protecting groups for thiols or carboxylic acids.6 In general,
hydrolysis of thioesters to thiols and carboxylic acids is
carried out under basic conditions. However, problems with
this method are that oxidation of thiols to disulfides is prone
to occur and that more than equimolar amounts of the
reagents are needed. Although acid-promoted hydrolysis of
thioesters provides an alternative important method, it is not
common because of high activation energies for the acid-
promoted hydrolysis,7,8 requiring the use of excess amounts
of strong acids such as 6 N HCl.9 Furthermore, acid-catalyzed
hydrolysis of water-insoluble thioesters in water without
using organic cosolvents is extremely difficult to realize.
Therefore, we undertook development of an acid catalyst for
hydrolysis of water-insoluble thioesters.
3600 mol %) (entries 5 and 6). In addition, a surfactant-
type Brønsted acid such as p-dodecylbenzenesulfonic acid
(DBSA), which is effective for several organic reactions in
water,10 was also inactive (entry 7). On the other hand, it
was exciting to find that a hydrophobic polystyrene-supported
sulfonic acid (PS-SO3H, 0.462 mmol/g) prepared by sul-
fonation of 1% DVB cross-linked polystyrene (200-400
mesh) was effective for the hydrolysis (entry 8). However,
a commercially available DOWEX 50W-X2 (a sulfonated,
cross-linked polystyrene, H form, 4.41 mmol/g) was inef-
fective (entry 9). Whereas PS-SO3H scarcely swelled in
water, DOWEX 50W-X2 swelled well in water because of
the difference in sulfonic acid content.11 This result indicates
that the highly hydrophobic nature of polymer-supported
catalysts plays a very important role for catalytic activity.5e
Another type of polymer-supported sulfonic acid, Nafion-
H,12 was found to be inactive (entry 10).
We examined the catalytic activity of various Brønsted
acids in a model reaction of hydrolysis of dodecyl thiolaurate
(Table 1). As expected, the hydrolysis did not proceed at all
Interestingly, mixed solvents such as H2O/1,4-dioxane
(1/1) and H2O/toluene (1/1), giving 21% and 33% yields
under reflux conditions for 24 h, respectively, were not good
for the PS-SO3H-catalyzed hydrolysis of the thioester,
indicating that pure water is the most effective solvent system
in this hydrolysis. This result is one of the characteristic
features of this system.
Table 1. Hydrolysis of Thioester with Various Brønsted Acid
Catalysts
Next, we investigated substrate generality in the PS-SO3H-
catalyzed hydrolysis of thioesters in water (Table 2). The
Table 2. PS-SO3H-Catalyzed Hydrolysis of Various Substrates
a NMR yield. b In 3 N H2SO4 (900 mol %). c In 6 N HCl (3600 mol %).
d 10 mol % of SO3H group.
without a catalyst (entry 1) or with several Brønsted acids
(entries 2-6) under water-reflux conditions for 24 h, even
when carried out in 3 N H2SO4 (the amount of the catalyst
is 900 mol %) or 6 N HCl (the amount of the catalyst is
(5) Polymer-supported sulfonic acid catalyzed hydrolysis of oxoesters
has been reported; see: (a) Thomas, G. G.; Davies, C. W. Nature 1947,
159, 372. (b) Haskell, V. C.; Hammett, L. P. J. Am. Chem. Soc. 1949, 71,
1284. (c) Sakurada, I.; Sakaguchi, Y.; Ono, T.; Ueda, T. Makromol. Chem.
1966, 91, 243. (d) Yoshikawa, S.; Kim, O.-K. Bull. Chem. Soc. Jpn. 1966,
39, 1515. Quite recently, we reported use of polymer-supported sulfonic
acids for oxoester formation in water: (e) Manabe, K.; Kobayashi, S. AdV.
Synth. Catal. 2002, 344, 270.
a Isolated yield. b 72 h. c Containing disulfide (2%). d 36 h. e 168 h.
f Under air. g PS-SO3H (2 mol %), 48 h. h PS-SO3H (20 mol %). i Containing
disulfide (5%).
(6) Greene, T. W.; Wuts, P. G. M. ProtectiVe Groups in Organic
Synthesis, 3rd ed.; John Wiley & Sons: New York, 1999.
(7) Bruice, T. C. In Organic Sulphur Compounds; Kharasch, N., Ed;
Pergamon Press: London, 1961; Vol. 1, p 421 and references therein.
(8) Recently, we have developed the first example of Brønsted acid
catalyzed intermolecular direct thioesterification of carboxylic acids with
thiols: Iimura, S.; Manabe, K.; Kobayashi, S. Chem. Commun. 2002, 94.
(9) For examples of acid-promoted hydrolysis of thioesters, see: (a)
Garbiras, B. J.; Marburg, S. Synthesis 1999, 270. (b) Bergeron, R. J.;
Wiegand, J.; Weimar, W. R.; Vinson, J. R. T.; Bussenius, J.; Yao, G.-W.;
McManis, J. S. J. Med. Chem. 1999, 42, 95. (c) Effenberger, F.; Isak, H.
Chem. Ber. 1989, 122, 553.
reactions proceeded smoothly to give the corresponding thiols
or carboxylic acids in high to excellent yields for various
types of thioesters. Although the reaction time was longer,
only 2 mol % of PS-SO3H was enough to catalyze the
hydrolysis (entry 7). It is also noteworthy that formation of
disulfides, which often occurs under basic conditions, was
not at all observed even when the hydrolysis of the substrate
102
Org. Lett., Vol. 5, No. 2, 2003