The Willgerodt-Kindler reaction in water: High chemoselectivity of benzaldehydes over acetophenones

Article abstract of DOI:10.1007/s00706-006-0560-7

Water has been found for the first time as a useful solvent in the Willgerodt-Kindler (WK) reaction for the synthesis of benzothiomorpholides in high yield at 80°C for 3 h. This novel approach confronts the WK protocol with a new situation in which water

Full text of DOI:10.1007/s00706-006-0560-7

Monatshefte f€ur Chemie 138, 61–65 (2007)
DOI 10.1007/s00706-006-0560-7
Printed in The Netherlands
Short Communication
The Willgerodt-Kindler Reaction in Water:
High Chemoselectivity of Benzaldehydes
over Acetophenones
Kioumars Aghapoor, Farshid Mohsenzadeh, Golriz Khanalizadeh,
ꢀ
and Hossein R. Darabi
Chemistry & Chemical Engineering Research Center of Iran, Tehran, Iran
Received July 23, 2006; accepted (revised) August 3, 2006
Published online January 2, 2007 # Springer-Verlag 2007
Summary. Water has been found for the first time as a useful solvent in the Willgerodt-Kindler (WK)
reaction for the synthesis of benzothiomorpholides in high yield at 80ꢁC for 3 h. This novel approach
confronts the WK protocol with a new situation in which water not only is not regarded as a serious
disadvantage but also is applied in this case as a useful solvent in the reaction. The basis of this finding
is the presence of a methylene chain in the carbonyl substrates, which leads to the high reaction
selectivity of benzaldehydes over acetophenones.
Keywords. Willgerodt-Kindler reaction; Selective thioamidation; Water.
Introduction
The three-component Willgerodt-Kindler (WK) reaction is well known as an impor-
tant method for the synthesis of thioamides [1, 2]. In the original reaction, an aryl
alkyl ketone or aryl aldehyde can be reacted with sulfur and a primary or secondary
amine, and the product is the terminal thioamide 1 or 2 (Fig. 1) [1]. The importance
of thioamides and their widespread applications as versatile intermediates in
medicine and organic synthesis [3–7] have enlarged the synthesis utility of the WK
reaction. In contrast, as the WK reaction is extendable to several substrates bearing
various functional groups, such as alkynes, alkenes, nitriles, or amines, the range of
synthetic routes toward the thioamides 1 and 2 becomes extended [1, 8–15].
One of the WK drawbacks is the presence of water in the reaction mixture,
which retains the carbonyl group of substrate unchanged and leads to the formation
ꢀ
Corresponding author. E-mail: darabi@ccerci.ac.ir

62
K. Aghapoor et al.
Fig. 1. The synthesis of terminal thioamides 1 and 2 under the WK reaction
Fig. 2. Isomerization and the effect of water on enamines
of undesired by-product [11, 16]. Generally, it is often commented that all the
experiments have to be carried out under anhydrous conditions. The excellent work
by Carmack et al. [16, 17] has proved this claim and demonstrated that enamine as
an intermediate plays a critical role in the migration of a carbonyl group back and
forth along a chain of methylene units via a facile isomerization. This intermediate
is unstable in the presence of water and hydrolyzes to the corresponding carbonyl
substrate as shown in Fig. 2.
As was noted in several publications, benzaldehydes give consistently higher
yields than acetophenones under anhydrous conditions in shorter periods of time
[12–15]. The reason appears only to be explained by the presence of a methylene
moiety in the carbonyl substrates.
In embracing the reaction principles and considering the important role of
water and as well methylene units, and in continuation of our investigation on this
reaction [8, 11, 14] we report a generally new approach to the synthesis of ben-
zothioamides in water. Among various thioamides, the benzothioamide moiety in
particular appears to be an interesting pharmacophore in medicinal chemistry, with
widespread applications including estrogen receptor antagonists [18], antifungal
[19] and antibacterial agents [20], and aldose reductase inhibitors [21]. Therefore,
the development of an effective WK method for the synthesis of benzothioamides
in aqueous media seems to be an important challenge.

The Willgerodt-Kindler Reaction in Water
63
Results and Discussion
We first studied the WK reaction of benzaldehyde by screening the reaction con-
ditions in water. In this study, morpholine as a secondary amine was applied be-
cause it has greater resistance to oxidation [22]. In an optimized experiment in
water, benzaldehyde was treated with 3 equiv. of sulfur and morpholine at 80ꢁC.
The reaction resulted in the formation of the corresponding thioamide 2 after 3 h
(Table 1, entry 1, 85%).
These preliminary results led us to extend the scope of the new synthesis sys-
tem to various substrates. The data in Table 1 clearly show that the reaction of
benzaldehyde derivatives in water gives the corresponding thioamides 2 (Table 1,
entries 1–6) in high yields. The yields are highly dependent on the substrate used.
For instance, aromatic heterocyclic substrates gave lower yields (Table 1, entries 7
and 8).
In sharp contrast, acetophenone, as expected, completely failed to produce
the corresponding thioamide 1 under the same reaction conditions. This result
Table 1. The WK reaction of benzaldehydes in water
Entry
Product 2a, b, c
Yield=%d
1
2
3
4
5
6
7
8
Ph.CS.M
4-Me.Ph.CS.M
4-MeO.Ph.CS.M
4-EtO.Ph.CS.M
4-Cl.Ph.CS.M
4-Me2N.Ph.CS.M
Py.CS.M
85
84
85
83
81
86
70
55
Th.CS.M
a)
b)
c)
d)
M ¼
;
Py ¼
;
Th ¼
;
isolated yields
Fig. 3. Chemoselective thioamidation of benzaldehyde in the presence of acetophenone in water

64
K. Aghapoor et al.
Table 2. The WK reaction of benzaldimines in water
Entry
Product 2a
Yield=%b
1
2
3
4
5
6
Ph.CS.M
80
82
81
80
79
83
4-Me.Ph.CS.M
4-MeO.Ph.CS.M
4-EtO.Ph.CS.M
4-Cl.Ph.CS.M
4-Me2N.Ph.CS.M
a)
b)
M ¼
;
isolated yields
prompted us to explore the chemoselective WK reaction of benzaldehydes over
acetophenones in water. For example, when an equimolar mixture of benzaldehyde
and acetophenone was allowed to react with sulfur and morpholine in water only
thioamide 2 was obtained, and acetophenone was recovered quantitatively (Fig. 3).
To extend this strategy, we carried out the WK reactions of aldimines in water
under our optimized reaction condition and obtained the thiomorpholides 2 in high
yields also (Table 2, entries 1–6).
In conclusion, we have established an applicable WK reaction method for the
synthesis of benzothioamides in water. Considering the role of the methylene chain,
we also discovered a simple and efficient method for the chemoselective thioamida-
tion of benzaldehydes over acetophenones in the WK reaction. Therefore, the general
WK protocol is confronted with a new situation in which water not only is not
regarded as a serious disadvantage, but also is applied in this case as a useful solvent
in the reaction. In general, we have presented a novel development in the application
of this reaction which provides a powerful tool for selective benzothioamide synth-
esis in water.
Further studies of the Willgerodt-Kindler reaction of new substrates are now in
progress in our laboratory to clarify the reaction mechanism of the present finding
and to develop the application of this reaction.
Experimental
Morpholine was purified by refluxing for 24 h over Na and distillation. Benzaldehydes and purified
sulfur were used. A GC-MS method for the analysis of mixtures was applied. A Fisons instruments gas
chromatograph 8000 connected to a mass detector (Trio 1000) with 70 eV was used. A 60mꢂ0.25 mm
column packed with WCOT fused silica CP-sil 5CB-MS was employed. Column temperature was
programmed from 80 to 270ꢁC at 10ꢁC=min. Injection was performed at 280ꢁC. The carrier gas was
1
He and the inlet pressure was 14 psi. H NMR spectra were recorded on Bruker 500 MHz spectro-
meters. All NMR samples were run in CDCl3 and chemical shifts are expressed in ppm relative to
internal TMS.

The Willgerodt-Kindler Reaction in Water
65
General Experimental Procedure for the Synthesis of 2 in Water
Caution: Experiments should be carried out in an efficient hood to avoid exposure to noxious hydrogen
sulfide vapors.
The aldehyde or aldimine (1mmol), 2 mmol sulfur, 3 mmol morpholine, and 5 cm3 H2O are placed
in a flask fitted with an air-cooled reflux condenser and stirrer. The mixture is heated at 80ꢁC for 3 h.
The dark-brown mixture is cooled to room temperature and the solid product is isolated by suction, and
recrystallized from hot ethanol to remove the unreacted sulfur. Further purification (if necessary) can
be achieved by recrystallization from n-hexane. The products 2 were generally pure as judged by TLC,
1
GC-MS and H NMR analysis.
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