A simple acylation of thiols with anhydrides

Article abstract of DOI:10.1016/j.tetlet.2010.07.126

Different thiols were efficiently acylated at room temperature with different anhydrides in the presence of potassium carbonate. Chemoselective protection of thiol in the presence of hydroxy group was achieved using di-tert-butyl dicarbonate and isatoic anhydride.

Full text of DOI:10.1016/j.tetlet.2010.07.126

Tetrahedron Letters 51 (2010) 5368–5371
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Tetrahedron Letters
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A simple acylation of thiols with anhydrides
*
Andrea Temperini , Diego Annesi, Lorenzo Testaferri, Marcello Tiecco
Dipartimento di Chimica e tecnologia del Farmaco, Sezione di Chimica Organica, Università di Perugia, via del Liceo 1, 06123 Perugia, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Different thiols were efficiently acylated at room temperature with different anhydrides in the presence
of potassium carbonate. Chemoselective protection of thiol in the presence of hydroxy group was
achieved using di-tert-butyl dicarbonate and isatoic anhydride.
Received 21 June 2010
Accepted 21 July 2010
Available online 7 August 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Thiol esters
Acylation
Thiols
Thiol esters are important intermediates in organic synthesis1
as well as biologically active compounds because of the high reac-
tivity toward various nucleophiles.2 Furthermore protection of thi-
ols as thiol esters is an important aspect in chemical self-assembly
procedure employed in the fabrication of nano and macromolecu-
lar structures, nanoparticulate composites, surface immobilization
of molecules, and metal surface modification.3 Most preparations
of thiol esters employ an activated acyl derivative such as acyl
halides4 with thiol salts or with thiols in the presence of a base.
Alternatively mixed anhydrides of carboxylic acids as well as cou-
pling reagents have been employed.5 Commonly used reagents are
anhydrides too,6 especially in the presence of suitable basic or
acidic catalysts although in the reaction one acyl moiety is lost.
Furthermore, a few examples of solvent and catalyst free reaction
of acetic anhydride with thiols at room temperature, or at 80 °C
or under microwave induction have been reported.7
We now report a simple and general method for the acylation of
thiols with different anhydrides in the presence of anhydrous
potassium carbonate (Scheme 1). We began our investigation by
treating thiophenol (1.0 equiv) with acetic anhydride (1.3 equiv)
in ethyl acetate (8 mL/mmol thiol) at room temperature. The corre-
sponding phenyl thioacetate was obtained in 95% yield after 19 h.
The same reaction performed in dichloromethane or in tetrahydro-
furan did not give satisfactory results. To assess the generality of
the method, we investigated the scope and limitations of the reac-
tion by treating various thiols 1 with nearly equimolecular amount
of acetic anhydride 2a, pivalic anhydride 2b, benzoic anhydride 2c,
and di-tert-butyl dicarbonate 2d at room temperature. In the case
of benzoylation and tert-butoxycarbonylation the reactions were
performed in acetonitrile to obtain better results. After complete
conversion of the thiol, the crude reaction mixture was filtered,
dried, and evaporated. The products were frequently obtained
without any further purification giving satisfactory results on
NMR and GC/MS analysis. Otherwise column chromatography
(eluent: ethyl acetate–petroleum ether, silica gel) was used. The
physical and spectroscopic data (mp, IR, NMR, and GC/MS) of the
known compounds were found to be identical with those reported
in the literature. Table 1 lists the substrates 1a–n used for acyla-
tion, the acid anhydrides 2a–d employed, and the acylation prod-
ucts 3a–v obtained.
Acetylation, pivalation, benzoylation, and tert-butoxycarbony-
lation proceeded with excellent yields starting from aromatic and
aliphatic thiols. The easy tert-butoxycarbonylation, especially for
aliphatic thiols represents an improved procedure for the protec-
tion of the sulfhydryl group to be employed in orthogonal protec-
tion approach.8 The mild experimental conditions employed are
compatible with different functional groups such as ester (entry
11–13 and 17), alkoxysilyl (entry 14–16), and amide group (entry
17). In order to explore the generality and scope of the proposed
method, the procedure has been extended to mercapto alcohols
1l–n. Thus, it was observed that the reaction is chemoselective
for the thiol group giving the S-tert-butoxycarbonyl derivatives
3t–v in excellent yields. However, reaction of thiols 1l and 1m with
equimolecular amount of acetic and pivalic anhydrides gave a
mixture of the S-acylated and the S/O-diacylated products while
K2CO3
(R2CO)2O
R1SH
R2COSR1
R2CO2H
MeCN or
EtOAc
1
2a-d
3
2
2a
2b
2c
2d
R : = Me,
= t-Bu, = Ph, = t-BuO
* Corresponding author. Tel.: +39 075 5855121; fax: +39 075 5855116.
E-mail address: tempa@unipg.it (A. Temperini).
Scheme 1. Acylation of thiols with different anhydrides.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.07.126

A. Temperini et al. / Tetrahedron Letters 51 (2010) 5368–5371
5369
Table 1
Acylationa of thiols 1a–n with anhydrides 2a–d at room temperature in EtOAc or MeCNb
Entry
Thiol 1c
Anhydride 2
(PhCO)2O 2c
(t-BuOCO)2O 2d
Time (h)
23
Product 3d
Yielde (%)
Lit. yieldf,g (%)
SH
SBz
1
2
1a
1a
1b
3a
3b
3c
89
96
(94)4a
968b
SBoc
SPv
22
SH
SH
3
4
(t-BuCO)2O 2b
24
23
96
93
(91)9
SBoc
1c
2d
3d
758c
Br
Br
SPv
SH
5
6
1d
1d
2b
2d
8
3e
3f
96
94
956e
SBoc
24
(60)10
SH
SPv
(CH2)10
(CH2)10
7
8
1e
1e
2b
2d
18
24
3g
3h
98
87h
(CH2)10 SBoc
SPv
SH
9
1f
1f
1g
2b
24
24
8
3i
95
(97)11
758a
SBoc
10
11
2d
3l
85h
91
O
O
(MeCO)2O 2a
3m
(85)12
SH
SAc
MeO
MeO
O
O
12
13
1g
1g
2b
2d
15
24
3n
3o
97
92
SPv
MeO
SBoc
MeO
(MeO)3Si
MeO2C
SH
(MeO)3Si
(MeO)3Si
(MeO)3Si
MeO2C
SAc
SBz
15
16
17
1h
1h
1h
2a
2c
2d
9
21
36
3p
3q
3r
96
84
88
SBoc
SH
SBz
18
1i
2c
26
3s
84
NHAc
NHAc
HO
HO
HO
HO
19
20
1l
2d
2d
19
24
3t
89
88
SH
SBoc
1m
3u
SH
SBoc
SH
OH
SBoc
OH
21
1n
2d
24
3v
90
(70)13
a
Reaction conditions: 1/2b or 2c (1:1.1), anhydrous K2CO3 (2 equiv) for pivalic anhydride 2b and benzoic anhydride 2c; 1/2a (1:1.3), anhydrous K2CO3 (2 equiv) for
acetylation and 1/2d (1:1), anhydrous K2CO3 (2 equiv) for di-tert-butyl dicarbonate 2d.
b
MeCN was used for acylation with benzoic anhydride 2c and with di-tert-butyl dicarbonate 2d.
c
Thiols were used as received (purity ranging from 95% to 99%).
d
All the products were characterized by IR, 1H and 13C NMR and GC/MS. Ac = MeCO; Pv = t-BuCO; Bz = PhCO; Boc = t-BuOCO.
e
Yields of isolated products; P97% pure material by 1H NMR.
f
Literature yields refer to catalyzed acylation with anhydrides.
Value in parentheses refers to the best result which do not employ anhydrides.
The product was purified by SiO2 gel chromatography.
g
h
reaction of 1l with a twofold excess of acetic anhydride gave the
expected diacetylated product in 93% yield. Finally the thiols 1b–
e, 1g–l, and 1o were reacted with isatoic anhydride 2e (Scheme
2) under the same experimental conditions and with comparable
reaction times.
All reactions of 2e with these thiols proceed by attack to the es-
ter-type carbon14 to give thiol esters 4 of anthranilic acid as con-
firmed by 1H and 13C spectroscopic data as well as by the
formation of the N-acetylated derivative 5 from 4d. Aliphatic, aro-
matic, and functionalized thiol esters 4 were obtained in high
yields in all cases (Table 2). These antranilic thiol ester derivatives
are useful substrates for the cross-coupling with organostannanes
to give ketones.15As previously reported for the tert-butoxycarb-
onylation, the reaction of isatoic anhydride with mercapto alcohol
1l occurred selectively at the sulfhydryl group without involving
the hydroxyl group. Furthermore the reaction of dithiol 1o with
2.2 equiv of isatoic anhydride gave the interesting diprotected
derivative 4o in excellent yield.
We have developed a simple and efficient procedure for the
protection of different thiols as thiol esters by simple reaction with
anhydrides in ethyl acetate or acetonitrile, in the presence of
potassium carbonate and at room temperature. Moreover the reac-
tion is chemoselective involving the sulfhydryl group without
affecting other functionalities present in the molecule. Tacking into
account the role of thiol esters as acylating agent in biochemical
process, their high reactivity with various nucleophiles and the
O
O
SR1
K2CO3
EtOAc
O
R1SH
+ CO2
N
H
O
NH2
1
2e
4
Scheme 2. Reaction of thiols with isatoic anhydride.

5370
A. Temperini et al. / Tetrahedron Letters 51 (2010) 5368–5371
Table 2
Acylation of thiols 1with isatoic anhydrides 2e at room temperature in EtOAca
Entry
1
Thiol 1
Time (h)
Product 4b
Yieldc (%)
98 (92)15
SH
O
S
1b
1c
22
4b
4c
NH2
SH
Br
O
2
24
94
Br
S
NH2
O
SH
S
3
4
5
6
7
8
9
1d
1e
1g
1h
1i
24
20
19
23
18
10
20
4d
4e
4g
4h
4i
98d
90e
95
NH2
O
SH
(CH2)10
S
(CH2)10
NH2
O
O
SH
OMe
O
MeO
S
NH2
O
(MeO)3Si
SH
S
Si(OMe)3
94
NH2
O
MeO2C
SH
NHAc
CO2Me
NHAc
80e
97d
95
S
NH2
O
HO
HS
SH
OH
S
1l
4l
NH2
O
SH
O
(CH2)3
S
S
1o
4o
H2N
NH2
a
b
c
Reaction conditions: 1/2e (1:1.1), anhydrous K2CO3 (2 equiv).
All the products were characterized by IR, 1H and 13C NMR and GC/MS.
Yields of isolated products; P97% pure material by 1H NMR. Value in parentheses refers to the best result in the literature.
d
e
No yield was reported in the literature.14,16
The product was purified by SiO2 gel chromatography.
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