Selective debenzylation of benzyl esters by silica-supported

sodium hydrogen sulphate

Yan Wei Hu a, Li Zuo b, De Yong Ye a,*, Wen Hu Duan b,c,*a Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 200032, China

b Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, Chinac Department of Pharmaceutical Sciences, School of Pharmacy, East China University of Science & Technology, Shanghai 200237, China

Received 17 February 2009

Abstract

A new debenzylation of benzyl esters by silica-supported sodium hydrogen sulfate is described. The debenzylation could be

achieved selectively and efficiently in good to excellent yields without affecting sensitive functional groups such as nitro,

unsaturated bonds, and ethyl ester.

# 2009 Wen Hu Duan. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.

Keywords: Debenzylation; Benzyl esters; Silica-supported sodium hydrogen sulphate

Protection of carboxylic acid is often necessary due to its high sensitivity towards other reagents and reaction

conditions in multi-step transformations and syntheses of complex organic molecules [1]. Formation of benzyl esters

is a common used method for this purpose. Such a protecting group features the ease of preparation and its chemical

stability toward a number of reaction conditions. The commonly used deprotection method is hydrogenolysis [2] (H2

in the presence of Pd/C or Raney Ni). Although the method is efficient, some problems are also realized. The

pyrophoric nature of these catalysts renders the use of relatively complicated experimental procedures to handle them.

Moreover, the clean removal of the toxic transition metal nano particles is a tedious and highly costly process. This is

particularly problematic in the synthesis of therapeutic agents. Third, the deprotection reaction condition is not

compatible with other functional groups such as nitro, unsaturated bonds, halogen, and etc. Other alternative strategies

are also available, generally harsh reaction conditions such as using Lewis acid [3] (AlCl3 or BCl3 in CH2Cl2), strong

acid [4] (CF3COOH in phenol), and base [5] (K2CO3 in aq. THF) are used, therefore leading to undesired reactions and

low reaction yields.

Inspired by acid mediated debenzlylation of benzyl esters [4], we envisioned that NaHSO4�SiO2 could be a useful

acidic reagent for the same purpose. Due to the nature of its environmental friendliness, easy preparation [6], and low

cost, NaHSO4�SiO2 has been widely used in a variety of organic reactions such as nitration, nitrosation, oxidation,

halogenation, and coupling of indoles in recent years [7]. In this communication, we wish to report an efficient and

selective debenzylation of benzyl esters by silica-supported sodium hydrogen sulfate (NaHSO4�SiO2).

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Chinese Chemical Letters 20 (2009) 1157–1160

* Corresponding authors.

E-mail addresses: dyye@shmu.edu.cn (D.Y. Ye), whduan@mail.shcnc.ac.cn (W.H. Duan).

1001-8417/$ – see front matter # 2009 Wen Hu Duan. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.

doi:10.1016/j.cclet.2009.04.028

In an exploratory study, a model reaction of benzyl 4-nitrobenzoate in the presence of NaHSO4�SiO2 in toluene was

carried out under reflux for 10 h. It was found that the reaction proceeded nicely (Table 1, entry 1), the product 2 was

obtained in high yield (96%). Optimization of reaction conditions revealed that the reaction was highly temperature

dependent. No reaction occurred at 80 8C and 100 8C. Among solvents probed, the yields in toluene and xylene were

higher than that in anisole (96% and 97% vs 84%). Because toluene was more readily removed by evaporation as a

result of its lower boiling point (110 8C) than xylene (140 8C), we selected toluene as reaction medium for further

study.

The optimized reaction conditions were used to probe the generality and selectivity of various benzylic esters

(Table 2). The results indicated that this method could served as general and efficient approach for the selective

removal of benzyl group of benzylic esters without affecting other functional groups. In all cases, good to high yields

(89–99%) were obtained without appreciable side products. Aryl halides (entries 4, 6 and 7) were stable in this reaction

condition. More importantly, the reaction conditions were compatible with nitro group (entry 2), double bond (entries

Y.W. Hu et al. / Chinese Chemical Letters 20 (2009) 1157–11601158

Table 1

Debenzylation of benzyl 4-nitrobenzoatea.

.

Entry Solvent Temperature (8C) Time (h) Yield 2 (%)b

1 Toluene 110 10 96

2 Toluene 80 2 NRc

3 Toluene 100 2 NRc

4 Xylene 130 12 97

5 Anisole 150 12 84

a Unless specified, see Ref. [8] for detailed reaction procedure.b Isolated yields.c No reaction.

Table 2

Selective cleavage of benzyl esters using NaHSO4�SiO2

a.

Entry 3 Productb Time (h) Yield (%)c

1 10 99

2 10 96

3 10 97

8, 9 and 10), and triple bond (entry 11). It is aware that incompatibility with those substrates containing such labile

functionalites is a major drawback for Pd/C catalyzed hydrogenation cleavage of benzyl group of benzylic esters.

Furthermore, the debenzylation process could be applied in the substrate with highly moisture-sensitive functionality

such as benzylic bromide (entry 5). Besides, we also found that the debenzylation proceeded much faster for benzyl

aliphatic carboxylates (entries 10–12) than for benzyl substituted-benzoate (entries 1–8). Finally, it should be noted

Y.W. Hu et al. / Chinese Chemical Letters 20 (2009) 1157–1160 1159

Table 2 (Continued )

Entry 3 Productb Time (h) Yield (%)c

4 10 99

5 10 93

6 10 97

7 10 94

8 10 89

9 7 93

10 4 92

11 4 99

12 4 98

13 10 NRd

14 10 NRd

a Unless specified, see Ref. [8] for detailed reaction procedure.b All products were identified in comparison with authentic commercially available samples and characterized by their spectra (1H NMR).c Isolated yields.d NR stands for no reaction.

that ethyl esters (entries 13 and 14) remained untouched in this reaction conditions, whereas their corresponding

benzyl esters (entries 1 and 9) were easily debenzylated.

The reaction mechanism may involve initial protonation at the oxygen atom of the benzyl ester followed by C–O

cleavage to generate the corresponding benzyl cation along with the desired carboxylic acid. At the same time, the

reaction solvent toluene can efficiently quench the benzyl cation. Whereas for ethyl ester, the formation of ethyl cation

is not as easy as formation of benzyl cation due to the instability of ethyl cation, ethyl ester could survive in this

reaction condition.

In conclusion, we have developed a simple and efficient process for selective cleavage of benzyl esters using

NaHSO4�SiO2 [8]. This strategy features good functional group tolerance, high yields, mild condition, and easy

workup. Therefore this method provides a choice for debenzylation of benzylic esters.

Acknowledgments

We are grateful for financial support from National Science Foundation of China (Nos. 03772648 and 30721005)

and Knowledge Innovation Program of the Chinese Academy of Sciences (No. 06G8031014).

References

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[8] Typical reaction procedure for debenzylation of benzylic esters by NaHSO4�SiO2:benzyl ester 1 (1 mmol, entry 1 in Table 2) was dissolved in

toluene (1 mL) and NaHSO4�SiO2 (50 mg) was added. The reaction system was equipped with reflux condenser and filled with argon. The

reaction mixture was stirred and refluxed under argon for 10 h and then cooled to room temperature. A solution of 1 mol/L sodium hydroxide

(10 mL) was added, the resulting solution was partitioned in separatory funnel. The aqueous layer was acidified with 1 mol/L HCl, the

precipitate was collected by filtration, the filtrate was extracted with ethyl ether and concentrated to dryness to give additional portion of white

solid, the two portions of product were combined and dried to afford the desired product 4a (121 mg, 99% yield).

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