One-step conversion of alcohols into thioesters

Article abstract of DOI:10.1055/s-0030-1259028

A one-step conversion of alcohols into thioesters under solvent-free conditions is reported. The alcohols were reacted with primary thioamides in the presence of p-toluenesulfonic acid under solvent-free conditions to produce the corresponding thioesters in good to excellent yields. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1259028

LETTER
2861
One-Step Conversion of Alcohols into Thioesters
O
ne-Ste
p
Convers
a
ionof Alco
s
hols intoT
s
hioestersan Zali Boeini,* Mehdi Mobin
Department of Chemistry, University of Isfahan, 81746-73441, Isfahan, Iran
Fax +98(311)6689732; E-mail: h.zali@chem.ui.ac.ir
Received 18 September 2010
actions for the synthesis of thioesters was the major goal
of the presented study. The aim was to build up a single-
step and efficient method for the synthesis of diverse
thioesters using alcohols as very safe and cheap starting
materials.
Abstract: A one-step conversion of alcohols into thioesters under
solvent-free conditions is reported. The alcohols were reacted with
primary thioamides in the presence of p-toluenesulfonic acid under
solvent-free conditions to produce the corresponding thioesters in
good to excellent yields.
Key words: alcohols, carbocations, esters, sulfur, green chemistry
Thioamides have proven to be extremely successful syn-
thons in organic synthesis and especially in the construc-
tion of heterocyclic compounds.19 Herein, we describe for
the first time to our knowledge, a straightforward and ver-
satile method for the conversion of alcohols into thioesters
using primary thioamides under solvent-free conditions in
the presence of equimolar amounts of p-toluenesulfonic
acid (p-TsOH).
Thioesters are well-known compounds due to their high
biological activity1–4 and huge potential for applications
in drug development5–9 and industry.10–12 Thioesters show
distinct chemical properties compared to oxoesters13 and
their enhanced reactivity has been employed successfully
in a wide range of synthetic organic transformations.14
Therefore, developing a simple and versatile method for
the preparation of such compounds is still an urgent need.
The primary thiomides used in this study were prepared
by known methods.20 The study was started by examining
the reaction of 4-nitrobenzyl alcohol (1a) with benzothio-
amide (2a) as a test primary thioamide under various
reaction conditions to produce the corresponding S-4-ni-
trobenzyl benzothioate (3a; Scheme 1). At the outset of
our study, N,N-dimethylformamide (DMF) was used as
the reaction medium. Therefore, the starting benzothioa-
mide, 1.2 equivalents of 4-nitrobenzyl alcohol, and an
equimolar amount of p-TsOH were dissolved in a small
amount of DMF and the reaction mixture was heated at
100 °C for 60 minutes. Thereafter, the reaction mixture
was poured into a mixture of ice–water to deposit the
crude thioester as a semisolid material which, after crys-
tallization in a suitable solvent (EtOH), gave the pure
compound 3a in moderate yield (57%). In addition to p-
TsOH and DMF, other acids and solvents were also exam-
ined as reaction media, and the screening results showed
a remarkable increase in the yields when the reaction was
conducted in polar solvents (Table 1).
Common approaches to the synthesis of thioesters are
concisely reviewed in our recently published article con-
cerning the synthesis of thioesters in water.15 More re-
cently, acyloxy phosphonium salts and benzyl-
triethylammonium tetrathiomolybdate have been success-
fully applied for the conversion of carboxylic acids into
the corresponding thioesters; however, this approach re-
quires a complex reaction media, expensive reagents, and
toxic alkyl halides in the course of reaction.16 Very recent-
ly, thioesters have been synthesized by the reaction of thi-
ols and acid halides promoted by silica gel.17 The only
reported procedure for the synthesis of thioesters using the
reaction of a thioamide and an alcohol has involved triflu-
oroacetic acid as both catalyst and solvent,18 but this
method suffers from the requirement to use large amounts
of thioamide and acid (10 equivalents), long reaction
times (24 h), and is restricted to a narrow substrate scope.
Although the latter protocols provide rather efficient ac-
cess to thioesters, they suffer from the requirement to use
corrosive reagents, harsh reaction conditions, expensive
catalysts or reagents, and environmentally problematic or-
ganic solvents. Furthermore, in most of previously men-
tioned methods, either thiols are used as starting materials,
which are very unpleasant and noxious compounds, or
alkyl halide derivatives are used as starting materials,
which are very lachrymatory, toxic, or carcinogenic.
Therefore, despite the efficiency of the latter protocols,
the development of safe, efficient, and less expensive re-
OH
NH2
S
O
acidic reagent
solvent
S
+
NO2
NO2
1a
22–88%
2a
3a
Scheme 1
It is notable that extending the reaction times or increasing
the temperature further did not cause an increase in the
yield of thioester, and our examinations demonstrated
that, under these conditions, the reaction mixture was con-
taminated with some colored or tarry materials. In view of
these results, we decided to investigate the reaction under
SYNLETT 2010, No. 19, pp 2861–2866
x
x
.x
x
.2
0
1
0
Advanced online publication: 03.11.2010
DOI: 10.1055/s-0030-1259028; Art ID: G24710ST
© Georg Thieme Verlag Stuttgart · New York

2862
H. Z. Boeini, M. Mobin
LETTER
The experimental results clearly show that only alcohols
giving a stable carbocation could be successfully applied
in the course of reaction, and that better results were ob-
tained with sterically less hindered benzylic alcohols. For-
tunately, exceptionally good results were obtained when
1-adamantanol, as a nonbenzylic, bulky alcohol, was re-
acted with thioamides to produce the corresponding
thioesters in very good to excellent yields (84–91%). As
expected, no reaction took place when the reactants were
heated at the same temperature or even at higher temper-
atures in the absence of p-TsOH.
Table 1 Solvent and Acid Screening in the Synthesis of Thioester
3aa
Entry Solventb
Acid
Temp (°C) Yield (%)
1
2
3
4
5
6
7
8
9
HOAc
HOAc
p-TsOH
p-TsOH
p-TsOH
p-TsOH
–
100
37
57
66
19
43
52
71
88
–
HOAc
100
DMF
100
H2O
reflux
reflux
100
H2O/HTAB
[bmim]HSO4
[bmim]HSO4
solvent-free
solvent-free
A mechanism is proposed to explain the role of p-TsOH,
which is shown in Scheme 3. Alcohol 1 is first protonated
by p-TsOH and fragments to generate a carbocation inter-
mediate. This intermediate then undergoes nucleophilic
attack by thioamide 2 to give thiouronium salt 4. Subse-
quent hydrolysis of this intermediate releases the corre-
sponding thioester 3 with elimination of ammonium salt.
It should mention that more water is available in the reac-
tion than is produced from the initial step of the mecha-
nism due the fact that p-TsOH is employed as its hydrate
(p-TsOH·H2O).
p-TsOH
p-TsOH
–
100
100
100
a Reaction conditions: thioamide (1 mmol), alcohol (1.2 mmol),
p-TsOH (1 mmol), 60 min.
b HTAB: Hexadecyl trimethylammonium bromide, bmim: 1-Butyl-3-
methylimidazolium.
solvent-free conditions to achieve an environmentally
friendly method for the preparation of thioesters. Interest-
ingly, it was found that a drastic increase in the yield of
thioester was accomplished when the reaction was con-
ducted under solvent-free conditions. This approach re-
moves the demand for organic solvents as reaction media
and, consequently, the method is quite eco-friendly.
The feasibility of applying this method on a preparative
scale was also investigated. To this end, the reaction of
benzhydrol with 4-methylbenzothioamide was carried out
on a 30-mmol scale. As anticipated, the reaction proceed-
ed efficiently, was comparable with the microscale reac-
tion (Table 2, entry 13), and gave the desired S-
benzhydryl 4-methylbenzothioate (3m) in 85% isolated
yield.
A range of substituted phenyl groups on the thioamides
were tolerated, and their reaction with various alcohols
led to the corresponding thioesters in short reaction times
(60 min; Scheme 2). The versatility of the method was
confirmed by the successful synthesis of several structur-
ally diverse thioesters (21 examples) in good to excellent
yields (70–91%); Table 2 summarizes the results.21,22
In addition to the simplicity of the method, high yields,
and easy work-up, the salient futures of this methodology
lie in the fact that the reactions are carried out with alco-
hols, which are safe starting materials, under solvent-free
conditions. Additionally, purification of the thioester
products can be achieved by simple recrystallization from
EtOH (95%). The method is compatible with many sub-
stituents, such as halogens, alkoxy, dialkylamino, and ni-
tro groups in the substrates. The directness and efficiency
of the presented method is illustrated in Scheme 4 by
comparison with a conventional synthesis of compound
3s, which requires at least three steps and uses the very
corrosive phosphorous trihalide and an acid chloride, to-
gether with the noxious thiol intermediate.
S
O
p-TsOH
100 °C
R
ROH
+
Ar
NH2
Ar
S
1
2
3
Scheme 2
p-TsO–
H+
+
p-TsOH
NH2
2
S
Ar
R1
+
Ar
R2
R3
H+
OH
OH2
R1
R3
+
R1
R1
– H2O
+
H2N
S
R2 R3
R2 R3
R2
H2O
4
1
R1
R1
O
R1
Ar
H2N
R2
R3
Ar
R2
R3
S
R2
R3
S
+NH4
p-TsO–
+
H3+N
Ar
S
+ OH2
OH
3
Scheme 3 Proposed mechanism
Synlett 2010, No. 19, 2861–2866 © Thieme Stuttgart · New York

LETTER
One-Step Conversion of Alcohols into Thioesters
2863
Table 2 Solvent-Free Conversion of Thioamides into Thioestersa
Entry
R
Ar
Productb Yield (%)c
O
S
1
4-nitrobenzyl
Ph
81
83
78
NO2
3a
O
S
2
3
4-nitrobenzyl
4-nitrobenzyl
4-tolyl
NO2
3b
O
S
4-ClC6H4
NO2
Cl
3c
O
S
4
4-nitrobenzyl
4-biphenyl
80
NO2
3d
3e
O
O
S
S
5
6
7
8
4-nitrobenzyl
4-nitrobenzyl
4-nitrobenzyl
benzyl
2-naphthyl
78
73
83
70
NO2
4-(i-Pr)C6H4
3,4-(MeO)2C6H3
4-(Me2N)C6H4
NO2
3f
O
MeO
S
NO2
MeO
3g
O
S
Me
N
Me
3h
O
S
9
benzyl
benzyl
4-biphenyl
2-naphthyl
82
76
3i
3j
O
10
S
Synlett 2010, No. 19, 2861–2866 © Thieme Stuttgart · New York

2864
H. Z. Boeini, M. Mobin
LETTER
Table 2 Solvent-Free Conversion of Thioamides into Thioestersa (continued)
Entry
11
R
Ar
Productb
Yield (%)c
75
O
O
S
S
4-chlorobenzyl
2-naphthyl
Cl
3k
3l
12
13
t-Bu
2-naphthyl
4-tolyl
73
88
O
benzhydryl
S
3m
O
14
benzhydryl
3,4-(MeO)2C6H3
85
MeO
S
MeO
3n
O
MeO
S
15
16
allyl
allyl
3,4-(MeO)2C6H3
2-naphthyl
73
75
MeO
3o
O
S
3p
O
S
17
18
19
1-adamantyl
1-adamantyl
1-adamantyl
Ph
90
91
87
3q
O
S
4-tolyl
3r
O
S
4-ClC6H4
Cl
3s
Synlett 2010, No. 19, 2861–2866 © Thieme Stuttgart · New York

LETTER
One-Step Conversion of Alcohols into Thioesters
2865
Table 2 Solvent-Free Conversion of Thioamides into Thioestersa (continued)
Entry
20
R
Ar
Productb
Yield (%)c
O
S
1-adamantyl
4-(i-Pr)C6H4
84
88
3t
O
OMe
OMe
S
21
1-adamantyl
3,4-(MeO)2C6H3
3u
a Reaction conditions: Thioamide derivative (1 mmol), alcohol (1.2 mmol), p-TsOH (1 mmol), 100 °C, 60 min.
b All products were characterized by IR, 1H NMR, 13C NMR, and elemental analyses.
c Pure isolated product.
O
Acknowledgment
OH
S
S
We are thankful to the University of Isfahan Research Council for
financial support of this work.
NH2
p-TsOH
+
Cl
100 °C
solvent-free
Cl
References and Notes
3s
PX3
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ditions. The approach is expected to be quite general for
the synthesis of diverse thioesters. Besides being an effi-
cient reaction that is easy to perform, the method benefits
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Synlett 2010, No. 19, 2861–2866 © Thieme Stuttgart · New York

2866
H. Z. Boeini, M. Mobin
LETTER
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(22) General Procedure: In a round-bottom flask, thioamide (1
mmol), alcohol (1.2 mmol), and p-TsOH (1 mmol) were
heated to melt and heating was continued at 100 °C for 60
min. The reaction mixture was then poured into H2O (10
mL) with vigorous stirring. Thereafter an oily residue was
left, which soon solidified to a semi-crystalline mass. The
solid was filtered and washed with H2O (2 × 10 mL). Finally
the solid compound was recrystallized from EtOH (95%) to
afford pure thioesters as white or pale-yellow needles with a
characteristic odor. Compound 3s: Mp 127–129 °C (EtOH);
1H NMR (400 MHz, CDCl3): d = 7.86 (d, J = 7.6 Hz, 2 H),
7.40 (d, J = 7.6 Hz, 2 H), 2.27 (m, 6 H), 2.11 (s, 3 H), 1.75–
1.85 (m, 6 H); 13C NMR (100 MHz, CDCl3): d = 191.3,
139.2, 136.7, 128.7, 128.3, 51.5, 41.9, 36.3, 29.9; Anal.
Calcd for C17H19ClOS: C, 66.54; H, 6.24; S, 10.45. Found:
C, 66.75; H, 6.09; S, 10.59
(d) Olsson, R.; Hansen, H. C.; Andersson, C. M.
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Kaushik, M. P. Tetrahedron Lett. 2006, 47, 2315.
(21) Complete experimental procedures and relevant 1H and
13C NMR spectra and elemental microanalyses for new
compounds are available in the Supporting Information
Synlett 2010, No. 19, 2861–2866 © Thieme Stuttgart · New York