Mild Meth od for th e Con ver sion of Am id es
to Th ioa m id es
Andre´ B. Charette* and Michel Grenon
De´partement de Chimie, Universite´ de Montre´al,
P.O. Box 6128, Station Downtown,
Montre´al, Que´bec, Canada H3C 3J 7
F IGURE 1. Pyridinium salts generated from the treatment
of amides with Pyr and Tf2O.
andre.charette@umontreal.ca
Received April 8, 2003
prior activation of the amide include combinations of
oxalyl chloride or phosphorus oxychloride with benzyl-
triethylammonium tetrathiomolybdate,11 phosphorus
oxychloride with hexamethyldisilathiane,12 and trialkyl-
oxonium tetrafluoroborates with sodium hydrosulfide.13
Abstr a ct: Aqueous ammonium sulfide was found to be an
ideal substitute for hydrogen sulfide for the thiolysis of
activated amides. High yields of the corresponding thioam-
ides were obtained for a broad range of substrates, using
two different procedures that are both operationally simple
and inexpensive, as well as amenable to large-scale prepara-
tion. Preliminary results indicate that aqueous ammonium
sulfide may also replace hydrogen sulfide in the synthesis
of thionoesters from amides.
Over the past several years, our research group has
enjoyed continued success in the area of amide activation
by using trifluoromethanesulfonic (triflic) anhydride in
the presence of pyridine. A wide variety of functional
group interconversions starting from amides were ren-
dered efficient by addition of the appropriate heteronu-
cleophile.14 The effectiveness of these reactions stems
from the highly electrophilic nature of pyridinium salts
A-C, formed from secondary and tertiary amides during
the activation process (Figure 1).15 In our initial proce-
dure for the conversion of amides to thioamides, we relied
on the use of hydrogen sulfide (H2S) to effect the thiolysis
of the pyridinium salts.16 However, the inability to deliver
a controlled amount of thionating reagent, combined with
the requirement of using specialized equipment, prompted
us to find a safer, cheaper, and more convenient alterna-
tive to effect this transformation.
Heterocycles containing both nitrogen and sulfur within
their backbones are found in all areas of chemistry, and
over the past several years, there have been many
synthetic strategies aimed at their preparation from
simple and readily available precursors. One such strat-
egy that has been used on numerous occasions involves
the use of thioamides as starting materials, where both
atoms can be introduced within the heterocyclic system
in a single step.1 In view of their synthetic importance,
many routes have been developed to gain access to
thioamides from various sources.2
Not surprisingly, one of the most exploited routes to
thioamides involves the thionation of their amide ana-
logues.3 These can be classified as either proceeding
through direct treatment of the amide with the thionat-
ing reagent or by prior activation of the amide with an
electrophilic reagent. Methods employing the former
strategy include treatment of the amide with P4S10, either
with or without additives,4 use of diethylthiocarbamoyl
chloride,5 ethylaluminum sulfide,6 or boron sulfide,7 and
use of Lawesson’s reagent.8 A polymer-supported thio-
nating reagent prepared from a commercially available
diamine resin and ethyl dichlorothiophosphate has also
recently been disclosed,9 along with procedures involving
microwave irradiation.10 Methods that proceed through
Initially, we focused on the use of anhydrous sodium
hydrosulfide (NaSH) and found that the addition of an
excess of this reagent to the activated amides produced
the desired thioamides in good yields.17 Unfortunately,
these reactions proceeded most efficiently with NaSH
prepared by reacting hydrogen sulfide with sodium
ethoxide in ethanol,18 since the commercial material was
found to be inadequate for our purposes. In addition, the
(5) Ogata, M.; Matsumoto, H. Heterocycles 1978, 11, 139.
(6) Hirabayashi, T.; Inoue, K.; Yokota, K. J . Organomet. Chem. 1975,
92, 139.
(7) (a) Steliou, K.; Mrani, M. J . Am. Chem. Soc. 1982, 104, 3104.
(b) Wojtkowski, P. W.; Dolfini, J . E.; Kocy, O.; Cimarusti, C. M. J . Am.
Chem. Soc. 1975, 97, 5628.
(8) Cava, M. P.; Levinson, M. I. Tetrahedron 1985, 41, 5061.
(9) Ley, S. V.; Leach, A. G.; Storer, R. I. J . Chem. Soc., Perkin Trans.
1 2001, 358.
(10) Varma, R. S.; Kumar, D. Org. Lett. 1999, 1, 697.
(11) Ilankumaran, P.; Ramesha, A. R.; Chandrasekaran, S. Tetra-
hedron Lett. 1995, 36, 8311.
* To whom correspondence should be addressed.
(1) For
a recent review on the synthesis of heterocycles from
thioamides, see: J agodzinski, T. S. Chem. Rev. 2003, 103, 197.
(2) For reviews on the preparation of thioamides, see: (a) Schau-
mann, E. In Comprehensive Organic Chemistry; Trost, B. M., Fleming,
I., Eds.; Pergamon Press: Oxford, 1991; Vol. 6; Chapter 2.4, pp 419-
434. (b) Bauer, W.; Ku¨hlein, K. In Methoden Org. Chem. 1985, E5,
1218. (c) Walter, W.; Bode, K.-D. Angew. Chem., Int. Ed. Engl. 1966,
5, 447. (d) Hurd, R. N.; De La Mater, G. Chem. Rev. 1961, 61, 45. (e)
see also ref 3 and 8.
(12) Smith, D. C.; Lee, S. W.; Fuchs, P. L. J . Org. Chem. 1994, 59,
348.
(13) Bodine, J . J .; Kaloustian, M. Synth. Commun. 1982, 12, 787.
(14) (a) Amidines, see: Charette, A. B.; Grenon, M. Tetrahedron Lett.
2000, 41, 1677. (b) Thiazolines, see: Charette, A. B.; Chua, P. J . Org.
Chem. 1998, 63, 908. (c) Esters, see: Charette, A. B.; Chua, P. Synlett
1998, 163. (d) Cyclic Ortho esters, see: Charette, A. B.; Chua, P.
Tetrahedron Lett. 1997, 38, 8499.
(15) Charette, A. B.; Grenon, M. Can. J . Chem. 2001, 79, 1694.
(16) Charette, A. B.; Chua, P. Tetrahedron Lett. 1998, 39, 245.
(17) For instance, thioamides 2c (80%), 2d (63%), 2f (94%), and 5b
(90%) were obtained after adding NaSH (3.0 equiv) to the activated
amides at 0 °C.
(3) For a review on thionation methods, see: Brillon, D. Sulfur Rep.
1992, 12, 297.
(4) (a) Hartke, K.; Gerber, H.-D. J . Prakt. Chem. 1996, 338, 763.
(b) Use of ultrasound, see: Raucher, S.; Klein, P. J . Org. Chem. 1981,
46, 3558. (c) Use of NaHCO3, see: Scheeren, J . W.; Ooms, P. H. J .;
Nivard, R. J . F. Synthesis 1973, 149. (d) Use of Na2CO3, see: Brillon,
D. Synth. Commun. 1990, 20, 3085. (e) Use of RLi, see: Goel, O. P.;
Krolls, U. Synthesis 1987, 162. (f) Use of (TMS)2O, see: Curphey, T.
J . J . Org. Chem. 2002, 67, 6461.
(18) Kleinberg, J . Inorg. Synth. 1963, 7, 128.
10.1021/jo0344485 CCC: $25.00 © 2003 American Chemical Society
Published on Web 06/14/2003
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J . Org. Chem. 2003, 68, 5792-5794