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secondary amines,2 MEM,3 and TMSEC.4,5 We herein report its usage as a mild deprotecting reagent for
t-butyl esters and ethers.
To explore optimal reaction conditions, we first examined the rate of cleavage and the effects of
excess reagent. We performed the deprotection of t-butyl benzoate (entry 1) using increasing amounts
of ZnBr2, assessing product formation at set intervals. As shown in Fig. 1, the initial rate is accelerated
with increasing amounts of ZnBr2. The cleavage rate quickly plateaued at a 5:1 ratio of ZnBr2 to the
substrate and the reaction was >75% complete in the first 6 h.
Next we examined how differing substitution on the phenyl ring affected the rate of deprotection.
Interestingly, compounds bearing electron donating groups are more efficiently cleaved than those
bearing electron withdrawing groups as shown in Table 1 (entries 2–4). This may suggest that formation
of the complex between ZnBr2 and substrate, not the subsequent water hydrolysis is the rate limiting step
in the deprotection (Scheme 1).
Scheme 1.
Similar to aromatic esters, aliphatic esters are deprotected as well (entry 5). As previously reported,2
Boc protecting groups on primary amines were unaffected in this mild reaction condition. We found entry
6 was selectively cleaved at the t-butyl ester, while the Boc group on the nitrogen remained intact. This
may be important for chemical transformation of various amino acids.
We have also demonstrated the deprotection of t-butyl ethers. Reactions were completed within 12–24
h. Phenyl and benzyl ethers were shown to be cleaved faster than the aliphatic ethers (entries 7–9). An
attempt was made to selectively cleave the t-butyl ester over the t-butyl ether, however it was not very
successful (entry 10). After 2 h, the ratio of starting material, mono-cleavage at the ester site and cleavage
at both sites was 1:2:1. No mono-cleavage at the t-butyl ether site was observed. Prolonged exposure to
ZnBr2 resulted in complete cleavage at both sites. This suggests that the cleavage rate for t-butyl esters
is faster than t-butyl ethers, but it was not selective.
In summary, we have developed a mild deprotection method for the cleavage of t-butyl esters and
ethers. We have also demonstrated the selective deprotection of t-butyl esters in the presence of primary
N-Boc groups.
Procedure: to a solution of tert-butyl benzoate (0.356 g, 0.002 mol) in 4 mL dichloromethane was
added zinc bromide (2.25 g, 0.01 mol) and the solution stirred for 24 h. At this time, 40 mL of water was
added and the mixture was stirred for 2 h. The layers were separated and the aqueous layer was extracted
with 3×40 mL of dichloromethane. The combined organic portions were dried over magnesium sulfate,
filtered and the solvent removed by evaporation to yield pure product. Yield: 0.21g (86%) of benzoic acid
as a white solid, which was identical to the commercial product.
References
1. Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis; John Wiley & Sons Inc.: New York, 1999; pp. 65–67
and 404–408.
2. Nigam, S. C.; Mann, A.; Taddei, M.; Wermuth, C. G. Synth. Commun. 1989, 3139.
3. Corey, E. J.; Gras, J. L.; Ulrich, P. Tetrahedron Lett. 1976, 809.
4. Kahn, H.; Patterson, I. Tetrahedron Lett. 1982, 2399, 5083.
5. Koshinen, A.; Lounasmaa, M. Tetrahedron Lett. 1983, 1951.
Wu, Yong-Qian
