Thiocarbamate-based synthesis of 2,4,5,6-tetrahydro-3H-1,2,4-triazepine-3-thiones

Article abstract of DOI:10.3184/174751917X14873588907729

A five-step synthesis of 5,7-diaryl-substituted 2,4,5,6-tetrahydro-3H-1,2,4-triazepine-3-thiones starting from ethyl thiocarbamate was developed. The synthesis included a three-component condensation of ethyl thiocarbamate with aromatic aldehydes and p-toluenesulfinic acid to give O-ethyl[(aryl)(tosyl)methyl]thiocarbamates which were transformed into the corresponding O-ethyl (3-phenyl-3-oxopropyl) thiocarbamates by treatment with the sodium enolate of dibenzoylmethane followed by base-promoted retro-Claisen condensation. Reaction of the prepared thiocarbamates with hydrazine and subsequent acid-catalysed cyclisation of the derived 4-[(3-hydrazono-3-phenyl)prop-1-yl]semicarbazides gave the target triazepines.

Full text of DOI:10.3184/174751917X14873588907729

JOURNAL OF CHEMICAL RESEARCH 2017
VOL. 41 MARCH, 149–156
RESEARCH PAPER 149
Thiocarbamate-based synthesis of 2,4,5,6-tetrahydro-3H-1,2,4-triazepine-3-
thiones
Ludmila A. Trafimova, Maxim O. Zimin and Anatoly D. Shutalev*
Department of Organic Chemistry, Moscow Technological University, 86 Vernadsky Avenue, 119571 Moscow, Russian Federation
A five-step synthesis of 5,7-diaryl-substituted 2,4,5,6-tetrahydro-3H-1,2,4-triazepine-3-thiones starting from ethyl thiocarbamate was
developed. The synthesis included a three-component condensation of ethyl thiocarbamate with aromatic aldehydes and p-toluenesulfinic
acid to give O-ethyl[(aryl)(tosyl)methyl]thiocarbamates which were transformed into the corresponding O-ethyl (3-phenyl-3-oxopropyl)
thiocarbamates by treatment with the sodium enolate of dibenzoylmethane followed by base-promoted retro-Claisen condensation.
Reaction of the prepared thiocarbamates with hydrazine and subsequent acid-catalysed cyclisation of the derived 4-[(3-hydrazono-3-
phenyl)prop-1-yl]semicarbazides gave the target triazepines.
Keywords: thiocarbamates, amidoalkylation, retro-Claisen reaction, thiosemicarbazides, 1,2,4-triazepine-3-thiones
The development of new general approaches to rare
heterocyclic scaffolds is one of the frontiers of contemporary
chemistry. Non-annulated 1,2,4-triazepines (for reviews, see
ref.1–5), particularly 1,2,4-triazepin-3-ones/thiones are typical
representatives of such scaffolds. Only a restricted number of
these compounds have been prepared by reaction of arylidene
ketones with N2H4·2HNCS,6 addition of (thio)semicarbazides
to α,β-unsaturated ketones or their synthetic equivalents,7–9
reaction of hydrazines with β-isocyanatoketones10,11 or
β-isothiocyanatoketones,12–16 condensation of 1,3-dicarbonyl
compounds with (thio)semicarbazides,17–24 CDI-mediated
cyclisation of 3-hydrazino-substituted amines,25–27 and reaction
of thiosemicarbazides with dimethyl acetylenedicarboxylate
and dibenzoylacetylene.28,29 Recently, we have developed a
new five-step approach to aryl substituted 2,4,5,6-tetrahydro-
3H-1,2,4-triazepin-3-ones 1 starting from ethyl carbamate.
The principal steps of this approach involved reaction of
ethyl [(3-oxo-3-phenyl)prop-1-yl]carbamates 2 with hydrazine
followed by acid-catalysed cyclisation of the prepared
prepared in three steps via formation of the amidoalkylation
reagents, ethyl N-(α-tosylbenzyl)carbamates 4.
It was important to extend the above methodology to
the preparation of 3-thioxo-analogues of compounds 1.
Herein, we report a five-step synthesis of aryl substituted
2,4,5,6-tetrahydro-3H-1,2,4-triazepine-3-thiones starting from
ethyl thiocarbamate.
Results and discussion
The first step of the triazepinethione synthesis involved
preparation of amidoalkylation reagents, the O-ethyl
(α-tosylbenzyl)thiocarbamates 9a–c (Scheme 2). Previously,
these compounds were obtained by Engberts and coworkers via
reaction of ethyl thiocarbamate with aromatic aldehydes and
sodium p-toluenesulfinate in aqueous formic acid.31 However,
some important experimental details (e.g. reaction time) and
relevant spectroscopic data of the compounds prepared were not
provided in the paper. Therefore, it was necessary to develop
suitable conditions for formation of thiocarbamates 9a–c.
Compound 9a was obtained by our convenient
modification30,32,33 of Engberts’ method31 using p-toluenesulfinic
4-[(3-hydrazono-3-phenyl)prop-1-yl]semicarbazides
3
into
the target triazepinones 1 (Scheme 1).30 Carbamates 2 were
Ph
H
H
H
H
Ar
N
NH
N2H4
Ph
N
N
Ph
TsOH
EtO
N
Ts
EtO
N
H2N
HN
Ar NNH2
O
Ar
O
Ar
O
O
O
4
2
3
1
Scheme 1 Synthesis of 2,4,5,6-tetrahydro-3H-1,2,4-triazepin-3-ones 1.
4-MeC H S(O)OH ( )
5
6
4
H2O, rt
Method A
O
O
H
O
H
EtO
NH2
EtO
N
S
+
R
4-MeC H S(O)ONa ( )
6
6
4
S
R
S
Me
rt
HCOOH/H
2O,
7
8a–c
9a–c
Method B
R = Ph, R = 4-MeC6H4, R = 4-MeOC6H4.
8–9a
b
c
Scheme 2 Synthesis of amidoalkylation reagents 9a–c.
* Correspondent. E-mail: shutalev@orc.ru

150 JOURNAL OF CHEMICAL RESEARCH 2017
acid 5 instead of its sodium salt 6 in the presence of HCOOH.
The three-component condensation of ethyl thiocarbamate 7
with equimolar amounts of benzaldehyde 8a and sulfinic acid 5
proceeded in water at room temperature for 24 h to give sulfone
9a (Scheme 2, Method A) which precipitated from the reaction
mixture and was isolated by filtration in 86% yield.
completion of the reaction between dibenzoylmethane and
NaH was hampered by formation of a dense suspension of
the enolate, reducing the yield and purity of the substitution
products. Sulfone 9a smoothly reacted with the sodium enolate
of acetylacetone in dry MeCN (r.t., 8 h) to give thiocarbamate
13 in 91% yield.
Under similar conditions, reaction of p-tolualdehyde 8b and
p-anisaldehyde 8c with ethyl thiocarbamate and sulfinic acid
5 gave condensation products as thick oils that could not be
solidified in any way. The use of 80% aqueous HCOOH as a
solvent afforded a positive result only in the case of aldehyde
8b. However, the yield of the obtained sulfone 9b did not
exceed 54% and its purity was not good enough for further
application. Our additional experimental studies showed that
compounds 9b,c could be prepared by reaction of aldehydes 8b
and 8c with equimolar amounts of ethyl thiocarbamate 7 and
sodium p-toluenesulfinate 6 in 16% aqueous HCOOH at room
temperature for 48 h (Scheme 2, Method B). Sulfones 9b and
9c precipitated from the reaction mixtures were isolated by
filtration in 70% and 65% yield, respectively.
O-Ethyl (3-oxo-3-phenylpropyl)thiocarbamates 14a–c were
prepared from 12a–c by retro-Claisen reaction using solutions
of KOH (5 equiv.) in 12–14% aqueous EtOH at room temperature
for 19–27 h. It should be noted that under all conditions
attempted, this reaction was accompanied by formation of
significant amounts of the corresponding chalcones arising
from base-catalysed eliminaton of ethyl thiocarbamate (7). As
a result, isolated yields of 12a–c were 35–48%. In contrast,
retro-Claisen reaction of 13 proceeded readily by treatment
with KOH (5.5 equiv.) in water at room temperature for 4 h to
give thiocarbamate 15 in high yield (86%).
Therefore, three-step syntheses of compounds 13a–c and
15, which are the first representatives of previously unknown
acyclic β-thiocarbamato ketones, have been developed.
Noteworthy, analogously to compounds 9a–c, thiocarbamates
12a–c, 13, 14a–c, and 15 were obtained as equilibrium mixtures
of two conformers around the thioamide C–N bond in ratios of
(62–71):(38–29) (NMR spectroscopic data for isolated crude
materials). These ratios did not change after recrystallisation of
these compounds.
Compounds 9a–c were obtained as white solids with
1
>95% purity according to H NMR spectroscopic data of the
crude products and used in the amidoalkylation step without
additional purification.
1
It should be noted that both H and 13C NMR spectra of
crude thiocarbamates 9a–c in DMSO-d6 at 25 °C, in contrast
to their carbamate analogues,30 showed the presence of two sets
of signals in a ratio of 80:20, 80:20, and 79:21, respectively.
These ratios did not change after recrystallisation of 9a–c from
ethanol. Therefore, it could be concluded that thiocarbamates
9a–c were formed as equilibrium mixtures of two conformers
that arise from a restricted rotation around the thioamide
C–N bond. Indeed, the DFT calculations at the B3LYP/6-
311++G(d,p) level of theory performed for two model
compounds, ethyl isopropylcarbamate i-PrNHCOOEt (10) and
O-ethyl isopropylthiocarbamate i-PrNHC(=S)OEt (11), in the
gas phase and also in DMSO solution using the PCM solvation
model showed that energy barriers of s-cis/s-trans (in respect to
the C–N bond) conformer interconversion are distinctly higher
for 11 than those for 10. For example, the Gibbs free energy
barriers of the s-trans to s-cis transformation for 10 and 11 in
DMSO are 16.9 and 20.5 kcal mol–1, respectively (298 K, 1 atm).
Reaction of sulfones 9a–c with the sodium enolate of
dibenzoylmethane, generated by treatment of dibenzoylmethane
with NaH, proceeded readily in dry THF at room temperature
for 8 h to afford the products of nucleophilic substitution of
the tosyl group, the thiocarbamates 12a–c, in 76–92% yields
(Scheme 3). When MeCN was used instead of THF, the
Next, we studied reaction of thiocarbamates 14a–c with excess
hydrazine resulting in the corresponding thiosemicarbazide
hydrazones 16a–c (Scheme 4).
We used anhydrous hydrazine as reagent and solvent that was
proved to be the best choice in the transformation of carbamates
2 into semicarbazides 3 (Scheme 1).30 However, in contrast to
carbamates 2, which gave semicarbazides 3 upon refluxing in
N2H4 for20–24h(28–46%yields),thereactionofthiocarbamates
14a–c with hydrazine proceeded under significantly milder
conditions, and in higher yields. Thus, treatment of 14a with
anhydrous N2H4 (80 equiv.) at room temperature for 2 h
followed by evaporation of all the volatiles under reduced
pressure and successive washing of the residue with diethyl
ether and water afforded thiosemicarbazide hydrazone 16a in
60% yield. The yield of 16a was slightly increased (70%) when
even milder reaction conditions were used (0 °C, 1 h). Under
similar conditions (0 °C, 1 h), thiocarbamates 14b and 14c were
transformed into thiosemicarbazides hydrazones 16b and 16c
in 58% and 65% yield, respectively.
We also studied the reaction of thiocarbamate 15 with
anhydrous hydrazine or hydrazine hydrate under various
conditions. However, despite numerous attempts, we failed
Ph
Ph
Ph
O
O
O
O
H
H
H
KOH
EtO
N
S
EtO
N
Ph
O
O
EtO
N
Ph
R
S
R
S
O
NaH, THF, rt
R
S
Me
9a–c
Me
12a–c
14a–c
Me
Me
O
H
N
KOH
H
EtO
Me
EtO
N
Me
O
O
Ph
S
O
Ph
S
O
NaH, MeCN, rt
13
15
12 14 a
b c
R = Ph, R = 4-MeC6H4, R = 4-MeOC6H4.
,
Scheme 3 Synthesis of β-thiocarbamato ketones 14a–c and 15.

JOURNAL OF CHEMICAL RESEARCH 2017 151
Ph
H
H
H
R
N
NH
N2H4
TsOH
N
N
Ph
EtO
N
Ph
H2N
HN
R
H2N
N
S
R
S
O
S
14a–c
16a–c
R = Ph, R = 4-MeC6H4, R = 4-MeOC6H4.
18a–c
16,18 a
b
c
H
N
H
H
N2H4
EtO
Me
N
N
Me
H2N
Ph
15
S
Ph NNH2
S
O
17
Scheme 4 Synthesis of 2,4,5,6-tetrahydro-3H-1,2,4-triazepine-3-thiones 18a–c.
referenced to the residual proton signal in DMSO-d6 (2.50 ppm).
In 13C NMR spectra, central signal of DMSO-d6 (39.50 ppm) was
used as a reference. Multiplicities are reported as singlet (s), doublet
(d), triplet (t), quartet (q), and some combinations of these, multiplet
(m). Selective 1H–1H decoupling and DEPT-135 experiments were
to develop a preparative procedure for the synthesis of
thiosemicarbazide hydrazone 17. The reaction proceeded very
fast, even at 0 °C, providing the target hydrazone 17 along with
a complex mixture of unidentified products.
According to 1H NMR spectroscopic data, thiosemicarbazides
16a–c were formed as mixtures of two geometric isomers
with significant predominance of the E-isomer (87–95%).
used to aid in the assignment of H and 13C NMR signals. H NMR
signals for thiocarbamates 9–15 may be followed by the symbols:
* indicates overlap with signals from the minor conformer, and §
indicates overlap with signals from the major conformer. Elemental
analyses (CHN) were performed by using a Thermo Finnigan Flash
EA1112 apparatus. Thin-layer chromatography was carried out on
Aldrich silica gel 60 F254 aluminum backed plates in CHCl3 and CHCl3/
MeOH (9:1, v/v) as solvent systems. Spots were visualised with UV
light or iodine vapours. Column chromatography was performed with
Macherey–Nagel silica gel 60 (0.063–0.200 mm) or Macherey–Nagel
aluminium oxide 90 neutral (activity 1). The DFT calculations were
carried out at the B3LYP level of theory using Gaussian 09 suite35
of quantum chemical programs. Pople’s basis set, 6-311++G(d,p),
was employed for geometry optimisation. The effect of continuum
solvation was incorporated by using the polarisable continuum
model (PCM). Enthalpies and Gibbs free energies were obtained by
adding unscaled zero-point vibrational energy corrections (ZPVE)
and thermal contributions to the energies. All yields refer to isolated,
spectroscopically and TLC pure compounds. All products were
colourless and obtained as white crystalline solids.
1
1
1
The stereochemical assignments were based on H and 13C
NMR spectroscopic data, 1H,1H NOESY experiment for 16a in
DMSO-d6, and comparison of 1H and 13C NMR spectra of 16a–
c with those of structurally similar semicarbazides.30 For the
major isomer of 16a, NOE was observed between the C=NNH2
and CH2 protons, and no NOE correlation was detected between
the ortho-phenyl protons of the PhC=N fragment and the
C=NNH2 protons, thus confirming the E-configuration of the
C=N double bond in this isomer.
Finally, we studied the heterocyclisation of 16a–c in the
presence of TsOH (1.05 equiv.). This reaction readily proceeded
in refluxing EtOH for 0.5–1 h to give triazepines 18a–c
(Scheme 4) which were isolated in 46–57% yields using column
chromatography on aluminium oxide or silica gel.
In summary, we have demonstrated that the acid-catalysed
cyclisation of the hydrazones of 4-(1,3-diaryl-3-oxopropyl)
thiosemicarbazides provides an efficient access to 5,7-diaryl-
substituted 2,4,5,6-tetrahydro-3H-1,2,4-triazepine-3-thiones.
The starting thiosemicarbazides were readily prepared
according to our original four-step approach involving
amidoalkylation of the sodium enolate of dibenzoylmethane
with O-ethyl[(aryl)(tosyl)methyl]thiocarbamates followed
by base-promoted retro-Claisen reaction and treatment of the
obtained N-(3-oxopropyl)thiocarbamates with hydrazine.
O-Ethyl [(phenyl)(tosyl)methyl]thiocarbamate (9a)
p-Toluenesulfinic acid (5) (17.83 g, 110 mmol) and H2O (50 mL) were
added to a stirred emulsion of benzaldehyde (8a) (12.11 g, 110 mmol)
in H2O (50 mL) and the resulting mixture was stirred for 30 min at
room temperature. Ethyl thiocarbamate (7) (12.01 g, 110 mmol) and
H2O (40 mL) were added to the formed suspension and the mixture was
stirred for 24 h at room temperature, cooled to 0 °C. The precipitate
was filtered, washed with ice-cold H2O and petroleum ether, and
dried to give thiocarbamate 9a (34.22 g, 86%) as a mixture of two
conformers in a ratio of 80:20. This product was used in the next step
without additional purification. An analytically pure sample (a 80:20
conformer mixture) was obtained after crystallisation from EtOH.
M.p. 154−155.5 °C (decomp., EtOH) (lit.31 145.5−147 °C); IR (Nujol)
Experimental
All solvents were distilled before use. p-Toluenesulfinic acid 5 was
synthesised by treatment of a saturated aqueous solution of sodium
p-toluenesulfinate 634 with hydrochloric acid at 0 °C, dried over P2O5,
and stored at 0 °C. Sodium hydride (60% suspension in mineral oil)
was thoroughly washed with dry hexane and dried under vacuum
prior to use. Anhydrous hydrazine was obtained by refluxing with
an equal weight of KOH pellets for 3 h under argon followed by
distillation, and this operation was repeated twice. All other reagents
and solvents were purchased from commercial sources and used
without further treatment. FTIR spectra were recorded using a
Bruker Vector 22 spectrophotometer in Nujol for solid samples.
Band characteristics in the IR spectra are defined as very strong
(vs), strong (s), medium (m), weak (w), shoulder (sh), and broad
ν
max/cm–1: 3296 (vs) (NH), 3086 (w), 3060 (w), 3040 (w), 3030 (w)
(CHarom), 1593 (m) (CCarom), 1506 (s) (thioamide-II), 1494 (m) (CCarom),
1316 (s), 1303 (s) (SO2), 1219 (s) (C–O), 1146 (s) (SO2), 809 (s), 703 (s)
(CHarom); 1H NMR of the major conformer (300.13 MHz, DMSO-d6) δ:
10.71 (1H, d, 3J = 10.6 Hz, NH), 7.38–7.79* (9H, m, ArH), 6.82 (1H, d,
3J = 10.6 Hz, CHN), 4.19–4.38 (2H, m, OCH2), 2.40 (3H, s, CH3 in Ts),
1.15 (3H, t, 3J = 7.1 Hz, CH3 in OEt); 1H NMR of the minor conformer
(300.13 MHz, DMSO-d6) δ: 10.44 (1H, d, 3J = 10.5 Hz, NH), 7.38–7.79§
(9H, m, ArH), 6.35 (1H, d, 3J = 10.5 Hz, CHN), 4.05–4.16 (1H, m, HA
in OCH2), 3.80–3.91 (1H, m, HB in OCH2), 2.41 (3H, s, CH3 in Ts),
0.97 (3H, t, 3J = 7.1 Hz, CH3 in OEt); 13C NMR of the major conformer
(75.48 MHz, DMSO-d6) δ: 191.50 (C=S), 144.90 (C), 133.70 (C),
1
(br). H NMR and proton-decoupled 13C NMR spectra (solutions in
DMSO-d6) were acquired using a Bruker DPX 300 spectrometer at
1
300.13 MHz (1H) and 75.48 MHz (13C). H NMR chemical shifts are

152 JOURNAL OF CHEMICAL RESEARCH 2017
129.81 (C), 129.73 (2CH), 129.63 (2CH), 129.58 (CH), 129.23 (2CH),
128.37 (2CH), 78.04 (CHN), 66.60 (OCH2), 21.17 (CH3 in Ts),
14.03 (CH3 in OEt); 13C NMR of the minor conformer (75.48 MHz,
DMSO-d6) δ: 187.87 (C=S), 144.97 (C), 134.07 (C), 130.03 (2CH),
129.69 (2CH), 129.13 (2CH), 128.23 (2CH), 74.78 (CHN), 66.80
(OCH2), 21.11 (CH3 in Ts), 13.40 (CH3 in OEt), signals of two carbons
are not resolved in the aromatic region. Anal. calcd for C17H19NO3S2: C,
58.43; H, 5.48; N, 4.01; found: C, 58.72; H, 5.60; N, 4.06%.
144.73 (C), 133.85 (C), 131.11 (2CH), 129.58 (2CH), 129.18 (2CH),
121.50 (C), 113.80 (2CH), 77.64 (CHN), 66.50 (OCH2), 55.23 (OCH3),
21.14 (CH3 in Ts), 14.02 (CH3 in OEt). Anal. calcd for C18H21NO4S2: C,
56.97; H, 5.58; N, 3.69; found: C, 57.16; H, 5.72; N, 3.76%.
O-Ethyl
(12a)
[(2-benzoyl-3-oxo-1,3-diphenyl)prop-1-yl]thiocarbamate
Dry THF (8 mL) was added to a mixture of dibenzoylmethane
(0.605 g, 2.70 mmol) and NaH (0.065 g, 2.70 mmol). The mixture
was stirred in an ice-cold bath for 30 min, and to the resulting solution
were added sulfone 9a (0.940 g, 2.69 mmol) and THF (4 mL). The
suspension was stirred at room temperature for 8 h, and solvent was
removed in a vacuum. Saturated aqueous NaHCO3 (4 mL) and
petroleum ether (4 mL) was added to a solid residue and the obtained
mixture was triturated until complete crystallisation and the resulting
suspension was cooled to 0 °C. The precipitate was filtered, washed
with ice-cold water and petroleum ether, and dried to give 12a
(1.039 g, 92%) as a mixture of two conformers in a ratio of 63:37. An
analytically pure sample (a 63:37 conformer mixture) was obtained
after crystallisation from EtOH. M.p. 109−111 °C (decomp., EtOH);
IR (Nujol) νmax/cm–1: 3302 (br vs) (NH), 3104 (w), 3060 (m), 3028 (w)
(CHarom), 1687 (vs), 1658 (m) (C=O), 1594 (s), 1578 (m) (CCarom), 1520
(s) (thioamide-II), 1495 (m) (CCarom), 1282 (s), 1188 (s) (C–O), 770
(m), 699 (s), 688 (s) (CHarom); 1H NMR of the major conformer (300.13
MHz, DMSO-d6) δ: 9.68 (1H, d, 3J = 8.5 Hz, NH), 7.94–8.01* (2H, m,
ArH), 7.70–7.77* (2H, m, ArH), 7.45–7.65* (4H, m, ArH), 7.31–7.43*
O-Ethyl [(4-methylphenyl)(tosyl)methyl]thiocarbamate (9b)
9.775 g of sodium p-toluenesulfinate hydrate (6) (86.2 wt%; 8.426 g,
47.28 mmol) was added to a stirred solution of p-tolyl aldehyde (8b)
(6.248 g, 52.0 mmol) in 81% aqueous HCOOH (11.8 mL). Ethyl
thiocarbamate (7) (4.973 g, 47.29 mmol) and H2O (47.5 mL) were
then added to the formed solution . An emulsion resulted, which
gradually turned into a suspension. The reaction mixture was stirred
for 48 h at room temperature and cooled to 0 °C. The precipitate
was filtered, washed with ice-cold H2O and petroleum ether, and
dried to give thiocarbamate 9b (12.015 g, 70%) as a mixture of two
conformers in a ratio of 80:20. This product was used in the next step
without additional purification. An analytically pure sample (a 80:20
conformer mixture) was obtained after crystallisation from EtOH.
M.p.136−138 °C (decomp., EtOH) (lit.31 138−139 °C); IR (Nujol) νmax
/
cm–1 : 3337 (br s) (NH), 3062 (w), 3033 (m) (CHarom), 1597 (m) (CCarom),
1506 (s) (thioamide-II), 1303 (s) (SO2), 1211 (s), 1188 (s) (C-O), 1144
1
(s) (SO2), 816 (s) (CHarom); H NMR of the major conformer (300.13
MHz, DMSO-d6) δ: 10.64 (1H, d, 3J = 10.6 Hz, NH), 7.19–7.77* (8H,
m, ArH), 6.76 (1H, d, 3J = 10.6 Hz, CHN), 4.19–4.37 (2H, m, OCH2),
2.40 (3H, s, CH3 in Ts), 2.32 (3H, s, CH3 in CH3C6H4), 1.14 (3H, t,
(4H, m, ArH), 7.03–7.22* (3H, m, ArH), 6.46 (1H, d, J = 10.3 Hz,
3
CHC=O), 6.15 (1H, dd, 3J = 10.3, 3J = 8.5 Hz, CHN), 4.16–4.39*
(2H, m, OCH2), 1.15 (3H, t, 3J = 7.1 Hz, CH3 in OEt); 1H NMR of the
minor conformer (300.13 MHz, DMSO-d6) δ: 9.74 (1H, d, 3J = 8.3 Hz,
NH), 7.94–8.01§ (2H, m, ArH), 7.70–7.77§ (2H, m, ArH), 7.45–7.65§
(4H, m, ArH), 7.31–7.43§ (4H, m, ArH), 7.03–7.22§ (3H, m, ArH),
1
3J = 7.1 Hz, CH3 in OEt); H NMR of the minor conformer (300.13
§
3
MHz, DMSO-d6) δ: 10.37 (1H, d, J = 10.4 Hz, NH), 7.19–7.77 (8H,
3
m, ArH), 6.29 (1H, d, J = 10.4 Hz, CHN), 4.05–4.15 (1H, m, HA in
3
3
3
OCH2), 3.79–3.89 (1H, m, HB in OCH2), 2.41 (3H, s, CH3 in Ts),
6.50 (1H, d, J = 10.4 Hz, CHC=O), 5.80 (1H, dd, J = 10.4, J = 8.3
2.32 (3H, s, CH3 in CH3C6H4), 0.97 (3H, t, J = 7.1 Hz, CH3 in OEt);
Hz, CHN), 4.16–4.39§ (2H, m, OCH2), 1.14 (3H, t, J = 7.1 Hz, CH3
3
3
13C NMR of the major conformer (75.48 MHz, DMSO-d6) δ: 191.42
(C=S), 144.79 (C), 139.15 (C), 133.81 (C), 129.60 (4CH), 129.19
(2CH), 128.90 (2CH), 126.74 (C), 77.86 (CHN), 66.52 (OCH2), 21.14
(CH3 in Ts), 20.81 (CH3 in CH3C6H4), 14.01 (CH3 in OEt). Anal. calcd
for C18H21NO3S2: C, 59.48; H, 5.82; N, 3.85; found: C, 59.48; H, 5.93;
N, 3.92%.
in OEt); 13C NMR of the major conformer (75.48 MHz, DMSO-d6) δ:
193.21 (C=O in Bz), 192.39 (C=O in Bz), 189.17 (C=S), 138.99 (C),
136.11 (C), 135.49 (C), 133.98 (CH), 133.88 (CH), 128.95 (2CH),
128.85 (2CH), 128.56 (2CH), 128.39 (2CH), 128.04 (4CH), 127.39
(CH), 65.46 (OCH2), 59.68 (CHBz2), 58.61 (CHN), 14.05 (CH3 in OEt);
13C NMR of the minor conformer (75.48 MHz, DMSO-d6) δ: 193.23
(C=O in Bz), 192.28 (C=O in Bz), 187.64 (C=S), 138.77 (C), 136.01
(C), 135.38 (C), 133.89 (CH), 128.98 (2CH), 128.86 (2CH), 128.53
(2CH), 128.46 (2CH), 128.24 (2CH), 127.68 (2CH), 127.61 (CH),
66.44 (OCH2), 59.30 (CHBz2), 56.71 (CHN), 13.92 (CH3 in OEt), a
signal of one aromatic carbon (CH) could not be detected. Anal. calcd
for C25H23NO3S: C, 71.92; H, 5.55; N, 3.36; found: C, 71.89; H, 5.66; N,
3.50%.
O-Ethyl [(4-methoxylphenyl)(tosyl)methyl]thiocarbamate (9c)
9.874 g of sodium p-toluenesulfinate hydrate (6) (86.2 wt%; 8.511
g, 47.76 mmol) was added to a stirred solution of p-anisaldehyde
(8c) (7.153 g, 52.54 mmol) in 81% aqueous HCOOH (12 mL). Ethyl
thiocarbamate (7) (5.023 g, 47.77 mmol) and H2O (48 mL) were
then added to the formed solution. An emulsion resulted, which
gradually turned into a suspension. The reaction mixture was stirred
for 48 h at room temperature and cooled to 0 °C. The precipitate
was filtered, washed with ice-cold H2O and petroleum ether, and
dried to give thiocarbamate 9c (11.850 g, 65%) as a mixture of two
conformers in a ratio of 79:21. This product was used in the next step
without additional purification. An analytically pure sample (a 79:21
conformer mixture) was obtained after crystallisation from EtOH.
M.p.130.5−132 °C (decomp., EtOH) (lit.31 133−134.5 °C); IR (Nujol)
O-Ethyl {[2-benzoyl-1-(4-methylphenyl)-3-oxo-3-phenyl]prop-1-yl}
thiocarbamate (12b)
Compound 12b (0.459 g, 76%) as a mixture of two conformers in a
ratio of 63:37 was prepared from dibenzoylmethane (0.316 g, 1.41
mmol), NaH (0.033 g, 1.38 mmol) and sulfone 9b (0.505 g, 1.39 mmol)
in dry THF (8 mL) (r.t., 8 h) as described for 12a. An analytically pure
sample (a 63:37 conformer mixture) was obtained after crystallisation
ν
max/cm–1: 3361 (sh), 3325 (br s) (NH), 3099 (w), 3081 (w), 3063 (w),
from EtOH. M.p. 118.5−120 °C (decomp., EtOH); IR (Nujol) νmax/
3045 (w), 3033 (w), 3011 (w) (CHarom), 1611 (s), 1596 (s), 1586 (m)
(CCarom), 1513 (s), 1505 (s) (thioamide-II), 1303 (s) (SO2), 1254 (s),
1208 (s), 1183 (s) (C–O), 1144 (SO2), 838 (s), 817 (s) (CHarom); 1H NMR
cm–1: 3350 (s), 3316 (s) (NH), 3103 (w), 3056 (m), 3034 (w), 3027 (w)
(CHarom), 1685 (vs), 1659 (m) (C=O), 1595 (s), 1578 (m) (CCarom), 1517
(s) (thioamide-II), 1282 (s), 1189 (s) (C–O), 826 (m), 767 (m), 707
3
1
of the major conformer (300.13 MHz, DMSO-d6) δ: 10.62 (1H, d, J
(s), 683 (s) (CHarom); H NMR of the major conformer (300.13 MHz,
= 10.6 Hz, NH), 7.38–7.76* (6H, m, ArH), 6.94–7.00* (2H, m, ArH),
6.74 (1H, d, 3J = 10.6 Hz, CHN), 4.19–4.37 (2H, m, OCH2), 3.77 (3H,
s, OCH3), 2.39 (3H, s, CH3 in Ts), 1.14 (3H, t, 3J = 7.1 Hz, CH3 in OEt);
1H NMR of the minor conformer (300.13 MHz, DMSO-d6) δ: 10.36
DMSO-d6) δ: 9.61 (1H, d, 3J = 8.6 Hz, NH), 7.95–8.02* (2H, m, ArH),
7.71–7.78* (2H, m, ArH), 7.37–7.65* (6H, m, ArH), 7.22–7.29* (2H, m,
ArH), 6.95–7.02* (2H, m, ArH), 6.44 (1H, d, 3J = 10.3 Hz, CHC=O),
6.14 (1H, dd, 3J = 10.3, 3J = 8.6 Hz, CHN), 4.15–4.38* (2H, m, OCH2),
§
§
3
3
(1H, d, J = 10.4 Hz, NH), 7.38–7.76 (6H, m, ArH), 6.94–7.00 (2H,
2.121 (3H, s, CH3 in CH3C6H4), 1.14 (3H, t, J = 7.1 Hz, CH3 in OEt);
3
m, ArH), 6.28 (1H, d, J = 10.4 Hz, CHN), 4.05–4.15 (1H, m, HA in
1H NMR of the minor conformer (300.13 MHz, DMSO-d6) δ: 9.67 (1H,
d, 3J = 8.4 Hz, NH), 7.95–8.02§ (2H, m, ArH), 7.71–7.78§ (2H, m, ArH),
7.37–7.65§ (6H, m, ArH), 7.22–7.29§ (2H, m, ArH), 6.95–7.02§ (2H,
m, ArH), 6.49 (1H, d, 3J = 10.5 Hz, CHC=O), 5.79 (1H, dd, 3J = 10.5,
OCH2), 3.79–3.89 (1H, m, HB in OCH2), 3.78 (3H, s, OCH3), 2.41 (3H,
3
s, CH3 in Ts), 0.97 (3H, t, J = 7.1 Hz, CH3 in OEt); 13C NMR of the
major conformer (75.48 MHz, DMSO-d6) δ: 191.36 (C=S), 160.21 (C),

JOURNAL OF CHEMICAL RESEARCH 2017 153
3J = 8.4 Hz, CHN), 4.15–4.38§ (2H, m, OCH2), 2.115 (3H, s, CH3 in
CH3C6H4), 1.16 (3H, t, 3J = 7.1 Hz, CH3 in OEt); 13C NMR of the major
conformer (75.48 MHz, DMSO-d6) δ: 193.10 (C=O in Bz), 192.52
(C=O in Bz), 189.07 (C=S), 136.50 (C), 136.14 (C), 136.06 (C), 135.59
(C), 133.88 (CH), 133.83 (CH), 128.92 (2CH), 128.87 (2CH), 128.61
(2CH), 128.57 (2CH), 128.40 (2CH), 127.97 (2CH), 65.39 (OCH2),
59.83 (CHBz2), 58.36 (CHN), 20.57 (CH3 in CH3C6H4), 14.05 (CH3
in OEt); 13C NMR of the minor conformer (75.48 MHz, DMSO-d6) δ:
193.13 (C=O in Bz), 192.39 (C=O in Bz), 187.55 (C=S), 136.74 (C),
136.04 (C), 135.84 (C), 135.49 (C), 133.96 (CH), 133.93 (CH), 128.95
(2CH), 128.88 (2CH), 128.79 (2CH), 128.57 (2CH), 128.47 (2CH),
127.63 (2CH), 66.42 (OCH2), 59.45 (CHBz2), 56.46 (CHN), 20.56
(CH3 in CH3C6H4), 13.95 (CH3 in OEt). Anal. calcd for C26H25NO3S: C,
72.36; H, 5.84; N, 3.25; found: C, 72.29; H, 5.90; N, 3.32%.
1701 (s) (C=O), 1584 (w) (CCarom), 1533 (m), 1521 (s) (thioamide-II),
1495 (m) (CCarom), 1262 (s), 1194 (s) (C–O), 769 (s), 702 (s) (CHarom);
1H NMR of the major conformer (300.13 MHz, DMSO-d6) δ: 9.72 (1H,
3
3
d, J = 8.9 Hz, NH), 7.21–7.3* (5H, m, ArH), 5.83 (1H, dd, J = 11.4,
3
3J = 8.9 Hz, CHN), 4.57 (1H, d, J = 11.4 Hz, CHC=O), 4.20–4.37*
(2H, m, OCH2), 2.23 (3H, s, CH3 in Ac), 1.874 (3H, s, CH3 in Ac),
1.20 (3H, t, 3J = 7.1 Hz, CH3 in OEt); 1H NMR of the minor conformer
(300.13 MHz, DMSO-d6) δ: 9.67 (1H, d, 3J = 8.3 Hz, NH), 7.21–7.39§
(5H, m, ArH), 5.36 (1H, dd, 3J = 11.4, 3J = 8.3 Hz, CHN), 4.67 (1H, d,
3J = 11.4 Hz, CHC=O), 4.20–4.37§ (2H, m, OCH2), 2.26 (3H, s, CH3
in Ac), 1.868 (3H, s, CH3 in Ac), 1.17 (3H, t, 3J = 7.1 Hz, CH3 in OEt);
13C NMR of the major conformer (75.48 MHz, DMSO-d6) δ: 201.09
(C=O in Ac), 200.95 (C=O in Ac), 189.26 (C=S), 139.07 (C), 128.33
(2CH), 127.82 (2CH), 127.70 (CH), 71.64 (CHAc2), 65.63 (OCH2),
57.56 (CHN), 31.03 (CH3 in Ac), 29.62 (CH3 in Ac), 14.09 (CH3 in
OEt); 13C NMR of the minor conformer (75.48 MHz, DMSO-d6) δ:
200.82 (C=O in Ac), 200.58 (C=O in Ac), 187.49 (C=S), 139.06 (C),
128.51 (2CH), 127.82 (CH), 127.51 (2CH), 70.51 (CHAc2), 66.36
(OCH2), 55.56 (CHN), 31.07 (CH3 in Ac), 30.56 (CH3 in Ac), 13.93
(CH3 in OEt). Anal. calcd for C15H19NO3S: C, 61.41; H, 6.53; N, 4.77;
found: C, 61.43; H, 6.71; N, 4.82%.
O-Ethyl {[2-benzoyl-1-(4-methoxyphenyl)-3-oxo-3-phenyl]prop-1-yl}
thiocarbamate (12c)
Compound 12c (4.367 g, 85%) as a mixture of two conformers in
a ratio of 62:38 was prepared from dibenzoylmethane (2.573 g,
11.47 mmol), NaH (0.275 g, 11.46 mmol) and sulfone 9c (4.350 g,
11.46 mmol) in dry THF (22 mL) (r.t., 8 h) as described for 12a. An
analytically pure sample (a 62:38 conformer mixture) was obtained
after crystallisation from EtOH. M.p. 125−127 °C (decomp., EtOH);
IR (Nujol) νmax/cm–1: 3276 (br vs) (NH), 3057 (m), 3009 (w) (CHarom),
1685 (vs), 1659 (m) (C=O), 1610 (m), 1593 (s), 1577 (m) (CCarom),
1517 (s) (thioamide-II), 1493 (w) (CCarom), 1280 (s), 1183 (s) (C–
O-Ethyl [(3-oxo-1,3-diphenyl)prop-1-yl]thiocarbamate (14a)
Thiocarbamate 12a (3.556 g, 8.52 mmol) and EtOH (4.2 mL) were
added to a stirred solution of KOH (2.374 g, 42.31 mmol) in H2O
(30 mL) at room temperature. A gummy substance resulted which
gradually solidified (in about 3.5 h). Then, the obtained solid was
triturated until complete crystallisation, and the resulting suspension
was stirred at room temperature. After 27 h 20 min from the beginning
of the reaction, the suspension was cooled to 0 °C. The precipitate
was filtered, washed with ice-cold water (4 × 5 mL), then washed
thoroughly with petroleum ether to remove chalcone, and dried to give
compound 14a (1.285 g, 48%) as a mixture of two conformers in a ratio
of 67:33. An analytically pure sample (a 67:33 conformer mixture) was
obtained after crystallisation from ethanol/water mixture (v/v = 8:3).
M.p. 94−95 °C (EtOH–H2O); IR (Nujol) νmax/cm–1: 3301 (br s), 3268
(sh) (NH), 3083 (w), 3056 (m), 3031 (m) (CHarom), 1690 (s) (C=O),
1595 (m), 1580 (w) (CCarom), 1537 (s) (thioamide-II), 1496 (m) (CCarom),
1227 (s), 1202 (s), 1175 (s) (C–O), 766 (s), 696 (s), 689 (s) (CHarom);
1H NMR of the major conformer (300.13 MHz, DMSO-d6) δ: 9.64 (1H,
d, 3J = 8.1 Hz, NH), 7.91–7.98* (2H, m, ArH), 7.60–7.68* (1H, m, ArH),
7.48–7.57* (2H, m, ArH), 7.19–7.39* (5H, m, ArH), 5.74 (1H, ddd,
3J = 8.9, 3J = 8.1, 3J = 5.4 Hz, CHN), 4.23–4.39* (2H, m, OCH2), 3.70
(1H, dd, 2J = 17.4, 3J = 8.9 Hz, HA in CH2C=O), 3.42 (1H, dd, 2J = 17.4,
1
O), 834 (s), 768 (s), 707 (s), 688 (s) (CHarom); H NMR of the major
conformer (300.13 MHz, DMSO-d6) δ: 9.60 (1H, d, 3J = 8.6 Hz, NH),
7.95–8.01* (2H, m, ArH), 7.72–7.78* (2H, m, ArH), 7.37–7.65* (6H,
m, ArH), 7.24–7.33* (2H, m, ArH), 6.70–6.77* (2H, m, ArH), 6.43
3
3
3
(1H, d, J = 10.3 Hz, CHC=O), 6.11 (1H, dd, J = 10.3, J = 8.6 Hz,
CHN), 4.16–4.40* (2H, m, OCH2), 3.611 (3H, s, OCH3), 1.15 (3H, t,
1
3J = 7.1 Hz, CH3 in OEt); H NMR of the minor conformer (300.13
MHz, DMSO-d6) δ: 9.64 (1H, d, 3J = 8.4 Hz, NH), 7.95–8.01§ (2H, m,
ArH), 7.72–7.78§ (2H, m, ArH), 7.37–7.65§ (6H, m, ArH), 7.24–7.33§
(2H, m, ArH), 6.70–6.77§ (2H, m, ArH), 6.47 (1H, d, J = 10.5 Hz,
3
CHC=O), 5.78 (1H, dd, 3J = 10.5, 3J = 8.4 Hz, CHN), 4.16–4.40§ (2H,
m, OCH2), 3.606 (3H, s, OCH3), 1.17 (3H, t, 3J = 7.1 Hz, CH3 in OEt);
13C NMR of the major conformer (75.48 MHz, DMSO-d6) δ: 193.13
(C=O in Bz), 192.49 (C=O in Bz), 188.99 (C=S), 158.34 (C), 136.16
(C), 135.61 (C), 133.83 (CH), 133.81 (CH), 130.97 (C), 129.23 (2CH),
128.90 (2CH), 128.84 (2CH), 128.55 (2CH), 128.38 (2CH), 113.39
(2CH), 65.34 (OCH2), 59.93 (CHBz2), 58.07 (CHN), 54.92 (OCH3),
14.03 (CH3 in OEt); 13C NMR of the minor conformer (75.48 MHz,
DMSO-d6) δ: 193.18 (C=O in Bz), 192.39 (C=O in Bz), 187.51 (C=S),
158.44 (C), 136.06 (C), 135.50 (C), 133.91 (CH), 133.90 (CH), 130.76
(C), 128.93 (2CH), 128.90 (2CH), 128.86 (2CH), 128.52 (2CH), 128.44
(2CH), 113.57 (2CH), 66.39 (OCH2), 59.55 (CHBz2), 56.14 (CHN),
54.92 (OCH3), 13.95 (CH3 in OEt). Anal. calcd for C26H25NO4S: C,
69.78; H, 5.63; N, 3.13; found: C, 69.69; H, 5.83; N, 3.06%.
3
3J = 5.4 Hz, HB in CH2C=O), 1.22 (3H, t, J = 7.1 Hz, CH3 in OEt);
1H NMR of the minor conformer (300.13 MHz, DMSO-d6) δ: 9.63 (1H,
d, 3J = 7.5 Hz, NH), 7.91–7.98§ (2H, m, ArH), 7.60–7.68§ (1H, m, ArH),
7.48–7.57§ (2H, m, ArH), 7.19–7.39§ (5H, m, ArH), 5.42 (1H, ddd, J
3
§
3
3
= 9.8, J = 7.5, J = 4.2 Hz, CHN), 4.23–4.39 (2H, m, OCH2), 3.79
(1H, dd, 2J = 17.8, 3J = 9.9 Hz, HA in CH2C=O), 3.30 (1H, dd, 2J = 17.8,
3J = 4.2 Hz, HB in CH2C=O), 1.12 (3H, t, J = 7.1 Hz, CH3 in OEt);
3
O-Ethyl [(2-acetyl-3-oxo-1-phenyl)but-1-yl]thiocarbamate (13)
13C NMR of the major conformer (75.48 MHz, DMSO-d6) δ: 196.70
(C=O), 189.04 (C=S), 141.94 (C), 136.48 (C), 133.33 (CH), 128.75
(2CH), 128.26 (2CH), 128.02 (2CH), 127.03 (CH), 126.92 (2CH),
65.26 (OCH2), 54.56 (CHN), 44.22 (CH2C=O), 14.21 (CH3 in OEt);
13C NMR of the minor conformer (75.48 MHz, DMSO-d6) δ: 196.64
(C=O), 142.21 (C), 128.75 (2CH), 128.42 (2CH), 128.02 (2CH), 127.17
(CH), 126.58 (2CH), 66.11 (OCH2), 52.32 (CHN), 43.85 (CH2C=O),
13.99 (CH3 in OEt), a signal of C=S carbon and two aromatic carbon
(C, CH) could not be detected. Anal. calcd for C18H19NO2S: C, 68.98;
H, 6.11; N, 4.47; found: C, 68.70; H, 6.44; N, 4.60%.
A solution of acetylacetone (0.887 g, 8.86 mmol) in MeCN (10
mL) was added to an ice-cooled stirred suspension of NaH (0.211 g,
8.79 mmol) in dry MeCN (10 mL) and the resulting mixture was
stirred for 25 min. The ice-bath was removed, and sulfone 9a (2.932 g,
8.39 mmol) and MeCN (10 mL) were added to the obtained suspension.
The mixture was stirred at room temperature for 8 h, and the solvent
was removed in vacuo. The oily residue was triturated with petroleum
ether (3 × 10 mL), petroleum ether was decanted, and saturated
aqueous NaHCO3 (10 mL) and petroleum ether (10 mL) were added.
The obtained mixture was triturated until crystallisation was complete,
left overnight at room temperature and cooled to 0 °C. The precipitate
was filtered, washed with ice-cold H2O and petroleum ether, and dried
to give compound 13 (2.237 g, 91%) as a mixture of two conformers
in a ratio of 70:30. An analytically pure sample (a 71:29 conformer
mixture) was obtained after crystallisation from ethanol/water mixture
(v/v = 7:5). M.p. 80.5−82.5 °C (EtOH-H2O); IR (Nujol) νmax/cm–1: 3310
(s), 3257 (br s) (NH), 3086 (w), 3060 (w), 3029 (m) (CHarom), 1726 (s),
O-Ethyl {[1-(4-methylphenyl)-3-oxo-3-phenyl]prop-1-yl}thiocarb-
amate (14b)
Compound 14b (0.056 g, 35%) as a mixture of two conformers in
a ratio of 67:33 was prepared by treatment of thiocarbamate 12b
(0.213 g, 0.50 mmol) with KOH (0.138 g, 2.46 mmol) in EtOH (0.2 mL)
and H2O (1.7 mL) (r.t., 19 h) as described for 14a. An analytically pure
sample (a 67:33 conformer mixture) was obtained after crystallisation

154 JOURNAL OF CHEMICAL RESEARCH 2017
from EtOH. M.p. 73−74 °C (EtOH); IR (Nujol) νmax/cm–1: 3267 (br s)
(NH), 3081 (w), 3060 (m), 3026 (m) (CHarom), 1691 (s) (C=O), 1594
(m), 1580 (w) (CCarom), 1538 (s), 1516 (m) (thioamide-II), 1491 (w)
(CCarom), 1229 (s), 1204 (s), 1178 (s) (C–O), 817 (m), 761 (s), 686 (s)
solid immediately started to precipitate. After 4 h from the beginning
of the reaction, the suspension was cooled to 0 °C. The precipitate
was filtered, washed with ice-cold water (4 × 4 mL), then washed
thoroughly with petroleum ether, and dried to give compound 15
(1.642 g, 86%) as a mixture of two conformers in a ratio of 70:30. An
analytically pure sample (a 70:30 conformer mixture) was obtained
after crystallisation from ethanol/water mixture (v/v = 3:2). M.p.
76.5−77.5 °C (EtOH–H2O); IR (Nujol) νmax/cm–1: 3219 (br s), 3056
(s) (NH), 3032 (m) (CHarom), 1719 (s) (C=O), 1604 (w) (CCarom), 1556
(s) (thioamide-II), 1494 (m) (CCarom), 1243 (s), 1196 (s) (C–O), 749
1
(CHarom); H NMR of the major conformer (300.13 MHz, DMSO-d6)
δ: 9.58 (1H, d, 3J = 8.0 Hz, NH), 7.89–7.97* (2H, m, ArH), 7.59–7.68*
(1H, m, ArH), 7.48–7.56* (2H, m, ArH), 7.21–7.28* (2H, m, ArH),
7.08–7.17* (2H, m, ArH), 5.71 (1H, ddd, 3J = 8.6, 3J = 8.0, 3J = 5.7 Hz,
CHN), 4.23–4.39* (2H, m, OCH2), 3.67 (1H, dd, 2J = 17.3, 3J = 8.6 Hz,
HA in CH2C=O), 3.41 (1H, dd, 2J = 17.3, 3J = 5.7 Hz, HB in CH2C=O),
3
1
2.26 (3H, s, CH3 in CH3C6H4), 1.22 (3H, t, J = 7.1 Hz, CH3 in OEt);
(s), 699 (s) (CHarom); H NMR of the major conformer (300.13 MHz,
1H NMR of the minor conformer (300.13 MHz, DMSO-d6) δ: 9.57 (1H,
d, 3J = 7.6 Hz, NH), 7.89–7.97§ (2H, m, ArH), 7.59–7.68§ (1H, m, ArH),
7.48–7.56§ (2H, m, ArH), 7.21–7.28§ (2H, m, ArH), 7.08–7.17§ (2H, m,
ArH), 5.39 (1H, ddd, 3J = 9.6, 3J = 7.6, 3J = 4.4 Hz, CHN), 4.23–4.39§
(2H, m, OCH2), 3.76 (1H, dd, 2J = 17.7, 3J = 9.6 Hz, HA in CH2C=O),
3.28 (1H, dd, 2J = 17.7, 3J = 4.4 Hz, HB in CH2C=O), 2.27 (3H, s, CH3 in
CH3C6H4), 1.14 (3H, t, 3J = 7.1 Hz, CH in OEt); 13C NMR of the major
conformer (75.48 MHz, DMSO-d6) δ3: 196.73 (C=O), 188.90 (C=S),
138.83 (C), 136.49 (C), 136.08 (C), 133.24 (CH), 128.73 (2CH), 128.70
(2CH), 127.95 (2CH), 126.81 (2CH), 65.15 (OCH2), 54.31 (CHN),
44.15 (CH2C=O), 20.62 (CH3 in CH3C6H4), 14.17 (CH3 in OEt);
13C NMR of the minor conformer (75.48 MHz, DMSO-d6) δ: 196.66
(C=O), 187.41 (C=S), 139.14 (C), 136.49 (C), 136.23 (C), 133.26 (CH),
128.89 (2CH), 128.70 (2CH), 127.94 (2CH), 126.47 (2CH), 65.05
(OCH2), 52.04 (CHN), 43.81 (CH2C=O), 20.63 (CH3 in CH3C6H4),
13.97 (CH3 in OEt). Anal. calcd for C19H21NO2S: C, 69.69; H, 6.46; N,
4.28; found: C, 69.61; H, 6.73; N, 4.38%.
DMSO-d6) δ: 9.59 (1H, d, 3J = 8.3 Hz, NH), 7.18–7.36* (5H, m, ArH),
5.58 (1H, ddd, 3J = 8.8, 3J = 8.3, 3J = 5.8 Hz, CHN), 4.24–4.40* (2H,
m, OCH2), 3.00 (1H, dd, 2J = 16.8, 3J = 8.8 Hz, HA in CH2C=O), 2.89
2
3
(1H, dd, J = 16.8, J = 5.8 Hz, HB in CH2C=O), 2.08 (3H, s, CH3
3
1
in Ac), 1.23 (3H, t, J = 7.1 Hz, CH3 in OEt); H NMR of the minor
3
conformer (300.13 MHz, DMSO-d6) δ: 9.56 (1H, d, J = 7.5 Hz, NH),
7.18–7.36§ (5H, m, ArH), 5.18 (1H, ddd, 3J = 9.5, 3J = 7.5, 3J = 4.8 Hz,
CHN), 4.24–4.40§ (2H, m, OCH2), 3.10 (1H, dd, 2J = 17.5, 3J = 9.5 Hz,
HA in CH2C=O), 2.77 (1H, dd, 2J = 17.5, 3J = 4.8 Hz, HB in CH2C=O),
2.07 (3H, s, CH3 in Ac), 1.10 (3H, t, 3J = 7.1 Hz, CH3 in OEt); 13C NMR of
the major conformer (75.48 MHz, DMSO-d6) δ: 205.40 (C=O), 189.07
(C=S), 141.76 (C), 128.23 (2CH), 127.01 (CH), 126.71 (2CH), 65.29
(OCH2), 54.35 (CHN), 48.87 (CH2C=O), 29.96 (CH3 in Ac), 14.19 (CH3
in OEt); 13C NMR of the minor conformer (75.48 MHz, DMSO-d6) δ:
205.20 (C=O), 187.49 (C=S), 142.12 (C), 128.36 (2CH), 127.09 (CH),
126.37 (2CH), 66.06 (OCH2), 52.13 (CHN), 48.29 (CH2C=O), 30.04
(CH3 in Ac), 13.91 (CH3 in OEt). Anal. calcd for C13H17NO2S: C, 62.12;
H, 6.82; N, 5.57; found: C, 61.95; H, 6.98; N, 5.65%.
O-Ethyl {[1-(4-methoxyphenyl)-3-oxo-3-phenyl]prop-1-yl}thiocarb-
amate (14c)
4-{[(3-Hydrazono-1,3-diphenyl)prop-1-yl]}thiosemicarbazide (16a)
Compound 14c (0.726 g, 35%) as a mixture of two conformers in a ratio
of 67:33 was prepared by treatment of thiocarbamate 12c (2.693 g,
6.02 mmol) with KOH (1.680 g, 29.94 mmol) in EtOH (3 mL) and
H2O (21 mL) (r.t., 22 h) as described for 14a. An analytically pure
sample (a 67:33 conformer mixture) was obtained after crystallisation
from EtOH. M.p. 88−89 °C (EtOH); IR (Nujol) νmax/cm–1: 3366 (br s)
(NH), 3082 (w), 3060 (m), 3035 (w), 3025 (w), 3016 (w) (CHarom), 1688
(s) (C=O), 1611 (m), 1596 (m), 1585 (m) (CCarom), 1526 (s), 1514 (s)
(thioamide-II), 1491 (w) (CCarom), 1229 (s), 1204 (s), 1178 (s) (C–O),
Method A: An ice bath cooled solution of thiocarbamate 14a (0.917 g,
2.93 mmol) in anhydrous N2H4 (7.8 mL) was stirred for 1 h, then N2H4
was removed in vacuo at about 60 °C (bath temperature), the oily
residue was co-evaporated 5–7 times with toluene until a white solid was
formed. The obtained solid was triturated with cold Et2O (5 mL) and the
resulting suspension was cooled (–18 °C). The precipitate was filtered,
washed with cold Et2O (4 × 5 mL) and dried on the filter by sucking air
through the filter. The powder product was washed on the filter with ice-
cold water (4 × 5 mL), petroleum ether, and dried to give 16a (0.645 g,
70%) as a mixture of (E)- and (Z)-isomers in a ratio of 95:5.
1
821 (s), 756 (s), 686 (s) (CHarom); H NMR of the major conformer
3
(300.13 MHz, DMSO-d6) δ: 9.57 (1H, d, J = 8.1 Hz, NH), 7.90–7.9*
Method B: Compound 16a (0.614 g, 60%) as a 92:8 mixture of (E)- and
(Z)-isomers was synthesised by treatment of thiocarbamate 14a (1.032 g,
3.29 mmol) with anhydrous N2H4 (8.3 mL) at room temperature for 2 h
as described in Method A. An analytically pure sample (a 99:1 isomeric
ratio) was obtained after crystallisation from EtOH. M.p. 172.5−173 °C
(decomp., EtOH); IR (Nujol) νmax/cm–1: 3432 (m), 3416 (m), 3309 (s),
3259 (sh), 3225 (s), 3191 (br s) (ν NH), 3107 (w), 3085 (w), 3065 (w),
3053 (w), 3027 (w) (ν CHarom), 1629 (s) (ν C=N, δ NH2), 1588 (m) (ν
CCarom), 1529 (br s) (thioamide-II), 1493 (s) (ν CCarom), 756 (s), 695 (s)
(2H, m, ArH), 7.60–7.68* (1H, m, ArH), 7.48–7.57* (2H, m, ArH),
7.25–7.32* (2H, m, ArH), 6.84–6.93* (2H, m, ArH), 5.70 (1H, ddd,
3J = 8.4, 3J = 8.1, 3J = 5.9 Hz, CHN), 4.23–4.39* (2H, m, OCH2), 3.72
2
3
(3H, s, OCH3), 3.67 (1H, dd, J = 17.2, J = 8.4 Hz, HA in CH2C=O),
3
3.41 (1H, dd, 2J = 17.2, J = 5.9 Hz, HB in CH2C=O), 1.21 (3H, t,
1
3J = 7.1 Hz, CH3 in OEt); H NMR of the minor conformer (300.13
MHz, DMSO-d6) δ: 9.55 (1H, d, 3J = 7.6 Hz, NH), 7.90–7.97§ (2H, m,
ArH), 7.60–7.68§ (1H, m, ArH), 7.48–7.57§ (2H, m, ArH), 7.25–7.32§
(2H, m, ArH), 6.84–6.93§ (2H, m, ArH), 5.38 (1H, ddd, 3J = 9.5,
1
(δ CHarom); H NMR of the major isomer (300.13 MHz, DMSO-d6) δ:
§
3
3J = 7.6, J = 4.6 Hz, CHN), 4.23–4.39 (2H, m, OCH2), 3.73 (3H, s,
OCH3), 3.76 (1H, dd, 2J = 17.7, 3J = 9.5 Hz, HA in CH2C=O), 3.29 (1H,
8.79 (1H, br s, NHNH2), 8.30 (1H, br d, 3J = 7.9 Hz, NHCH), 7.49–7.55
(2H, m, ArH), 7.12–7.38 (8H, m, ArH), 6.69 (2H, br s, NH2N=C), 5.71
(1H, ddd, 3J = 8.0, 3J = 7.9, 3J = 7.7 Hz, CHN), 4.50 (2H, br s, NH2NH),
3.29 (1H, dd, 2J = 14.3, 3J = 7.7 Hz, HA in CH2), 3.11 (1H, dd, 2J = 14.3,
3J = 8.0 Hz, HB in CH2); 13C NMR of the major isomer (75.48 MHz,
DMSO-d6) δ: 180.57 (C=S), 142.19 (C), 141.67 (C=N), 138.99 (C),
128.11 (2CH), 127.83 (2CH), 127.01 (CH), 126.79 (2CH), 126.69 (CH),
125.01 (2CH), 54.02 (CHN), 31.50 (CH2). Anal. calcd for C16H19N5S: C,
61.32; H, 6.11; N, 22.35; found: C, 61.37; H, 6.30; N, 22.39%.
2
3
3
dd, J = 17.7, J = 4.6 Hz, HB in CH2C=O), 1.16 (3H, t, J = 7.1 Hz,
CH3 in OEt); 13C NMR of the major conformer (75.48 MHz, DMSO-d6)
δ: 196.80 (C=O), 188.80 (C=S), 158.26 (C), 136.51 (C), 133.76 (C),
133.25 (CH), 128.71 (2CH), 128.11 (2CH), 127.96 (2CH), 113.56
(2CH), 65.15 (OCH2), 55.01 (OCH3), 54.05 (CHN), 44.17 (CH2C=O),
14.19 (CH3 in OEt); 13C NMR of the minor conformer (75.48 MHz,
DMSO-d6) δ: 196.73 (C=O), 187.33 (C=S), 158.31 (C), 136.51 (C),
134.10 (C), 133.27 (CH), 128.71 (2CH), 127.95 (2CH), 127.77 (2CH),
113.71 (2CH), 66.06 (OCH2), 55.04 (OCH3), 51.75 (CHN), 43.85
(CH2C=O), 14.00 (CH3 in OEt). Anal. calcd for C19H21NO3S: C, 66.45;
H, 6.16; N, 4.08; found: C, 66.48; H, 6.21; N, 4.11%.
4-{[3-Hydrazono-1- (4-methylphenyl) -3-phenyl]prop-1-yl}
semicarbazide (16b)
Compound 16b (1.407 g, 58%) as a 90:10 mixture of (E)- and (Z)-
isomers was prepared by treatment of thiocarbamate 14b (2.426 g, 7.41
mmol) with anhydrous N2H4 (19 mL) (0 °C, 1 h) as described for 16a
in Method A. An analytically pure sample (a 93:7 isomeric ratio) was
obtained after crystallisation from EtOH. M.p. 148.5−150 °C (decomp.,
EtOH); IR (Nujol) νmax/cm–1: 3432 (m), 3419 (sh), 3379 (w), 3312 (s),
O-Ethyl [(3-oxo-1-phenyl)but-1-yl]thiocarbamate (15)
Thiocarbamate 13 (2.233 g, 7.61 mmol) was added to a stirred solution
of KOH (2.341 g, 41.73 mmol) in H2O (36.5 mL) at room temperature.
A homogeneous solution formed for several minutes, from which

JOURNAL OF CHEMICAL RESEARCH 2017 155
3233 (br s), 3192 (br s) (ν NH), 3103 (w), 3051 (w), 3021 (w) (ν CHarom),
1626 (s) (ν C=N, δ NH2), 1590 (m) (ν CCarom), 1530 (br s) (thioamide-II),
1492 (s) (ν CCarom), 802 (s), 765 (s), 697 (s) (δ CHarom); 1H NMR of the
major isomer (300.13 MHz, DMSO-d6) δ: 8.73 (1H, br s, NHNH2), 8.21
(1H, br d, 3J = 8.5 Hz, NHCH), 7.49–7.57 (2H, m, ArH), 7.00–7.28 (7H,
m, ArH), 6.64 (2H, br s, NH2N=C), 5.66 (1H, ddd, 3J = 8.5, 3J = 8.2, 3J
= 7.6 Hz, CHN), 4.47 (2H, br s, NH2NH), 3.26 (1H, dd, 2J = 14.3, 3J =
7.6 Hz, HA in CH2), 3.09 (1H, dd, 2J = 14.3, 3J = 8.2 Hz, HB in CH2), 2.23
(3H, s, CH3); 13C NMR of the major isomer (75.48 MHz, DMSO-d6) δ:
180.50 (C=S), 141.72 (C=N), 139.06 (C), 138.99 (C), 136.02 (C), 128.62
(2CH), 127.78 (2CH), 126.65 (3CH), 125.01 (2CH), 53.77 (CHN), 31.48
(CH2), 20.62 (CH3). Anal. calcd for C17H21N5S: C, 62.36; H, 6.46; N,
21.39; found: C, 62.03; H, 6.73; N, 21.51%.
with petroleum ether-CHCl3 (from 3:1 to 1:1) (note: purification of
the crude product was also performed using aluminium oxide column
chromatography eluting with petroleum ether-CHCl3 [from 3:1 to 1:1]).
An analytically pure sample was obtained by crystallisation from EtOH.
M.p. 198.5−200 °C (decomp., EtOH); IR (Nujol) νmax/cm–1: 3190 (br
vs), 3104 (m) (ν NH), 1619 (m) (ν C=N), 1572 (m) (ν CCarom), 1548 (s)
(thioamide-II), 1513 (m) (ν CCarom), 1177 (s) (δ NH + ν CN), 815 (m),
767 (s), 702 (s) (δ CHarom); 1H NMR (300.13 MHz, DMSO-d6) δ: 10.87
(1H, br d, 4J = 2.0 Hz, N(2)H), 9.06 (1H, br dd, 3J = 5.0, 4J = 2.0 Hz, N(4)
H), 7.37–7.44 (2H, m, ArH), 7.22–7.34 (3H, m, ArH), 7.03–7.13 (4H, m,
ArH), 4.90 (1H, ddd, 3J = 6.2, 3J = 5.0, 3J = 2.6 Hz, H-5), 3.53 (1H, ddd,
2J = 14.8, 3J = 6.2, 4J = 0.9 Hz, HA-6), 3.20 (1H, dd, 2J = 14.8, 3J = 2.6 Hz,
HB-6), 2.19 (3H, s, CH3); 13C NMR (75.48 MHz, DMSO-d6) δ: 177.00
(C-3), 157.98 (C-7), 139.10 (C), 137.31 (C), 136.31 (C), 129.28 (CH),
128.72 (2CH), 128.14 (2CH), 125.92 (2CH), 125.81 (2CH), 58.68 (C-5),
36.88 (C-6), 20.55 (CH3). Anal. calcd for C17H17N3S: C, 69.12; H, 5.80;
N, 14.22; found: C, 69.08; H, 6.00; N, 14.42%.
4-{[3-Hydrazono-1- (4-methoxyphenyl)-3-phenyl]prop-1-yl}
semicarbazide (16c)
Compound 16c (0.332 g, 65%) as a 87:13 mixture of (E)- and (Z)-
isomers was prepared by treatment of thiocarbamate 14c (0.510 g,
1.49 mmol) with anhydrous N2H4 (3.8 mL) (0 °C, 1 h) as described
for 16a in Method A. An analytically pure sample (a 98:2 isomeric
ratio) was obtained after crystallisation from EtOH. M.p. 77−79 °C
(decomp., EtOH); IR (Nujol) νmax/cm–1: 3305 (m), 3262 (m), 3195 (br s)
(ν NH), 3052 (w), 3033 (w) (ν CHarom), 1650 (m) (ν C=N, δ NH2), 1612
(m), 1585 (m) (ν CCarom), 1536 (br s) (thioamide-II), 1514 (s), 1500 (sh)
(ν CCarom), 1252 (s), 1033 (m) (ν C–O), 827 (m), 766 (m), 700 (m) (δ
CHarom); 1H NMR of the major isomer (300.13 MHz, DMSO-d6) δ: 8.74
(1H, br s, NHNH2), 8.18 (1H, br d, 3J = 7.9 Hz, NHCH), 7.49–7.55 (2H,
m, ArH), 7.12–7.29 (5H, m, ArH), 6.77–6.83 (2H, m, ArH), 6.65 (2H,
5- (4-Methoxyphenyl)-7-phenyl-2,4,5,6-tetrahydro-3H-1,2,4-
triazepine-3-thione (18c)
Compound 18c (0.262 g, 57%) was obtained from hydrazone 16c
(0.508 g, 1.48 mmol) and TsOH·H2O (0.296 g, 1.56 mmol) in EtOH
(15 mL) (reflux, 30 min) as described for 18a. The crude product was
purified using column chromatography on silica gel (13.5 g) eluting
with petroleum ether-CHCl3 (from 3:1 to 1:1) (note: purification of
the crude product was also performed using aluminium oxide column
chromatography eluting with petroleum ether-CHCl3 [from 3:1 to 1:1]).
An analytically pure sample was obtained by crystallisation from
EtOH. M.p. 163.5−165.5 °C (decomp., EtOH); IR (Nujol) νmax/cm–1:
3181 (br vs), 3097 (m) (ν NH), 1612 (m) (ν C=N), 1579 (s), 1566 (m)
(thioamide-II), 1512 (s), 1486 (m) (ν CCarom), 1251 (s) (ν C–O), 1174 (s)
(δ NH + ν CN), 1037 (s) (ν C–O), 832 (m), 769 (s), 698 (s) (δ CHarom);
1H NMR (300.13 MHz, DMSO-d6) δ: 10.88 (1H, br d, 4J = 2.0 Hz, N(2)
3
3
3
br s, NH2N=C), 5.64 (1H, ddd, J = 8.4, J = 7.9, J = 7.3 Hz, CHN),
2
4.47 (2H, br s, NH2NH), 3.69 (3H, s, OCH3), 3.25 (1H, dd, J = 14.2,
3J = 7.3 Hz, HA in CH2), 3.10 (1H, dd, J = 14.2, J = 8.4 Hz, HB in
CH2); 13C NMR of the major isomer (75.48 MHz, DMSO-d6) δ: 180.36
(C=S), 158.26 (C), 141.71 (C=N), 139.02 (C), 134.02 (C), 127.99
(2CH), 127.82 (2CH), 126.67 (CH), 125.03 (2CH), 113.48 (2CH), 55.02
(OCH3), 53.47 (CHN), 31.53 (CH2). Anal. calcd for C17H21N5OS: C,
59.45; H, 6.16; N, 20.39; found: C, 59.53; H, 6.35; N, 20.20%.
2
3
3
4
H), 9.04 (1H, br dd, J = 5.0, J = 2.0 Hz, N(4)H), 7.38–7.44 (2H, m,
ArH), 7.22–7.34 (3H, m, ArH), 7.10–7.16 (2H, m, ArH), 6.78–6.85 (2H,
m, ArH), 4.89 (1H, ddd, 3J = 6.3, 3J = 5.0, 3J = 2.6 Hz, H-5), 3.66 (3H, s,
OCH3), 3.50 (1H, ddd, 2J = 14.7, 3J = 6.3, 4J = 0.9 Hz, HA-6), 3.20 (1H,
dd, 2J = 14.7, 3J = 2.6 Hz, HB-6); 13C NMR (75.48 MHz, DMSO-d6) δ:
176.90 (C-3), 158.36 (C-7), 158.23 (C), 137.29 (C), 134.17 (C), 129.33
(CH), 128.18 (2CH), 127.12 (2CH), 125.96 (2CH), 113.57 (2CH), 58.49
(C-5), 55.05 (OCH3), 37.00 (C-6). Anal. calcd for C17H17N3OS: C,
65.57; H, 5.50; N, 13.49; found: C, 65.57; H, 5.73; N, 13.36%.
5,7-Diphenyl-2,4,5,6-tetrahydro-3H-1,2,4-triazepine-3-thione (18a)
A solution of hydrazone 16a (0.641 g, 2.05 mmol) and TsOH·H2O
(0.411 g, 2.16 mmol) in EtOH (5 mL) was stirred under reflux for
35 min, and the solvent was removed in vacuum. The residue was
triturated with saturated aqueous NaHCO3 (4 mL) upon cooling
until crystallisation was completed, and the obtained suspension
was cooled. The precipitate was filtered, washed with ice-cold
H2O (4 × 4 mL), petroleum ether (4 × 4 mL), and dried. The crude
product was purified using column chromatography on silica gel
(22 g) eluting with petroleum ether-CHCl3 (1:1) to give triazepine
18a (0.274 g, 48%) (note: purification of the crude product was also
performed using aluminium oxide column chromatography eluting
with petroleum ether-CHCl3, 3:1). An analytically pure sample was
obtained by crystallisation from EtOH. M.p. 168−170 °C (decomp.,
EtOH); IR (Nujol) νmax/cm–1: 3361 (s), 3129 (br s), 1619 (m) (ν C=N),
1577 (m), 1549 (s) (thioamide-II), 1187 (s) (δ NH + ν CN), 764 (s),
Acknowledgements
This research was financially supported by the Russian
Foundation for Basic Research (grant no. 16-33-00360) and the
Ministry of Education and Science of the Russian Federation
(project part of government order, 4.1849.2014/K).
Electronic supplementary information
1
The ESI (copies of IR, H and 13C NMR spectra of all the
synthesised compounds) is available through:
stl.publisher.ingentaconnect.com/content/stl/jcr/supp-data.
1
690 (s) (δ CHarom); H NMR (300.13 MHz, DMSO-d6) δ: 10.92 (1H,
4
3
4
br d, J = 2.0 Hz, N(2)H), 9.10 (1H, br dd, J = 4.9, J = 2.0 Hz, N(4)
H), 7.34–7.39 (2H, m, ArH), 7.12–7.32 (8H, m, ArH), 4.96 (1H, ddd,
3J = 6.2, 3J = 4.9, 3J = 2.7 Hz, H-5), 3.54 (1H, ddd, 2J = 14.7, 3J = 6.2,
4J = 1.0 Hz, HA-6), 3.24 (1H, dd, 2J = 14.7, 3J = 2.7 Hz, HB-6); 13C NMR
(75.48 MHz, DMSO-d6) δ: 177.00 (C-3), 158.35 (C-7), 142.03 (C),
137.22 (C), 129.32 (CH), 128.20 (2CH), 128.13 (2CH), 127.27 (CH),
125.91 (4CH), 59.04 (C-5), 36.84 (C-6). Anal. calcd for C16H15N3S: C,
68.30; H, 5.37; N, 14.93; found: C, 67.95; H, 5.62; N, 15.18%.
Received 28 October 2016; accepted 29 January 2017
Paper 1604399 DOI: 10.3184/174751917X14873588907729
Published online: 3 March 2017
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