Selective Debenzylation of Benzyl Esters by Silica-Supported Sodium

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Chinese Chemical Letters 20 (2009) 1157–1160 www.elsevier.com/locate/cclet

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, China c 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 NaHSO4ÁSiO2 could be a useful acidic reagent for the same purpose. Due to the nature of its environmental friendliness, easy preparation [6], and low cost, NaHSO4ÁSiO2 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 (NaHSO4ÁSiO2).

* Corresponding authors. E-mail addresses: [email protected] (D.Y. Ye), [email protected] (W.H. Duan).

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1158 Y.W. Hu et al. / Chinese Chemical Letters 20 (2009) 1157–1160

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.

In an exploratory study, a model reaction of benzyl 4-nitrobenzoate in the presence of NaHSO4ÁSiO2 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

Table 2

Selective cleavage of benzyl esters using NaHSO4ÁSiO2

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

1 10 99

2 10 96

3 10 97 中国科技论文在线 http://www.paper.edu.cn

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

9 793

10 492

11 499

12 498

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.

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 中国科技论文在线 http://www.paper.edu.cn

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

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 NaHSO4ÁSiO2 [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 NaHSO4ÁSiO2:benzyl ester 1 (1 mmol, entry 1 in Table 2) was dissolved in toluene (1 mL) and NaHSO4ÁSiO2 (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).