Direct thioesterification from carboxylic acids and thiols catalyzed by a Bronsted acid

Article abstract of DOI:10.1039/b109834a

In the presence of a catalytic amount of trifluoromethanesulfonic acid, free carboxylic acids reacted with free thiols directly to afford the corresponding thioesters in high yields.

Full text of DOI:10.1039/b109834a

Direct thioesterification from carboxylic acids and thiols catalyzed by a
Brønsted acid
Shinya Iimura, Kei Manabe and Shu¯ Kobayashi*
Graduate School of Pharmaceutical Sciences, The University of Tokyo, CREST, Japan Science and
Technology Corporation (JST), Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
E-mail: skobayas@mol.f.u-tokyo.ac.jp
Received (in Cambridge, UK) 29th October 2001, Accepted 28th November 2001
First published as an Advance Article on the web 21st December 2001
In the presence of a catalytic amount of trifluoromethane-
sulfonic acid, free carboxylic acids reacted with free thiols
directly to afford the corresponding thioesters in high
yields.
to find that Brønsted acids were effective for the present
reaction (entries 2–6). Among Brønsted acids tested, tri-
fluoromethanesulfonic acid (TfOH) was the most effective in
this thioesterification (entry 4). It was interesting to find that
Nafion-H was also effective, but that longer reaction time was
needed (entry 6).8 It is noteworthy that the TfOH-catalyzed
reaction proceeded in 10 mmol-scale without any difficulties,
and that only 1 mol% of TfOH was enough to catalyze the
reaction to afford the desired thioester in 94% yield (entry 4).
On the other hand, when this TfOH-catalyzed reaction was
carried out without a solvent at the same temperature, the
thioester was obtained in only 43% yield. In addition, Lewis
acids such as TiCl4, ZrCl4, HfCl4, NbCl5, and SnCl4 were less
active or inert (entries 7–11).
Next, we investigated substrate generality in TfOH-catalyzed
direct thioesterification of carboxylic acids with thiols (1+1) in
toluene under azeotropic reflux conditions (Table 2).† The
reactions proceeded not only for primary and sterically hindered
secondary aliphatic but also for aromatic thiols to give the
corresponding thioesters in high to excellent yields (entries
1–4). The reaction also proceeded using various carboxylic
acids (entries 5–11). Although sterically crowded and aromatic
carboxylic acids were less reactive than linear aliphatic
substrates, their reactions proceeded smoothly although their
reaction times were longer (entries 7–9). a,b-Unsaturated
carboxylic acids reacted smoothly under the conditions (entries
10 and 11). It is noted that equimolar amounts of free carboxylic
acids and free thiols reacted directly to afford the corresponding
thioesters in high to excellent yields.
Thioesters are synthetically useful as well as biologically
important compounds because of their high reactivity toward
various nucleophiles. For the preparation of thioesters, the most
popular method is the reaction of acyl chlorides with thiols or
the reaction of carboxylic acids with thiols in the presence of a
stoichiometric amount of a condensing agent such as 1,3-dicy-
clohexylcarbodiimide (DCC).1 From the atom-economical2 and
environmental points of view, direct thioester formation from
free carboxylic acids and free thiols is desirable.3 However, to
the best of our knowledge, although there have been a few
reports on synthesis of thiolactones by acid-accelerated intra-
molecular thioesterification,4 there have been no reports on
catalytic intermolecular direct thioesterification of carboxylic
acids with thiols.5,6 This is probably because equilibrium in the
reactions of carboxylic acids with thiols is not favourable for
thioester formation, and a large activation barrier exists between
the materials (carboxylic acids and thiols) and the products
(thioesters).7 In this paper, we report the first example of
Brønsted acid-catalyzed intermolecular direct thioesterification
of carboxylic acids with thiols, that proceeds smoothly in
toluene under azeotoropic reflux conditions.
First, we examined the catalytic activity of several Brønsted
acids and Lewis acids (10 mol%) in a model reaction of lauric
acid (1.0 equiv) with dodecanethiol (1.0 equiv) in toluene at
reflux for 6 h with removal of water (Table 1). As expected, the
reaction did not proceed at all without a catalyst (entry 1). This
result indicates that direct thioesterification is difficult under
simple azeotropic reflux conditions to shift the equilibrium from
the materials to the products. On the other hand, it was exciting
In summary, direct thioesterification of carboxylic acids with
thiols is efficiently catalyzed by TfOH in toluene under
azeotropic reflux conditions. This method provides not only an
Table 2 TfOH-catalyzed direct thioesterification in toluene
Table 1 Direct thioesterification using various catalystsa
Entry R1COOH
R2SH
Time/h
Yield (%)
1
2
3
CH3(CH2)10COOH
CH3(CH2)10COOH
CH3(CH2)10COOH
CH3(CH2)11SH
PhCH2SH
6
6
12
97 (94)a
95
93
Entry
Catalyst
Yield (%)
4
5
6
7
CH3(CH2)10COOH
PhCH2CH2COOH
PhCH2CH2COOH
PhSH
CH3(CH2)11SH
PhCH2SH
6
6
6
76
93
94
96
1
2
3
None
TsOH
H2SO4
TfOH
0
16
67
CH3(CH2)11SH
12
4
97 (95b, 94c)
5
6
7
8
9
10
11
C8F17SO3H
Nafion-H
TiCl4
ZrCl4
HfCl4
94
69 (91)d
8
CH3(CH2)11SH
36
92
0
10
0
10
0
9
10
11
PhCOOH
CH3(CH2)11SH
(E)-PhCHNCHCOOH CH3(CH2)11SH
(E)-PhCHNCHCOOH
48
8
10
87
76
80
NbCl5
SnCl4
a 0.5 mmol-scale. b 10 mmol-scale. c One mol% of TfOH was used. The
reaction time was 12 h. d The reaction time was 24 h.
a One mol% of TfOH was used. The reaction time was 12 h.
94
CHEM. COMMUN., 2002, 94–95
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3 Recently, direct esterification of carboxylic acids with alcohols has been
reported. See: K. Ishihara, S. Ohara and H. Yamamoto, Science, 2000,
290, 1140; K. Wakasugi, T. Misaki, K. Yamada and Y. Tanabe,
Tetrahedron Lett., 2000, 41, 5249; J. Otera, Angew. Chem., Int. Ed.,
2001, 40, 2044; K. Manabe, X.-M. Sun and S. Kobayashi, J. Am. Chem.
Soc., 2001, 123, 10101.
atom-economical process but also a simple and practical
protocol for thioester synthesis.
This work was partially supported by a Grant-in-Aid for
Scientific Research from Japan Society of the Promotion of
Science.
4 P. Catsoulacos and Ch. Camoutsis, J. Heterocycl. Chem., 1976, 13, 1315;
S. Karel and P. Miroslav, CS Patent, 194006; Chem. Abstr., 1982, 97,
109888z.
Notes and references
† General procedure: A flame-dried, 20 mL, single-necked, round-
bottomed flask fitted with a stir bar and a 10 mL pressure-equalized addition
funnel (containing a cotton plug and 2 g of 4 Å molecular sieves)
surmounted by a reflux condenser was charged with a carboxylic acid (0.5
mmol), a thiol (0.5 mmol), and TfOH (0.05 mmol) in toluene (5 mL). The
mixture was brought to reflux with removal of water. After 6–48 h, the
resulting mixture was cooled to rt, and an aqueous solution of saturated
NaHCO3 was added. The resultant mixture was extracted with ethyl acetate,
and the organic layer was dried over anhydrous Na2SO4. The solvents were
evaporated, and the residue was purified by preparative TLC on silica gel to
give the pure product.
5 J. Voss, Comprehensive Organic Synthesis, ed. B. M. Trost and I.
Fleming, Pergamon, Oxford, 1991, vol. 6, p. 435. In fact, the difficulty of
acid-catalyzed direct thioesterification was stated as follows: ‘Unlike
carboxylic esters, open-chained S-alkyl thiocarboxylates cannot be
obtained by direct proton-catalyzed esterification’.
6 Lipase-catalyzed direct thioesterification was reported. However, this
method still lacks substrate generality, and requires rather delicate
reaction conditions. See: M. Caussette, A. Marty and D. Combes, J.
Chem. Tech. Biotechnol., 1997, 68, 257; N. Weber, E. Klein, K. Vosmann
and K. D. Mukherjee, Biotechnol. Lett., 1998, 20, 687; N. Weber, E.
Klein and K. D. Mukherjee, Appl. Microbiol. Biotechnol., 1999, 51, 401;
N. Weber, E. Klein and K. D. Mukherjee, J. Am. Oil Chem. Soc., 1999,
76, 1297.
1 O. Jeger, J. Norymberski, S. Szpilfogel and V. Prelog, Helv. Chim. Acta,
1946, 29, 684; J. R. Grunwell and D. L. Foerst, Synth. Commun., 1976,
6, 453; T. Imamoto, M. Kodera and M. Yokoyama, Synthesis, 1982,
134.
7 T. C. Bruice, Organic Sulphur Compounds, ed. N. Kharasch, Pergamon,
London, 1961, vol. 1, p. 421.
8 G. A. Olah, P. S. Iyer and G. K. S. Prakash, Synthesis, 1986, 513 and
references therein.
2 B. M. Trost, Science, 1991, 254, 1471.
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