Full Paper

Received: 7 February 2012 Revised: 23 February 2012 Accepted: 23 February 2012 Published online in Wiley Online Library: 27 June 2012

(wileyonlinelibrary.com) DOI 10.1002/aoc.2846

Mixed metal MgO–ZrO2 nanoparticle-catalyzedO-tert-Boc protection of alcohols and phenolsunder solvent-free conditionsManoj B. Gawande,a* Sharad N. Shelke,b Paula S. Branco,a Anuj Rathic andRajesh K. Pandeyd

An environmentally benignmethod forO-tert-Boc protection of alcohols and phenols catalyzed byMgO–ZrO2 nanoparticles undersolvent-free conditions is described. A variety of phenols, alcohols (aliphatic and aromatic) were converted to corresponding

O-tert-Boc products in good to excellent yield (50–95%). The present protocol is expedient, simple, and efficient under solvent-freeconditions. The MgO–ZrO2 Nps are easily prepared from inexpensive precursors, and are reusable, recyclable and chemoselective.Copyright © 2012 John Wiley & Sons, Ltd.

Supporting information may be found in the online version of this article.

Keywords: O-tert-butoxycarbonylation; phenol and alcohol; mixed metal oxides; nanoparticles; solvent-free; reusable and recyclable

* Correspondence to: Manoj B. Gawande, REQUIMTE, Departamento de Química,Faculdade de Ciênciase Tecnologia, FCT, Universidade Nova de Lisboa, Portugal.E-mail: m.gawande@fct.unl.pt; mbgawande@yahoo.co.in

a REQUIMTE, Departamento de Química, Faculdade de Ciênciase Tecnologia,FCT, Universidade Nova de Lisboa, Portugal

b Department of Chemistry, SSGM College, Kopargaon, MH-423601, India

c Jubilant Chemsys Ltd., B-34, Sector-58, New Delhi, Noida-201301, India

d Department of Chemistry, Marquette University, Milwaukee, WI-53233, USA

395

Introduction

Functional group protection strategies are synthetically impor-tant in targeting molecule synthesis. The protection of alcoholsis imperative and useful in organic synthesis.[1,2] Protection anddeprotection of alcohols and phenols have received great atten-tion in recent years, not only because of their fundamentalimportance but also for their role in multistep drug synthesis.High selectivity is frequently requested for a given hydroxy groupin polyol chemistry, as well as simplicity and mildness in preparingand removing the specific function.

Among the many protecting groups for alcohol, organic car-bonates are important, since they are more stable than thecorresponding esters under basic conditions.[3] In addition; theirimportance has been increasing in the past few years both inindustry and in academic research.[4]

Traditionally, organic carbonates were prepared by using verytoxic reagents,[5] such as phosgene, pyridine and carbon monox-ide; thus much effort has been devoted recently to developingmore environmentally friendly procedures for their synthesis.[6]

Most methods for the synthesis of mixed carbonates sufferdrawbacks, such as low selectivity, limited scope and limitedavailability of the substrate. Among carbonic acid derivatives usedas protecting groups, tert-butyl carbonates (O-Boc alcohols) andcarbamates (N-Boc amines) are of great importance in organicchemistry. Although N-Boc derivatives are extensively used forprotecting amino groups,[7] O-Boc protection is restricted to arylalcohols. All these methodologies work in basic media[8] or inthe presence of a Lewis base.[9] Various acylating groups havebeen used for the protection of hydroxyl groups, but forthe deprotection of these acylating reagents strong basicconditions are needed. Recently, oxometallic species such asoxovanadium[10] and oxomolybdenum[11a] were introducedas amphoteric catalysts for nucleophilic acyl substitutions ofanhydrides and dicarbonates.

Appl. Organometal. Chem. 2012, 26, 395–400

In brief, an efficient and simple protocol for the synthesis oftert-butyl carbonates under environmentally friendly conditionsis still lacking. O-tert-Butoxycarbonylation is a suitable alternativeas the O-tert-Boc moiety is compatible with reaction conditionsroutinely adopted in organic synthesis. A literature surveyrevealed that a mild method has been used for protection ofalcohols as t-butyl ethers.[11b]

Recently, Chakraborti et al briefly studied butoxycarbonylationof alcohols[12a] and amines using Lewis acid and protic acid typecatalysts.[12b–e]

In continuation of our efforts for greener organic transforma-tions[13] and design of heterogeneous catalysts for importantorganic raw materials,[14] we present herein an ecofriendly,chemoselective and simple O-tert-butoxycarbonylation of phe-nols and alcohols over MgO–ZrO2 nanoparticles (NPs) undersolvent-free conditions. The MgO–ZrO2 NPs have been preparedby a simple ultradilution procedure by using inexpensiveprecursors and characterized by several techniques such asX-ray diffraction (XRD), FT-IR, scanning electron microscopy–energy dispersive spectroscopy (SEM-EDS), X-ray photoelectronspectroscopy and transmission electron microscopy (TEM) tech-niques[15] (supporting information). The TEM image of nanoMgO–ZrO2 is depicted in Fig. 1. The TEM image of MgO–ZrO2

Copyright © 2012 John Wiley & Sons, Ltd.

Figure 1. TEM of nano MgO–ZrO2 at 100 nm.

M. B. Gawande et al.

396

mixed metal oxides reveals that the size of the MZ catalyst is inthe nano range (20–35 nm).Recently, Bartoli et al.[11b] reported the synthesis of t-butyl octyl

ether using tert-butyl dicarbonate 3 over Mg(ClO4)2. In ourcase, by using MgO–ZrO2 NPs under solvent-free conditions,we selectively obtained 4-methoxy phenol O-tert-Boc protectedproduct 2, not t-butyl octyl ether 3 (Scheme 1).

2. Solvent-free

3 . 60 oC

O

OH

1. (Boc)2OO

O

O

O

O

O

X1

3

2

MgO-ZrO2

Scheme 1. Chemoselective Boc protection of 4-methoxyphenol.

Table 1. O-tert-Butoxycarbonylation of phenola

No. Catalyst Tempe

1 Catalyst-free, solvent-free Room t

2 Catalyst-free, solvent-free 60�C3 MgO–ZrO2 NPs (20–35 nm) Room t

4 MgO–ZrO2 NPs (20–35 nm) 60�C5 MgO nano (25–40 nm ) 60�C6 ZrO2 nano (25–45 nm) 60�C7 MgO 60�C8 ZrO2 60�C

aReaction conditions: phenol = 10mmol, (Boc)2O= 12mmol, catalyst = 20w

OH

+OO

O

O

O

4 5

Scheme 2. O-tert-Butoxycarbonylation of phenol.

wileyonlinelibrary.com/journal/aoc Copyright © 2012 John W

For optimization of the reaction conditions, we have chosen themodel reaction of phenol (4) and Boc anhydride (5), to yield tert-butylphenyl carbonate (6a) (Scheme 2). The results are depicted in Table 1.

Initially, we tested the reaction under catalyst-free and solvent-free condition at room temperature, but no corresponding productformation was observed (Table 1, entry 1). The same reaction wasrepeated at 60�C, but we observed only a trace amount of product(Table 1, entry 2). With MgO–ZrO2 NPs (TEM, 20–35nm) at roomtemperature after 24 h yield of 6a was 85% (Table 1, entry 3), whileat 60�C after 2 h the yield was 92% (Table 1, entry 4).

The effect of normal component, nano component and nanomixed oxides over O-tert-butoxycarbonylation of phenol wasstudied. Notably, mixed oxide MgO–ZrO2 NPs is a better candi-date compared to its component oxides. For MgO, ZrO2, nanoMgO, nano ZrO2 and MgO-ZrO2, 58%, 35%, 68%, 43% and 92%yield corresponding to O-tert-Boc-phenol was obtained (Table 1,entries 4–8). The stirring effect over Boc protection of phenoland other optimized conditions are briefly described in supportinginformation (ESI†). Thus, on the whole, nano MgO–ZrO2 catalyst ismore effective and efficient in terms of yield as compared to itscomponent nano oxides (nano MgO, nano ZrO2, and mechanicalmixture of nano MgO–ZrO2). Even a stoichiometric amount ofcomponent oxides for protection of phenol possesses lower yieldsthan that of nano MgO–ZrO2 (supporting information and Table 1,entries 6–8). We therefore explored further the substrate scopefor O-tert-butoxycarbonylation of phenol and alcohols, as shownin Table 2.

MgO–ZrO2 NPs were used for O-tert-Boc protection of variousstructurally and electronically diverse aliphatic and aromatichydroxy compounds under solvent-free condition (Table 2, entries1–21). The results are reported herein.

The reaction of phenol with Boc2O gives a 92% yield of thedesired product within 2 h (Table 2, entry 1). Aryl alcoholspossessing electron-donating and electron-withdrawing groupssuch as -Cl, -NO2, -OMe, -CN, -CH3 and Br afforded good to excellentyields of the desired products (Table 2, entries 2–10). Phenols

rature Time (h) Isolated yield 6a (%)

emp. 24 NR

24 Trace

emp. 24 85

2 92

2 68

2 43

2 58

2 35

t% with respect to phenol, NR= No reaction.

MgO-ZrO2

Solvent-free

O O

O

6a60 oC

iley & Sons, Ltd. Appl. Organometal. Chem. 2012, 26, 395–400

Table 2. O-tert-Butoxycarbonylation of alcohols and phenols on MgO–ZrO2a

No. Hydroxy compounds Product Time (h) Isolated yield (%)

16a

2 92[16]

2 6b 2 90[16]

3 6c 2 84[16]

4 6d 2 82[16]

5 6e 1.5 93[16]

6 6f 1.5 91[20]

7 6g 1.5 90[16]

8 6h 1.5 94[16]

9 6i 1.5 85[16]

10 6j 1.5 92[16]

11 6k 1.5 90[16]

12 6l 1.5 91[17]

13 6m 1.5 93[18]

14 6n 2.0 93[18]

15 6o 2.0 95[19]

16 6p 2.0 90[19]

17 6q 2.0 94[18]

18 6r 4 50[17]

19 6s 3 90[18]

MgO–ZrO2 nanoparticle-catalyzed O-tert-Boc protection of alcohols and phenols

Appl. Organometal. Chem. 2012, 26, 395–400 Copyright © 2012 John Wiley & Sons, Ltd. wileyonlinelibrary.com/journal/aoc

397

Table 2. (Continued)

No. Hydroxy compounds Product Time (h) Isolated yield (%)

20 6t1.5 87[19]

216u

1.5 93[18]

aReaction conditions: Hydroxy compound= 10mmol; Boc2O= 12mmol; nano MgO–ZrO2 = 20wt% w.r.t. hydroxyl compounds, solvent-free, 60�C.

M. B. Gawande et al.

398

having functional groups such as -OMe, -Cl, -CH3 and -Br werewell tolerated, affording their corresponding -O-Boc derivatives inexcellent yield. The presence of a substituent -NO2 group at thepara and meta position of the phenol did not have much effecton the reaction (Table 2, entries 3 and 4).The O-tert-butoxycarbonylation of a bulky phenol such as

2-naphthol also proceeded smoothly under the present reactionconditions, providing 2-naphthyl tert-butyl carbonate in 90% yieldwithin 1.5 h (Table 2, entry 11). Various substituted benzyl alcoholsafforded excellent yields of the desired products (Table 2, entries12–14). Unsaturated alcohols such as cinnamyl alcohol also easilyunderwent Boc protection without affecting the ethylenic bondand afforded 90% yields of the desired product (Table 2, entry 16).Primary and secondary aliphatic alcohols also reacted smoothly

under the present conditions, giving the corresponding O-Bocderivatives in moderate to good yield (Table 2, entries 17–21). Thusboth primary and secondary alcohols were viable partners for thistransformation. The scope of this methodology was furtherextended by investigating the possible chemoselectivity of the

O

ZrO2

Mg O

I

H

- HOO

O

O

O

ZrO2

OO

O

O

OO

Scheme 4. Possible mechanism Boc protection of phenol.

OH+

O

OH

5 mmol 5 mmol

1. MgO-Z2. (Boc)2O

3. solven

Scheme 3. Chemoselective O-tert-butoxycarbonylation of alcohols.

wileyonlinelibrary.com/journal/aoc Copyright © 2012 John W

MgO–ZrO2-mediated O-tert-butoxycarbonylation by carrying outcompetitive reaction of 2-isopropyl-5-methylcyclohexanol and4-methoxyphenol (Scheme 3). Notably, 4-methoxyphenol reactedexclusively in the presence of 2-isopropyl-5-methylcyclohexanol,which was confirmed by thin-layer chromatography (TLC) andNMR. Thus this chemoselective process can be useful for selectiveprotection of the aromatic alcohol group in the presence ofaliphatic alcohol, in natural product chemistry and variousdrug intermediates.

We have proposed the possible mechanism for Boc protectionof phenol as depicted in Scheme 4.

In the first step, the -OH group of phenol and carbonyl oxygenof Boc anhydride is adsorbed on MgO–ZrO2 nano catalyst asshown in I. It is well known that functional groups containingelectronegative atoms such as N, O and S are adsorbed on ametal or Lewis acid site and hydrogen adsorbed on oxygen ofthe catalyst.[21] Then, in a second step, electrophilicity of carbonylcarbon of Boc anhydride is increased, generating an intermediatestate, which, finally yields the final product along with liberation

ZrO2

O O

O

+ CO2 + HO

Reusedand Recycle

+

rO2 ( 20 wt %)

5 mmol

O

OO

O

O

O

O

100 %

0 %

t-free, 60 oC

iley & Sons, Ltd. Appl. Organometal. Chem. 2012, 26, 395–400

Figure 2. Reusability of MgO–ZrO2 NPs.

MgO–ZrO2 nanoparticle-catalyzed O-tert-Boc protection of alcohols and phenols

of CO2 and tert-butanol. MgO–ZrO2 catalysts participate in allthese steps by weakening the chemical bonds of reactants andsubsequently lowering the activation energy.

In order to prove that the reaction is heterogeneous, a standardleaching experiment was conducted by the filtration method. Themodel reaction of phenol and Boc anhydride proceeded for10min in the presence of the MgO–ZrO2 at 60�C. The reactionmixture was then filtered under suction to remove the catalyst.The filtered reaction mixture was then stirred without catalyst for12 h. Notably, no formation of O-Boc corresponding product wasobserved even after 12 h, indicating that no homogeneous catalystwas involved. The reusability of catalyst was tested for the reactionof phenol and Boc anhydride under solvent-free conditions at 60�C.After completion of reaction the catalyst was filtered off, washedwith ethyl acetate two to three times, and then dried at 120�C inan oven for 3 h, then again used for the next cycle. The catalyticactivity slightly decreased even after six cycles (Fig. 2).

Conclusions

We have described a simple chemoselective O-tert-Boc protectionof alcohols and phenols using MgO–ZrO2 NPs under solvent-freeconditions. This protocol offers several advantages such as use ofa heterogeneous, reusable catalyst, high chemoselectivity, greatersubstrate compatibility, high reaction rates, operational simplicityandmild reaction conditions. Further work is in progress to explorethis novel catalyst for use in other organic transformations.

399

Experimental

General Methods

All commercial reagents were used as received unless otherwisementioned. For analytical and preparative TLC, Merck 0.2mm and0.5mm Kieselgel GF 254 pre-coated were used, respectively. Thespots were visualized using UV light. TEM experiments wereperformed on a Hitachi 8100 microscope with Rontec standardEDS detector and digital image acquisition. Nitrogen adsorptionmeasurements were carried out at �196�C using MicromeriticsASAP 2020. The BET surface area, SBET, was obtained by applyingthe BET equation.

Experimental Procedure

Catalyst Preparation

In a typical experiment, for the preparation of MgO–ZrO2 an appro-priate amount of magnesium nitrate [Mg(NO3)2.6H2O] (3.10g) and

Appl. Organometal. Chem. 2012, 26, 395–400 Copyright © 2012 Jo

zirconium oxychloride [ZrOCl2.8H2O] (8.11g) were dissolvedtogether in a 2 l flask with 1 l deionized water. Dilute ammoniasolution was added dropwise with vigorous stirring (RPM-5000)until the precipitation was complete (around 6–8h and pH 10.0).The resultant precipitate was filtered and washed with distilledwater until free from chloride ions. The residue was dried for 24hat 383K in an oven and the obtained precipitate of metal hydroxideswas heated in a porcelain crucible progressively to 873K for 10h. TheXRD profile and TEM analysis is given in supporting information.

General Procedure for Boc Protection of Alcohols

Boc2O (12mmol), MgO–ZrO2 NPs (20 wt% of phenol or alcohol) atroom temperature were added to a mixture of phenol/alcohol(10mmol), and the reaction was stirred under solvent-freeconditions at 60�C for an appropriate time (Table 2). After com-pletion of the reaction, as monitored by TLC, ethyl acetate(10ml) was added to the reaction mixture and the catalystseparated by simple filtration. The reaction mixture was washedwith a brine solution and the product extracted in ethyl acetate(3� 10ml) and concentrated under reduced pressure to givethe crude product, which was purified over a silica-gel columnto afford the corresponding tert-O-Boc derivatives in good toexcellent yield.

Acknowledgements

Manoj B. Gawande thanks FCT, Lisbon, Portugal, for the award ofa research grant (SFRH/BPD/64934/2009) and financial assistance.

References[1] A. R. Katritzky, C. M. Otto, W. R. Charles, Comprehensive Organic

Transformations, Vol. 5, Wiley, New York, 1996.[2] L. A. Paquette, Encyclopedia of Reagents for Organic Synthesis, Vol. 7,

Wiley-Interscience, New York, 1995, pp. 5525.[3] A. A. G. Shaikh, S. Sivaram, Chem. Rev. 1996, 96, 951.[4] J. P. Parrish, R. N. Salvatore, K. W. Jung, Tetrahedron 2000, 56, 8207.[5] A. F. Hegarty in Comprehensive Organic Chemistry, Vol. 2 (Ed.: I. O.

Sutherland), Pergamon, London, 1979, pp. 1067.[6] a) P. Tundo, L. Rossi, A. Loris, J. Org. Chem. 2005, 70, 2219; b) B. Veldurthy,

F. Figueras, Chem. Commun. 2004, 734; c) M. O. Bratt, P. C. Taylor, J. Org.Chem. 2003, 68, 5439.

[7] T. W. Greene, P. G. M. Wuts, Protective Groups in Organic Synthesis ,3rd edn, Wiley, New York, 1999, pp. 518.

[8] F. Houlihan, F. Bouchard, J. M. Frechet, C. G. Willson, Can. J. Chem.1985, 65, 153.

[9] Y. Basel, A. Hassner, J. Org. Chem. 2000, 65, 6368.[10] C. T. Chen, J. H. Kuo, C. H. Li, N. B. Barhate, S. W. Hon, T. W. Li, S. D.

Chao, C. C. Liu, Y. C. Li, I. H. Chang, J. S. Lin, C. J. Liu, Y. C. Chou,Org. Lett. 2001, 3, 3729.

[11] a) C. T. Chen, J. H. Kuo, V. D. Pawar, Y. S. Munot, S. S. Weng, C. H. Ku,C. Y. Liu, J. Org. Chem. 2005,70, 1188; b) G. Bartoli, M. Bosco,M. Locatelli, E. Marcantoni, P. Melchiorre, L. Sambri, Org. Lett.2005, 7, 427.

[12] a) R. Chebolu, S. V. Chankeshwara, A. K. Chakraborti, Synthesis 2008,1448; b) S. V. Chankeshwara, A. K. Chakraborti, Synthesis 2006, 2784;c) A. K. Chakraborti, S. V. Chankeshwara, Org. Biomol. Chem. 2006, 4,2769; d) S. V. Chankeshwara, A. K. Chakraborti, J. Mol. Catal. A: Chem.2006, 253, 198.

[13] a) M. B. Gawande, P. S. Branco, Green Chem. 2011, 13, 3355; b)M. B. Gawande, V. Polshettiwar, R. S. Varma, R. V. Jayaram, TetrahedronLett. 2007, 48, 8170; c) J. J. Shrikhande, M. B. Gawande, R. V. Jayaram,Tetrahedron Lett. 2008, 49, 4799; d) R. K. Pandey, S. P. Dagade,R. K. Upadhyay, M. K. Dongare, P. Kumar, Arkivoc 2002, vii, 2; e)M. B. Gawande, R. K. Pandey, R. V. Jayaram, Catal. Sci. Technol.2012 DOI: 10.1039/C2CY00490A

[14] a) M. B. Gawande, S. S. Deshpande, S. U. Sonavane, R. V. Jayaram, J.Mol. Catal. A: Chem. 2005, 241, 151; b) M. B. Gawande, R. V. Jayaram,Catal. Commun. 2006, 7, 933; c) M. B. Gawande, S. S. Deshpande, J. R.

hn Wiley & Sons, Ltd. wileyonlinelibrary.com/journal/aoc

M. B. Gawande et al.

400

Satam, R. V. Jayaram, Catal. Commun. 2007, 8, 576; d) S. U. Sonavane,M. B. Gawande, S. S. Deshpande, A. Venkataraman, R. V. Jayaram,Catal. Commun. 2007, 8, 1803.

[15] M. B. Gawande, P. S. Branco, K. Parghi, J. J. Shrikhande, R. K. Pandey,C. A. A. Ghumman, N. Bundaleski, O. M. N. D. Teodoro, R. V. Jayaram,Catal. Sci. Technol. 2011, 1, 1653.

[16] S. V. Chankeshwara, R. Chebolu, A. K. Chakraborti, J. Org. Chem. 2008,73, 8615.

wileyonlinelibrary.com/journal/aoc Copyright © 2012 John W

[17] G. Bartoli, M. Bosco, A. Carlone, R. Dalpozzo, M. Locatelli, P. Melchiorre,P. Palazzi, L. Sambri, Synlett 2006, 2104.

[18] N. Suryakiran, P. Prabhakar, Y. Venkateshwarlu, Synth. Commun.2007, 38, 177.

[19] S. Singh, R. V. Jayaram, Tetrahedron Lett. 2008, 49, 4249.[20] A. Procopio, G. Cravotto, M. Oliverio, P. Costanzo, M. Nardi, R.

Paonessa, Green Chem. 2011, 13, 436.[21] K. Tanabe, W. F. Holderich, Appl. Catal. A: Gen. 1999, 181, 399.

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