A superior procedure for the conversion of 3-oxoesters to 3H-1,2-dithiole-3-thiones

Article abstract of DOI:10.1016/S0040-4039(00)01813-X

The combination of P₄S₁₀, sulfur, and hexamethyldisiloxane converts 3-oxoesters to 3H-1,2-dithiole-3-thiones in yields generally superior to those obtained with Lawesson's reagent and without the need for chromatography to remove large amounts of phosphorous-containing byproducts. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01813-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 9963–9966
A superior procedure for the conversion of 3-oxoesters to
3H-1,2-dithiole-3-thiones
Thomas J. Curphey
Department of Pathology, Dartmouth Medical School, Hanover, NH 03755, USA
Received 18 September 2000; accepted 3 October 2000
Abstract
The combination of P4S10, sulfur, and hexamethyldisiloxane converts 3-oxoesters to 3H-1,2-dithiole-3-
thiones in yields generally superior to those obtained with Lawesson’s reagent and without the need for
chromatography to remove large amounts of phosphorous-containing byproducts. © 2000 Elsevier
Science Ltd. All rights reserved.
Keywords: dithioles; sulfur compounds; sulfur heterocycles; keto acids and derivatives.
The dithiolethiones (3H-1,2-dithiole-3-thiones, 1) are a class of chemoprotective agents which
display marked activity against a variety of animal models of cancer.1 One representative of this
class of heterocyclic sulfur compounds (Oltipraz 1, R1=pyrazinyl, R2=methyl) is currently
undergoing human trials in an area of China having a high incidence of liver cancer.2
Unfortunately, the existing methods for synthesis of this ring system leave much to be desired,3
especially for the preparation of the large quantities of material needed for biological testing. We
have attempted to develop new procedures for synthesis of the dithiolethione ring system with
some success,4–6 but there still remains a need for methods that can be adapted to large-scale
synthesis. This communication reports the discovery of such a method.
Of the usual procedures for synthesis of the dithiolethiones one of the most general and
widely used is the reaction of a 3-oxoester with P4S10 and sulfur (Eq. 1), generally conducted in
boiling toluene or xylene.7,8
(1)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01813-X

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However, even in highly favorable cases the yields are seldom above 50% and are typically in
the range of 0–20%.7 A potential solution to this problem was published by Lawesson some time
ago, who found that by replacing P4S10 in Eq. (1) with 2,4-bis(4-methoxyphenyl)-1,3,2,4-
dithiadiphosphetane-2,4-disulfide (Lawesson’s reagent), yields of dithiolethiones could be made
nearly quantitative.9 Unfortunately, the high equivalent weight of Lawesson’s reagent and the
need to use 2 full moles of the reagent per mole of 3-oxoester means that the dithiolethione
comprises only a small percentage by weight of the crude reaction mixture. Because the
reagent-derived byproducts cannot be removed by any extractive procedure, the total reaction
mixture must be subjected to chromatography to isolate the dithiolethione, and the method
becomes impractical for large scale preparations.
A simple solution to these difficulties has now been discovered. Addition of hexamethyldi-
siloxane (HMDO) to the P4S10–sulfur mixture of Eq. (1) both greatly increases the yield of
dithiolethione 1 and greatly simplifies workup of the reaction mixture.10 Using the production of
5-methyl-3H-1,2-dithiole-3-thione (1, R1=Me, R2=H) from ethyl acetoacetate as a model, it
was found that 0.6 moles of P4S10 per mole of 3-oxoester was optimum. Addition of elemental
sulfur up to 1 g atom per mole of 3-oxoester had a beneficial effect on yield, as had been found
for Lawesson’s reagent9 and for P4S10 alone,7 but more than this had no effect. By direct GC
analysis of the reaction mixture it was established that 2–2.5 moles of HMDO per mole of
3-oxoester were consumed. Xylene was found to be the most commonly useful solvent, although
Table 1
Preparation of 3H-1,2-dithiole-3-thiones from 3-oxoesters, P4S10, sulfur and HMDOa
Timeb (h)
Yields (%)
Isolatedd
Entry
R1
R2
HPLCc
LRe
84
1
2
3
Me
Et
Ph
t-Bu
1-Adamantyl
Ferrocenyl
Me
H
H
H
H
H
H
Me
i-Pr
1
2
1
8
5
0.5
2
2
1
98
98
83
93
78
45
95
86
98
83
19
80
74
70
83
70
36
87
72
86
71
–
80
79
4
5f
6g
7
8
9
10
11
Me
80
73
ꢀ(CH2)4ꢀ
ꢀ(CH2)3ꢀ
Pyrazinyl
2
1
Me
2.5
a See text for conditions.
b Reaction time in refluxing xylene.
c Yield determined by HPLC using the external standards method.
d Yield of distilled or recrystallized material. Physical properties (boiling point or melting point) were in good
agreement with literature values.
e Maximum HPLC yield obtained with Lawesson’s reagent.
1
f New substance: mp 141–142°C; H NMR (CDCl3) l 1.76 (m, 6H), 2.00 (s, 6H), 2.13 (s, 3H), 7.13 (s, 1H); 13C
NMR (CDCl3) l 28.73, 36.28, 40.91, 43.99, 136.03, 189.47, 215.86. Anal. calcd for C13H16S3: C, 58.16; H, 6.01; S,
35.83. Found: C, 58.27; H, 6.10; S, 35.70.
1
g New substance: mp 157–159°C; H NMR (CDCl3) l 4.24 (s, 5H), 4.61 (t, J=2 Hz, 2H), 4.73 (t, J=2 Hz, 2H),
7.21 (s, 1H); 13C NMR (CDCl3) l 68.96, 71.41, 72.47, 75.11, 133.79, 176.96, 214.05. Anal. calcd for C13H10FeS3: C,
49.06; H, 3.17; S, 30.22. Found: C, 48.99; H, 3.28; S, 30.38.

9965
the reaction has been successfully run in toluene, ethyl benzene, chlorobenzene, HMDO, dioxane,
and 1,1,2,2-tetrachloroethane. The optimum procedure involved refluxing a xylene solution of the
3-oxoester with 0.6 moles of P4S10, 1 g atom of sulfur, and 3 moles of HMDO per mole of 3-oxoester
until HPLC analysis showed the reaction to be over. Results obtained with representative
3-oxoesters are shown in Table 1.
In all but two cases (entries 6 and 11) the chromatographic yields were quite high. Some evidence
of a steric effect was apparent, with dithiolethiones having bulky alkyl groups (entries 4 and 5)
requiring significantly longer reaction times. Except for entries 5 and 6, isolation of the pure
dithiolethiones did not require chromatography. The phosphorus-containing byproducts formed
during the reaction were easily removed during workup, most expeditiously by exposure to aqueous
K2CO3, which hydrolyzed them to water soluble derivatives. After removing small amounts of
dark colored polar materials by filtration through a short plug of silica gel plus activated carbon,
the final product was then readily purified by distillation, sublimation, and/or recrystallization.
A direct comparison of this new procedure for dithiolethione synthesis with that using
Lawesson’s reagent was made for six 3-oxoester substrates (entries 1, 3, 4, 8, 9, and 11). In all
the cases examined, chromatographic yields using Lawesson’s reagent (last column of Table 1)
were inferior to those obtained with the P4S10–HMDO combination.11 The one case for which
the P4S10–HMDO method proved ineffective was in the synthesis of Oltipraz (entry 11). Although
the P4S10–HMDO combination did give a better yield than Lawesson’s reagent, the yield obtained
was not significantly different from that obtained with P4S10 alone.12
With regard to the way in which HMDO acts to increase the yield of dithiolethione, GC
examination established that P4S10 and HMDO, with or without sulfur, do not react in the absence
of the 3-oxoester, ruling out prior modification of P4S10 by HMDO as an explanation. Instead,
it is proposed (Eq. 2) that pyrophosphate intermediates formed during the course of the thionation
reaction are responsible for yield-lowering side reactions and that HMDO converts these
pyrophosphates to innocuous trimethylsilylated derivatives.13
(2)
Alternatively, and in addition, the trimethylsilyl thiophosphates which result from this
scavenging reaction may themselves be active thionating agents,14 and may thus play a role in
modifying the reactivity of the P4S10.
In conclusion, the combination of P4S10, sulfur, and HMDO is highly effective in converting
3-oxoesters to dithiolethiones 1. An investigation of the beneficial effects of HMDO on other
thionation reactions of P4S10 is currently underway, the results of which will be reported in due
course.
Acknowledgements
Financial support for this work was provided by the National Science Foundation (CHE-
9904454) and by the National Cancer Institute (CA39416).

9966
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