Selective Deprotection of Aryl Acetates, Benzoates, Pivalates, and Tosylates under Nonhydrolytic and Virtually Neutral Conditions†

Deprotection of functional groups1 is one of the most important and widely carried out synthetic transformations in preparative organic chemistry. In the synthesis of multifunctional molecules, the problem regularly arises that a given functional group has to be deprotected in the presence of others. Of the many methods available for protection of phenolic hydroxyl group, esters have still retained a position of prominence due to their ease of formation as their rich choices of a whole array of different esters such as acetates, benzoates, pivalates, and sulfonates. The methods available for deprotection of aryl acetates involve treatment with Zn-MeOH,1a LiBH4, p-TsOH-SiO2-H2O, BBTO,2 NaHTe,3 borohydride-exchanged resin,4 Al2O3/μw, metal complexes,6 enzymes,7 metalloenzymes,8 antibodies,9 and cyclodextrin10 and micelle-catalyzed saponification.11 Deprotection of aryl benzoates is carried out by treatment with acids,1a bases,1a and NaHTe,3 and the scanty choices left for depivalylation include alkaline hydrolysis1a or irradiation under microwave.5 The limited options available for cleavage of aryl sulfonates are treatment with aqueous alkali,1a PhLi/PhMgBr,1a and reducing agents.1a,12 However, these methods suffer from the disadvantages of harsh reaction conditions, use of costly reagents, and not always being effective for multifunctional substrates. We report herein that aromatic thiols (e.g., PhSH, 4-MeC6H4SH, and 2-NH2C6H4SH) in the presence of a catalytic amount of K2CO3 in dipolar aprotic solvents constitute an efficient protocol for selective cleavage of aryl ester (Table 1). The deprotection was carried out by heating the reaction mixture at 200 °C in DMPU, DMEU (1,3-dimethyl-2-imidazolidinone), HMPA, and sulfolane or under reflux in NMP and DMF for 5-15 min. With 2-NH2-C6H4SH, the deprotection could be carried out at 100 °C although a longer time was required. Both K2CO3 and the thiol are essential for deprotection to take place. The results of deprotection of several aryl acetates, benzoates, pivalates, and tosylates in the presence of chloro, nitro, aldehyde, and acetyl groups are summarized in Table 2. Excellent chemoselectivity was observed for substrates bearing nitro and chloro groups (entries 1, 3, 6-8, 14, and 17) wherein selective deprotection of aryl esters took place without any competitive aromatic nucleophilic substitution of the nitro13 or chloro14 groups or reduction of the nitro15 group despite the known SET property of thiolate anions.16 The reaction may be thought to proceed as depicted in Scheme 1. The proton exchange between K2CO3 and the thiol (path a) generates ArS-. Nucleophilic attack by ArSat the ester carbonyl (path b) liberates ArO-, which in turn undergoes proton exchange (path c) with ArSH to replenish the thiolate anion. This “demand-based” in situ generation of ArSas the effective nucleophile makes the method highly chemoselective. The importance of the use of NMP as solvent may be realized through the efficient proton exchange (path c) between ArSH and the liberated ArOduring which the equilibrium [ArSH + ArO) ArS+ ArOH] is shifted to the right as a result of better solvation of ArScompared to that of ArO-.17 The lack * To whom correspondence should be addressed. Fax: +91-(0)172677185. E-mail: niper@chd.nic.in. † NIPER Communication No. 27. ‡ National Institute of Pharmaceutical Education and Research. § The University of Burdwan. (1) (a) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 2nd ed.; John Wiley: New York, 1991. (b) Kocieneski, P. J. Protecting Groups; Thieme: Stuttgart, 1994. (2) Salomon, C. J.; Mata, E. G.; Mascaretti, O. A. Tetrahedron Lett. 1991, 32, 4239. (3) Shobana, N.; Shanmugam, P. Indian J. Chem. 1985, 24B, 690. (4) Salunkhe, M. M.; Wadgaonkar, P. P.; Sagar, A. D. Eur. Polym. J. 1994, 30, 967. (5) (a) Ley, S. V.; Mynett, D. M. Synlett 1993, 793. (b) Varma, R. S.; Varma, Manju.; Chatterjee, A. K. J. Chem. Soc., Perkin Trans. 1 1993, 999. (6) (a) Boisselier, V. L.; Postel, M.; Dunach, E. Tetrahedron Lett. 1997, 38, 2981. (b) Koike, T.; Kimura, E. J. Am. Chem. Soc. 1991, 113, 8935. (c) Suh, J.; Cho, Y.; Lee, K. J. J. Am. Chem. Soc. 1991, 113, 4198. (7) Parmer, V. S.; Prasad, A. K.; Sharma, N. K.; Bisht, K. S.; Pati, H. N.; Taneja, P. Bioorg. Med. Chem. Lett. 1993, 3, 585. (8) Crampton, M. R.; Holt, K. E.; Percy, J. M. J. Chem. Soc., Perkin Trans. 2 1990, 1701. (9) Guo, J.; Huang, W.; Scanlan, T. S. J. Am. Chem. Soc. 1994, 116, 6062. (10) (a) Tee, O. S.; Mazza, C.; Lozano-Hemmer, R.; Giorgi, J. B. J. Org. Chem. 1994, 59, 7602. (b) Tee, O. S.; Mazza, C.; Du, X.-x. J. Org. Chem. 1990, 55, 3603. (11) Kunitake, T.; Okahata, Y.; Sakamoto, T. J. Am. Chem. Soc. 1976, 98, 7799. (12) Sridhar, M.; Kumar, B. A.; Narender, R. Tetrahedron Lett. 1998, 39, 2847. (13) Cogolli, P.; Testaferri, L.; Tingoli, M.; Tiecco, M. J. Org. Chem. 1979, 44, 2636. (14) Cogolli, P.; Maiolo, F.; Testaferri, L.; Tingoli, M.; Tiecco, M. J. Org. Chem. 1979, 44, 2642. (15) (a) Hwu, J. R.; Wong, F. F.; Shiao, M.-J. J. Org. Chem. 1992, 57, 5254. (b) Shiao, M.-J.; Lai, L.-L.; Ku, W.-S.; Lin, P.-Y.; Hwu, J. R. J. Org. Chem. 1993, 58, 4742. (16) Surdhar, P. S.; Armstrong, D. A. J. Phys. Chem. 1986, 90, 5915. (17) Sears, P. G.; Woldford, R. K.; Dawson, L. R. J. Electrochem. Soc. 1956, 103, 633. Table 1. Effect of Thiol, Base, Solvent, and Temperature on Deprotection of 2-Naphthyl Benzoate