QUIMICA CON MICROONDAS

1

Ana Cuadro 1

Universidad de AlcalUniversidad de AlcalááDoctorado QuDoctorado Quíímica Mmica Méédicadica

QUIMICA CON MICROONDASQUIMICA CON MICROONDAS

SINTESIS CON DERIVADOS ORGANOMETALICOS SINTESIS CON DERIVADOS ORGANOMETALICOS EN PRESENCIA DE MICROONDASEN PRESENCIA DE MICROONDAS

Ana MarAna Maríía Cuadroa Cuadro-- Junio 2011Junio 2011

Ana Cuadro 2

Síntesis con derivados organometálicos en presencia de microondas

1855

Beyond Bunsen burners

2011

The Bunsen burners of the XXI st century

Síntesis OrgánicaQuímica MédicaQuímica Combinatoria

2000

2

Ana Cuadro 3


Automatic Microwave Reactor

transferencia de calor

-Técnica lenta-Gradiente de temperatura (sobrecalentamiento local)

Radiación de microondas

La Energía atraviesa las paredes del matrazcalentando únicamente reactivos y disolventes

Domestic microwave oven

Ana Cuadro 4


Microwave-Assisted Organic Chemistry

Control de temperatura ( potencia)Sistemas en atmosfera inerteReacciones sin disolventeSistema de reflujoSistemas de flujo continuo etc....

-rediseñar procesos conocidos-reducir tiempos de reacción-mejorar rendimientos, pureza de los productosy rendimiento energético de los procesos

-química verde

3

Ana Cuadro 5


- AUMENTO DE LA VELOCIDAD DE REACCIÓN

- AUMENTO DE LA SEGURIDAD

- MEJORA DE LA REPRODUCIBILIDAD

- REDUCCIÓN DE COSTES

- BENEFICIOS MEDIOAMBIENTALES

DESARROLLO DE EQUIPOS MICROONDAS

Ana Cuadro 6


“Microwave-Assisted Organic Synthesis”, Lidstrom, P., Tierney, J. P. (Eds.), Blackwell Scientific, 2005.

"Microwaves in Organic and Medicinal Chemistry”, Kappe, C. O.; Stadler, A. Wiley-VCH, Weinheim, 2005.

Microwave-Assisted Organic Synthesis - One Hundred Reaction Procedures. Dariusz Bogdal, 2006.

“Microwaves in Organic Synthesis “Vol. I y II, 2da, Ed. 2006

Loupy, A. (Ed), Wiley-VCH, Weinheim,.

4

Ana Cuadro 7


“Practical Microwave Synthesis for Organic Chemists: Strategies, Instruments, and Protocols “Kappe, C. Oliver; Dallinger, Doris; Murphree, S. Shaun; Editors. 2009

Microwave Heating as a Tool for Sustainable Chemistry. N. Leadbeater, ed. CRC Press, 2010.

“Microwaves in Organic Synthesis “Vol. I y II, 2da, Ed. 2006

Loupy, A. (Ed), Wiley-VCH, Weinheim,.

Chapter 7. Gregory l. Powell in Microwave heating as a toolfor Inorganic and Organometallic syntheis. Pag.175

Ana Cuadro 8


Review (organic synthesis)

"Microwave-Assisted Chemical Reactions"Chem. Eng. Technol. 2003, 26, 1208-1216.

"Microwave Assisted Synthesis - A Criticl Technology Overview" Green Chem. 2004, 6, 128-141.

"Recent Advances in Microwave-Assisted Synthesis" Aldrichim. Acta 2004, 37, 66-77.

"Controlled Microwave Heating in Modern Organic Synthesis"Angew. Chem. Int. Ed. 2004, 43, 6250-6285.

General characteristics and applications of microwaves in organic synthesisActa Chimica Slovenica , 2009, 56(4), 749-764.

Microwave-assisted synthesis of organometallic complexes.chimica Oggi / CHEMISTRY to day – 2010, vol 28 n 3 –O. Navarro

5

Ana Cuadro 9


Referencias -Junio 2011

Publicaciones organometálicos/ microondas(control de temperatura/potencia, cavidad mono-o multimodo)

en disolución, sin disolvente (soportadas o mezcla de reactivos)

Ana Cuadro 10


R3 X R1 Sn (R2)3 R3 R1+Pd(0)

R2 X R1HPd(0)/Cu(I)

R2 R1+base

R X R´

R

R´+

Pd

R2 X R1 B(OH)2 R2 R1+Base

Pd(0)

R ZnXAr X'PdCl2(PPh3)2

R Ar+

R BrMgAr X' R Ar+Pd

TRANSITION METAL CATALYST Standard C-C bond Forming reactionTRANSITION METAL CATALYST TRANSITION METAL CATALYST Standard CStandard C--C C bondbond FormingForming reactionreaction

StilleStilleStille

SuzukiSuzukiSuzuki

NegishiNegishiNegishi

KumadaKumadaKumada

SonogashiraSonogashiraSonogashira

HeckHeckHeck

6

Ana Cuadro 11


R1 MM X

Pd(0)Ln

R2 Pd(II)Ln R1R2 Pd(II)Ln X

R2 R1 R2 X

Transmetalación

Eliminación reductora Adición oxidante

TRANSITION METAL CATALYST Standard C-C bond Forming reactionTRANSITION METAL CATALYST TRANSITION METAL CATALYST Standard CStandard C--C C bondbond FormingForming reactionreaction

Ana Cuadro 12


R X R´

R

R´+

Pd

MW

M. Larhed, A. Hallberg, J. Org. Chem. 1996, 61, 9582

Acc. Chem. Res. 2002, 35, 717 – 727;

in Microwave-Assisted OrganicSynthesis (Eds.: P. Lidstrom, J. P. Tierney), Blackwell, Oxford,2004, Chap. 2.

A. Stadler, et al .O. Kappe, Org. Process Res. Dev. 2003, 7,707 – 716.

X

BrNC

1a; X= H, 1b; X= F

+ CO2HX

NC CO2H

2a; X= H, 2b; X= F, 55%

82%

Pd(OAc)2 + P(o-toly)3

TEA, MeCN

MW, 180ºC, 15 min

5% Pd/C ( <0.1 mol% conc. Pd cat.)

samall-scale (2 mmol) single mode conditionssacle-up 80 mmol multimode batch reactor

HECK COUPLING HECK COUPLING HECK COUPLING

Standard Heck couplingStandard Standard HeckHeck couplingcoupling

7

Ana Cuadro 13


X

O

OBuRO

OBu R

X= Br, I

+PdCl2 + P(o-tolyl)3[bmim]PF6,

6 ejemplos (39-95%)X= I, 5 minX= Br, 20 min

without ligan 45 min.

Et3N

MW, 180-220ºC, 5-20 min

K. S. A. Vallin, P. Emilsson, M. Larhed, A. Hallberg, J. Org. Chem. 2002, 67, 6243 6.

Pd/C as catalyst: Tetrahedron Lett. 2004, 45, 809

MW, 225 or 375 W, 1.5 min.

Pd/C (n-Bu)3N

[Omim]BF4 9 ejemplos (30-89%)DOM

HECK COUPLING HECK COUPLING HECK COUPLING Ionic Liquid as Reaction mediumIonic Liquid as Reaction medium

green solvents

Sistema reciclable

Ana Cuadro 14


Heck vinylation of aryl chlorides under air-Stable catalytic system

Cl

O

OBuR O

OBu

R+[bmim]PF6

MW, 180ºC, 30-60 min 14 ejemplos (60-95%)electron rich and electron poor

(1.5-10 mol%) Herrmann´s palladacycle(3-20%)[(t-Bu)3PH]BF4

Cy2NMe,

Dioxane

sealed-vessel ( no inert gas atmosphere)

G. K. Datta, K. S. A. Vallin, M. Larhed, Mol. Diversity . 2003, 7, 107 – 114.

HECK COUPLING HECK COUPLING HECK COUPLING Ionic Liquid as Reaction mediumIonicIonic LiquidLiquid as as ReactionReaction mediummedium

8

Ana Cuadro 15


OH PdN

Cl

OH

Me

2

catalyst

Botella, L. ; Nájera, C. Tetrahedron Lett. 2004 , 45, 1833

Botella, L. ; Nájera, C. Tetrahedron. 2004 , 45, 5563

Biologically active (E) -stilbenes

I

R

O

OBu

R

O

OBu+Cy2NMe, H2O

0.01mol % Pd(OAc)2 or "catalyst"

MW, 120ºC, 10 min

I

MeO

MeO

OMeOMe

MeO

MeOMW, 120ºC, 10 min

0.5mol % "catalyst"Cy2NMe,DMA H2O+

IO

OBu

O

OBu

MW, 120ºC, 10 min+

1mol % "catalyst"Cy2NMe, H2O

-diarilationβ, β

HECK COUPLING HECK COUPLING HECK COUPLING Water as reaction mediumWaterWater as as reactionreaction mediummedium

OHOH

OHResveratrol

(chemoprotective agent)

Ana Cuadro 16


HECK COUPLING HECK COUPLING HECK COUPLING Solvent-Free, Open-Vessel Microwave-Promoted HeckCouplings: From the mmol to the mol ScaleSolventSolvent--Free, OpenFree, Open--VesselVessel Microwave-Promoted HeckCouplings: From the mmol to the mol Scale

I

MeO

O

OBu

MeO

O

OBu+

15 ejemplos (15-98%)MW, 90 s,

solvent free

Pd (OAc)2

Na2CO3, Bu3N, TBAB

90%

Leadbeater, N. E and cols. Synlett, 2006, 2953

Reactions are performed using 0.1 mol% palladium acetate as the catalyst, sodium carbonate and tributylamine as bases and tetrabutylammonium bromide as an additive.

9

Ana Cuadro 17

Br

( 2-5 equiv)

N

O

Ar1

α

β

5a, Ar1= Phenyl5b, Ar1= 2-naphthyl

+

N

O

Ar1

8 examples (25-75%)(high α, β-selectivity)

(E/Z mixtures)

(0.5%) Herrmann´s Catalyst

K3CO3, 10% aq. DMF

LiCl, NaOAcMW, 160-200ºC, 10-55 min.

65 2

unsymmetrical products


PPd

o-Tol o-TolOAc

Svennebring, A.; Nilsson,P.; Larhed, M. J. Org. Chem. 2004, 69, 3345

N

O

Br

N

O

Rα

β

( 5 equiv)

(0.5%) Herrmann´s Catalyst

K3CO3, 10% aq. DMF

LiCl, NaOAc

MW, 160-200ºC, 10-55 min.

α

β

2a-e 4a-e5 examples(36-80%)(high α, β-selectivity)

+

symmetrical β, β-arylation

R= p-MeO, p- OCH, p-Cl, 0-Me1

Smith Synthesizer

HECK COUPLING HECK COUPLING HECK COUPLING Symetric chelation-controlled double Arylation of vinyl ethersSymetric chelation-controlled double Arylation of vinyl ethers

β- Arylation of Monoarylated vinyl etersβ- Arylation of Monoarylated vinyl eters

Ana Cuadro 18


Svennebring, A.; Nilsson,P.; Larhed, M. J. Org. Chem. 2004, 69, 3345

PPd

o-Tol o-TolOAc

N PdX

ArO

Ar1

N

O

Ar1

BrN

O

Ar1

Ar1= phenyl, 2-naphthyl

5

Water

" Pd(0)"

6

2

+

β- Arylation of Monoarylated vinyl eters

Serves as a source of weakly coordinated palladium (0) in the process

H2O, is crucial for catalyts activity

The high regiocontrol indicates that catalyst acts as reservoir for Pd(0)and the releases of the metal is accelerated by watter under high-temperature conditions


10

Ana Cuadro 19


Gracias,V.; Moore, J.D.; Djuric, S.W. Tetrahedron Lett. 2004, 45, 417–420

I

CO2HMeO2C N

NH

O

PhPh

O

I (Br)

H

O N C

NH2MeO2CMeO2C

NH

O

PhPh

ON

MeOH, r.t

+ _

Ugi product (99%)

Pd(OAc)2, PPh3

MW, 125ºC,25min.-1 h

Et3N, MeCN

98%

Seven-membered ring closure.

HECK COUPLING HECK COUPLING HECK COUPLING Intramolecular Heck ReactionsIntramolecular Heck Reactions

Ugi reaction/ Heck cyclizationUgi reaction/ Heck cyclization

Ana Cuadro 20


Arvela, R.K.; Leadbeater, N. J. Org. Chem. 2005, 70, 1786

Microwave-Promoted Heck Coupling Using UltralowMetal Catalyst ConcentrationsMicrowave-Promoted Heck Coupling Using UltralowMetal Catalyst Concentrations


Br R´R R

R´+MW

Pd, H2O, TBAB, Na2CO3

“homeopathic” quantities of palladium

04CC1559

Ligand-free Heck reactions using low Pd-loading

11

Ana Cuadro 21


Andappan, M.M.S.; Nilsson, P.; von Schenck, H.; Larhed, M. J. Org. Chem. 2004, 69, 5212

Oxidative Heck ArylationsOxidative Heck Arylations HECK COUPLING HECK COUPLING HECK COUPLING

- Primer ej, arilacion interna Pd(II)-utilizacion de O2 molecular para regeneracion Pd(II)-Arilacion interna favorecida por EDGEDG in el alqueno (Cα)

18 h (50 °C, oxygen balloon)1h (100 °C, 3 bar oxygen pressure).

Ana Cuadro 22


V. Declerck ; P. Ribière; Y. Nédellec; H. Allouchi; J. Martinez; F: Lamaty. Eur. J. Org. Chem. 2007, 201

A Microwave-Assisted Heck Reaction in PEGs for theSynthesis of BenzazepinesA A MicrowaveMicrowave--AssistedAssisted HeckHeck ReactionReaction in in PEGsPEGs forfor thetheSynthesisSynthesis ofof BenzazepinesBenzazepines


NSES

Br

RCO2Me

NSES

RCO2Me

Br Br

K2CO3

N

R

SES

CO2Me

Br

NSES

RCO2Me

NH

RCO2Me

SES= 2(trimehylsily)ethanesulphonyll

cyclizationalkilation Pd(OAc)2

PEG 3400-OHMW

RCM

PEGS can substitute volatile organic solvents. They present some commom characteristics withionic liquid (high polarity, high boiling points) and low toxicity.

12

Ana Cuadro 23



(J. Org. Chem. 2008, 73, 3854-3858.

Synthesis of Nonsymmetrically Substituted Stilbenes

J. Org. Chem. 2008, 73, 3854-3858.

styrenes (2) were synthesized selectively by employing ethene

For aryl iodides (1) as coupling partners, 0.02 mol% Pd using an ICP standard and 125 °C were required for obtaining thecoupled products 2

aryl bromides (1) 0.5 mol% of the Herrmann´s catalyst and 150 °C are necessary

styrenes 2 are coupled with aryl bromides using a 1:1 molar ratio and Herrmann´s catalyst in the same reaction vial to get stilbenes 3.

Ana Cuadro 24


N. E. Leadbeater, M. Marco, J. Org. Chem. 2003, 68, 888 and Org. Lett. 2002, 4, 2973 –2976.

X

R

(OH)2B

R

X= Br, I

+

0.4 mol % Pd(OAc)2TBAB,

H2O

MW, 150ºC, 5-10 min.

25 examples(45-95% yield)X= Cl

Na2CO3

MW, 175ºC, 5-10 min.

60 W1 -10 mmol

(1 equiv.)

small (1 mmol) and larger (10-20 mmol) scales.

DOM(open vessels)

SUZUKI COUPLING SUZUKI COUPLING SUZUKI COUPLING water as solvent and Ligand-free Suzuki reactionswater as solvent and Ligand-free Suzuki reactions

L. Bai, J.-X. Wang, Y. Zhang, Green Chem. 2003, 5, 615 – 617.

Nicholas E. Leadbeater, Chem. Commun., 2005, 2881Fast, easy, clean chemistry by using water as a solvent and microwave heating: the Suzuki coupling as an illustration

Br

R

(OH)2B

R+

TBAB, H2O

MW, 750 W, 10 min.

10 examples(88-94% yield)

Na2CO3,

PdCl2(PPh3)2 , N2

with TBAB as an additive

See also : J. Org. Chem. 2006, 71, 3994-3997

- facilitate the solubility of the organic substrates

- activation of boronic

[R4N]+[ArB(OH)3-

13

Ana Cuadro 25


N. E. Leadbeater, M. Marco, J. Org. Chem. 2003, 68, 5660

the reaction is limited to couplings between aryl halides and aryl boronic

R

Br R+

H2O

MW, 150ºC, 5 min.


Na2CO3

MBPh4

M= Na, K

R= COMe, Me, OMe, COOH,

NaBPh4 can be used in the place of phenylboronic acid as an phenylating agent.

X

R

(OH)2B

R

X= Br, I

+

TBAB,H2O

MW, 150ºC, 5 min.

18 examples(3-95% yield)X= Cl

Na2CO3

SUZUKI COUPLING SUZUKI COUPLING SUZUKI COUPLING Transition-Metal-FreeTransition-Metal-Free

Ana Cuadro 26


NHC:N-Heterocyclic carbene

The conventionally heated reactions (60 °C) required several hours to reach completion.

Cl

MeMe

MW, 120ºC, 2 min.

(iPr)pd(allyl)ClNaOtBu, 2-propamol

100% conv.(GC)

N N.. iPr=

catalytic dehalogenation processes, affording yields similar to those of the conventionally heated analogous reactions.

Navarro, O. ; Kaur, H.; Mahjoor,P.; Nolan, S.P. J. Org. Chem. 2004, 69, 3173

Cl

R

(OH)2B

R+

MW, 120ºC,1. 5 min.4 examples(88-97% yield)

R= H, Me, Cl, OMe

(iPr)pd(allyl)ClNaOtBu, dioxano

SUZUKI COUPLING SUZUKI COUPLING SUZUKI COUPLING Copupling of the Aryl Chlorides using NHC LigansCopupling of the Aryl Chlorides using NHC Ligans

dehalogenations of aryl chlorides dehalogenations of aryl chlorides

14

Ana Cuadro 27


NHC:N-Heterocyclic carbene

N N.. iPr=

Navarro, O. ; Kaur, H.; Mahjoor,P.; Nolan, S.P. J. Org. Chem. 2004, 69, 3173

General Structure of the (NHC)Pd(allyl)Cl Complexes

Cl

R

(OH)2B

R+

MW, 120ºC,1. 5 min.4 examples(88-97% yield)

R= H, Me, Cl, OMe

(iPr)pd(allyl)ClNaOtBu, dioxano

BT-S

SUZUKI COUPLING SUZUKI COUPLING SUZUKI COUPLING Copupling of the Aryl Chlorides using NHC LigansCopupling of the Aryl Chlorides using NHC Ligans

Ana Cuadro 28


OH

R1

(OH)2B

RO

SO O

C8F17

R1

MW, 100-150ºC,10 min.


R= H, Me, Cl, OMe

K3CO·, DMF

C8F17SO2F

70 ºC, 5 h

Pd(dppf)Cl2

Toluene, acetone, H2O

Fluorous Suzukiu-Type coupling Reactions

Zhang,W.; Hiu-Tung Chen, C.; Lu, Y.; Nagashima, T. Org. Lett. 2004, 6, 1473

microwave reaction with easy fluorous separation

Both intermediates and products are purified by solid-phase extraction over FluoroFlash silica gel (F-SPE).

Halide equivalents

- aryl triflates (ArOSO2CF3)-aryl nonaflates (ArOSO2(CF2)3CF3

(Arylperfluoroalkylsulfonates)

SUZUKI COUPLING SUZUKI COUPLING SUZUKI COUPLING

[1,1-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) PdCl2(dppf).

15

Ana Cuadro 29


High levels of functional group compatibility

An initial screen of some typical palladium catalysts e.g., Pd(OAc)2, Pd(Ph3P)4, tris(dibenzylideneacetone)-dipalladium (0)] gave low yields of the coupled product (10-15%).

β-aryl/alkylarylidene malonates 1,precursors for the synthesis of a wide range of

heterocycles possessing biological activity.Poondra, R.R.; Fischer,P.M.; Turner,N.J.J. Org. Chem. 2004, 69, 6920

O

O

OEt

OEt

R

O

ClO

O

OEt

OEt

R

O

O

O

OEt

OEt

R

Cl

O

O

OEt

OEt

R

Cl

(OH)2B

R1

O

O

OEt

OEt

R

R1

MgCl2, Et3N

POCl3, Bu3N

4 5 2

2 1, 5 equiv.

POPd( 1mol%)K2CO3 (3 equiv.)

THF, 100ºC

MW, 30 min.3 1

+

15 examples (50-72%)

electron -rich-deficient andsterically demanding systems

coupling of an arylboronic acid to β ‚-chloroalkyl/ arylidene malonate

Air-stable an commercially available palladium(II) complex [(t-Bu)2P(OH)]2PdCl2abbreviated as POPd).(Active to promote standard Suzuki of aryl chlorides under microwaves conditions)

Knoevenagel limited in scope(methyl Ketones andcyclohexanone derivatives)


Ana Cuadro 30


Microwave enhanced palladium catalysed coupling reactions: A diversity-oriented synthesis approach to functionalised flavones

Air-stable an commercially available palladium(II) complex [(t-Bu)2P(OH)]2PdCl22abbreviated as POPd).


R. J. Fitzmaurice; Z. C. Etheridge; E. Jumel; D. N. Woolfson; S. Caddick. Chem. Comm. 2006, 4814

(OH)2BO

O

Br

O

O

POPd, CsF

THF, 85ºCMW, 30 min.

+

98%

18 examples (33-98%)

16

Ana Cuadro 31


Suzuki cross coupling reaction catalyzed by PDHC-Pd nanoparticles

poly(N,N-dihexylcarbodiimide)effectivepolimeric ligand for preparing palladiumnanoparticle(1-5 nm) (PDHC–Pd).

Liu, Y.; Khemtong, C.; Hu, J. Chem. Commun. , 2004, 3 98

X

R

B(OH)2

RR´R´

X= IR= H

+

MW, 40 min.

95% yield

PDHC-Pd

K2CO3Dioxane,

reflux

The same coupling reaction required about 20 hours refluxing to achieve the same degreeof conversion.


Ana Cuadro 32


Suzuki-Couplings with Organotrifluoroborates SUZUKI COUPLING SUZUKI COUPLING SUZUKI COUPLING

using potassium organotrifluoroborates as an alternative to boronic acids and ultra low palladium loading (2.5 ppm), efficient coupling with arylhalides could be performed in 5 minutes at 150 °C under microwave irradiation in water

Tetrahedron Lett. 2006, 47, 217Nicholas E. Leadbeater and co-workers,

X

R

BF3K

RR R+

MW, H2O, 5 min

ppm levels of Pd

Br

MeO

BF3KMeO+

MW, 125ºC, MeOH-H2O, 20 min

PdCl2, K2CO3

R. L. Harker, R.D. Crouch, Synthesis, 2007, 43

17

Ana Cuadro 33


Suzuki-Couplings with Organotrifluoroborates SUZUKI COUPLING SUZUKI COUPLING SUZUKI COUPLING

Potassium Vinyltrifluoroborates and Allyl Acetates: A New Route to 1,4-Pentadienes

(12 examples 56-97%)

G. W. Kabalka; M. Al-Masum. Org. Lett. 2006, 11-13

See also, Tetrahedron Lett. 2006, 47, 1133

Ana Cuadro 34


Suzuki-Couplings with Organotrifluoroborates SUZUKI COUPLING SUZUKI COUPLING SUZUKI COUPLING Microwave-Promoted Palladium(II)-Catalyzed C-P Bond Formationby Using Arylboronic Acids or Aryltrifluoroborates)

M. Andaloussi, J. Lindh, J. Sävmarker, Per J. R. Sjöberg and M. Larhed, Chem. Eur.J. 2009, 15, 13069

James M. Salovich, Craig W. Lindsley, Corey R. Hopkins, Tetrahedron lett. 2010, 3796

Otros ejemplos

Synthesis of 1,3-diarylsubstituted indazoles utilizing aSuzuki cross-coupling/deprotection/N-arylation sequence

18

Ana Cuadro 35



Suzuki Coupling of Aryl Chlorides with Phenylboronic Acid in Water,Using Microwave Heating with Simultaneous Cooling

Suzuki Coupling of Aryl Chlorides with Phenylboronic Acid in in WaterWater,,Using Microwave Heating with Simultaneous Cooling

Arvela, R.K.; Leadbeater,N. E.; Org. Lett. 2005, 2101

use ofsimultaneous cooling in conjunction with microwave heatings hown prolongs thelifetime of the aryl chloride substrates during the course of the reaction. As a result, with substrates bearing electron-neutral or electron-donating substituents, yields of the desired biaryl can be increased

in in WaterWater,,

Ana Cuadro 36


Microwave-Assisted Suzuki Couplings with Simultaneous CoolingMicrowave-Assisted Suzuki Couplings with Simultaneous Cooling


Steven V. Ley et al. Chem. Eur. J. 2006, 12, 4407.

For those compounds giving low purities under conventional microwave conditions A, higher purities could beachieved by performing the reactions at 50 W (reaction temperature did not exceed 76 °C) withsimultaneous cooling (compressed air, B) by preventing otherwise occurring thermal decompositions. Evenhigher purities were obtained by conducting the reactions via a flow-through approach again in combination with cooling (C) due to shorter reaction times (ca. 1 min) and therefore diminished side reactions.

19

Ana Cuadro 37


Copper(II)-Mediated Cross-Coupling of ArylboronicAcids and 2(1H)-Pyrazinones Facilitated by Microwave

Irradiation with Simultaneous Cooling

Copper(II)-Mediated Cross-Coupling of ArylboronicAcids and 2(1H)-Pyrazinones Facilitated by Microwave

Irradiation with Simultaneous Cooling


B. K. Singh, P. Appukkuttan, S. Claerhout, V. S. Parmar, E. Van der Eycken. Org. Lett.; 2006, 1863 - 1866;

microwave heating (300 W) with intensive simultaneous cooling at 0 °C .Due to prevented product decomposition, excellent yields could be achieved compared to reactions at rtor elevated temperatures, respectively.

N-Arylations utilizing arylboronic acids

Figure 1. 2(1H)-Pyrazinone series with nonnucleosideHIV-1 reverse transcriptase inhibitory activity (NNRTIs).

Ana Cuadro 38



Catalyst- and Base-Free Suzuki-Type CouplingCatalyst- and Base-Free Suzuki-Type Coupling

Eur. J. Org. Chem. 2006, 2060.

Both symmetrical and unsymmetrical biaryls could be synthesized by coupling of sodium tetraphenylborate with hypervalen iodonium salts or iodanes under mild reaction conditions

Jie Yan and co-workers

20

Ana Cuadro 39


General General protocolprotocol, 2001 , 2001

Erdelyi, M.; Gogoll,A. J. Org. Chem. 2001, 66, 4165 – 4169.

Domino Sonogashira strategy

synthesis of bis(aryl)acetylenes

M. Erdlyi, V. Langer, A. KarlMn, A. Gogoll, New. J. Chem. 2002, 26, 834

I

NH2

H SiMe3 SiMe3

NH2

NH2

H I

MeO2C MeO2C

NH2

Pd(PPh3)2Cl2, CuIDMF, Et3N

MW, 120ªC, 5 min.+

98%

KF, H2O/MeOH

r.t. 7h

+


MW, 120ªC, 5 min. 78%

SONOGASHIRA COUPLING SONOGASHIRA COUPLING SONOGASHIRA COUPLING

Ana Cuadro 40


O. S. Miljanic´, K. P. C. Vollhardt, G. D. Whitener, Synlett 2003, 29

Double Sonogashira Strategy

Reaction carried out at 2.5 bar Propyne atmosphera

I

I

Br

Br

H Me

Br

Br

Me

Me

Br

Br

BrBr

Br

Br


MW, 110ªC, 20 min.+

60%

(2.5 bar)

alkyne Metathesis

precursor tribenzocyclyne


21

Ana Cuadro 41


b) P. Appukkuttan, W. Dehaen, E. Van der Eycken, Eur. J. Org. Chem. 2003, 4713

R1 H XR2

R1R2

MW, 170ºC, 5 min.

+

10 examples(8-91%)

R1= Ph, n-Bu, TMSR2= H, acyl, Me, OMe

NaOH, PEG, H2O

300 W

H X R R+

X= Br, I

R= aryl, het-aryl

MW, 170ºC, 10-25 min.

Na2CO3, TBAB, H2O

12 examples(52-83%yield)

a) N. E. Leadbeater, M. Marc, B. J. Tominack, Org. Lett. 2003, 5, 3919 – 3922;


Transition-Metal-free Sonogashira reactionTransition-Metal-free Sonogashira reaction

Ana Cuadro 42


PalladiumPalladium--MetalMetal--freefree Sonogashira reaction

IR1

HR2

R1

R2+

MW, 195ºC, 2-6 h min.

10 mmol% CuI, Cs2CO3

15 examples(43-85%)

NMP

H. He, Y.-J. Wu, Tetrahedron Lett. 2004, 45, 3237 – 3239.

the same reaction carried out using a preheated oil bath under identical conditions(10 mol% CuI, 2 equiv Ca2CO3, 195 C, 2.5 h), a lower yield (71%) was obtained.

WithoutWithout CuICuI catalysiscatalysis, no , no reactionreaction occurredoccurred under microwave irradiation.

In the absence of Cs2CO3, only 5% conversion was observed by HPLC

Wang procedure require addition of ligandsWang, J.; Liu, Z.; Hu, Y.; Wei, B.; Kang, L. Synth. Commun. 2002, 32, 1937

BT-SSmith creator


22

Ana Cuadro 43


CopperCopper--Free PalladiumFree Palladium--CatalyzedCatalyzed Sonogashira-Type Coupling

Ulrich S. Sorenson and Esteban Pombo-Villar


Tetrahedron , 2005, 61, 2697.

A direct coupling of activated aryl- and heteroaryl bromides and iodides with1-aryl-2-trimethylsilylacetylenes has been developed for the synthesis ofdiarylacetylenes, avoiding the use of copper (I) iodide as a cocatalyst. Microwave dielectric heating has shown improvement in reaction yields over the conventional oil bath heating.

Ana Cuadro 44


poly(p-phenylene ethynylene)s which displayed interesting macromolecularphotophysical properties.

Kwan,P.H.; MacLachlan,M.J.; Swager, T.M.J. Am. Chem. Soc. 2004, 126, 8638

Diiodo rotaxane

Double Sonogashira Strategy(Rotaxanated Polymers)

CEM-S


23

Ana Cuadro 45


S BrBrn

S HPd(PPh3)2Cl2, PPh3 CuI

i-Pr2NH( l )

MW, 50ºC, 5 min.

S SSn

n=2, 68%n= 3, 71%

Oligothiophene Synthesis

Melucci, M. At al , J. Org. Chem. 2004, 69, 4821N

N OH

Cl Cl

Ph

H Ph

Pd(OAc), PPh3, CuI

DMF, TEA

MW, 120ºC, 15 min. N

N OH

Cl

Ph

Ph

PdCl2( PPh3)2, CuI

DMF, TEA

MW,40ªC, 5 min.

N

N

IH

X R2R1

O

N

N

H

X R2R1

O R2

11 examples(48-82%)

H R3

R3= Ph, TMS, CH2OHR1= H, glycosylR2= H, Me

X= OH, SH, OMe, SMe

Mol. Diversity, 2003, 7 125

Tetrahedron Lett. 2003, 44, 9181

Pyrimidone functionalization

Pyrazinone functionalization

Additional examples

CEM-S


Heterocycles, 2010, 1651

Ana Cuadro 46


N

N OH

Cl Cl

Ph

H Ph

Pd(OAc), PPh3, CuI

DMF, TEA

MW, 120ºC, 15 min. N

N OH

Cl

Ph

Ph

Tetrahedron Lett. 2003, 44, 9181

Pyrazinone functionalization

Additional examples

CEM-S


Microwave-Assisted Selective Synthesis of 2H-Indazoles via Double Sonogashira Couplingof 3,4-Diiodopyrazoles

)

and Bergman–Masamune CycloaromatizationHayato Ichikawa, Haruhiko Ohfune, and Yoshihide Usami

Heterocycles, 2010, 1651

24

Ana Cuadro 47


R3 X R1 Sn (R2)3 R3 R1+Pd(0)

M. Larhed, C. Moberg, A. Hallberg, Acc. Chem. Res. 2002, 35, 717

R ZnX + Ar X'PdCl2(PPh3)2

R Ar

R BrMg+ Ar X' R ArPd

STILLE REACTION STILLE REACTION STILLE REACTION

NEGISHI REACTION NEGISHI REACTION NEGISHI REACTION

KUMADA REACTION KUMADA REACTION KUMADA REACTION

N

ZnX

F

Pd( PPh3)4 THF

MW, 160ºC, 1 min.

X= I (Cl)

+ N

NCl

Cl

N

NCl

N F

P. Stanetty, M. SchnLrch, M. D. Mihovilovic, Synlett, 2003, 1862 – 1864.


Ana Cuadro 48


Walla, P.; Kappe, O. Chem. Commun. 2004, 654

ClR

R2XZn RR1

R1= NO2, CN, OMe R2= (het)aryl, alkyl

+

NiCl2dppf

THF, MW, 160ºC, 3min.

Pd2(dba)3/ t-Bu3P.HBF4

THF/NMP, MW, 175ºC, 10 min.

a)

b)

75-890%X= Cl, I

8 examples

XFG

ZnXFG

FG= CN, CO2Et, CO2Me, OMe

X= Br, I

Zn*

Zn* = Rieke zinc dust

THFMW, 180ºC, 10 min.

(2 equiv.)

> 99 % conversion

conventional heating 3 equiv. Zn*, reflux 3h

Preparation of organozinc reagents


Ni and Pd-Catalyzed Couplings of Aryl Chlorides (solution/solid phase)NiNi and Pd-Catalyzed Couplings of Aryl Chlorides (solution/solid phase)

25

Ana Cuadro 49


IR R H

OZnI

R

Pd(PPh3)2Cl2

Ni(PPH3)2Cl2

BrH

O MW, 80-125ºC, 2-15 min.MW, 100-120ºC, 5-15 min.

57-95%

12 examples

Zn-Cu

DMF or THF-TMEDA

or

DMF or THF

Mutule, I.; Suna, E. Tetrahedron Lett. 2004, 3909–3912

NEGISHI REACTION NEGISHI REACTION NEGISHI REACTION Aryl zinc generation-Negishi coupling protocolAryl zinc generation-Negishi coupling protocol

Ana Cuadro 50


(1 mol%)Pd2(dba)3/ (4 mol%)t-Bu3P.HBF4

THF/NMP,

OMe

BrMg OMe MW, 175ºC, 10 min.

Cl

+

Walla, P.; Kappe, O. Chem. Commun. 2004, 654

BrMeOMW, 60 ºC, 20 min.

Mg, THFMgBrMeO

Preparation of Grignard Reagents

KUMADA REACTION KUMADA REACTION KUMADA REACTION Pd-Catalyzed Couplings of Aryl ChloridesPd-Catalyzed Couplings of Aryl Chlorides

26

Ana Cuadro 51


Palladium-Catalyzed Cross-Coupling ofAryl Triethylammonium Bis(catechol)Silicates with Aryl Bromides

W. M. Seganish.; P. DeShong, Organic Lett. 2004, 6,4379

Bis(catecol)silicates

HIYAMA COUPLING HIYAMA COUPLING HIYAMA COUPLING

Ana Cuadro 52


C-N/C-O Coupling

XNH

R3R2N

R2

R1

R1

R1

N

NR

R

Pd

N

NR

R

Pd

R1, R2 = H, alkyl, aryl

MW,130-180ºC, 4-5 min.+

X= Cl, Pd(dba) or Pd(carb)2

KOtBu, DMF

KOtBu, DMF, DME

X= Br, Pd(OAc)2, binap

Pd(carb)2

X= Br, 13 examples(48-85%)

X= Cl, 10 examples (37-81%)

R= 1-(2,6-diisopropylphenyl)

Y.Wan, M. Alterman, A. Hallberg, Synthesis 2002, 1597 – 1600.

A. J. McCarroll, D. A. Sandham, L. R. Titcomb, A. K. de K. Lewis, F. G. N. Cloke, B. P. Davies, A. P. de Santana, W. Hiller,S. Caddick, Mol. Diversity 2003, 7, 115 – 123.

Buchwald-Hartwig AminationsBuchwaldBuchwald--Hartwig Hartwig AminationsAminations

27

Ana Cuadro 53


C-N coupling

N

XBr

R

NH

R2R1

N

XN

R

R1 R2

+

X= Y= CH, NR1, R2 = H. alkyl, aryl

Pd2(dba)3

NaO t-Bu Toluene

MW, 120ºC, 10 min.

(S)-(R)-PPFA

16 examples

47-92% yield

Wang, T.; Magnin, D.R.; Hamann, L.G. Organic Lertt. 2003, 5, 897

Shi, l.; Wang, m.; Fan,C-A.; Zhang, F-M.; Tu, Y-O. Organic Lertt. 2003, 5, 3515

BrR

NH

R2R1 NR2

R1

R

R, R1, R2 = H, alkyl, aryl

NaO t-Bu DMSO

MW,120ºC, 5-20 min.+

PdCl2 + P(o-Tolyl)3


Ana Cuadro 54


C-N coupling

Niels Skjaerbaek and coworkers, J. Org. Chem. 2004, 69, 4936.

Amination reaction s of AminobenzophenonesBuchwald-Hartwig AminationsBuchwaldBuchwald--Hartwig Hartwig AminationsAminations

28

Ana Cuadro 55


C-N coupling

Pd-Catalyzed Amination of Aryl Nonaflates

Buchwald and coworkers J. Org. Chem. 2005, 71, 430

a fast protocol for the coupling of (hetero)aryl nonaflates and amines

using the catalyst systems Pd2dba3with ligands 1, 2 or 3 respectively,

and the soluble amine bases DBU (1,8-diazabicyclo[5.4.0]undec-7-ene)and MTBD (7-methyl-1,5,7-tri

azabicyclo[4.4.0]dec-5-ene).


Ana Cuadro 56


C-N coupling

Pyke and col.J. Org. Chem. 2008, 73, 8880–8892

Selective Buchwald-Hartwig AminationsSelectiveSelective BuchwaldBuchwald--Hartwig Hartwig AminationsAminations

Crucial for the selective amination at the 6-position is the choicechoiceofof thethe solventsolvent.. ByBy changing from toluene to benzotrifluoride (BTF)

An extensive optimizationoptimization studystudy toward the synthesis of 6-heterocyclicsubstituted 2-aminoquinolines via Buchwald-Hartwig amination of6-bromo-2-chloroquinoline with cyclic amines

the reaction can be performed in the microwave at 150 °C due to the bettermicrowave absorbance characteristics of BTF compared to toluene

29

Ana Cuadro 57


AminocarbonilationsAminocarbonilationsAminocarbonilations

Microwave-Enhanced Aminocarbonylations in WaterMicrowave-Enhanced Aminocarbonylations in Water

Mats Larhed and co-workers, Org. Lett, 2005, 3327

Despite the use of water as solvent, aminocarbonylation strongly dominated overhydroxycarbonylation, providing good yields of both secondary and tertiary model benzamides. This air-tolerant aqueous aminocarbonylation protocol provides operational convenienceand increased safety for small-scale high-speed synthesis.

PPd

o-Tol o-TolOAc

dimer

Ana Cuadro 58



Synthesis of Acyl Sulfonamides via CarbonylationSynthesis of Acyl Sulfonamides via Carbonylation

Mats Larhed and co-workers, J. Org. Chem. 2005, 70, 3094

Good to excellent yields of acyl sulfonamide products were achieved by employing microwave heating for 15 minutes at 110-140 °C and using Mo(CO)6 as the CO source.

Utilizing this protocol, also a novel hepatitis C virus NS3 protease inhibitor including acyl sulfonamideelements was synthesized.

30

Ana Cuadro 59



Synthesis of benzamides via aminocarbonylationsSynthesis of benzamides via aminocarbonylations

Mats Larhed and co-workers, Organometallics 2006, 25, 1434

By either using the aryl halide or amine as limiting reagent, accompanied with the proper Pd-catalyst,hydroxycarbonylations could be suppressed as side reactions and even theotherwise unreactive aryl chlorides could be employed under these conditions.

.

Mo(CO)6 as solid CO sourceand water as solvent

Ana Cuadro 60

CH2 MLn

CH2 CH2

MLn

MLn

MLn


Mecanismo

MLn

disolvente

M = Mo, Ru

RCM

Ring Closing Olefin MetatheisRingRing ClosingClosing OlefinOlefin MetatheisMetatheis

31

Ana Cuadro 61


Ring-Closing Olefin Metathesis (RCM)

RuPCy3

PCy3

ClCl

Ph

1

RuPCy3

ClCl

Ph

NN MesMes

2

X

X

Grubbs Catalyst 1 and 21-3 mol%

DCM or bmimBF4

DCM: MW 2min

bmimBF4; MW 15-45 min

S. Garbacia, B. Desai, O- Lavastre, C. Oliver Kappe*,‡J. Org. Chem. 2003, 68, 9136

Mayo, K.G.; Nearhoof, E.H.; Kiddle, J.J.. Org.Lett. 2002, 4, 1567

G.Vo Thanh.; A.Loupy. Tetrahedron Letters. 2003, 44, 9091 X= O

Ana Cuadro 62


D. Balan.; H.Adolfsson. Tetrahedron Letters , 2004, 45, 3089–3092

formation of functionalized 2,5-dihydropyrroles usingruthenium-catalyzed ring-closing metathesis

RuPCy3

ClCl

Ph

NN MesMes

2

Aza-Baylis-Hillman reaction


32

Ana Cuadro 63


Mecanismo

RuL

CH2PCy3

ClCl

R'R

R'

R

R RuR'

Ru R'

R

Ru

R'

R

R'

RuR

R'Ru

R

RuR'

R

MLn

disolvente

M = Mo, Ru

Enyne Metathesis reaction

R'

R

R'R


Ana Cuadro 64


Enyne RCM

NS

NR2

R1

O OR2

O O

NS

N

R1

3-4 mol% Grubbs 2

MW, 100ºC, 0.5-1 h

BnBn


+ cross metathesis by-products R1= H

R1= Me, HR2= Boc, Me, Bn

RuPCy3

ClCl

Ph

NN MesMes

2

Enyne Cross Metathesis

NS

NR2

R1

O O6 mol% Grubbs 2

MW, 100ºC, 0.5-1 h

Bn

R2O O

NS

N

R3

Bn

5 examples(54-83 % yield)

+R3

R1= Me, HR2= Boc, Me, Bn

DCM

R3= Ph, CO2Me

Bt-S Salim, S.S.; Belligham, R.K.; Brown, R.C.D. Eur. J. Org. Chem. 2004, 800

33

Ana Cuadro 65


By applying microwave irradiation, reaction rates could be enhanced compared to classical heating, showing superior yields for the Hoveyda-Grubbs catalyst 1 than for 2nd generation Grubbs´ catalyst.

Cross-Metathesis Reactions

(J. Org. Chem. 2005, 70, 9636

Ana Cuadro 66



RING-CLOSING OLEFIN METATHESISRINGRING--CLOSING OLEFIN METATHESISCLOSING OLEFIN METATHESIS

J. Org. Chem. 2005, 70, 9636

Synthesis of N-Shifted Buflavine Analogues

Suzuki-Miyaura cross-coupling and ring-closing metathesis (RCM) as the key steps in the synthesis of buflavine analogues

the generation of the rigid, medium-sized ring system by RCM was enhanced by employing microwave heating for 5 minutes at 150 °C using 3 mol % of Grubbs-2 catalyst.

Appukkuttan, P. ; Dehaen, W.; Van der Eycken, E. Chem. Eur. J. 2007, 13, ASAP.

34

Ana Cuadro 67


boronic acids as source of the nucleophilic aryl species formed by a boron-zinc exchange reaction withdiethylzinc(a) Bolm, C.; Rudolph, J. J. Am. Chem. Soc. 2002, 124, 14850. (b)Schmidt, F.; Rudolph, J.; Bolm, C. AdV. Synth. Catal. 2007, 349, 703.

Arylation of aromatic aldehydes via arylzinc addition using an aziridine-based ligand

arylzinc species are generated from aryl boronic acids and Et2Zn in only 10 min followed by the addition of the aldehyde andligand and further microwave heating for 5 min. The reaction time can be reduced from 1 dayconventionally to only 15 min under microwave

Antonio L. Braga and cols. J. Org. Chem. 2008, 73, 2879.

Ana Cuadro 68


Pd-catalyzed α-arylation of benzyl ketones

Jason R. Schmink and Nicholas E. Leadbeater*, Org. Lett. 2009, 2575

novel route to the synthesis of diarylmethanes via Pd

to circumvent the need for a transmetalating reagent such as boron for the coupling

found in a range of biologicallyactive compounds and pharmaceuticals

35

Ana Cuadro 69


Jason R. Schmink and Nicholas E. Leadbeater*, Org. Lett. 2009, 2575

novel route to the synthesis of diarylmethanes via Pd

observation of diarylmethanes as byproduct.

Ana Cuadro 70


Preparation of cisplatin

►Microwave heating used for the small-scale synthesis of cis-platin, [cis-PtCl2(NH3)2]. ►Continuous-flow processing used for scale-up. ►Product is isomerically pure. ►Product is formed in short reaction times. ►No formation of Magnus’ salt [Pt(NH3)4][PtCl4] when using optimized conditions.

Pedricka and Leadbeater,Inorganic Chemistry Communications , 2011, 481

Cisplatin, [cis-PtCl2(NH3)2], is one of the mostwidely used anticancer drugs in the world dueto its efficacy and surprisingly broadapplicability

36

Ana Cuadro 71


R ZnX

Pd(0)/Cu(I)

R1 B(OH)2

R1 Sn (R2)3

Pd

Ru

R BrMg

Ana Cuadro 72


Ugi reaction

.

QUIMICA CON MICROONDAS

Documents

Transcript of QUIMICA CON MICROONDAS