J . Org. Chem. 1999, 64, 8027-8030
8027
Ta ble 1. Effect of Th iol, Ba se, Solven t, a n d Tem p er a tu r e
on Dep r otection of 2-Na p h th yl Ben zoa te
Selective Dep r otection of Ar yl Aceta tes,
Ben zoa tes, P iva la tes, a n d Tosyla tes u n d er
Non h yd r olytic a n d Vir tu a lly Neu tr a l
Con d ition s†
time yield
T (°C) (min) (%)
entry
thiol
PhSH
PhSH
Nil
basea
K2CO3 NMP
Nil NMP
K2CO3 NMP
K2CO3 NMP
K2CO3 DMPU
K2CO3 HMPA
K2CO3 DMEU
solvent
1
2
3
reflux
reflux
reflux
100
200
200
15 96
60 trace
60 trace
180 20
15 95
Asit K. Chakraborti,*,‡,§ Mrinal K. Nayak,§ and
Lalima Sharma‡
4
5
6
7
8
9
10
11
12
13
14
PhSH
PhSH
PhSH
PhSH
PhSH
PhSH
4-MeC6H4SH
2-NH2C6H4SH K2CO3 NMP
2-NH2C6H4SH K2CO3 NMP
2-NH2C6H4SH K2CO3 NMP
Department of Medicinal Chemistry, National Institute of
Pharmaceutical Education and Research, Sector 67, S. A. S.
Nagar 160 062, India, and Department of Chemistry,
The University of Burdwan, Burdwan 713 104, India
15 98
15 80
200
K2CO3 sulfolane reflux
15 70
15 88
15 95
K2CO3 DMF
K2CO3 NMP
reflux
reflux
reflux
100
5
95
Received May 12, 1999
45 100
360 trace
60 trace
Deprotection of functional groups1 is one of the most
important and widely carried out synthetic transforma-
tions 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
LiBH4,1a p-TsOH-SiO2-H2O,1a BBTO,2 NaHTe,3 boro-
hydride-exchanged resin,4 Al2O3/µw,5 metal complexes,6
enzymes,7 metalloenzymes,8 antibodies,9 and cyclodex-
trin10 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 How-
ever, these methods suffer from the disadvantages of
harsh reaction conditions, use of costly reagents, and not
always being effective for multifunctional substrates.
rt
EtSH
K2CO3 NMP
reflux
a
Used in catalytic amount (5 mol %).
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 sum-
marized in Table 2. Excellent chemoselectivity was
observed for substrates bearing nitro and chloro groups
(entries 1, 3, 6-8, 14, and 17) wherein selective depro-
tection of aryl esters took place without any competitive
aromatic nucleophilic substitution of the nitro13 or chlo-
ro14 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 ArS-
at 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 ArS- as 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
* To whom correspondence should be addressed. Fax: +91-(0)172-
677185. E-mail: niper@chd.nic.in.
† NIPER Communication No. 27.
‡ National Institute of Pharmaceutical Education and Research.
§ The University of Burdwan.
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10.1021/jo990780y CCC: $18.00 © 1999 American Chemical Society
Published on Web 09/21/1999