PAPER
1127
Rapid Chemoselective Deprotection of Benzyl Esters by Nickel Boride
C
hemosel
iective
D
t
eprote
e
ction of Be
n
nzyl
E
sters
b
d
y Nickel Bo
e
ride r M. Khurana,* Reema Arora
Department of Chemistry, University of Delhi, Delhi 110007, India
E-mail: jmkhurana1@yahoo.co.in
Received 30 October 2008; revised 24 November 2008
to completion as reactions in other solvents were predom-
inantly incomplete and in some cases resulted in a mixture
of products. Cleavage of 1a with nickel boride in 1:3:9 ra-
tio (1a/NiCl2·6 H2O/NaBH4) in methanol was rapid (5
Abstract: Benzyl esters of a variety of acids can be chemoselec-
tively cleaved on treatment with nickel boride in methanol at ambi-
ent temperature to give the parent carboxylic acids in high yields.
Other protecting functionalities such as methyl, ethyl, tert-butyl,
and trityl esters as well as benzyl ethers, tert-butyl ethers, and N- min), as monitored by TLC, and 3-chlorobenzoic acid
benzylamides are unaffected under these conditions.
(2a) was obtained in 89% yield. The reaction was incom-
plete even after two hours when a lower molar ratio of
nickel boride (1:2:6) was used. Cleavage was undoubtedly
proceeding due to the involvement of nickel boride gener-
ated in situ as no deprotection was observed in the reac-
tions of 1a with nickel(II) chloride hexahydrate and
sodium borohydride alone.
Key words: benzyl esters, chemoselectivity, carboxylic acids,
cleavage, nickel boride
Protection and deprotection are unavoidable sequences in
the synthesis of complex synthetic targets. Benzyl esters
are frequently used as carboxylic acid protecting groups1
because of their ready accessibility by various classical
methods. The common deprotection protocols for benzyl
esters include catalytic hydrogenolysis,2 catalytic transfer
hydrogenation,3 application of strong Lewis acids4 like
aluminum trichloride or boron trichloride, bis(tributyltin)
oxide,5 aluminum trichloride/N,N-dimethylaniline,6 rhe-
nium carbonyl complexes/iron(III) chloride,7 BS2 es-
terase/CAL-A lipase enzymes8 etc. The limitations of
some of the reported methods are the use of expensive re-
agents, long reaction times, high temperatures, and other
side reactions. In recent years, we have developed new
synthetic strategies using nickel boride as the reagent.9
Therefore, we decided to investigate the versatility of
nickel boride for O–C bond cleavage in different esters
and ethers.
Subsequently, a variety of differently substituted aromatic
as well as aliphatic benzyl esters 1b–r were subjected to
identical deprotection conditions. The reactions were
complete in 5–60 minutes at ambient temperature. The re-
actions were clean and high yields of the corresponding
acids 2b–r were obtained (Scheme 1). Benzyl 4-nitroben-
zoate (1s) and benzyl 4-hydroxybenzoate (1t) resulted in
a mixture of products under these conditions (Table 1, en-
tries 19 and 20). The deprotection of dibenzyl esters 1u–x
was also equally efficient and rapid, but required higher
molar ratios of the reagent (Scheme 1, Table 1, entries
21–24). These results are summarized in Table 1.
NiCl2⋅6H2O, NaBH4
RCO2Bn
RCO2H
MeOH, r.t.
1a–r
2a–r
R = aryl, benzyl, alkyl
We report herein a novel, mild, and chemoselective ap-
proach to the cleavage of benzyl esters with nickel boride
in methanol at ambient temperature to give the corre-
sponding parent carboxylic acids in high yields. Nickel
boride was generated in situ from nickel(II) chloride
hexahydrate and sodium borohydride. Methyl, ethyl, tert-
butyl, and trityl esters are unaffected under these condi-
tions. Benzyl ethers and N-benzylamides are also unaf-
fected, thus enhancing its chemoselectivity. The
deprotection of benzyl 3-chlorobenzoate (1a) to give 3-
chlorobenzoic acid (2a) was chosen as the standard reac-
tion. The optimal reaction conditions were identified by
performing reactions of benzyl 3-chlorobenzoate (1a) in
different solvents (THF, CH2Cl2, EtOH, DMF, MeCN,
and MeOH) and by varying molar ratios of nickel(II)
chloride hexahydrate and sodium borohydride. Methanol
is the solvent of choice to bring the unmasking reactions
NiCl2⋅6H2O, NaBH4
MeOH, r.t.
R(CO2Bn)2
1u–x
R(CO2H)2
2u–x
R = o-aryl, (CH2)n; n = 0, 1
Scheme 1
Reactions of methyl, ethyl, tert-butyl, and trityl esters of
substituted benzoic acids were also attempted with nickel
boride, even in high molar ratios, but none of these
showed any reaction and the starting esters were recov-
ered. Similarly, N-benzylbenzamide, benzyl 2-naphthyl
ether, and benzyl 4-tolyl ether were also stubbornly resis-
tant to the action of nickel boride under different condi-
tions.
The drastic difference between the reactivity of benzyl es-
ters and the above mentioned protecting groups towards
nickel boride prompted us to investigate the selective de-
blocking of benzyl esters. A reaction of equimolar mix-
ture of benzyl benzoate (1g) and methyl benzoate (1:1)
SYNTHESIS 2009, No. 7, pp 1127–1130
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Advanced online publication: 02.03.2009
DOI: 10.1055/s-0028-1087982; Art ID: Z23308SS
© Georg Thieme Verlag Stuttgart · New York