Interesting behavior of acetone under the Willgerodt-Kindler reaction conditions

Article abstract of DOI:10.1515/znb-2004-0521

A one-pot synthesis of thiomorpholides 1-3 is introduced. The Willgerodt-Kindler reaction of acetone with sulfur and morpholine gives selectively one of the products 1-4 depending upon the proper choice of the reaction condition. The formed products are strongly dependent on the experimental conditions. The pathways of the reaction toward the formation of each product are also proposed.

Full text of DOI:10.1515/znb-2004-0521

Interesting Behavior of Acetone under the Willgerodt-Kindler Reaction
Conditions
Hossein Reza Darabi, Kioumars Aghapoor, and Leila Nakhshab
Chemistry & Chemical Engineering Research Center of Iran, P.O. Box 14335-186, Tehran, Iran
Reprint requests to Dr. H. R. Darabi. E-mail: darabi@ccerci.ac.ir
Z. Naturforsch. 59b, 601 – 605 (2004); received September 29, 2003
A one-pot synthesis of thiomorpholides 1 – 3 is introduced. The Willgerodt-Kindler reaction of
acetone with sulfur and morpholine gives selectively one of the products 1 – 4 depending upon the
proper choice of the reaction condition. The formed products are strongly dependent on the experi-
mental conditions. The pathways of the reaction toward the formation of each product are also pro-
posed.
Key words: Acetone, Willgerodt-Kindler Reaction, Thiomorpholides
◦
Introduction
and sulfur in DMF at 80 C for 1 h in 53% yield (Ta-
ble 1, entry 1) [12].
Since thioamides have found widespread applica-
tions as versatile intermediates in medicine and or-
ganic synthesis [1 – 4], their syntheses have attracted
attention in the various field of chemistry [5 – 8]. Al-
though many different methods to prepare thioamides
have been reported in the literature [9], the Willgerodt-
Kindler reaction has so far found little attention. It
has a rather bad reputation for not being very use-
ful for preparative purpose due to the high reaction
temperatures and long reaction periods together with
poor yields [10]. In its original form, straight- or
branched-chain aryl alkyl ketones were found to react
with sulfur and secondary amines to give the terminal
thioamides as a result of oxidation and rearrangement.
The reaction is of wide scope and can be conducted
with a variety of substrates and under different reac-
tion conditions [10]. In some cases, unlike the normal
Willgerodt-Kindler reaction, the carbonyl group has
remained in the skeleton of the thioamide. Two fac-
tors have been suggested to keep the carbonyl group
intact; one is the steric effect in hindered ketones [11]
and the second is the donor group effect in adjacent to
the carbonyl group [12].
Herein, in an effort to improve the usefulness of the
Willgerodt-Kindler reaction of acetone and to throw
light on the reaction pathway, we have made a full
study of the effects of the heating mode, time of re-
action, and proportions of reagents to acetone, DMF,
and water effect on the reaction.
There is, to the best of our knowledge, no report on
the direct synthesis of 1 – 3 from the acetone. How-
ever, dithiomorpholide 3 has been prepared from the
treatment of 1,3-dichloroacetone with morpholine and
sulfur in DMF at room temperature in 31% yield [17].
Moreover, thiomorpholide 1 has been prepared from
α-substituted acetone in 52% yield [17].
Result and Discussion
Optimization of the reaction
In order to find the optimal reaction conditions, we
have considered several possible variations (e.g., heat-
ing mode, time of reaction, proportions of reagents to
acetone, and solvent effect), which may influence po-
tentially on the reaction. Since the detailed mechanism
of the reaction is not known, one cannot exclude inter-
actions between the experimental variables. Therefore,
any attempts at optimizing the reaction must make use
of multivariate optimization strategies because adjust-
ing one variable at a time usually fails to attain a true
optimum in this reaction. The optimal condition of
each product was achieved via several examinations
and combination of these variations. The crude reac-
In continuation of our investigation on this reac-
tion [13– 16], acetone has attracted our attention be-
cause it is of special interest due to the existence of
acidic α-carbon at both side of its carbonyl group.
Among four possible products 1 – 4, to the best of our
knowledge, synthesis of dithiomorpholide 4 was re-
ported during the reaction of acetone with morpholine
c
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602
H. R.Darabi et al. · Interesting Behavior of Acetone under the Willgerodt-Kindler Reaction Conditions
Scheme 1.
Table 1. Reaction conditions for the selective preparation of
products 1 – 4a.
Entry Reagents Solvent Reaction Time
Yield
(%)c
Ref.
ratiob
temperature (min)
1
–
–
2
–
82
3
–
–
1
51
73
4
1
2
3
4
5
1:5:4
1:5:4
1:2:2
1:5:4
1:5:4
DMF
DMF
–
H2O
H2O
80 ◦C
MWd
25 ◦C
80 ◦C
MW
60
5
53 12
–
–
–
–
Scheme 2.
1440 71 3.5
180 35
–
–
may offer the possibility of obtaining one product se-
lectively. When the solvent-free reaction was carried
out at room temperature for 24 h, thioamide 1 was
formed as a major product, as judged by GC-MS mea-
surement (Scheme 2, entry 3). The product 1 was sep-
arated chromatographically.
In addition to 1, small amounts of 2 and 3 were de-
tected on GC-MS analysis (1:2:3 = 70:3.5:1). Under
higher energy conditions, such as microwave heating
or reflux, 1 was converted to 3 completely.
5
7
a
The reactions were monitored by TLC and the products identified
b
by GC-MS and NMR;
reagents = acetone: sulfur: morpholine,
cyields are based on GC-MS analysis; d MW = microwave heating.
tion mixtures were directly analyzed by GC-MS and/or
subjected to column chromatography. The identifica-
tion of the isolated products was generally performed
1
by H NMR and MS spectral analyses. Table 1 lists
some selected reaction conditions.
In an effort to optimize the order of addition of sub-
strate and reagents in the reaction mixture, we con-
sidered the following five possible reaction sequences
(acetone: sulfur: morpholine = 1:5:4): In the first set, a
Synthesis of thioamide 2
Viehe and co-workers have reported that the reflux-
ing reaction of acetone with morpholine and sulfur in
DMF gave dithiomorpholide 4 as the sole product (Ta-
ble 1, entry 1) [12]. Surprisingly, when the reaction
was carried out under microwave heating, the product
2, instead of 4, was obtained in 82% yield as the major
product (Table 1, entry 2). When the excess of morpho-
line (10 equivalents) was employed a somewhat higher
yield of product was obtained; however, the purity of
the isolated thioamide 1 did not improve. The similar
reaction in absence of DMF gave thiomorpholide 2 in
40% yield together with dithiomorpholide 3 in 45%
yield [16]. These results show that DMF is an impor-
tant parameter in the formation of products 2 and 4.
◦
mixture of morpholine and acetone was stirred at 20 C
and then sulfur and DMF were added and stirred for
18 h at 20 ◦C. A mixture of 1 (50%) and 2 (11%) were
prepared. In the second set, a mixture of DMF, acetone
◦
and morpholine was stirred at 20 C and then◦sulfur
was added. The mixture was heated for 2 h at 80 C and
gave 2 (43%) and 4 (56%). In the third set, acetone was
added to a mixture of DMF, sulfur and morpholine and
heated for 2 h at 80 ◦C and gave 2 (57%). In the fourth
set, a mixture ◦of DMF, sulfur and acetone was stirred
for 2 h at 20 C, and then morpholine was added to
◦
it. This mixture was heated for 2 h at 80 C and gave 2
(57%). In the fifth set, acetone and, the reagents (sulfur,
morpholine) were added to DMF and then the mixture
◦
Synthesis of dithioamide 3
was stirred for 12 h at 20 C to give 2 in 80% yield.
We found some amounts of thioamide byproduct de-
rived from dimethylamine as impurities, in all experi-
mental sets except the fifth one, because of DMF de-
composition. In the fourth set, this impurity was high.
The optimum condition for product 3 appears to
be the solvent-free reaction of acetone. Under mi-
crowave heating for 5 min, 3 was obtained in 73% yield
(Scheme 2, entry 5). As we mention later, the first stage
of this reaction is the formation of enamine and water.
This water in the reaction mixture should have an ef-
Synthesis of thioamide 1
Our initial experiment was carried out based on the fect on the formation of 1 and 3, because it may retain
◦
last experimental set. Conducting the reaction at 20 C the carbonyl group unchanged. Entry 4 in Table 1 con-
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H. R.Darabi et al. · Interesting Behavior of Acetone under the Willgerodt-Kindler Reaction Conditions
603
Scheme 3.
Scheme 4.
firms the strong effect of water in the reaction: When reaction of ketones. When we examined the reaction
the reaction was carried out at 80 ◦C for 3 h in presence of acetone and morpholine at room temperature, the
of water, it gave the products 1 and 3.
enamine 5 was detected as determined by GC-MS
technique in 65% yield. The solvent-free reaction of
enamine 5 with sulfur under microwave heating for
3 min, gave a mixture of products 1 (39%), 2 (25%),
Reaction pathway
The mechanism of the Willgerodt-Kindler reaction 3 (7%) and 4 (1.5%). When we treated enamine 5 with
sulfur in presence of water, products 1 and 3 were ob-
has been the subject of much discussion and, al-
though many suggestions have been put forward, no tained in 39% and 10% yield, respectively. The reac-
single mechanism accounts for all of the observa- tion of enami◦ne 5 with sulfur and morpholine at DMF
tions [10, 18, 19]. We feel that further extensions of for 2 h at 80 C gave products 2 and 4, in 60 and 30%
yield, respectively. These results show that the pres-
ence of water in the reaction mixture will retain the
carbonyl group unchanged. Therefore, DMF can trap
water and deactivates its effect on the reaction.
To answer the question whether a carbonyl group
alone could be reduced to a methylene group,
dithiomorpholide 3 was subjected to the same reac-
tion condition. Treatment of 3 with sulfur and morpho-
the Willgerodt-Kindler reaction may be of assistance
in elucidating the mechanisms of this reaction.
As shown in Scheme 3, Carmack has proposed
a possible mechanism for the formation of simple
thioamides, such as 2 [20]. Although the formation 2
is completely in agreement with this proposition, it is
probably unreasonable to expect a single mechanism
for this reaction to form all products 1 – 4.
In line with numerous publications, we believe that line, under similar reaction conditions, failed to give 4
reversible enamine formation is the first step of the (Scheme 6).
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604
H. R.Darabi et al. · Interesting Behavior of Acetone under the Willgerodt-Kindler Reaction Conditions
Scheme 5.
used. A 60 m×0.25 mm column packed with WCOT fused
silica CP-sil 5CB was employed. The carrier gas was helium
Scheme 6.
and the inlet pressure was 14 psi.
Caution: Experiments should be carried out in an efficient
hood to avoid exposure to noxious vapors of hydrogen sul-
fide.
Preparation of enamine 5: 1.16 g (20 mmol) of acetone
was warmed with 3.48 g (40 mmol) of morpholine in 50 ml
of DMF at 30 ◦C for 8 h. When the mixture was analyzed by
We conclude that formation of 4 should pass
through the formation of intermediate 8. This result
supports our suggested reaction pathway. The proba-
ble pathway of this reaction is outlined in Schemes 4
and 5.
In contrast to 3, when 2 was subjected to the similar GC-MS, it was found to consist of acetone (10%) in addition
to the expected enamine 5 (65%).
reaction conditions, a mixture of products 2 and 4 was
formed. Therefore, we found that existence of hydro-
gen(s) on α-carbon at least on one side of the carbonyl
group is necessary not only to promote the reaction
but also to reduce the carbonyl group to a methylene
group. While reduction of imines 7 or 8 in the pres-
ence of hydrogen sulfide may give products 2 and 4,
their oxidation by water leads to formation of prod-
ucts 1 and 3. Therefore, attack on α-carbon is com-
mon to this reaction. Hydrogen sulfide can be produced
from the morpholine/sulfur mixtures [21]. As shown
in Scheme 5, the reduction of the iminium ion 7 or 8
to the methylene group can occur by the exothermic
desulfurization of C=S group with H2S in the presence
of amines [19]. The results show that at any time sub-
sequent to formation of enamine 5, the initial attack at
the α-carbon could occur.
Reaction of enamine 5 with sulfur and morpholine: 1.27 g
(10 mmol) of enamine 5 was heated with 1.28 g of sulfur
(40 mmol) and 4.35 g (50 mmol) of morpholine in 50 ml of
DMF at 80 ◦C for 1 h. The products 2 and 4 were formed as
determined by GC-MS.
Preparation of 1: Acetone (0.58 g, 10 mmol) was heated
with sulfur (0.6◦4 g, 20 mmol) and morpholine (1.74 g,
20 mmol) at 20 C for 8 h. The reaction was monitored by
GC showing 71% yield. The reaction mixture was purified by
flash chromatography on silica gel using hexane-ether (1:1)
and gave pure product 1 in 67% yield. M.p. 149 – 151 ◦C. –
1H NMR (90 MHz, CDCl3): δ = 2.46 (s, 3H), 3.65 (m, 6H),
4.20 (d, 2H). – MS (EI): m/z (%) = 173 (15) [M+], 130 (30),
115 (15), 86 (45), 43 (100).
Preparation of 2: A mixture of 0.58 g (10 mmol) of ace-
tone and 1.60 g (50 mmol) of sulfur and 3.12 g (40 mmol) of
morpholine in 10 ml of DMF was exposed to microwave irra-
diation for 5 min. The reaction was monitored by GC show-
ing 82% yield. The reaction mixture was purified by flash
chromatography on silica gel using hexane-ether (2:1) and
gave pure product 2 in 76% yield [16].
Preparation of 3: A mixture of acetone (0.58 g, 10 mmol)
and sulfur (1.60 g, 50 mmol) and morpholine (3.12 g,
40 mmol) in presence of a trace amount of water was ex-
posed to microwave irradiation for 5 min. The reaction was
monitored by GC showing 73% yield. The product was pu-
rified by flash chromatography on silica gel using ether as
eluent to afford 3 as a yellow solid. After recrystallization
from ethanol, the pure product 3 was obtained in 55% yield.
In conclusion, we optimized the one-pot synthesis
of products 1 – 3 from acetone together with the de-
velopment of a general mechanism of the Willgerodt-
Kindler reaction.
Experimental Section
Morpholine was purified by refluxing for 24 h over
sodium and distillation. Anhydrous acetone and purified sul-
fur was used. A GC-MS method for the analysis of mixtures
was applied; a Fisions instruments gas chromatograph 8000
connected to a mass detector (Trio 1000) with 70 EV was
[1] A. Padwa, L. Scott Beall, T. M. Heidelbaugh, B. Liu,
S. M. Sheehan, J. Org. Chem. 65, 2684 (2000).
[2] P. J. May, M. Bradley, D. C. Harrowven, D. Pallin,
Tetrahedron Lett. 41, 1627 (2000).
[3] D. C. Harrowven, M. C. Lucas, P. D. Howes, Tetrahe-
dron Lett. 40, 4443 [1999].
[4] P. Metzner, Synthesis 1185 (1992).
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Download Date | 6/22/16 7:23 AM

H. R.Darabi et al. · Interesting Behavior of Acetone under the Willgerodt-Kindler Reaction Conditions
605
[5] A. F. Spatola, in B. Weinstein (ed.): Chemistry and Bio-
chemistry of Aminoacids, Peptides and Proteins, Vol.
[13] M. Nooshabadi, K. Aghapoor, H. R. Darabi, M. M.
Mojtahedi, Tetrahedron Lett. 40, 7549 (1999).
7, p. 267 – 357, Marcel Dekker, New York (1983), and [14] H. R. Darabi, K. Aghapoor, K. Tabar-Heydar, Phospho-
references cited therein.
[6] T. Hoeg-Jensen, C. Olsen, A. Holm, J. Org. Chem. 59,
1257 (1994).
[7] A. L. Katritzky, J. L. Moutou, Z. Yang, Synlett 99
(1995).
[8] M. C. Murguia, R. A. Rossi, Tetrahedron Lett. 38, 133
(1997).
[9] E. Schaumann, In B. M. Trost, I. Fleming (eds): Com-
prehensive Organic Synthesis, Vol. 6, p. 419-434, Perg-
amon Press, Oxford (1991).
[10] E. V. Brown, Synthesis 358 (1975), and references
cited therein.
[11] W. G. Dauben, J. B. Rogan, J. Am. Chem. Soc. 78,
4135 (1956).
[12] F. Dutron-Woitrin, R. Merenyi, H. G. Viehe, Synthesis
77 (1985).
rus, Sulfur and Silicon 177, 1189 (2002).
[15] K. Aghapoor, H. R. Darabi, M. Nooshabadi, K. Tabar-
heydar, Phosphorus, Sulfur and Silicon 177, 1183
(2002).
[16] K. Aghapoor, H. R. Darabi, K. Tabar-Heydar,
L. Nakhshab, Sulfur Lett. 25, 259 (2002).
[17] G. Motte-Coppe, F. Dutron-Woitrin, T. G. C Bird, H. G.
Viehe, J. P. Declercq, G. Germain, M. Van Meerssche,
Tetrahedron 41, 693 (1985).
[18] F. Asinger, H. Offermanns, Angew. Chem. Int. Ed. 6,
907 (1967).
[19] F. Asinger, W. Scha¨fer, K. Halcour, A. Saus, H. Triem,
Angew. Chem. Int. Ed. 3, 19 (1964).
[20] M. Carmack, J. Heterocyclic Chem. 26, 1319 (1989).
[21] R. E. Davis, H. F. Naksbendi, J. Am. Chem. Soc. 84,
2085 (1962).
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