Synthesis of phenylthioacetomorpholide: Effect of substrate on the Willgerodt-Kindler reaction

Article abstract of DOI:10.1080/10426500211706

The effect of substrates on the Willgerodt-Kindler reaction was studied. The existence of acidic protons on these substrates accerelates the formation of thiomorpholide was found.

Full text of DOI:10.1080/10426500211706

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Phosphorus, Sulfur, and Silicon and the Related
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Synthesis of Phenylthioacetomorpholide: Effect of
Substrate on the Willgerodt-Kindler Reaction
a
a
a
Hossein Reza Darabi , Kioumars Aghapoor , Kourosh Tabar-Heydar & Masoud Nooshabadi
a
a
Chemistry and Chemical Engineering Research Center of Iran, Tehran, Iran
Version of record first published: 27 Oct 2010.
To cite this article: Hossein Reza Darabi , Kioumars Aghapoor , Kourosh Tabar-Heydar & Masoud Nooshabadi (2002): Synthesis
of Phenylthioacetomorpholide: Effect of Substrate on the Willgerodt-Kindler Reaction, Phosphorus, Sulfur, and Silicon and the
Related Elements, 177:5, 1189-1192
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Phosphorus, Sulfur and Silicon, 2002, Vol. 177:1189–1192
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DOI: 10.1080/10426500290092479
SYNTHESIS OF PHENYLTHIOACETOMORPHOLIDE:
EFFECT OF SUBSTRATE ON THE
WILLGERODT-KINDLER REACTION
Hossein Reza Darabi, Kioumars Aghapoor,
Kourosh Tabar-Heydar, and Masoud Nooshabadi
Chemistry and Chemical Engineering Research Center of Iran,
Tehran, Iran
(Received January 24, 2001; accepted April 22, 2001)
The effect of substrates on the Willgerodt-Kindler reaction was stud-
ied. The existence of acidic protons on these substrates accerelates the
formation of thiomorpholide was found.
Keywords: Phenylthioacetomorpholide; the Willgerodt-Kindler
reaction
Considering high usage potential of thioamides as intermediates in
1
–4
medicine and organic synthesis, we believe that the limited applica-
tion of the Willgerodt-Kindler will be sharply increased if the synthetic
5
problems are overcome.
Recently, we showed the efficiency of microwave heating for the
Willgerodt-Kindler reaction of aryl alkyl ketones, compare to conven-
6
tional heating. In that article, we optimized the reaction by exami-
nation of parameters, such as the ratio of sulfur and morpholine to
substrates and the time of irradiation.
Here, in an effort to throw light on the substrate effect, we se-
lected substrates, which contain different functional groups. All of the
Address correspondence to H. R. Darabi, Chemistry and Chemical Engineering Re-
search Center of Iran, Faculty of Science, PO Box 14335-186, Tehran, Iran.
E-mail: darabi@ccerci.ac.ir
1
189

1
190
H. R. Darabi et al.
substrates have the same number of carbon atoms in their skeleton
and are expected, under the same reaction conditions, to give product
1. Among these substrates, to the best of our knowledge, the Willgerodt-
Kindler reaction of only three compounds 1c–1e were studied by us and
others.5
–10
We carried out the reactions under both microwave and classical
heating. The reaction conditions and yields are given in Table I. The
conclusions, which we have been able to draw from these data are:
TABLE I The Willgerodt-Kindler Reaction of the
Substrates 1a–1g with Morpholine and Sulfura
Yield of 2 (%)
Entry
a
Substrates 1
MWb
14
Refluxc
11
b
c
90
82
93
88
77
52
63
62
d
e
f
8
5
g
40
27
a
The reactions were monitored by TLC and the product identi-
8
fied by GC-Mass and NMR. (GC-Mass Analysis: A fisons instru-
ments gas chromatograph 8000 equipped to mass detector (Trio
1
000) with 70 ev was used. A 60 m � 0.25 mm column packed
with WCOT fused silica CP-sil 5 CB was employed. Carrier gas
was helium and inlet pressure was 14 psi.)
b
The reaction mixture was exposed to microwave irradiation
at 900 W for 4 min.
cThe reaction mixture was refluxed for 2 h.

Phenylthioacetomorpholide
1191
1
2
3
. The compounds 1b–1e give excellent yield of phenylthioacetomor-
pholide 2.
. Although the thiolation of 1a is very difficult, the thiolated ethylben-
zene, 1b, is very active and gives 2 in excellent yield.
. Phenylacetylene 1d is much more acidic than styrene 1c, which in
turn is more acidic than ethyl benzene 1a. This effect on the yield of
product is clear.
4
. Hydrogens at �-position of carbonyl group of 1e are acidic, which can
be thiolated easier than that of ethyl benzene (1a). This fact shows
the carbonyl group serves to activate the �-carbon.
5
. The reaction of 1f easily gave compound 3 as a main product in
excellent yield. The reaction proceeds even at room temperature.
It shows that existence of a leaving group at the �-position of the
carbonyl group accelerates the nucleophilic substitution.
. In the case of epoxide 1g, the low yield of the product 2 is due to
formation of by-product 4. The substrate undergoes the nucleophilic
substitution and gives 4 in 42% yield.
6
In the case of 1e, a GLC analysis of the reaction mixtures, conducted
at room temperature, at various time intervals shows that the amount
of 3 is higher than that of 2 up to first 2 h. It gradually decreased during
2
4 h. These facts show that carbonyl group is left, at first, intact and
therein reduced to a methylene group by H2S in the final step.
Finally, we concluded the existence of a leaving group or acidic pro-
tons may accelerate the reaction.
Further work on the Willgerodt-Kindler reaction is in progress to
extend the scope of the reaction by the use of different substrates.
GENERAL PROCEDURE
(
Caution: Experiments should be carried out in an efficient hood to avoid
exposure to noxious vapors of hydrogen sulfide.)
In a typical experiments, a mixture of 1b (2 mmol), morpholine
(
6 mmol), and sulfur (4 mmol) in an open pyrex glass flask was ex-
�
posed to microwave irradiation at 900 W for 4 min. After cooling, the
�
The microwave oven used for this study was a domestic National Model NN-6755
with 7 power settings (90-900 W).

1
192
H. R. Darabi et al.
reaction product 2 was purified by silica gel chromatography by eluting
with petroleum ether-ethyl acetate (8:2). The fractions were monitored
by TLC.
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