Deacetylation of thioacetate using acetyl chloride in methanol

Article abstract of DOI:10.1080/00397910600602735

A highly efficient method for the deacetylation of thioacetate is reported under mild acidic conditions employing acetyl chloride in methanol. Some of the major advantages are mild conditions, high efficiency, high yields, and easy operations. Copyright Taylor & Francis Group, LLC.

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Deacetylation of Thioacetate using Acetyl
Chloride in Methanol
Neera Tewari a , Hashim Nizar a , Avinash Mane a , Vinod George a & Mohan
Prasad a
a Chemical Research Division, Ranbaxy Research Laboratories, Gurgaon,
Haryana, India
Published online: 18 Aug 2006.
To cite this article: Neera Tewari , Hashim Nizar , Avinash Mane , Vinod George & Mohan Prasad (2006):
Deacetylation of Thioacetate using Acetyl Chloride in Methanol, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 36:13, 1911-1914
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Synthetic Communicationsw, 36: 1911–1914, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910600602735
Deacetylation of Thioacetate using Acetyl
Chloride in Methanol
Neera Tewari, Hashim Nizar, Avinash Mane, Vinod George,
and Mohan Prasad
Chemical Research Division, Ranbaxy Research Laboratories,
Gurgaon, Haryana, India
Abstract: A highly efficient method for the deacetylation of thioacetate is reported
under mild acidic conditions employing acetyl chloride in methanol. Some of the
major advantages are mild conditions, high efficiency, high yields, and easy operations.
Keywords: Acetyl chloride, carbapenem intermediate, deacetylation, thioacetate, thiol
INTRODUCTION
The acetyl group has been frequently employed as a protecting group
for alcohols and thiols based upon its ready installation and cleavage.[1]
The acetylation/deacetylation protocol has gained popularity in organic
synthesis because of readily available precursors. The different reagents
employed in deacetylation[2] of thioacetate includes dil. NaOH, aqueous
ammonia, HBr in acetic acid, and trifluoro acetic acid in phenol. Cleavage
of thioacetate under basic conditions often suffers from poor chemoselectivity.
Base-catalysed hydrolysis of S-acetylcysteine occurs with b-elimination to
give an undesired olefinic side product.[3]
Conditions for cleaving thioacetates modeled from the literature
(NaHCO3/H2O/CH3CN or NaOMe/MeOH) were either too slow or led to
the formation of undesired disulphides.[2–4]
Received in India December 26, 2005
Address correspondence to Neera Tewari, Chemical Research Division, Ranbaxy
Research Laboratories, Plot No. 20, Sector-18, Udyog Vihar Industrial Area, Gurgaon
122 001 Haryana, India. Tel./Fax: (91-124) 4011832; E-mail: neera.tiwari@ranbaxy.com
1911

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N. Tewari et al.
Consequently, there is a need to develop alternative methods that could
work under mild conditions and with less expensive reagents. A combination
of acetyl chloride with methanol has been used for a variety of organic trans-
formation reactions. A catalytic quantity of acetyl chloride in methanol is used
for the deprotection of tert-butyldimethylsilylether and t-butyldiphenylsilyl
ethers.[5] This system is effectively used for the cleavage of N-t-BOC
protection[6] and carboxylate ester formation. Recently the chemoselective
deacetylation of primary, secondary, aromatic, and sugar acetyl to correspond-
ing alcohols is reported using acetyl chloride in methanol.[7]
We have utilized this synthetic protocol for the deprotection of thioacetate
to thiols. The reaction of benzyl thioacetate with 15 mol% of acetyl chloride in
methanol gave benzyl thiol after stirring for 3 h at room temperature with
excellent yield (Table 1). The rate of deacetylation of p-nitrobenzyl thioacetate
Table 1. Deprotection of thioacetate using acetyl chloride in methanol
Amount
of AcCl,
reaction
time
Yield
(%)a
Entry
Substrate (1)
Product (2)
15 mol%,
3 h
a
96
94
15 mol%,
12 h
b
c
50 mol%,
6 h
80
30 mol%,
5 h
d
e
92
50 mol%,
2 h
88b
aYields refer to isolated products. Final products were characterized by spectral
analysis (reaction at 25–308C).
bReaction under reflux condition.

Deacetylation of Thioacetate using Acetyl Chloride
1913
was slow (12 h) (entry b, Table 1). The secondary thioacetates were also
cleaved under these conditions. The rate of the reaction can be accelerated
by increasing the quantity of acetyl chloride or by increasing the temperature.
(2S,4S)-Dimethylaminocarbonyl-4-thioacetyl-1-p-nitrobenzyloxycarbo-
nylpyrrolidine (entry 1c), precursor for the side chain of carbapenem antibiotic
meropenem,[8] was deacetylated earlier under alkaline hydrolysis conditions
at 0–58C; however, disulphide and other oxidative impurities resulted.[8]
We have investigated the utility of acetyl chloride in methanol for this
substrate (entry 1c) and observed less disulphide impurity (,1%).
In summary, we have described a new and efficient protocol for the depro-
tection of thioacetate using acetyl chloride in methanol.
EXPERIMENTAL
Reagents were used as such without further purification. Melting points were
determined on a Buchi melting-point 535 apparatus and are uncorrected.
1H NMR and 13C NMR spectra were recorded using a Brucker 300-MHz
instrument. The chemical shift data is reported as d (ppm) downfield from
tetramethylsilane. Mass spectra were recorded using API 2000 (MDS
SCIEX) instrument. (2S,4S)-4-Acetylthio-2-hydroxymethyl-1-(4-nitrobenzy-
loxycarbonyl)pyrrolidine (1d) and (2S,4S)-4-acetyl thio-2-(N-sulfamoyl-
t-butoxycarbonylaminomethyl)-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1e)
were prepared by the reported procedure.[9]
General Procedure for the Deacetylation
A mixture of benzyl thioacetate (5 g, 30 mmol), acetylchloride (0.36 g,
4.5 mmol), and methanol (25 mL) were stirred at room temperature. After
completion of the reaction, the mixture was added to methylene chloride
and water (50 mL each). An aqueous NaHCO3 solution was added until the
reaction attained pH 7.0. The organic layer was washed with water (25 mL)
and concentrated to afford the product 2a.
Data
(2S,4S)-2-Dimethylaminocarbonyl-4-mercapto-1-p-nitrobenzyloxycarbo-
1
nylpyrrolidine(2c). Mp 118–1198C (Lit.[8] mp 118.5–119.58C). H NMR
(CDCl3): d 1.88 (br, 1H), 2.72 (t, 2H), 2.90 (s, 3H), 3.10 (s, 3H), 3.26
(t, 1H), 3.41 (t, 1H), 4.06 (t, 1H), 4.62 (m, 1H), 4.70 (m, 1H), 5.21 (s, 2H),
7.50 (d, 2H), 8.15 (d, 2H), 13C NMR (CDCl3): d 36.76, 36.96, 40.15, 41.01,
56.53, 65.67, 123.68, 127.93, 144.01, 144.74, 153.37, 171.14. Mass (m/e): 353.
(2S,4S)-4-Mercapto-2-hydroxymethyl-1-(4-nitrobenzyloxycarbonyl)pyr-
1
rolidine (2d). Mp 99.5–1008C. H NMR (CDCl3): d 1.67 (m, 1H), 2.50

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N. Tewari et al.
(m, 1H), 3.16–3.29 (m, 2H), 3.71 (m, 2H), 4.0 (m, 2H), 4.23 (m, 1H), 5.23
(s, 2H), 7.52 (d, 2H), 8.23 (d, 2H), 13C NMR (CDCl3): d 34.20, 39.20,
56.24, 61.56, 66.23, 123.84, 128.25, 143.45, 147.69, 155.77. Mass (m/e): 312.
(2S,4S)-4-Mercapto-2-(N-sulfamoyl-aminomethyl)-1-(4-nitrobenzyloxycar-
bonyl)pyrrolidine (2e).[10] Oil. 1H NMR (CDCl3): d 1.65 (m, 1H), 1.74
(m, 1H), 2.60 (m, 1H), 3.20–3.43 (m, 4H), 4.10 (m, 2H), 4.80 (m, 1H), 5.21
(s, 2H), 7.53 (d, 2H), 8.34 (d, 2H), 13C NMR (CDCl3): d 36.54, 40.06, 47.13,
54.93, 58.06, 66.06, 123.85, 128.20, 143.44, 147.66, 155.01. Mass (m/e): 390.
ACKNOWLEDGEMENT
We are grateful to the Analytical Division of Ranbaxy Research Laboratories
for their analytical and spectral support.
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