Mild and chemoselective deacetylation method using a catalytic amount of acetyl chloride in methanol

Article abstract of DOI:10.1055/s-2005-869838

Efficient deacetylation of alcohol acetates under mild acidic conditions was accomplished with a catalytic amount of acetyl chloride in methanol. Acetates of various primary, secondary, aromatic and sugar alcohols were successfully deprotected. Highly chemoselective removal of acetyl groups in presence of other commonly employed esters was also achieved in excellent yields. The reactivity of this transesterification-mediated deacetylation was found to be directly dependent upon the electronic and steric nature of the acetates. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-869838

LETTER
1527
Mild and Chemoselective Deacetylation Method Using a Catalytic Amount of
Acetyl Chloride in Methanol
Chemoselective
D
h
eacetylation
a
U
sing
A
ce
n
tyl Chloride
ginMethanol-Eun Yeom, So Young Lee, Young Jong Kim, B. Moon Kim*
School of Chemistry, College of Natural Sciences, Seoul National University, Seoul, 151-747, Korea
Fax +82(2)8727505; E-mail: kimbm@snu.ac.kr
Received 30 March 2005
From our ongoing research on the development of effi-
Abstract: Efficient deacetylation of alcohol acetates under mild
acidic conditions was accomplished with a catalytic amount of
acetyl chloride in methanol. Acetates of various primary, second-
ary, aromatic and sugar alcohols were successfully deprotected.
cient protocol for the cleavage of alcoholic protecting
groups, we encountered fast deprotection of acetate
simply through the use of a catalytic amount of acetyl
Highly chemoselective removal of acetyl groups in presence of chloride in methanol. This is quite intriguing since the
other commonly employed esters was also achieved in excellent
acetyl chloride is usually utilized as an acetylating
yields. The reactivity of this transesterification-mediated deacetyl-
reagent. On a model study, when acetyl chloride was in-
ation was found to be directly dependent upon the electronic and
troduced to the methanolic solution containing acetic acid
steric nature of the acetates.
3-phenyl propyl ester, the acetyl group was deprotected
cleanly within three hours at room temperature
(Equation 1). Moreover, only a catalytic amount (15
Key words: acetyl chloride, acetate, catalytic, chemoselective, pro-
tecting group
mol%) of acetyl chloride was required for the removal of
an acetyl group. This preliminary result prompted us to
Acetyl group has been frequently employed as a protect-
investigate the scope and selectivity of this protocol.
ing group for alcohols based upon its ready installation
First, various solvents were examined and methanol was
and cleavage.1 The acetylation/deacetylation protocol has
found to be an essential element for effective deacetyl-
gained much popularity in organic synthesis due to readily
ation. It was also found that the rate of acetate cleavage
available precursors, clean spectroscopic indication of
depends highly upon the Lewis basicity of the alcohol
the products, and addition of minimal molecular weight,
oxygen and steric environment. Deacetylation results on
especially in carbohydrate chemistry.
various substrates under optimized conditions are summa-
However, in cases where different esters are present in
rized in Table 1. Unhindered primary acetates (entries 1
one molecule, cleavage of an acetate under basic condi-
and 3–6) underwent deacetylation smoothly with 15
tions often suffers from poor chemoselectivity. In relation
mol% of acetyl chloride in methanol within a few hours.
to this, many methods have been developed for selective
Hindered primary (entry 7) or secondary acetates (entries
deacetylation in presence of other esters, in particular ben-
2, 8, and 14) were also cleaved satisfactorily with slightly
zoate ester, such as 50% NH3,2a guanidine,2b guanidine/
increased amount of acetyl chloride in prolonged reaction
guanidinium nitrate,2c DBU,2d Sm/I2,2e Bu2SnO,2f and
periods. In case of benzylic acetates, a significant influ-
ence of the para-substitution was noted on the rate of the
reaction; while p-methylbenzyl alcohol acetate underwent
deacetylation in 3.5 hours (entry 3), it took 20 hours for
magnesium in methanol.2g Most of the protocols men-
tioned above involve either basic or reductive methods.
After a brief report on HCl-mediated deprotection of an
acetate during leukotriene C-1 synthesis,3a,b several meth-
the p-nitro-substituted derivative (entry 4). This strongly
ods have successfully achieved selective acetyl cleavage
indicates that the rate-determining step involves the initial
3c,d
under acidic conditions, including HBF4·OEt2 and p-
protonation of the carbonyl oxygen. Allylic (entry 5) and
propargylic (entry 6) acetates were deprotected without
TsOH.3e,f
any structural rearrangement. Moreover, acetate removal
of a serine derivative (entry 7) proceeded with no loss of
0.15 equiv AcCl
OAc
OH
stereochemical integrity, which is often a problem in basic
hydrolysis. Application of this protocol to phenolic ace-
tates was also successful. As in the case of benzylic
acetates, the electronic nature of the substituents appeared
to govern the rate of cleavage; electron donating methoxy
group at the para-position of the benzene ring greatly
accelerated the reaction (entry 10), whereas electron-
withdrawing nitro group slowed the rate significantly
(entry 12).
MeOH, r.t., 3 h
96%
Equation 1
SYNLETT 2005, No. 10, pp 1527–1530
1
7
.0
6
.2
0
0
5
Advanced online publication: 12.05.2005
DOI: 10.1055/s-2005-869838; Art ID: U09305ST
© Georg Thieme Verlag Stuttgart · New York

1528
C.-E. Yeom et al.
LETTER
Table 1 Deprotection of Various Acetates Using a Catalytic Amount of Acetyl Chloride in Methanol
Entry
1
Substrate
Producta
Amount of AcCl, reaction time
15 mol%, 3 h
Yield (%)b
96
OAc
OH
2
3
30 mol%, 4.5 h
15 mol%, 3.5 h
89
93
Cbz
Me
N
OAc
OAc
Cbz
Me
N
OH
OH
4
15 mol%, 21 h
96
OAc
OAc
OH
OH
O2N
BnO
O2N
BnO
5
6
15 mol%, 4.5 h
15 mol%, 4.5 h
88
93
BnO
BnO
OAc
OH
7c
15 mol%, 15 h
91
H
N
H
N
CO2Me
OH
CO2Me
OAc
Cbz
Cbz
8
9
30 mol%, 18 h
10 mol%, 4.5 h
82
74
OH
OAc
AcO
HO
10
11
12
13
15 mol%, 2 h
15 mol%, 5 h
15 mol%, 16 h
15 mol%, 3.5 h
96
99
98
98
MeO
OAc
MeO
OH
MeO2C
O2N
OAc
MeO2C
O2N
OH
OAc
OAc
OH
OH
14d
Cholestrol-Ac
Cholesterol
30 mol%, 16 h
91
a All products were identified by 1H NMR and 13C NMR spectra.
b Yields of isolated alcohols.
c No epimerization occurred during deacetylation; [a]D28 12.5 (c 1.00, MeOH).4
d Reaction was carried out in CH2Cl2–MeOH, 3:2 due to poor solubility of cholesterol in methanol.
To screen the chemoselectivity of the deacetylation reac- benzoyl groups under the selective acetate cleavage con-
tions, 1,6-hexanediol monoacetates with various w-alco- ditions (Table 3). Due to steric congestion in the sugar de-
hol substituents were examined (Table 2). Notably, when rivative, 30–50 mol% acetyl chloride and longer reaction
the deacetylation was carried out in the presence of benzyl times were required for the removal of acetates. However,
(entry 1), p-toluenesulfonyl (entry 2), pivaloyl (entry 3), primary acetate moiety of glucose and galactose deriva-
benzoyl (entry 4) and methyl ester (entry 7 of Table 1) tives (entries 1 and 4, respectively) and both primary and
groups, all the functional groups survived the deacetyl- secondary acetate moieties of glucose derivative (entry 2)
ation conditions and the desired monoalcohols were were cleanly deprotected without touching the benzoyl
obtained in excellent yields (Table 2).
group. Chemoselective removal of the 2,3-diacetates in
the presence of primary benzoate group of glucose deriv-
ative was also successful providing 73% yield of the de-
sired diol (entry 3). It is of a particular note that the
deacetylation of the sugar derivatives occurred without
any hint of epimerization at the anomeric stereocenter.
Chemoselective deacetylation of sugar acetate derivatives
is important in light of the growing interest in glycopep-
tides and oligosaccharides. Extending our methodology
toward sugar chemistry, we have examined various
monosaccharide derivatives possessing both acetyl and
Synlett 2005, No. 10, 1527–1530 © Thieme Stuttgart · New York

LETTER
Chemoselective Deacetylation Using Acetyl Chloride in Methanol
1529
Table 2 Chemoselective Cleavage of Acetates in Presence of Other Estersa
Entry
1
Substrate
Product
Amount of AcCl, reaction time
15 mol%, 5 h
Yield (%)b
94
OAc
OH
BnO
BnO
2
3
4
15 mol%, 4 h
15 mol%, 4.5 h
15 mol%, 4.5 h
94
94
92
OAc
OAc
OAc
OH
OH
OH
TsO
PivO
BzO
TsO
PivO
BzO
a All products were identified by 1H NMR and 13C NMR spectra.
b Yields of isolated alcohols.
Table 3 Chemoselective Cleavage of Acetates in Sugar Derivatives in the Presence of Benzoyl Groupa
Entry
15a
Substrate
Productb
Amount of AcCl , reaction time
30 mol%, 22 h
Yield (%)c
93
OH
OAc
O
O
BzO
BzO
BzO
BzO
OBz
OBz
OMe
OMe
25b
50 mol%, 22 h
50 mol%, 24 h
30 mol%, 22 h
89
73
93
OAc
OBz
OH
O
O
AcO
BzO
HO
BzO
OBz
OBz
OMe
OMe
3
OBz
O
O
BzO
AcO
BzO
HO
OAc
OH
OMe
OMe
45c
OAc
OH
BzO
BzO
BzO
BzO
O
O
OMe
OMe
OBz
OBz
a Reaction was carried out in CH2Cl2–MeOH, 1:1 due to poor solubility of sugars in methanol.
b All products were identified by 1H NMR and 13C NMR spectra.
c Yields of isolated alcohols.
In summary, a simple and efficient deacetylation method
was established using acetyl chloride in methanol, which
is operationally very straightforward and chemoselective,
utilizing only a catalytic amount of the reagent. The only
by-product is methyl acetate, which can be easily re-
moved by simple evaporation. Therefore in almost all the
cases basic extraction and filtration through a pad of silica
gel is sufficient to provide the desired alcohols in pure
form.6
References
(1) (a) Greene, T. W.; Wuts, P. G. M. Protective Groups in
Organic Synthesis, 3rd ed.; Wiley and Sons: New York,
1999. (b) Kocienski, P. J. Protecting Groups; Georg Thieme
Verlag: New York, 1994.
(2) (a) Neilson, T.; Werstiuk, E. S. Can. J. Chem. 1971, 49, 493.
(b) Kunesch, N.; Meit, C.; Poisson, J. Tetrahedron Lett.
1987, 28, 3569. (c) Ellervik, U.; Magnusson, G.
Tetrahedron Lett. 1997, 38, 1627. (d) Baptistella, L. H. B.;
dos Santos, J. F.; Ballabio, K. C.; Marsaioli, A. J. Synthesis
1989, 436. (e) Yanada, R.; Negoro, N.; Bessho, K.; Yanada,
K. Synlett 1995, 1261. (f) Perez, M. G.; Maier, M. S.
Tetrahedron Lett. 1995, 36, 3311. (g) Xu, Y.-C.; Bizuneh,
A.; Walker, C. J. Org. Chem. 1996, 61, 9086.
Acknowledgment
Generous financial support from the Korea Research Fund (2004-
015-C00273) is gratefully acknowledged. C.-E.Y., S.Y.L., and
Y.J.K. thank the BK21 Fellowships from the Ministry of Education,
Republic of Korea.
Synlett 2005, No. 10, 1527–1530 © Thieme Stuttgart · New York

1530
C.-E. Yeom et al.
LETTER
(5) Spectroscopic data of products are identical to reported
(3) (a) Corey, E. J.; Clark, D. A.; Goto, G.; Marfat, A.;
Mioskowski, C.; Samuelsson, B.; Hammerstrom, C. J. Am.
Chem. Soc. 1980, 102, 1436. (b) Byramova, N. E.;
Ovchinnikov, M. V.; Backinowsky, L.; Kochetkov, N. K.
Carbohydr. Res. 1993, 124, C8. (c) Pozsgay, V.; Coxon, B.
Carbohydr. Res. 1994, 257, 189. (d) Pozsgay, V. J. Am.
Chem. Soc. 1995, 117, 6673. (e) Blay, G.; Cardona, M. L.;
Garcia, M. B.; Pedro, J. P. Synthesis 1989, 438.
(f) González, A. G.; Brouard, I.; León, F.; Padrón, J. I.;
Bermejo, J. Tetrahedron Lett. 2001, 42, 3187.
values: (a) Verduyn, R.; Douwes, M.; van der Klein, P. A.
M.; Mösunger, E. M.; van der Marel, G. A.; van Boom, J. H.
Tetrahedron 1993, 49, 7301. (b) Cicero, D.; Varela, O.; De
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(c) Nashed, E. M.; Glaudemans, C. P. J. J. Org. Chem. 1987,
52, 5255.
(6) Representative Procedure.
To a magnetically stirred solution of acetic acid 3-phenyl-
propyl ester (1.43 g, 8.00 mmol) in MeOH (8 mL), was
added acetyl chloride (0.084 mL, 1.2 mmol) at r.t. The
mixture was stirred for 3 h at r.t. and the reaction was
quenched upon addition of sat. aq NaHCO3 solution (20
mL). The mixture was extracted with CH2Cl2 (2 × 20 mL).
The combined organic extract was dried over anhyd MgSO4,
filtered and concentrated. The resulting residue was purified
through a pad (ca. 5 cm) of silica gel column to provide the
desired alcohol (1.05 g, 96% yield).
(4) Demirci, F.; Haines, A. H.; Jia, C.; Wu, D. Synthesis 1995,
189.
Synlett 2005, No. 10, 1527–1530 © Thieme Stuttgart · New York