Willgerodt-kindler's microwave-enhanced synthesis of thioamide derivatives

Article abstract of DOI:10.1080/10426500490466995

The Willgerodt-Kindler reaction was applied to a series of aromatic aldehydes and ketones. The reactions were performed in a dipolar aprotic solvent (mainly DMF) in the presence of a base catalyst (4-methylmorpholine) and utilized microwave (mw) irradiation. The pulsed mw technique rather than the continuous irradiation was preferred because it limited side reactions and hydrogen sulfide production. While not always superior to the thermal activation of the reaction, the procedure involving repetitive short pulses of microwave irradiation was found to be faster and result in consistently cleaner products. The technique can be easily applied in a fast parallel synthesis process.

Full text of DOI:10.1080/10426500490466995

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Phosphorus, Sulfur, and Silicon and the Related
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WILLGERODT-KINDLER'S MICROWAVE-ENHANCED
SYNTHESIS OF THIOAMIDE DERIVATIVES
Jacques H. Poupaert a , Sandro Duarte a , Evelina Colacino a , Patrick Depreux b , Christopher
R. McCurdy c & Didier L. Lambert a
a Ecole de Pharmacie, Université Catholique de Louvain, Bruxelles, Belgium
b Institut de Chimie Pharmaceutique Albert Lespagnol, Lille, France
c Department of Medicinal Chemistry, University of Mississippi, Mississippi, USA
Published online: 16 Aug 2010.
To cite this article: Jacques H. Poupaert , Sandro Duarte , Evelina Colacino , Patrick Depreux , Christopher R. McCurdy &
Didier L. Lambert (2004) WILLGERODT-KINDLER'S MICROWAVE-ENHANCED SYNTHESIS OF THIOAMIDE DERIVATIVES, Phosphorus,
Sulfur, and Silicon and the Related Elements, 179:10, 1959-1973, DOI: 10.1080/10426500490466995
To link to this article: http://dx.doi.org/10.1080/10426500490466995
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Phosphorus, Sulfur, and Silicon, 179:1959–1973, 2004
ꢀC
Copyright Taylor & Francis Inc.
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500490466995
WILLGERODT-KINDLER’S MICROWAVE-ENHANCED
SYNTHESIS OF THIOAMIDE DERIVATIVES
Jacques H. Poupaert,a Sandro Duarte,a Evelina Colacino,a
Patrick Depreux,b Christopher R. McCurdy,c
and Didier L. Lamberta
Ecole de Pharmacie, Universite´ Catholique de Louvain,
Bruxelles, Belgium;a Institut de Chimie Pharmaceutique Albert
Lespagnol, Lille, France;b and Department of Medicinal
Chemistry, University of Mississippi, Mississippi, USAc
(Received January 29, 2004; accepted February 20, 2004)
The Willgerodt-Kindler reaction was applied to a series of aromatic
aldehydes and ketones. The reactions were performed in a dipolar
aprotic solvent (mainly DMF) in the presence of a base catalyst
(4-methylmorpholine) and utilized microwave (mw) irradiation. The
pulsed mw technique rather than the continuous irradiation was pre-
ferred because it limited side reactions and hydrogen sulfide produc-
tion. While not always superior to the thermal activation of the reaction,
the procedure involving repetitive short pulses of microwave irradiation
was found to be faster and result in consistently cleaner products. The
technique can be easily applied in a fast parallel synthesis process.
Keywords: Catalysis; microwave; sulfur; thioamide; Willgerodt-
Kindler
INTRODUCTION
A recent study based on the analysis of a large virtual library con-
structed with frequently occurring pharmacophores in drug molecules
concluded that amides incorporating a basic amine moiety constitute
an interesting family of potentially CNS-active molecules amenable to
combinatorial chemistry.1 However, the therapeutic utility of amides
is somewhat limited due to their extensive degradation in plasma, es-
pecially when the amide function is formulated in a peptide structure.
One approach to increase the plasma half-life of such compounds is to
Address correspondence to Jacques H. Poupaert, Ecole de Pharmacie, Universite´
Catholique de Louvain, B-1200 Bruxelles, Belgium.
1959

1960
J. H. Poupaert et al.
substitute one or more amide linkage(s) by thioamide linkage(s), a mod-
ification leading to improved metabolic resistance.2 The thioamide NH
is a stronger hydrogen bond donor than the amide NH, and the larger
and less electronegative sulfur atom, relative to oxygen, is a weaker
hydrogen bond acceptor.3 These two factors combined may alter not
only the hydrogen bonding ability at the receptor or enzyme level but
also induce conformational changes and higher lipophilicity in the mod-
ified molecule.4,5 As a result, the substitution of thioamides for amides
appears to be a promising and productive tool in drug discovery and
especially in the search for novel CNS-active drugs, with particular
emphasis on generating compounds with improved capacity to cross
physiological barriers, including the brain–blood barrier.6
The thiobenzamide moiety in particular appears to be an interesting
pharmacophore in medicinal chemistry, with widespread applications
including estrogen receptor antagonists,7 antifungal8 and antibacterial
agents,9 aldose reductase inhibitors,10 etc. Access to thioamides is well
documented in the literature.11–13 For the construction of thioamides
of pharmacological interest, the most employed method is based on
the thionation of an amide precursor using P4S10 or a variant such as
Lawesson’s reagent14 or by means of a solid-supported thiophosphate.15
The latter approach was used recently to synthesize a library of
thioamide pharmacological probes. This method implies, however, the
prior construction of the amide precursor.16 In this connection, the
Willgerodt-Kindler (WK) reaction offers a more convergent alternative
to the above approach.17
The WK reaction involves the reaction of an aldone (aldehyde or
ketone), sulfur, and a primary or secondary amine to yield chiefly
a thioamide derivative (Scheme 1).18 When applied to an arylalkyl-
ketone,19 this reaction behaves as an autoredox system in which the
carbonyl of the ketone is reduced while the terminal methyl group of
the alkyl side chain is oxidized.20 The reaction can also be applied to
aldehydes.21 Sulfur has been also substituted by selenium.22 It is note-
worthy that the yield drops sharply when the number of methylenes
linking the carbonyl to the terminal methyl group increases.23,24 As a
matter of fact, the reaction is useful only when the number of methylene
groups is equal to 0–2.25 Practically, the WK reaction with morpholine
is used to transform acetophenones to phenylacetic acids via the in-
termediate phenylacetothiomorpholide, which is hydrolyzed either in
acidic or basic solution to the desired acid.26,27 One of the drawbacks of
the reaction is that the amine itself is often partially oxidized by sul-
fur, and this in turn produces hydrogen sulfide. This is the reason for
the popularity of morpholine as the amine partner, due precisely to its
greater resistance to oxidation.28

Thioamides
1961
SCHEME 1 Willgerodt-Kindler (WK) synthesis of thioamides from an aro-
matic aldone (aldehyde or ketone) precursor.
While the Willgerodt-Kindler reaction has suffered in the past from
a bad reputation, several recent developments have rendered the (WK)
reaction a more attractive reaction to the medicinal chemist:
1. The reaction shows a high degree of tolerance as to the nature of the
aryl precursor and amine, as illustrated in the Scheme 2 for benzylic
SCHEME 2 WK synthesis of thiobenzamides from benzylic precursors.

1962
J. H. Poupaert et al.
substrates.29−31 In the case of WK’s synthesis of thiobenzamides,
the aryl precursor can be either mono- or disubstituted on the ben-
zylic carbon. The amine can be either primary or secondary.
2. The reaction can be improved when run in dipolar aprotic solvents
such as DMF.
3. The reaction can also be improved when run in the presence of a
basic catalyst such as triethylamine.32
4. Limited examples using simple arylalkylketones and morpholine
showed the usefulness of microwave heating in the WK reaction.33
In this article, we report applications of the WK reaction to acetophe-
nones implementing the improvements mentioned in points 2–4.
RESULTS AND DISCUSSION
During the first stage of this research, different attempts on simple
model compounds showed the difficulty of applying the microwave
technique to the WK reaction in spite of several anterior reports.33−36
Reaction in neat phase with continuous irradiation led to black tar
containing too many components to be effectively useful, and in-
deed Nooshabadi et al.33 used column chromatography to purify the
thiomorpholides.
Model substrates taken from previous publications or Vogel’s
textbook18 were therefore selected as “benchmarks” to test the value of
using microwave activation versus thermal heating. Improved “actual
yields” obtained this way reflect practical improvements of the reaction,
as the same straightforward recovery procedure was always applied
during the course of this research (ethanol precipitation and recrystal-
lization; for further details see the Experimental section below). Three
procedures were compared, involving: (1) heating in neat phase a mix-
ture of a benzaldehyde or acetophenone, sulfur, and morpholine (for the
ratio of reagents and reaction conditions, see the Experimental section
below) at 135◦C; (2) same procedure as in (1), the reaction medium be-
ing diluted with equal volume of DMF and 4-methylmorpholine (4 MM);
(3) same procedure as in (2), but applying pulsed microwave irradi-
ation. The choice of 4 MM in (3) was motivated by its suitable boil-
ing point and the fact that tertiary amines, while catalyzing the WK
reaction, also undergo extensive thionation on the methylene vicinal
to the basic nitrogen. This side reaction was minimized when using
4 MM.
Based on a tentative mechanism proposed earlier, it was concluded
that the reaction, when applied to arylalkylketones, proceeds via an

Thioamides
1963
aziridinium-thiolate betaine37 intermediate possessing a high dipole
moment (see the Experimental section below), which strongly sug-
gested that the reaction was amenable to microwave (mw) enhance-
ment (Scheme 3). The polar nature of this key intermediate was also
consistent with the improvement of the yields observed when running
the WK reaction in polar aprotic solvents such as DMF.37
SCHEME 3 Proposal of mechanism for the WK reaction.
The pulse technique for mw irradiation was chosen for thermal equi-
libration, minimizing hydrogen sulfide production, which gives rise to
side reactions.21 Indeed, we noted that hydrogen sulfide production was
strongly diminished when using mw compared to the thermal condi-
tions in (1). The continuous irradiation process, especially in solvent-
free conditions, led to complex product mixtures and, in agreement with
a previous study,37 the thiomorpholide had to be isolated by chromato-
graphic techniques.
As is apparent from Table I, while not always superior to (2), proce-
dure (3) was found to proceed faster and result in consistently cleaner
products that were more easily purified. However, both methods (2) and
(3) failed to give a solid material when applied to propiophenone.
The technique (3) can be easily applied in a fast parallel synthe-
sis process. As was noted in previous publications,37–39 benzaldehy-
des gave in general consistently higher yields than acetophenones.
Moreover, when applying the mw method in (3), the time of reaction

1964
J. H. Poupaert et al.
TABLE I Structure and Yield of Thiomorpholides
Yields (%)
Method (2)
#
X
n
Method (1)
Method (3)
1
2
3
4
5
6
7
8
9
10
11
12
13
15
16
17
18
19
20
21
22
23
24
H
0
0
0
0
0
0
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
85
83
67
72
73
87
51
55
62
48
50
42
62
nd
nd
nd
nd
nd
nd
nd
nd
nd
nd
83
87
77
82
83
92
67
65
67
62
58
56
70
nd
nd
nd
nd
nd
nd
nd
nd
nd
nd
85
85
72
88
79
86
65
62
72
68
62
58
72
63
43
55
49
62
35
58
61
65
89
4-OCH3
4-OH
2-OH, 4-Cl
4-Br
4-N(CH3)2
H
4-CH3
4-OCH3
4-Cl
4-Br
4-C6H5
2-Acetylnaphtalene
CH3CH2
CH3CH2CH2
CH3(CH2)3
CH3(CH2)5
CH3(CH2)7
CH3CH2CH(CH3)
(CH3)2CH(CH2)2
Tetrahydronaphthyl
Cyclohexyl
2-OH, 5-Cl
was considerably shorter for benzaldehydes than acetophenones. While
2 h was necessary for conversion of acetophenones, 30 min was suffi-
cient for benzaldehydes. This approach therefore appears very attrac-
tive for the N-benzoylation of amines and compares favorably with
N-thioacylphthalimides.37
When we tried to extend the mw technique to other amines, and
especially benzylamine, we encountered a special problem in that
when applying the recommendation of Nooshabadi et al.33 regard-
ing the molar ratio of reagents (ketone:sulfur:amine, 1:2:3) in the
reaction of benzaldehyde with benzylamine, the actual yield was

Thioamides
1965
superior to 100%! Closer examination of the literature revealed the
benzylamine autocondenses in the presence of sulfur to produce
N-thiobenzoylbenzylamine (Scheme 4). We have reproduced this re-
action (see the Experimental section below). While it is a low-yield
process, this indicates that especially when running the reaction un-
der drastic temperature conditions (such as under continuous mw
irradiation) and considerable excess of sulfur and amine, the ex-
tent of amine oxidation can produce high-yield impurities. As noted
previously, sulfur excess also increase the generation of thiophene
impurities.
SCHEME 4 WK reaction of benzaldehyde and benzylamine, and oxidative
autocondensation of benzylamine in the presence of sulfur.
CONCLUSION
An interesting aspect associated with the combination of an aprotic
polar solvent such as DMF, the use of a base catalyst resistant to sul-
fur oxidation, and microwave was the ease of recovery of the thiomor-
pholides along with the minimization of H2S production. However, the
yields were not substantially higher by the mw technique (3) than by the
improved thermal method (2). Additionally, in view of the high yields
and short reaction time when using the mw method (3), the WK reac-
tion applied to benzaldehydes provides an efficient technique for ben-
zoylation of amines. While this point was not addressed here, the mw
technique can probably be easily applied in a fast parallel synthesis
process.

1966
J. H. Poupaert et al.
EXPERIMENTAL
Melting points were determined using an Electrothermal melting point
apparatus and are uncorrected. IR spectra were recorded on a Perkin-
Elmer 457 spectrometer using KBr pellets. Wave numbers are ex-
1
pressed in cm−1. H and 13C NMR spectra were recorded at ambient
temperature on a Bruker AC-300 spectrometer. Compounds were dis-
solved in DMSO-d6 or CDCl3. Chemical shifts are expressed in the δ
scale with TMS as internal standard. Thin layer chromatography anal-
yses were performed on Merck TLC plates (silica gel, 60 F 254, E. Merck,
Darmstadt, ref. 5735). All the compounds reported here were routinely
checked in two standard solvents: acetone/toluene/cyclohexane (solvent
A, 5:2:3, v/v/v) and methanol/chloroform equilibrated with ammonia
(solvent B, 1:9, v/v). High performance reverse-phase thin-layer chro-
matography conditions were: HPTLC plates RP-18 F-254 S (Merck),
methanol:water (75/25, v/v). All compounds reported were found ho-
mogenous under such TLC and HPTLC conditions. All reagents were
purchased from Aldrich. All solvents were of the A. C. S. reagent grade
(Aldrich). Elemental analyses were obtained by courtesy of Prof. B.
Masereel (FUNDP, Namur, Belgium). The microwave used for this
study was a 750 W MX B-54 (2450 MHz) model. 4-Methylmorpholine
(4 MM) was dried by refluxing over KOH for 1 h prior to distillation
at atmospheric pressure. The preparation of 1 and 12 is representa-
tive of the synthesis of all other entries (see Table I). The isolation and
purification procedure is quite similar to that employed by Rolfs and
Liebscher in Organic Syntheses.
2-Phenyl-4-yl-1-morpholin-4-yl-ethanethione
[(1, C12H15NOS), mw Condition (3)]
A mixture of 48.0 g (0.4 mol) of acetophenone, 12.8 g (0.4 mol) of sulfur,
72.0 g (0.82 mol) of morpholine and 25 ml of DMF was mixed thoroughly
in a wide-bore 500 ml flask. The flask was placed on the rotating plateau
of a microwave oven and irradiated according to the following scheme:
after an initial pulse of 1 min at 750 W and 3.0 min rest, 25 pulses
of 90 W of 1.5 min spaced out by 3.0 min were applied. During ther-
mal equilibration after each pulse, the dark red reaction mixture was
stirred. The hot reaction mixture was allowed to cool and was washed
successively by 200 ml of distilled water, 200 ml of 0.1N HCl, 200 ml of
brine, and 200 ml of distilled water. On standing at room temperature
for 12 h, the oil crystallized. The solid material was triturated with
150 ml of absolute ethanol to discharge the dark red oily contaminant,
and the suspension was left in a refrigerator overnight. The resulting

Thioamides
1967
yellow powder was collected on a Bu¨chner filter and washed with 125 ml
of cold 1-chlorobutane. The air-dried powder was recrystallized from
600 ml of methanol to give 57.2 g (65% yield) of a yellow crystalline
material, m.p. 77–79◦C. On standing for 72 h, the methanol mother
liquors deposited additional material (3.7 g, m.p. 75–78◦C). Spectral
1
data: H NMR (500 MHz, CDCl3) δ: 3.37 (m, 2H, H-5ꢁ), 3.61 (m, 2H,
H-6ꢁ), 3.72 (m, 2H, H-2ꢁ), 4.34 (s, 2H, H-2), 4.25 (m, 2H, H-3ꢁ), 7.23 (m,
1H, ArH), 7.31 (m, 4H, ArH); 13C NMR (125 MHz, CDCl3) δ: 50.06
(C-2)ꢁꢁ, 50.50 (C-6ꢁ), 50.70 (C-3ꢁ), 65.99 (C-5ꢁ), 66.21 (C-2ꢁ), 127.01
(C-4 ), 127.11 (C-3ꢁꢁ), 127.66 (C-5ꢁꢁ), 128.84 (C-2ꢁꢁ and C-6ꢁꢁ), 135.70
(C-1ꢁꢁ), 199.91 (C S). Yield, 85%.
2-Biphenyl-4-yl-1-morpholin-4-yl-ethanethione
[(12, C18H19NOS), Thermal Conditions (1) and (2)]
A mixture of 26.5 g (0.135 mol) of 4-acetylbiphenyl, 8.0 g (0.25 mol) of
sulfur, and 40.0 g (0.46 mol) of morpholine was stirred and heated in an
oil bath at 135◦C for 6 h. The hot dark red reaction mixture was allowed
to cool overnight. On standing at room temperature for 12 h, the oil so-
lidified. This solid material was crystallized from 400 ml of absolute
ethanol. Overnight cooling in a refrigerator produced yellow crystals,
which were collected and washed twice with 125 ml of cold diethyl ether
to yield 34.1 g of a yellow gray material. A second crystallization from
700 ml of absolute ethanol gave 19.76 g, m.p. 73–74◦C, lit. 73–74◦C. In
method (2), 12.5 ml of DMF and 12.5 ml of 4 MM were added to the
reaction medium. The other conditions were the same as above. The
1
yield was 56%. Spectral data: H NMR (300 MHz, DMSO-d6) δ: 3.44
ꢁ
ꢁ
= 4.41 Hz, H-6ꢁ), 3.75
= 4.41 Hz, H-3ꢁ), 4.39
ꢁ
ꢁ
ꢁ
ꢁ
(t, 2H, J
(t, 2H, J
= 4.41 Hz, H-5 ), 3.67 (t, 2H, J
5 −6
6 −5
ꢁ
ꢁ
ꢁ
ꢁ
= 4.41 Hz, H-2 ), 4.37 (t, 2H, J
2 −3
3 −2
(s, 2H, H-2), 7.32–7.52 (m, 9H, ArH); 13C NMR (300 MHz, DMSO-d6)
δ: 50.18 (C-2), 50.27 (C-6ꢁ), 50.85 (C-3ꢁ), 66.19 (C-5ꢁ), 66.38 (C-2ꢁ), 127.01
(C-4ꢁꢁ), 127.46 (C-3ꢁꢁ and C-3ꢁꢁꢁ), 127.65 (C-5ꢁꢁ and C-5ꢁꢁꢁ), 128.24 (C-2ꢁꢁ
and C-6ꢁꢁ), 128.82 (C-2ꢁꢁꢁ and C-6ꢁꢁꢁ), 134.90 (C-4ꢁꢁꢁ), 140.14 (C-1ꢁꢁꢁ), 198.52
(C S). IR (cm−1) 3032, 1609, 1495 (s), 1446, 1435, 1112 (s); MS, m/e
(relative intensity) 221 (93), 188 (24), 134 (46), 130 (62), 91 (100),
86 (66).
2-Biphenyl-4-yl-1-morpholin-4-yl-ethanethione
[(12, C18H19NOS), mw Condition (3)]
A mixture of 26.5 g (0.135 mol) of 4-acetylbiphenyl, 8.0 g (0.25 mol) of
sulfur, 40.0 g (0.46 mol) of morpholine and 25 ml of DMF was placed
on the rotating plateau of a microwave oven and irradiated according

1968
J. H. Poupaert et al.
to the following scheme: after an initial pulse of 1 min at 750 W and
3.0 min rest, 25 pulses of 90 W of 1.5 min spaced out by 3.0 min were
applied. During thermal equilibration after each pulse, the dark red
reaction mixture was stirred. The hot reaction mixture was allowed
to cool overnight. On standing at room temperature for 12 h, the oil
crystallized. The solid material was triturated with 150 ml of absolute
ethanol to discharge the dark red oily contaminant, and the suspension
was left in a refrigerator overnight. The resulting yellow powder was
collected on a Bu¨chner filter and washed with 125 ml of cold diethyl
ether to give 28.1 g of rough material, which was recrystallized from
600 ml of absolute ethanol to give 25.0 g of a yellow crystalline material
(m.p. 74–75◦C). By reprocessing the mother liquors, an additional 2.4
g was obtained. The total yield was 27.39 g (58%). A lower yield (52%)
was registered when 25 pulses of 30 s at 240 W were applied.
N-Thiobenzoylbenzylamine [(14, C14H13NS), Oxidative
Self-Condensation]
A mixture of 80 g (74.6 mmol) of benzylamine and 40 g (124.7 mmol)
of sulfur were stirred magnetically for 15 min at room temperature,
during which time a reddish color soon developed and the smell of am-
monia was noticed. The reaction mixture was then stirred and heated
in an oil bath to 130◦C for 2 h. Throughout the whole process, the flask
was connected to a water aspirator to remove any hydrogen sulfide
and ammonia formed during the reaction. After partial cooling, the
reaction mixture was diluted with 250 ml of absolute ethanol and fil-
tered to remove some unreacted sulfur by paper filtration. On cooling
overnight, the filtrate deposited a yellow precipitate, which was col-
lected on a filter, dried, and recrystallized from petroleum ether to give
24.8 g (29%) of the desired compound. m.p. 85–87◦C. Rf = 0.45 (solvent
A), 0.67 (solvent B). The reaction gave a modest 23% yield by the mw
technique.
This material (entry 1) was similar in all respects to that obtained
by reacting benzaldehyde with benzylamine in the presence of sul-
fur (either by method (1) or method (3)). For method (3), 10 pulses of
240 W spaced out by 3 min were applied.
2-(4-Ethyl-phenyl)-1-morpholin-4-yl-ethanethione
[(15, C14H19NOS), mw Condition (3)]
m.p. 92.3◦C. Spectral data: 1H NMR (300 MHz, DMSO-d6) δ: 1.24
(t, 3H, J = 7.35 Hz, CH3), 2.69 (q, 2H, J = 7.35 Hz, CH2CH3), 3.39
ꢁ
= 4.41 Hz, H-6ꢁ), 3.72
ꢁ
ꢁ
ꢁ
ꢁ
(t, 2H, J
= 4.41 Hz, H-5 ), 3.61 (t, 2H, J
5 −6
6 −5

Thioamides
1969
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
(t, 2H, J
= 4.41 Hz, H-2 ), 4.31 (s, 2H, H-2), 4.34 (t, 2H, J
=
2 −3
3 −2
4.41 Hz, H-3ꢁ), 7.01–7.15 (m, 5H, ArH). 13C NMR (300 MHz, DMSO-d6)
δ: 15.15 (CH3), 27.87 (CH2CH3), 50.18 (C-2), 50.40 (C-6ꢁ), 50.77 (C-3ꢁ),
66.12 (C-5ꢁ), 66.36 (C-2ꢁ), 127.81 (C-3ꢁꢁ and C-5ꢁꢁ), 129.11 (C-2ꢁꢁ and C-6ꢁꢁ),
134.88 (C-1ꢁꢁ), 137.20 (C-4ꢁꢁ), 199.98 (C S). IR (cm−1): 3084, 2966, 2851,
1603 (C S), 1463, 1428. Yield, 63%.
2-(4-Propyl-phenyl)-1-morpholin-4-yl-ethanethione
[(16, C15H21NOS), mw Condition (3)]
m.p. 90.2◦C. Spectral data: 1H NMR (300 MHz, DMSO-d6) δ: 0.89
(t, 3H, J = 7.35 Hz, CH3), 1.64 (m, 2H, J = 7.35 Hz, CH2CH3), 2.55
= 4.41 Hz, H-5ꢁ),
= 4.41 Hz, H-2ꢁ),
ꢁ
ꢁ
(t, 2H, J = 7.35 Hz, CH2CH2CH3), 3.37 (t, 2H, J
5 −6
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
3.62 (t, 2H, J
= 4.41 Hz, H-6 ), 3.71 (t, 2H, J
6 −5
2 −3
4.31 (s, 2H, H-2), 4.35 (t, 2H, J
= 4.41 Hz, H-3ꢁ), 7.09–7.23 (m, 4H,
ꢁ
ꢁ
3 −2
ArH). 13C NMR (300 MHz, DMSO-d6) δ: 13.89 (CH3), 24.47 (CH2CH3),
37.65 (CH2CH2CH3), 50.21 (C-2), 50.41 (C-6ꢁ), 50.79 (C-3ꢁ), 66.12 (C-
5ꢁ), 66.38 (C-2ꢁ), 127.45 (C-3ꢁꢁ and C-5ꢁꢁ), 129.01 (C-2ꢁꢁ and C-6ꢁꢁ), 132.90
(C-1ꢁꢁ), 141.88 (C-4ꢁꢁ), 200.44 (C S). IR (cm−1): 3043, 2956, 1602, 1497,
1458, 1432 cm−1. Yield, 43%.
2-(4-Butyl-phenyl)-1-morpholin-4-yl-ethanethione
[(17, C16H23NOS), mw Condition (3)]
m.p. 94.2◦C. Spectral data: 1H NMR (300 MHz, DMSO-d6) δ: 0.93
(t, 3H, J = 7.35 Hz, CH2CH3), 1.34 (m, 2H, CH2CH3), 1.59 (m, 2H,
CH2CH2CH3), 2.56 (t, 2H, J = 7.35 Hz, CH2CH2CH2CH3), 3.38
ꢁ
= 4.41 Hz, H-6ꢁ),
ꢁ
ꢁ
ꢁ
ꢁ
(t, 2H, J
= 4.41 Hz, H-5 ), 3.63 (t, 2H, J
5 −6
6 −5
= 4.41 Hz, H-2ꢁ), 4.31 (s, 2H, H-2), 4.36 (t, 2H,
ꢁ
ꢁ
3.70 (t, 2H, J
2 −3
ꢁ
ꢁ
J
= 4.41 Hz, H-3ꢁ), 7.09–7.23 (m, 5H, ArH). 13C NMR (300 MHz,
3 −2
DMSO-d6) δ: 13.91 (CH3), 22.37 (CH2CH−3), 33.31 (CH2CH2CH3),
35.60 (CH2CH2CH2CH3), 50.20 (C-2), 50.39 (C-6ꢁ), 50.79 (C-3ꢁ), 66.12
(C-5ꢁ), 66.38 (C-2ꢁ) 128.36 (C-3ꢁꢁ and C-5ꢁꢁ), 129.65 (C-2ꢁꢁ and C-6ꢁꢁ), 133.02
(C-1ꢁꢁ), 136.40 (C-4ꢁꢁ), 140.89 (C-Ar), 200.35 (C S). IR (cm−1): 3051, 2921,
1609, 1497, 1459, 1439. Yield, 55%.
2-(4-Hexyl-phenyl)-1-morpholin-4-yl-ethanethione
[(18, C18H27NOS), mw Condition (3)]
m.p. 86.3◦C. Spectral data: 1H NMR (300 MHz, DMSO-d6) δ: 0.87
(t, 3H, J = 7.35 Hz, CH3), 1.29 [q, 6H, J = 7.35 Hz, (CH2)3CH3],
1.58 [m, 2H, J = 7.35 Hz, CH2(CH2)3CH3], 2.57 [t, 2H, J = 7.35 Hz,
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
CH2(CH2)4CH3], 3.38 (t, 2H, J
= 4.41 Hz, H-5 ), 3.63 (t, 2H, J
=
5 −6
6 −5
ꢁ
= 4.41 Hz, H-2ꢁ), 4.32 (s, 2H, H-2), 4.35
ꢁ
ꢁ
4.41 Hz, H-6 ), 3.73 (t, 2H, J
2 −3

1970
J. H. Poupaert et al.
= 4.41 Hz, H-3ꢁ), 7.11–7.26 (m, 4H, J = 7.35 Hz, ArH).
ꢁ
ꢁ
(t, 2H, J
3 −2
13C NMR (300 MHz, DMSO-d6) δ: 14.10 (CH3), 22.58 (CH2CH3), 28.29
(CH2CH2CH3), 31.38 [CH2(CH2)2CH3], 31.70 [CH2(CH2)3CH3], 35.59
[CH2(CH2)4CH3], 50.21 (C-2), 50.40 (C-6ꢁ), 50.79 (C-3ꢁ), 66.12 (C-5ꢁ),
66.38 (C-2ꢁ), 127.65 (C-3ꢁꢁ and C-5ꢁꢁ), 129.01 (C-2ꢁꢁꢁꢁ and C-6ꢁꢁ), 132.89
(C-1ꢁꢁ), 141.89 (C-4ꢁꢁ), 200.44 (C S). IR (cm−1): 2956, 2921, 1605, 1512,
1486, 1433. Yield, 49%.
2-(4-Octyl-phenyl)-1-morpholin-4-yl-ethanethione
[(19, C20H31NOS), mw Condition (3)]
m.p. 89.1◦C. Spectral data: 1H NMR (300 MHz, DMSO-d6) δ: 0.88
(t, 3H, J = 7.35 Hz, CH3), 1.26 [pm, 10H, (CH2)5CH3], 1.59 [t, 2H, J =
7.35 Hz, CH2(CH2)5CH3], 2.57 (t, 2H J = 7.35 Hz, CH2(CH2)6CH3),
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
3.40 (t, 2H, J
= 4.41 Hz, H-5 ), 3.63 (t, 2H, J
= 4.41 Hz,
5 −6
6 −5
H-6ꢁ), 3.73 (t, 2H,
J
2 −3
= 4.41 Hz, H-2ꢁ), 4.29 (s, 2H, H-2),
ꢁ
ꢁ
ꢁ
ꢁ
4.35 (t, 2H, J
= 4.41 Hz, H-3ꢁ), 7.12–7.23 (m, 4H, ArH). 13C
3 −2
NMR (300 MHz, DMSO-d6) δ: 14.03 (CH3), 22.65 (CH2CH3), 29.24
[(CH2)3(CH2)2CH3], 29.44 [(CH2)2(CH2)4CH3], 31.38 [CH2(CH2)5CH3],
31.83 [CH2CH2CH3], 35.52 [CH2(CH2)6CH3], 50.34 (C-2ꢁ and C-6ꢁ),
50.79 (C-2), 66.12 (C-3ꢁ), 66.32 (C-5ꢁ), 127.59 (C-3ꢁꢁ and C-5ꢁꢁ), 128.95
(C-2ꢁꢁ and C-6ꢁꢁ), 199.89 (C S). IR (cm−1): 2989, 2916, 1608, 1497, 1459,
1440. Yield, 62%.
2-[4-(2-Methyl-butyl)-phenyl]-1-morpholin-4-yl-
ethanethione [(20, C17H25NOS), mw Condition (3)]
m.p. 117.0◦C. Spectral data: 1H NMR (300 MHz, DMSO-d6) δ: 0.81
(t, 3H, J = 7.35 Hz, CH3CH2), 1.25 (d, 3H, J = 7.35 Hz, CH3CH), 1.61
ꢁ
ꢁ
(m, 2H, CH3CH2), 2.53 (m, 1H, CH3CH), 3.38 (t, 2H, J
= 4.41 Hz,
= 4.41 Hz,
5 −6
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
H-5 ), 3.62 (t, 2H, J
= 4.41 Hz, H-6 ), 3.72 (t, 2H, J
6 −5
2 −3
ꢁ
ꢁ
ꢁ
H-2 ), 4.31 (s, 2H, H-2), 4.35 (t, 2H, J
= 4.41 Hz, H-3ꢁ), 7.09–7.25
3 −2
(m, 4H, ArH). 13C NMR (300 MHz, DMSO-d6) δ: 12.16 (CH3CH2), 21.61
(CH3CH), 30.92 (CH2CH3), 42.31 (CH2CH), 50.20 (C-2), 50.33 (C-6ꢁ),
50.85 (C-3ꢁ), 66.24 (C-5ꢁ), 66.38 (C-2ꢁ), 127.59 (C-3ꢁꢁand C-5ꢁꢁ), 129.44
(C-2ꢁꢁand C-6ꢁꢁ), 133.48 (C-1ꢁꢁ), 138.22 (C-4ꢁꢁ), 200.31 (C S). IR (cm−1):
3082, 1603, 1485, 1462, 1434. Yield, 35%.
2-[4-(3-Methyl-butyl)-phenyl]-1-morpholin-4-yl-
ethanethione [(21, C17H25NOS), mw Condition (3)]
m.p. 78◦C. Spectral data: 1H NMR (300 MHz, DMSO-d6) δ: 0.88 (d, 6H,
J = 5.88 Hz, CH3), 1.86 (m, 1H, CH), 2.45 (t, 2H, CH2CH), 3.39 (t, 2H,

Thioamides
1971
ꢁ
= 4.41 Hz, H-6ꢁ), 3.73 (t, 2H,
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
J
J
= 4.41 Hz, H-5 ), 3.62 (t, 2H, J
5 −6
6 −5
ꢁ
ꢁ
ꢁ
ꢁ
= 4.41 Hz, H-2 ), 4.32 (s, 2H, H-2), 4,35 (t, 2H, J
= 4.41 Hz, H-
2 −3
3 −2
3ꢁ), 7.08–7.23 (m, 4H, ArH). 13C NMR (300 MHz, DMSO-d6) δ: 22.32
(CH3), 30.15 (CH), 45.03 (CH2CH), 50.21 (C-2), 50,40 (C-6ꢁ) 50.78
(C-3ꢁ), 66.12 (C-5ꢁ), 66.38 (C-2ꢁ), 127.53 (C-3ꢁꢁ and C-5ꢁꢁ), 129.66 (C-2ꢁꢁ
and C-6ꢁꢁ), 133.02 (C-1ꢁꢁ), 140.59 (C-4ꢁꢁ), 200.44 (C S). IR (cm−1): 3084,
1603, 1488, 1463, 1434. Yield, 58%.
1-Morpholin-4-yl-2-(5,6,7,8-tetrahydro-naphthalen-2-yl)-
ethanethione [(22, C16H21NOS), mw Condition (3)]
m.p. 111.8◦C. Spectral data: 1H NMR (300 MHz, DMSO-d6) δ: 1.80
(t, 4H, J = 5.88 Hz, C-6ꢁꢁ and C-7ꢁꢁ), 2.73 (t, 4H, C-5ꢁꢁ and C-8ꢁꢁ), 3.44 (t,
ꢁ
= 4.41 Hz, H-6ꢁ), 3.74 (t,
ꢁ
ꢁ
ꢁ
ꢁ
2H, J
2H, J
= 4.41 Hz, H-5 ), 3.65 (t, 2H, J
5 −6
6 −5
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
= 4.41 Hz, H-2 ), 4.27 (s, 2H, H-2), 4.35 (t, 2H, J
= 4.41 Hz,
2 −3
3 −2
H-3ꢁ), 6.99–7.03 (m, 3H, ArH). 13C NMR (300 MHz, DMSO-d6) δ: 23.16
(2CH2), 29.05 (CH2), 29.44 (CH2), 50.21 (C-2), 50.34 (C-6ꢁ), 50.79 (C-3ꢁ),
66.25 (C-5ꢁ), 66.38 (C-2ꢁ), 124.87 (C-2ꢁꢁ), 128.30 (C-3ꢁꢁ and C-9ꢁꢁ), 129.59
(C-1ꢁꢁ), 135.00 (C-4ꢁꢁ), 137.75 (C-9ꢁꢁ), 200.57 (C S). IR (cm−1): 2925, 2855,
1610, 1488, 1459, 1434. Yield, 61%.
2-(4-Cyclohexyl-phenyl)-1-morpholin-4-yl-ethanethione
[(23, C18H25NOS), mw Condition (3)]
m.p. 107.1◦C. Spectral data: 1H NMR (300 MHz, DMSO-d6) δ: 1.38
(t, 6H, J = 8.82 Hz, H-3ꢁꢁꢁ, H-4ꢁꢁꢁ and H-5ꢁꢁꢁ), 1.76 (pt, 4H, J = 7.35 Hz, H-
ꢁꢁꢁ
ꢁꢁꢁ
ꢁ
ꢁ
2 and H-6 ), 2.63 (m, 1H, J = 7.35 Hz, CH), 3.39 (t, 2H, J
= 4.41 Hz,
= 4.41 Hz, H-5 ), 3.74 (t, 2H, J 6 =−54.41 Hz, H-
ꢁ
ꢁ
ꢁ
ꢁ
5 −6
2ꢁ−3ꢁ
H-6 ), 3.36 (t, 2H, J
ꢁ
= 4.41 Hz, H-3ꢁ), 7.14–7.26 (m,
ꢁ
ꢁ
2 ), 4.31 (s, 2H, H-2), 4.35 (t, 2H, J
3 −2
4H, ArH). 13C NMR (300 MHz, DMSO-d6) δ: 26.14 (C-3ꢁꢁꢁ and C-5ꢁꢁꢁ),
26.85 (C-4ꢁꢁꢁ), 34.49 (C-2ꢁꢁꢁ and C-6ꢁꢁꢁ), 44.19 (CH), 50.21 (C-2), 50.34
(C-6ꢁ), 50.85 (C-3ꢁ), 66.12 (C-5ꢁ), 66.38 (C-2ꢁ), 127.39 (C-3ꢁꢁ and C-5ꢁꢁ),
127.71 (C-2ꢁꢁ and C-6ꢁꢁ), 133.02 (C-1ꢁꢁ), 147.06 (C-4ꢁꢁ), 200.37 (C S). IR
(cm−1): 3005, 2851, 1602, 1512, 1488, 1446. Yield, 65%.
(5-Chloro-2-hydroxy-phenyl)-morpholin-4-yl-
ethanethione [(24, C11H12ClNO2S), mw Condition (3)]
TLC system: CH2 Cl2:AcOEt 80:20 v/v Rf = 0.7; m.p. 186–190◦C. Spec-
tral data: 1H NMR (300 MHz, DMSO-d6) δ: 10.14 (Sbroad, 1H, OH), 7.20
(d, 2 H, J = 8.82 Hz, H-4 and H-6), 6.84 (d, 1 H, J = 8.82 Hz, H-3),
4−3
= 4.41 Hz, H-3 ), 3.73 (t, 2H, J 4−3= 4.41 Hz, H-2ꢁ),
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
4.25 (m, 2H, J
3 −2
= 4.41 Hz, H-4 ), 3.46 (t, 2H, J 2 =−34.41 Hz, H-5ꢁ); 13
C
ꢁ
ꢁ
ꢁ
4 −5
5ꢁ−4ꢁ
3.58 (t, 2H, J

1972
J. H. Poupaert et al.
NMR (300 MHz, DMSO-d6) δ: 193.51 (C S), 149.52 (C-2), 129.07 (C-6
and C-4), 127.78 (C-1), 122.34 (C-5), 117.10 (C-3), 65.86 (C-2ꢁ), 65.54
(C-5ꢁ), 51.56 (C-3ꢁ), 48.65 (C-4ꢁ). Yield, 89%.
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