Tetrahedron Letters
DMF-mediated deprotection of bulky silyl esters under neutral
and fluoride-free conditions
a
a
b
a,b,
⇑
Bo Chen , Hui-Xia Sun , Jian-Feng Qin , Bing Wang
a
Department of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433, China
Institutes of Biomedical Sciences, Fudan University, 138 Yixueyuan Road, Shanghai 200032, China
b
a r t i c l e i n f o
a b s t r a c t
Article history:
Bulky TBDPS and TIPS carboxylic esters were efficiently cleaved by a green and mild protocol using only
Received 8 October 2015
Revised 9 November 2015
Accepted 16 November 2015
Available online 17 November 2015
DMF–H
2
O (20:1) at 70 °C. The neutral conditions tolerate various common acid- and base-labile function-
alities, including alkyl and aryl silyl ethers.
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
Protective groups
Lewis base
Synthetic methods
Green chemistry
Trialkylsilyls are among the most frequently used protective
groups in organic synthesis,1 whereas most attention has been
devoted to their applications in the protection of alcohols and phe-
nols. Compared to the wide variety of alkyl/aryl esters currently
employed as the protection of carboxylic acids, the use of silyls
Guided by our previous mechanistic analysis of the deprotec-
tion of aryl silyl ethers, we probed the viability of Lewis base-cat-
alyzed hydrolysis of silyl carboxylic esters.
Alkali metal acetates were initially tested, and were found quite
effective for this purpose as expected (Table 1). For example, under
2
3
for this purpose is rather limited. Only bulky silyls such as TBDPS
2
the catalysis of 10 mol % LiOAc in DMF–H O (50:1), TBDPS ester 1a
4
and TIPS are sufficiently robust to withstand reasonably harsh
conditions and to serve as protecting groups proper, while the
esters derived from smaller silyls (TMS, TES, and TBS) are much
was hydrolyzed in 30 min at rt to afford the free acid 1 in an almost
quantitative yield. The analogous TIPS ester 1b was also cleaved
under the same condition (entry 2). Other alkali metal acetates
gave comparable results but offered no obvious advantage over
LiOAc (entries 3 and 4). However, it was found that in the absence
of acetates, the ‘background’ reaction cannot be ignored. The reac-
tion went to about 25% conversion after 8 h at rt. Raising the tem-
perature to 70 °C drove the reaction to completion in 1–2 h, and
the yields were excellent (entries 5–7). The simplicity and mild-
ness of this condition rendered it preferable to that using LiOAc,
since the latter could act as a nucleophile even at rt (see below).
The participation of DMF was demonstrated by a control experi-
ment run with 95% aqueous ethanol as the solvent, in which the
substrate remained unchanged after prolonged heating. On the
other hand, DMSO, another Lewis base, behaved similarly to
DMF. Due to its ease of workup, DMF was chosen in the subsequent
study.
5
less stable and are regarded as transient protections at most.
One probable cause for the unpopularity of bulky silyl esters is that
3
their removal usually requires excess fluoride sources (HF,
6
7
8
9
5b
TBAF, PyÁHF, MF ), strong acids or bases, which are often
incompatible with other common protective groups and fragile
1
0
structures.
In addition, these fluoride reagents are often a
concern in terms of environmental-friendliness, operating cost,
and simplicity. Thus, a mild and fluoride-free de-silylation protocol
is highly desirable and would greatly expand the utility of silyl
ester in both academia and industry. We have recently developed
efficient and chemoselective Lewis base-catalyzed deprotection
protocols for aryl TBS and TIPS ethers, respectively.11 As our con-
tinued endeavor in the chemistry of protective groups, herein we
report a novel, green, and inexpensive deprotection method for
bulky TBDPS and TIPS esters, using aqueous DMF alone.
The scope of this DMF-mediated de-silylation protocol was
examined, using structurally divergent substrates possessing a
wide variety of electronic and steric effects (Table 2). The parent
carboxylic acids were obtained in excellent to near quantitative
yields under mild conditions for both TBDPS and TIPS esters, while
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040-4039/Ó 2015 Elsevier Ltd. All rights reserved.
0