Willgerodt-Kindler reaction at room temperature: Synthesis of thioamides from aromatic aldehydes and cyclic secondary amines

Article abstract of DOI:10.1016/j.tet.2019.130575

A simple method for the synthesis of thioamide derivatives in DMSO at room temperature and at 120 °C has been developed. Total 27 compounds were prepared under both conditions via a one-pot, three component reaction between substituted aromatic aldehydes,

Full text of DOI:10.1016/j.tet.2019.130575

Tetrahedron xxx (xxxx) xxx
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Willgerodt-Kindler reaction at room temperature: Synthesis of
thioamides from aromatic aldehydes and cyclic secondary amines
Arun D. Kale, Yogesh A. Tayade, Sachin D. Mahale, Rahul D. Patil, Dipak S. Dalal*
Department of Organic Chemistry, School of Chemical Sciences, Kavayitri Bahinabai Chaudhari North Maharashtra University, Jalgaon 425 001, MS, India
a r t i c l e i n f o
a b s t r a c t
A simple method for the synthesis of thioamide derivatives in DMSO at room temperature and at 120 ꢀC
has been developed. Total 27 compounds were prepared under both conditions via a one-pot, three
component reaction between substituted aromatic aldehydes, elemental sulfur powder, and cyclic sec-
ondary amines. By optimizing the mole ratio of sulfur powder and amines, we have successfully carried
out Willgerodt-Kindler reaction of aromatic aldehydes at room temperature. At 120 ꢀC, it is catalyst free
reaction with lower reaction time whereas at room temperature, due to the additional amine molecule,
Willgerodt-Kindler reaction of aromatic aldehydes is successfully carried out at room temperature. On
gram-scale, the reaction is successfully attempted under both conditions with good yields.
© 2019 Elsevier Ltd. All rights reserved.
Article history:
Received 7 April 2019
Received in revised form
28 August 2019
Accepted 29 August 2019
Available online xxx
Keywords:
Willgerodt-Kindler reaction
Catalyst-free
Room temperature
Thioamide synthesis
Aromatic aldehydes
Cyclic secondary amines
1. Introduction
synthesized under solvent-free and non-catalyst conditions using
IR energy as a source of activation [10]. Synthesis of thiomorpholide
Thioamides have attracted the attention of scientific community
from a long time due to its broad range of biological activities such
as antioxidant, antimicrobial, anticonvulsant, antithyroid, anti-
cancer activities [1], tuberculosis and leprosy [2]. Thioamides are
also found in vital biological and pharmaceutical molecules, such as
closthioamide [3a], hydroxymethyl thiolactam cyclothialidine [3b],
and N-cyclohexylethyl-ETAV [3c], etc. Thioamides are key in-
termediates and valuable building blocks for preparation of bio-
logically relevant heterocyclic scaffolds [4]. Thioamides have
attracted recent attention in transition-metal coordination chem-
istry [5], polymer synthesis [6], inclusion chemistry and materials
science [7]. Therefore, various approaches for the synthesis of thi-
oamides have been developed.
from substituted acetophenones in PEG-600 was also achieved [11].
Takaki Kanbara et al. [12] have reported the synthesis of thio-
benzanilides from anilines and benzaldehydes in presence of cat-
alytical amount of Na2S$9H2O. V. V. Kulganek and L. A. Yanovskaya
[13] reported synthesis of thioamide derivatives by using p-toluene
sulfonic acid as catalyst at different temperature (Scheme 1-a). The
synthesis of thioamide was also attempted using 1-methyl-2-
pyrrolidone as solvent under harsh reaction conditions, such as
high temperature or microwave irradiation (Scheme 1-b) [14]. H. R.
Darabi et al. [15] have used water as a solvent to carry out the
Willgerodt-Kindler reaction (Scheme 1-c). The thioamides were
synthesized by using primary amines, aldehyde, sulfur powder and
K2CO3 in water (Scheme 1-d) [16]. Thioamides were also obtained
by reaction of nitriles (Scheme 1-e) [17], arylacetic acids (Scheme 1-
f) [18] and alkynes (Scheme 1-g) [19]. However, nitriles, arylacetic
acids, and alkynes are not cheap starting materials. S. Chen et al.
[20] reported synthesis of thioamide by using 1, 2-
dibenzyldisulfane and difurfuryl disulfide using iodine as oxidant
in DMSO as solvent (Scheme 1-h). Marta Feroci et al. [21] have
recently reported synthesis of thioamide with three different pro-
tocols by using aldehydes, elemental sulfur and cyclic secondary
amines (Scheme 1-i). In continuation of our work on thioamide
synthesis [22], we have recently reported synthesis of thioamides
The Willgerodt reaction was first described by Conrad Will-
gerodt in 1887, which involved the oxidation/rearrangement of a
ketone to form a terminal amide [8]. After that in 1923, K. Kindler
reported a modification of this reaction, which involved the reac-
tion of aryl alkyl ketone, sulfur and a primary or secondary amine to
afford the thioamide derivatives [9].
a-Ketothioamides were
* Corresponding author.
E-mail addresses: dsdalal2007@gmail.com, dsdalal@nmu.ac.in (D.S. Dalal).
https://doi.org/10.1016/j.tet.2019.130575
0040-4020/© 2019 Elsevier Ltd. All rights reserved.
Please cite this article as: A.D. Kale et al., Willgerodt-Kindler reaction at room temperature: Synthesis of thioamides from aromatic aldehydes
and cyclic secondary amines, Tetrahedron, https://doi.org/10.1016/j.tet.2019.130575

2
A.D. Kale et al. / Tetrahedron xxx (xxxx) xxx
Scheme 1. Previous work and our work for synthesis of thioamides.
using
b
-cyclodextrin as supramolecular catalyst in water (Scheme
(Scheme 2). Willgerodt-Kindler reaction at room temperature and
1-j) [22d].
All reported methods for the synthesis of thioamide derivatives
at 120 ꢀC is significant for large scale preparation of thioamide
derivatives.
from aromatic aldehydes, nitriles, arylacetic acids, alkynes, and 1, 2-
dibenzyldisulfane obtained satisfactory results. However, the syn-
thetic methods reported in literature involved use of acid, base or
neutral catalyst, higher reaction temperature, microwave irradia-
tion, nitrogen atmosphere, requires higher reaction time and
resulted in lower yields. For the first time, we are reporting the
synthesis of thioamides using aromatic aldehydes, elemental sulfur
and cyclic secondary amines at room temperature (1:4:2) and as
well as at 120 ꢀC (1:4:1) under catalyst free in DMSO solvent
2. Results & discussion
After studying the literature reports, it reveals that thioamide
synthesis was carried out at higher temperature using acid, base or
neutral catalyst. To attempt reaction at room temperature, we have
optimized the solvent, temperature and mole ratios of aldehyde,
secondary amine and sulfur. We have performed the model reac-
tion using 4-chlorobenzaldehyde (1a; 1.0 equiv.), elemental sulfur
Please cite this article as: A.D. Kale et al., Willgerodt-Kindler reaction at room temperature: Synthesis of thioamides from aromatic aldehydes
and cyclic secondary amines, Tetrahedron, https://doi.org/10.1016/j.tet.2019.130575

A.D. Kale et al. / Tetrahedron xxx (xxxx) xxx
3
Scheme 1. (continued).
powder (2; 4.0 equiv.), and morpholine (3; 1.0 equiv.) in the
absence of any catalyst in DMSO (10 mL) at room temperature.
Interestingly, the reactants resulted in the formation of desired
compound, 4-chlorophenyl (morpholino)methanethione (4a) in
78% yield on stirring for 56 h (Table 1, entry 1). Thus, to improve the
reaction yield and time, in second experiment a mixture of 4-
chlorobenzaldehyde (1a; 1.0 equiv.), elemental sulfur powder (2;
4.0 equiv.), and morpholine (3; 1.5 equiv.) in DMSO (10 mL) was
stirred at room temperature for 24 h affording the 4-chlorophenyl
(morpholino)methanethione (4a) in 90% yield (Table 1, entry 2).
The best result was obtained with 4-chlorobenzaldehyde (1a; 1.0
equiv.), elemental sulfur powder (2; 4.0 equiv.), and morpholine (3;
2.0 equiv.) in DMSO (10 mL) at room temperature after 6 h affording
the 4-chlorophenyl (morpholino)methanethione (4a) in 92% yield
(Table 1, entry 3). This decrease in reaction time up to 6 h at room
temperature (Table 1, entry 1 & 3) indicates that loading of second
equivalent of amine increases the rate of reaction. Thereafter, the
model reaction was carried out in different solvents at room tem-
perature (Table 1, entries 4e14). The results showed that DMSO is
the efficient solvent for the synthesis of aim product. However, the
yield of aim product in DMSO was a bit higher than that of in DMF.
No product formation was observed in EtOH, water, MeOH, DCM
and THF (Table 1, entries 10e14). Whereas, trace product formation
was observed in 1, 4-dioxane, toluene and ethyl acetate (Table 1,
entries 7e9). Considering toxicity and yield of product, DMSO was
chosen as optimizing solvent, while other solvents, such as EtOH,
acetonitrile, 1,4-dioxane, water, MeOH, toluene, acetone, DCM,
ethyl acetate, THF were not suitable for application of this synthesis
(Table 1, entry 4e14), hence all the reactions were carried out in
DMSO at room temperature.
We noted that the nucleophilicity of cyclic secondary amine is
the key factor for the Willgerodt-Kindler reaction at room tem-
perature. Too understood this, we have performed some control
experiments using primary amines like aniline, 4-methoxy aniline
and ethyl amine and acyclic secondary amines like diphenyl amine
and diethyl amine at room temperature using 1:4:2 proportion of
4-chlorobenzaldehyde:sulfur:amine. Initially the colour of reaction
mixture is colourless and it remains same after addition of sulfur
powder. This indicates that the selected primary amines and acyclic
secondary amines are not sufficiently nucleophilic to form poly-
sulfide anions. Therefore, after 24 h of stirring in DMSO solvent, no
product is obtained. Whereas in case of cyclic secondary amines,
Please cite this article as: A.D. Kale et al., Willgerodt-Kindler reaction at room temperature: Synthesis of thioamides from aromatic aldehydes
and cyclic secondary amines, Tetrahedron, https://doi.org/10.1016/j.tet.2019.130575

4
A.D. Kale et al. / Tetrahedron xxx (xxxx) xxx
Scheme 2. General scheme for the synthesis of thioamide derivatives.
Table 1
Reaction optimization at room temperature.
Entry
Solvent
Mole Ratio 1a: 2 : 3
Time (h)
Yielda (%)
1
2
3
4
5
6
7
8
DMSO
DMSO
DMSO
Acetonitrile
DMF
Acetone
1,4-Dioxane
Toluene
Ethyl acetate
EtOH
1:4:1
1:4:1.5
1:4:2
1:4:2
1:4:2
1:4:2
1:4:2
1:4:2
1:4:2
1:4:2
1:4:2
1:4:2
1:4:2
1:4:2
56
24
6
24
6
24
24
24
24
24
24
24
24
24
78
90
92
30
91
65
Trace
Trace
Trace
N.P.
N.P.
N.P.
N.P.
N.P.
9
10
11
12
13
14
Water
MeOH
DCM
THF
Reaction conditions: 4-Chlorobenzaldehyde (2 mmol), Morpholine (4 mmol), Sulfur powder (8 mmol) and Solvent (10 mL).
a
Isolated yield.
the colourless reaction mass after addition of elemental sulfur
powder turns to the reddish-brown colour.
The reaction of benzaldehyde, morpholine and elemental sulfur
was successfully scaled-up (50 mmol) at room temperature
(Scheme 3, yield 90%).
excess of cyclic secondary amine from the reaction, we have again
optimized the solvent, temperature and mole ratios of aldehyde,
secondary amine and sulfur. So, in our efforts, we have carried out
optimization of the reaction conditions employing 4-chloro benz-
aldehyde (1a), elemental sulfur powder (2), and morpholine (3) as
model reactants by varying different parameters (Table 2). In a first
After getting the success at room temperature and to avoids the
Scheme 3. Gram-scale reaction for the synthesis of 4b at room temperature.
Please cite this article as: A.D. Kale et al., Willgerodt-Kindler reaction at room temperature: Synthesis of thioamides from aromatic aldehydes
and cyclic secondary amines, Tetrahedron, https://doi.org/10.1016/j.tet.2019.130575

A.D. Kale et al. / Tetrahedron xxx (xxxx) xxx
5
Table 2
Reaction optimization at higher Temperatures.
Entry
Solvent
Mole Ratio 1a: 2 : 3
Temp (ꢀC)
Time (h)
Yielda (%)
1
2
3
4
5
6
7
8
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
Toluene
1,4-Dioxane
DMF
1:2:1
1:2:1
1:3:1
1:4:1
1:5:1
1:4:1
1:4:1
1:4:1
1:4:1
1:4:1
1:4:1
1:4:1
1:4:1
1:4:1
100
120
120
120
120
80
100
130
140
110
100
100
120
100
24
24
3
0.5
0.5
6
52
64
85
93
93
75
90
93
92
31
70
85
90
60
1
0.5
0.5
30
15
1
9
10
11
12
13
14
DMF
Water
1
12
Reaction conditions: 4-Chlorobenzaldehyde (2 mmol), Morpholine (2 mmol), Sulfur powder (8 mmol) and Solvent (10 mL).
a
Isolated yield.
experiment, 4-chloro benzaldehyde (1a; 1.0 equiv.), elemental
sulfur powder (2; 2.0 equiv.), and morpholine (3; 1.0 equiv.) were
heated at 100 ꢀC with constant stirring for 24 h in DMSO (10 mL),
the expected product 4-chlorophenyl (morpholino)methanethione
(4a) was obtained in 52% yield (Table 2, entry 1). Thus, to increase
the reaction yield, we studied the influence of reaction temperature
at 120 ꢀC and observed that after 24 h, the reaction yield increased
moderately to 64% (Table 2, entry 2). The amount of elemental
sulfur powder was playing the important role in the reaction.
Hence, the amount of sulfur powder was optimized. Initially, the
reaction by employing 3.0 equivalent of elemental sulfur powder at
120 ꢀC gives 85% yield of product in 3 h (Table 2, entry 3). As the
amount of elemental sulfur powder increases from 3.0 equivalents
to 4.0 equivalents, it was observed that the yield of product in-
creases with decrease in the reaction time (Table 2, entry 4). The
93% yield of product was obtained in the absence of a catalyst in
DMSO at 120 ꢀC within 30 min, the best molar ratio was found to be
1:4:1 (Table 2, entry 4). Further increase in the amount of element
sulfur powder 5.0 equivalent, failed to improve the yield of product
and time (Table 2, entry 5). Temperature is playing very important
role in this transformation, at the low temperature (80 ꢀC) there
was a formation of 75% of product and required higher reaction
time (Table 2, entry 6). As the temperature increases from 100 ꢀC to
120 ꢀC, the yields were found to increase while reaction time de-
creases (Table 2, entry 4 & 7). However, further increase of the
temperature to 130 ꢀC and 140 ꢀC failed to improve the yield of
product and time (Table 2, entry 8 & 9). We obtained the best
results at 120 ꢀC (Table 2, entry 4).
We next are inventing the possibility of improving the yield of
the reaction at reflux in different solvents such as toluene, DMF, 1,4-
dioxane and water at various temperatures. Among all these sol-
vents (Table 2, entry, 10, 11, 12, 13 & 14), DMSO was found to be the
best in terms of the yield of the product and time of completion
compared with other organic solvents. In relation to the effect of
different solvents, the use of DMF and DMSO encouraged the re-
action to a high extent. When the reaction was carried out in DMF
solvent at 120 ꢀC (Table 2, entry 13), higher yields 90% was ob-
tained. In 1, 4-dioxane after 15 h gives 70% yield of product (Table 2,
entry 11). A lowest yield of 31% in 30 h (Table 2, entry 10) was
obtained in non-polar toluene solvent. Also, when reactants were
heated at 100 ꢀC in water, only 60% yield of the product was ob-
tained (Table 2, entry 14). Most importantly, for only few de-
rivatives water is suitable solvent. However, none of used solvents
could match the yield obtained in DMSO (Table 2, entry 4), hence all
the reactions were performed in DMSO at the 120 ꢀC. Thus, the
catalyst free condition was achieved at 120 ꢀC.
The reaction of benzaldehyde, morpholine and elemental sulfur
was successfully scaled-up (50 mmol) at 120 ꢀC (Scheme 4, yield
92%).
Aromatic aldehydes containing the electron donating, with-
drawing, halogen, nitrile substituents on the aromatic ring were
tested to afford the thioamide products. The position of the sub-
stituents on the aromatic ring was noticed to have some effects on
the product yield and reaction time. As can be seen from Table 3,
Scheme 4. Gram-scale reaction for the synthesis of 4b at 120 ꢀC.
Please cite this article as: A.D. Kale et al., Willgerodt-Kindler reaction at room temperature: Synthesis of thioamides from aromatic aldehydes
and cyclic secondary amines, Tetrahedron, https://doi.org/10.1016/j.tet.2019.130575

6
A.D. Kale et al. / Tetrahedron xxx (xxxx) xxx
Table 3
Synthesis of various thioamide derivatives in DMSO.
Entry
4a
Product
Reaction Time
Product Yield (%)
M. P. ꢀC
RT (h)
6
120 ꢀC (min)
30
RT
92
120 ꢀ
93
C
138e140[13]
4b
4c
6
7
30
91
86
91
84
136e138[23]
126e128[23]
120
4d
14
120
91
91
154e156[22d]
4e
4f
10
16
120
180
83
89
80
88
100e102[24]
152e154[21]
4g
6
30
88
87
198e200[21]
4h
4i
6
30
81
84
80
80
83
77
96e98[13]
11
11
180
160
168e170[22d]
132e134[26]
4j
6a
6b
9
6
90
30
83
91
80
90
84e86[27]
176e178[22d]
6c
6
60
89
89
90e92[28]
Please cite this article as: A.D. Kale et al., Willgerodt-Kindler reaction at room temperature: Synthesis of thioamides from aromatic aldehydes
and cyclic secondary amines, Tetrahedron, https://doi.org/10.1016/j.tet.2019.130575

A.D. Kale et al. / Tetrahedron xxx (xxxx) xxx
7
Table 3 (continued )
Entry
Product
Reaction Time
Product Yield (%)
M. P. ꢀC
RT (h)
6
120 ꢀC (min)
140
RT
85
120 ꢀ
84
C
6d
6e
96e98[28]
14
120
86
87
98e100[29]
6f
11
15
160
180
83
85
82
83
110e112[22d]
152e154[22d]
6g
6h
6i
15
10
7
90
81
84
82
79
85
81
118e120[22d]
158e160[22d]
74e76[21]
140
70
6j
8a
8b
7
6
30
60
94
88
93
80
84e86[22d]
94e96[30]
8c
13
6
120
30
80
90
78
88
124e126
8d
148e150[21]
8e
8f
15
120
110
84
85
83
82
96e98[22d]
6
146e148[22d]
(continued on next page)
Please cite this article as: A.D. Kale et al., Willgerodt-Kindler reaction at room temperature: Synthesis of thioamides from aromatic aldehydes
and cyclic secondary amines, Tetrahedron, https://doi.org/10.1016/j.tet.2019.130575

8
A.D. Kale et al. / Tetrahedron xxx (xxxx) xxx
Table 3 (continued )
Entry
Product
Reaction Time
Product Yield (%)
M. P. ꢀC
RT (h)
7
120 ꢀC (min)
60
RT
83
120 ꢀ
84
C
8g
102e104[21]
aromatic aldehydes containing electron-donating or electron-
withdrawing substituents reacted successfully with cyclic second-
ary amines (morpholine, piperidine and pyrrolidine) to give cor-
responding thioamides in high yields and in short reaction time.
The results showed that the aromatic aldehydes having substituent
such as 4-NO2 reacted speedily with morpholine/piperidine/pyr-
rolidine affording thioamide products with same reaction time (6 h
and 0.5 h) at room temperature and 120 ꢀC respectively (Table 3,
entry 4a, 6b, 8d). Amongst all reactions, the reaction of 4-(dime-
thylamino)benzaldehyde with morpholine/piperidine/pyrrolidine
at room temperature as well as at 120 ꢀC required highest reaction
time (Table 3, entry 4f, 6g, 8e). 3, 4-Dimethoxybenzaldehyde
reacted with morpholine/piperidine at 120 ꢀC to give 91% and
87% yields within 2 h and at room temperature to give 91% and 86%
yields within 14 h respectively (Table 3, entry 4d and 6e). Aromatic
aldehydes with electron-withdrawing groups at meta-position take
more time for completion of reaction as compared to para-position
(Table 3, entry 6j, 6b and 8g, 8d). This may be due to the increased
reactivity of electron deficient aldehydes. Further, the heterocyclic
aldehyde like thiophene-2-carboxaldehyde (Table 3, entries 6a and
8a) also gives smooth reaction to obtained corresponding products
in high yields. However, reaction of 2-chlorobenzaldehyde with
elemental sulfur powder and morpholine/piperidine/pyrrolidine in
DMSO at room temperature as well as at 120 ꢀC, no product for-
mation was observed which may be due to the steric effect. Mor-
pholino(4-nitrophenyl)methanethione (Table 3, entry 4g) has
found to melt at higher temperature (198e200 ꢀC) as compared to
other derivatives. Lower melting point (72e74 ꢀC) was observed for
(4-chlorophenyl)(pyrrolidin-1-yl)methanethione (Table 3, entry
8b). During all addition of aromatic aldehydes with cyclic second-
ary amines in DMSO, the colourless reaction mass was observed
and after addition of elemental sulfur powder, the reddish-brown
colour of reaction mass was observed. After completion of reac-
tion, the reaction mass is poured in to ice-water to obtain light
yellow or off white or light brown solid. The residue was passed
through the column chromatography with hexane as eluent to
remove unreacted sulfur and to obtained yellow solid products. In
all cases, the conversions were completed within 6e16 h at room
temperature and 30e180 min at 120 ꢀC with good to excellent
yields of products. The temperature and mole ratios of reactants are
playing key role in these reactions. The synthesized compounds
were identified by their physical constants, FT-IR, 1H NMR, 13C NMR,
CHNS elemental analysis, HRMS and comparison with authentic
samples.
2.1. Plausible mechanism
Based on the previous literature [12,25], a possible mechanism
is proposed in Fig. 1. The first step of this Willgerodt-Kindler re-
action at room temperature is considered to involve cleavage of the
SeS bond of elemental sulfur III caused by nucleophilic attack of
morpholine II to form polysulfide anion IV in a reversible way.
Meanwhile, the aldehyde I react with second molecule of mor-
pholine II to form V. Intermediate V easily converted to interme-
diate VI in the presence of an amino sulfur species. Then, the
nucleophilic attack of IV on VI affords intermediate VII. Due to the
presence of the extra hydrogen on the methylene group of the
imine, the intermediate VII oxidizes to release the final product 4a.
The used of two equivalents of cyclic secondary amine increases the
rate of reaction and the Willgerodt-Kindler reaction take place at
room temperature.
Fig. 1. Plausible mechanism for the formation of 4a.
Please cite this article as: A.D. Kale et al., Willgerodt-Kindler reaction at room temperature: Synthesis of thioamides from aromatic aldehydes
and cyclic secondary amines, Tetrahedron, https://doi.org/10.1016/j.tet.2019.130575

A.D. Kale et al. / Tetrahedron xxx (xxxx) xxx
9
3. Conclusion
4.4. Gram-scale synthesis of morpholino(phenyl)methanethione
(4b) at room temperature
In summary, we have developed a newer method for one-pot
synthesis of thioamides from aromatic aldehydes, cyclic second-
ary amines, and elemental sulfur powder without using any
external catalyst in DMSO solvent. All thioamides were synthesized
under catalyst free conditions within 0.5e3 h at 120 ꢀC with
77e93% yields and within 6e16 h at room temperature with
80e94% yields of products. The mole ratio for aldehydes: sulfur:
amines was kept 1:4:1 at 120 ꢀC and 1:4:2 at room temperature. By
optimizing the mole ratios of aldehydes, sulfur and amine, we have
carried out Willgerodt-Kindler reaction of aromatic aldehydes un-
der catalyst-free condition at 120 ꢀC. To best of our knowledge, this
is first report on Willgerodt-Kindler reaction at room temperature.
On gram-scale, the reaction is successfully attempted.
To a 100 mL round bottom flask containing DMSO (50 mL),
benzaldehyde (50 mmol), added slowly morpholine (100 mmol),
during the addition of morpholine exotherm is observed at
25e35 ꢀC and then added slowly elemental sulfur powder
(200 mmol). The resulting reaction mixture was continuously stir-
red at room temperature for 6 h. After completion of the reaction,
the reaction mixture was poured into ice-water mixture under
vigorous stirring. The solid product was obtained by simple filtra-
tion, washed with water, dried and second lot extracted with ethyl
acetate from filtrate removed the solvent under vacuum obtained
crude product. The residue was passed through column chroma-
tography to remove unreacted sulfur using hexane as eluent, and
the pure product (4b) was obtained by passing ethyl acetate
through the column (weight of product ¼ 9.31 g, 90% yield).
4. Experimental section
4.1. General information
4.5. Gram-scale synthesis of morpholino(phenyl)methanethione
(4b) at 120 ꢀC
All reactions were performed in DMSO and monitored by TLC
analysis using Merck silica gel 60 F254 plates with fluorescent in-
dicator (254 nm) and visualized with a UV lamp and without any
special precautions in an atmosphere of air. All Chemicals were
purchased from Spectrochem and DMSO (99.97%) and used as
received without further purification. Melting points were
measured in open capillary tubes and uncorrected. FT-IR spectra
were obtained on Shimadzu IR-Affinity spectrometer (KBr Pellets).
CHNS elemental analysis was performed on Thermo Finnigan CHNS
analyzer model Flash 2000. 1H NMR and 13C NMR were recorded a
Bruker Avance-II spectrophotometer operating at 400, 500 MHz
and 100, 125 MHz. High resolution mass spectra (HRMS) were
recorded a quadrupole time-of-flight (Q-TOF) mass spectrometer.
To a 100 mL round bottom flask containing DMSO (50 mL),
benzaldehyde (50 mmol), added slowly morpholine (50 mmol),
during the addition of morpholine exotherm is observed at
25e32 ꢀC and then added slowly elemental sulfur powder
(200 mmol). The resulting reaction mixture was continuously stir-
red at 120 ꢀC for 30 min. After completion of the reaction, the re-
action mixture was poured into ice-water mixture under vigorous
stirring. The solid product was obtained by simple filtration,
washed with water, dried and second lot extracted from filtrate
with ethyl acetate, removed the solvent under vacuum obtained
crude product. The residue was passed through column chroma-
tography to remove unreacted sulfur using hexane as eluent, and
the pure product (4b) was obtained by passing ethyl acetate
through the column (weight of product ¼ 9.50 g, 92% yield).
4.2. General procedure for synthesis of thioamide derivatives at
room temperature
4.6. Spectral data of compounds
To a 25 mL round bottom flask containing DMSO (10 mL), aro-
matic aldehyde (2 mmol), morpholine or piperidine or pyrrolidine
(4 mmol), and elemental sulfur powder (8 mmol) were added. The
resulting reaction mixture was continuously stirred at room tem-
perature and the progress of reaction was monitored by TLC (hex-
ane:ethyl acetate, 8:2 ratio). After completion of the reaction, the
reaction mixture was poured into ice-water mixture under
vigorous stirring. The solid product was obtained by simple filtra-
tion, washed with water, and dried. The residue was passed
through column chromatography to remove unreacted sulfur using
hexane as eluent, and the pure product was obtained by passing
ethyl acetate through the column.
4.6.1. 4-Chlorophenyl (morpholino)methanethione (4a) [13]
M.P. 138e140 ꢀC; IR (KBr): 3012, 2949, 2835, 1591, 1477, 1438,
1226, 1116, 1089, 844, 819, 721 cmꢁ1 1H NMR (CDCl3, 400 MHz,
;
ppm)
d
: 7.34 (2H, dt, J ¼ 8.56 & 2.17 Hz), 7.23 (2H, dt, J ¼ 8.60 &
2.18 Hz), 4.41 (2H, t, J ¼ 4.88 Hz), 3.88 (2H, t, J ¼ 4.92 Hz), 3.65e3.58
(4H, m); 13C NMR (CDCl3, 100 MHz)
127.4, 66.6, 66.4, 52.6, 49.6.
d: 199.5, 140.7, 134.9, 128.8,
4.6.2. Morpholino(phenyl)methanethione (4b) [23]
M.P. 136e138 ꢀC; IR (KBr): 3059, 2983, 2920, 2852, 1492, 1479,
1433, 1386, 1290, 1226, 1112, 871, 759, 696 cmꢁ1 1H NMR (CDCl3,
;
400 MHz, ppm) d: 7.37e7.33 (3H, m), 7.28e7.26 (2H, m), 4.43 (2H, t,
4.3. General procedure for synthesis of thioamide derivatives at
120 ꢀC
J ¼ 4.75 Hz), 3.87 (2H, t, J ¼ 5.00 Hz), 3.63 (2H, t, J ¼ 4.50 Hz), 3.58
(2H, t, J ¼ 4.75 Hz); 13C NMR (CDCl3, 100 MHz)
d: 200.9, 142.4, 128.8,
128.5, 125.8, 66.7, 66.5, 52.5, 49.5.
To a 25 mL round bottom flask containing DMSO (10 mL), aro-
matic aldehyde (2 mmol), morpholine or piperidine or pyrrolidine
(2 mmol), and elemental sulfur powder (8 mmol) were added. The
resulting reaction mixture was continuously stirred at 120 ꢀC and
the progress of reaction was monitored by TLC (hexane:ethyl ace-
tate, 8:2 ratio). After completion of the reaction, the reaction
mixture was poured into ice-water mixture under vigorous stirring.
The solid product was obtained by simple filtration, washed with
water, and dried. The residue was passed through column chro-
matography to remove unreacted sulfur using hexane as eluent,
and the pure product was obtained by passing ethyl acetate
through the column.
4.6.3. Morpholino(p-tolyl)methanethione (4c) [23]
M.P. 126e128 ꢀC; IR (KBr): 2978, 2918, 2856, 1510, 1483, 1435,
1388, 1294, 1226, 1111, 1033, 873, 812 cmꢁ1 1H NMR (CDCl3,
;
400 MHz, ppm) d: 7.19e7.18 (2H, m), 7.16e7.14 (2H, m), 4.42 (2H, t,
J ¼ 5.00 Hz), 3.86 (2H, t, J ¼ 5.00 Hz), 3.62 (4H, brs), 2.34 (3H, s); 13
C
NMR (CDCl3, 100 MHz)
52.5, 49.7, 21.2.
d: 201.3, 139.7, 139.0, 129.1, 126.0, 66.7, 66.5,
4.6.4. (3,4-Dimethoxyphenyl)(morpholino)methanethione (4d)
[22d]
M.P. 154e156 ꢀC; IR (KBr): 2993, 2958, 2866, 2833, 1598, 1514,
Please cite this article as: A.D. Kale et al., Willgerodt-Kindler reaction at room temperature: Synthesis of thioamides from aromatic aldehydes
and cyclic secondary amines, Tetrahedron, https://doi.org/10.1016/j.tet.2019.130575

10
A.D. Kale et al. / Tetrahedron xxx (xxxx) xxx
1483, 1440, 1301, 1269, 1111, 1062, 1020, 850, 763 cmꢁ1
(CDCl3, 400 MHz, ppm)
: 6.91 (1H, d, J ¼ 1.50 Hz), 6.84e6.81 (2H,
m), 4.41 (2H, brs), 3.88 (8H, brs), 3.65 (4H, brs); 13C NMR (CDCl3,
100 MHz) : 200.9, 149.7, 148.7, 135.0, 118.5, 110.6, 110.3, 66.7, 66.4,
;
1H NMR
6.2; N-6.6; S, 30.3; Found: C, 56.75; H, 6.2; N, 6.6; S, 30.35.
d
4.6.12. (4-Nitrophenyl)(piperidin-1-yl)methanethione (6b) [22d]
M.P. 176e178 ꢀC; IR (KBr): 3061, 2935, 2856, 1591, 1512, 1438,
d
56.0, 52.8, 49.9.
1340, 1249, 1207, 1103, 1012, 852, 752 cmꢁ1 1H NMR (CDCl3,
;
400 MHz, ppm)
d
: 8.21 (2H, dt, J ¼ 8.50 & 2.25 Hz), 7.41 (2H, dt,
4.6.5. (4-Methoxyphenyl)(morpholino)methanethione (4e) [24]
M.P. 100e102 ꢀC; IR (KBr): 3007, 2956, 2848, 2825, 1606, 1508,
1479, 1433, 1303, 1228, 1112, 1031, 873, 833, 783, 723 cmꢁ1; 1H NMR
J ¼ 8.50 & 2.25 Hz), 4.34 (2H, t, J ¼ 5.50 Hz), 3.48 (2H, t, J ¼ 5.75 Hz),
1.86e1.81 (2H, m), 1.80e1.75 (2H, m), 1.61e1.57 (2H, m); 13C NMR
(CDCl3, 100 MHz)
25.4, 24.0.
d: 195.9, 148.9, 147.2, 126.2, 124.0, 53.3, 50.3, 26.8,
(CDCl3, 400 MHz, ppm)
d: 7.28e7.26 (2H, m), 6.87e6.85 (2H, m),
4.41 (2H, brs), 3.86 (2H, brs), 3.81 (3H, s), 3.65 (4H, brs); 13C NMR
(CDCl3, 100 MHz)
52.8, 50.0.
d: 201.1, 160.3, 134.8, 128.1, 113.7, 66.7, 66.5, 55.4,
4.6.13. (4-Chlorophenyl)(piperidin-1-yl)methanethione (6c) [28]
M.P. 120e122 ꢀC; IR (KBr): 3074, 3018, 2935, 2858, 1589, 1454,
1433, 1298, 1240, 1141, 835, 810, 720 cmꢁ1 1H NMR (CDCl3,
;
4.6.6. 4-(Dimethylamino)phenyl (morpholino)methanethione (4f)
[21]
400 MHz, ppm)
4.33 (2H, t, J ¼ 5.44 Hz), 3.51 (2H, t, J ¼ 5.62 Hz), 1.84e1.72 (4H, m),
1.59e1.54 (2H, m); 13C NMR (CDCl3, 100 MHz)
: 198.1, 141.6, 134.3,
128.6, 126.9, 53.2, 50.7, 26.9, 25.4, 24.1; Anal. calcd. For C12H14NSCl:
C, 60.1; H, 5.9; N, 5.8; S, 13.4; Found: C, 60.0; H, 5.9; N, 5.8; S, 13.4.
d
: 7.33e7.30 (2H, m), 7.21 (2H, dt, J ¼ 8.32 & 2.0 Hz),
M.P. 152e154 ꢀC; IR (KBr): 3093, 2962, 2850, 1604, 1517, 1433,
d
1282, 1219, 1114, 1033, 821, 802 cmꢁ1
;
1H NMR (CDCl3, 400 MHz,
ppm) d: 7.29e7.27 (2H, m), 6.62e6.60 (2H, m), 4.41 (2H, brs), 3.76
(6H, brs), 2.97 (6H, s); 13C NMR (CDCl3, 100 MHz)
129.6, 128.6, 111.0, 66.6, 53.0, 50.1, 40.2.
d: 202.0, 151.1,
4.6.14. Piperidin-1-yl(p-tolyl)methanethione (6d) [28]
M.P. 96e98 ꢀC; IR (KBr): 3020, 2933, 2893, 1604, 1506, 1433,
4.6.7. Morpholino(4-nitrophenyl)methanethione (4g) [21]
1296, 1139, 1111, 1006, 950, 829, 810 cmꢁ1 1H NMR (CDCl3,
;
M.P. 198e200 ꢀC; IR (KBr): 3086, 3059, 2924, 2860, 1593, 1506,
500 MHz, ppm)
d
: 7.17 (2H, d, J ¼ 8.00 Hz), 7.13 (2H, d, J ¼ 8.00 Hz),
1444, 1346, 1296, 1236, 1209, 1107, 1033, 879, 850, 825 cmꢁ1
;
1H
4.34 (2H, t, J ¼ 5.5 Hz), 3.53 (2H, t, J ¼ 5.5 Hz), 2.34 (3H, s), 1.82e1.78
NMR (CDCl3, 400 MHz, ppm) d: 8.24e8.21 (2H, m), 7.45e7.43 (2H,
(2H, m), 1.75e1.71 (2H, m), 1.57e1.53 (2H, m); 13C NMR (CDCl3,
m), 4.42 (2H, t, J ¼ 4.94 Hz), 3.90 (2H, t, J ¼ 4.94 Hz), 3.67 (2H, t,
125 MHz)
24.1, 21.4.
d: 199.9, 140.6, 138.4, 128.9, 125.5, 53.2, 50.7, 26.9, 25.5,
J ¼ 4.80 Hz), 3.56 (2H, t, J ¼ 4.80 Hz); 13C NMR (CDCl3, 100 MHz)
d:
197.3, 147.9, 147.4, 126.7, 124.1, 66.5, 66.4, 52.5, 49.2.
4.6.15. (3,4-Dimethoxyphenyl)(piperidin-1-yl)methanethione (6e)
[29]
4.6.8. (4-Fluorophenyl)(morpholino)methanethione (4h) [13]
M.P. 96e98 ꢀC; IR (KBr): 3032, 2918, 2862, 1600, 1510, 1487,
M.P. 98e100 ꢀC; IR (KBr): 3076, 2949, 2937, 2848, 1598, 1514,
1435, 1290, 1226, 1111, 1033, 875, 833, 785 cmꢁ1
;
1H NMR (CDCl3,
1485, 1269, 1232, 1147, 1018, 840, 825, 761 cmꢁ1 1H NMR (CDCl3,
;
400 MHz, ppm) : 7.31e7.27 (2H, m), 7.06e7.03 (2H, m), 4.42 (2H, t,
d
400 MHz, ppm)
t, J ¼ 5.06 Hz), 3.88 (6H, s), 3.57 (2H, t, J ¼ 5.46 Hz), 1.82e1.73 (4H,
m), 1.59e1.58 (2H, m); 13C NMR (CDCl3, 100 MHz)
: 199.6, 149.3,
148.6, 136.0, 118.1, 110.6, 109.8, 56.0, 55.9, 53.3, 51.0, 27.0, 25.5, 24.2;
Anal. calcd. For C14H19NO2S: C, 63.4; H, 7.2; N, 5.3; S, 12.1; Found: C,
63.35; H, 7.2; N, 5.3; S, 12.1.
d
: 6.88 (1H, d, J ¼ 1.72), 6.85e6.80 (2H, m), 4.34 (2H,
J ¼ 4.75 Hz), 3.88 (2H, t, J ¼ 4.75 Hz), 3.64 (2H, d, J ¼ 5.00 Hz), 3.61
(2H, d, J ¼ 5.00 Hz); 13C NMR (CDCl3, 100 MHz)
d
: 199.9, 163.8, 161.8,
d
138.5, 128.2, 128.1, 115.6, 115.4, 66.6, 66.4, 52.6, 49.7.
4.6.9. 4-(Morpholine-4-carbonothloyl)benzonirile (4i) [22d]
M.P. 168e170 ꢀC; IR (KBr): 3014, 2980, 2846, 2227, 1506, 1487,
1446, 1288, 1232, 1120, 1033, 877, 821 cmꢁ1
;
1H NMR (CDCl3,
4.6.16. (4-Methoxyphenyl)(piperidin-1-yl)methanethione (6f)
[22d]
400 MHz, ppm)
d
: 7.68e7.65 (2H, m), 7.38 (2H, dt, J ¼ 8.44 &
1.69 Hz), 4.40 (2H, t, J ¼ 4.94 Hz), 3.88 (2H, t, J ¼ 4.94 Hz), 3.65 (2H, t,
M.P. 110e112 ꢀC; IR (KBr): 3010, 2939, 2850, 1608, 1510, 1487,
J ¼ 4.80 Hz), 3.54 (2H, t, J ¼ 4.80 Hz); 13C NMR (CDCl3, 100 MHz)
d:
1438, 1298, 1236, 1107, 1028, 835, 813 cmꢁ1 1H NMR (CDCl3,
;
197.7, 146.2, 132.5, 126.5, 118.1, 112.3, 66.5, 66.3, 52.5, 49.2.
400 MHz, ppm) d: 7.20e7.17 (2H, m), 6.79e6.76 (2H, m), 4.26 (2H, t,
J ¼ 5.25 Hz), 3.73 (3H, s), 3.50 (2H, t, J ¼ 5.50 Hz), 1.73e1.71 (2H, m),
4.6.10. (3-Methoxyphenyl)(morpholino)methanethione (4j) [26]
1.69e1.65 (2H, m), 1.52e1.48 (2H, m); 13C NMR (CDCl3, 100 MHz)
d:
M.P. 132e134 ꢀC; IR (KBr): 3080, 2972, 2908, 2858, 1604, 1577,
199.8, 159.8, 135.9, 127.5, 113.6, 55.4, 53.3, 51.0, 26.9, 25.5, 24.2.
1483, 1427, 1292, 1228, 1199, 1107, 1002, 842, 788, 700 cmꢁ1
;
1H
NMR (CDCl3, 400 MHz, ppm) : 7.28e7.24 (1H, m), 6.88e6.85 (1H,
d
4.6.17. 4-(Dimethylamino)phenyl (piperidin-1-yl)methanethione
m), 6.82e6.80 (2H, m), 4.42 (2H, t, J ¼ 4.92 Hz), 3.87 (2H, t,
(6g) [22d]
J ¼ 4.92 Hz), 3.80 (3H, s), 3.64e3.62 (2H, m), 3.60e3.59 (2H, m); 13
C
M.P. 152e154 ꢀC; IR (KBr): 3010, 2943, 2848, 1606, 1519, 1481,
NMR (CDCl3, 100 MHz)
d: 200.4, 159.5, 143.6, 129.6, 117.7, 114.5,
1444, 1359, 1300, 1234, 1209, 1136, 1014, 850, 806, 746 cmꢁ1
NMR (CDCl3, 400 MHz, ppm) : 7.27e7.24 (2H, m), 6.63e6.61 (2H,
m), 4.31 (2H, brs), 3.65 (2H, brs), 2.97 (6H, s), 1.79e1.58 (6H, m); 13
NMR (CDCl3, 100 MHz)
40.3, 27.0, 25.5, 24.3.
;
1H
111.4, 66.7, 66.4, 55.3, 52.4, 49.4; Anal. calcd. For C12H15NO2S: C,
60.7; H, 6.4; N, 5.9; S, 13.5. Found: C, 60.8; H, 6.4; N, 5.9; S, 13.5.
HRMS (ESI) calculated For C12H15NO2S [MþH]: 238.0902, Found:
238.0910.
d
C
d: 200.8, 150.8, 131.0, 128.1, 111.1, 53.6, 51.4,
4.6.11. Piperidin-1-yl(thiophen-2yl)methanethione (6a) [27]
M.P. 74e76 ꢀC; IR (KBr): 3095, 2937, 2850, 1517, 1479, 1442, 1176,
4.6.18. (4-Bromophenyl)(piperidin-1-yl)methanethione (6h) [22d]
M.P. 118e120 ꢀC; IR (KBr): 3070, 2943, 2852, 1583, 1498, 1435,
1290, 1242, 1136, 1010, 825, 808, 702, 588, 513 cmꢁ1 1H NMR
(CDCl3, 400 MHz, ppm)
1134, 1008, 844, 719 cmꢁ1; 1H NMR (CDCl3, 400 MHz, ppm)
d
: 7.37
;
(1H, dd, J ¼ 5.12 & 1.12 Hz), 7.05 (1H, dd, J ¼ 3.64 & 1.12 Hz), 6.95
d
: 7.47 (2H, dt, J ¼ 8.56 & 2.14 Hz), 7.15 (2H,
(1H, dd, J ¼ 5.10 & 3.66 Hz), 4.27 (2H, brs), 3.84 (2H, brs), 1.76 (6H,
dt, J ¼ 8.44 & 2.12 Hz), 4.32 (2H, t, J ¼ 5.50 Hz), 3.51 (2H, t,
s); 13C NMR (CDCl3, 100 MHz)
d: 190.4, 145.0, 128.6, 126.4, 125.5,
J ¼ 5.62 Hz), 1.82e1.73 (4H, m), 1.59e1.54 (2H, m); 13C NMR (CDCl3,
53.7, 52.2, 26.9, 25.6, 24.2; Anal. calcd. For C10H13NS2: C, 56.8; H,
100 MHz) d: 197.9, 142.0, 131.5, 127.1, 122.4, 53.2, 50.6, 26.8, 25.4,
Please cite this article as: A.D. Kale et al., Willgerodt-Kindler reaction at room temperature: Synthesis of thioamides from aromatic aldehydes
and cyclic secondary amines, Tetrahedron, https://doi.org/10.1016/j.tet.2019.130575

A.D. Kale et al. / Tetrahedron xxx (xxxx) xxx
11
24.0.
4.6.26. 4-(Pyrrolidine-1-carbonothioyl)benzonitrile (8f) [22d]
M.P. 146e148 ꢀC; IR (KBr): 3040, 2980, 2916, 2877, 2223, 1604,
1506, 1483, 1436, 1271, 1174, 1109, 1041, 823 cmꢁ1; 1H NMR (CDCl3,
4.6.19. 4-(Piperidin-1-carbonothioyl)benzonitrile (6i) [22d]
M.P. 158e160 ꢀC; IR (KBr): 2987, 2933, 2858, 2223, 1600, 1504,
1487, 1436, 1242, 1205, 1109, 1010, 840, 729 cmꢁ1; 1H NMR (CDCl3,
400 MHz, ppm)
d
: 7.66 (2H, dt, J ¼ 8.44 & 1.68 Hz), 7.46 (2H, dt,
J ¼ 8.52 & 1.77 Hz), 3.95 (2H, t, J ¼ 7.08 Hz), 3.42 (2H, t, J ¼ 6.76 Hz),
2.12e2.09 (2H, m), 2.03e1.99 (2H, m); 13C NMR (CDCl3, 100 MHz)
d:
400 MHz, ppm) d: 7.65e7.63 (2H, m), 7.37e7.35 (2H, m), 4.33 (2H, t,
194.3, 147.6, 132.3, 126.3, 118.3, 112.1, 53.7, 53.4, 26.5, 24.5.
J ¼ 5.50 Hz), 3.46 (2H, t, J ¼ 5.75 Hz), 1.85e1.80 (2H, m), 1.79e1.74
(2H, m), 1.60e1.55 (2H, m); 13C NMR (CDCl3, 100 MHz)
d: 196.4,
4.6.27. (3-Nitrophenyl)(pyrrolidin-1yl)methanethione (8g) [21]
147.2, 132.4, 126.0, 118.3, 111.8, 53.2, 50.3, 26.8, 25.4, 24.0.
M.P. 102e104 ꢀC; IR (KBr): 3074, 2974, 2870, 1525, 1492, 1444,
1354, 1265, 1151, 1076, 1024, 808, 731 cmꢁ1
;
1H NMR (CDCl3,
4.6.20. (3-Nitrophenyl)(piperidin-1-yl)methanethione (6j) [21]
M.P. 74e76 ꢀC; IR (KBr): 3082, 3022, 2945, 2856, 1573, 1512,
400 MHz, ppm) : 8.23e8.22 (1H, m), 8.20e8.18 (1H, m), 7.72 (1H,
d
dt, J ¼ 7.72 & 1.32 Hz), 7.56 (1H, t, J ¼ 7.90 Hz), 3.98 (2H, t,
J ¼ 7.08 Hz), 3.49 (2H, t, J ¼ 6.72 Hz), 2.15e2.07 (2H, m), 2.06e2.02
1450, 1352, 1010, 808, 734, 686 cmꢁ1 1H NMR (CDCl3, 400 MHz,
;
ppm)
(1H, t, J ¼ 7.84 Hz), 4.36 (2H, t, J ¼ 5.50 Hz), 3.52 (2H, t, J ¼ 5.62 Hz),
1.87e1.75 (4H, m), 1.63e1.61 (2H, m); 13C NMR (CDCl3, 100 MHz)
d: 8.18e8.16 (1H, m), 8.12 (1H, m), 7.62e7.59 (1H, m), 7.55
(2H, m); 13C NMR (CDCl3, 100 MHz)
d: 193.6, 147.8, 144.9, 131.7,
129.6, 123.3, 120.7, 53.9, 53.6, 26.5, 24.6.
d:
195.7, 147.9, 144.4, 131.4, 129.6, 123.0, 120.5, 53.4, 50.6, 26.8, 25.4,
23.9.
Acknowledgment
The authors are grateful to University Grants Commission, New
Delhi, India for financial assistance under Major Research Project [F.
No. 43e173/2014 (SR)], entitled, Synthesis, Docking Studies and
Antituberculosis Evaluation of Some Newer Promising Heterocycles
Derived from Isoniazid and Ethyl 2-cyano-3, 3-Bis(methylthio)
acrylate. The authors are also grateful UGC Special Assistance Pro-
gramme SAP-DSA-I and Department of Science and Technology
(DST), Government of India for infrastructural facilities under the
FIST programme to KBC NMU. We are also grateful to SAIF-Punjab
University, Chandigarh for characterization support for this work.
4.6.21. Pyrrolidin-1yl(thiophen-2-yl)methanethione (8a) [22d]
M.P. 84e86 ꢀC; IR (KBr): 3101, 2962, 2862, 1517, 1467, 1444, 1244,
1193, 1072, 844, 719 cmꢁ1 1H NMR (CDCl3, 400 MHz, ppm)
; d: 7.42
(1H, dd, J ¼ 5.12 & 1.08 Hz), 7.28e7.27 (1H, m), 7.01 (1H, dd, J ¼ 5.08
& 3.84 Hz), 4.02e3.98 (2H, m), 3.89e3.85 (2H, m), 2.08e2.03 (4H,
m); 13C NMR (CDCl3, 100 MHz)
54.3, 26.8, 24.4.
d: 186.6, 146.4, 130.4, 126.8, 55.2,
4.6.22. (4-Chlorophenyl)(pyrrolidin-1yl)methanethione (8b) [30]
M.P. 72e74 ꢀC; IR (KBr): 3093, 3043, 2970, 2872, 1591, 1452,
1325, 1265, 1220, 1172, 1141, 1089, 958, 875, 817, 771, 435 cmꢁ1; 1H
Appendix A. Supplementary data
NMR (CDCl3, 500 MHz, ppm)
J ¼ 8.50 Hz), 3.94 (2H, t, J ¼ 7.25 Hz), 3.46 (2H, t, J ¼ 6.75 Hz),
2.10e2.05 (2H, m), 2.00e1.95 (2H, m); 13C NMR (CDCl3, 125 MHz)
d: 7.32 (2H, d, J ¼ 8.50 Hz), 7.29 (2H, d,
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tet.2019.130575.
d:
195.8, 142.2, 134.8, 128.4, 127.2, 53.8, 53.5, 26.5, 24.6; Anal. calcd.
For C11H12NSCl: C, 58.5; H, 5.4; N, 6.2; S, 14.2; Found: C, 58.6; H, 5.4;
N, 6.2; S, 14.2.
References
[1] (a) D.C. Schroeder, Chem. Rev. 55 (1955) 181e228;
(b) K. Gibinski, Curr. Med. Res. Opin. 7 (1981) 516e519;
(c) M. Shekarchi, M. Pirali-Hamedani, L. Navidpour, N. Adib, A. Shafiee, J. Iran.
Chem. Soc. 5 (2008) 150e158;
4.6.23. (4-Bromophenyl)(pyrrolidin-1yl)methanethione (8c)
M.P. 124e126 ꢀC; IR (KBr): 3041, 2968, 2872, 1737, 1585, 1471,
1450, 1392, 1325, 1269, 1220, 1172, 1147, 1070, 1001, 941, 873, 844,
(d) G. Brunhofer, C. Studenik, G. Ecker, T. Erker, Eur. J. Pharm. Sci. 42 (2011)
37e44;
(e) M.S. Chernovyants, N.V. Aleshina, J. Anal. Chem. 67 (2012) 214e218;
(f) M.S. Chernov’yants, A.O. Dolinkin, J. Struct. Chem. 51 (2010) 1176e1190;
(g) G.J. Corban, S.K. Hadjikakou, A.C. Tsipis, M. Kubicki, T. Bakas, N. Hadjiliadis,
New J. Chem. 35 (2011) 213e224;
813, 727 cmꢁ1 1H NMR (CDCl3, 500 MHz, ppm)
; d: 7.47 (2H, d,
J ¼ 8.00 Hz), 7.24 (2H, d, J ¼ 8.50 Hz), 3.94 (2H, t, J ¼ 7.25 Hz), 3.45
(2H, t, J ¼ 6.75 Hz), 2.09e2.04 (2H, m), 2.00e1.96 (2H, m); 13C NMR
(CDCl3, 125 MHz) d: 195.7, 142.7, 131.4, 127.4, 122.8, 53.8, 53.5, 26.5,
(h) W. Hu, H. Yu, Y. Chen, Y. Tsai, Y. Chen, C. Liao, L. Chang, J. Wang, Bioorg.
Med. Chem. 16 (2008) 5295e5302.
24.6; Anal. calcd. For C11H12NSBr: C, 48.9; H, 4.5; N, 5.2; S, 11.9;
Found: C, 48.8; H, 4.5; N, 5.2; S, 11.9.
[2] (a) H.V. Barnes, T. Bledsoe, J. Clin. Endocrinol. Metab. 35 (1972) 250e255;
(b) F. Wang, R. Langley, G. Gulten, L.G. Dover, G.S. Besra, W.R. Jacobs,
J.C. Sacchettini, J. Exp. Med. 204 (2007) 73e78.
4.6.24. (4-Nitrophenyl)(pyrrolidin-1yl)methanethione (8d) [21]
M.P. 148e150 ꢀC; IR (KBr): 3070, 3057, 2956, 2872, 1593, 1512,
[3] (a) T. Lincke, S. Behnken, K. Ishida, M. Roth, C. Hertweck, Angew. Chem. 122
(2010) 2055e2057;
(b) P. Angehrn, E. Goetschi, H. Gmuender, P. Hebeisen, M. Hennig, B. Kuhn,
T. Luebbers, P. Reindl, F. Ricklin, A. Schmitt-Hoffmann, J. Med. Chem. 54
(2011), 2207-2024;
1438, 1342, 1103, 1037, 850, 827, 754, 725 cmꢁ1 1H NMR (CDCl3,
;
400 MHz, ppm)
d
: 8.22 (2H, dt, J ¼ 8.80 & 2.14 Hz), 7.52 (2H, dt,
(c) A. Bach, J.N.N. Eildal, N. Stuhr-Hansen, R. Deeskamp, M. Gottschalk,
S.W. Pedersen, A.S. Kristensen, K. Strømgaard, J. Med. Chem. 54 (2011)
1333e1346.
J ¼ 8.80 & 2.15 Hz), 3.96 (2H, t, J ¼ 7.08 Hz), 3.44 (2H, t, J ¼ 6.76 Hz),
2.14e2.06 (2H, m), 2.06e2.01 (2H, m); 13C NMR (CDCl3, 100 MHz)
d:
193.9, 149.3, 147.3, 126.6, 123.8, 53.7, 53.3, 26.5, 24.5.
ꢀ
[4] T.S. Jagodzinski, Chem. Rev. 103 (2003) 197e228.
[5] K. Okamoto, J. Kuwabara, T. Kanbara, Chem. Lett. 44 (2015) 102e110.
[6] L. He, H. Zhao, P. Theato, Angew. Chem. 130 (2018) 2e5.
[7] (a) M. Akaiwa, T. Kanbara, H. Fukumoto, T. Yamamoto, J. Organomet. Chem.
690 (2005) 4192e4196;
4.6.25. 4-(Dimethylamino)phenyl (pyrrolidin-1yl)methanethione
(8e) [22d]
(b) K. Okamoto, T. Kanbara, T. Yamamoto, A. Wada, Organometallics 25 (2006)
4026e4029.
M.P. 96e98 ꢀC; IR (KBr): 3034, 2974, 2870, 2804, 1606, 1523,
1442, 1267, 1124, 1022, 823 cmꢁ1
;
1H NMR (CDCl3, 400 MHz, ppm)
[8] C. Willgerodt, Ber. Dtsch. Chem. Ges. 20 (1887) 2467e2470.
[9] K. Kindler, Justus Liebig’s Ann. der Chemie. 431 (1923) 187e230.
d
: 7.39e7.37 (2H, m), 6.62e6.60 (2H, m), 3.96 (2H, t, J ¼ 7.08 Hz),
ꢀ
ꢀ
[10] J.E. Valdez-Rojas, H. Ríos-Guerra, A.L. Ramírez-Sanchez, G. García-Gonzalez,
3.61 (2H, t, J ¼ 6.68 Hz), 2.97 (6H, s), 2.07e2.03 (2H, m), 1.95e1.91
ꢀ
ꢀ
ꢀ
C. Alvarez-Toledano, J.G. Lopez-Cortes, R.A. Toscano, J.G. Penieres-Carrillo,
Can. J. Chem. 90 (2012) 567e573.
(2H, m); 13C NMR (CDCl3, 100 MHz)
110.8, 54.2, 53.9, 40.3, 26.6, 24.7.
d: 197.5, 150.9, 131.4, 128.1,
[11] S.S. Gawande, B.P. Bandgar, P.D. Kadam, S.S. Sable, Green Chem. Lett. Rev. 3
Please cite this article as: A.D. Kale et al., Willgerodt-Kindler reaction at room temperature: Synthesis of thioamides from aromatic aldehydes
and cyclic secondary amines, Tetrahedron, https://doi.org/10.1016/j.tet.2019.130575

12
A.D. Kale et al. / Tetrahedron xxx (xxxx) xxx
(2010) 315e318.
[25] (a) J. Liu, S. Zhao, X. Yan, Y. Zhang, S. Zhao, K. Zhuo, Y. Yue, Asian J. Org. Chem.
6 (2017) 1764e1768;
[12] K. Okamoto, T. Yamamoto, T. Kanbara, Synlett 17 (2007) 2687e2690.
[13] V.V. Kul’ganek, L.A. Yanovskaya, Bull. Acad. Sci. USSR Div. Chem. Sci. 28 (1979)
2402e2403.
[14] O.I. Zbruyev, N. Stiasni, C.O. Kappe, J. Comb. Chem. 5 (2003) 145e148.
[15] K. Aghapoor, F. Mohsenzadeh, G. Khanalizadeh, H.R. Darabi, Monatshefte für
Chemie - Chem. Mon. 138 (2007) 61e65.
(b) M. Carmack, J. Heterocycl. Chem. 26 (1989) 1319e1323;
(c) M. Carmack, M. Behforouz, G.A. Berchtold, S.M. Berkowitz, D. Wiesler,
R. Barone, J. Heterocycl. Chem. 26 (1989) 1305e1318;
(d) X. Li, Q. Pan, R. Hu, X. Wang, Z. Yang, S. Han, Asian J. Org. Chem. 5 (2016)
1353e1358.
[16] H. Xu, H. Deng, Z. Li, H. Xiang, X. Zhou, Eur. J. Org. Chem. 2013 (2013)
7054e7057.
[26] (a) Brown, David; Hargreaves, Rodney B.; McLoughlin, Bernard J.; Mills, Stuart
D,; US 4489074 A 19841218, 1984.
[17] K. Mahammed, V. Jayashankara, N. Premsai Rai, K. Mohana Raju,
P. Arunachalam, Synlett 2009 (2009) 2338e2340.
(b) Brown, David; Hargreaves, Rodney B.; McLoughlin, Bernard J.; Mills, Stuart
D.; Eur. Pat. Appl. EP 80296 A1 19830601, 1983.
[18] T. Guntreddi, R. Vanjari, K.N. Singh, Org. Lett. 16 (2014) 3624e3627.
[19] T.B. Nguyen, M.Q. Tran, L. Ermolenko, A. Al-Mourabit, Org. Lett. 16 (2014)
310e313.
[20] S. Chen, Y. Li, J. Chen, X. Xu, L. Su, Z. Tang, C.-T. Au, R. Qiu, Synlett 27 (2016)
2339e2344.
[21] M. Papa, I. Chiarotto, M. Feroci, ChemistrySelect 2 (2017) 3207e3210.
[22] (a) A.D. Jangale, P.P. Kumavat, Y.B. Wagh, Y.A. Tayade, P.P. Mahulikar,
D.S. Dalal, Synth. Commun. 45 (2015) 376e385;
[27] A.R. Katritzky, R.M. Witek, V. Rodriguez-Garcia, P.P. Mohapatra, J.W. Rogers,
J. Cusido, A.A.A. Abdel-Fattah, P.J. Steel, J. Org. Chem. 70 (2005) 7866.
[28] (a) S. Kato, H.K. Shibahashi, T.T. Tomonori, I. Noda, M. Mizuta, M. Goto, Liebigs
Ann. Chem. 7 (1982) 1229e1244;
(b) D.V. Ramana, S.K. Viswanadham, Org. Mass Spectrom. 9 (1982) 409e415;
(c) A. Pal, N.D. Koduri, Z. Wang, E.L. Quiroz, A. Chong, M. Vuong, N. Rajagopal,
M.R. Nguyen, P. Kenneth, S.R. Hussaini, Tetrahedron Lett. 58 (2017) 586e589.
[29] (a) C. Cercasov, G. Constantinescu, C. Doneanu, An. Univ. Bucur. Chim. 7 (1998)
71e78;
(b) P.P. Kumavat, A.D. Jangale, D.R. Patil, K.S. Dalal, J.S. Meshram, D.S. Dalal,
Environ. Chem. Lett. 11 (2013) 177e182;
(c) A.D. Jangale, Y.B. Wagh, Y.A. Tayade, D.S. Dalal, Synth. Commun. 45 (2015)
1876e1886;
(b) S.M. Lempert, K. Lempert, P. Bruck, G. Toth, Electron deficient hetero-
aromatic ammonioamidates, XIV, Acta Chim. Acad. Sci. Hung. 94 (1977)
391e401.
(d) Y.A. Tayade, A.D. Jangale, D.S. Dalal, ChemistrySelect 3 (2018) 8895e8900.
[23] F. Matloubi Moghaddam, L. Hojabri, M. Dohendou, Synth. Commun. 33 (2003)
4279e4284.
[24] S.D. Fazylov, O.A. Nurkenov, Z.S. Akhmetkarimova, D.R. Zhienbaeva, Russ. J.
Gen. Chem. 82 (2012) 781e782.
[30] (a) T. Hori, Y. Otani, M. Kawahata, K. Yamaguchi, T. Ohwada, J. Org. Chem. 73
(2008) 9102e9108;
(b) P.K. Bhattacharya, S. Bandyopadhyay, S.C. Pakrashi, Indian J. Chem. Sect. B
Org. Chem. Incl. Med. Chem. 28 (1989) 673e674.
Please cite this article as: A.D. Kale et al., Willgerodt-Kindler reaction at room temperature: Synthesis of thioamides from aromatic aldehydes
and cyclic secondary amines, Tetrahedron, https://doi.org/10.1016/j.tet.2019.130575