177.2 mg, 1.21

mmol). m.p. 132-134°C 1H NMR (300 MHz, DMSO) δ 13.81 (br, s, 1H), 7.63 (d, J = 7.4 Hz,

1H), 7.55 (t, J = 6.8 Hz, 1H), 7.47 (t, J = 7.5 Hz, 1H). 13


133.04, 131.36, 129.48, 119.40, 84.84, 82.18.

Chapter E

153

3-(p-Tolyl)propiolic acid (Table 1, 2b). From 4-ethynyltoluene (164.9 mg, 1.42 mmol) and

LiHMDS. Work up A resulted in the title compound as white solid in 81% (184.0 mg, 1.15

mmol). m.p. 143-144°C1H NMR (300 MHz, DMSO) δ 13.75 (br, s, 1H), 7.52 (d, J = 8.1 Hz,

2H), 7.28 (d, J = 8.0 Hz, 2H), 2.35 (s, 2H).13

C NMR (75 MHz, DMSO) δ 154.81, 141.62,

133.04, 130.11, 116.33, 85.31, 81.86, 21.66.

3-(4-Chlorophenyl)propiolic acid (Table 1, 1c). From 1-chloro-4-ethynylbenzene (194.0

mg, 1.42 mmol) and LiHMDS. Work up A resulted in the title compound as white solid in

78% (199.2 mg, 1.10 mmol). m.p. 184-186°C1H NMR (300 MHz, DMSO) δ 13.93 (br, s,

1H), 7.66 (d, J = 8.5 Hz, 2H), 7.55 (d, J = 8.4 Hz, 2H).13


136.28, 134.82, 129.71, 118.32, 83.55, 83.01.

3-(4-Methoxyphenyl)propiolic acid (Table 1, 1d). From 4-ethynylanisole (187.5 mg, 1.42

mmol) and LiHMDS. Work up A resulted in the title compound as off-white solid in 84%

(211.1 mg, 1.20mmol). m.p. 139-140°C1H NMR (300 MHz, DMSO) δ 13.63 (br, s, 1H), 7.59

(d, J = 8.8 Hz, 2H), 7.02 (d, J = 8.9 Hz, 2H), 3.81 (s, 1H).13


161.66, 154.96, 135.12, 115.19, 111.00, 85.75, 81.51, 55.94, 55.89.

3-(4-(Trifluoromethyl)phenyl)propiolic acid (Table 1, 1f). From 4-ethynyl-α,α,α-

trifluorotoluene (240.9 mg, 1.42 mmol) and LiHMDS. Work up A resulted in the title

compound as white solid in 89% (270.3 mg, 1.26mmol). m.p. 142-145°C1H NMR (300 MHz,

DMSO) δ 14.11 (br, s, 1H), 7.92 – 7.79 (m, 4H).13


133.78, 131.11, 130.68, 126.36, 126.32, 126.27, 126.22, 125.94, 123.81, 123.79, 122.33,

83.91, 82.72.

3-(Thiophen-3-yl)propiolic acid (Table 1, 1g). From 3-ethynylthiophene (153.2 mg, 1.42

mmol) and LiHMDS. Work up B resulted in the title compound as off-white solid in 81%

(174.6 mg, 1.15mmol).m.p. 133-135°C1H NMR (300 MHz, DMSO) δ 13.76 (br, s, 1H), 8.20

(dd, J = 2.8, 1.0 Hz, 1H), 7.71 (dd, J = 5.0, 2.9 Hz, 1H), 7.33 (dd, J = 5.0, 1.0 Hz, 1H).13

C

NMR (75 MHz, DMSO) δ 154.84, 135.34, 130.38, 128.23, 118.35, 82.00, 80.77.

Chapter E

154

3-Cyclohexylpropiolic acid (Table 1, 1i). From ethynylcyclohexane (153.6 mg, 1.42 mmol)

and LiHMDS. Work up A resulted in the title compound as yellow oil in 90% (193.6 mg, 1.27

mmol).1H NMR (300 MHz, DMSO) δ13.38 (br, s, 1H), 2.68 – 2.55 (m, 1H), 1.77 (m, 2H),

1.63 (m, 2H), 1.53 – 1.21 (m, 6H). 13

C NMR (75 MHz, DMSO) δ 154.82, 91.72, 74.61, 31.51,

28.21, 25.52, 24.53.

3-Cyclopentylpropiolic acid (Table 1, 1j). From ethynylcyclopentene (133.6 mg, 1.42

mmol) and LiHMDS. Work up A resulted in the title compound as off-white solid in 66%

(128.9 mg, 0.93mmol). m.p. 55-57°C 1H NMR (300 MHz, DMSO) δ 13.33 (br, s, 1H), 2.93 –

2.68 (m, 1H), 2.07 – 1.78 (m, 2H), 1.77 – 1.42 (m, 6H).13


92.31, 74.15, 33.09, 29.27, 25.16.

Thiophene-2-carboxylic acid (Figure 3, 4a). From thiophene (119.3 mg, 1.42 mmol) and

LDA. Work up B resulted in the title compound as white solid in 79% (143.8 mg, 1.12mmol).

m.p. 125-127°C. 1H NMR (300 MHz, DMSO) δ 13.02 (s, 1H), 7.88 (d, J = 4.9 Hz, 1H), 7.73

(d, J = 2.5 Hz, 1H), 7.18 (m, 1H). 13

C NMR (75 MHz, DMSO) δ 163.37, 135.08, 133.73,

133.66, 128.68.

5-Methylthiophene-2-carboxylic acid (Figure 3, 4b). From 2-methylthiophene (138.9 mg,

1.42 mmol) and LDA. Work up A resulted in the title compound as off-white solid in 48%

(95.6 mg, 0.67mmol). m.p. 132-134°C. 1H NMR (300 MHz, CDCl3) δ 10.41 (s, 1H), 7.73 (d,

J = 3.7 Hz, 1H), 6.83 (d, J = 3.7 Hz, 1H), 2.57 (s, 3H). 13

C NMR (75 MHz, CDCl3) δ 167.60,

149.98, 135.60, 130.02, 126.79, 15.95.

4-Methylthiophene-2-carboxylic acid (Figure 3, 4c). From3-methylthiophene (139.1 mg,

1.42 mmol) and LDA. Work up A resulted in the title compound as off-white solid in 43%

(85.7 mg, 0.60mmol). m.p. 118-120°C. 1H NMR (300 MHz, DMSO) δ 12.96 (s, 1H), 7.56 –

7.53 (m, 1H), 7.47 (s, 1H), 2.23 (s, 3H). 13

C NMR (75 MHz, DMSO) δ 163.38, 138.68,

135.42, 134.60, 129.07, 15.66.

Chapter E

155

5-Chlorothiophene-2-carboxylic acid (Figure 3, 4d). From2-chlorothiophene (167.8 mg,

1.42 mmol)and LDA. Work up A resulted in the title compound as light brown solid in 72%

(166.7 mg, 1.03mmol). m.p. 149-151°C. 1H NMR (300 MHz, DMSO) δ 13.45 (s, 1H), 7.61

(d, J = 4.0 Hz, 1H), 7.23 (d, J = 4.0 Hz, 1H). 13

C NMR (75 MHz, DMSO) δ 162.25, 135.25,

133.88, 133.66, 128.96.

Benzo[b]thiophene-2-carboxylic acid (Figure 3, 4e). Frombenzo[b]thiophene(190.3 mg,

1.42 mmol) and LDA. Work up A resulted in the title compound as white solid in 70% (176.2

mg, 0.99mmol). m.p. 238-240°C. 1H NMR (300 MHz, DMSO) δ 13.47 (s, 1H), 8.12 (s, 1H),

8.08 – 7.98 (m, 2H), 7.56 – 7.42 (m, 2H). 13

C NMR (75 MHz, DMSO) δ 163.99, 141.77,

139.18, 135.18, 130.72, 127.49, 126.20, 125.53, 123.44.

Benzofuran-2-carboxylic acid (Figure 3, 4f) From benzofuran(190.3 mg, 1.42 mmol) and

LDA. Work up A resulted in the title compound as yellow solid in 46% (105.3 mg,

0.65mmol). m.p. 190-192°C. 1H NMR (300 MHz, DMSO) δ 13.58 (s, 1H), 7.79 (d, J = 7.6

Hz, 1H), 7.74 – 7.64 (m, 2H), 7.51 (t, J = 7.6 Hz, 1H), 7.35 (t, J = 7.5 Hz, 1H). 13

C NMR (75

MHz, DMSO) δ 160.54, 155.42, 146.60, 128.02, 127.29, 124.28, 123.55, 113.97, 112.53.

References

[S1] http://www.thalesnano.com

[S2] http://www.uniqsis.com

Chapter F

157

F. Continuous Synthesis of Hydantoins: Intensifying the Bucherer-Bergs

Reaction

Graphical Abstract

Abstract

A continuous Bucherer-Bergs hydantoin synthesis utilizing intensified conditions is reported.

The methodology is characterized by a 2-feed flow approach to independently feed the

organic substrate and the aqueous reagent solution. The increased interfacial area of the

biphasic reaction mixture and the lack of headspace enabled almost quantitative conversions

within ~30 min at 120°C and 20 bar even for unpolar starting materials. In addition, a

selective N(3)-monoalkylation of the resulting heterocycles under batch microwave conditions

is reported yielding potential acetylcholinesterase inhibitors.

Chapter F

159

1. Introduction

The hydantoin scaffold is an important structural motif with a broad range of biological

activities.[1]

Potential applications for medicinal purposes include the utilization as androgen

receptor modulators,[2]

anticonvulsant-,[3]

antidiabetic-,[4]

or anticancer agents.[5]

From an

industrial point of view, one of the simplest representatives of this compound class, 5,5-

dimethylhydantoin (DMH), is a key intermediate in the synthesis of several commodity

chemicals such as 1,3-dichloro-5,5-dimethylhydantoin, 1-bromo-3-chloro-5,5-

dimethylhydantoin and 1,3-dibromo-5,5-dimethylhydantoin. These N,N’-dihalogenated

analogues of DMH are widely used as biocides for e.g. water treatment [6]

and have also

shown high potential as halogenation agents or oxidants in organic synthesis.[7]

A plethora of synthetic strategies are known to construct the heterocyclic core

structure from a broad range of precursor molecules.[1,8]

Among those, the Bucherer-Bergs

reaction is presumably the most commonly used methodology to generate hydantoins from

aldehydes or ketones (Scheme 1).[1]

Mechanistically, the carbonyl compound initially reacts

with ammonia and the cyanide anion forming an α-aminonitrile.[1,9]

Nucleophilic addition of

this intermediate to CO2 generates a cyano-carbamic acid which undergoes a cyclization-

rearrangement sequence to finally result in the hydantoin scaffold. From a practical point of

view, the reaction is generally carried out by heating a mixture of the starting material,

potassium cyanide and ammonium carbonate −which thermally decomposes into ammonia

and carbon dioxide− in a mixture of water and ethanol at reflux for several hours or even

days.[1]

It has to be stressed that significant amounts of ammonia and carbon dioxide are lost

due to their volatility using traditional batch techniques. The highly polar reaction mixture can

cause severe solubility problems for certain substrates resulting in a rather inefficient

processes.[8c]

Moreover, heating an aqueous solutions of potassium cyanide poses severe

safety hazards especially on larger scales.

Scheme 1. Synthesis of hydantoins via the Bucherer-Bergs reaction.

Chapter F

160

We hypothesized that a continuous process using microreactor technology can potentially

overcome limitations associated with this multicomponent reaction.[10-12]

In continuous flow

mode reactions can be easily conducted without any headspace at high temperatures, while

working at high pressure conditions to keep the gaseous reagents in solution.[10]

Such “novel

process windows” enable intensified processes even far above the boiling point of the reaction

medium in a safe and scalable manner.[10,13]

Biphasic liquid/liquid reactions can be efficiently

carried out by generating a segmented flow pattern with significantly larger interfacial areas

compared to traditional batch techniques.[14]

Consequently, a modified Bucherer-Bergs

reaction in continuous flow utilizing an aqueous solution of KCN and (NH4)2CO3 in

combination with an organic solution of the carbonyl compound would result in a efficient

protocol even for highly unpolar starting materials which often suffer from low conversions in

the traditional batch protocol.


To confirm these assumptions, a two-feed setup was assembled utilizing high pressure syringe

pumps for both the organic (feed A) and the aqueous stream (feed B) in order to precisely

control reagent stoichiometry.[15]

The solutions were merged in a T-shaped mixing unit and

the combined stream then entered a heated Hastelloy coil (16 mL) to perform the

multicomponent hydantoin synthesis. The reaction mixture left the continuous flow system

through an adjustable stainless steel back pressure regulator. Acetophenone (1a) was chosen

as starting material for an initial process intensification study under continuous flow

conditions (Table 1). Since the liquid starting material can be easily pumped without the need

of any organic solvent, the neat ketone was first utilized for feed A (Entry 1). Unfortunately,

the resulting heterocycle (2a) precipitated inside the flow system resulting in reactor clogging.

Thus, various alcohols were tested for their applicability as suitable (co-)solvents (Entry 2-4).

By additionally heating the back pressure regulating unit to 100-120°C on a standard hot plate

blocking of the system could be avoided for all tested alcohols and promising conversions

were obtained. However, we realized that mixing of the two phases led to a poorly defined

flow pattern since the alcohol dissolved in the aqueous phase whereas the relatively unpolar

starting material travels slowly on the channel wall.[16]

Hence, different residence times for

the aqueous and the organic phase were observed making a precise control of reagent

stoichiometry impossible. Gratifyingly, by using ethyl acetate as organic solvent a well-

defined segmented flow pattern was obtained allowing for accurate processing of the reaction

mixture (Entry 5).[16]

Chapter F

161

Table 1. Optimization of the Bucherer-Bergs reaction in continuous flow.

Entry Solvent

(M)

Feed A/B

(µL min-1

)

tRes

[min]

KCN/(NH4)2CO3

(equiv.)

Conversion

(%)a

1 - 166 / 834 16 1.2 / 3.0 clogging

2b

EtOH (4) 166 / 834 16 1.2 / 3.0 90

3b

MeOH (4) 166 / 834 16 1.2 / 3.0 93

4b i-PrOH (4) 166 / 834 16 1.2 / 3.0 92

5 EtOAc (4) 166 / 834 16 1.2 / 3.0 72

6 EtOAc (4) 83 / 417 32 1.2 / 3.0 80

7c EtOAc (4) 83 / 417 32 1.2 / 3.0 55

8d EtOAc (4) 83 / 417 32 1.2 / 3.0 60

9 EtOAc (5) 83 / 417 32 1.2 / 3.0 88

10 EtOAc (5) 70 / 430 32 1.2 / 3.0 87

11 EtOAc (5) 70 / 430 32 1.5 / 3.5 96 (91)e

12 EtOAc (5) 70 / 490 29 1.5 / 4.0 95 aDetermined as HPLC peak area percent at 215 nm.

bAccurate control of the stoichiometry was

impossible due to an undefined flow pattern. cReaction was performed at 100°C.

dReaction was

performed at 140°C.eIsolated yield in parentheses.

Systematic optimization of the reaction parameters resulted in an almost quantitative

consumption of 1a within 32 min and excellent isolated yields were obtained for the

corresponding hydantoin 2a (Entry 5-11). Notably, under the final conditions a saturated

aqueous solution of KCN and (NH4)2CO3 was utilized resulting in a productivity of ~19 mmol

h-1

. A batch control experiment employing a dedicated 10 mL microwave autoclave resulted

in significantly lower conversions (~40%) using a 3.5 mL reaction volume under identical

conditions.[17-19]

This is presumably resulting from the lower interfacial area of the biphasic

mixture and the fact that a significant amount of (NH4)2CO3 sublimed at the top of the 10 mL

reaction vessel.[18]

Reduction of the headspace by using a larger reaction volume (7 mL) gave

even lower conversion (15%), likely due to inefficient stirring of the biphasic reaction

mixture.[18]

Utilization of an improved stir bar design which was recently developed in our

laboratories improved the hydantoin formation to 77% which is still significantly below the

performance of the continuous flow reactor (96%).[18,20]

Chapter F

162

Table 2. Scope of the continuous Bucherer-Bergs reaction.a

Entry Substrate Solvent c [M]b

Yield (%)c

1

EtOAc

5 91

2

EtOAc

5 72

3

EtOAc

5 90

4

EtOAc

5 78

5

EtOAc

5 95

6

EtOAc

( 5 88

7

EtOAc

3 92

8

EtOAc

2 99

9

DMF:EtOAc (2:1) 0.5 96

10

neat neat 82

aFlow reactions were performed using two independent pumps for the aqueous and organic feed.

All reactions were performed in a 16 mL Hastelloy coil. To avoid clogging the back pressure

regulator was heated to ~120 °C. cSubstrate concentration in feed A.

cIsolated yields.

Chapter F

163

Encouraged by these promising results, the applicability of the optimized protocol was further

tested to demonstrate the versatility of the continuous strategy (Table 2).[21]

Gratifyingly,

various aromatic and aliphatic carbonyl compounds could be processed without the need for

any re-optimization and the desired hydantoins were obtained in good to excellent isolated

yields (Entry 1-6). In case of 3-methoxybenzaldehyde (1h), the low solubility of the resulting

heterocycle required a less concentrated organic feed to avoid clogging of the reactor (Entry

7). The same issue necessitated even lower concentrations or a different solvent system for

the synthesis of spirohydantoins 2i and 2j in almost quantitative yields (Entry 8-9). In

contrast, for the industrially relevant hydantoin DMH (2k) no organic solvent was required

resulting in an efficient, gram-scale continuous flow process (Entry 10). It has to be pointed

out that no segmented flow pattern was observed in this case since the starting material,

acetone (1k), was completely soluble in the aqueous reagent mixture.[16]

However, a

quantitative multicomponent reaction was observed and DMH (2k) could be isolated in 60 %

by crystallization from the reaction mixture which is in good agreement with data reported in

the literature.[22]

By carefully extracting the mother liquor multiple times with EtOAc the

yield could be further increased to 82 % resulting in a productivity of 20 mmol h-1

.

Noteworthy, it was recently reported that hydantoins can possibly be applied to treat

neurodegenerative disorders such as Alzheimer’s or Parkinsons’s disease, by inhibition of

acetylcholinesterase enzyme (AChE), which is mainly responsible for regulation of the

neurotransmitter acetylcholine (ACh).[23]

In this context, preliminary unpublished results from

our laboratories, employing an immobilized acetylcholinesterase capillary reactor,[24]

indicated that the heterocyclic compounds 2a and 2k show moderate activity for the inhibition

of AChE. We hypothesized that installing an aliphatic tertiary amine group mimicking the

ACh scaffold increases the affinity to AChE, simultaneously improving their biological

activity (Scheme 2). Similar structural motifs were already demonstrated to exhibit significant

antimicrobiological activity.[25]

Scheme 2. Structural modification of hydantoins to mimic acetylcholine (ACh).

Chapter F

164

Initial experiments using (2-bromoethyl)trimethylammonium bromide (n=2) suffered from

extremely low conversions presumably due to steric hindrance of the brominated carbon

atom.[25]

However, by using (5-bromopentyl)trimethylammonium bromide (3, n=5) satisfying

conversions were determined by HPLC analysis.[26]

A subsequent optimization study with the

aid of microwave dielectric heating technology utilizing a dedicated batch reactor, resulted in

an efficient, selective N(3)-monoalkylation of hydantoins 2a-k (Scheme 3).[17,27]

Scheme 3. Synthesis of N(3)-substituted hydantoins in batch. aAn insoluble material was

obtained. bReaction resulted in a complex mixture.

Chapter F

165

Depending on the starting material 10-45 min at 120°C in acetonitrile were sufficient to

synthesize several hitherto undisclosed hydantoins (4a, 4c-f, 4i-k) using 1.2 equiv. of 3 and

1.1 equiv. of K2CO3 as base. In case of 2g, a complex reaction mixture was observed and the

corresponding ammonium salt (4g) could not be isolated. For the structurally similar

hydantoins 4b and 4h an insoluble white solid was obtained which could not be characterized

by NMR analysis.

3. Conclusion

In conclusion, a highly intensified continuous variant of the Bucherer-Bergs hydantoin

synthesis was developed. Key to the success was the utilization of a well-defined segmented

flow pattern to overcome solubility issues for unpolar starting materials and to significantly

increase the interfacial areas compared to traditional batch techniques. The lack of gaseous

headspace under high pressure conditions avoids sublimation/volatilization of the in situ

generated gaseous reagents (NH3, CO2). In addition, a microwave batch protocol for the

selective N(3)-monoalkylation of the resulting hydantoin scaffolds is presented resulting in a

series of potential acetylcholinesterase inhibitors. The biological activity of the final N-

substituted hydantoins is currently under investigation in our laboratories.

4. References

[1] (a) M. Meusel, M. Gütschow, Org. Prep. Proc. Int. 2004, 36, 391; (b) E. Ware, Chem.

Rev. 1950, 46, 403.

[2] (a) F. Nique, S. Hebbe, C. Peixoto, D. Annoot, J.-M. Lefrancois, E. Duval, L.

Michoux, N. Triballeau, J.-M. Lemoullec, P. Mollat, M. Thauvin, T. Prange, D.

Minet, P. Clement-Lacroix, C. Robin-Jagerschmidt, D. Fleury, D. Guedin, P.

Deprez, J. Med. Chem. 2012, 55, 8225; (b) F. Nique, S. Hebbe, N. Triballeau, C.

Peixoto, J.-M. Lefrancois, H. Jary, L. Alvey, M. Manioc, C. Housseman, H.

Klaassen, B. K. Van, D. Guedin, F. Namour, D. Minet, d. A. E. Van, J. Feyen, S.

Fletcher, R. Blanque, C. Robin-Jagerschmidt, P. Deprez, J. Med.

Chem. 2012, 55, 8236.

[3] (a) M. Dhanawat, A. G. Banerjee, Med. Chem. Res. 2012, 21, 2807. (b) J. C.

Thenmozhiyal, P. T.-H. Wong, W.-K. Chui, J. Med. Chem. 2004, 47, 1527.

Chapter F

166

[4] Z. Iqbal, S. Ali, J. Iqbal, Q. Abbas, I. Z. Qureshi, S. Hameed, Bioorg. Med. Chem.

Lett. 2013, 23, 488.

[5] (a) A. A. Sallam, M. M. Mohyeldin, A. I. Foudah, M. R. Akl, S. Nazzal, S. A. Meyer,

Y.-Y. Liu, K. A. El Sayed, Org. Biomol. Chem. 2014, 12, 5295; (b) M.

Azizmohammadi, M. Khoobi, A. Ramazani, S. Emami, A. Zarrin, O. Firuzi, R. Miri,

A. Shafiee, Eur. J. Med. Chem. 2013, 59, 15.

[6] Y. Ura, G. Sakata, “Chloroamines”, Ullmann’s Enzyclopedia of Industrial Chemistry,

Wiley-VCH, Weinheim, 2000.

[7] For selected examples, see: (a) Z. Xu, D. Zhang, X. Zou, Synth. Commun. 2006, 36,

255; (b) D. M. Barnes, A. C. Christesen, K. M. Engstrom, A. R. Haight, M. C. Hsu, E.

C. Lee, M. J. Peterson, D. J. Plata, P. S. Raje, E. J. Stoner, J. S. Tedrow, S. Wagaw,

Org. Process Res. Dev. 2006, 10, 803; (c) G. Hernández-Torres, B. Tan, C. F. Barbas

III, Org. Lett. 2012, 14, 1858; (d) T. Maegawa, Y. Koutani, K. Otake, H. Fujioka, J.

Org. Chem. 2013, 78, 3384.

[8] For recent, illustrative examples, see: (a) L. Konnert, B. Reneaud, R. M. de

Figueiredo, J.-M. Campagne, F. Lamaty, J. Martinez, E. Colacino, J. Org. Chem.

2014, 79, 10132; (b) M. C. Hillier, H.-H. Gong, D. S. Clyne, M. J. Babcock,

Tetrahedron 2014, 70, 9413. (c) J. Safari, L. Javadian, RSC Adv. 2014, 4, 48973; (d) S.

Gore, K. Chinthapally, S. Baskaran, B. König, Chem. Commun. 2013, 49, 5052; (e) M.

Gao. Y. Yang. Y.-D. Wu, C. Deng, W.-M. Shu, D.-X. Zhang, L.-P. Cao, N.-F. She,

A.-X. Wu, Org. Lett. 2010, 12, 4026; (f) S. M. Dumbris, D. J. Díaz, L. McElwee-

White, J. Org. Chem. 2009, 74, 8862; (g) B. Zhao, H. Du, Y. Shi, J. Am. Chem. Soc.

2008, 130, 7220; (h) R. G. Murray, D. M. Whitehead, F. Le Strat, S. J. Conway, Org.

Biomol. Chem. 2008, 6, 988; (i) D. Zhang, X. Xing, G. D. Cuny, J. Org. Chem. 2006,

71, 1750. (j) C. Montagne, M. Shipman, Synlett 2006, 14, 2203.

[9] F. L. Chubb, J. T. Edward, S. C. Wong, J. Org. Chem. 1980, 45, 2315.

[10] For recent reviews on flow chemistry, see: (a) B. Gutmann, D. Cantillo, C. O. Kappe,

Angew. Chem. Int. Ed. 2015, 54, 6688; (b) K. F. Jensen, B. J. Reizmana, S. G.

Newman, Lab Chip 2014, 14, 3206; (c) C. Wiles, P. Watts, Green Chem. 2014, 16, 55;

(d) S. G. Newman, K. F. Jensen, Green Chem. 2013, 15, 1456; (e) I. R. Baxendale, L.

Brocken, C. J. Mallia, Green Proc. Synth. 2013, 2, 211; (f) D. T. McQuade, P. H.

Seeberger, J. Org. Chem. 2013, 78, 6384; (g) J. C. Pastre, D. L. Browne, S. V. Ley,

Chem. Soc. Rev. 2013, 42, 8849.

Chapter F

167

[11] For selected examples of multicomponent reactions in flow, see: (a) C. E. M.

Salvador, B. Pieber, P. M. Neu, A. Torvisco, C. K. Z. Andrade, C. O. Kappe, J. Org.

Chem. 2015, 80, 4590; (b) G. C. O. Silva, J. R. Correa, M. O. Rodrigues, H. G. O.

Alvim, B. C. Guido, C. C. Gatto, K. A. Wanderley, M. Fioramonte, F. C. Gozzo, R. O.

M. A. de Souza, B. A. D. Neto, RSC Adv. 2015, 5, 48506; (c) S. Sharma, R. A.

Maurya, K.-I. Min, G.-Y. Jeong, D.-P. Kim, Angew. Chem. Int. Ed. 2013, 52, 7564;

(d) N. Pagano, A. Herath, N. D. P. Cosford, J. Flow Chem. 2011, 1, 28; (e) M.

Baumann, I. R. Baxendale, A. Kirschning, S. V. Ley, Wegner, J. Heterocycles, 2011,

82, 1297; (f) A. Herath, N. D. P. Cosford, Org. Lett. 2010, 12, 5182.

[12] For continuous flow reactions involving cyanides, see: (a) T. S. A. Heugebaert, B. I.

Roman, A. De Blieck, C. V. Stevens, Tetrahedron Lett. 2010, 51, 4189; (b) C. Wiles,

P. Watts, Eur. J. Org. Chem. 2008, 5597; (c) C. Wiles, P. Watts, Org. Process Res.

Dev. 2008, 12, 1001; (d) D. R. J. Acke, C. V. Stevens, Green Chem. 2007, 9, 386.

[13] V. Hessel, D. Kralisch, N. Kockmann, T. Noel, Q. Wang, ChemSusChem, 2013, 6,

746.

[14] For selected examples of biphasic liquid/liquid reactions in flow, see: (a) F. E. A. Van

Waes, S. Seghers, W. Dermaut, B. Cappuyns, C. V. Stevens, J. Flow Chem. 2014, 4,

118; (b) M. Damm, B. Gutmann, C. O. Kappe, ChemSusChem, 2013, 6, 978; (c) H.

Mehenni, L. Sinatra, R. Mahfouz, K. Katsiev, O. M. Bakr, RSC Adv. 2013, 3, 22397;

(d) B. Reichart, C. O. Kappe, T. Glasnov, Synlett, 2013, 24, 2393.

[15] For details about the continuous flow setup, see the Supporting Information.

[16] The flow regimes were monitored in a transparent perfluoroalkoxy tubing between the

mixing unit and the Hastelloy coil.

[17] For a recent discussion on microwave assisted organic synthesis, see: C. O. Kappe, B.

Pieber, D. Dallinger, Angew. Chem. Int. Ed. 2013, 52, 1088; and references therein.

[18] For details, see Table S1 and Figure S2 in the Supporting Information.

[19] In many cases microwave chemistry examples can be directly translated to continuous

flow applications: T. N. Glasnov, C. O. Kappe, Chem. Eur. J. 2011, 17, 11956.

[20] D. Obermayer, M. Damm, C. O. Kappe, Org. Biomol. Chem. 2013, 11, 4949.

[21] General Experimental Procedure for the Continuous Bucherer Bergs reaction:

Feed A consisting of the carbonyl compound (1a-k) dissolved in ethyl acetate was

pumped with a flow rate of 70 μL min–1

and merged in a T-shaped mixing unit with a

second feed (430 µL min-1

) containing an aqueous solution of ammonium carbonate

(3.5 equiv.) and potassium cyanide (1.5 equiv.). The combined mixture was passed

Chapter F

168

through a coil reactor made out of Hastelloy (16 mL internal volume, 32 min residence

time) at 120°C and 20 bar back pressure. To avoid precipitation of the corresponding

hydantoin, the back pressure regulating unit was heated to 120 °C. The reaction

mixture was collected in a sealed flask and subsequently acidified with concentrated

hydrochloric acid. Work-up by extraction with EtOAc or crystallization afforded the

respective hydantoins (2a-k) in analytical purity.

[22] The solubility of DMDH in water causes relatively low isolated yields and recovery

rates: E. C. Wagner, M. Baizer, Org. Synth. 1940, 20, 42.

[23] (a) M. A. Khanfar, B. A. Asal, M. Mudit, A. Kaddoumi, K. A. El Sayed, Biorg. Med.

Chem. 2009, 17, 6032; (b) G. S. Hamilton, US 20020058685, 2002.

[24] K. Vanzolini, L. C. C. Vieira, C. L. Cardoso, A. G. Correa, Q. B. Cass, J. Med. Chem.

2013, 56, 2038.

[25] R. K. Jain, E. Low, C. Francavilla, T. P. Shiau, B. Kim, S. K. Nair, WO 2010054009,

2010.

[26] Very recently, a similar observation was reported for the N-alkylation of Riboflavin

derivatives: A. V. Silva, A. López-Sánchez, H. C. Junqueira, L. Rivas, M. S. Baptista,

G. Orellana, Tetrahedron, 2015, 71, 457.

[27] General Experimental Procedure for the selective N(3)-monoalkylation of

hydantoins: A sealed 10 mL microwave process vial containing a mixture of the

respective hydantoin (0.5 mmol-1.0 mmol), potassium carbonate (1.1 equiv.), and (5-

bromopenthyl)trimethylammonium bromide (1.2 equiv.) in 2 mL MeCN was heated

for 10-45 min at 120 °C using a single mode microwave reactor. After cooling to room

temperature, the reaction mixture was concentrated. The organic material was

dissolved in acetonitrile and the inorganic salts were separated by filtration.

Evaporation of the solvent resulted in a solid material which was carefully washed

with cold ethanol before drying affording the respective N-substituted hydantoins (4a-

k) in analytical purity.

Chapter F

169


General Remarks. All compounds and solvents were obtained from standard commercial

vendors and used without further purification. 1H-NMR and

13C spectra were recorded on a

300 MHz instrument using D2O or DMSO-d6 as solvent. Chemical shifts (δ) are expressed in

ppm downfield from TMS as internal standard. The letters s, d, t, q, qt and m are used to

indicate a singlet, doublet, triplet, quadruplet, quintuplet and multiplet, respectively. Melting

points were determined on a standard melting point apparatus. Analytical HPLC analysis was

carried out on a C-18 reversed-phase (RP) analytical column (150 × 4.6 mm, particle size 5

μm) at 37 °C using a mobile phase A (water/acetonitrile 90:10 (v/v) + 0.1 % TFA) and B

(MeCN + 0.1 % TFA) at a flow rate of 1.0 mL min-1

. The following gradient was applied:

linear increase from solution 30% B to 100% B in 8 min, hold at 100% solution B for 2 min.

For new compounds, HRMS experiments were performed on a TOF LC/MS instrument

equipped with an APCI ion source (positive ionization mode).

Continuous Flow Experiments. For continuous flow experiments, two high pressure syringe

pumps (SyrDosTM

, HiTec Zang), a sample loop (0.5 or 3 mL) and a Hastelloy tube reactor (16

mL) mounted on a dedicated heating module were used (Asia Flow Chemistry modules,

Syrris). The back pressure was controlled using an adjustable regulation unit (Swagelok)

placed on a standard hotplate set at 120°C. A detailed experimental setup is shown in Figure

S1.

Figure S1. Detailed Description of the 2-feed continuous flow reactor for continuous

hydantoin synthesis.

Chapter F

170

Microwave Autoclave Experiments. All experiments were carried out in a Monowave 300

single-mode microwave reactor using 10 mL Pyrex vessels (Anton Paar GmbH). The

reaction temperature was monitored by an external infrared sensor (IR) housed in the side-

walls of the microwave cavity measuring the surface temperature of the reaction vessel.

Table S1. Comparison of the Bucherer-Bergs hydantoin synthesis under batch and continuous

flow conditions.

Entry Condition Conversion (%)a

A Microwave Batch, 3.5 mL 39

B Microwave Batch, 7 mL 15

C Microwave Batch, 7mL, improved stir barS1

77

D Continuous Flow 96 aDetermined as HPLC-UV/VIS peak area percent at 215nmm

Figure S2. Picture of the reaction mixtures after heating at 120°C for 32 minutes in batch.

Chapter F

171

General Experimental Procedure for the Continuous Synthesis of Hydantoins (Table 2,

2a-2i). Feed A consisting of the carbonyl compound dissolved in ethyl acetate was pumped

with a flow rate of 70 μL min–1

and merged in a T-shaped mixing unit with a second feed

(430 µL min-1

) containing an aqueous solution of ammonium carbonate (3.5 equiv.) and

potassium cyanide (1.5 equiv.). The combined mixture was passed through a coil reactor

made out of Hastelloy (16 mL internal volume, 32 min residence time) at 120°C and 20 bar

back pressure. To avoid precipitation of the corresponding hydantoin, the back pressure

regulating unit was heated to 120 °C. The reaction mixture was collected in a sealed flask and

subsequently acidified with concentrated hydrochloric acid. Work-up by extraction with

EtOAc or crystallization afforded the respective hydantoins in analytical purity.

5-Methyl-5-phenylimidazolidine-2,4-dione (Table 2, 2a). Feed A: acetophenone (2.53 mmol,

5.0 M in EtOAc). Feed B: KCN (1.24 M), (NH4)2CO3 (2.88 M) in H2O. Isolation by

extraction afforded the title compound in 91 % yield (440 mg, 2.31 mmol) as a colorless

solid. Mp: 197-199 oC (lit.

S2 196-198 °C).

1H NMR (300 MHz, DMSO) δ 10.77 (s, 1H), 8.62

(s, 1H), 7.48 (m, 2H), 7.36 (m, 3H), 1.66 (s, 3H); 13


156.69, 140.37, 128.93, 128.26, 125.77, 64.35, 25.39.

5-Phenyl-imidazolidine-2,4-dione (Table 2, 2b). Feed A: benzaldehyde (2.51 mmol, 5.0 M in

EtOAc). Feed B: KCN (1.24 M), (NH4)2CO3 (2.88 M) in H2O. Isolation by extraction

afforded the title compound in 91 % yield (401 mg, 2.28 mmol) as colorless solid. Mp: 180-

183 oC (lit.

S2 176-178 °C).

1H NMR (300 MHz, DMSO) δ 10.79 (s, 1H), 8.41 (s, 1H), 7.38

(m, 5H), 5.16 (s, 1H); 13

C NMR (75 MHz, DMSO) δ 174.65, 157.95, 136.50, 129.11, 128.70,

127.15, 61.64.

5-Benzyl-imidazolidine-2,4-dione (Table 2, 2c). Feed A: phenylacetaldehyde (2.52 mmol,


extraction afforded the title compound in 72 % yield (346 mg, 1.82 mmol) as yellow solid.

Mp: 186-188 o

C (lit.S3

181-183 °C). 1

H NMR (300 MHz, DMSO) δ 10.43 (s, 1H), 7.92 (s,

1H), 7.25 (m, 5H), 4.33 (t, J = 4.6 Hz, 1H), 3.93 (m, 2H); 13


175.63, 157.56, 136.07, 130.18, 128.52, 127.10, 58.84, 36.86.

Chapter F

172

5-Ethyl-5-phenylimidazolidine-2,4-dione (Table 2, 2d). Feed A: propiophenone (2.48 mmol,


extraction afforded the title compound in 90 % yield (455 mg, 2.23 mmol) as a colorless

solid. Mp: 193-195 o

C (lit.S2

194-196 °C). 1H NMR (300 MHz, DMSO) δ 10.80 (s, 1H), 8.62

(s, 1H), 7,50 (m, 2H), 7.35 (m, 3H), 2.07 (dq, J = 7.2, 14.4 Hz, 1H), 1.89 (dq, J = 7.4, 14.7,

Hz, 1H), 0.81 (t, J = 7.3 Hz, 3H); 13

C NMR (75 MHz, DMSO) δ 176.96, 176.96, 157.43,

139.62, 128.85, 128.15, 125.85, 68.46, 31.61, 8.50.

5-(4-Fluoro-phenyl)-5-methyl-imidazolidine-2,4-dione (Table 2, 2e). Feed A: 4-

fluoroacetophenone (2.47 mmol, 5.0 M in EtOAc). Feed B: KCN (1.24 M), (NH4)2CO3 (2.88

M) in H2O. Isolation by crystallization afforded the title compound in 78 % yield (400 mg,

1.92 mmol) as yellow solid. Mp: 209-210 o

C (lit.S4

212-215 °C). 1H NMR (300 MHz,

DMSO) δ 10.80 (s, 1H), 8.64 (s, 1H), 7.51 (m, 2H), 7.23 (t, J = 8.9 Hz, 2H), 1.64 (s, 3H); 13

C

NMR (75 MHz, DMSO) δ 177.29, 163.76, 160.53, 156.59, 136.62, 136.58, 128.02, 127.91,

115.83, 115.55, 63.96, 25.64.

5-(2-Hydroxy-phenyl)-5-methyl-imidazolidine-2,4-dione (Table 2, 2f). Feed A: 2´-

hydroxyacetophenone (2.54 mmol, 5.0 M in EtOAc). Feed B: KCN (1.24 M), (NH4)2CO3

(2.88 M) in H2O. Isolation by extraction afforded the title compound in 95 % yield (500 mg,

2.42 mmol) as a yellow solid. Mp: 232-234 o

C (lit.S5

229-230 °C). 1H NMR (300 MHz,

DMSO) δ 10.52 (s, 1H), 9.84 (s, 1H), 7.88 (s, 1H), 7.31 (dd, J = 1.4, 7.7 Hz, 1H), 7.17 (td, J =

1.6, 7.7 Hz, 1H), 6.80 (m, 2H), 1.63 (s, 3H); 13

C NMR (75 MHz, DMSO) δ 178.99, 157.32,

156.13, 129.83, 128.00, 125.49, 118.94, 116.11, 62.13, 24.15. HRMS (APCI): m/z: calcd for

C10H10N2O3 [(M+H)]+: 207,076419, found: 207,076455.

5-Methyl-5-[4]pyridyl-imidazolidine-2,4-dione (Table 2, 2g). Feed A: 4-acetylpyridine (2.53

mmol, 5.0 M in EtOAc). Feed B: KCN (1.24 M), (NH4)2CO3 (2.88 M) in H2O. Isolation by

extraction afforded the title compound in 88 % yield (428 mg, 2.24 mmol) as colorless solid.

Mp: 232-234 oC (lit.

S6 234-235 °C).

1H NMR (300 MHz, DMSO) δ 10.93 (s, 1H), 8.73 (s,

1H), 8.60 (dd, J = 1.6, 4.5 Hz, 2H), 7.48 (dd, J = 1.7, 4.5 Hz, 2H), 1.66 (s, 3H). 13

C NMR (75

MHz, DMSO) δ 176.31, 156.58, 150.37, 148.92, 120.89, 63.90, 25.13. HRMS (APCI): m/z:

calcd for C9H9N3O2 [(M+H)]+: 192.076753, found: 192.076861.

Chapter F

173

5-(3-Methoxyphenyl)-imidazolidine-2,4-dione (Table 2, 2h). Feed A: m-anisaldehyde (1.52

mmol, 3.0 M in EtOAc). Feed B: KCN (0.74 M), (NH4)2CO3 (1.73 M) in H2O. Isolation by

extraction afforded the title compound in 92 % yield (287 mg, 1.40 mmol) as yellow solid.

Mp: 129-131 o

C. 1H NMR (300 MHz, DMSO) δ 10.77 (s, 1H), 8.41 (s, 1H), 7.32 (t, J = 7.9

Hz, 1H), 6.91 (m, 3H), 3.76 (s, 3H); 13

C NMR (75 MHz, DMSO) δ 174.44, 159.85, 157.93,


C10H10N2O3 [(M+H)]+: 207.076419, found: 207.076566.

1,3-Diazaspiro [4,5] decane-2,4-dione (Table 2, 2i). Feed A: cyclohexanone (1.01 mmol, 2.0

M in EtOAc). Feed B: KCN (0.49 M), (NH4)2CO3 (1.15 M) in H2O. Isolation by

crystallization afforded the title compound in 99 % yield (168 mg, 0.99 mmol) as a colorles


C (lit.S8

220 °C). 1H NMR (300 MHz, DMSO) δ 10.51 (s, 1H), 8.39 (s,

1H), 1.54 (m, 8H), 1.25 (m, 1H); 13

C NMR (75 MHz, DMSO) δ 178.95, 156.78, 62.46, 33.68,

24.91, 21.28.

Continuous Flow Synthesis of Spiro(hydantoin-5,2’-tetraline (Table 2, 2j). Feed A

consisting of β-tetralone (1.47 mmol, 0.5 M, 3.0 mL sample loop) dissolved in EtOAc/DMF

(1:2) was pumped with a flow rate of 200 μL min–1

and merged in a T-shaped mixing unit

with a second feed with an flow rate of 300 µL min-1

containing an aqueous solution of

ammonium carbonate (1.14 M, 3.5 equiv.) and potassium cyanide (0.49 M, 1.5 equiv.). The

combined mixture was passed through a coil reactor made out of Hastelloy (16 mL internal

volume, 32 min residence time) at 120oC and 20 bar back pressure. To avoid precipitation of

the corresponding hydantoin, the back pressure regulating unit was heated to 120 °C as well.

The product was collected in a sealed flask. Work-up by crystallization afforded the title

compound in 96 % yield (304 mg, 1.40 mmol) as colorless solid. Mp: 258-260 oC (lit.

S9 267

°C). 1H NMR (300 MHz, DMSO) δ 10.71 (s, 1H), 8.32 (s, 1H), 7.10 (m, 4H), 3.11 (d, J =

16.9 Hz, 1H), 2.91 (dd, J = 5.9, 10.5 Hz, 2H), 2.77 (d, J = 17.0 Hz, 1H), 2.91 (m, 1H), 1.95

(m, 1H), 1.81 (m, 1H); 13

C NMR (75 MHz, DMSO) δ 178.65, 156.77, 135.30, 133.06,

129.42, 129.03, 126.41, 126.32, 61.18, 37.28, 30.49, 25.16.

Chapter F

174

Continuous Flow Synthesis of 5,5-Dimethyl-2,4-imidazolidinedione (Table 2, 2k). Feed A

consisting of acetone (40.8 mmol, 3.0 mL) was pumped with a flow rate of 30 μL min–1

and

merged in a T-shaped mixing unit with a second feed with a flow rate of 470 µL min-1

containing an aqueous solution of ammonium carbonate (3.0 M, 3.5 equiv.) and potassium

cyanide (1.30 M, 1.5 equiv.). The combined mixture was passed through a coil reactor made

out of Hastelloy (16 mL internal volume, 32 min residence time) at 120oC and 20 bar back

pressure. To avoid precipitation of the corresponding hydantoin, the back pressure regulating

unit was heated to 120 °C as well. The product was collected in a sealed flask. After remained

collection was finished, the solvent was removed and the product was crystalized. The

aqueous face was concentrated and extracted with EtOAc (2x 3 times) afforded the respective

hydantoin in 82 % yield (4.31 g, 33.6 mmol) as a colorless solid. Mp: 170-172 oC (lit.

S10 171-

172 °C). 1H NMR (300 MHz, DMSO) δ 7.87 (s, 1H), 1.24 (s, 6H);

13C NMR (75 MHz,

DMSO) δ 180.20, 157.15, 59.27, 25.11.

General Experimental Procedure for the Selective N(3)-Monoalkylation of Hydantoins

(Scheme 2). A sealed 10 mL microwave process vial containing a mixture of the respective

hydantoin (2a-j, 0.5 mmol; 2k, 1.0 mmol), potassium carbonate (1.1 equiv.), and (5-

bromopenthyl)trimethylammonium bromide (1.2 equiv.) in 2 mL MeCN was heated for 10-45

min at 120 °C using a single mode microwave reactor. After cooling to room temperature, the

reaction mixture was concentrated. The organic material was dissolved in acetonitrile and the

inorganic salts were separated by filtration. Evaporation of the solvent resulted in a solid

material which was carefully washed with cold ethanol before drying affording the respective

N-substituted hydantoins in analytical purity.

5-(4-methyl-2,5-dioxo-4-phenylimidazolidin-1-yl)-N,N,N-trimethylpentan-1-aminium

bromide (Scheme 3, 4a): Reaction time: 10 min. Yield: 66 % (130 mg, 0.33 mmol) as white


C. 1H NMR (300 MHz, DMSO) δ 8.90 (s, 1H), 7.40 (m, 5H), 3.37 (m,

4H), 3.22 (m, 2H), 3.02 (s, 9H), 1.68 (s, 3H), 1.55 (m, 2H), 1.20 (m, 2H). 13

C NMR (75 MHz,

DMSO) δ 175.85, 156.11, 140.06, 133.97, 129.05, 128.43, 125.81, 65.46, 63.14, 52.60, 52.56,

52.52, 37.94, 27.54, 25.40, 23.42, 22.03. HRMS (APCI): m/z: calcd for C18H28N3O2+ [(M-Br

-

)]+: 318.217604, found: 318.217459.

Chapter F

175

5-(4-benzyl-2,5-dioxoimidazolidin-1-yl)-N,N,N-trimethylpentan-1-aminium bromide

(Scheme 3, 4c): Reaction time: 45 min. Yield: 48 % (95.2 mg, 0.24 mmol) as white solid.

Mp: 197-199 o

C. 1H NMR (300 MHz, D2O) δ 7.23 (m, 3H), 7.12 (dd, J = 1.9, 7.5 Hz, 2H),

4.43 (t, J = 4.3 Hz, 1H), 3.23 (dt, J = 6.2, 14.0 Hz, 1H), 3.11 (dd, J = 6.5, 7.6 Hz, 1H), 3.05

(d, J = 4.2 Hz, 2H), 3.01 (d, J = 3.5 Hz, 2H), 2.98 (s, 9H), 1.49 (m, 2H), 1.09 (m, 2H), 0.62

(m, 2H). 13

C NMR (75 MHz, D2O) δ 176.45, 158.83, 134.03, 130.01, 128.42, 127.30, 66.26,

57.71, 52.77, 52.72, 52.67, 37.60, 35.63, 26.38, 22.09, 21.60. HRMS (APCI): m/z: calcd for

C18H28N3O2+ [(M-Br

-)]

+: 318.217604, found: 318.217337.

5-(4-ethyl-2,5-dioxo-4-phenylimidazolidin-1-yl)-N,N,N-trimethylpentan-1-aminium

bromide (Scheme 3, 4d): Reaction time: 30 min. Yield: 82 % (170 mg, 0.41 mmol). Mp. 230-

232 oC.

1H NMR (300 MHz, D2O) δ 7.39 (m, 5H), 3.43 (td, J = 2.6, 6.7 Hz, 2H), 3.05 (dd, J =

8.5, 17.3 Hz, 2H), 2.93 (s, 9H), 2.20 (dq, J = 7.3, 14.5 Hz, 1H), 2.05 (dq, J = 7.4, 14.7 Hz,

1H), 1.58 (m, 4H), 1.13 (m, 2H), 0.78 (t, J = 7.4 Hz, 3H). 13

C NMR (75 MHz, D2O) δ 177.83,

158.47, 137.24, 129.11, 128.77, 125.40, 68.15, 66.25, 52.74, 52.69, 52.64, 37.96, 29.88,

26.49, 22.48, 21.54, 7.16. HRMS (APCI): m/z: calcd for C19H30N3O2+ [(M-Br

-)]

+:

332.233254, found: 332.233085.

5-(4-(4-fluorophenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)-N,N,N-trimethylpentan-1-

aminium bromide (Scheme 3, 4e): Reaction time: 45 min. Yield: 52 % (109 mg, 0.26 mmol)

as white solid. Mp: 223-225 o

C. 1H NMR (300 MHz, D2O) δ 7.41(m, 2H), 7.08 (m, 2H), 3.42

(td, J = 2.3, 6.8 Hz, 2H), 3.09 (m, 2H), 2.95 (s, 9H), 1.71 (s, 3H), 1.65 (m, 2H), 1.54 (m, 2H),

1.14 (m, 2H). 13

C NMR (75 MHz, D2O) δ 178.42, 164.14, 160.89, 157.95, 133.84, 133.80,

127.45, 127.34, 115.89, 115.60, 66.23, 63.43, 52.75, 52.70, 52.65, 38.00, 26.51, 22.97, 22.46,

21.58. HRMS (APCI): m/z: calcd for C18H27FN3O2+ [(M-Br

-)]

+: 336.208182, found:

336.208143.

5-(4-(2-hydroxyphenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)-N,N,N-trimethylpentan-1-

aminium bromide (Scheme 3, 4f): Reaction time: 30 min. Yield: 65 % (134 mg, 0.32 mmol)

as white solid. Mp: 265 oC (decomp.).

1H NMR (300 MHz, D2O) δ 7.40 (d, J = 7.6 Hz, 1H),

7.24 (t, J = 7.6 Hz, 1H), 6.91 (t, J = 7.5 Hz, 1H), 6.81 (d, J = 7.9 Hz, 1H), 3.49 (m, 2H), 3.20

(m, 2H), 3.00 (s, 9H), 1.78 (m, 2H), 1.71 (s, 3H), 1.61 (m, 2H), 1.32 (m, 2H). 13

C NMR (75

MHz, D2O) δ 180.93, 158.71, 154.48, 130.85, 128.07, 123.35, 120.24, 116.23, 66.39, 61.52,


C18H28N3O3+ [(M-Br

-)]

+: 334.212518, found: 334.212404.

Chapter F

176

5-(2,4-dioxo-1,3-diazaspiro[4.5]decan-3-yl)-N,N,N-trimethylpentan-1-aminium bromide

(Scheme 3, 4i): Reaction time: 30 min. Yield: 58 % (110 mg, 0.29 mmol) as white solid. Mp:

150-152 oC.

1H NMR (300 MHz, D2O) δ 3.40 (t, J = 6.9 Hz, 2H), 3.19 (m, 2H), 3.00 (s, 9H),

1.68 (m, 11H), 1.27 (m, 5H). 13

C NMR (75 MHz, D2O) δ 180.38, 158.03, 66.28, 62.50, 52.79,

52.74, 52.69, 37.73, 32.55, 26.63, 23.89, 22.49, 21.69, 20.94. HRMS (APCI): m/z: calcd for

C16H30N3O2+ [(M-Br

-)]

+: 296.233254, found: 296.233369.

5-(2,5-dioxo-3',4'-dihydro-2'H-spiro[imidazolidine-4,1'-naphthalen]-1-yl)-N,N,N-

trimethylpentan-1-aminium bromide (Scheme 3, 4j): Reaction time: 45 min. Yield: 40 %

(83.6 mg, 0.20 mmol) as white solid. Mp: 181-183 o

C. 1

H NMR (300 MHz, D2O) δ 7.12 (m,

3H), 7.07 (t, J = 5.9 Hz, 1H), 3.44 (t, J = 6.9 Hz, 2H), 3.21 (m, 2H), 3.14 (d, J = 16.4 Hz, 1H),

3.00 (s, 9H), 2.90 (m, 2H), 2.77 (d, J = 16.3 Hz, 1H), 2.03 (m, 1H), 1.87 (m, 1H), 1.73 (m,

2H), 1.59 (m, 2H), 1.26 (m, 2H). 13

C NMR (75 MHz, D2O) δ 179.48, 158.11, 134.59, 131.90,

129.25, 128.77, 126.73, 126.31, 66.37, 60.96, 52.80, 52.74, 52.69, 37.89, 36.21, 29.49, 26.68,

24.49, 22.55, 21.70. HRMS (APCI): m/z: calcd for C20H30N3O2+ [(M-Br

-)]

+: 344.233254,

found: 344.233240.

5-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)-N,N,N-trimethylpentan-1-aminium bromide

(Scheme 3, 4k): Reaction time: 45 min. Yield: 58 % (195 mg, 0.58 mmol) as white solid. Mp:

198-200 oC.

1H NMR (300 MHz, D2O) δ 3.40 (t, J = 6.9 Hz, 2H), 3.20 (m, 2H), 3.00 (s, 9H),

1.73 (m, 2H), 1.57 (m, 2H), 1.30 (s, 6H), 1.23 (m, 2H). 13

C NMR (75 MHz, D2O) δ 181.01,

157.68, 66.35, 59.03, 52.83, 52.78, 52.72, 37.88, 26.66, 23.37, 22.53, 21.73. HRMS (APCI):

m/z: calcd for C13H26N3O2+ [(M-Br

-)]

+: 256.201954, found: 256.201924.

Chapter F

177

References

[S1] D. Obermayer, M. Damm, C. O. Kappe, Org. Biomol. Chem. 2013, 11, 4949.

[S2] R. G. Murray, D. M. Whitehead, F. Le Strat, S. J. Conway, Org. Biomol. Chem. 2008,

6, 988.

[S3]

(a) L. Konnert, B. Reneaud, R. M. Figueiredo, J. Campagne, F. Lamaty, J. Martinez,

E. Colacino, J. Org. Chem. 2014, 79, 10132; (b) T. Suzuki, K. Igarashki, K. Hase, K.

Tuzimura, Agric. Biol. Chem. 1973, 37, 411.

[S4] M. K. Kashif, A. Hussain, M. K. Rauf, M. Ebihara, S. Hameed Acta Cryst. 2008, 64,

444.

[S5] W. Persch, A. Schmidt, US2687416 A, 1954.

[S6] C. Chu, C. P. Teag, J. Org. Chem. 1958, 23, 1578.

[S7] M. J. Gracia, R. Azerad, Tetrahedron: Asymmetry 1997, 8, 85.

[S8] J. Safari, S. Gandomi‐Ravandi, L. Javadian, Synth. Commun., 2013, 43, 3115.

[S9] A. Pesquet, A. Daïch, L. van Hijfte, J. Org. Chem. 2006, 71, 530.

[S10] E. C. Wagner, M. Baizer, Org. Synth. 1955, 3, 323.

Part 2

179

Part 2

Homogeneous and

Solid/Liquid Reactions in

Continuous Flow

Chapter G

181

G. Copper-Catalyzed Formation of C-O Bonds by Direct α-C-H Bond

Activation of Ethers Using Stoichiometric Amounts of Peroxide in

Batch and Continuous-Flow Formats

Graphical Abstract

Abstract

2-Carbonyl-substituted phenols and β-ketoesters can be reacted safely with ethers in a

microreactor environment using a copper catalyst and an organic peroxide (TBHP). This

protocol results in unsymmetrical acetal scaffolds not easily available otherwise.

Chapter G

183

1. Introduction

Numerous synthetic strategies for transition-metal-catalyzed CC as well as Cheteroatom

bond formation have been advanced during the last decades.[1]

Apart from the well-established

classical cross-coupling protocols involving pre-functionalized starting materials,[1]

the direct

functionalization of the CH bond (“CH activation”) for the atom- and step-economical

synthesis of functionalized molecules has attracted significant interest in the synthetic

community.[2]

Among the many CH bond activation protocols which have been developed

over the past few years, catalytic cross-dehydrogenative-coupling (CDC) reactions have been

shown to be particularly useful,[3]

and have been extensively utilized in various CC bond

forming protocols.[4]

The α-functionalization of amines, for example, is a widely investigated

CC bond-forming method using the CDC approach under oxidative conditions (Scheme 1,

Method A).[5]

In addition, several methods involving the concept of CH bond activation for

the construction of CO bonds have appeared in the literature.[6-10]

For example, the synthesis

of 2,3-dihydrobenzofurans via intramolecular oxidative CO coupling involving activation of

an aromatic CH bond was recently described.[6]

Similarly, intermolecular CO couplings

have been reported for the acetoxylation of aromatic and aliphatic CH bonds using

transition-metal catalysts.[7]

These and related methods for the α-functionalization of ethers

via CH bond activation have recently been reviewed.[8]

In this context, CDC methods have

demonstrated to be very efficient for the formation of CC bonds (Scheme 1, Method B).[9]

However, the α-functionalization of ethers toward the formation of a CO bond has rarely

been disclosed in the literature (Scheme 1, Method C).[10]

The only known example involves

the Bu4NI-catalyzed formation of esters from carboxylic acids and ethers requiring 20 mol%

of the catalyst, 2.2 equiv of tert-butyl hydroperoxide (TBHP) as oxidant and a typical reaction

time of 12 h at 80 °C temperature.[10]

R1 XR2

H

X = O

Method A

Method B

X = N

C C

C O

X = OMethod CR1 N

R2

C

R1 OR2

CR1 O

R2

O

Scheme 1. Cross-dehydrogenative-coupling (CDC) approaches for CC and CO bond

formation via α-CH bond activation.

Chapter G

184

Herein, we present a novel copper-catalyzed oxidative CO bond formation protocol in which

2-carbonyl-substituted phenols and -ketoesters are directly coupled with simple ethers to

generate hitherto undisclosed unsymmetrical acetal scaffolds (Scheme 2). Under optimized

conditions, catalyst amounts as low as 1 mol% of Cu(OAc)2 can be employed, resulting in

high product yields within 20-30 min in an elevated temperature regime. Since a key

requirement to the success of this oxidative CO bond forming protocol is the use of 2-3

equiv of TBHP as oxidant, an obvious safety issue results from the combination of a peroxide

with ethers at high temperatures. Therefore, the synthesis was successfully translated to a

continuous flow/microreactor protocol providing a means to safely scale this process to

synthetically useful quantities of acetal products, and to best of our knowledge represents the

first application of continuous flow processing to CH activation chemistry.[11]

R1 R3

OOH

R2

Cu(OAc)2, TBHP

R1 R3

OO

R2

O

R5

R4

R4O R5

batch orcontinuous flow

1, 4

(2)

3, 5

Scheme 2. Copper-catalyzed oxidative cross-dehydrogenative-coupling of -ketoesters or 2-

carbonyl-substituted phenols with ethers.


Previous investigations from our laboratory on the copper-catalyzed CDC reaction of -

dicarbonyl derivatives or 2-carbonyl-substituted phenols with N,N’-disubstituted formamides

mediated by stoichiometric amounts of TBHP have indicated that the carbonyl group adjacent

to the hydroxy moiety acts as directing group, and therefore constitutes an essential

functionality for efficient coupling reactions.[12]

In order to explore the ability of these

substrates in a putative CDC reaction with ethers, the coupling behavior of 2-

hydroxyacetophenone (1a) and 1,4-dioxane (2a) under different conditions was evaluated

(Table 1). Gratifyingly, the use of 10 mol% of Cu(OAc)2 as catalyst in combination with

aqueous (70%) TBHP at 80 °C for 3 h did indeed afford the desired acetal (3a) in moderate

yield (Table 1, entry 1). Surprisingly, all other tested CuII species, with the exception of

Cu(OAc)2 hydrate, were completely inactive (Table 1, entries 2 and 3, see also Table S1 in the

Supporting Information), whereas several CuI

catalysts showed moderate catalytic activity

Chapter G

185

(Table 1, entry 4 and Table S1). The nature of the oxidant was also found to be a crucial

factor in this transformation; no desired product was observed by replacing TBHP with a

variety of other common oxidants (Table 1, entries 5-7, see also Table S1). Moving from

aqueous TBHP to a commercially available solution of TBHP in decane (5-6 M), the product

yield could be slightly increased (Table 1, entry 8) and further experiments at elevated

temperature clearly demonstrated a reaction enhancement using the water-free variant (Table

1, entries 9 and 10). A systematic reaction optimization using both increased temperatures and

higher amounts of oxidant in combination with a significantly reduced catalyst loading

ultimately resulted in virtually full substrate conversion and a 81% isolated yield of the

desired acetal 3a (Table 1, entry 10, see also Table S1). The lack of product formation in

control experiments without oxidant clearly underlines the importance of both, metal catalyst

and oxidant (Table 1, entries 11 and 12).

Table 1. Optimization of reaction conditions.[a]

OH O

+O

OCu catalyst

oxidant

80-100 °C, 3 h

OO

O

O

1a 2a 3a

Entry Catalyst [mol%] Oxidant [equiv] T [°C] 3a [%][b]

1 Cu(OAc)2 (10) TBHP in water (1.5) 80 29

2 Cu(OAc)2 H2O (10) TBHP in water (1.5) 80 24

3 CuCl2 (10) TBHP in water (1.5) 80 -

4 CuCl (10) TBHP in water (1.5) 80 24

5 Cu(OAc)2 (10) H2O2 (1.5) 80 -

6 Cu(OAc)2 (10) NaOCl (1.5) 80 -

7 Cu(OAc)2 (10) DTBP[c]

(1.5) 80 -

8 Cu(OAc)2 (10) TBHP in decane (1.5) 80 31



11 - TBHP in decane (2.2) 100 -

12 Cu(OAc)2 (5) - 100 -

[a] Reaction conditions: 1a (1 mmol), 2a (2 mL), 3 h, unless noted otherwise. [b] Isolated

yields after chromatograhpy. [c] Di-tert-butyl hydroperoxide.

Chapter G

186

Encouraged by the results obtained in the optimization experiments described above, a

number of analogous CDC transformations varying both reaction partners were studied (Table

2). Cyclic ethers such as 1,4-dioxane (2a) and THF (2b) reacted smoothly with different 2-

carbonyl-substituted phenol derivatives (1a-e) to provide the corresponding acetal products

(3a-j) in moderate to excellent yields. Linear, unsymmetrical ethers such as 1,2-

dimethoxyethane (DME) (2c) furnished a mixture of products resulting from competitive

CH activation of the internal methylene and the terminal methyl group, respectively (3k-3n).

Methyl tert-butyl ether (MTBE) (bp. 56 °C) as well as simple Et2O (bp. 35 °C) remained

completely unreactive under these reaction conditions operating at the reflux temperature of

the solvent (3p-3q). Subsequently, without further reoptimization, the substrate scope was

further extended to -ketoesters 4a-h (Scheme 3).

Table 2. Substrate scope in the Cu(OAc)2-catalyzed coupling of 2-carbonyl-substituted

phenols with ethers.[a]

R2

O

+

OH

R4

O

R3

1a-e 2a-d

R1

R2

OO

3a-qR1

R3

OR4

Cu(OAc)2 (5 mol%)TBHP/decane (2.2 equiv)

reflux, 3 h

Entry 1 2 Product Yield [%][b]

1

OOH

1a

O

O

2a

H

3a 79

2

OOH

MeO 1b

3b 80

3 OMe

OOH

1c

3c 55

4 OMe

OOH

MeO 1d

3d 85

5 NH

OOH

1e

Ph

3e 28

6 1a

O

2b

H

3f 74

7 1b 3g 66

8 1c 3h 39

9 1d 3i 82

10 1e 3j 45

Chapter G

187

Entry 1 2 Product Yield [%][b]

11 1a

O

O HH

2c

65

12

12 1b

41

18

13 1c

35

14 1d

64

20

15 1a O

2dH

3o 76

16

1a OH

2e

3p -

17

1a O

2fH

3q -

[a] Reaction conditions: 1a-e (1 mmol), 2a-d (2 mL), reflux temperature of the respective ether. [b] Isolated

yields after chromatography. [c] Amount of terminal coupling product too low for isolation.

Chapter G

188

R2

OCu(OAc)2 (5 mol%)

TBHP/decane (2.2 equiv)

100 °C, 3 h+

O O O

R2

O O

O

O O

O

R1

O

O

O

O

O

O

O

O

R1

O O

O

O

O

O O

O

O

O O O

O

O

O O O

O

O

O

O O

O

O

O

O O

O

O

O

53% (5a) 60% (5b)37% (5c)

55% (5d) 61% (5e)

60% (5f)

54% (5g) 25% (5h)

4a-h 2a 5a-h

Scheme 3. Substrate scope in the Cu(OAc)2-catalyzed coupling of ß-ketoesters with dioxane.

In order to move this potentially hazardous coupling protocol involving a peroxide/ether

mixture to a safe and scalable continuous flow regime,[13]

we first attempted to reduce the

initially optimized reaction time of 3 h under reflux conditions (Table 1) to something more

suitable for a continuous processing approach (< 30 min). Therefore the CDC of 2-

hydroxyacetophenone (1a) and 1,4-dioxane (2a) was reevaluated more closely under sealed-

vessel microwave conditions paying particular attention to the reaction time.[14]

An initial

temperature screen using accurate internal temperature monitoring[15]

indicated that the

optimum temperature window for the oxidative coupling is between 120 and 135 °C. At

lower, as well as higher temperatures, a drop in conversion was observed (see Table S2 and

Figure S1 in the Supporting Information). We presume that the decomposition of TBHP is

faster than the desired CDC reaction at higher temperatures.[16]

However, further optimization

at 135 °C showed almost full conversion within only 15 min when the amount of TBHP

oxidant was increased to 3 equiv, and was added portionwise (3 1 equiv).[16]

In addition,

under these intensified conditions it was possible to decrease the amount of Cu(OAc)2 catalyst

to 1 mol% at the expense of a 30 min reaction time. Ultimately, keeping the desire of

throughput in the flow process in mind, a catalyst loading of 2.5 mol% and a reaction time of

Chapter G

189

20 min were chosen.[16]

Under these high-temperature conditions in the sealed microwave

vial, substrate 1a was also successfully coupled not only with THF (2b) providing a 96%

isolated yield of acetal 3b, but also with MTBE (2e) and diethyl ether (2f), furnishing the

desired target molecules 3p and 3q in moderate yields (Table S5 in the Supporting

Information).

The optimized microwave batch protocols were then translated to a continuous flow

regime (“microwave-to-flow” paradigm)[17]

in a Uniqsis FlowSyn reactor equipped with a 20

mL internal volume stainless steel coil (i.d.1.0 mm) operating at 130 °C coil temperature.[18]

In order to avoid large volumes of ether/peroxide mixtures, a two-feed strategy as shown in

Figure 1 was devised. Therefore, a solution of the Cu catalyst and 2-hydroxyacetophenone

substrate (1a) in 1,4-dioxane (Feed A, flow rate: 0.8 mL min-1

), and commercially available

TBHP in decane (Feed B, flow rate 0.2 mL min-1

) were passed through a glass static mixer

(M) and subsequently heated in the above-mentioned coil reactor (RC). Within the 20 min

residence time of this flow experiment, conversion/yields similar to those obtained under

microwave batch conditions were obtained, considering that multiple additions of oxidant

were possible in the batch experiment.[16]

MBPR

RC

Feed Aether (2), Cu(OAc)2

substrate 1a

Feed BTBHP/decane

OO

O

O OO

O

OO

O

3a 3f 3q

flow 82% flow 84% flow 36%

MW[a] 82% MW[a] 96% MW[a] 54%

130 °C

17 bar

0.8 mL min-1

0.2 mL min-1

OO

3a,f,q

R3

OR4

Figure 1. Schematic diagram for the two-feed continuous flow oxidative CO coupling of 2-

hydroxyacetophenone 1a. For more details, see the Supporting Information. [a]

TBHP was

added portionwise in the batch experiments, explaining the higher yields, see also Tables S7

and S8.

Chapter G

190

3. Conclusion

In summary, we have demonstrated the efficient construction of CO bonds via -CH bond

activation of simple ethers using an inexpensive copper catalyst in combination with a

commercially available decane solution of TBHP as stoichiometric oxidant. This protocol

allows the generation of unsymmetrical acetal scaffolds not easily available by other methods.

In order to make this potentially hazardous synthetic protocol scalable, a two-feed high-

temperature/pressure microreactor approach was developed that provided the desired acetals

in yields similar to those obtained in the batch protocols.

4. References

[1] (a) Metal-Catalyzed Cross-Coupling Reactions, (Eds: A. de Meijere, F. Diederich),

Wiley-VCH, Weinheim, 2004; (b) R. Jana, T. P. Pathak, M. S. Sigman, Chem. Rev.

2011, 111, 1417; c) I. P. Beletskaya, A. V. Cheprakov, Coord. Chem. Rev. 2004,

248, 2337.

[2] (a) CH Activation (Eds.: J-Q. Yu, Z.-J. Shi), Top. Curr. Chem. 2010, 292; (b)

Handbook of C-H Transformations: Applications in Organic Synthesis, (Ed: G.

Dyker), Wiley-VCH, Weinheim, 2005; (c) A. M. R. Smith, K. K. Hii, Chem. Rev.

2011, 111, 1637; (d) C. L. Sun, B. J. Li, Z. J Shi, Chem. Rev. 2011, 111, 1293; (e) L.

Ackermann, Chem. Rev. 2011, 111, 1315; (f) X. Chen, K. M. Engle, D. H. Wang, J. Q.

Yu, Angew. Chem. Int. Ed. 2009, 48, 5094 (g) A. E. Wendlandt, A. M. Suess, S. S.

Stahl, Angew. Chem. Int. Ed. 2011, 50, 11062.

[3] (a) C. S. Yeung, V. M. Dong, Chem. Rev. 2011, 111, 1215; (b) C. J. Scheuermann,

Chem. Asian J. 2010, 5, 436; (c) J. L. Bras, J. Muzart, Chem. Rev. 2011, 111, 1170.

[4] (a) C. J. Li, Acc. Chem. Res. 2009, 42, 335 and references therein; (b) W. Han, P.

Mayer, A. R. Ofial, Angew. Chem. Int. Ed. 2011, 50, 2178; (c) K. M. Engle, D. H.

Wang, J. Q Yu, Angew. Chem. Int. Ed. 2010, 49, 6169; (d) G. Deng, L. Zhao, C. J. Li,

Angew. Chem. Int. Ed. 2008, 47, 6278; (e) T. W. Lyons, K. L. Hull, M. S. Sanford, J.

Am. Chem. Soc. 2011, 133, 4455; (f) Z. Li, C. J. Li, J. Am. Chem. Soc. 2006, 128, 56;

(g) M. Kitahara, N. Umeda, K. Hirano, T. Satoh, M. Miura, J. Am. Chem. Soc. 2011,

133, 2160; (h) N. Borduas D. A. Powell, J. Org. Chem. 2008, 73, 7822.

[5] (a) J. Xie, H. Li, J. Zhou, Y. Cheng, C. Zhu, Angew. Chem. Int. Ed. 2012, 51, 1252;

(b) O. Basle, C. J. Li, Green Chem. 2007, 9, 1047; (c) S. B. Park, H. Alper, Chem.

http://doi.wiley.com/10.1002/anie.201103945

http://doi.wiley.com/10.1002/anie.201107605

Chapter G

191

Commun. 2005, 1315; (d) S. I. Murahashi, N. Komiya, H. Terai, Angew. Chem. Int.

Ed. 2005, 44, 6931; (e) Z. Li, C. J. Li, J. Am. Chem. Soc. 2005, 127, 6968; (f) Z. Li, D.

S. Bohle, C. J. Li, Proc. Natl. Acad. Sci. 2006, 103,8928; (g) N. Sasamoto, C. Dubs,

Y. Hamashima, M. Sodeoka, J. Am. Chem. Soc. 2006, 128, 14010.

[6] X. Wang, Y. Lu, H. X. Dai, J. Q. Yu, J. Am. Chem. Soc. 2010, 132, 12203.

[7] (a) R. Giri, J. Liang, J. G. Lei, J. J. Li, D. H. Wang, X. Chen, I. C. Naggar, C. Guo, B.

M. Foxman, J. Q. Yu, Angew. Chem. Int. Ed, 2005 44, 7420; (b) X. Chen, X. S. Hao,

C. E. Goodhue, J. Q. Yu, J. Am. Chem. Soc. 2006, 128, 6790; (c) A. R. Dick, K. L.

Hull, M. S. Sanford, J. Am. Chem. Soc. 2004, 126, 2300; (d) L. V. Desai, K. L. Hull,

M. S. Sanford, J. Am. Chem. Soc. 2004, 126, 9542.

[8] S. Y. Zhang, F. M. Zhang, Y. Q. Tu, Chem. Soc. Rev. 2011, 40, 1937.

[9] (a) Y. Zhang, C. J. Li, Angew. Chem. Int. Ed. 2006, 45, 1949; (b) Y. Zhang, C. J. Li, J.

Am. Chem. Soc. 2006, 128, 4242; (c) Z. Li, R. Yu, H. Li, Angew. Chem. Int. Ed. 2008,

47, 7497.

[10] L. Chen, E. Shi, Z. Liu, S. Chen, W. Wei, H. Li, K. Xu, X. Wan, Chem. Eur. J. 2011,

17, 4085.

[11] For selected recent reviews on continuous flow/microreactor chemistry, see: (a) C.

Wiles, P. Watts, Green Chem. 2012, 14, 38; (b) T. Noël, S. L. Buchwald, Chem. Soc.

Rev. 2011, 40, 5010; (c) M. Baumann, I. R. Baxendale, S. V. Ley, Mol. Divers. 2011,

15, 613; (d) R. L. Hartman, J. P. McMullen, K. F. Jensen, Angew. Chem. Int. Ed.

2011, 50, 7502; (e) C. Wiles, P. Watts, Chem. Commun. 2011, 47, 6512; (f) J. Wagner,

S. Ceylan, A. Kirschning, Chem. Commun. 2011, 47, 4583; (g) J.-I. Yoshida, H. Kim,

A. Nagaki, ChemSusChem 2011, 4, 331.

[12] G. S. Kumar, C. U. Maheswari, R. A. Kumar, M. L. Kantam, K. R. Reddy, Angew.

Chem. Int. Ed. 2011, 50, 11748.

[13] For selected examples of reactions involving peroxides in continuous flow, see: (a) R.

Mello, A. Olmos, J. Parra-Carbonell, M. E. Gonzales-Nunez, G. Asensio, Green

Chem. 2009, 11, 994; (b) K. Yube, K. Mae, Chem. Eng. Technol. 2005, 28, 331; (c) J.

Zhang, W. Wu, G. Qian, X.-G. Zhou, J. Hazard. Mater. 2010, 181, 1024.

[14] C. O. Kappe, A. Stadler, D. Dallinger, Microwaves in Organic and Medicinal

Chemistry, 2nd

Ed., Wiley-VCH, 2012.

[15] For the importance of internal temperature monitoring in microwave chemistry, see:

(a) D. Obermayer, C. O. Kappe, Org. Biomol. Chem. 2010, 8, 114; (b) D. Obermayer,

B. Gutmann, C. O. Kappe, Angew. Chem. Int. Ed. 2009, 48, 8321.

Chapter G

192

[16] For a complete optimization data set, see Tables S2–S8 in the Supporting Information.

[17] T. N. Glasnov, C. O. Kappe, Chem. Eur. J. 2011, 17, 11956.

[18] For further details on the FlowSyn reactor configuration and experimental setup, see:

B. Gutmann, J.-P. Roduit, D. Roberge, C. O. Kappe, J. Flow Chem. 2012, 2, 8; and the

Supporting Information.

Chapter G

193


General Remarks. All chemicals were purchased from Sigma-Aldrich, S.D. Fine chemicals,

Pvt. Ltd, or AVRA Chemicals Pvt. Ltd, India. Reagents were weighed and handled in air at

room temperature. Column chromatography was performed on ACME silica gel (100 ~ 200

mesh) and TLC was carried out on Merck pre-coated silica gel 60-F254 plates. Silica gel flash

chromatography separations were performed on a Biotage SP1 instrument using petroleum

ether/ethyl acetate mixtures as eluent. Proton and carbon magnetic resonance spectra (1H

NMR and 13

C NMR) were recorded on an Avance-300, Inova-500 or Bruker 300 MHz

spectrometer, using tetramethylsilane (TMS) as internal standard (1H NMR: TMS at 0.00

ppm, CDCl3 at 7.26 ppm; 13

C NMR: CDCl3 at 77.0 ppm, DMSO at 39.43). CDCl3 was used as

solvent in all NMR experiments. Chemical shifts (δ) are expressed in ppm downfield from

TMS as internal standard. The letters s, d, t, q, and m are used to indicate singlet, doublet,

triplet, quadruplet, and multiplet, respectively. Analytical HPLC (Shimadzu LC20) analysis

was carried out on a C18 reversed-phase (RP) analytical column (150 × 4.6 mm, particle size

5 μm) at 25 °C using a mobile phase A (water/acetonitrile 90:10 (v/v) + 0.1 % TFA) and B

(MeCN + 0.1 % TFA) at a flow rate of 1.0 mL min-1

. The following gradient was applied:

linear increasefrom solution 30% B to 100 % B in 8 min, hold at 100% solution B for 2 min.

For microwave irradiation experiments, a Monowave 300 single-mode microwave reactor

from Anton Paar GmbH (Graz, Austria) was used. The reaction temperature was monitored

by an external infrared sensor (IR) housed in the side-walls of the microwave cavity

measuring the surface temperature of the reaction vessel as well as an internal fiber-optic

(FO) temperature probe (ruby thermometer).[S1]

Flow chemistry experiments were performed

in a Uniqsis FlowSyn reactor (for further information on configuration, see Figure S2).[S2]

Chapter G

194

Table S1. Optimization of reaction conditions.[a]

OH O

+O

Ocatalystoxidant

80-100°C, 3h

OO

O

O

1a 2a 3a

Entry Catalyst [mol%] Oxidant [equiv] Temperature

[°C]

Yield

[%][b]

1 Cu(OAc)2 (10) TBHP[c]

in water (1.5) 80 29

2 Cu(OAc)2.H2O (10) TBHP in water (1.5) 80 24

3 CuCl2 (10) TBHP in water (1.5) 80 n.d

4 CuBr2 (10) TBHP in water (1.5) 80 n.d

5 Cu(ClO4)2 . 6H2O (10) TBHP in water (1.5) 80 n.d

6 Cu(OTf)2 (10) TBHP in water (1.5) 80 n.d

7 CuSO4 . 5H2O (10) TBHP in water (1.5) 80 n.d

8 Cu(OAc) (10) TBHP in water (1.5) 80 20

9 CuCl (10) TBHP in water (1.5) 80 24

10 CuBr (10) TBHP in water (1.5) 80 15

11 CuI (10) TBHP in water (1.5) 80 n.d


13 Cu(OAc)2 (10) H2O2 (1.5) 80 n.d

14 Cu(OAc)2 (10) NaOCl (1.5) 80 n.d

15 Cu(OAc)2 (10) DTBP[d]

(1.5) 80 n.d

16 Cu(OAc)2 (10) DTAP[e]

(1.5) 80 n.d

17 Cu(OAc)2 (10) DDQ[f]

(1.5) 80 n.d

18 Cu(OAc)2 (10) O2 (atmospheric) 80 n.d

19 Cu(OAc)2 (10) m-CBPA[g]

(1.5) 80 n.d

20[h]

Cu(OAc)2 (10) TBHP in water (1.5) 80 41

21[h]

Cu(OAc)2 (10) TBHP in decane (1.5) 80 51




25 Cu(OAc)2 (5) -- 100 n.d

26 -- TBHP in water (2.2) 100 n.d

[a] Reaction conditions: 1a (120 µL, 1 mmol), 2a (2 mL), 3 h, unless otherwise noted.

[b] Isolated yields.

n.d. = not detected in crude NMR. [c]

tert-butyl hydroperoxide. [d]

di-tert-butyl hydroperoxide. [e]

di-tert-

amoyl peroxide.[f]

2,3-Dichloro-5,6-dicyano-1,4-benzoquinone. [g]

meta-Chloroperoxybenzoic acid. [h]

9

h reaction time

Chapter G

195

Table S2. Temperature screening for the synthesis of 1-(2-(1,4-dioxan-2-

yloxy)phenyl)ethanone (3a) using microwave irradiation.[a]

OH O

O

OO O

O

O+

5 mol% Cu(OAc)22.2 eq TBHP in decane

30 min, MW

1a 3a2a

Entry T [°C] Conversion [%] [b]

3a [%][b]

1 110 44 41

2 120 65 61

3 130 65 60

4 135 66 60

5 140 61 55

6 150 61 56

7 160 55 47 [a]

Conditions: 2-hydroxyacetophenone (1a) (120 µL, 1 mmol), Cu(OAc)2 (9 mg, 5 mol%),1,4-

dioxane (2 mL), TBHP 5-6 M in decane (400 µL, 2.2 eq). [b]

HPLC peak area percent at 254

nm. See also Figure S1.

Table S3. Varying time, amount of oxidant and addition frequency.[a]

OH O

O

OO O

O

O+

5 mol% Cu(OAc)2TBHP in decane

1a 3a2a

135 °C, MW

Entry t [min] TBHP [equiv] Conversion [%][b]

3a [%][b]

7 30 3 75 71

8 20 3 79 77

9 10 3 78 76

10 2 x 15 2 x 1.5 93 87

11 3 x 10 3 x 1 97 94

12 5 x 10 5 x 0.5 98 93

13 3 x 10 1 x 1.5 + 2 x 0.5 88 84

14 3 x 5 1 x 1.5 + 2 x 0.5 84 78

15 3 x 5 3 x 1 97 92

16 3 x 5 2 x 1 + 1 x 0.5 88 83

17 3 x 2 3 x 1 68 66 [a]

Conditions: 2-hydroxyacetophenone (1a) (120 µL, 1 mmol), Cu(OAc)2 (9 mg, 5

mol%),1,4-dioxane (2 mL), TBHP 5-6 M in decane (540 µL, ~3 equiv). [b]

HPLC peak

area percent at 254 nm.

Chapter G

196

Table S4. Reduction of Cu(OAc)2 catalyst.[a]

OH O

O

OO O

O

O+

Cu(OAc)23 equiv TBHP in decane

1a 3a2a

135 °C, MW

Entry catalyt [mol%] time [min ][b]

Conversion [%][c]

3a [%][c]

14 5 3 x 5 97 92

18 2.5 3 x 5 90 87

19 2.5 2 x 5 + 1 x 10 97 94 (82)[d]

20[e]

2.5 2 x 5 + 1 x 10 98 88

21 1 2 x 5 + 1 x 10 74 71

22 1 3 x 10 99 95(80)[d]

23 0 2 x 5 + 1 x 10 2 <1 [a]

Conditions: 2-hydroxyacetophenone (1a) (120 µL, 1 mmol), Cu(OAc)2 (0 - 9 mg), 1,4-dioxane

(2 mL), TBHP 5-6 M in decane (540 µL, 3 equiv). [b]

1 equiv TBHP per run. [c]

HPLC peak area

percent at 254 nm. [d]

Isolated yield in parentheses. [e]

Reaction was performed in a reaction vessel

made out of sintered silicon carbide.

Chapter G

197

Table S5. Scope of microwave irradiation experiments[a]

OH O O OCu(OAc)2 (2.5 mol%)TBHP (3 equiv)

R4CH2OR5

OR4

R5

1a 3

Entry Ether T

[°C]

p

[bar]

time

[min][b] Product

Isolated

yield

[%]

1

135 2 2 x 5 + 1 x 10

82

2

135 6 2 x 5 + 1 x 10

96

3

135 9 3 x 5 [c]

20

4

100[d]

7 2 x 5 + 1 x 10

54

5

135 1 2 x 5 + 1 x 10

No reaction

[a] Conditions: 2-hydroxyacetophenone (1a) (120 µL, 1 mmol), Cu(OAc)2 (4.5 mg, 2.5 mol%), ether 2 (2 mL),

TBHP 5-6 M in decane (540 µL, 3equiv). [b]

1 equiv TBHP per run. [c]

longer reaction times resulted in

substrate (re-)formation. [d]

An explanation for the lower reaction temperature is given in Scheme S1.

Chapter G

198

Determination of Catalytical Limitation at Elevated Temperatures (Table S6). Three

experiments with 2 heating cycles where carried out to determine the limiting reactant in this

reaction. In the first cycle either the catalyst (entry 1), the oxidant (entry 2) or a combination

of both (entry 3) were heated for 30 minutes at 135 °C in 1,4-dioxane. Afterwards, the

missing reagent as well as the substrate was added before another cycle (135 °C, 30 min) was

executed. The conversion was determined by HPLC (Table 6, entries 1-3). As pointed out in

Table 6, when just the catalyst was heated in the first cycle, the same conversion was obtained

as in the control experiment (entry 4). If the oxidant is pre-heated, the conversion decreases

dramatically, indicating the peroxide decomposition as limiting factor in this kind of CDC

reaction at elevated temperatures.

Table S6. Determination of catalytical limitations.[a]

Cycle 1 Cycle 2

Entry Cu(OAc)2

[mol %]

TBHP

[equiv]

Cu(OAc)2

[mol %]

TBHP

[equiv]

Conversion

[%][b]

3a [%]

[b]

1 5 -- -- 3 76 72

2 -- 3 5 -- 3 3

3 5 3 -- -- 19 18

4

5 3 75 71 [a]

Conditions: 2-hydroxyacetophenone (1a) (120 µL, 1 mmol), Cu(OAc)2 (9 mg, 5 mol%), 1,4-dioxane

(2 mL), TBHP 5-6 M in decane (540 µL, 3 equiv). [b]

HPLC peak area percent at 254 nm.

Table S7. Comparison of Microwave and Continuous Flow Chemistry.

OH O O O

Cu(OAc)2TBHP

1,4-dioxane (2a)

O

O

MW orcontinuous flow

1a 3a

Entry Type 2a

[ml] 1a

[mmol]

Catalyst

[mol%]

TBHP

[equiv]

T

[°C]

time

[min]

Conv.

[%][a]

Yield

[%][a][b]

A

Flow

1 Feed 20 10 2.5 3 130 20 89 86(81)

Flow

2 Feeds

TM[c]

20 10 2.5 3 130 20 71 69

Flow

2 Feeds

GSM[d]

20 10 2.5 3 130 20 91 87(82)

MW

2 1 2.5 3 130 20 87 85(75)

B Flow 20 10 2.5 3 135 20 82 77(74)

MW[e]

2 1 2.5 3 135 20 80 77 [a]

HPLC peak area percent at 254 nm. [b]

Isolated yield in parentheses. [c]

T-Mixer for combining streams

A and B. [d]

Glass static mixer for combining streams A and B. [e]

Whole amount of oxidant added in 1

portion for better comparability

Chapter G

199

Table S8. Scope of continuous flow experiments.[a]

OH O O OCu(OAc)2 (5 mol%)

TBHP (3 equiv)

OR4

R4OCH2R5, 20 min, flow

R5

1a 3a

Entry Ether Product T

[°C]

Isolated yield

[%]

1

135 82

2

135 84

3[b]

100 36

[a] Conditions: 2-hydroxyacetophenone (1a) (1.2 mL, 10 mmol),

Cu(OAc)2 (45 mg, 2.5 mol%),1,4-dioxane (20 mL), TBHP 5-6 M in

decane (5.4 mL, 3 equiv). Experiments were performed either using a

one-feed or two feed (Figure 1) strategy with equal success. [b]

2 mL

MeOH were added to obtain a completely homogenous reaction mixture.

OH O

O O

Cu(OAc)2 (2.5 mol%)TBHP (3 equiv)

Et2O, 135 °C

OO O

O

135 °C1a

3q6

Scheme S1. The reaction of 1a with Et2O under sealed vessel microwave conditions was

carried out at 100°C because at 135°C a subsequent hydrolysis reaction resulting in 2-

acetylphenyl acetate was observed. Further, it was necessary to add 2 mL of MeOH in order

to obtain a completely homogeneous reaction mixture.

Chapter G

200

Figure S1. Reaction mixtures after 30 min (hold time) microwave irradiation at different

temperatures (see Table S2). The optimum reaction temperature and catalyst/TBHP lifetime is

135 °C.

Figure S2. UniqsisFlowSyn reactor equipped with a Stainless steel coil reactor (with glass

cover) and glass static mixer.[S2]

Each pump allows flow rates from 0.02 to 10 mL min-1

giving a total maximum flow rate of 20 mL min-1

. The T-mixer to combine the two reagent

streams at room temperature is attached to the front panel (behind the coil heater module)

and is attached to a pressure transducer (further transducers are integrated in each pump

priming valve). The system constantly monitors the pressure and will stop if the pressure

either rises above or falls below the global limits (set in the configuration page). The coil

heater contains heating elements and temperature sensors and is used to heat the coil

reactors. The coil reactors consist of tubing wound in a helical groove on an aluminum

mandrel. Coil reactors are available in a range of pre-wound sizes and materials and are

easily fitted and removed from the heating module. Back pressure can be varied by fitting

different fixed back pressure cartridges (40–1000 psi cartridges are available). The maximum

allowed temperature and pressure is determined by the material of the column and the coil

reactor but the upper limit is 69 bars and 260 °C. Inlet selection valves and outlet selection

valves are used to control the feed to the pumps (e.g. either solvent or reagent) and between a

waste and a collection bottle. Pumps, inlet and outlet selection valves are controlled either

manually or automatically using the AutoExperiment mode.

0 ° 0 ° 0° 5 ° 40 ° 50°

Chapter G

201

General Procedure for the Acetal Synthesis (3a-3o) in a Standard Oil Bath (Table 2 and

Scheme 3). A solution of 2-carbonyl-substituted phenol (1a-e) or β-keto ester (4a-h) (1.0

mmol), Cu(OAc)2 (9 mg, 5 mol%) in 2 mL of the respective ether 2 (1,4-dioxane, THP,

DME) was stirred at room temperature. To the same solution, a 5-6 M TBHP solution in

decane (2.2 mmol) was added dropwise before the mixture was heated at the reflux

temperature of the respective ether (oil bath) for 3 h. After cooling to room temperature, the

reaction mixture was extracted with ethyl acetate and dried over anhydrous Na2SO4. Removal

of the solvent under reduced pressure afforded the crude product, which was purified by

preparative column chromatography on silica gel (hexane/ethyl acetate 9:1).

1-(2-(1,4-Dioxane-2-yloxy)phenyl)ethanone: (Table 2, Entry 1, 3a)

Isolated yield = 79% ; 1H NMR (300 MHz, CDCl3) 7.74 (dd, J =

2.26, 7.55 Hz, 1H), 7.44 (td, J = 2.26, 7.55, 15.86 Hz, 1H), 7.19 (d, J

= 7.55 Hz, 1H), 7.06 (t, J = 7.55 Hz, 1H), 5.4 (t, J = 2.26 Hz, 1H), 4.1

( m, 1H ), 3.91 (d, J = 2.26 Hz, 2H), 3.81 (m, 2H), 3.63 (dt, J = 3.02,

12.08 Hz, 1H), 2.69 (s, 3H). 13

C NMR (75 MHz ,CDCl3): 199.6,

155.5, 133.3, 130.1, 121.8, 114.8, 93.4, 68.4, 65.9, 61.2, 31.9. MS

(ESI): m/z = 245 (M+Na)+. HRMS ESI (M+Na)

+ m/z calcd for

C12H14O4Na (M+Na)+= 245.07843, found = 245.07833.

(2-(1,4-Dioxane-2-yloxy)-4-methoxyphenyl)(phenyl)methanone:

(Table 2, Entry 2, 3b) Isolated yield = 80% ; 1H NMR (300 MHz,

CDCl3) 7.73 (m, 2H), 7.46 (m, 4H), 6.80 (d, J = 2.26 Hz, 1H), 6.67

(dd, J = 2.26, 8.30 Hz, 1H), 5.06 (t, J = 2.26 Hz, 1H), 3.99 (m, 1H),

3.86 (s, 3H), 3.6 (m, 3 H), 3.45 (dd, J = 2.26, 11.13 Hz, 1H), 3.11 (dd,

J = 3.02, 12.08 Hz, 1H). 13

C NMR (75 MHz, CDCl3): 195.6, 163.1,

156.8, 139.2, 132.1, 131.7, 129.1, 127.9, 122.6, 107.2, 103, 94.9, 67.7,

65.6, 61.3, 55.4. MS (ESI):m/z = 337 (M+Na)+. HRMS ESI (M+Na)

+

m/z calcd for C18H18O5Na (M+Na)+= 337.10464,found = 337.10416

Methyl 2-(1,4-Dioxane-2-yloxy)-5-methylbenzoate: (Table 2, Entry

3, 3c) Isolated yield = 55% ; 1H NMR (300 MHz, CDCl3) 7.6 (br,

1H), 7.25 (m, 1H), 7.12 (d, J = 8.3 Hz, 1H), 5.17 (t, J = 2.26 Hz, 1H),

4.20-4.28 (m, 1H), 3,85-3.97 (m, 5H), 3.77-3.8 (m, 2H), 3.62 (dt, J =

3.21, 11.7 Hz, 1H), 2.32 (s, 3H). 13

C NMR (75 MHz CDCl3): 166.5,

154.1, 133.7, 132, 131.5, 121.9, 119, 95.8, 68.5, 65.9, 61.4, 51.9, 20.3.

MS (ESI): m/z = 275 (M+Na)+. HRMS ESI (M+Na)

+ m/z calcd for

C13H16O5Na (M+Na)+

= 275.08899, found = 275.08872.

Chapter G

202

Methyl 2-(1,4-Dioxan-2-yloxy)-4-methoxybenzoate: (Table 2, Entry

4, 3d) Isolated yield = 85% ; 1H NMR (300 MHz, CDCl3) 7.84 (d,

J = 8.8 Hz, 1H), 6.77 (d, J = 2.4 Hz, 1H), 6.61 (dd, J = 8.8, 2.4 Hz,

1H), 5.22 (t, J = 2.5 Hz, 1H), 4.31 – 4.17 (m, 1H), 4.02 – 3.70 (m,

11H), 3.68 – 3.58 (m, 1H). 13

C NMR (75 MHz, CDCl3) 165.86,

163.79, 158.58, 133.38, 114.22, 107.69, 104.88, 95.71, 68.56, 66.03,

61.57, 55.50, 51.71. HRMS EI M+ m/z calcd for C13H16O6 M

+ =

268.0947, found = 268.0960.

2-(1,4-Dioxane-2-yloxy)-N-phenylbenzamide: (Table 2, Entry 5, 3e)

Isolated yield = 28% ; 1H NMR (300 MHz, CDCl3) 10.31 (br, 1H),

8.35 (dd, J = 1.51, 8.3 Hz, 1H), 7.84 (dd, J = 1.51, 9.06 Hz, 2H), 7.47

(td, J = 2.26, 9.6, 6.79 Hz, 1H), 7.35 (t, J = 7.55 Hz, 2H), 7.08-7.28

(m, 3H), 5.64 (br, 1H), 4.09-4.18 (m, 2H), 3.88-4 (m, 3H), 3.6 (dt, J =

2.26, 12.08 Hz, 1H). 13

C NMR (75 MHz, CDCl3): 162.8, 153.6,

138.8, 133. 132.6, 128.9, 123.9, 122.6, 119.9, 114.4, 93.1, 68.6, 66.2,

60.6. MS (ESI): m/z = 322 (M+Na)+. HRMS ESI (M+Na)

+ m/z calcd

for C17H17NO4Na (M+Na)+

= 322.10498, found = 322.10453.

1-(2-(Tetrahydrofuran-2-yloxy)phenyl)ethanone: (Table 2, Entry 6,

3f) Isolated yield = 74% ; 1H NMR (300 MHz, CDCl3) 7.7 (dd, J =

1.51, 7.55 Hz, 1H), 7.43 (td, J = 2.26, 9.06 Hz, 1H), 7.25 (d, J = 7.55

Hz, 1H), 7.01 (t, J = 7.55 Hz, 1H), 5.89-5.91 (m, 1H), 3.95-4.09 (m,

2H), 2.59 (s, 3H), 2.14-2.28 (m, 3H), 1.97-2.06 (m, 1H). 13

C NMR

(75 MHz, CDCl3): 199.5, 156.2, 133.2, 129.8, 128.7, 121, 115.1,

102.3, 68.1, 32.5, 31.5, 23.2. MS (ESI): m/z = 229 (M+Na)+. HRMS

ESI (M+Na)+ m/z calcd for C12H14O3Na (M+Na)

+ = 229.08352, found

= 229.0856.

(4-Methoxy-2-(tetrahydrofuran-2-yloxy)phenyl)(phenyl)

methanone: (Table 2, Entry 7, 3g) Isolated yield = 66% ; 1H NMR

(300 MHz, CDCl3) 7.70-7.73 (m, 2H), 7.37-7.53 (m, 4H), 6.79 (d, J

= 2.26 Hz, 1H), 6.62 (dd, J = 2.26, 8.3 Hz, 1H), 5.64 (d, J = 4.53 Hz,

1H), 3.86 (s, 3H), 3.81 (t, J = 6.79 Hz, 2H), 1.65-1.81 (m, 2H), 1.46-

1.57 (m, 2H). 13

C NMR (75 MHz, CDCl3): 195.6, 163, 156.8, 139.3,

131.5, 131.4, 128.8, 127.5, 121.9, 106.5, 102.1, 101.3, 67.9, 55.1,

31.9, 22.4. MS (ESI): m/z = 321 (M+Na)+. HRMS ESI (M+Na)

+ m/z

calcd for C18H18O4Na (M+Na)+

= 321.10973, found = 321.10919.

O

NH

O

O

O

O O

O

O O

O

O

Chapter G

203

Methyl 5-Methyl-2-(tetrahydrofuran-2-yloxy)benzoate: (Table 2,

Entry 8, 3h) Isolated yield = 39 % ; 1H NMR (300 MHz, CDCl3)

7.57 (br, 1H), 7.23 (dd, J = 2.26, 9.06 Hz, 1H), 7.12 (d, J = 8.8 Hz,

1H), 5.76 (d, J = 3.77 Hz, 1H), 4.04-4.11 (m, 1H), 3.9-3.97 (m, 1H),

3.86 (s, 3H), 2.3 (s, 3H), 1.91-2.23 (m, 4H). 13

C NMR (75 MHz,

CDCl3): 166.8, 154.4, 133.7, 131.4, 131, 121.5, 118, 103.8, 68.1,

51.7, 32.6, 23.2, 20.3. MS (ESI): m/z = 259 (M+Na)+. HRMS ESI

(M+Na)+ m/z calcd for C13H16O4Na (M+Na)

+ = 259.09408, found =

259.09374.

Methyl 4-Methoxy-2-(tetrahydrofuran-2-yloxy)benzoate: (Table 2,

Entry 9, 3i) Isolated yield = 82 % ; 1H NMR δ

(300 MHz, CDCl3) 7.83

(d, J = 8.8 Hz, 1H), 6.80 (d, J = 2.4 Hz, 1H), 6.57 (dd, J = 8.8, 2.4 Hz,

1H), 5.82 (d, J = 4.7 Hz, 1H), 4.16 – 4.04 (m, 1H), 4.02 – 3.91 (m,

1H), 3.88 – 3.81 (m, 6H), 2.38 – 2.08 (m, 3H), 2.03 – 1.87 (m, 1H). 13

C NMR δ (75 MHz, CDCl3) 166.12, 163.81, 158.97, 133.34, 113.62,

107.02, 103.64, 103.45, 68.36, 55.47, 51.55, 32.81, 23.35. HRMS EI

M+ m/z calcd for C13H16O5 M

+ = 252.0998, found = 252.1001.

N-Phenyl-2-(tetrahydrofuran-2-yloxy)benzamide: (Table 2, Entry

10, 3j) Isolated yield = 45% ; 1H NMR (300 MHz, CDCl3) 9.79 (br,

1H), 8.25 (dd, J = 1.51, 7.55 Hz, 1H), 7.66 (d, J = 7.55 Hz, 2H), 7.26-

7.48 (m, 4H), 7.09-7.17 (m, 2H), 6 (dd, J = 1.51, 3.77 Hz, 1H), 4.12-

4.19 (m, 1H), 4-4.08 (m, 1H), 2.03-2.37 (m, 4H). 13

C NMR (75

MHz, CDCl3): 163.2, 154.7, 138.4, 133, 132.1, 129, 124, 122.3,

119.8, 115.6, 103.8, 68.7, 33.1, 23.2. MS (ESI): m/z = 306 (M+Na)+.

HRMS ESI (M+Na)+ m/z calcd for C17H17NO3Na (M+Na)

+ =

306.11006, found = 306.10954.

1-(2-(1,2-Dimethoxyethoxy)phenyl)ethanone: (Table 2, Entry 11,

3kA) Isolated yield = 65% ; 1H NMR (300 MHz, CDCl3) 7.70 (dd, J

= 1.51, 7.55 Hz, 1H), 7.41-7.47 (m, 1H), 7.16 (d, J = 8.3 Hz, 1H),

7.04-7.1 (m, 1H), 5.4 (t, J = 5.28 Hz, 1H), 3.61-3.73 (m, 2H), 3.45 (s,

3H), 3.42 (s, 3H), 2.65 (s, 3H). 13

C NMR (75 MHz, CDCl3): 199.8,

156, 132.2, 130.6, 122, 116.1, 101.5, 72, 59.2, 53.9, 31.6.. MS (ESI):

m/z = 247 (M+Na)+. HRMS ESI (M+Na)

+ m/z calcd for C12H16O4Na

(M+Na)+

= 247.09408, found = 247.09399.

O O

O

O

O

NH

O

O

OO

O

O

Chapter G

204

1-(2-((2-Methoxyethoxy)methoxy)phenyl)ethanone: (Table 2, Entry

11, 3kB) Isolated yield = 12 % ; 1H NMR (300 MHz, CDCl3) 7.7

(dd, J = 1.51, 7.55 Hz, 1H), 7.41-7.47 (m, 1H), 7.23 (d, J = 8.3 Hz,

1H), 7.05 (t, J = 7.55 Hz, 1H), 5.38 (s, 2H), 3.84-3.87 (m, 2H), 3.55-

3.58 (m, 2H), 3.38 (s, 3H), 2.63 (s, 3H). 13

C NMR (75 MHz ,CDCl3):

199.8, 156.2, 133.4, 130, 129, 121.6, 114.8, 93.4, 71.4, 68, 59,

31.7.MS (ESI): m/z = 247 (M+Na)+. HRMS ESI (M+Na)

+ m/z calcd

for C12H16O4Na (M+Na)+

= 247.09408, found = 247.09399.

(2-(1,2-Dimethoxyethoxy)-4-methoxyphenyl)(phenyl) methanone:

(Table 2, Entry 12, 3lA) Isolated yield = 41 % ; 1H NMR (300 MHz,

CDCl3) 7.76 (d, J = 7.17 Hz, 2H), 7.53 (t, J = 7.93 Hz, 1H), 7.38-7.44

(m, 3H), 6.77 (d, J = 2.26 Hz, 1H), 6.65 (dd, J = 2.26, 8.3 Hz, 1H),

5.19-5.22 (m, 1H), 3.85 (s, 3H), 3.32-3.38 (m, 1H), 3.28 (s, 3H), 3.26

(s, 3H), 3.1-3.15 (m, 1H). 13

C NMR (75 MHz, CDCl3): 195.4,

162.9, 156.5, 138.9, 132.1, 131.6, 129.3, 127.8, 122.7, 107, 102.8,

100.9, 71, 59, 55.3, 52.7. MS (ESI): m/z = 339 (M+Na)+. HRMS ESI


+ = 339.12029, found =

339.11966.

(4-Methoxy-2-((2-methoxyethoxy)methoxy)phenyl)(phenyl)

methanone: (Table 2, Entry 12, 3lB) Isolated yield = 18 % ; 1H NMR

(300 MHz, CDCl3) 7.78 (d, J = 7.3 Hz, 2H), 7.53 (t, J = 7.3 Hz, 1H),

7.41 (t, J = 8.1 Hz, 3H), 6.8 (d, J = 2 Hz, 1H), 6.62 (dd, J = 2, 8.4 Hz,

1H), 5.11 (s, 2H), 3.85 (s, 3H), 3.6-3.63 (m, 2H), 3.45-3.48 (m, 2H),

3.34 (s, 3H). 13

C NMR (75 MHz CDCl3): 195.5, 163, 157, 138.8,

132.3, 131.6, 129.5, 128, 122.3, 106.8, 101.6, 93.7, 71.3, 67.7, 58.8,


+ m/z calcd

for C18H20O5Na (M+Na)+

= 339.12029, found = 339.11982.

1-(2-(1,2-Dimethoxyethoxy)-5-methylphenyl)propan-1-one: (Table

2, Entry 13, 3m) Isolated yield = 35% ; 1H NMR (300 MHz, CDCl3)

7.57 (br, 1H), 7.23-7.27 (m, 1H), 7.08 (d, J = 8.49 Hz, 1H), 5.27 (t, J =

4.72 Hz, 1H), 3.88 (s, 3H), 3.61-3.72(m, 2H), 3.46 (s, 3H), 3.42 (s,

3H), 2.31 (s, 3H). 13

C NMR (75 MHz ,CDCl3): 166.6, 154, 133.6,

131.4, 122, 118.4, 102.6, 72.1, 59.2, 53.9, 51.8, 20.2. MS (ESI): m/z =

277 (M+Na)+. HRMS ESI (M+Na)


(M+Na)+

= 277.10464, found = 277.10429.

Chapter G

205

Methyl 2-(1,2-Dimethoxyethoxy)-4-methoxybenzoate: (Table 2,

Entry 14, 3nA) Isolated yield = 64% ; 1H NMR δ (300 MHz, CDCl3)

7.84 (d, J = 8.8 Hz, 1H), 6.75 (d, J = 2.4 Hz, 1H), 6.61 (dd, J = 8.8,

2.4 Hz, 1H), 5.34 (dd, J = 5.9, 4.5 Hz, 1H), 3.87 (s, 3H), 3.85 (s, 3H),

3.76 (dd, J = 10.6, 6.0 Hz, 1H), 3.68 (dd, J = 10.6, 4.4 Hz, 1H), 3.48

(s, 3H), 3.45 (s, 3H). 13

C δ NMR (75 MHz, CDCl3) 165.99, 163.79,

158.64, 133.40, 114.15, 107.39, 104.25, 102.39, 72.14, 59.46, 55.52,

53.82, 51.72. HRMS EI M+ m/z calcd for C13H18O6 M

+ = 270.1104,

found = 270.1103.

Methyl 4-Methoxy-2-((2-methoxyethoxy)methoxy)benzoate (Table

2, Entry 14, 3nB) Isolated yield = 20% ; 1H NMR δ (300 MHz,

CDCl3) 7.83 (d, J = 8.7 Hz, 1H), 6.79 (d, J = 2.3 Hz, 1H), 6.58 (dd, J

= 8.8, 2.3 Hz, 1H), 5.35 (s, 2H), 3.94 – 3.87 (m, 2H), 3.86 (s, 3H),

3.84 (s, 3H), 3.62 – 3.53 (m, 2H), 3.39 (s, 3H). 13

C NMR δ (75 MHz,

CDCl3) 165.89, 163.80, 158.97, 133.34, 113.33, 107.13, 102.64,

94.18, 71.50, 67.94, 59.00, 55.53, 51.71. HRMS EI M+ m/z calcd for

C13H18O6 M+

= 270.1104, found = 270.1104.

1-(2-(Tetrahydro-2H-pyran-2-yloxy)phenyl)ethanone: (Table 2,

Entry 15, 3o) Isolated yield = 76%; 1H NMR (300 MHz, CDCl3)

7.71 (dd, J = 1.51, 7.55 Hz, 1H), 7.43 (td, J = 2.26, 9.06 Hz, 1H),

7.23-7.26 (m, 1H), 7-7.05 (m, 1H), 5.55 (t, J = 3.77 Hz, 1H), 3.88 (td,

J = 3.02, 11.3 Hz, 1H), 3.64-3.71(m, 1H), 2.67 (s, 3H), 1.91-1.97 (m,

3H), 1.61-1.8 (m, 5H). 13

C NMR (75 MHz, CDCl3):199.5, 156.1,

133.3, 129.7, 128.4, 121, 114.8, 96.4, 61.7, 31.7, 29.9, 24.7, 18.6. MS


+ m/z calcd for

C13H16O3Na (M+Na)+

= 243.09917, found = 243.09909.

(Z)-Ethyl 3-(1,4-Dioxan-2-yloxy)-3-phenylacrylate: (Scheme 3, 5a)

Isolated yield = 53%; 1H NMR (300 MHz, CDCl3) 7.56-7.6 (m, 2H),

7.37-7.43 (m, 3H), 5.69 (s, 1H), 5.26 (t, J = 2.07 Hz, 1H), 4.36 (td, J =

3.21, 9.63 Hz, 1H), 4.21 (qd, J = 1.13, 7.17 Hz, 2H), 4.03 (dd, J =

2.67, 11.89 Hz, 1H), 3.67-3.84 (m, 3H), 3.49 (dt, J = 2.83, 11.7 Hz,

1H), 1.31 (t, J = 7.17 Hz, 3H). 13

C NMR (75 MHz, CDCl3): 164.8,

164.6, 134.8, 133.6, 130.1, 128.6, 128.4, 127.3, 103.3, 95.7, 67.9,

65.8, 61.4, 59.7, 14.1. MS (ESI): m/z = 301 (M+Na)+. HRMS ESI


+ = 301.10464, found =

301.10407.

O

OO

O

O

OO

O

Chapter G

206

(Z)-Benzyl 3-(1,4-dioxan-2-yloxy)but-2-enoate: (Scheme 3, 5b)

Isolated yield = 60%; 1H NMR (300 MHz, CDCl3) 7.26-7.36 (m,

5H), 5,25 (s, 1H), 5.08-5.18 (m, 3H), 4.12-4.2 (m, 1H), 3.7-3.88 (m,

4H), 3.52 (d, J = 11.3 Hz, 1H), 2.06 (s, 3H). 13

C NMR (75

MHz ,CDCl3): 165.2, 164.4, 136.3, 128.2, 127.9, 127.7, 99.8, 93,

67.6, 65.6, 65.1, 61.2, 19.4. MS (ESI): m/z = 301 (M+Na)+. HRMS

ESI (M+Na)+ m/z calcd for C15H18O5Na (M+Na)

+ = 301.10464, found

= 301.10426.

(Z)-Ethyl 3-(1,4-Dioxan-2-yloxy)-2-methylbut-2-enoate: (Scheme 3,

5c) Isolated yield = 37%; 1H NMR (300 MHz, CDCl3) 5.04 (t, J =

2,26 Hz, 1H), 4.13-4.23 (m, 3H), 3.77 (d, J = 2.26 Hz, 2H), 3.7-3.73

(m, 2H), 3.55 (dt, J = 3.02, 12.08 Hz, 1H), 2.01 (s, 3H), 1.83 (s, 3H),

1.3 (t, J = 6.79 Hz, 3H). 13

C NMR (75 MHz, CDCl3): 168.2, 155.7,

110.6, 94.2, 68.2, 65.8, 61.5, 60.1, 16, 14.5, 14.1. MS (ESI): m/z =

253 (M+Na)+. HRMS ESI (M+Na)


(M+Na)+

= 253.10464, found = 253.10443.

(Z)-Ethyl 3-(1,4-dioxan-2-yloxy)but-2-enoate: (Scheme 3, 5d)

Isolated yield = 55%; 1H NMR (300 MHz, CDCl3) 5.27 (br, 1H),

5.09 (s, 1H), 4.08-4.25 (m, 3H), 3.69-3.92 (m, 4H), 3.56 (dt, J = 2.26,

12.08 Hz, 1H), 2.06 (s, 3H), 1.26 (t, J = 6.04 Hz, 3H). 13

C NMR (75

MHz, CDCl3): 164.7, 100.5, 93, 67.7, 65.7, 61.2, 59.2, 19.4, 14.1. MS


+ m/z calcd for

C10H16O5Na (M+Na)+

= 239.08899, found = 239.08879.

(Z)-tert-Butyl 3-(1,4-Dioxan-2-yloxy)but-2-enoate: (Scheme 3, 5e)

Isolated yield = 61%; 1H NMR (300 MHz, CDCl3) 5.24 (t, J = 2,26

Hz, 1H), 5.01 (s, 1H), 4.13-4.21 (m, 1H), 3.72-3.91 (m, 4H), 3.56 (dt,

J = 3.02, 11.7 Hz, 1H), 2.02 (s, 3H), 1.47 (s, 9H). 13

C NMR (75

MHz, CDCl3): 164.1, 163.1, 102.2, 92.9, 79.1, 67.7, 65.6, 61.2, 28,


+ m/z calcd

for C12H20O5Na (M+Na)+= 267.12029, found = 267.12.

(Z)-Ethyl 3-(1,4-Dioxan-2-yloxy)-2-benzylbut-2-enoate: (Scheme 3,

5f) Isolated yield = 60%; 1H NMR (300 MHz, CDCl3) 7.14-7.29 (m,

5H), 5.1 (t, J = 2.26 Hz, 1H), 4.1-4.24 (m, 3H), 3.8 (t, J = 3.58 Hz,

2H), 3.71-3.76 (m, 2H), 3.65 (d, J = 4.72 Hz, 2H), 3.57 (dt, J = 3.02,

11.7 Hz, 1H), 2.07 (s, 3H), 1.2 (t, J = 7.17 Hz, 3H). 13

C NMR (75

MHz, CDCl3): 167.6, 157.5, 139.5, 128.2, 127.8, 125.9, 114.2, 94,

68.1, 65.8, 61.4, 60.1, 34.4, 16, 14. MS (ESI):m/z = 329 (M+Na)+.

HRMS ESI (M+Na)+ m/z calcd for C17H22O5Na (M+Na)

+ =

329.13594, found = 329.13547.

O

OO

O

O

O

OO

O

O

O

O

O

O

O

O

O

O

O

O

Chapter G

207

(Z)-Isopropyl 3-(1,4-Dioxan-2-yloxy)but-2-enoate: (Scheme 3, 5g)

Isolated yield = 61%; 1H NMR δ (300 MHz, CDCl3) 5.35 – 5.20 (m,

1H), 5.18 – 4.96 (m, 2H), 4.34 – 4.16 (m, 1H), 4.00 – 3.68 (m, 4H),

3.64 – 3.50 (m, 1H), 2.09 (s, 3H), 1.27 (s, 3H), 1.25 (s, 3H). 13

C NMR

δ (75 MHz, CDCl3) 164.43, 101.41, 93.37, 68.02, 66.48, 65.93, 61.53,

29.70, 22.00, 19.74. HRMS EI M+ m/z calcd for C11H18O5 M

+ =

230.1154, found = 230.1185.

(Z)-Allyl 3-(1,4-Dioxan-2-yloxy)but-2-enoate: (Scheme 3, 5h)

Isolated yield = 61%; 1H NMR (300 MHz, CDCl3).

1H NMR δ (300

MHz, CDCl3) 6.05 – 5.85 (m, 1H), 5.41 – 5.02 (m, 4H), 4.60 (dd, J =

5.6, 1.0 Hz, 2H), 4.21 (ddd, J = 11.7, 8.5, 3.5 Hz, 1H), 3.95 – 3.65 (m,

4H), 3.56 (dt, J = 11.6, 3.0 Hz, 1H), 2.08 (s, 3H). 13

C NMR δ (75

MHz, CDCl3) 165.33, 164.37, 132.76, 117.65, 100.31, 93.35, 67.97,

65.90, 64.24, 61.55, 29.69. HRMS EI M+ m/z calcd for C11H16O5 M

+ =

228.0998, found = 228.1010.

General Procedure for Acetal Synthesis under Microwave Irradiation (Table S5): A 10

mL Pyrex vessel was equipped with 2-hydroxyacetophenone (1a) (120 µL, 1 mmol) and

Cu(OAc)2 (4.5 mg, 2.5 mol%). Afterwards the respective ether (2 mL) and 180 µL (1 equiv)

of a 5-6 M tert-butylhydroperoxide solution in decane were added. The vials were closed and

irradiated in a single-mode microwave reactor for 5 min (fixed hold time) at 135 °C (internal

reaction temperature). After cooling to 45 °C by compressed air, an additional amount of 180

µL of a 5-6 M tert-butylhydroperoxide solution in decane was added before a second

irradiation cycle for 5 min (fixed hold time) at 135 °C was carried out. The mixture was

treated a third time with 180 µL of a 5-6 M tert-butylhydroperoxide solution in decane and

heated for 10 min (fixed hold time) at 135 °C. The cooled reaction mixture was concentrated

under vacuum before the desired products were isolated by silica gel flash column

chromatography using petroleum ether/ ethyl acetate as eluent.

Characterization data for 3p and 3q not obtainable using the reflux method:

1-(2-(tert-Butoxymethoxy)phenyl)ethanone (Table S5, Entry 3, 3p)

Isolated yield: 20%; 1H NMR (300 MHz, CDCl3) δ 7.72 (d, J = 6.0

Hz, 1H), 7.45 (t, J = 7.8 Hz, 1H), 7.32 – 7.22 (m, incl. CHCl3), 7.03 (t,

J = 7.5 Hz, 1H), 5.43 (s, 2H), 2.63 (s, 3H), 1.32 (s, 9H). 13

C NMR (75

MHz, CDCl3) δ 200.07, 157.00, 133.50, 130.03, 128.77, 121.12,

114.94, 88.14, 75.90, 32.00, 28.55. HRMS EI M+ m/z calcd for

C13H18O3 M+

= 222.1256, found = 222.1260.

O

O

O

O

O

Chapter G

208

1-(2-(1-Ethoxyethoxy)phenyl)ethanone (Table S5, Entry 4, 3q)

Isolated yield: 54%; 1H NMR (300 MHz, CDCl3) δ 7.72 (d, J = 6.1

Hz, 1H), 7.44 (t, J = 7.0 Hz, 1H), 7.16 (d, J = 8.3 Hz, 1H), 7.04 (t, J =

7.8 Hz, 1H), 5.54 (q, J = 5.3 Hz, 1H), 3.83 – 3.68 (m, J = 14.1, 7.1 Hz,

1H), 3.64 – 3.50 (m, 1H), 2.66 (s, 3H), 1.58 (d, J = 5.3 Hz, 3H), 1.21

(t, J = 7.0 Hz, 3H). 13

C NMR (75 MHz, CDCl3) δ 200.27, 156.21,

133.36, 130.20, 129.69, 121.51, 115.81, 99.61, 61.13, 31.95, 20.12,

15.19. HRMS EI M+ m/z calcd for C12H16O3 M

+ = 208.1099, found =

208.1106.

General Procedure for Acetal Synthesis Using a One or Two-feed Method in the

FlowSyn Reactor (Figure 1 and Table S8). Feed A consisted of 2-hydroxyacetophenone

(1a) (1.2 mL, 10 mmol) and Cu(OAc)2 (45 mg, 2.5 mol%) dissolved in 20 mL of the

respective ether, whereas feed B was simply composed of the commercial available 5-6 M

tert-butylhydroperoxide solution in decane. Streams A and B were mixed together at a flow

rate of 0.80 and 0.20 mL min-1

, respectively in a 2 mL glass static mixer at room temperature

and the resulting stream (1.0 mL min-1

) was passed through the stainless steel reactor coil

(~20 mL heated volume, 20 min residence time) at 130 °C (in case of 1 feed experiments all

components were mixed before entering the flow reactor (1 mL min-1

) and the glass static

mixer/T-mixer was removed). The reaction mixture left the reactor through a 17 bar back

pressure regulator (for 1 feed experiments a 34 bar back pressure regulator was used). The

cooled reaction mixture was concentrated under vacuum before the desired products were

isolated by silica gel flash column chromatography using petroleum ether/ ethyl acetate as

eluent. Nearly equal results were obtained using the one- and two-feed strategies.

References

[S1] For further details on the Monowave 300 microwave reactor, see: (a) D. Obermayer,

C. O. Kappe, Org. Biomol. Chem. 2010, 8, 114; (b) D. Obermayer, B. Gutmann, C.

O. Kappe, Angew. Chem. Int. Ed. 2009, 48, 8321.

[S2] For further details on the specific FlowSyn reactor configuration, see: B. Gutmann, J.-

P. Roduit, D. Roberge, C. O. Kappe, J. Flow Chem. 2012, 2, 8; and

www.uniqsis.com.

http://www.uniqsis.com/

Chapter H

209

H. Immobilized Iron Oxide Nanoparticles as Stable and Reusable

Catalysts for Hydrazine-mediated Nitro Reductions in Continuous

Flow

Graphical Abstract

Abstract

An experimentally easy to perform method for the generation of alumina supported Fe3O4

nanoparticles (6 1 nm size, 0.67 wt.%) and the use of this material in hydrazine-mediated

heterogeneously catalyzed reductions of nitroarenes to anilines under batch and continuous

flow conditions is presented. The bench stable, re-useable nano-Fe3O4@Al2O3 catalyst can

selectively reduce functionalized nitroarenes at 1 mol% catalyst loading using 20 mol%

excess of hydrazine hydrate in an elevated temperature regime (150 °C, reaction time 2-6 min

in batch). For continuous flow processing the catalyst material is packed into dedicated

cartridges and used in a commercially available high-temperature/pressure flow device. In

continuous mode reaction times can be reduced to less than one minute at 150 °C (30 bar

back pressure) in a highly intensified process. The nano-Fe3O4@Al2O3 catalyst demonstrated

stable reduction of nitrobenzene (0.5 M in MeOH) for more than 10 h on stream at a

productivity of 30 mmol h-1

(0.72 mol per day). Importantly, virtually no leaching of the

catalytically active material could be observed by ICPMS monitoring.

Chapter H

211

1. Introduction

Continuous processing is a long and well-established technique for the synthesis of

commodity chemicals on industrial scale. The more recent fusion of continuous processing

with microfabrication technology has resulted in an increasing implementation of

microreactors for the synthesis of not only commodity chemicals, but also fine chemicals and

pharmaceuticals.[1,2]

In these devices, where channel or capillary diameters are typically

below 1000 μm, heat and mass transfer can be orders of magnitude higher as compared to

classical batch reactors, thereby allowing exquisite control over chemical reactivity. Flow

chemistry under these conditions often benefits from extremely fast mixing of reagent streams

as well as very accurate reaction time (residence time) and temperature control. This allows

chemists to carry out chemical transformations with a level of selectivity which typically is

impossible to reproduce in a traditional stirred batch reactor.[3]

Furthermore, combustion and

explosion hazards are reduced in microreactors and, consequently, unusually harsh process

conditions, for example, reactions in the explosive or thermal runaway regime, can be

exploited in a safe and controllable manner.[4]

Hazardous reagents can be generated on

demand leading to a significantly reduced operator exposure and no need for storage or

shipping of such materials.[1,2,4]

As flow reactors can easily operate at higher pressures, low

boiling solvents or even supercritical fluids can be used in a high-temperature regime,

resulting in more convenient isolation processes. Therefore, continuous flow chemistry seems

to be an ideal tool for sustainable chemical synthesis.[5]

A key feature of this enabling technology is the straightforward implementation of

heterogeneous catalysis in a continuous flow transformation, since the catalyst can be easily

immobilized in a specific regions of the flow path.[6]

The separation of the reaction mixture

from the solid catalyst occurs simultaneous to the desired chemical transformation with the

catalytically active material remaining in the flow reactor system. Several different catalyst

immobilization techniques in conjunction with microreactor technology have been described,

including for example the use of packed-bed catalyst cartridges or the direct immobilization

of catalysts inside the channels of microreactors.[6]

Owing to the large interfacial areas and the

short path required for molecular diffusion in the narrow microchannel space very efficient

liquid/solid (i.e., substrate/catalyst) interaction takes place which is not attainable in normal

batch systems.[6]

A particularly attractive theme in this context is the use of immobilized

nanometer-sized metal catalysts in continuous flow mode. The nanosize of these catalyst

materials leads to a vast surface area to volume ratio and, therefore, to an enhanced contact

between reactants and catalyst which may increase the activity dramatically.[7,8]

Finely

Chapter H

212

dispersed metal (including metal oxide) nanoparticles (NPs) can be readily supported and

stabilized on e.g., porous silica, alumina, zeolithes, or a variety of mesopouros materials, and

thus appear to be almost ideal catalysts for packed-bed flow reactors.[9]

These often extremely

active catalytic systems can be considered as a bridge between homogeneous and

heterogeneous catalysis, combining several of the key advantages of both types of

catalysis.[7,8]

Nanoscale-iron based catalysts in particular are of considerable current interest as iron

is an abundant, eco-friendly, relatively non-toxic, and inexpensive element, and thus a very

welcome alternative for the use of precious metal catalysts.[10,11]

In this context we have

recently demonstrated that colloidal nano-Fe3O4 is as a highly reactive catalyst for the

selective reduction of aromatic nitro groups to anilines employing hydrazine as a reducing

agent.[12]

Functionalized anilines are key intermediates in the synthesis of dyes, pigments,

agrochemicals, and pharmaceuticals, and the reduction of aromatic nitro compounds clearly is

the most commonly used method of preparation.[13,14]

Our new iron-based method therefore

has the potential to replace traditional precious metal-based hydrogenation protocols that rely

on the use of palladium, platinum, ruthenium, or other expensive, scarce and toxic transition

metals. In our 2012 protocol, magnetic nano-Fe3O4, was generated in situ from the reaction of

an iron salt and hydrazine hydrate (N2H4·H2O) in methanol at elevated temperature.[12]

The

highly reactive colloidal catalyst induced complete and selective reduction of a large array of

nitroarenes to the corresponding anilines within 2-8 min at 150 °C employing only 0.25 mol%

of catalyst and 20 mol% excess of N2H4·H2O, reaching catalyst turnover frequencies (TOF) of

up to 12000 h-1

(Figure 1a).[12]

This method only generates nitrogen gas as stoichiometric

byproduct, and can be performed in both batch and continuous flow mode. In the continuous

process, the catalyst precursor Fe(acac)3, N2H4·H2O and the substrate were dissolved in

methanol and pumped through a heated (150 °C) stainless steel coil using a single HPLC

pump. After exiting the flow device the catalyst aggregated allowing for an easy retrieval of

the magnetic material.[12]

In order to simplify the continuous flow procedure for this

industrially relevant reduction process the development of a stable and robust heterogeneous

(i.e., immobilized) version of the nano-Fe3O4 catalyst would be highly desirable.

Chapter H

213

Previous work

Current work

NO2

R

Fe(acac)3N2H4 · H2O

NO2

R

N2H4 · H2O

inert Al2O3 support

nano-Fe3O4

NH2

R

aggregatednano-Fe3O4

NH2

R

Pump

Heated stainlesssteel coil

Heat exchanger

Back pressureregulator

Packed bed reactor

a) Continuous flow: nitro reduction using hydrazine and colloidal iron oxide nanoparticles

nano-Fe3O4in situ

b) Batch: nitro reduction using hydrazine and supported iron oxide nanoparticles

c) Continuous nitro reduction using hydrazine and supported iron oxide nanoparticles

Pump Back pressureregulator

NO2

R

Fe on support

N2H4 · H2O

batch

NH2

R

Kappe et al. [ref. 14]

TOF = 12000 h-1

Beller et al. [ref. 20]

Fe(OAc)2/1,10-phenanthroline on Vulcan XC72R: TOF 10 h-1

Chen et al. [ref. 21]

Fe3O4 on graphene oxide composite: TOF 218 h-1

Figure 1. Previous and current strategies for the reduction of nitroarenes with iron oxide

catalysts and hydrazine.

Several reports in the literature describe the use of iron-based catalysts in combination with

hydrazine as reducing agent for the preparation of anilines from nitroarenes in batch mode.[15-

19] Notably, Beller and co-workers have described the selective reduction of nitroarenes with

hydrazine using pyrolyzed carbon–supported Fe(OAc)2-phenanthroline complexes as a

recyclable catalysts.[18]

Excellent selectivities were achieved at 100 °C using a 1 mol% Fe

loading and a 10 h reaction time. Another example of an immobilized iron oxide catalyst was

recently presented by Chen and coworkers using graphene oxide as support.[19]

Their protocol

allows nitro reductions within 18-40 min in excellent yields and selectivities. From an

industrial point of view, these catalysts lack the necessary efficiency to be practical on

production scale as the calculated turnover frequencies (TOF) range from 5 h-1

to 218 h-1

and

are therefore too low to be of practical use for manufacturing purposes (Figure 1b).[15-19]

Herein, we present a protocol for the rapid preparation of a highly efficient nano-

Fe3O4 catalyst immobilized on basic alumina for the continuous reduction of nitroarenes to

anilines using hydrazine hydrate as hydrogen donor and methanol as solvent. The shelf stable

Chapter H

214

and reusable catalyst can be employed as a packed-bed catalyst for continuous processing

under high –temperature/high-pressure conditions. This heterogeneous system shows

excellent performance and turnover frequencies for the production of anilines with residence

times in the range of 10-70 seconds at 150 °C and 30 bar back pressure (Figure 1c). Using

carefully optimized reaction conditions virtually no decrease in catalyst activity was observed

for several hours.


2.1 Synthesis, Evaluation and Characterization of Supported Fe3O4

Nanoparticles

In an initial study, the ability of traditional chromatography grade silica, mesopourus silica

(SBA15), aluminum-substituted mesoporous silica (Al-SBA15) and basic alumina to function

as support materials for iron oxide nanocrystals was carefully investigated (see the

Experimental Section on the specifics of these support materials). As previously reported by

our group, treatment of iron salts with N2H4 · H2O at high temperatures (methanol, 150 °C,

sealed vessel microwave irradiation) effectively generates colloidal Fe3O4 NPs (62 nm) more

or less immediately, which subsequently slowly start to agglomerate upon cooling.[12]

We

therefore assumed that the colloidal Fe3O4 NPs produced in this way could be stabilized and

immobilized onto an appropriate support material by simple adding the support to the

microwave-assisted nanoparticle generation step. Thus, the respective inert material (500 mg),

the catalyst precursor Fe(acac)3 (0.065 mmol) and hydrazine monohydrate (1 mmol) were

heated in 5 mL of methanol under sealed-vessel microwave conditions in order to obtain a

supported catalyst with a nominal Fe3O4 loading of 1 wt.% (nominal Fe loading 0.73 wt.%).

The mixture was irradiated for 10 min at 150 °C (~16 bar) in a single mode microwave

reactor (Monowave 300, Anton-Paar) using an optimized heating ramp.[20,21]

This

impregnation methodology resulted in a visually uniform material when SBA15, Al-SBA15

or alumina was used as support. In contrast, in the case of silica a non-uniform

catalyst/support mixture was obtained. It appears that in the latter case the Fe3O4 NPs simply

agglomerated without quantitative fixation on the surface of the inert material. This support

material was therefore not considered any further.

With three types of supported Fe3O4 catalysts in hand we moved on to explore the

suitability of these materials for the hydrazine-mediated reduction of nitroarenes. The

Chapter H

215

synthesis of aniline from nitrobenzene was chosen as representative model reaction to

evaluate the catalytic efficiency as well as any potential loss of activity or leaching during

catalyst recycling (Figure 2).

Figure 2. Catalyst recycling for the hydrazine-mediated reduction of nitrobenzene using

Fe3O4 NPs on different supports.

The hydrazine mediated reactions were carried out on a 2 mmol scale in methanol using 20

mol% stoichiometric excess of hydrazine hydrate (3.6 mmol)[22]

and 500 mg of the respective

supported catalyst which theoretically corresponds to 1 mol% Fe3O4 catalyst loading

assuming a nominal Fe3O4 loading of 1wt% (0.065 mmol of the iron precursor, Fe(acac)3,

corresponds to 0.022 mmol Fe3O4). The individual reaction mixtures were heated to 150 °C

using controlled microwave irradiation for 2 min. Due to the exothermic nature of these

hydrazine-based nitro reductions at high-temperature, the so-called “simultaneous cooling”

technique was used.[23]

By applying this procedure the reaction mixture is cooled with

compressed air during microwave heating to avoid the occurrence of exotherms which results

in reproducible heating profiles and safe processing of the microwave experiments.[24]

The catalyst support screening showed a quantitative conversion of the nitroarene

when alumina was used as support material as determined by GC-FID analysis. Mesoporous

silica and its alumina-substituted analog resulted in conversions around 90 %. In order to

Chapter H

216

determine a possible loss of activity or leaching of the catalytically active species from the

support, 10 cycles were carried out with each catalyst support. For this purpose, the solid

material was retrieved after each reaction by filtration and washed several times with

methanol before adding a fresh solution of nitrobenzene and hydrazine hydrate in methanol.

As clearly demonstrated in Table 1 standard chromatography grade basic alumina is far

superior as support material compared to SBA15 and Al-SBA15.[25]

Quantitative conversions

were obtained for 8 cycles utilizing the same recycled catalyst material, with very minor

losses of activity being observed for the 9th

and 10th

cycle. In fact, alumina was already

applied successfully as support for Fe2O3 nanocrystals for the production of olefins from

synthesis gas (H2/CO),[26]

but to the best of our knowledge immobilization of magnetite

(Fe3O4) on this support has so far not been reported. In contrast to alumina, SBA15 and Al-

SBA15 showed an unsatisfactory recycling behavior. After 5 cycles the conversion of the

nitroarene was already reduced to less than 50%. This is presumably a result of leaching of

the catalytically active species from the support during the reaction, leading to homogenous

iron oxide colloids which were removed by the applied washing procedure. Although SBA15

and Al-SBA15 have previously been successfully used as support for iron oxide

nanoparticles,[27]

it appears that under our reaction conditions the metal particles are either not

properly immobilized or leach during the reduction process.

Figure 3. TEM images of the nano-Fe3O4@Al2O3 particles at different degrees of

magnification. The active catalyst is largely dispersed and homogeneously distributed over

the alumina surface. The average Fe3O4 particle size is ca. 6±1 nm. For an XRD

characterization of the nano-Fe3O4 particles without support see ref. 12.

Chapter H

217

Aluminum oxide appears to be an appropriate material for this experimentally very simple

immobilization technique and analysis of the iron oxide supported on alumina (nano-

Fe3O4@Al2O3) by transmission electron microscopy (TEM) indeed showed finely dispersed

and homogeneously distributed nanoparticles on the alumina surface (Figure 3). The average

particle size was determined as 6±1nm and is therefore in good agreement with previous

observations of unsupported (colloidal) Fe3O4 nanoparticles which were synthesized by a

similar method (6±2 nm).[12]

Analysis of the iron content of the supported material by ICPMS

showed an iron loading of 0.67 ± 2 wt.% (corresponding to 0.93 wt.% of Fe3O4) which is in

good agreement with the theoretical value (73 wt.% Fe/1 wt.% Fe3O4). A further ICPMS

screening on possible catalytically active transition metal impurities showed no significant

amounts of other metal species (see Experimental Section for details).

2.2 Bench Stability of nano-Fe3O4@Al2O3

The efficient and reusable nano-Fe3O4@Al2O3 system was further analyzed by a simple set of

experiments concerning its sensitivity to air and humidity over a longer time period to

determine a possible change in the catalytic activity. Therefore, 5 g of the alumina supported

catalyst were prepared and stored in an open flask. During a period of 10 weeks, 500 mg of

nano-Fe3O4@Al2O3 were taken every 7 days and applied for the batch reduction of

nitrobenzene. Conditions were similar to the support evaluation experiments described above.

Gratifyingly, the activity of the catalytic system was very stable during the whole period

showing only a slight decrease in activity after the first 5 weeks, then stagnating at 95%

conversion (Figure 4).

Figure 4. Shelf stability of nano-Fe3O4@Al2O3 over a period of 10 weeks.

0

20

40

60

80

100

1 2 3 4 5 6 7 8 9 10

Co

nve

rsio

n [

%]

Week

Chapter H

218

2.3 Scope and Limitations in Batch

With the highly active and stable supported nano-Fe3O4 catalyst in hand we moved on to

evaluate the synthetic applicability and functional group tolerance of the system on a series of

nitroarenes. Special emphasis was placed on the homogeneity of the reaction mixture (except

for the nano-Fe3O4@Al2O3) in order to later translate the batch microwave conditions to a

flow protocol following the well-established “microwave-to-flow paradigm”.[28]

We therefore

carried out several microwave batch experiments using 1 mmol of the respective nitroarene in

the presence of 1.8 equivalents hydrazine hydrate (20 mol% excess) and 500 mg nano-

Fe3O4@Al2O3 (0.93 wt.% of Fe3O4 loading, corresponding to 2 mol%) for an initial screening

of the reaction conditions (Table 1).

Table 1. Reduction of nitroarenes with N2H4·H2O catalyzed by nano-Fe3O4@Al2O3 using

batch microwave heating[a]

Entry Substrate t [min] Solvent Conversion

(Selectivity)[b]

[%]

1 C6H5 2 MeOH >99 (>99)

2 2-Cl-C6H4 4 MeOH >99 (>99)

3 3,4-(Cl)2-C6H3 3 MeOH >99 (>99)

4 6-quinolinyl 3 DMF >99 (>99)

5 4-(pyridin-4-ylmethyl) 3 MeCN:DMF (20:1) >99 (>99)

6 4-MeO-C6H4 6 MeCN:DMF (20:1) >99 (>99)

7 2,5-(EtO)2-C6H3 6 MeOH >99(>99)

8 3-(CO2Me)-C6H4 3 CH3CN >99 (>99)

9 3-NC-C6H4 2 CH3CN:DMF (20:1) >99 (>99)

10 4-NH2-C6H4 6 MeOH:DMF (20:1) >99 (>99)

11 4-F-C6H4 2 MeOH 95 (>99)

[a] Conditions: 1 mmol ArNO2, 1.8 mmol of N2H4·H2O, 2 mL solvent, 500 mg nano-Fe3O4@Al2O3 (0.93 wt.%

Fe3O4), single-mode microwave heating at 150 °C with simultaneous cooling (Monowave 300). [b]

Determined

as GC-FID peak area percent

Chapter H

219

In some cases (entries 4-6 and 8-10) the solvent system had to be changed in order to fully

dissolve the substrate and/or the resulting amine product. Excellent selectivities were reached

with high to full conversion within reaction times of 2 to 6 min at the conditions discussed

above (GC-FID). Importantly, we could neither observe dehalogenation for chloro- or fluoro-

substituted nitroarenes (entries 2, 3, and 11), nor other possible side reactions for cyano-,

amino-, ether-, ester-, or even heterocyclic moieties. Evidently, the hydrazine-based reduction

protocol will lead to the formation of hydrazone derivatives when ketone or aldehyde

functionalities are present in the starting material. Thus, other protocols using alternative

reducing agents such as silanes,[29]

siloxanes,[30]

or even molecular hydrogen[31]

in

combination with an iron catalyst could be used in such cases. The presence of unsaturated

carboncarbon bonds will also be troublesome, as diimide can be readily generated by

hydrazine oxidation with air, which would subsequently reduce olefinic double bonds in the

substrate or product.[32]

2.4 Continuous Flow Reactor

Continuous flow reactions were performed in an X-Cube™ flow reactor (ThalesNano, Figure

5A)[33]

which allows to perform heterogeneously catalyzed reactions using CatCart™

cartridges (ThalesNano, Figure 5B) at temperatures and pressures up to 200 °C and 150

bar.[34]

The cartridges (70 mm 4 mm with a total inner volume of 0.88 mL) were packed

with approximately 920 mg of nano-Fe3O4@Al2O3 (Figure 5C) and placed in the dedicated

heating zones. Determination of the dead volume of a representative packed cartridge

produced a value of around 600 µL. During a standard flow experiment, the reaction mixture

is pumped by a built-in HPLC pump (allowing flow rates from 0.1 to 3 mL min-1

) through the

heated catalyst cartridge and collected after passing the pressure regulating unit before

analysis or isolation of the desired amine species. A significant benefit from this continuous

flow-type processing is that the exothermicity of the nitro group reduction can be

appropriately controlled owing to the high surface-to-volume ratio inside the packed-bed

reactor and the resulting efficient heat transfer.[1,2,6]

In batch mode this phenomena has to be

controlled by “simultaneous cooling” (see above) even at small scales and thus a scale-up in

such traditional environments is troublesome.

Chapter H

220

Figure 5. Schematic description of the continuous flow setup performed in the X-Cube flow

reactor (A) using an exchangeable catalyst cartridge (CatCart®) system (B) containing

around 920 mg of nano-Fe3O4@Al2O3 (0. 67wt.% Fe/0.93 wt.% Fe3O4) (C).

2.5 Process Intensification in Continuous Flow

A continuous flow protocol for rapid nitroarene to aniline reductions is clearly of potential

industrial importance as several relevant molecules such as the fungicide Boscalid,[34d]

the

muscle relaxant Tizanidine,[35]

or the antibiotic Linezolid[36]

have nitroarene reductions as

intermediate steps in their production. Thus, an immobilized inexpensive iron oxide-based

catalyst inside a packed-bed reactor enables a synthetic procedure with a minimum of work-

up steps as catalyst separation is avoided. Furthermore, the protocol benefits from the fact that

only nitrogen and water are produced as waste, resulting in evaporation as the, in principal,

only necessary purification step. We therefore turned our attention into intensifying the

reduction process in a continuous flow regime. Thus, solutions of nitrobenzene and N2H4 ·

H2O (20 mol% excess) in methanol were pumped through the heated catalyst cartridge at

different conditions and analyzed by GC-FID (Table 2). Initial investigations were carried out

using different substrate concentrations employing a 0.5 mL min-1

flow rate at 150 °C and 30

Chapter H

221

bar back pressure (entries 1-3). Gratifyingly, even at a 1 molar concentration aniline was

formed quantitatively. Subsequently, the flow rate was increased to higher values giving full

conversion of the starting material in every case (entries 4-6). As the dead volume of the

heated cartridge where the reaction takes place is in the range of 600 µL, a flow rate of 1 or 2

mL min-1

corresponds to a residence time of ~35 and ~20 s, respectively. Event at the

maximum flow rate of the flow instrument, 3 mL min-1

(corresponding to ~10 s residence

time), we could not detect any decrease in the substrate consumption. As proof of principle

the product of the experiment using a 1 mL min-1

flow rate was isolated by filtering the

reaction mixture through a plug of silica to remove unreacted hydrazine. After careful

evaporation of the solvent quantitative amounts of analytically pure aniline were obtained. As

the X-Cube continuous flow reactor is essentially made out of stainless steel, a blank

experiment using a cartridge filled with untreated Al2O3 was additionally carried out to

exclude any catalytic effects by the reactor itself (5% conversion, entry 7). Further attempts to

reduce the reaction temperature resulted in a significant decrease in conversion (entry 8-9).

Table 2. Continuous flow optimization for the reduction of nitrobenzene using hydrazine

hydrate and nano-Fe3O4@Al2O3.[a]

Entry PhNO2 [M] Flow rate [mL min-1

]

T [°C] Conv.[b]

[%]

1 0.2 0.5 150 >99

2 0.5 0.5 150 >99

3 1 0.5 150 >99

4 1 1 150 >99(99)[c]

5 1 2 150 >99

6 1 3 150 >99

7[d]

1 1 150 5

8 1 3 120 36

9 1 3 100 4

[a] Reactions were carried out on a 0.2-1 mmol nitroarene scale in 1 mL MeOH using a 20mol%

excess N2H4 · H2O, and ~920 mg nano-Fe3O4@Al2O3 as catalyst (0. 67wt.% Fe/0.93 wt.% Fe3O4) in

a catalyst cartridge. [b]

Determined as GC-FID peak area percent. [c]

Isolated yield in parentheses.[d]

Cartridge filled with untreated Al2O3 for a catalyst-free control experiment.

Chapter H

222

2.6 Scope and Limitations in Continuous Flow

In order to test the applicability of the continuous flow procedure on more sophisticated

substrates we moved on to carry out several nitroarene reductions under the intensified

conditions (Table 3). As already pointed out during experiments in batch mode, the main

limitation of the above described procedure is the low solubility of either the substrate or the

respective amine in pure methanol. The only example using a concentration of 1 M was 1-

chloro-2-nitrobenzene which underwent quantitative conversion at a flow rate of 1 mL min-1

at 150 °C and 30 bar back pressure using 20 mol% excess of hydrazine hydrate. In cases

where batch experiments could be carried out successfully using other solvents or solvent

combinations (Table 1, entries 4-6 and 8-10) the flow approach showed some drawbacks as

these solvents did not allow the use of a catalyst cartridge for extended time periods.

Table 3. Reduction of nitroarenes with hydrazine hydrate catalyzed by nano-Fe3O4@Al2O3 in

continuous flow.[a]

Ar NO2

N2H4 .H2O (20% excess)

Ar NH2continuous flow, MeOH, 150°C, 30 bar

nano-Fe3O4@Al2O3

Entry Ar Flow rate [mL min-1

] Conv.

[c]

[%]

Yield[d]

[%]

1[b]

2-Cl-C6H4 1 >99 99

2 3,4-(Cl)2-C6H3 1 >99 97

3 4-(pyridin-4-ylmethyl) 1 >99 98

4 4-MeO-C6H4 0.5 97 92

5 2,5-(EtO)2-C6H3 0.5 98 95

6 3-(CO2Me)-C6H4 0.5 >99 98

7 3-NC-C6H4 1 >99 97

8 4-NH2-C6H4 1 >99 98

9 4-F-C6H4 1 95 90

[a] Reactions were carried using 0.1 M solutions of ArNO2 in MeOH with 20 mol% excess N2H4 · H2O, using

~920 mg nano-Fe3O4@Al2O3 (0. 67wt.% Fe/0.93 wt.% Fe3O4) in a catalyst cartridge at 150 °C and 30 bar back

pressure. [b] A 1 M solution of the substrate in MeOH was used.[c] Determined as GC-FID peak area percent. [d]

Isolated yield.

Chapter H

223

In particular, a significant decrease in conversion was observed when DMF was used as

solvent during the continuous processing. As this is presumably a reason of catalyst leaching

or inactivation (e.g. passivation) of the catalytically active Fe3O4 nanocrystals we decided to

perform all further flow experimentation using pure methanol as solvent. Thus, a significantly

lower substrate concentration (0.1 M) was employed in order to avoid possible clogging of

the flow apparatus. Despite this limitation, most reactions gave excellent conversions while

maintaining the high selectivity observed in the batch experiments described above. As

expected from the microwave batch experiments, where 1-methoxy-4-nitrobenzene (Table 1,

entry 6) and 1,3-diethoxy-5-nitrobenzene (Table 1, entry 5) had to be reacted for longer times

(6 min), also the continuous processing needed a slight re-optimization by lowering the flow

rate to 0.5 mL min-1

resulting in a theoretical residence time of ca. 70 s (Table 3, entry 4,5). In

addition, 3-nitrobenzoate was also less active but again reducing the throughput resulted in

quantitative conversion to the desired aniline derivative (Table 3, entry 6). Surprisingly, in the

case of 4-nitroaniline (Table 3, entry 8) the parameters did not require any readjustment

although earlier studies on theses substrate suggested a low reaction rate (Table 1, entry 10).

2.6 Catalyst Stability in Continuous Flow

One of the most important features of immobilized catalysts in continuous applications is,

apart from the activity of the catalyst, the ability to be used over several hours or even days.

We therefore placed special emphasis on monitoring the nano-Fe3O4@Al2O3 catalyzed

reduction of nitrobenzene over a prolonged time period. Initially, an investigation on the

influence of the liquid flow rate and the substrate concentration was carried out (Figure 6, A).

Each experiment was performed with a fresh catalyst cartridge. Iron leaching was determined

by ICPMS analysis of the processed reaction mixture after solvent removal. In addition, the

conversion was measured during the respective experiments by separately collecting a small

amount of the reaction mixture (~200 µL) which was immediately analyzed by gas

chromatography. At the maximum possible flow rate (3 mL min-1

) a dramatic decline in the

substrate consumption was observed after a total processing time of 30 min using a

nitrobenzene concentration of 1 M. Determination of the iron content in the processed

reaction mixture resulted in a value of 88 µg iron. Assuming a total iron content of ~6.2 mg in

the nano-Fe3O4@Al2O3 cartridge (~920 mg with 0.67 wt.% Fe loading) the rationalization for

the significant drop in conversion is likely a result of mechanical deactivation[37]

.

Furthermore, oversaturation of the catalytically active species or a deactivating mechanism

could be a possible explanation for the observed decrease in conversion, albeit the stable

Chapter H

224

reaction during the first 30 min is inconsistent with such phenomena. Therefore, the molarity

of the reaction mixture as well as the liquid flow rate was reduced to 0.5 M and 2 mL min-1

,

respectively. The modified conditions resulted in a stable reaction for about one hour until a

similar activity loss was observed. Again, analysis of the Fe content in the processed reaction

mixture (73 µg) suggests that the reduced conversions are not directly related to iron leaching

from the catalytic support. Gratifyingly, further reduction of the liquid flow rate to 1 mL min-1

gave stable conversions over a time period of 300 min, indicating that the problems observed

above are indeed caused by mechanical stress. We thus extended this experiment and were

pleased to find that the activity of the nano-Fe3O4@Al2O3 system under these conditions (0.5

M substrate concentration in methanol, 1 mL min-1

flow rate) did not change even after 10 h

of processing (Figure 6, B). This corresponds to a productivity of 30 mmol h-1

(72 mmol per

day) for the continuous reduction of nitrobenzene. ICPMS analysis of the crude product

mixture processed for 10 h resulted in a rather insignificant amount of iron (15 µg) leached

from the reactor. A control experiment pumping the reaction mixture under exactly the same

conditions for 10 h through a cartridge filled with untreated alumina showed similar results

(18 µg), indicating that the small amount of detected Fe is likely to be derived from the

stainless steel-based continuous flow reactor itself.

Figure 6. Long run studies for the continuous reduction of nitrobenzene at different

concentrations and flow rates (A) and a comparison of MeOH and MeCN as solvents (B).

Chapter H

225

Since the use of other solvents or solvent mixtures resulted in decreased activity during

previous experiments (see above), another continuous experiment was carried out using

acetonitrile as reaction medium (Figure 6B). Surprisingly, the drop in conversion was not as

sudden as in the experiments using methanol at higher flow rates and molarities. The

conversion pattern of this stability study showed a linear decrease, resulting in 82% after 10 h.

Only 4 µg of iron were washed out from the continuous flow apparatus which is comparable

the values obtained using methanol. Due to the obtained linear decrease in conversion, the

catalyst seems to slowly lose its activity, presumably as a result of a poisoning or deactivation

mechanisms not caused by mechanical stress.[37]

3. Conclusion

In summary, an extremely rapid and experimentally easy to perform method for the

generation of alumina supported Fe3O4 nanoparticles and their use in heterogeneously

catalyzed nitroarene to aniline reductions in batch and continuous flow mode was studied.

The immobilized metal nanoparticles can be easily prepared by a simple impregnation method

on basic Al2O3 using Fe(acac)3 as iron precursor and hydrazine hydrate in methanol at high

temperatures. Analysis of the material shows finely dispersed and homogeneously distributed

Fe3O4 nanoparticle on the surface of the immobilization matrix. Batch experiments for the

hydrazine hydrate-mediated transformation of nitroarenes to their corresponding anilines

catalyzed by nano-Fe3O4@Al2O3 exhibit excellent yields and high selectivities in only 2-6

min under single-mode microwave irradiaton at 150 °C. Furthermore it was shown, that the

bench stable supported nano-Fe3O4 catalyst can be conveniently recycled by a simple

filtration step. However, since batch experiments require simultaneous cooling from the

outside in order to control the exotherm in these reactions, batch scale-up is likely to be

impractical and potentially hazardous. This limitation can be avoided by translating batch

conditions to a continuous flow format by packing the supported iron oxide nanocrystals in a

heatable and pressure stable catalyst cartridge resulting in a simple and scalable reduction

process. Reaction times could be decreased to less than one minute in most cases by pumping

a mixture of the respective nitroarene and hydrazine hydrate in methanol through the packed

bed reactor at 150 °C and 30 bar back pressure resulting in a more or less work-up free

procedure. Careful optimization of all relevant process parameters resulted in a stable reaction

for more than 10 h at a productivity rate of 30 mmol h-1

. Analysis of the processed reaction

mixture showed virtually no leaching of the active material.

Chapter H

226

4. Experimental Section

General experimental details: All solvents and substrates were obtained from standard

commercial vendors and were used without any further purification. Fe(acac)3 (99.9+% metal

basis), aluminum oxide (activated, basic Brockmann I, standard grade, ca. 150 mesh) and high

purity silica (pore size 60 Å, 60-100 mesh) were purchased from Sigma-Aldrich. SBA15, and

Al-SBA15) were obtained from the Unversity of Cordona, Spain with specifications as

described in ref.[38]

Microwave experiments were carried out using a Monowave 300 (Anton

Paar) single-mode microwave reactor fitted with a built-in camera and equipped with a fiber

optic (ruby) thermometer for internal online temperature monitoring.[21]

GC-FID analysis was

performed on a Trace-GC (ThermoFisher) with a flame ionization detector using a HP5

column (30 m × 0.250 mm × 0.025 μm). After 1 min at 50°C the temperature was increased in

25°C min−1

steps up to 300°C and kept at 300°C for 4 min. The detector gas for the flame

ionization is H2 and compressed air (5.0 quality). 1H-NMR and

13C spectra were recorded on a

Bruker 300 MHz instrument using DMSOd6 or CDCl3 as solvent. Chemical shifts (δ) are

expressed in ppm downfield from TMS as internal standard. The letters s, d, t, q, and m are

used to indicate singlet, doublet, triplet, quadruplet, and multiplet, respectively. The high-

resolution transmission electron microscopy (HRTEM) images were collected using a Tecnai

G220-Twin microscope working at an accelerating voltage of 200 kV. For TEM analysis, the

particles were dispersed in water, one drop was placed on the lacey carbon coated Cu grid

(Agar Scientific, 300 mesh), and was dried at room temperature for 48h. ICP-MS analyses

were performed in an Agilent 7500ce inductively coupled plasma mass spectrometer. All

synthesized compounds have been characterized by 1H and

13C NMR analysis and identified

by data reported in literature.

Catalyst preparation: A 500 mg sample of the support (basic alumina, high purity silica,

SBA15 or Al-SBA15, 23 mg (0.065 mmol) of the iron precursor Fe(acac)3 (to achieve a ca. 1

wt.% nominal loading), 50 µL (1 mmol) of N2H4 · H2O and 5 mL MeOH were transferred to a

30 mL Pyrex microwave vessel equipped with a stir bar. The vessel was subsequently sealed

with a Teflon septum and heated to 150 °C by microwave irradiation using a 3 min ramp time

and a hold time of 10 min. After cooling, the resulting supported NPs were centrifuged at

3000g for 10 min to separate unsupported Fe3O4 particles, filtered off and thoroughly washed

with methanol. The prepared Fe3O4 NPs supported on basic alumina have a ~0.673wt.%

content of Fe (0.926 wt.% of Fe3O4) as determined by ICP-MS. Additional ICP-MS analysis

Chapter H

227

demonstrates that the amount of other catalytically active metal species apart from Ni (0.61

ppm), Cu (1.69 ppm), and Mn (1.77 ppm) is below 0.01 ppm.

General procedure for reduction of nitroarenes using batch microwave heating: The

respective nitroarene (2.0 mmol), N2H4 · H2O (0.175 mL, 3.6 mmol, 1.8 equiv), the supported

catalyst (500 mg) and MeOH (5 mL) were placed into a 30 mL microwave process vial

equipped with a magnetic stir bar. The vial was capped with a Teflon septum and heated at

150 °C for the specified time in “as-fast-as-possible” mode. For avoiding of

exotherms/overheating, the reaction vessel was simultaneously cooled with a flow of

compressed air (6 bar).[24]

After completion, the mixture was cooled to 55 °C by compressed

air. The solvent was evaporated under reduced pressure and the crude mixture was dissolved

in ethyl acetate and then filtered through a plug of silica gel (10 g) to obtain the pure amine

after careful evaporation of the solvent.

Catalyst stability and recycling: A 5 g sample of the nano-Fe3O4@Al2O3 was prepared as

described above (10 batches at 500 mg each) and stored at room temperature in an open

vessel. 500 mg samples of this catalyst were used for the reduction of the nitrobenzene as

described above. The experiment was repeated during ten weeks (one reduction each week) to

check the stability of the catalyst. For recycling experiments (Table 1) reduction of

nitrobenzene to aniline using supported Fe3O4 NPs was carried out utilizing 2 mmol of

nitrobenzene (205 µL), 3.6 mmol of N2H4 · H2O (175 µL), Fe3O4 NPs (1 wt.%) supported on

basic alumina, SBA15 or Al-SBA15. Methanol (5 mL) was added to a 30 mL microwave

vessel and heated up to 150 °C with “as-fast-as-possible” mode and held at this temperature

for 3 min and then cooled down to 50 °C using compressed air. Afterwards, the catalyst was

recycled by filtration through a filter paper and the fresh substrate, hydrazine hydrate and

methanol was added before further processing.

Description of the continuous flow reactor: The ThalesNano X-cubeTM

reactor[33]

(see

Figure 3. A) contains two main parts: 1) the built-in dual HPLC pump system for delivering

of the substrates with 0.1-3 mL/min flow rates; 2) the reactor box which consist of two

heating units that can be heated up to 200 °C which encapsulate so called CatCartTM

systems

packed with nano-Fe3O4@Al2O3. Additionally the whole system can be pressurized up to 150

bar using a back pressure regulator.

Chapter H

228

Dead volume determination of a packed CatCartTM

cartridge: The sealing and filter unit

of a representative cartridge was carefully removed at one end. Afterwards, the nano-

Fe3O4@Al2O3 material from the cartridge was filled in a pre-weight volumetric flask (2 mL).

After weighing, MeOH was added to result in an overall volume of 2 mL. The mass of the

added solvent was determined to calculate the volume of nano-Fe3O4@Al2O3 (~270 µL). This

results in a dead volume of ~600 µL as the total volume of a CatCartTM

cartridge is 880 µL.

Representative procedure for the reduction of nitroarenes using continuous flow

conditions (Table 3): For a typical experiment, 3 mL of a 0.1 M solution of the respective

nitroarene in methanol containing 1.8 equiv of N2H4 H2O was pumped through a fresh

catalyst cartridge (CatCart, filled with ∼920 mg of nano-Fe3O4@Al2O3) at 150°C at a flow

rate of 0.5-1 mL min-1

. After passing a back pressure regulator (30 bar), the reaction mixture

was collected and the solvent was removed carefully under reduced pressure. The crude

mixture was dissolved in ethyl acetate and filtered through a plug of silica gel (10 g). Unless

otherwise noted, the pure amine was isolated after careful evaporation of the solvent.

Aniline (Table 3, entry 1): From a solution of 1 M nitrobenzene in MeOH with a flow rate of

1 mL min-1

; yield: 277 mg (99%); 1H NMR (300 MHz, CDCl3) δ 7.24 – 7.12 (m, 2H), 6.83 –

6.75 (m, 1H), 6.71 (ddd, J = 4.3, 3.2, 1.7 Hz, 2H), 3.66 (s, 2H). 13C NMR (75 MHz, CDCl3) δ

146.27, 129.10, 118.39, 114.78.

2-Chloroaniline (Table 3, entry 2): From a solution of 1 M 1-chloro-2-nitrobenzene in

MeOH at a flow rate of 1 mL min-1

; yield: 379 mg (99%); 1H NMR (300 MHz, CDCl3) δ 7.27

(dd, J = 7.8, 1.2 Hz, 1H), 7.09 (td, J = 8.0, 1.4 Hz, 1H), 6.78 (dd, J = 8.0, 1.5 Hz, 1H), 6.71

(ddd, J = 7.9, 7.4, 1.5 Hz, 1H), 4.06 (s, 2H). 13

C NMR (75 MHz, CDCl3) δ 142.87, 129.43,

127.64, 119.29, 118.95, 115.87.

3,4-Dichloroaniline (Table 3, entry 3): From a solution of 0.1 M 1,2-dichloro-4-

nitrobenzene in MeOH at a flow rate of 1 mL min-1

; yield: 47 mg (97%); 1H NMR (300 MHz,

DMSO) δ 7.18 (d, J = 8.7 Hz, 1H), 6.74 (d, J = 2.3 Hz, 1H), 6.52 (dd, J = 8.7, 2.4 Hz, 1H),

5.54 (s, 2H). 13

C NMR (75 MHz, DMSO) δ 149.60, 131.32, 130.94, 116.38, 114.94, 114.49.

Chapter H

229

4-(Pyridin-4-ylmethyl)aniline (Table 3, Entry 4): From a solution of 0.1 M 4-(4-

Nitrobenzyl) pyridine in MeOH at a flow rate of 1 mL min-1

; yield: 54 mg (98%); 1H NMR

(300 MHz, DMSO) δ 8.42 (dd, J = 4.5, 1.5 Hz, 1H), 7.18 (d, J = 5.8 Hz, 1H), 6.88 (d, J = 8.3

Hz, 1H), 6.50 (d, J = 8.3 Hz, 1H), 4.94 (s, 1H), 3.75 (s, 1H). 13


151.14, 149.79, 144.88, 129.98, 128.40, 123.95, 115.23, 40.55.

4-Methoxyaniline (Table 3, entry 5): From a solution of 0.1 M 1-methoxy-4-nitrobenzene in

MeOH at a flow rate of 0.5 mL min-1

; yield: 35 mg (92%) after column chromatography); 1H

NMR (300 MHz, CDCl3) δ 6.86 – 6.73 (m, 2H), 6.71 – 6.62 (m, 2H), 3.77 (s, 3H), 3.42 (s,

2H). 13

C NMR (75 MHz, CDCl3) δ 152.51, 139.77, 116.46, 114.81, 55.46.

2,5-Diethoxyaniline (Table 3, entry 6). From a solution of 0.1 M 1,3-diethoxy-5-

nitrobenzene in MeOH at a flow rate of 0.5 mL min-1

; yield: 52 mg (95%); 1H NMR (300

MHz, DMSO) δ 6.62 (t, J = 13.4 Hz, 1H), 6.26 (t, J = 11.7 Hz, 1H), 6.02 (dd, J = 8.6, 2.7 Hz,

1H), 4.69 (s, 2H), 3.87 (dq, J = 13.8, 6.9 Hz, 4H), 1.28 (dt, J = 9.6, 7.0 Hz, 6H). 13

C NMR (75

MHz, DMSO) δ 153.85, 140.01, 139.33, 113.63, 101.47, 101.17, 64.60, 63.30, 15.42, 15.31.

Methyl 3-aminobenzoate (Table 3, entry 7): From a solution of 0.1 M methyl 3-

nitrobenzoate in MeOH at a flow rate of 0.5 mL min-1

; yield: 44.5 mg (98%); 1H NMR (300

MHz, DMSO) δ 7.22 – 7.04 (m, J = 13.1, 7.6, 1.6 Hz, 3H), 6.93 – 6.39 (m, 1H), 5.37 (s, 2H),

3.80 (s, 3H). 13

C NMR (75 MHz, DMSO) δ 167.19, 149.35, 130.82, 129.32, 118.79, 116.59,

114.34, 52.15.

3-Aminobenzonitrile (Table 3, entry 8): From a solution of 0.1 M 3-nitrobenzonitrile in


; yield: 34.5 mg (97%); 1H NMR (300 MHz, CDCl3) δ

7.36 – 7.15 (m, 1H), 7.09 – 6.98 (m, 1H), 6.94 – 6.81 (m, 2H).3.81 (s, 2H). 13

C NMR (75

MHz, CDCl3) δ 146.72, 130.07, 121.91, 119.26, 119.23, 117.28, 112.61.

1,4-Diaminobenzene (Table 3, entry 9): From a solution of 0.1 M 4-nitroaniline in MeOH at

a flow rate of 1 mL min-1

; yield: 32 mg (98%); 1H NMR (300 MHz, DMSO) δ 6.35 (s, 4H),

4.18 (s, 4H). 13

C NMR (75 MHz, DMSO) δ 139.37, 115.70.

Chapter H

230

4-Fluoroaniline (Table 3, entry 10): From a solution of 0.1 M 4-fluoro-4-nitrobenzene in


; yield: 30 mg (90%) after column chromatography; 1H

NMR (300 MHz, DMSO) δ 6.89 – 6.76 (m, 1H), 6.59 – 6.49 (m, 1H), 4.93 (s, 1H). 13

C NMR

(75 MHz, DMSO) δ 156.28, 152.97, 145.61,145.63, 115.68, 115.39, 115.08, 114.98.

Long term stability and leaching study in continuous flow (Figure 6): Solutions of

nitrobenzene in MeOH or MeCN (0.5 - 1 M) containing 1.8 equiv of N2H4 H2O were passed

through the continuous reactor equipped with a fresh catalyst cartridge (CatCart, filled with

~920 mg of nano-Fe3O4@Al2O3) for 1-10 h with a 1-3 mL min-1

flow rate at 150 °C and 30

bar back pressure. Every 60 min, the conversion was determined by GC-FID. For ICP-MS

determination of iron leaching, 50 mL of the collected solution were evaporated carefully and

analyzed after dissolving the solid residue in 1mL HNO3.

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Glasnov, C. O. Kappe, Adv. Synth. Catal. 2010, 352, 3089; (e) M. Oliverio, A.

Procopio, T. N. Glasnov, W. Goessler, C. O. Kappe, Aust. J. Chem. 2011, 64,

1522; See also ref. 27a and b.

[35] L. Kamen, H. R. Henney, J. D. Runyan, Curr. Med. Res. Opin. 2008, 24, 425.

[36] R. C. Moellering, Ann. Intern. Med. 2003, 138, 135.

[37] For general discussion about catalyst deactivation, see: (a) J. A. Moulijn, A. E. van

Diepen, F. Kapteijn, Appl. Catal. A 2001, 212, 3; (b) C. H. Bartholomew, Appl. Catal.

A 2001, 212, 17.

[38] (a) A. M. Balu, A. Pineda, K. Yoshida, J. M. Campelo, P. L. Gai, R. Luque, A. A.

Romero, Chem.Commun. 2010, 46, 7825; (b) D. Zhao, Q. Huo, J. Feng, B. F.

Chmelka, G. D. Stucky, J. Am. Chem. Soc. 1998, 120, 6024.

Chapter I

235

I. A Sequential Ugi Multicomponent/Cu-Catalyzed Azide-Alkyne

Cycloaddition Approach for the Continuous Flow Generation of

Cyclic Peptoids

Graphical Abstract

Abstract

The development of a continuous flow multi-step strategy for the synthesis of linear peptoids

and their subsequent macrocyclization via Click chemistry is described. The central

transformation of this process is an Ugi four-component reaction generating the

peptidomimetic core-structure. In order to avoid exposure to the often toxic and malodorous

isocyanide building blocks, the continuous approach was telescoped by the dehydration of the

corresponding formamide. In a concurrent operation, the highly energetic azide moiety

required for the subsequent intramolecular copper-catalyzed azidealkyne cycloaddition

(Click reaction) was installed by nucleophilic substitution from a bromide precursor. All steps

yielding to the linear core-structures can be conveniently coupled without the need for

purification steps resulting in a single process generating the desired peptidomimetics in

good to excellent yields within 25 minutes reaction time. The following macrocyclization was

realized in a coil reactor made of copper without any additional additive. A careful process

intensification study demonstrated that this transformation occurs quantitatively within 25

minutes at 140 °C. Depending on the resulting ring strain, either a dimeric or a monomeric

form of the cyclic product was obtained.

Chapter I

237

1. Introduction

Proteins and peptides are key building blocks for life and therefore omnipresent in humans,

animals, plants and microorganisms. These classes of biooligomers possess a vast diversity of

different functions including catalysis (enzymes), transport and storage of atoms/molecules,

communication between tissues and organs (hormones), or defending the body from antigens

(antibodies).[1]

A significant number of these tasks is regulated by protein-protein interactions.

Consequently, abnormalities in these interactions can lead to a variety of diseases.[2]

It is

therefore apparent that a detailed understanding of the underlying mechanisms of protein-

protein interactions is of importance for the development of potential therapies.

Unfortunately, naturally occurring peptides are often not ideal candidates for drug discovery

due to their low stability against proteolysis and their poor bioavailability. To circumvent

these issues, so called peptidomimetics are often used as non-natural alternatives. These

compounds mimic natural occurring proteins having the ability to bind to the same target

molecules resulting in identical biological effects.[1,3]

Oligomers of N-substituted alkyl

glycines (alias peptoids) are among the most promising examples to study the biological

functions of peptides.[4]

Structurally, peptoids are substituted at the amide nitrogen atom

instead of the α-carbon like their natural occurring analogs.

Peptoids comprise a vast array of interesting non-natural oligomeric structures, which

have a huge variety of biological activities and potential application for drug discovery.[4,5]

This feature comes from the ability of this class of poly-N-substituted glycine compounds to

mimic the primary structure of peptides and their main advantages include ease of synthesis,

long half-lives due to high proteolytic stability and a much higher bioavailability compared to

the natural peptides.[3a,5,6]

Furthermore, the presence of tertiary amines lowers the number of

intramolecular hydrogen bonds, increasing the membrane permeability by passive diffusion

and, consequently, enhancing their pharmacological potential.[7]

Analogously to peptides and

proteins, peptoids bearing chiral side chains may form secondary structures assuming

helicoidal conformations.[8]

The synthesis of peptoid motifs is traditionally carried out using sub-monomer solid-

phase synthesis.[6b,9]

A possibly more straightforward alternative for such sequential

approaches are isocyanide-based multi-component reactions (IMCRs).[10]

Among these, the

Ugi four-component reaction (U-4CR) is one of the most versatile examples for constructing

peptoid scaffolds in a highly efficient manner.[11]

This generally high yielding reaction has a

high functional group tolerance allowing to cover a broad range of chemical space.[11]

It may

combine efficient and environmentally benign techniques like microwaves and continuous

Chapter I

238

flow processing,[11d,12]

and has an intrinsically efficient ability to assess complex molecules in

tandem processes.[11c,g,13]

Despite the advantages associated with the use of peptoids as peptidomimetics, the

conformational flexibility and the lack of secondary interactions of linear peptoids decrease

their capacity of interaction and molecular recognition with potential pharmaceutical

targets.[14]

To overcome this limitation, the peptoid backbone cyclization has been employed

as a strategy to restrict conformations of linear peptoids, regidifying their structure and

allowing a selective molecular recognition.[15]

In fact, the backbone cyclization in several

cyclic molecules is considered as the most challenging aspect in the synthesis of this class of

compounds.[15b]

Cyclic peptoids are resistant to protease degradation and show high conformational

stability.[15b,16]

For this reason, an increase in their affinity to the protein domains may occur

due to the low entropy loss during the bonding process.[17]

Thus, the structural stability may

allow the design of compounds that present favorable interactions with the molecular target.

In this sense, there has been a considerable interest in the development of this class of

compounds, which can be confirmed by the recent increase in the number of publications

dealing with the synthesis of cyclic peptoids.[14,18]

Additionally, a recent study revealed that

cyclic peptoids show complexation properties allowing their effective use in phase transfer

catalysis.[19]

In fact, the macrocyclization approach has been applied to the synthesis of

numerous biologically active peptidomimetics.[20]

The most common ways to obtain a macrocycle from acyclic molecules involve

lactonization and lactamization, but other strategies include ring closing metathesis (RCM),

cycloadditions (mainly “click” chemistry) and nucleophilic displacement reactions.[3b]

More

recently, the intramolecular Ugi reaction has proven to be an efficient synthetic methodology

to assess these compounds as well.[11c,g,18b]

In particular, the multiple multicomponent

macrocyclizations including bifunctional building blocks strategy (MiB) has proved to be

very useful in the construction of macrocyclic diversity.[21]

Another appealing structural motif which is frequently applied in peptidomimetic

chemistry is those of 1,2,3-triazoles having similar electronic and structural characteristics as

peptides.[22]

These heterocyclic scaffolds can be efficiently synthesized using so-called

copper-catalyzed azide alkyne cycloadditions (CuAACs).[23]

As one of the model reactions

within the “Click Chemistry” concept, the CuAAC is an ideal chemical transformation in

peptidomimetic chemistry.[24,25]

Applications range from ligation of oligomers to foldamer

generation, conjugation reactions and macrocyclizations.[24]

In the case of peptoid chemistry,

Chapter I

239

the latter transformation results in cyclic scaffolds often forcing the molecule into a well-

defined secondary structure.[25]

When an amide bond of a peptide or peptoid is substituted by a triazole ring, rigidity is

introduced in the molecule, which can mimic the amide bond either in its cis or trans-like

configuration.[26]

An interesting example of this feature is the synthesis of a macrocyclic

peptidomimetic, which showed significant antibacterial activity against Staphylococcus

aureus.[20b]

Furthermore, a library of 16 stereoisomeric somatostatine analogues embedding a

triazole unit were prepared and screened for binding activity with the human somatostatine-

receptor subtypes with interesting results.[27]

In order to combine the above mentioned synthetic strategies, we turned our attention

to the development of U-4CR protocols generating linear peptoids of type 5 from an

isocyanide (1), an acid (2), an amine (3), and an oxo-component (4), simultaneously installing

an alkyne as well as an azide group for subsequent intramolecular CuAAC (Scheme 1).

Similar strategies were already used for linear peptidomimetic scaffolds,[28]

but applications

for cyclic derivatives (6) are however scarce in the literature.[29]

Scheme 1. General Synthetic Strategy for the Sequential Synthesis of Linear and Cyclic

Peptidomimetic Scaffolds.

Traditionally, such reactions are carried out batchwise using an iterative series of reaction and

work-up steps. A more and more popular alternative for such habitual processes is performing

organic reactions in continuous flow devices.[30,31]

These methodologies offer the possibility

to carry out multi-step reaction sequences by employing several reactors in a linear

arrangement circumventing tedious and unnecessary isolation procedures.[32]

This is of

particular importance when hazardous reagents or intermediates are involved, making the

scale-up of such transformations difficult.[30-32]

Herein, we present the development of a multistep continuous flow procedure for the

synthesis of linear and cyclic peptoids using the microwave-to-flow paradigm.[33]

The

described methodology includes the continuous formation of an isocyanide as well as of an

Chapter I

240

azide-functionalized carboxylic acid, which are subsequently used in an U-4CR. The obtained

linear peptoids can be further cyclized without the addition of any additive using a residence

time unit made out of copper.


The original concept of our continuous flow approach was based on 4 separate liquid feeds

each delivering a unique building block for the U-4CR (Scheme 2). After mixing of the

reagents, a heated residence time unit was to be used for the IMCR. The resulting peptoid can

subsequently be converted into the cyclic isomer using an intramolecular version of the

CuACC process. For the latter transformation we intended to use a flow reactor made out of

copper, circumventing the necessity of adding the catalytically active Cu metal species

separately.[34]

As it is known that macrocyclizations of this type often require special ligands

in order to achieve acceptable yields and selectivities,[35]

we also considered the need for an

additional feed. Since the multicomponent reaction involves isocyanides which are often

characterized by an unpleasant odor and can be quite toxic, we additionally decided to

telescope our original strategy by an upstream flow dehydration step of the respective

formamide 7 (Scheme 2), thereby generating the required isonitrile 1 in situ.[12c]

Similarly, the

potentially hazardous azide building block 2 was also prepared in-line via an upstream

nucleophilic substitution from readily available halide precursors 8 (Scheme 2).[36]

Scheme 2. Continuous Strategy for the Modular Synthesis of Linear and Cyclic Peptoids

Consisting of Isocyanide Synthesis (red), Azide Preparation (green), Ugi Reaction (blue) and

Final CuAAC Macrocyclization (orange)

Chapter I

241

2.1 Peptoid Synthesis

Initially, we optimized the reaction parameters for the IMCR using microwave dielectric

heating methodologies (Table 1).[37]

To generate the peptoid scaffold and simultaneously

install the alkyne and azide functionalities for the following intramolecular Click reaction,

isocyanide 1a and 2-azidoacetic acid (2a) were selected for the U-4CR. Paraformaldehyde

(4a) as oxo-component and tert-butyl amine (3a) completed the building blocks for the model

reaction system resulting in peptoid 5a.

An early temperature screening using equimolar amounts of all starting materials

exhibited that the multicomponent reaction has an optimum temperature of ca. 80 °C (Table 1,

entries 1-3).[38]

A longer reaction time was not considered as a relatively high throughput is

desirable for any continuous process. Thus, reagents 2a-4a were added in excess to

isocyanide 1a in order to drive the reaction to completion. As expected, when 1.5 equiv were

used, a significantly higher conversion was obtained (entry 4). A further increase to 2 equiv of

the acid, the amine as well as the aldehyde resulted in the total consumption of the limiting

building block within 30 min (entry 5). Concurrently the reaction time could be dramatically

reduced to 4 min maintaining a quantitative reaction of isocyanide 1a and a high purity profile

(entries 6 and 7). Work-up of the crude reaction mixture by column chromatography resulted

in 84% of the functionalized peptoid 5a.

Table 1. Batch Microwave Optimization of the Peptoid Synthesisa

entry stoichiometry

[1a:2a:3a:4a] T [°C] t [min] conversion [%]

b

1 1:1:1:1 70 30 12

2 1:1:1:1 80 30 54

3 1:1:1:1 100 30 38

4 1:1.5:1.5:1.5 80 30 68

5 1:2:2:2 80 30 >99

6 1:2:2:2 80 15 >99

7 1:2:2:2 80 4 >99(84)c

aReactions were carried out using 0.5 mmol of isocyanide 1a in 2 mL MeCN/MeOH.

bDetermined based

on isocyanide 1a as HPLC peak area percent at 215 nm. cIsolated yield in parentheses.

Chapter I

242

Encouraged by these promising results, we applied the optimized conditions to various

combinations of starting materials as shown in Table 2.

Table 2. Scope of the Optimized U-4CR Peptoid Synthesisa

entry isocyanide acid amine Peptoid

1

2

3

4

5

6

7

8

aConditions: isocyanide (1, 0.5 mmol), carboxylic acid (2, 1.0 mmol), amine (3, 1.0 mmol) and

paraformaldehyde (4a, 1.0 mmol) in 2 mL MeCN/MeOH (1:1).

Chapter I

243

Several peptoids (5a-5e) with different chain lengths on the azide-containing carboxylic acids

(2a-2e) were prepared without the need of any re-optimization (Table 2, entries 1-5). These

compounds were specifically prepared for the subsequent copper-catalyzed Click reactions in

order to examine the role of the chain-length on the cyclization characteristics. Furthermore,

we introduced the alkyne moiety by the amine building block, simultaneously varying the

isocyanide for a more diverse set of peptidomimetic compounds (entries 6-8). The oxo-

component was limited to paraformaldehyde (4a) as other aldehydes or ketones would not

result in the desired peptoid scaffold. The resulting - hitherto undisclosed linear peptoids -

were isolated in good to excellent yields proving the robustness of the Ugi multi-component

reaction. The next step was to translate the optimized batch protocol into a continuous flow

process. Thus, we assembled a flow reactor with 3 separate liquid feeds as shown in Scheme

3.[39]

The number of required feeds resulted from the fact that our ultimate goal was to prepare

the azide moiety as well as the isocyanide group prior to the IMCR in telescoped upstream

flow transformations (Scheme 3).

Scheme 3. Synthesis of Linear Peptoid 5a via U-4CR in Continuous Flow Mode

Therefore, the amine- and oxo-building blocks were combined into one feed. In order to

obtain a proper stoichiometry, a 0.125 M solution of the limiting isocyanide in acetonitrile

was pumped with 0.5 mL min-1

and all other reagents with a concentration of 0.5 M and a

flow rate of 0.25 mL min-1

. As residence time unit (RTU), a 4 mL perfluoroalkoxy (PFA) coil

with an inner diameter of 0.8 mm was used in order to allow a similar reaction time as in the

microwave batch experiments. Since the optimum temperature of 80 °C is more or less equal

to the boiling point of acetonitrile (82 °C) and above the boiling point of MeOH (65 °C) a 7

bar back pressure regulator (BPR) was applied to accurately control the residence time.

Chapter I

244

Gratifyingly, the limiting isocyanide was quantitatively consumed resulting in a similar

isolated yield as in the batch microwave experiment under identical processing conditions.[33]

2.2 Isocyanide Preparation

Having an optimized protocol for the peptoid formation in hand, we turned our attention to

the upstream synthesis of isocyanide 1a from the corresponding formamide 7a. Using

traditional batch techniques, several literature procedures for this dehydration were evaluated

for their suitability in a continuous process (Table 3). When triphenylphosphine[40]

was used

as dehydration agent we observed low isolated yields, even after 12 h. In addition, the

resulting triphenylphosphinoxide would likely cause problems in a continuous process due to

its low solubility. No product formation could be observed in the case of 2,4,6-

trichloro[1,3,5]triazine (cyanuric chloride, TCT)[41]

However, phosphoryl chloride[42]

as well

as the Burgess reagent (methyl N-(triethylammoniumsulfonyl)carbamate)[43]

delivered

promising isolated yields in this initial screening. We decided to carry out further experiments

using the Burgess reagent as its application is far more convenient and in contrast to the use

of POCl3 a totally homogenous reaction was observed.

Table 3. Screening of Dehydration Reagents for Isocyanide Formation

As displayed above, the majority of literature dehydration protocols are typically conducted in

dichloromethane. Since the U-4CR was already successfully optimized using a polar solvent

combination (MeOH/MeCN), we decided to switch to acetonitrile for the process

intensification experiments (Table 4). An initial experiment employing one equiv of the

entry experimental conditions yield [%]a

1 CCl4, Et3N, PPh3, CH2Cl2, 12 h reflux 34

2 TCTb, pyridine, CH2Cl2, 12 h, reflux --

c

3 TCTb, Et3N, CH2Cl2, 12 h, reflux --

c

4 POCl3, Et3N, CH2Cl2, 12 h, -78 to 25 °C 76

5 Burgess reagentd, CH2Cl2, 80 min, reflux 67

aIsolated yield.

bTCT=2,4,6-trichloro[1,3,5]triazine.

cNo product formation observed.

dMethyl N-(triethylammoniumsulfonyl)carbamate.

Chapter I

245

dehydrating agent at 50 °C indicated that the reaction indeed also results in the desired

isonitrile molecule using a polar solvent (Table 4, entry 1). Unfortunately, neither an elevated

temperature, nor a longer reaction time provided reasonable conversions of formamide 7a

(entries 2-4). By increasing the amount of the Burgess reagent stepwise to 2 equiv it was

demonstrated that a quantitative dehydration can be achieved within 20 min at 50 °C (entry

7). These optimized conditions were subsequently tested in a continuous protocol keeping the

optimized conditions of the continuous U-4CR in mind (Scheme 4).[39]

Since the flow rate for

the isocyanide feed in the multicomponent reaction was 0.5 mL min-1

the continuous

dehydration protocol needed to be adjusted in order to result in the same overall liquid flow.

We thus decided to use the same flow rate for the formamide as well as the Burgess reagent

feed (250 µL min-1

), controlling the stoichiometry by employing a 2-fold concentration of the

latter reagent. In order to reach the necessary reaction time of 20 min, a 10 mL PFA coil was

installed and heated in an oil bath to the desired temperature. To match the conditions of the

peptoid synthesis, the same back pressure was used (7 bar). Gratifyingly, these reaction

conditions resulted in full conversion of the isocyanide precursor and provided similar

isolated yields for 1a after column chromatography (Scheme 4).

Table 4. Batch Process Intensification for Formamide Dehydration Using Burgess Reagenta

entry Burgess reagent

[equiv] T [°C] t [min] conversion [%]

b

1 1 50 10 50

2 1 80 10 51

3 1 100 10 53

4 1 50 25 64

5 1.5 50 15 77

6 1.5 50 20 81

7 2 50 20 >99(93)c

8 2 50 15 84 aReactions were carried out using 2 mmol of formamide 7a in 2 mL MeCN; Burgess reagent = methyl N-

(triethylammoniumsulfonyl)carbamate. b

Determined as HPLC peak area percent at 215 nm. cIsolated yield in

parentheses.

Chapter I

246

Scheme 4. Continuous Isocyanide Synthesis Employing Burgess Reagent

2.3 Azide Formation

To complete our continuous concept for the synthesis of the linear peptidomimetics a

continuous azide formation had to be developed. Due to their easy accessibility, we decided to

synthesize these highly energetic compounds from their corresponding bromides. Usually

such nucleophilic substitutions of halides are conducted using NaN3 in DMSO or mixtures of

H2O and DMSO in flow mode.[36,44]

To circumvent solubility issues throughout the overall

continuous process using our solvent system (MeCN/MeOH), we decided to use

tetrabutylammonium azide (TBAA) instead of inorganic azide salts.[45]

Optimization of all

reaction parameters was once again carried out in acetonitrile employing batch microwave

technology as demonstrated in Table 5.

Table 5. Optimization of Azide Formation Using TBAAa

Entry TBAA [equiv] T [°C] t [min] conversion [%]b

1 1 80 5 72

2 1 80 15 83

3 1 80 20 81

4 1 100 15 84

5 1.5 100 15 >99(92)c

6 1.5 80 15 93

7 1.5 100 10 89 aReactions were carried out using 1 mmol of bromoacetic acid (8a) in 2 mL

MeCN; TBAA = tetrabutylammonium azide. b

Determined as HPLC peak area

percent at 215 nm. cIsolated yield in parentheses.

Chapter I

247

Bromoacetic acid (8a) and one equivalent of TBAA were dissolved in 2 mL MeCN for a first

set of experiments. A quantitative reaction would result in a 0.5 M solution of azide 2a as

used in the continuous U-4CR described above (Scheme 3). These initial experiments resulted

in 72-84% of the desired product depending on the reaction time and temperature (Table 5,

entries 1-4). By increasing the amount of the organic salt to 1.5 equiv a quantitative reaction

was observed at 100 °C within 15 min (entry 5). A further reduction of both reaction and

temperature resulted in incomplete reactions (entries 6-7).

Translation of the batch conditions to a continuous flow methodology was

straightforward (Scheme 5).[39]

A 100 µL min-1

stream of a 0.5 M bromide solution was

mixed with a 100 µL min-1

stream of TBAA in MeCN (0.75 M) and pumped through a 3 mL

PFA coil set at 100 °C. After exactly 15 min the reaction mixture left the heated reaction zone

and was subsequently collected after passing a 7 bar BPR. Isolation afforded azidoacetic acid

2a in excellent yield confirming the results obtained in batch.

Scheme 5. Continuous Synthesis of 2-Azidoacetic Acid

2.4 Multistep Synthesis of Linear Peptoids in Continuous Flow

Having suitable flow processes for the continuous U-4CR, the upstream azide and isocyanide

formations in hand, we next aimed for combining all continuous protocols, resulting in a

single flow process (Scheme 6). We employed the azide synthesis described above (Scheme

5) as basis for calculating all flow rates and coil lengths in order to obtain the necessary

stoichiometry and residence times. Thus, a 0.25 M solution of formamide 7a in acetonitrile

was pumped with 200 µL min-1

and mixed with the Burgess reagent (0.5 M in MeCN)

resulting in an overall flow rate of 400 µL min-1

for the isocyanide formation. After passing

an 8 mL RTU (20 min residence time) set at 50 °C, the stream was directly mixed with the

outcome of the azide formation and a 0.5 M solution of paraformaldehyde (4a) and tert-

Chapter I

248

butylamine (3a). The resulting output stream with an overall flow rate of 0.8 mL min-1

was

then heated in a 4 mL PFA tubing (5 min residence time) to 80 °C executing the intensified

U-4CR protocol. Analysis of the collected reaction mixture indicated a quantitative reaction

with the limiting formaldehyde reagent 7a being fully converted into peptoid 5a. After

purification, 80% of the target molecule was obtained which is in good agreement with the

previous batch and flow experiments. Notably, no purification step was required when

combining the different transformations and the fully continuous protocol afforded the

peptidomimetic compound within only 25 min overall reaction time in a process that avoided

the handling of potentially toxic and/or explosive intermediates.

Scheme 6. Synthesis of Linear Peptoid 5a via Isocyanide Synthesis (red), Azide Preparation

(green), and an U-4CR (blue) in a Single Continuous Operation

Chapter I

249

2.5 CuAAC in Continuous Flow

Copper-catalyzed 1,3-dipolar cycloadditions resulting in the 1,4-substituted 1,2,3-triazole

scaffold were carried out for the first time in a copper coil in 2009 by Bogdan and Sach,[46]

and since then have been applied in a multitude of synthetic strategies.[34]

Continuous

preparations of macrocyclic compounds using the copper-catalyzed Click strategy were

intensively studied by the groups of Collins[47,48]

and James.[35,49,50]

In the latter case, the use

of flow reactors made out of elemental copper turned out to be highly beneficial as the nature

of the coil itself avoided the necessity to add additional catalytically active species. Earlier

work from our laboratories revealed that these cycloadditions are not catalyzed by zerovalent

copper but more likely by a surface layer of Cu2O.[51]

Thus, a homogeneous reaction

mechanism was postulated resulting in leaching of the metal species when carried out

continuously.[51,52]

For the optimization study of the intermolecular CuAAC of linear peptoid 5a, a simple

continuous setup consisting of a syringe pump, a 20 mL copper coil and an adjustable back

pressure regulator was assembled (Table 6). Since literature conditions are typically carried

out in the presence of tris[(1-tert-butyl-1H-1,2,3-triazolyl)methyl]amine (TTTA) as ligand

and N,N-diisopropylethylamine (DIPEA) as base for better monomer-to-dimer ratios we

initiated our macrocyclization attempts using a similar approach (Table 6, entry 1).

Unfortunately, these conditions resulted in dimer 6a as main product in addition to the

generation of various unidentified byproducts. These compounds are most likely related to

higher oligomers or even polymeric material but could not be clearly identified.[53]

The

selectivity was even worse when we changed the ligand from TTTA to TBTA

(tris(benzyltriazolylmethyl)amine, entry 2). Interestingly, when the reaction using TTTA was

carried out without the addition of the base, a better conversion to the CuAAC products 6aα

and 6aβ was observed (entry 3). We next decided to process more diluted reaction mixtures

which demonstrated a slightly improved selectivity for monomer 6aβ (entries 4-5). Notably,

when we carried out a control experiment in the absence of TTTA only very small amounts of

the desired molecule were detected by HPLC analysis, almost selectively forming 6aα (entry

6). We concluded that a protocol selectively yielding monomer 6aβ with a suitable throughput

would not be achievable, and thus decided to intensify this additive-free process in order to

fully consume the linear precursor 5a. We anticipated that the resulting protocol would yield

the desired monomeric scaffold for homologs 5b-e as the resulting ring structures may be less

strained.[50]

Increasing the temperature to 140 °C resulted in full consumption of linear

peptoid 5a yielding 6aα almost selectively (entry 7). Since we realized that a slightly shorter

Chapter I

250

residence time provided significantly inferior results, we decided to extend the residence time

to 25 min to avoid incomplete cyclization procedures by using a flow rate of 0.8 mL min-1

(entries 8-9). Isolation using chromatographic techniques provided good isolated yields for

the complex cyclic peptoid 6aα.

Table 6. Process Intensification for the Continuous Macrocyclization Using a Copper Coila

entry c

[mM]

additive

(10mol%)

T

[°C]

t

[min] 5a

[%]b

6a[%]

b

6a[%]

b

1c

62.5 TTTA

100 20 17 44 5

2c 62.5 TBTA

100 20 9 27 8

3 62.5 TTTA 100 20 12 59 9

4 2.0 TTTA 100 20 3 67 23

5 2.0 TTTA 120 20 2 70 19

6 2.0 - 120 20 10 72 5

7 2.0 - 140 20 0 83 3

8 2.0 - 140 16 2 74 7

9 2.0 - 140 25 0 86(74)d 2

a Reactions were performed on a 0.140 mmol scale in MeCN/MeOH (1:1).

b Determined as peak area percent at

215 nm. c

2 equiv of DIPEA were added to the reaction mixture. d Isolated yield in parentheses. TTTA=(tris((1-

tert-butyl-1H-1,2,3-triazolyl)methyl)amine); TBTA = (tris(benzyltriazolylmethyl)amine)

When the same conditions were employed for the CuAAC of linear peptoid 5b - which only

differs from 5a by a single CH2 group - our hypothesis was confirmed (Table 7, entry 2).

Careful analysis revealed that the monomeric cyclopeptoid 6b was selectively formed instead

of the dimeric derivative. The same selectivity was obtained for linear peptoids 5c-5e and the

cyclic products 6c-6e could be isolated in good to excellent yields (entries 3-5). The structure

of compound 6e was confirmed X-ray crystallography.[54]

Not surprisingly, the structurally

different peptoids 5f and 5g smoothly cyclized leading to the desired 6- and 7-membered ring

structures (entries 6-7). A high ring strain may also be the reason for compound 5h to not

form a monomeric cyclopeptoid. However, also in this case reasonable amounts of the

dimeric structure 6h could be isolated.

Chapter I

251

Table 7. Continuous CuAAC Macrocyclization of Linear Peptoids using a Copper Coila

entry substrate product

1

2

3

4

5

6

Chapter I

252

entry substrate product

7

8

a Reactions were carried out using 2 mM solutions of the linear peptoids 5a-h in

MeCN:MeOH (1:1).

3. Conclusion

In summary, we have developed an efficient fully continuous multi-step strategy for the

synthesis of linear peptoids and a subsequent copper-catalyzed dipolar cycloaddition resulting

in their cyclic analogs. The whole continuous process is based on the synthesis of the peptoid

scaffold using an U-4CR. The limiting isocyanide was synthesized in a continuous process by

the dehydration of the corresponding amide using Burgess reagent. Since the following

CuAAC cyclization requires a potentially hazardous azide functionality, we developed a flow

protocol for its in-line synthesis by the nucleophilic substitution of a bromide precursor with

tetrabutylammonium azide. The individual steps could be successfully coupled without the

need of isolating any synthetic intermediate. The resulting convergent continuous synthesis is

characterized by an overall processing time of ca. 25 min generating the desired

peptidomimetics in good to excellent yields. The subsequent CuAAC macrocyclization was

realized using a continuous flow reactor made of copper avoiding a separate addition of a

catalytically active species. Depending on the nature of the linear precursor and the resulting

ring strain, either a dimeric or a monomeric form of the cyclic product was obtained.

Chapter I

253

4. Experimental Section

General Remarks. All Microwave-assisted reactions were carried out in a Biotage Initiator

2.5 instrument in Pyrex vessels (2-5 mL). Reaction temperature was controlled by an external

IR sensor. For continuous flow experiments, commercially available syringe pumps reagent

injector units and tube reactors were used (Asia Flow Chemistry modules, Syrris). The back

pressure was either controlled using static or adjustable regulation units.[39]

1H-NMR and

13C

spectra were recorded on a 300 MHz instrument using CDCl3 or DMSO-d6 as solvent.

Chemical shifts (δ) are expressed in ppm downfield from TMS as internal standard. The

letters s, d, t, q, qt and m are used to indicate a singlet, doublet, triplet, quadruplet, quintuplet

and multiplet, respectively. Melting points were determined on a standard melting point

apparatus. Analytical HPLC analysis was carried out on a C-18 reversed-phase (RP)

analytical column (150 × 4.6 mm, particle size 5 μm) at 37 °C using a mobile phase A

(water/acetonitrile 90:10 (v/v) + 0.1 % TFA) and B (MeCN + 0.1 % TFA) at a flow rate of 1.0

mL min-1

. The following gradient was applied: linear increase from solution 30% B to 100%

B in 8 min, hold at 100% solution B for 2 min. HRMS experiments were performed on an

TOF LC/MS instrument equipped with an ESI ion source (positive ionization mode). X-ray

diffraction measurements were performed on a standard CCD diffractometer by using

graphite monochromatized Mo Kα radiation. Column chromatography was carried out using

an automated flash chromatography system using petroleum ether/ethyl acetate mixtures as

eluent. Preparative HPLC separations were carried on a C-18 reversed-phase column (250 ×

16 mm, particle size 5 μm) at 25 °C using a mobile phase A (water/acetonitrile 90:10 (v/v))

and B (MeCN) at a flow rate of 8.0 mL min-1

. The following gradient was applied: linear

increase from solution 30% B to 100% B in 18 min, hold at 100% solution B for 4 min. TLC

analysis was performed on silica gel F254 plates. All compounds and solvents were obtained

from standard commercial vendors and used without further purification. Proof of purity was

obtained by 1H NMR and HPLC−UV spectroscopy.

Starting Materials. 4-(Prop-2-yn-1-yloxy)benzonitrile,[55]

(4-(prop-2-yn-1-yloxy)phenyl)-

methanamine,[56]

3-azidopropionic acid,[57]

4-azidobutanoic acid, 5-azidopentanoic acid,[58]

6-

azidohexanoic acid[59]

were prepared and characterized according to literature procedures.

Chapter I

254

N-(4-(Prop-2-yn-1-yloxy)benzyl)formamide (7a): A stirred mixture of 4-(prop-2-yn-1-

yloxy)phenyl)methanamine (1.7 g, 10.6 mmol) in 5 mL ethyl formate was refluxed overnight.

Afterwards, the solvent was removed under reduced pressure and the residue was purified by

flash chromatography to give the title compound in 90% yield (1.8 g, 9.5 mmol) as a colorless

solid, mp. 93-94 °C, Rf: 0.42 (95% EtOAc/petroleum ether). HRMS (ESI): m/z: calcd for

C11H12NO2 [M+H]+: 190.086255, found: 190.086639.

1H NMR (300 MHz, CDCl3, presence

of rotamers) δ 8.21 (s, 0.9H), 8.15 (d, J = 12 Hz, 0.1H), 7.30 – 7.13 (m, 2H), 6.98 – 6.88 (m,

2H), 6.10 (brs, 1H), 4.80 and 4.70 (2 d, J = 2.5 Hz, 2H), 4.41 and 4.35 (2 d, J = 5.8 Hz, 2H),

2.53 (t, J = 2.5 Hz, 1H). 13

C NMR (75 MHz, CDCl3, presence of rotamers) 164.6, 161.1,

157.2, 157.0, 130.7, 130.5, 129.1, 128.3, 115.3, 115.1, 114.9, 78.4, 75.7, 58.9, 55.8, 45.1,

41.5; FT-IR (KBr, cm−1

) 3269, 3217, 3041, 2920, 2889, 2111, 1642, 1538, 1218, 1174, 1113,

1026, 812, 787, 601.

Microwave Assisted Synthesis of 1-(Isocyanomethyl)-4-(prop-2-yn-1-yloxy)benzene 1a.

N-(4-(Prop-2-yn-1-yloxy)benzyl)formamide (7a) (0.5 mmol, 94 mg) and methyl N-

(triethylammoniumsulfonyl)carbamate (0.75 mmol, 179 mg) were dissolved in acetonitrile (2

ml) and heated to 50 °C for 20 min using microwave irradiation. The obtained yellow solution

was concentrated in vacuum and purified by flash chromatography to give the title compound

in 93% yield (79.0 mg, 0.46 mmol) as colorless solid, mp. 58-60 °C, Rf: 0.36 (10%

EtOAc/petroleum ether). HRMS (APCI): m/z: calcd for C10H9O [M-NC+H]+: 145.064791,

found: 145.064668; calcd for C8H9O [M-propargyl]-: 132.045487, found: 132.045744;

1H

NMR (300 MHz, CDCl3) δ 7.30 (d, J = 8.7 Hz, 2H), 7.02 (d, J = 8.7 Hz, 2H), 4.73 (d, J = 2.4

Hz, 2H), 4.60 (brs, 2H), 2.55 (t, J = 2.4 Hz, 1H). 13

C NMR (75 MHz, CDCl3) δ 157.5, 157.2,

128.1, 125.5, 115.4, 78.2, 75.8, 55.9, 44.9; FT-IR (KBr, cm−1

) 3249, 3071, 2963, 2922, 2865,

2159, 2123, 2039, 1613, 1588, 1509, 1453, 1184, 940, 778, 635.

Microwave Assisted Synthesis of 2-Azidoacetic Acid 2a. 2-Bromoacetic acid (1.0 mmol,

0.137 mg) and N,N,N,N-tetrabutylammonium azide (1.5 mmol, 0.426 mg) were dissolved in

acetonitrile (2 ml) and heated to 100 °C for 15 min using microwave irradiation. After cooling

to room temperature, the solvent was evaporated. The concentrate was dissolved in H2O and

acidified with HCl to pH = 1. The solution was extracted 3 x with Et2O and the combined

organic phases were dried over Na2SO4. Careful solvent evaporation under reduced pressure

resulted in 92% yield of the title compound (93 mg, 0.92 mmol). The data obtained by NMR

is identical to those reported in literature.[60]

Chapter I

255

General Procedure for Preparation of Linear Peptoids by the U-4CR in Batch (Table 2).

A sealed 2-5 mL microwave process vial containing a mixture of the isocyanide (1, 0.5

mmol), the corresponding acid (2, 1.0 mmol), the amine (3, 1.0 mmol), and paraformaldehyde

(4, 1.0 mmol) in 2 mL MeOH/MeCN (1:1) was kept for 4 min at 80 °C using a single mode

microwave reactor. After cooling to room temperature, the reaction mixture was concentrated

under reduced pressure and purified by flash column chromatography using petroleum

ether/ethyl acetate gradients to yield the corresponding linear peptoids.

2-Azido-N-(tert-butyl)-N-(2-oxo-2-((4-(prop-2-yn-1-yloxy)benzyl)amino)ethyl)acetamide

(5a). Prepared from paraformaldehyde (4a, 30 mg, 1.0 mmol), tert-butylamine (3a, 73 mg,

1.0 mmol), 2-azidoacetic acid (2a, 101 mg, 1.0 mmol) and isocyanide 1a (85 mg, 0.5 mmol).

Peptoid 5a was isolated in 84% yield (150 mg, 0.42 mmol) as a colorless oil. Rf: 0.50 (50%

EtOAc/petroleum ether). HRMS (ESI): m/z: calcd for C18H23N5O3Na [M+Na]+: 380.169311,

found: 380.169070. 1H NMR (300 MHz, CDCl3) δ 7.20 (d, J = 8.5 Hz, 2H), 6.93 (d, J = 8.5

Hz, 2H), 6.75 – 6.64 (m, 1H), 4.67 (d, J = 2.3 Hz, 2H), 4.36 (d, J = 5.6 Hz, 2H), 3.90 (s, 2H),

3.81 (s, 2H), 2.53 (t, J = 2.3 Hz, 1H), 1.38 (d, J = 11.6 Hz, 9H). 13


168.8, 168.7, 157.1, 156.9, 130.7, 129.1, 115.2, 78.4, 77.5, 77.1, 76.7, 75.7, 75.7, 58.8, 55.8,

52.6, 47.8, 43.1, 28.4; FT-IR (KBr, cm−1

) 3294, 2102, 1654, 1509, 1396, 1363, 1215, 1190,

1023, 933, 829, 641.

3-Azido-N-(tert-butyl)-N-(2-oxo-2-((4-(prop-2-yn-1-loxy)benzyl)amino)ethyl)propanamide (5b).

Prepared from paraformaldehyde (4a, 30 mg, 1.0 mmol), tert-butylamine (3a, 73 mg, 1.0

mmol), 3-azidopropionic acid (2b, 115 mg, 1.0 mmol), and isocyanide 1a (85 mg, 0.5 mmol).

Peptoid 5b was isolated in 86% yield (0.159 g, 0.43 mmol) as a colorless solid, mp. 92-94 °C.

Rf: 0.37 (50% EtOAc/petroleum ether). HRMS (ESI): m/z: calcd for C19H25N5O3Na [M+Na]+:

394.184961, found: 394.185216. 1H NMR (300 MHz, CDCl3) δ 7.21 (d, J = 8.4 Hz, 2H), 6.94

(d, J = 8.4 Hz, 2H), 6.46 (brt, J = 5.1 Hz, 1H), 4.68 (t, J = 2.4 Hz, 2H), 4.40 (d, J = 5.7 Hz,

2H), 3.98 (s, 2H), 3.60 (t, J = 6.2 Hz, 2H), 2.53 (t, J = 2.4 Hz, 1H), 2.46 (t, J = 6.2 Hz, 2H),

1.41 (s, 9H). 13

C NMR (75 MHz, CDCl3) δ 171.7, 169.1, 157.1, 130.6, 129.1, 115.2, 78.4,

75.7, 58.3, 55.8, 49.0, 47.6, 43.2, 35.3, 28.6; FT-IR (KBr, cm−1

) 3292, 2973, 2928, 2098,

1649, 1586, 1543, 1509, 1405, 1362, 1328, 1297, 1113, 807, 731, 671.

4-Azido-N-(tert-butyl)-N-(2-oxo-2-((4-(prop-2-yn-1-yloxy)benzyl)amino)ethyl)butanamide (5c).


mmol), 4-azidobutanoic acid (2c, 129 mg, 1.0 mmol) and isocyanide 1a (0.085 g, 0.5 mmol).

Chapter I

256

Peptoid 5c was isolated in 95% yield (181 mg, 0.47 mmol) as a colorless solid, mp. 93-95 °C,

Rf: 0.40 (50% EtOAc/petroleum ether). HRMS (ESI): m/z: calc. for C20H27N5O3Na [M+Na]+:

408.200611, found: 408.200814. 1H NMR (300 MHz, CDCl3) δ 7.15 (d, J = 8.6 Hz, 2H), 6.87

(d, J = 8.4 Hz, 2H), 6.44 (brt, J = 5.4 Hz, 1H), 4.61 (d, J = 2.4 Hz, 2H), 4.35 (d, J = 5.8 Hz,

2H), 3.91 (s, 2H), 3.17 (t, J = 6.4 Hz, 2H), 2.46 (t, J = 2.4 Hz, 1H), 2.22 (t, J = 6.8 Hz, 2H),

1.82 (qt, J = 6.6 Hz, 2H), 1.33 (s, 9H). 13

C NMR (75 MHz, CDCl3) δ 173.4, 169.5, 157.1,

130.8, 129.2, 115.2, 78.4, 75.7, 58.1, 55.8, 50.9, 49.1, 43.0, 32.8, 28.6, 24.4; FT-IR (KBr,

cm−1

) 3317, 3255, 3072, 2968, 2908, 2087, 1663, 1643, 1512, 1266, 1240, 1193, 1179, 1116,

934, 813, 607, 553.

5-Azido-N-(tert-butyl)-N-(2-oxo-2-((4-(prop-2-yn-1-yloxy)benzyl)amino)ethyl)pentanamide (5d).


mmol), 5-azidopentanoic acid (2d, 143 mg, 1.0 mmol) and isocyanide 1a (85 mg, 0.5 mmol).

Peptoid 5d was isolated in 86% yield (171 mg, 0.43 mmol) as a colorless solid, mp. 72-74 °C,


422.216281, found: 422.216353. 1H NMR (300 MHz, CDCl3) δ 7.24 – 7.18 (m, 2H), 6.98 –

6.93 (m, 2H), 6.36 (brt, J = 5.5 Hz, 1H), 4.69 (d, J = 3.1 Hz, 2H), 4.43 (d, J = 5.8 Hz, 2H),

4.00 (s, 2H), 3.25 (t, J = 5.4 Hz, 2H), 2.53 (t, J = 2.4 Hz, 1H), 2.24 (t, J = 7.1 Hz, 2H), 1.70 –

1.60 (m, 2H), 1.58 – 1.48 (m, 2H), 1.41 (s, 9H). 13

C NMR (75 MHz, CDCl3) δ 174.0, 169.6,

157.2, 130.7, 129.1, 115.2, 78.3, 75.7, 58.0, 55.8, 51.2, 49.1, 43.1, 35.4, 28.8, 28.3, 22.4; FT-

IR (KBr, cm−1

) 3281, 3068, 2928, 2871, 2091, 1724, 1678, 1611, 1585, 1454, 1359, 1211,

1177, 1024, 752, 655, 576.

6-Azido-N-(tert-butyl)-N-(2-oxo-2-((4-(prop-2-yn-1-yloxy)benzyl)amino)ethyl)hexanamide (5e).


mmol), 6-azidohexanoic acid (2e, 155 mg, 1.0 mmol) and isocyanide 1a (85 mg, 0.5 mmol).

Peptoid 5e was isolated in 80% yield (165 mg, 0.40 mmol) as a colorless solid, mp. 88-90 °C,


436.230574, found: 436.231116.1H NMR (300 MHz, CDCl3) δ 7.23 – 7.14 (m, 2H), 6.97 –

6.88 (m, 2H), 6.38 (brt, J = 5.6 Hz, 1H), 4.67 (d, J = 2.4 Hz, 2H), 4.40 (d, J = 5.8 Hz, 2H),

3.97 (s, 2H), 3.23 (t, J = 6.8 Hz, 2H), 2.53 (t, J = 2.4 Hz, 1H), 2.19 (t, J = 7.3 Hz, 2H), 1.65 –

1.50 (m, 4H), 1.39 (s, 9H), 1.35 – 1.25 (m, 2H). 13

C NMR (75 MHz, CDCl3) δ 174.2, 169.6,

157.1, 130.7, 129.1, 115.2, 78.4, 75.7, 57.9, 55.8, 51.2, 49.1, 43.0, 35.9, 28.8, 26.3, 24.7. FT-

IR (KBr, cm−1

) 3273, 3074, 2932, 2867, 2092, 1726, 1679, 1585, 1555, 1421, 1212, 1114,

1021, 751, 579, 552.

Chapter I

257

2-Azido-N-(2-(cyclohexylamino)-2-oxoethyl)-N-(prop-2-yn-1-yl)acetamide (5f). Prepared

from paraformaldehyde (4a, 30 mg, 1.0 mmol), propargylamine (3b, 55 mg, 1.0 mmol), 2-

azidoacetic acid (2a, 101 mg, 1.0 mmol) and cyclohexyl isocyanide (1b, 55 mg, 0.5 mmol).

Peptoid 5f was isolated in 90% yield (125 mg, 0.45 mmol) as a colorless solid, mp. 125-127

°C, Rf: 0.42 (50% EtOAc/petroleum ether). HRMS (ESI): m/z: calcd for C13H20N5O2 [M+H]+:

278.161151, found for [M+H]+: 278.161152.

1H NMR (300 MHz, CDCl3 mixture of rotamers)

1H NMR (300 MHz, CDCl3) δ 6.01 and 5.98 (2 brs, 1H), 4.25 and 4.09 (2 brs, 2H), 4.04 and

4.01 (2 s, 2H), 3.93 and 3.87 (2 brs, 2H), 3.82 – 3.54 (m, 1H), 2.33 and 2.26 (2 brs, 1H), 1.88

– 1.77 (m, 2H), 1.72 – 1.47 (m, 3H), 1.40 – 1.17 (m, 2H), 1.19 – 0.96 (m, 3H). 13

C NMR (75

MHz, CDCl3 mixture of rotamers) δ 168.1, 166.8, 165.9, 74.1, 73.7, 50.4, 50.1, 50.1, 48.9,

48.5, 38.2, 36.6, 32.9, 25.4, 24.7; FT-IR (KBr, cm−1

) 3298, 3259, 2927, 2852, 2102, 1670,

1637, 1554, 1457, 1370, 1082, 891, 657, 559.

3-Azido-N-(2-(cyclohexylamino)-2-oxoethyl)-N-(prop-2-yn-1-yl)propanamide (5g).

Prepared from paraformaldehyde (4a, 30 mg, 1.0 mmol), propargylamine (3b, 55 mg, 1.0

mmol), 3-azidopropionic acid (2b, 115 mg, 1.0 mmol) and cyclohexyl isocyanide (1b, 55 mg,

0.5 mmol). Peptoid 5g was isolated in 88% yield (128 mg, 0.44 mmol) as a colorless solid,

mp. 109-111 °C, Rf: 0.30 (50% EtOAc/petroleum ether). HRMS (ESI): m/z: calcd for

C14H22N5O2 [M+H]+: 292.176801, found 292.176016.

1H NMR (300 MHz, CDCl3 mixture of

rotamers) δ 5.97 (brs, 1H), 4.24 and 4.12 (2 d, J = 2.4 Hz, 2H), 4.00 and 3.91 (2 brs, 2H), 3.82

– 3.65 (m, 1H), 3.67 – 3.55 (m, 2H), 2.67 (t, J = 6.3 Hz, 1H), 2.45 (t, J = 6.2 Hz, 1H), 2.30

and 2.24 (2 t, J = 2.4 Hz, 1H), 1.90 – 1.75 (m, 2H), 1.72 – 1.48 (m, 3H), 1.39 – 1.19 (m, 2H),

1.17 – 0.96 (m, 3H). 13

C NMR (75 MHz, CDCl3 mixture of rotamers) δ 170.9, 170.7, 167.2,

166.4, 78.3, 73.7, 73.5, 51.3, 50.4, 48.8, 48.3, 47.1, 38.9, 36.6, 32.9, 32.8, 32.7, 32.5, 25.4,

25.3, 24.8, 24.7; FT-IR (KBr, cm−1

) 3316, 3239, 2942, 2925, 2855, 2114, 2084, 1649, 1549,

1463, 1433, 1237, 1053, 882, 720, 617.

Methyl-2-(2-(4-Azido-N-(2-ethynylphenyl)butanamido) acetamido)acetate (5h): Prepared

from paraformaldehyde (4a, 30 mg, 1.0 mmol), 2-ethynylaniline (3c, 117 mg, 1.0 mmol), 4-

azidobutanoic acid (2c, 129 mg, 1.0 mmol), methyl isocyanoacetate (1c, 50 mg, 0.5 mmol).

Peptoid 5f was isolated in 81% yield (146 mg, 0.41 mmol) as a brownish oil, Rf: 0.32 (50%

EtOAc/petroleum ether). HRMS (ESI): m/z: calcd for C17H20N5O4 [M+H]+: 358.150981,

found 358.151069. 1H NMR (300 MHz, CDCl3 mixture of rotamers) δ 7.54 and 7.52 (2 brs,

1H), 7.43 – 7.37 (m, 2H), 7.35 – 7.27 (m, 1H), 6.95 (brs, 1H), 4.77 (d, J = 15.5 Hz, 1H), 4.11

Chapter I

258

(dd, J = 18.2, 6.0 Hz, 1H), 3.88 (dd, J = 18.2, 4.9 Hz, 1H), 3.76 (d, J = 15.5 Hz, 1H), 3.69 (s,

3H), 3.26 (s, 1H), 3.25 – 3.16 (m, 2H), 2.20 – 2.07 (m, 2H), 1.88 – 1.76 (m, 2H). 13

C NMR

(75 MHz, CDCl3 mixture of rotamers) δ 173.3, 170.2, 168.9, 144.1, 134.1, 130.7, 129.1,

128.8, 121.3, 83.2, 79.4, 53.1, 52.4, 50.6, 41.1, 30.6, 24.3; FT-IR (KBr, cm−1

) 3288, 2951,

2094, 1746, 1654, 1532, 1485, 1448, 1435, 1252, 1020, 755, 657, 631.

Synthesis of Linear Peptoid 5a in a Continuous Multi-Step Approach (Scheme 5).

Isocyanide generation: A feed consisting of formamide 7a (0.25 mmol) dissolved in

acetonitrile (1 mL) was pumped with a flow rate of 200 µL min-1

and mixed in a T-shaped

mixing unit with a second feed with an identical flow rate containing a 0.5 M solution of

Burgess reagent (0.5 mmol in 1 mL acetonitrile). For a better control of the process, the

reagents were each stored in a 1 mL sample loop connected via a 6-way valve and

simultaneously injected into the flow system. After mixing, the resulting 400 µL min-1

stream

was passed through a PFA coil (0.8 mm inner diameter; 8 mL reactor volume, 20 min

residence time) set at 50 °C using an oil bath, theoretically resulting in an isocyanide stream

of 0.05 mmol min-1

.

Azide formation: A feed consisted of 2-bromoacetic acid 8a (2.0 mmol) dissolved in

acetonitrile (2 mL) was pumped with a flow rate of 100 µL min-1

and mixed in a T-shaped

mixing unit with a second feed with an identical flow rate containing a 1.5 M solution of

tetrabutylammonium azide (3.0 mmol in 2 mL acetonitrile). For a better control of the

process, the reagents were each stored in a 2 mL sample loop connected via a 6-way valve

and simultaneously injected into the flow system. After mixing, the resulting 200 µL min-1

stream was passed through a PFA coil (0.8 mm inner diameter; 3 mL reactor volume, 15 min

residence time) set at 100 °C using an oil bath, theoretically resulting in an azide stream of 0.1

mmol min-1

(2 equiv).

U-4CR: A solution of tert-butylamine 3a (0.5 M) and paraformaldehyde 4a (0.5 M) in

methanol was constantly pumped with a flow rate of 200 µL min-1

(0.1 mmol min-1

, 2 equiv)

and mixed with the outcome of the isocyanide generation and the azide formation in a cross

shaped mixing device. The resulting reaction stream (800 µL min-1

) was heated at 80 °C in a

PFA coil (0.8 mm inner diameter, 4 mL reactor volume, 5 min residence time). The reaction

mixture was collected after depressurization by passing a static 7 bar backpressure regulator.

Purification by flash column chromatography resulted in linear peptoid 5a in 80% yield(71

mg, 0.2 mmol) as a colorless oil. Data obtained by mass spectrometry, 1H NMR and

13C NMR

are identical to those from the corresponding batch experiment (see above).

Chapter I

259

General Procedure for the Continuous CuAAC Using a Copper Coil. A solution of the

respective linear peptoid 5a-h in MeCN/MeOH (1:1; 2 mM) was pumped with 800 µL min-1

through a copper coil (2 mm inner diameter, 20 ml internal volume) heated at 140 °C in a GC

oven. After passing a back pressure regulator set at 10 bar, the reaction mixture was collected

and the solvent removed under reduced pressure. Isolation by preparative HPLC resulted in

the cyclic peptoids 6a-h in analytical purity.

Cyclic Peptoid 6a: Prepared from peptoid 5a (50 mg, 0.140 mmol) in 70 mL MeCN/MeOH

(1:1). Isolation afforded the title compound in 74% yield (37 mg, 0.052 mmol) as a colorless

solid, mp. 254-256 °C (dec.). HRMS (ESI): m/z: calcd for C36H47N10O6 [M+H]+: 715.367456,

found: 715.360619. 1H NMR (300 MHz, DMSO-d6) δ 8.59 (brs, 2H), 8.10 (s, 2H), 7.25 (d, J

= 8.4 Hz, 4H), 7.03 (d, J = 8.4 Hz, 4H), 5.35 (s, 4H), 5.11 (s, 4H), 4.35 – 4.20 (m, 4H), 4.15

(s, 4H), 1.32 (s, 18H). 13

C NMR (75 MHz, DMSO-d6) δ 169.3, 167.1, 157.7, 142.7, 131.7,

129.2, 126.8, 115.0, 61.4, 58.2, 52.9, 47.2, 42.3, 28.4; FT-IR (KBr, cm−1

) 3303, 3075, 2977,

2931, 1658, 1612, 1585, 1543, 1509, 1463, 1435, 1364, 1218, 1191, 812, 586

Cyclic Peptoid 6b: Prepared from peptoid 5b (50 mg, 0.135 mmol) in 67.5 mL

MeCN/MeOH (1:1). Isolation afforded the title compound in 81% yield (39 mg, 0.11 mmol)

as a colorless solid, mp. 240-242 °C. HRMS (ESI): m/z: calcd for C19H26N5O3 [M+H]+:

372.201679, found: 372.202446.1H NMR (300 MHz, DMSO-d6) δ 8.43 (brs, 1H), 8.18 (s,

1H), 7.17 (d, J = 8.3 Hz, 2H), 6.97 (d, J = 8.3 Hz, 2H), 5.08 (s, 2H), 4.53 (t, J = 6.5 Hz, 2H),

4.23 (d, J = 4.9 Hz, 2H), 4.01 (s, 2H), 2.93 (d, J = 6.7 Hz, 2H), 1.31 (s, 9H). 13

C NMR (75

MHz, DMSO-d6) δ 171.1, 169.7, 157.5, 142.9, 131.9, 129.1, 125.2, 115.0, 61.5, 57.5, 48.0,

46.5, 42.2, 35.9, 28.6; FT-IR (KBr, cm−1

) 3318, 3131, 3076, 2970, 1676, 1637, 1606, 1509,

1294, 1093, 817, 596.

Cyclic Peptoid 6c: Prepared from peptoid 5c (50 mg, 0.130 mmol) in 65 mL MeCN/MeOH


solid, mp. 259-261 °C. HRMS (ESI): m/z: calcd for C20H28N5O3 [M+H]+: 386.218666, found:

386.218942. 1H NMR (300 MHz, DMSO-d6) δ 8.26 (brs, 1H), 7.68 (s, 1H), 7.10 (d, J = 7.9

Hz, 2H), 6.81 (d, J = 7.9 Hz, 2H), 5.26 (s, 2H), 4.23 (s, 2H), 3.99 (brs, 2H), 3.75 (s, 2H), 1.91

(brs, 2H), 1.56 (brs, 2H), 1.29 (s, 9H). 13

C NMR (75 MHz, DMSO-d6) δ 172.7, 169.8, 157.5,

143.1, 132.0, 129.1, 128.9, 124.9, 115.0, 61.6, 57.3, 49.5, 48.1, 42.2, 32.3, 28.6, 26.4; FT-IR

(KBr, cm−1

) 3293, 2962, 2929, 1645, 1585, 1508, 1458, 1421, 1394, 1334, 1216, 1176, 999,

807, 668, 509.

Chapter I

260

Cyclic Peptoid 6d: Prepared from peptoid 5d (50 mg, 0.125 mmol) in 62.5 mL

MeCN/MeOH (1:1). Isolation afforded the title compound in 80% yield (40 mg, 0.10 mmol)

as a colorless solid, mp. 213-215 °C. HRMS (ESI): m/z: calcd for C21H30N5O3 [M+H]+:

400.234316, found: 400.234235. 1H NMR (300 MHz, DMSO-d6) δ 8.39 (brs, 1H), 8.20 (s,

1H), 7.19 (d, J = 8.2 Hz, 2H), 6.98 (d, J = 8.3 Hz, 2H), 5.09 (s, 2H), 4.34 (t, J = 6.2 Hz, 2H),

4.23 (d, J = 4.9 Hz, 2H), 3.98 (s, 2H), 2.30 – 2.15 (m, 2H), 1.83 – 1.70 (m, 2H), 1.54 – 1.36

(m, 2H), 1.30 (s, 9H). 13

C NMR (75 MHz, DMSO-d6) δ 173.4, 170.0, 157.5, 143.1, 132.1,

129.1, 124.8, 115.0, 61.6, 57.1, 49.7, 48.1, 42.2, 34.7, 29.8, 28.7, 22.2; FT-IR (KBr, cm−1

)

3353, 3125, 3078, 2978, 2965, 2938, 1645, 1508, 1300, 1060, 1032, 993, 979, 881.

Cyclic Peptoid 6e: Prepared from peptoid 5e (50 mg, 0.121 mmol) in 61 mL MeCN/MeOH


solid, mp. 268-270 °C. HRMS (ESI): m/z: calcd for C22H32N5O3 [M+H]+: 414.248629, found:

414.249174.1H NMR (300 MHz, DMSO-d6) δ 8.42 (t, J = 6.2 Hz, 1H), 8.11 (s, 1H), 7.15 (d, J

= 8.6 Hz, 2H), 6.86 (d, J = 8.6 Hz, 2H), 5.31 (s, 2H), 4.31 (brs, 2H), 4.10 (brs, 2H), 3.85 (s,

2H), 1.80 – 1.60 (m, 4H), 1.37 (s, 9H), 1.29 – 1.18 (m, 2H), 0.66 – 0.52 (m, 2H).13

C NMR (75

MHz, DMSO-d6) δ 173.7, 170.0, 157.5, 143.0, 132.1, 129.1, 124.8, 114.9, 61.6, 57.0, 49.7,

48.1, 42.1, 35.2, 30.1, 28.7, 26.0, 24.6; FT-IR (KBr, cm−1

) 3348, 3130, 3077, 2940, 2873,

1508,1465, 1438, 1418, 1170, 1089, 846, 704, 580.

Cyclic Peptoid 6f: Prepared from peptoid 5f (50 mg, 0.180 mmol) in 90 mL MeCN/MeOH



found: 278.160641.1H NMR (300 MHz, DMSO-d6) δ 7.92 (d, J = 7.8 Hz, 1H), 7.71 (s, 1H),

5.13 (s, 2H), 4.73 (s, 2H), 4.08 (s, 2H), 3.61 – 3.45 (m, 1H), 1.75 – 1.60 (m, 4H), 1.60 – 1.50

(m, 1H), 1.33 – 1.01 (m, 5H). 13

C NMR (75 MHz, DMSO-d6) δ 166.4, 163.0, 129.2, 129.0,

49.2, 48.7, 48.2, 43.5, 32.9, 25.6, 25.0; FT-IR (KBr, cm−1

) 3294, 2927, 2855, 1643, 1556,

1494, 1444, 1422, 1410, 1375, 1348, 1304, 1275, 1252, 1098, 988, 828, 693.

Cyclic Peptoid 6g: Prepared from peptoid 5g (50 mg, 0.172 mmol) in 86 mL MeCN/MeOH


solid, mp. 151-153 °C. HRMS (ESI): m/z: calcd for C14H22N5O2 [M]+: 292.176801, found:

292.176707.1H NMR (300 MHz, CDCl3) δ 7.47 (s, 1H), 5.87 (d, J = 7.8 Hz, 1H), 4.69 (s,

2H), 4.67 – 4.61 (m, 2H), 4.00 (s, 2H), 3.68 – 3.53 (m, 1H), 3.17 – 3.09 (m, 2H), 1.79 – 1.68

Chapter I

261

(m, 2H), 1.66 – 1.46 (m, 3H), 1.33 – 1.16 (m, 2H), 1.13 – 0.92 (m, 3H). 13

C NMR (75 MHz,

CDCl3) δ 171.6, 166.7, 131.7, 131.5, 51.6, 48.5, 45.4, 43.0, 32.8, 32.6, 25.4, 24.7; FT-IR

(KBr, cm−1

) 3297, 3067, 2930, 2854, 11646, 1540, 1449, 1292, 1239, 1133, 1047, 891, 726,

644.

Cyclic Peptoid 6h: Prepared from peptoid 5h (50 mg, 0.14 mmol) in 70 mL MeCN/MeOH



found: 715.294219. 1H NMR (300 MHz, DMSO-d6) δ 8.35 (t, J = 5.8 Hz, 2H), 8.06 – 8.00

(m, 2H), 7.80 (s, 2H), 7.63 – 7.55 (m, 2H), 7.53 – 7.35 (m, 4H), 4.89 and 4.84 (2 s, 2H), 4.63

– 4.51 (m, 2H), 4.32 – 4.17 (m, 2H), 3.95 – 3.79 (m, 4H), 3.63 (s, 6H), 2.30 – 1.78 (m, 8H),

1.31 – 1.12 (m, 2H). 13

C NMR (75 MHz, DMSO-d6) δ 171.5, 170.6, 168.7, 142.6, 138.8,

130.8, 129.6, 129.4, 128.7, 122.0, 52.2, 51.3, 48.6, 30.0, 25.4; FT-IR (KBr, cm−1

) 3282, 3083,

2932, 1750, 1658, 1552, 1487, 1372, 1175, 970, 759, 662, 552.

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Chapter I

267


X-ray Crystallography. Crystals suitable for single crystal X-ray diffractometry were

removed from a vial and immediately covered with a layer of silicone oil. A single crystal was

selected, mounted on a glass rod on a copper pin, and placed in the cold N2 stream provided

by the cryometer. XRD data collection was performed on a diffractometer with use of Mo Kα

radiation (λ= 0.71073 Å) and a CCD area detector. Empirical asorption corrections were

applied using SADABS.[S1,S2]

The structures were solved with use of either direct methods or

the Patterson option in SHELXS and refined by the full-matrix least-squares procedures in

SHELXL.[S3,S4]

The space group assignments and structural solutions were evaluated using

PLATON.[S5,S6]

Non-hydrogen atoms were refined anisotropically. The hydrogen atom bonded

to N5 was located in a difference map. All other hydrogen atoms were located in calculated

positions corresponding to standard bond lengths and angles. CCDC 1050000 contains the

supplementary crystallographic data. This data can be obtained free of charge from The

Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.

Table S1. Crystallographic data and details of measurement for compound 6e.

Mo K(=0.71073Å). R1 = / |Fo|- |Fc|/||Fd; wR2 = [w(Fo2-F2

2)2/w(Fo

2)2]

1/2

Compound 6e

Formula C22H31N5O3

Fw (g mol-1

) 413.52

a (Å) 16.3367(10)

b (Å) 13.1395(9)

c (Å) 10.2258(6)

α (°) 90

β (°) 90.818(2)

γ (°) 90

V (Å3) 2194.8(2)

Z 4

Crystal size (mm) 0.10 × 0.09 × 0.06

Crystal habit Colourless block

Crystal system Monoclinic

Space group P21/c

dcalc (mg/m3) 1.251

μ (mm-1

) 0.09

T (K) 100(2)

2θ range (°) 2.5–31.5

F(000) 888

Rint 0.046

independent reflns 7349

No. of params 278

R1, wR2 (all data) R1 = 0.0595, wR2 = 0.1239

R1, wR2 (>2σ)

R1 = 0.0455, wR2 = 0.1155

Chapter I

268

Figure S1. Crystal structure of 6e. All non-carbon atoms shown as 30% shaded ellipsoids.

Figure S2. Detailed description of the Synthesis of Linear Peptoid 5a via U-4CR in

Continuous Flow Mode

Chapter I

269

Figure S3. Detailed description of the Continuous Isocyanide Synthesis Employing Burgess

Reagent

Figure S4. Detailed description of the Continuous Synthesis of 2-Azidoacetic Acid

Chapter I

270

Figure S5. Detailed description of the Synthesis of Linear Peptoid 5a via Isocyanide

Synthesis (red), Azide Preparation (green), and an U-4CR (blue) in a Single Continuous

Operation

Figure S6. Detailed description of the Continuous CuAAC Macrocyclization of Linear

Peptoids using a Copper Coila

Chapter I

271

References

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[S3] G. Sheldrick, Acta Crystallogr. Sect. A 1990, 46, 467.

[S4] G. Sheldrick, Acta Crystallogr. Sect. A 2008, 64, 112.

[S5] A. L. Spek, J. Appl. Crystallogr. 2003, 36, 7.

[S6] A. L. Spek, Acta Crystallogr. Sect. D 2009, 65, 148-155.

Summary & Concluding Remarks

273


Many petrochemical products and bulk chemicals are prepared on an enormous scale by

continuous routes due to the numerous advantages related to environmental and economic

factors, safer processing and scalability. Meanwhile, the pharmaceutical and fine chemical

industry persists on conventional batch operations due to low production quantities and the

high flexibility gained by such standard techniques.

Nevertheless, within the last decades the advantages of flow processing were also

recognized in the synthetic community and small scale continuous flow devices (also referred

to as microreactors) entered many research laboratories.[1,2]

The multitude of benefits gained

by microreactor technology as the easy access of high temperature/pressure conditions,

excellent mass and heat transfer, reduction of safety hazards and scalability led to a plethora

of protocols for its implementation in organic synthesis. This is not just true for simple single

stage reactions but also for sophisticated multi-step protocols and even for total synthesis of

natural products.[3,4]

Moreover, modular approaches utilizing different continuous synthesis

and purification platforms where shown to be connected in an interchangeable fashion thus

providing high flexibility for fine chemical production.[5]

However, it has to be kept in mind

that not for all reactions a translation from batch to continuous flow mode is reasonable. The

decision whether to use a round-bottom flask or a microreactor has to be made on a case-by-

case basis. A categorization of organic transformation based on the reaction rate identifies

three reaction types which can benefit from continuous flow chemistry.[6]

Type A reactions are extremely fast (< 1s) and the overall rate is controlled by

mixing/mass transfer characteristics. Such transformations clearly benefit from the

enhanced mixing characteristics, and the improved heat transfer gained by

microreactor technology.

Type B reactions are slower (seconds to minutes) but often exothermic. Mixing is

less important than for type A reactions but heat transfer is of crucial importance to

avoid undesired temperature gradients.

Type C reactions are slow (minutes to hours) and continuous flow chemistry can

bring clear safety advantages especially in case of hazardous reagents/intermediates or

if process intensification under harsh conditions is of interest.


274

Another driver for continuous flow chemistry is its application for multiphasic reaction

environments. In a Type C-single phase transformation safety concerns are clearly the most

important reasons for flow approaches. On the contrary, in case of e.g. biphasic gas/liquid

reactions the improved interfacial area can significantly contribute to process intensification.

Moreover, the easy access of high pressure regimes and the straightforward control of gaseous

reagents by thermal mass flow controlling units or membrane reactors is highly beneficial for

several transformations.

The first part of this thesis describes examples for gas/liquid reactions in continuous

flow and starts with a theoretical discussion of recent literature examples on aerobic oxidation

in such devices (Chapter A).

In chapter B the direct aerobic oxidation of 2-benzylpyridine derivatives could be

dramatically enhanced using a continuous flow methodology in a high temperature process

window at 200°C. The reaction time could be significantly reduced from hours to minutes and

molecular oxygen could be replaced by synthetic air as sole oxygen source. A crucial point

was the fact that conventional polar, aprotic solvents like NMP or DMSO were prone to

decomposition under the harsh reaction conditions. To overcome these issues, propylene

carbonate, a high boiling solvent with excellent oxidation stability could be utilized as

sustainable alternative. Good to excellent isolated yields for potential drug precursor

molecules were obtained within 13 min in a stainless steel coil, significantly enhancing the

original batch protocol.

A catalyst-free flow process for the in situ generation of diimide from hydrazine

hydrate and molecular oxygen and its application for the selective reduction of unsaturated

carboncarbon bonds could be successfully carried out as described in chapter C and D.

Various simple alkenes can be selectively reduced within 10 minutes at 100-120 °C and 20-25

bar in a virtually work-up free procedure. Moreover, it could be shown that the oxidation of

hydrazine hydrate, a time consuming step under conventional batch conditions, can be

dramatically enhanced. The obtained kinetic information led to the development of a multi-

injection principle applying periodic additions of fresh hydrazine hydrate to overcome

limitations due to over-oxidation and disproportionation of the reactive intermediate. Thus, an

increased effective residence times could be obtained in cases where less reactive olefins need

to be reduced.

As illustrative example, the selective reduction of artemisinic acid yielding the direct

precursor molecule for the antimalarial drug artemisinin could be successfully accomplished.

This industrially relevant reduction was achieved by using four consecutive liquid feeds and


275

residence time units with 2 equivalents of O2, a total amount of 5 equivalents N2H4 H2O and

an overall reaction time of ~40 min. A comparison with other published procedures for this

reduction shows a >20 fold higher space-time-yield for the continuous process.

The examples in chapter B-D not only show how continuous flow processing can be

used to facilitate aerobic oxidation procedures but also how to circumvent severe explosion

risks of chemical transformations utilizing molecular oxygen. Since the possibility for flame

propagation is minimized in the small channel dimensions of a continuous flow microreactor

such oxidations can be carried out at high temperature/pressure conditions in a safe and

controllable manner.

A type A reaction sequence involving a gaseous reagent was described in chapter E.

Various carboxylic acids could be synthesized from terminal alkynes and heterocycles by an

lithiation-carboxylation sequence within ~3.5 seconds at room temperature. Similar reactions

in batch have to be carried out at very low temperatures temperatures to ensure adequate

mixing of the reactants and to prevent local overheating. By utilizing microreactor technology

a highly efficient mixing of two or more reagent streams can be easily achieved as diffusion

paths are reduced by order of magnitudes compared to conventional batch reactors.[1,2]

Consequently, continuous flow processing enables a very accurate control of the reaction time

(= residence time, tRes) allowing to perform such transformations at relatively high

temperatures. The presented method is characterized by mixing the substrate with a suitable

organolithium compound and the subsequent addition of CO2 as electrophile before

quenching with water. Importantly, low excess of the organometallic base and the gaseous

reagent could be used due the precise stoichiometry control in the continuous microreactor.

A different type of gas/liquid processing is reported in chapter F for the continuous

Bucherer-Bergs hydantoin synthesis. In this example a biphasic liquid/liquid reaction mixture

– consisting of an organic substrate (aldehyde or ketone) and an aqueous reagent stream

containing KCN and (NH4)2CO3 - enters the heated reaction zone. The utilization of a well-

defined segmented flow pattern circumvents solubility issues for unpolar starting materials

and significantly increases the interfacial area. Upon heating in the coil reactor, ammonium

carbonate decomposes into the final gaseous reagents (NH3, CO2). The lack of gaseous

headspace under high pressure conditions avoids sublimation/volatilization as observed in

batch procedures enabling a significant process intensification.

The construction of CO bonds via -CH bond activation of simple ethers using an

inexpensive copper catalyst in combination with a commercially available decane solution of

TBHP as stoichiometric oxidant in a single phase reaction is presented in batch and flow


276

mode (Chapter G). For this type C reaction the potentially hazardous combination of an

organic peroxide and ethers as reagent/solvent at temperatures above 100°C was the main

driver for the development of a continuous flow protocol. Moreover, in case of low boiling

ethers, the necessary reaction temperature is inaccessible under standard reflux conditions.

Gratifyingly, high pressure flow protocols allow heating of the reaction mixture far above the

boiling point of such solvents in a safe and controllable manner offering the opportunity to

perform such reactions even on higher scales.

A solid/liquid protocol for the reduction of nitroarenes to the corresponding aniline

derivatives exemplifies the advantages of heterogeneous catalysis in continuous flow (Chapter

H).[1,2,7]

Thus, alumina supported Fe3O4 nanoparticles were prepared by a simple

impregnation methodology and filled into a dedicated packed-bed reactor. Continuous

reductions were performed utilizing hydrazine hydrate as reducing agent at 150°C at a back

pressure of 30 bar. Batch experiments are rather impractical and potentially hazardous as they

require simultaneous cooling from the outside in order to control the exotherm in these

reactions. Further, the continuous experiments do not require a catalyst separation resulting in

a more or less work-up free procedure. Careful optimization of all relevant process parameters

resulted in a stable reaction for more than 10 h at a productivity rate of 30 mmol h-1

and

virtually no leaching of the active material could be detected.

In the final section of this thesis a fully continuous multi-step strategy for the synthesis

of linear peptoids and a subsequent copper-catalyzed dipolar cycloaddition resulting in their

cyclic analogs is presented (Chapter I). The central transformation for the preparation of the

linear peptidomimetic compounds is an Ugi four component reaction which requires a toxic

and malodorous isocyanide building block. Moreover an azide functionality is necessary for

the final cyclization step. In order to avoid exposure to this hazardous intermediates, a

telescoped continuous multistep procedure not only provides a safer process but also avoids

unnecessary and time-consuming isolation steps for the preparation of such linear peptoids.

Thus, the azide functionalized carboxylic acid was prepared by a nucleophilic substitution of

the corresponding bromide in a coil reactor. Simultaneously, amide dehydration resulted in

the isocyanide building block in another flow unit. The resulting streams were merged with a

solution of an amine and an aldehyde for the final multicomponent reaction in a single, fully

continuous procedure. The convergent three-step procedure could be conveniently performed

within a total processing time of 25 minutes by connecting three independently optimized

flow protocols. The subsequent CuAAC macrocyclization was realized using a continuous

flow reactor made of copper avoiding a separate addition of a catalytically active species.


277

Depending on the nature of the linear precursor and the resulting ring strain, either a dimeric

or a monomeric form of the cyclic product could be obtained at 140°C in 10 minutes.

In summary, this thesis provides several examples of synthetic transformations where

flow processing provides advantages compared to traditional flask chemistry. The main

drivers are on the one hand that safety concerns can be significantly reduced when working

with a continuous flow (micro-) reactor. Moreover, fast and exothermic reactions are easily

controlled by the excellent mass and heat transfer and the small volumes and channel

dimensions. On the other hand, working at elevated temperatures and high pressures can be

easily achieved often resulting in improved and highly intensified protocols. For biphasic

reactions the increased interfacial area provides another important reason to utilize this

enabling technology.

Several technologies and reactor designs have been used in the respective examples.

Noteworthy, a universal reactor design does not exist and all reaction parameters have to be

taken into account for developing a suitable continuous flow reactor. Thus, strong

collaborations between chemists and process engineers are of utmost importance for this

rapidly growing area.

References

[1] For reviews on flow chemistry, see: (a) B. Gutmann, D. Cantillo, C. O. Kappe, Angew.

Chem. Int. Ed. 2015, 54, 6688; (b) K. F. Jensen, B. J. Reizmana, S. G. Newman, Lab

Chip 2014, 14, 3206; (c) C. Wiles, P. Watts, Green Chem. 2014, 16, 55; (d) S. G.

Newman, K. F. Jensen, Green Chem. 2013, 15, 1456; (e) I. R. Baxendale, L. Brocken,

C. J. Mallia, Green Proc. Synth. 2013, 2, 211.




Weinheim, 2013; (c) Microreactors in Organic Synthesis and Catalysis, 2n Ed. (Ed.:

T. Wirth), Wiley-VCH, Weinheim, 2013; (d) Handbook of Micro Reactors (Eds.: V.


2009; (e) Chemical Reactions and Processes under Flow Conditions (Ed.: S. V. Luis,

E. Garcia-Verdugo), RSC Green Chemistry, 2010.


278



2010, 1, 675; (c) D. T. McQuade, P. H. Seeberger, J. Org. Chem. 2013, 78, 6384;

[4] (a) J. C. Pastre, D. L. Browne, S. V. Ley, Chem. Soc. Rev. 2013, 42, 8849; (b) S.

Newton, C. F. Carter, C. M. Pearson, L. de C. Alves, H. Lange, P. Thansandote, S. V.

Ley, Angew. Chem. Int. Ed. 2014, 53, 4915.

[5] (a) D. Ghislieri, K. Gilmore, P. H. Seeberger, Angew. Chem. Int. Ed. 2015, 54, 678.

(b) K. Gilmore, D. Kopetzki, J. W. Lee, Z. Horvath, D. T. McQuade, A. Seidel-


[6] P. Plouffe, A. Macchi, D. M. Roberge, Org. Proces. Res. Dev. 2014, 18, 1286.


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