Synthesis of aryl substituted 2,4,5,6-tetrahydro-3H-1,2,4-triazepine-3-thiones/ones starting from chalcone-derived β-isothiocyanato ketones

Article abstract of DOI:10.1016/j.tet.2016.10.021

A general two-step synthesis of 7-aryl substituted 2,4,5,6-tetrahydro-3H-1,2,4-triazepine-3-thiones from 1-aryl-3-isothiocyanatopropan-1-ones has been developed. The synthesis involved reaction of these isothiocyanato ketones with hydrazines followed by a

Full text of DOI:10.1016/j.tet.2016.10.021

Accepted Manuscript
Synthesis of aryl substituted 2,4,5,6-tetrahydro-3H-1,2,4-triazepine-3-thiones/ones
starting from chalcone-derived β-isothiocyanato ketones
Anastasia A. Fesenko, Mikhail S. Grigoriev, Anatoly D. Shutalev
PII:
S0040-4020(16)31043-2
10.1016/j.tet.2016.10.021
TET 28162
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 26 July 2016
Revised Date: 29 September 2016
Accepted Date: 10 October 2016
Please cite this article as: Fesenko AA, Grigoriev MS, Shutalev AD, Synthesis of aryl substituted 2,4,5,6-
tetrahydro-3H-1,2,4-triazepine-3-thiones/ones starting from chalcone-derived β-isothiocyanato ketones,
Tetrahedron (2016), doi: 10.1016/j.tet.2016.10.021.
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ACCEPTED MANUSCRIPT
Synthesis of aryl substituted 2,4,5,6-tetrahydro-3H-1,2,4-triazepine-3-thiones/ones starting from
chalcone-derived β-isothiocyanato ketones
Anastasia A. Fesenko, Mikhail S. Grigoriev, Anatoly D. Shutalev
1

ACCEPTED MANUSCRIPT
Synthesis of aryl substituted 2,4,5,6-tetrahydro-3H-1,2,4-triazepine-3-thiones/ones starting from
chalcone-derived β-isothiocyanato ketones
Anastasia A. Fesenkoa, Mikhail S. Grigorievb, Anatoly D. Shutaleva,*
a Department of Organic Chemistry, Moscow Technological University, 86 Vernadsky Ave., 119571
Moscow, Russian Federation
b A. N. Frumkin Institute of Physical Chemistry and Electrochemistry, Russian Academy of Sciences,
31 Leninsky Ave., 119071 Moscow, Russian Federation
Abstract: A general two-step synthesis of 7-aryl substituted 2,4,5,6-tetrahydro-3H-1,2,4-triazepine-3-
thiones from 1-aryl-3-isothiocyanatopropan-1-ones has been developed. The synthesis involved
reaction of these isothiocyanato ketones with hydrazines followed by acid-catalyzed heterocyclization
of the prepared 4-(3-oxopropyl)thiosemicarbazides or their hydrazones. Triazepine-3-thiones were
converted into their 3-oxo analogs by oxidation with H2O2 under basic conditions. Conformations of
the obtained triazepine-3-thiones/ones in DMSO solution and in solid state were established using 1H
NMR spectroscopy and single crystal X-ray diffraction.
Keywords: Isothiocyanato ketones; Thiosemicarbazides; Hydrazones; 1,2,4-Triazepine-3-thiones/ones
1. Introduction
1,2,4-Triazepines,1 particularly 1,2,4-triazepin-2-ones/thiones are the subject of intensive studies
due to their diverse pharmacological properties. These compounds are effective antagonists of
parathyroid hormone 1 (PTH1R)2 and holecystokinin hormone 2 (CCK2)3 receptors. They possess
antioxidant,4 antipsychotic,5 and HIV protease inhibitory activities.6 The reported approaches to 1,2,4-
triazepin-2-one/thione backbone include reaction of β-isocyanato or β-isothiocyanato ketones with
hydrazines,7,8 condensation of (thio)semicarbazides with various 1,3-dicarbonyl compounds or their
derivatives,4,9 reaction of arylidene ketones with N2H4·2HNCS,10 addition of (thio)semicarbazides to
α,β-unsaturated carbonyl compounds or their synthetic equivalents,11 reaction of γ-hydrazino-
substituted amines with phosgene equivalents,3a,6,12 intramolecular cyclization of 4-(γ-
oxoalkyl)(thio)semicarbazides and their derivatives.7b,8d,13
______________________________
* Corresponding author. Tel.: +7 495 246 0555x908; fax: +7 495 246 0555x909.
E-mail address: anatshu@gmail.com, shutalev@orc.ru (A.D. Shutalev).
2

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Various benzo- and hetero-fused 1,2,4-triazepin-2-ones/thiones were prepared using the above
methods. In contrast, only a few specific types of monocyclic triazepin-2-ones/thiones were described.
Besides, some of the reported results on the triazepine formation from acyclic precursors were proved
to be incorrect. For example, it was demonstrated that the reaction of 2-substituted thiosemicarbazides
with malonyl chlorides provided four-membered imides9i instead of triazepines,14 and condensation of
acetylacetone with 2-methylsemicarbazides did not afford any triazepines (ref. 15 vs ref. 9d). Thus, the
development of reliable and practical approaches to monocyclic triazepines remains a challenge.
Previously, we showed that aryl substituted 2,4,5,6-tetrahydro-3H-1,2,4-triazepin-3-ones 2 can be
obtained by acid-catalyzed cyclization of hydrazones of 4-[(1,3-diaryl-3-oxo)prop-1-yl]semicarbazides
1 (Scheme 1).13
Scheme 1. Synthesis of 2,4,5,6-tetrahydro-3H-1,2,4-triazepin-3-ones 2.
We studied this cyclization under various conditions and found that the reaction temperature and
concentration of the starting material 1 had a dramatic effect on the yield of triazepines 2. However,
under all conditions tested, the yield of the products did not exceed 45%. Besides, synthesis of
semicarbazides 1 involved substitution of the ethoxy group in the corresponding ethyl N-(3-
oxopropyl)carbamates 3 under the action of refluxing anhydrous hydrazine for 20–24 h. Because of the
harsh reaction conditions the starting carbamates partially decomposed, and therefore semicarbazides 1
were obtained in only 28–46% yield. Thus, the low availability of starting material remained the
principal limitation of 1,2,4-triazepine synthesis by the cyclization of 4-[(1,3-diaryl-3-oxo)prop-1-
yl]semicarbazide hydrazones. We hypothesized that triazepines could be obtained from thioxo analogs
of 1 whose simple synthesis could be based on the reaction of readily available 1,3-diaryl-3-
isothiocyanatopropan-1-ones16 with hydrazines. Here, we report synthesis of aryl substituted 2,4,5,6-
tetrahydro-3H-1,2,4-triazepine-3-thiones and their oxidative transformation into the corresponding 3-
oxo derivatives starting from 1,3-diaryl-3-isothiocyanatopropan-1-ones.
2. Results and discussion
2.1. Synthesis of 4-(3-aryl-3-oxopropyl)thiosemicarbazides and their hydrazones
3

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4-(3-Aryl-3-oxopropyl)thiosemicarbazides and their hydrazones were obtained from 1,3-diaryl-3-
isothiocyanatopropan-1-ones 4a-i (Scheme 2). Isothiocyanates 4a-i were synthesized by the addition of
HNCS to the corresponding chalcones following our previously reported procedure.16
Scheme 2. Synthesis of 4-(3-aryl-3-oxopropyl)thiosemicarbazides 5a-e and their hydrazones 7a-k.
The reaction of isothiocyanates 4a,g with 1 equivalent of hydrazine hydrate readily proceeded in
EtOH at room temperature for 1 h to give 4-(3-oxopropyl)thiosemicarbazides 5a,b in excellent yields
(Scheme 2, Table 1).
Table 1. Reaction of isothiocyanato ketones 4a,b,g with hydrazine hydrate or methyl hydrazine.a
Table 1. Reaction of isothiocyanato ketones 4a,b,g with hydrazine hydrate or methyl hydrazine.a
_______________________________________________
Entry
4
R
R1
R3
Product(s) 5/6
Yield
ratiob
(%)c
___________________________________________________________
1
2
3
4
5
4a
4g
4a
4b
4g
H
Me
H
H
Me
H
Me
H
Me
Me
H
H
Me
Me
Me
5a + 6a
5b + 6b
5c
5d
5e
89:11d
99
98
99
98
98
95:5e
-
-
-
___________________________________________________________
a 1:1 molar ratio of reagents, EtOH, rt, 1 h.
b According to 1H NMR spectroscopic data for the crude products.
c Isolated yields.
d Diastereomeric ratio for 6a was 69:31.
e Diastereomeric ratio for 6b was 67:33.
It should be noted that preparation of oxo-analogs of 5a,b, namely 4-(3-oxopropyl)semicarbazides,
by the reaction of ethyl N-(3-oxopropyl)carbamates with hydrazine (see Scheme 1) did not work since
substitution of the ethoxy group by hydrazine proceeded much slower than formation of hydrazone
moiety.13
According to 1H NMR data, initially formed thiosemicarbazides 5a,b partly cyclized into 1-amino-
6-hydroxypyrimidines 6a,b (11 and 5 mol%, respectively). Pyrimidines 6a,b were obtained as mixtures
4

ACCEPTED MANUSCRIPT
of two diastereomers (69:31 for 6a, 67:33 for 6b). The major diastereomer of 6a,b had (4R*,6R*)-
configuration with equatorial orientations of the aryl groups and axial position of the hydroxyl group
(3JH 4,H 5 = 11.8–12.1, 3JN(3)H,H 4 = 0, 4JH 5,OH = 1.5 Hz)17,18 in DMSO-d6 solution. The minor
‑
‑
‑
‑
diastereomer had (4R*,6S*)-configuration with equatorial orientations of the hydroxyl group and 4-aryl
substituent (3JH 4,H 5 = 11.6–12.0, 3JN(3)H,H 4 = 0, 4JH 5,OH = 0 Hz). Since the ratios of acyclic and two
‑
‑
‑
‑
cyclic isomers did not change after crystallization we suppose that these three isomers were formed
under thermodynamic control.
Isothiocyanates 4a,b,g reacted with methyl hydrazine (EtOH, rt, 1 h) with complete regioselectivity
to give 2-methyl-substituted thiosemicarbazides 6c-e in 98–99% yields (Scheme 2, Table 1).
Hydrazones of 4-(3-aryl-3-oxopropyl)thiosemicarbazides 7a-i were obtained by the reaction of
isothiocyanates 4a-i with excess hydrazine hydrate (20 equiv.) in refluxing EtOH for 3 h in 89–94%
yields (Scheme 2; Table 2, entries 1, 3–10). The crude thiosemicarbazides 7a-i were isolated as
mixtures of E- and Z-isomers with significant predominance of one of them (83–97%). At room
temperature isothiocyanate 4a reacted with N2H4·H2O (20 equiv.) in EtOH for 24 h to give hydrazone
7a as a single isomer (entry 2).
Table 2. Synthesis of 4-(3-aryl-3-oxopropyl)thiosemicarbazide hydrazones 7a-k by reaction of isothiocyanates 4a-i or thiosemicarbazides 5c,d with excess
hydrazine.a
_______________________________________________
Entry Starting
compd
R
R1
R2
R3
Product Isomer Yield
ratiob (%)c
___________________________________________________________
1
4a
4a
4b
4c
4d
4e
4f
4g
4h
4i
H
H
H
H
H
H
Me
Me
Me
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
7a
7a
7b
7c
7d
7e
7f
87:13
100:0
83:17
84:16
84:16
90:10
97:3
83:17
88:12
83:17
78:22
78:22
92
84
91
94
89
89
93
89
89
92
94
97
2d
3
Me
OMe
OMe OMe
t-Bu
H
Me
OMe
OMe OMe
H
Me
4
5
6
7
8
9
10
11
12
H
H
H
H
7g
7h
7i
5c
5d
H
H
Me 7je
H
Me 7kf
___________________________________________________________
a 20 equiv. of N2H4·H2O, EtOH, reflux, 3 h.
b According to 1H NMR spectra of the crude products.
c Isolated yields.
d 20 equiv. of N2H4·H2O, EtOH, rt, 24 h.
e Along with 5 mol% of 7a.
f Along with 5 mol% of 7b.
Treatment of 2-methyl thiosemicarbazides 5c,d with hydrazine hydrate (20 equiv.) in refluxing
EtOH for 3 h led to formation of hydrazones 7j,k (two geometric isomers, 78:22) along with small
amounts of the corresponding thiosemicarbazides 7a,b (5%) (entries 11, 12). Crystallization of the
crude products from EtOH afforded pure 7j,k. The formation of 7a was not observed when 5c reacted
with excess hydrazine hydrate at room temperature, but this reaction proceeded very slowly to give 7j
(80% conversion after 24 h according to 1H NMR spectrum of isolated product).
5

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The C=N double bond geometries in the major and minor isomers of hydrazones 7a-k were
determined as E and Z, respectively. The assignments were based on 1H and 13C NMR spectroscopic
data, 1H,1H NOESY experiment for 7a in DMSO-d6, DFT calculations of hydrogen and carbon
chemical shifts for both E-7a and Z-7a, and comparison of 1H and 13C NMR spectra of 7a-k with those
of structurally similar semicarbazides.13 For the major isomer of 7a, 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.19 Comparison of the experimental carbon chemical shift for the CH2 group in 7a
(31.5 ppm in DMSO-d6) with that calculated by the GIAO method at the DFT B3LYP/6-
311++G(2df,p) level using the DFT B3LYP/6-311++G(d,p) optimized geometries for E-7a and Z-7a in
the gas phase (33.7 and 54.0 ppm, respectively) also proved the E-configuration of the major isomer of
7a. The assignment of the stereochemistry of other thiosemicarbazides 7b-k followed from similarity
of the 1H and 13C NMR spectra of the major and minor isomers of 7a with those of 7b-k.
It is noteworthy that the 1H NMR signal of the C=NNH2 group for E-7a-k (6.45–6.67 ppm) was
downfield shifted compared with that for Z-7a-k (5.59–5.67 ppm) (see also ref. 13). This significant
shift (about +1 ppm) could be explained by decrease in electron density on the NH2 nitrogen due to the
strong conjugation in the ArC=NNH2 moiety of E-7a-k. Indeed, DFT B3LYP/6-311++G(d,p)
calculations showed that the ArC=NNH2 fragment in E-7a is almost planar while in Z-7a the planes of
the phenyl ring and C=N bond form an angle of about 65°, resulting in a sharp decrease in the
conjugation.
2.2. Acid-catalyzed cyclization of 4-(3-aryl-3-oxopropyl)thiosemicarbazides or their hydrazones
into 2,4,5,6-tetrahydro-3H-1,2,4-triazepine-3-thiones
We found that hydrazones of 4-(3-aryl-3-oxopropyl)thiosemicarbazides 7a-k could be readily
cyclized in the presence of acid (>1 equiv.) to give the corresponding 2,4,5,6-tetrahydro-3H-1,2,4-
triazepine-3-thiones 8a-k (Scheme 3).
6

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Scheme 3. Synthesis of 2,4,5,6-tetrahydro-3H-1,2,4-triazepine-3-thiones 8a-k from hydrazones of 4-(3-
aryl-3-oxopropyl)thiosemicarbazides 7a-k.
According to the 1H NMR spectroscopic data for isolated crude materials under all studied
conditions some amount of unidentified side products always formed along with triazepines 8a-k. The
characteristic feature of these spectra was an increase in the relative integral intensity of the aromatic
protons region. The reaction conditions including catalyst, solvent, temperature, substrate
concentration, and amount of catalyst were optimized with hydrazone 7a. The experimental data are
summarized in Table 3.
Table 3. Acid-catalyzed cyclization of hydrazones of 4-(3-aryl-3-oxopropyl)thiosemicarbazides 7a-k into 2,4,5,6-tetrahydro-3H-1,2,4-triazepine-3-thiones
8a-k.
___________________________________________________________________________________________________________________________
Entry 7a
R
R1
R2
R3
Solvent
Acid (equiv.)
Conc. of 7
(mol/L)
Reaction
conditions
8
Purity
Yieldc
of 8b (%) (%)
___________________________________________________________________________________________________________________________
1
2
3
4
5
6
7
8
7a
7a
7a
7a
7ad
7a
7a
7a
7a
7b
7c
7d
7e
7f
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
EtOH
MeCN
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
AcOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
MeCN
MeOH
EtOH
MeCN
TsOH (1.05)
TsOH (1.03)
TsOH (1.05)
TsOH (1.10)
TsOH (1.11)
TsOH (1.52)
TsOH (1.07)
HCl (1.05)
0.300
0.300
0.300
0.097
0.097
0.098
0.054
0.107
0.100
0.095
0.098
0.091
0.096
0.098
0.097
0.095
0.098
0.092
0.095
0.102
0.092
rt, 2 h
rt, 2 h
8a
8a
8a
8a
8a
8a
8a
8a
8a
8b
8c
8d
8e
8f
37
35
61
79
78
77
80
72
68
80
75
74
80
84
81
81
83
78
75
72
71
–
–
–
–
76
–
–
–
–
76
75
73
78
81
76
81
82
72
–
reflux, 1.5 h
reflux, 1.5 h
reflux, 1.5 h
reflux, 1.5 h
reflux, 1.5 h
reflux, 1.5 h
reflux, 1.67 h
reflux, 1.5 h
reflux, 1.5 h
reflux, 1.5 h
reflux, 1.5 h
reflux, 1.5 h
reflux, 1.5 h
reflux, 1.5 h
reflux, 1.5 h
reflux, 1.5 h
reflux, 1.5 h
reflux, 1.5 h
reflux, 1.5 h
9
H
Me
OMe
OMe OMe
t-Bu
H
Me
OMe
OMe OMe
H
AcOH
10
11
12
13
14
15
16
17
18
19
20
21
TsOH (1.10)
TsOH (1.10)
TsOH (1.15)
TsOH (1.12)
TsOH (1.12)
TsOH (1.11)
TsOH (1.12)
TsOH (1.11)
TsOH (1.12)
TsOH (1.11)
TsOH (1.11)
TsOH (1.12)
H
H
H
H
H
Me
Me
Me
Me
H
H
H
H
7g
7h
7i
7j
7j
8g
8h
8i
8j
8j
H
H
H
H
H
Me
Me
Me
Me
H
H
Me
7j
7k
8j
8k
–
48
___________________________________________________________________________________________________________________________
a The crude products obtained by the reaction of 4a-i or 6c,d with excess N2H4 in refluxing EtOH were used. Their E/Z ratios are presented in Table 2
(enties 2, 3–12).
b
Purity of the isolated crude product was estimated as ratio of the expected integral intensity of the aromatic protons region (10 H for 8a,j, 9 H for
8b,c,e,f,k, 8 H for 8d,g,h, and 7 H for 8i) to the observed integral intensity in this region in the 1H NMR spectrum of the crude product multiplied by 100.
In all cases complete conversion of the starting material was observed.
c Isolated yield (after column chromatography).
d The crude product obtained by the reaction of 4a with excess N2H4 in EtOH at rt was used (Table 2, entry 2).
At room temperature in the presence of TsOH (1.03–1.05 equiv.) the reaction of 7a completed for 2
h. Both in MeCN and in EtOH, considerable amount of side products formed along with 8a (estimated
yields 35–37%) (entries 1 and 2). At reflux the yield of 8a significantly increased (entry 3 vs entry 1).
Decrease in the concentration of the starting material from 0.300 to 0.097 mol/L led to the increase in
the amount of 8a in the crude product from 61 to 78% (entry 3 vs entry 4). Further dilution (up to 0.054
mol/L) of the reaction mixture (entry 4 vs entry 7), use of higher excess of TsOH or other acidic
catalysts had no effect on the product yield (entries 6, 8, and 9). It is noteworthy that the yield of
7

ACCEPTED MANUSCRIPT
triazepine 8a did not depend on the configuration of the starting hydrazone 7a since both E/Z-7a and E-
7a gave 8a in close estimated yields (column 12 in Table 3, entry 4 vs entry 5).
Thus, under optimal reaction conditions hydrazones 7a-i cyclized in refluxing EtOH for 1.5 h in the
presence of TsOH (1.10–1.15 equiv.) to give triazepines 8a-i which were isolated in 73–82% yields
using column chromatography on aluminium oxide (entries 5, 10–17). Purification of triazepine 8a by
chromatography on silica gel with various eluting systems (CHCl3-petroleum ether, EtOAc-petroleum
ether, acetone-petroleum ether) failed to give pure product.
2-Methylthiosemicarbazide 7j cyclized in the presence of TsOH (1.12 equiv.) to give 2-
methyltriazepine 8j. In this case the yield of the product was slightly higher in refluxing MeCN
compared with that in EtOH or MeOH (entries 18, 19, and 20). Thus, compounds 8j and 8k were
obtained from 7j and 7k (MeCN, reflux, 1.5 h) after purification using column chromatography on
aluminium oxide in 71% and 48% yield, respectively (entries 18 and 21).
Obviously, acid-catalyzed transformation of 7a-k into 8a-k can proceed via two possible pathways
with participation of the NH2 group of either thiosemicarbazide or hydrazone moiety. Formation of 8j,k
from 7j,k proves that the cyclization of 7a-k involves nucleophilic attack of the thiosemicarbazide
amino group on the electrophilic carbon of the C=N double bond.
The obtained data clearly show that hydrazones of 4-(3-aryl-3-oxopropyl)thiosemicarbazides have a
stronger tendency to cyclize into triazepines under acidic conditions compared with analogous
hydrazones of semicarbazides (see ref. 13). For example, thiosemicarbazide 7a was converted into
triazepine-2-thione 8a in 76% isolated yield (Table 3, entry 5), while under similar conditions 4-[(3-
oxo-1,3-diphenyl)prop-1-yl]semicarbazide hydrazone (9) gave 5,7-diphenyl-2,4,5,6-tetrahydro-3H-
1,2,4-triazepin-3-one (10) only in 28% estimated yield.13 At room temperature, traces of triazepinone
10 formed from semicarbazide 9 under the action of TsOH in EtOH,13 while compound 7a gave about
37% of the expected product 8a (entry 1).
The differences in the reactivity of thiosemicarbazide hydrazones 7 and their oxo-analogs (e.g., 9)
can be explained by different basicities of these compounds. Similar basicities20 of the semicarbazide
NH2 group and nitrogen atom of the C=N double bond in 9 lead to protonation of the NH2 group in
considerable extent under strong acidic conditions21 resulting in decrease in cyclization rate. In
contrast, significant difference in the basicities22 of the corresponding nitrogen atoms in 7 provides a
greater tendency to give triazepines.
A plausible pathway for the acid-catalyzed cyclization of E-7a into 8a is shown in Scheme 4. We
suppose that this reaction includes initial protonation of compound 7a under the action of acid (HA) to
give one of two possible cations A or B. The calculations performed at the DFT B3LYP/6-
311++G(d,p) level of theory using the PCM solvation model showed that cation B is significantly less
stable than cation A (ꢀG = 8.8 kcal/mol in EtOH, 298 K and 1 atm),23 therefore its formation can be
8

ACCEPTED MANUSCRIPT
excluded. The initially formed cation A cyclizes into 8a via the intermediate triazepine C. Clearly, the
acid-catalyzed cyclization of 7b-k into triazepines 8b-k proceeds analogously.
Scheme 4. A plausible pathway for the acid-catalyzed (HA) cyclization of E-7a into 8a.
Thus, we showed that 2,4,5,6-tetrahydro-3H-1,2,4-triazepine-3-thiones 8 can be readily prepared
from hydrazones of 4-(1,3-diaryl-3-oxopropyl)thiosemicarbazides 7. Obviously, thiosemicarbazides
5a-e could also serve as a precursors for the triazepine synthesis. Reported data indicated that
thiosemicarbazide 5a did not cyclize under acidic or basic conditions.24 Later, the cyclization of
thiosemicarbazides 5a and 5c into triazepines 8a (no yield given) and 8g (30% yield) by heating in
dioxane or isopropyl alcohol in the presence of TsOH was scarcely described without any experimental
details.8d
We studied transformation of thiosemicarbazides 5a-e into the corresponding triazepines 8a,g,j-l
(Scheme 5) under different conditions varying solvent, catalyst and its amount, additive, substrate
concentration, and reaction time.
Scheme 5. Synthesis of 2,4,5,6-tetrahydro-3H-1,2,4-triazepine-3-thiones 8a,g,j-l from 4-(3-aryl-3-
oxopropyl)thiosemicarbazides 5a-e.
In initial experiments, we found that triazepine 8a formed only in 17–23% estimated yields from
thiosemicarbazide 5a along with considerable amounts of unidentified side products in refluxing EtOH
or MeCN in the presence of TsOH (0.10–0.11 equiv.) for 1 h (Table 4, entries 1 and 2). One of the
9

1
ACCEPTED MANUSCRIPT
characteristic features of H NMR spectra of the isolated crude materials was an increase in the relative
integral intensity of the aromatic protons region. The yield of 8a slightly increased when various
TsOH–N2H4 combinations were tested (entries 3–5).
Table 4. Acid-catalyzed cyclization of 4-(3-aryl-3-oxopropyl)thiosemicarbazides 5a-e into 2,4,5,6-tetrahydro-3H-1,2,4-triazepine-3-thiones 8a,g,j-l.a
___________________________________________________________________________________________________________________________
Entry
5
R
R1
R3
Solvent Acid (equiv.)
Additive
(equiv.)
Reaction
time (h)
Conv.b
(%)
8
Purity
Yieldd
of 8c (%) (%)
___________________________________________________________________________________________________________________________
1
2
3
4
5
6
7
8
5a
5a
5a
5a
5a
5a
5a
5a
5b
5c
5c
5c
5c
5c
5d
5e
H
H
H
H
H
H
H
H
Me
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
Me
H
H
H
H
H
Me
Me
H
H
H
H
H
H
H
H
EtOH
MeCN
EtOH
EtOH
MeCN
EtOH
EtOH
MeCN
EtOH
EtOH
MeCN
EtOH
MeCN
EtOH
EtOH
EtOH
TsOH (0.11)
TsOH (0.10)
TsOH (1.12)
TsOH (1.00)
TsOH (1.04)
AcOH (4.05)
AcOH (4.10)
AcOH (4.14)
AcOH (4.13)
TsOH (0.10)
TsOH (0.10)
AcOH (4.01)
AcOH (4.13)
AcOH (10.40)
AcOH (10.62)
AcOH (10.16)
–
–
1
1
1
1
1
1
3
3
3
1
1
1
5
8
8
8
100
100
100
100
100
87
100
55
100
85
100
39
21
100
100
100
8a
8a
8a
8a
8a
8a
8a
8a
8g
8j
8j
8j
8j
8j
8k
8l
17
23
32
33
26
68
85
22
83
31
58
26
10
89
89
88
–
–
–
–
–
–
83
–
79
–
–
–
–
89
82
81
N2H4·H2O (1.01)
N2H4·H2O (1.01)
N2H4·H2O (1.04)
–
–
–
–
–
–
–
–
–
–
–
9
H
10
11
12
13
14
15
16
Me
Me
Me
Me
Me
Me
Me
___________________________________________________________________________________________________________________________
a The reactions were performed at reflux with concentrations of the starting material ranging from 0.091 to 0.136 mol/L.
b Level of conversion of the starting material according to 1H NMR of the crude product.
c Purity of the isolated crude product was estimated as ratio of the expected integral intensity of the aromatic protons region (10 H for 8a,j, 9 H for 8k, 8 H
for 8g,l) to the observed integral intensity in this region in the 1H NMR spectrum of the crude product multiplied by 100.
d Isolated yield (after column chromatography).
The use of AcOH as the catalyst led to a significant increase in the yield of 8a. The treatment of 5a
with AcOH (4.05 equiv.) in refluxing EtOH for 1 h resulted in a 87% conversion of the starting
material (8a/5a = 84:16) and 68% purity of 8a (entry 6). Under these conditions, the reaction
completed in 3 h and triazepine 8a was isolated using column chromatography on silica gel in 83%
yield (entry 7). Analogously, triazepine 8g was obtained from 5b in 79% isolated yield (entry 9).
Though the yields of triazepines 8a,g prepared from thiosemicarbazides 5a,b are comparable with those
obtained from hydrazones 7a,g (Table 3, entries 5 and 15), the isolation of compounds 8a,g when
thiosemicarbazides 5a,b were used as starting materials was much more easy. It is noteworthy that the
cyclization of 5a into 8a under the action of AcOH proceeded significantly slower in refluxing MeCN
compared with that in EtOH (Table 4, entry 7 vs entry 8).
In contrast to 5a, TsOH-catalyzed cyclization of 2-methylthiosemicarbazide 5c in refluxing MeCN
or EtOH gave the expected triazepine 8j in higher yields (entry 1 vs entry 10, entry 2 vs entry 11).
However, the best results were also achieved with AcOH. In this case, the rate of cyclization of 2-
methylthiosemicarbazide 5c decreased compared with 2-unsubstituted compounds 5a,b (entry 6 vs
entry 12, entry 8 vs entry 13). The use of a 10-fold excess of AcOH and prolongating of the reaction
time (8 h) resulted in the smooth formation of 2-methyl-substituted triazepines 8j-l starting from
thiosemicarbazides 5c-e (entries 14–16). Compounds 8j-l were isolated in 81–89% yields by column
10

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chromatography on silica gel. The obtained data show that preparation of 2-methyl-substituted
triazepines 8j,k starting from 4-(3-aryl-3-oxopropyl)thiosemicarbazides 5c,d is more preferable than
from their hydrazones 7j,k.
All attempts to convert compound 5a into 8a under basic conditions failed; for example, based on
our experience8a we tried to cyclize 5a under the action of KOH (3.02 equiv.) in EtOH at room
temperature (2 h). However, a complex mixture of products was obtained containing only 7% of the
expected triazepine 8a (1H NMR spectroscopic data). Low conversion of 5a into 8a (< 8%) was
observed when compound 5a was heated at reflux in pyridine for 2 h or in EtOH in the presence of
aniline (0.15 equiv.) for 4 h.
2.3. Synthesis of 5-unsubstituted 2,4,5,6-tetrahydro-3H-1,2,4-triazepine-3-thione
Next we studied the effect of substituent at the α-position to nitrogen on the cyclization of 4-(3-
aryl-3-oxopropyl)thiosemicarbazides or their hydrazones. Previously, we described regioselective
synthesis of β-unsubstituted β-isothiocyanatoketones from α,β-unsaturated ketones by addition of HN3
followed by reaction of the obtained β-azidoketones with CS2 and PPh3.25 Using this reaction sequence
we prepared isothiocyanatoketone 11 from phenylvinylketone and then reacted it with N2H4·H2O. The
reaction smoothly proceeded in MeCN (0 °C, 10 min) to give thiosemicarbazide 12 in quantitative
yield (Scheme 6).
Scheme 6. Synthesis of 5-unsubstituted triazepine 15 from isothiocyanate 11.
According to 1H NMR spectroscopic data, thiosemicarbazide 12 was formed along with small
amount (2 mol%) of its 6-membered cyclic isomer, 1-amino-6-hydroxypyrimidine 13. It is noteworthy
that the isomeric ratio did not change after crystallization from EtOH indicating that these isomers are
in equilibrium.
At room temperature thiosemicarbazide 12 slowly reacted with N2H4·H2O (10.0 equiv.) in EtOH
for 24 h affording a mixture of 14 and 12 in a ratio 25:75 (1H NMR data). In refluxing EtOH the
reaction completed in 6 h 20 min to give hydrazone of thiosemicarbazide 14 in 90% yield as a mixture
11

1
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of E and Z isomers in a ratio of 92:8, respectively. The stereochemical assignments were based on H
and 13C NMR spectroscopic data, particularly by comparing these spectra with those of 7a-k (see
above). As for 7a-k, the 1H NMR signal of the C=NNH2 group for E-14 (6.84 ppm) was significantly
downfield shifted compared with that for Z-14 (5.74 ppm).
We studied the cyclization of ketone 12 and its hydrazone 14 under the action of TsOH (1.1 equiv.).
All reactions were performed with concentrations of the starting material ranging from 0.090–0.150
mol/L which was found to be optimal for the cyclization of 7a-k and 5a-e (see Table 3 and Table 4).
At room temperature in EtOH and MeCN in the presence of TsOH the reaction of hydrazone 14
completed for 1 h 45 min. However, besides the expected triazepine 15, considerable amount of side
products formed. According to 1H NMR spectroscopic data, the estimated yield of 15 in isolated crude
materials was 24% (in EtOH) and 55% (in MeCN). In contrast to the TsOH-catalyzed cyclization of
7a-k (Table 3) the estimated yield of 15 significantly decreased (30%) when hydrazone 14 was treated
with TsOH in refluxing MeCN for 2 h.
We found that the cyclization of 12 into 15 under the action of TsOH in EtOH at room temperature
proceeded quite slowly and gave significant amounts of side products. In refluxing MeCN or EtOH in
the presence of TsOH (0.1 equiv.) reaction completed for 1 h to afford triazepine 15 in low yields (27–
33%, 1H NMR estimated). Use of AcOH as the catalyst resulted in significant increase in the yield of
15. Triazepine 15 was obtained by the reaction of thiosemicarbazide 12 with AcOH (4.09 equiv.) in
refluxing EtOH for 3 h in 74% yield after column chromatography on silica gel.
2.4. Synthesis of 2,4,5,6-tetrahydro-3H-1,2,4-triazepin-3-ones
The obtained triazepine-3-thiones 8a-l, 15, containing reactive thiosemicarbazone fragment, can
serve as versatile starting materials for syntheses of a large variety of triazepines and related
compounds. As an example we carried out oxidative transformation of triazepine-3-thiones 8a-c,e,f into
their 3-oxo-analogs 16a-e (Scheme 7).
Scheme 7. Transformation of 2,4,5,6-tetrahydro-3H-1,2,4-triazepine-3-thiones 8a-c,e,f into their 3-
oxo-analogs 16a-e.
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The oxidation of 8a-c,e,f proceeded at room temperature for 1.5–2.5 h under the action of excess of
H2O2 (10 equiv.) in EtOH–H2O solution in the presence of KOH (5 equiv.) to give the corresponding
triazepinones 16a-e in good yields (Table 5). Compounds 16a-c,e were isolated with 98% purity (1H
NMR spectroscopic data). Column chromatography on silica gel was used only for isolation of
compound 16d.
Table 5. Oxidative transformation of triazepine-3-thiones 8a-c,e,f into their 3-oxo-analogs 16a-e.a
_______________________________________________
Entry
8
R
R1
Product
Yieldb (%)
___________________________________________________________
1
2
3
4
5
8a
8b
8c
8e
8f
H
H
H
H
H
16a
16b
16c
16d
16e
89
87
88
58
93
Me
OMe
t-Bu
H
Me
___________________________________________________________
a Reaction conditions: H2O2 (10 equiv.), KOH (5 equiv.), EtOH/H2O, rt, 1.5–2.5 h.
b Isolated yield (for 16d after column chromatography).
Previously, we prepared triazepinones 16a,b using carbamate method in overall yields of 11–15%
starting from corresponding ethyl N-[(aryl)(tosyl)methyl]carbamates.13 All our attempts to prepare
triazepinones 16c and 16d by the carbamate method failed. The described above approach to 2,4,5,6-
tetrahydro-3H-1,2,4-triazepin-3-ones is significantly more effective and flexible. Indeed, triazepinones
16a,b were obtained in 61–68% overall yields starting from isothiocyanatoketones 4a,b.
2.5. Structure of 2,4,5,6-tetrahydro-3H-1,2,4-triazepine-3-thiones/ones
The triazepine structure of compounds 8a-l, 15, 16a-e was established by 1H and 13C NMR
spectroscopy. For example, the 1H NMR spectra of 8a-i, 15, 16a-e in DMSO-d6 show a long-range
coupling between the N(2)H and N(4)H protons (4J = 2.0–2.1 Hz) typical for cyclic (thio)ureas,
particularly, 2,3,4,5-tetrahydro- and 2,3-dihydro-1H-1,3-diazepin-2-ones,26 hexahydro- and 1,2,3,4-
tetrahydropyrimidine-2-thiones/ones,25-27 2,4,5,6-tetrahydro-3H-1,2,4-triazepine-3-thiones/ones,8a,13
etc. The proton spin system of the HN(4)-C(5)H-C(6)H(A)H(B) fragment in triazepines 8a-l, 15, and
16a-e is characterized by a long-range coupling between the N(4)H proton and one of the protons of
CH2 group (4J = 0.7–1.0 Hz), as well as a high geminal coupling constant between the C(6)H(A) and
C(6)H(B) protons (2J = 13.5–14.7 Hz), indicating that these protons are located at α-position to a
double bond.28
The structures of compounds 8b, 8i, and 8j were independently confirmed by X-ray single-crystal
analyses (Fig. 1−3).29,30 The crystal of 8b (monoclinic, noncentrosymmetric space group P21) is a
racemic twin. The unit cell contains both enantiomers (Fig. 1). Note, the conformations of these
13

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enantiomers are significantly different; the triazepine ring in both isomers adopts a puckered
conformation with a pseudo equatorial position of the p-tolyl group for R-8b (C8–C5–C6–C7 torsion
angle is 173.4°) (Fig. 1a) and a pseudo axial orientation of this group for S-8b (C8–C5–C6–C7 torsion
angle is 53.4°) (Fig. 1b), while the C7, N1, N4, and C5 atoms in R-8b are located in one plane
(maximal deviation from the plane is 0.013 Å), and the N2, C3, and C6 atoms deviate from the plane
by 0.618, 0.428, and 0.746 Å in the same direction, respectively. Therefore, the triazepine ring in R-8b
has a distorted boat conformation. In contrast to R-8b, the seven-membered ring in S-8b adopts a
distorted envelope conformation where the C6 and C7 atoms deviate from the mean-square plane
formed by the other ring atoms (maximal deviation from the plane is 0.016 Å) by 0.943 and 0.395 Å,
respectively.
Figure 1. Views of molecular X-ray structures of R-8b (a) and S-8b (b) with ellipsoids drawn at the
50% probability level.
14

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Figure 2. A view of molecular X-ray structure of 8i with ellipsoids drawn at the 50% probability level.
Figure 3. A view of molecular X-ray structure of 8j with ellipsoids drawn at the 50% probability level.
Only R-isomer is represented.
The crystal of R-8i obtained by crystallization of racemic 8i was triclinic with the space group P-1.
Conformation of R-8i is close to that of R-8b (see above), the triazepine ring adopts a distorted boat
conformation where the N2, C3, and C6 atoms deviate from the mean-square plane formed by the other
ring atoms (maximal deviation from the plane is 0.017 Å) by 0.681, 0.504, and 0.709 Å, respectively.
The dimethoxyphenyl substituent has a pseudo equatorial orientation (C8–N5–C6–C7 dihedral angle is
177.0°) (Fig. 2).
The unit cell of the crystal of 8j (monoclinic, space group P21/c) contains both enantiomers (Fig. 3).
Conformations of R-8j and S-8j are very close. Analogously to R-8b,i, the seven-membered ring in R-
8j and S-8j adopts a distorted boat conformation where the C7, N1, N4, and C5 atoms are located in
one plane, and the N2, C3, and C6 atoms deviate from this plane. However, in contrast to R-8b,i, the
C5 substituent in 8j has a pseudo axial position (C8–C5–C6–C7 torsion angles in R-8j and S-8j are
70.5° and -72.4°, respectively).
The values of couplings between the N(4)H, C(5)H, C(6)H(A), and C(6)H(B) protons (3JN(4)H,H-5
=
2.2–2.5, 3JH-5,H(A)-6 = 4.4–4.6, and 3JH-5,H(B)-6 = 9.0–9.3 Hz) in 1H NMR spectra of 2-methyl-substituted
triazepinethiones 8j-l in DMSO-d6 prove that they exist predominantly in a puckered conformation
with a pseudo equatorial orientation of the C5 substituent. It is noteworthy that conformations of 8j in
DMSO solution and in solid state (see above) are different. According to 1H NMR spectroscopic data,
2-unsubstituted triazepinethiones/ones 8a-i, 16a-e in DMSO-d6 have a pseudo axial position of the C5
substituent (3JN(4)H,H-5 = 3.2–5.0, 3JH-5,H(A)-6 = 6.2–7.0, and 3JH-5,H(B)-6 = 2.6–3.4 Hz).
15

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3. Conclusion
A general synthesis of 7-aryl substituted 2,4,5,6-tetrahydro-3H-1,2,4-triazepine-3-thiones and their
3-oxo analogs has been developed. The key step of the synthesis includes acid-catalyzed cyclizations of
4-(3-oxopropyl)thiosemicarbazides or their hydrazones to give corresponding 1,2,4-triazepine-3-
thiones in high yields. Under optimal reaction conditions 4-(3-oxopropyl)thiosemicarbazide hydrazones
are cyclized in refluxing EtOH for 1.5 h in the presence of TsOH (1.10–1.15 equiv.), and 4-(3-
oxopropyl)thiosemicarbazides are converted into the target products under reflux in EtOH for 3–8 h
using AcOH (4.10–10.62 equiv.) as a catalyst. Both triazepine precursors can be prepared in excellent
yields by reaction of readily available 1-aryl-3-isothiocyanatopropan-1-ones with hydrazine or methyl
hydrazine in EtOH at room temperature or at reflux. 1,2,4-Triazepin-3-ones are obtained in good yields
by oxidation of 3-thioxo derivatives with excess of H2O2 in EtOH–H2O solution in the presence of
KOH at room temperature (1.5–2.5 h). Conformational analysis of the obtained triazepine-3-
thiones/ones in DMSO solution and solid state based on 1H NMR spectroscopic data and single crystal
X-ray diffraction shows that the triazepine ring adopts a puckered conformation (distorted boat or
distorted envelope) with a pseudo axial or pseudo equatorial orientation of substituent at the C5 carbon.
4. Experimental section
4.1. General
All solvents were distilled before use. 95% EtOH was used unless otherwise indicated. The petroleum
ether had a distillation range of 40–60 °C. 100% hydrazine hydrate was used. Isothiocyanatoketones
4a-i were prepared as described in ref. 16. Isothiocyanatoketone 11 was prepared as described in ref.
25. All other reagents were purchased from commercial sources and used without additional
purification. IR spectra (Nujol) were recorded using a BrukerVector 22 spectrophotometer. Band
characteristics in the IR spectra are defined as very strong (vs), strong (s), medium (m), weak (w), and
shoulder (sh). 1H NMR and proton decoupled 13C NMR spectra (solutions in DMSO-d6) were acquired
using a Bruker DPX 300 spectrometer at 300.13 MHz (1H) and 75.48 MHz (13C). 1H NMR chemical
shifts are referenced to the residual proton signal in DMSO-d6 (2.50 ppm). In 13C NMR spectra, central
signals of DMSO-d6 (39.50 ppm) were used as references. 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 used to aid in the assignment of 1H and 13C NMR signals.
Elemental analyses (CHN) were performed using a Thermo Finnigan Flash EA1112 apparatus. Thin-
16

ACCEPTED MANUSCRIPT
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 visualized with UV light or iodine vapors.
Column chromatography was performed with Macherey–Nagel silica gel 60 (0.063–0.200 mm) or
Macherey–Nagel aluminium oxide 90 neutral (activity 1). X-ray diffraction experiments were carried
out on an automatic four-circle diffractometer with area detector Bruker KAPPA APEX II at 100 K,
MoKα radiation, graphite monochromator. Unit cell parameters were refined over the whole datasets.31
The structures were solved using direct method (SHELXS9732) and refined using full-matrix least-
squares method (SHELXL-201433) on F2 over the whole dataset in the anisotropic approximation for
all nonhydrogen atoms. H atoms were introduced in geometrically calculated positions with isotropic
temperature factors UH = 1.5Ueq(C) for CH3 groups and UH = 1.2Ueq(C,N) for CH, NH, CH2 and NH2
groups. Suitable single crystals were obtained from slow evaporation of saturated solutions in MeCN
(for 8b,i) and EtOH (for 8j) at room temperature. All yields refer to isolated, spectroscopically and
TLC pure compounds. The color of solid substances was white, if not otherwise mentioned. The
geometry optimizations of R-7a and S-7a, cations A and B (Scheme 4) were carried out at the B3LYP
level of theory using Gaussian 09 suite34 of quantum chemical programs. Pople’s basis set, 6-
311++G(d,p), was employed for geometry optimization. The effect of continuum solvation was
incorporated by using the polarizable 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.
4.2. Synthesis of 4-(3-aryl-3-oxopropyl)thiosemicarbazides 5a-e
4.2.1. 4-[(3-Oxo-1,3-diphenyl)prop-1-yl]thiosemicarbazide (5a). To a stirred suspension of
isothiocyanatoketone 4a (1.51 g, 5.66 mmol) in EtOH (20 mL) was added a solution of N2H4·H2O
(0.290 g, 5.80 mmol) in EtOH (5 mL) over 1 min. The resulting mixture was stirred at room
temperature for 1 h and the solvent was removed in vacuum. The obtained solid residue was triturated
with H2O and the suspension was cooled. The precipitate was filtered, washed with ice-cold H2O,
petroleum ether, and dried to give product (1.68 g, 99%) as a 89:11 mixture of thiosemicarbazide 5a
and 1-amino-6-hydroxy-4,6-diphenylhexahydropyrimidine-2-thione (6a) (two diastereomers in a ratio
of 69:31). After crystallization from EtOH the isomeric ratio did not change. Mp 151−152 °C (dec,
EtOH) (lit.24 153 °C); IR (Nujol) ν, cm–1: 3340 (s), 3316 (m), 3293 (br s), 3173 (br s), 3148 (sh) (ν
NH), 3085 (w), 3061 (w), 3055 (sh), 3030 (w) (ν CHarom), 1662 (s) (ν C=O), 1632 (m) (δ NH2), 1597
(m), 1578 (m) (ν CCarom), 1519 (s) (thioamide-II), 1494 (m), 1485 (m) (ν CCarom), 744 (s), 699 (m) (δ
CHarom); 1H NMR of thiosemicarbazide 5a (300.13 MHz, DMSO-d6) δ: 8.80 (1H, br s, NHNH2), 8.40
(1H, br d, 3J = 9.5 Hz, NHCH), 7.93–7.99 (2H, m, ArH), 7.59–7.66 (1H, m, ArH), 7.47–7.55 (2H, m,
17

3
3
3
ACCEPTED MANUSCRIPT
ArH), 7.16–7.43 (5H, m, ArH), 6.02 (1H, ddd, J = 9.5, J = 6.5, J = 6.1 Hz, CHN), 4.55 (2H, br s,
NH2), 3.89 (1H, dd, 2J = 17.3, 3J = 6.1 Hz, HA in CH2), 3.61 (1H, dd, 2J = 17.3, 3J = 6.5 Hz, HB in
CH2); 1H NMR of the major isomer of pyrimidine 6a (300.13 MHz, DMSO-d6) δ: 8.71 (1H, br d, 4J =
2.0 Hz, N(3)H), 6.97 (1H, d, 4J = 1.5 Hz, OH), 4.73 (2H, br s, NH2), 4.72 (1H, dd, 3J = 11.8, 3J = 4.2 Hz,
H-4), 2.18 (1H, ddd, 2J = 13.6, 3J = 11.8, 4J = 1.5 Hz, Hax-5), 2.08 (1H, ddd, 2J = 13.6, 3J = 4.2, 4J = 2.0
Hz, Heq-5), signals of aromatic protons overlap with proton signals of the acyclic isomer; 1H NMR of
the minor isomer of pyrimidine 6a (300.13 MHz, DMSO-d6) δ: 6.80 (1H, s, OH), 5.14 (2H, br s, NH2),
3.98 (1H, dd, 3J = 11.6, 3J = 4.2 Hz, H-4), 2.46 (1H, dd, 2J = 13.8, 3J = 11.6 Hz, Hax-5, signals partly
overlap with residual proton signals in DMSO), 2.29 (1H, ddd, 2J = 13.8, 3J = 4.2, 4J = 1.8 Hz, Heq-5),
signals of other protons overlap with proton signals of the acyclic isomer; 13C NMR of
thiosemicarbazide 5a (75.48 MHz, DMSO-d6) δ: 198.0 (C=O), 180.6 (C=S), 142.5 (C), 136.6 (C),
133.4 (CH), 128.7 (2CH), 128.1 (2CH), 128.0 (2CH), 126.8 (2CH), 126.7 (CH), 52.7 (CHN), 43.6
(CH2). Anal. Calcd for C16H17N3OS: C, 64.19; H, 5.72; N, 14.04. Found: C, 64.38; H, 5.88; N, 14.17.
4.2.2. 4-{[1,3-Di(4-methylphenyl)-3-oxo]prop-1-yl}thiosemicarbazide (5b). The reaction of
isothiocyanatoketone 4g (0.989 g, 3.35 mmol) with N2H4·H2O (0.172 g, 3.43 mmol) in EtOH (25 mL)
(rt, 1 h) to give product (1.08 g, 98%) as a 95:5 mixture of thiosemicarbazide 5b and 1-amino-6-
hydroxy-4,6-[di(4-methylphenyl)]hexahydropyrimidine-2-thione (6b) (two diastereomers in a ratio of
67:33) was performed as described for the synthesis of 5a. Crystallization of the crude product from
EtOH afforded a 94:6 mixture of thiosemicarbazide 5b and pyrimidine 6b (two isomers, 67:33). Mp
162.5−163.5 °C (dec, EtOH); IR (Nujol) ν, cm–1: 3331 (m), 3313 (s), 3249 (br s), 3179 (br s) (ν NH),
3098 (w), 3055 (w), 3024 (w) (ν CHarom), 1669 (s) (ν C=O), 1626 (s) (δ NH2), 1606 (s), 1571 (sh) (ν
CCarom), 1528 (br s) (thioamide-II), 818 (s), 805 (s) (δ CHarom); 1H NMR of thiosemicarbazide 5b
(300.13 MHz, DMSO-d6) δ: 8.77 (1H, br s, NHNH2), 8.34 (1H, br d, 3J = 8.7 Hz, NHCH), 7.83–7.88
(2H, m, ArH), 7.23–7.34 (4H, m, ArH), 7.05–7.11 (2H, m, ArH), 5.95 (1H, ddd, 3J = 8.7, 3J = 6.8, 3J =
5.8 Hz, CHN), 4.53 (2H, br s, NH2), 3.81 (1H, dd, 2J = 17.1, 3J = 5.8 Hz, HA in CH2), 3.54 (1H, dd, 2J
= 17.1, 3J = 6.8 Hz, HB in CH2), 2.36 (3H, s, CH3), 2.24 (3H, s, CH3); 1H NMR of the major isomer of
pyrimidine 6b (300.13 MHz, DMSO-d6) δ: 8.59 (1H, br d, 4J = 2.0 Hz, N(3)H), 6.89 (1H, d, 4J = 1.5 Hz,
OH), 4.70 (2H, br s, NH2), 4.67 (1H, dd, 3J = 12.1, 3J = 3.8 Hz, H-4), 2.16 (1H, ddd, 2J = 13.4, 3J =
12.1, 4J = 1.5 Hz, Hax-5), 2.01 (1H, ddd, 2J = 13.4, 3J = 3.8, 4J = 2.0 Hz, Heq-5), 2.27 (6H, s, two CH3),
signals of aromatic protons overlap with proton signals of the acyclic isomer; 1H NMR of the minor
isomer of pyrimidine 6b (300.13 MHz, DMSO-d6) δ: 6.71 (1H, s, OH), 5.10 (2H, br s, NH2), 3.94 (1H,
dd, 3J = 12.0, 3J = 4.0 Hz, H-4), 2.33 (3H, s, CH3), 2.26 (3H, s, CH3), signals of other protons overlap
with proton signals of the acyclic isomer; 13C NMR of thiosemicarbazide 5b (75.48 MHz, DMSO-d6)
δ: 197.5 (C=O), 180.5 (C=S), 143.7 (C), 139.4 (C), 135.8 (C), 134.1 (C), 129.2 (2CH), 128.6 (2CH),
18

ACCEPTED MANUSCRIPT
128.1 (2CH), 126.7 (2CH), 52.6 (CHN), 43.4 (CH2), 21.1 (CH3), 20.6 (CH3). Anal. Calcd for
C18H21N3OS: C, 66.03; H, 6.46; N, 12.83. Found: C, 66.07; H, 6.60; N, 12.93.
4.2.3. 2-Methyl-4-[(3-oxo-1,3-diphenyl)prop-1-yl]thiosemicarbazide (5c). Compound 5c (1.29 g, 99%)
was prepared from isothiocyanatoketone 4a (1.10 g, 4.13 mmol) and methyl hydrazine (0.197 g, 4.27
mmol) in EtOH (25 mL) (rt, 1 h) as described for 5a. Mp 167−168 °C (dec, EtOH); IR (Nujol) ν, cm–1:
3346 (s), 3245 (s), 3171 (m), 3142 (m) (ν NH), 3083 (w), 3062 (w), 3052 (w), 3030 (w) (ν CHarom),
1680 (s) (ν C=O), 1642 (m) (δ NH2), 1599 (w), 1579 (w) (ν CCarom), 1523 (s) (thioamide-II), 1496 (w)
(ν CCarom), 744 (m), 697 (m) (δ CHarom); 1H NMR (300.13 MHz, DMSO-d6) δ: 8.76 (1H, br d, 3J = 9.0
Hz, NH), 7.93–7.98 (2H, m, ArH), 7.59–7.66 (1H, m, ArH), 7.47–7.54 (2H, m, ArH), 7.35–7.41 (2H,
m, ArH), 7.24–7.31 (2H, m, ArH), 7.15–7.22 (1H, m, ArH), 5.93 (1H, ddd, 3J = 9.0, 3J = 6.5, 3J = 6.1
Hz, CHN), 4.95 (2H, br s, NH2), 3.88 (1H, dd, 2J = 17.3, 3J = 6.1 Hz, HA in CH2), 3.59 (1H, dd, 2J =
17.3, 3J = 6.5 Hz, HB in CH2), 3.44 (3H, s, CH3); 13C NMR (75.48 MHz, DMSO-d6) δ: 198.0 (C=O),
180.2 (C=S), 142.6 (C), 136.6 (C), 133.4 (CH), 128.7 (2CH), 128.1 (2CH), 128.0 (2CH), 126.8 (2CH),
126.7 (CH), 54.2 (CHN), 43.7 (CH2), 42.5 (CH3). Anal. Calcd for C17H19N3OS: C, 65.15; H, 6.11; N,
13.41. Found: C, 65.22; H, 6.31; N, 13.46.
4.2.4. 2-Methyl-4-{[1-(4-methylphenyl)-3-oxo-3-phenyl]prop-1-yl}thiosemicarbazide (5d). Compound
5d (0.913 g, 98%) was prepared from isothiocyanatoketone 4b (0.803 g, 2.85 mmol) and methyl
hydrazine (0.139 g, 3.01 mmol) in EtOH (20 mL) (rt, 1 h) as described for 5a. Mp 145−146 °C (dec,
EtOH); IR (Nujol) ν, cm–1: 3340 (s), 3287 (m), 3261 (m), 3155 (s), 3127 (s) (ν NH), 3083 (w), 3051
(w), 3026 (w) (ν CHarom), 1682 (s) (ν C=O), 1626 (m) (δ NH2), 1595 (m), 1579 (w) (ν CCarom), 1512 (br
s) (thioamide-II), 822 (m), 746 (s), 686 (m) (δ CHarom); 1H NMR (300.13 MHz, DMSO-d6) δ: 8.68 (1H,
br d, 3J = 8.9 Hz, NH), 7.92–7.98 (2H, m, ArH), 7.59–7.66 (1H, m, ArH), 7.47–7.54 (2H, m, ArH),
7.23–7.29 (2H, m, ArH), 7.05–7.11 (2H, m, ArH), 5.88 (1H, ddd, 3J = 8.9, 3J = 6.8, 3J = 5.9 Hz, CHN),
4.92 (2H, br s, NH2), 3.83 (1H, dd, 2J = 17.1, 3J = 5.9 Hz, HA in CH2), 3.57 (1H, dd, 2J = 17.1, 3J = 6.8
Hz, HB in CH2), 3.44 (3H, s, NCH3), 2.24 (3H, s, CH3); 13C NMR (75.48 MHz, DMSO-d6) δ: 198.0
(C=O), 180.1 (C=S), 139.4 (C), 136.6 (C), 135.7 (C), 133.2 (CH), 128.62 (2CH), 128.58 (2CH), 127.9
(2CH), 126.6 (2CH), 53.9 (CHN), 43.6 (CH2), 42.4 (NCH3), 20.5 (CH3). Anal. Calcd for C18H21N3OS:
C, 66.03; H, 6.46; N, 12.83. Found: C, 66.00; H, 6.75; N, 12.79.
4.2.5. 2-Methyl-4-{[1,3-di(4-methylphenyl)-3-oxo]prop-1-yl}thiosemicarbazide (5e). Compound 5e
(1.11 g, 98%) was prepared from isothiocyanatoketone 4g (0.977 g, 3.31 mmol) and methyl hydrazine
(0.157 g, 3.41 mmol) in EtOH (25 mL) (rt, 1 h) as described for 5a. Mp 166−167.5 °C (dec, EtOH); IR
(Nujol) ν, cm–1: 3326 (s), 3294 (s), 3258 (m), 3167 (s), 3131 (w) (ν NH), 3090 (w), 3071 (w), 3050 (w),
19

ACCEPTED MANUSCRIPT
3023 (w) (ν CHarom), 1669 (s) (ν C=O), 1630 (s) (δ NH2), 1605 (s), 1574 (w) (ν CCarom), 1514 (br s)
(thioamide-II), 815 (s), 804 (m) (δ CHarom); 1H NMR (300.13 MHz, DMSO-d6) δ: 8.69 (1H, br d, 3J =
8.9 Hz, NH), 7.82–7.88 (2H, m, ArH), 7.28–7.33 (2H, m, ArH), 7.22–7.27 (2H, m, ArH), 7.04–7.10
(2H, m, ArH), 5.86 (1H, ddd, 3J = 8.9, 3J = 6.9, 3J = 5.8 Hz, CHN), 4.91 (2H, br s, NH2), 3.79 (1H, dd,
2J = 17.0, 3J = 5.8 Hz, HA in CH2), 3.51 (1H, dd, 2J = 17.0, 3J = 6.9 Hz, HB in CH2), 3.44 (3H, s,
NCH3), 2.36 (3H, s, CH3), 2.23 (3H, s, CH3); 13C NMR (75.48 MHz, DMSO-d6) δ: 197.5 (C=O), 180.1
(C=S), 143.6 (C), 139.4 (C), 135.7 (C), 134.1 (C), 129.2 (2CH), 128.6 (2CH), 128.1 (2CH), 126.6
(2CH), 54.0 (CHN), 43.4 (CH2), 42.4 (NCH3), 21.1 (CH3), 20.5 (CH3). Anal. Calcd for C19H23N3OS: C,
66.83; H 6.79; N, 12.31. Found: C, 66.97; H, 7.02; N, 12.39.
4.3. Synthesis of hydrazones of 4-(3-aryl-3-oxopropyl)thiosemicarbazides 7a-k
4.3.1. Hydrazone of 4-[(3-oxo-1,3-diphenyl)prop-1-yl]thiosemicarbazide (7a). A solution of
isothiocyanatoketone 4a (2.05 g, 7.67 mmol) and N2H4·H2O (7.69 g, 153.6 mmol) in EtOH (35 mL)
was stirred under reflux for 3 h, and the liquids were removed in vacuum (temperature of bath about
50–55 °C). The residue was co-evaporated with toluene (4 × 15 mL), the resulting oily solid was
triturated with ether until crystallization was completed. The suspension was cooled (–15 °C). The
precipitate was filtered, and washed with cold (–15 °C) ether (3 × 10 mL). Ether was removed from
solid by passing the air through the filter, and then the solid was washed with ice-cold H2O (4 × 10
mL), petroleum ether, and dried to give hydrazone 7a (2.22 g, 92%) as a 87:13 mixture of geometric
isomers. After crystallization from MeCN the isomeric ratio changed to 98:2, respectively. Mp
172.5−173.5 °C (dec, MeCN); IR (Nujol) ν, cm–1: 3433 (m), 3416 (m), 3309 (s), 3258 (sh), 3224 (s),
3192 (br s) (ν NH), 3107 (w), 3084 (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) (δ CHarom);
1H NMR of the major isomer (300.13 MHz, DMSO-d6) δ: 8.77 (1H, br s, NHNH2), 8.29 (1H, br d, 3J =
7.9 Hz, NHCH), 7.49–7.55 (2H, m, ArH), 7.31–7.37 (2H, m, ArH), 7.12–7.29 (6H, m, ArH), 6.67 (2H,
br s, NH2N=C), 5.72 (1H, ddd, 3J = 8.0, 3J = 7.9, 3J = 7.7 Hz, CHN), 4.49 (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); 1H NMR
of the minor isomer (300.13 MHz, DMSO-d6) δ: 8.68 (1H, br s, NHNH2), 8.20 (1H, br d, 3J = 8.3 Hz,
NHCH), 7.39–7.46 (2H, m, ArH), 5.66 (2H, br s, NH2N=C), 5.49 (1H, ddd, 3J = 8.3, 3J = 7.5, 3J = 6.9
Hz, CHN), 2.99 (1H, dd, 2J = 14.6, 3J = 7.5 Hz, HA in CH2), 2.96 (1H, dd, 2J = 14.6, 3J = 6.9 Hz, HB in
CH2), signals of other protons overlap with proton signals of the major isomer; 13C NMR of the major
isomer (75.48 MHz, DMSO-d6) δ: 180.6 (C=S), 142.2 (C), 141.7 (C=N), 139.0 (C), 128.1 (2CH), 127.8
(2CH), 127.0 (CH), 126.8 (2CH), 126.7 (CH), 125.0 (2CH), 54.0 (CHN), 31.5 (CH2). Anal. Calcd for
C16H19N5S: C, 61.32; H, 6.11; N, 22.35. Found: C, 61.30; H, 6.17; N, 22.35.
20

ACCEPTED MANUSCRIPT
4.3.2. Hydrazone of 4-{[1-(4-methylphenyl)-3-oxo-3-phenyl]prop-1-yl}thiosemicarbazide (7b).
Compound 7b (2.09 g, 91%) as a 83:17 mixture of geometric isomers was prepared from
isothiocyanatoketone 4b (1.96 g, 6.98 mmol) and N2H4·H2O (7.00 g, 139.8 mmol) in EtOH (30 mL)
(reflux, 3 h) as described for 7a. After crystallization from EtOH the isomeric ratio changed to 90:10,
respectively. Mp 163−163.5 °C (dec, EtOH); IR (Nujol) ν, cm–1: 3432 (m), 3419 (sh), 3380 (w), 3312
(s), 3233 (br s), 3191 (br s) (ν NH), 3102 (w), 3079 (w), 3051 (w), 3021 (w) (ν CHarom), 1626 (s) (ν
C=N, δ NH2), 1589 (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: 8.75 (1H, br s, NHNH2), 8.22
(1H, br d, 3J = 8.5 Hz, NHCH), 7.50–7.57 (2H, m, ArH), 7.03–7.27 (7H, m, ArH), 6.45 (2H, br s,
NH2N=C), 5.66 (1H, ddd, 3J = 8.5, 3J = 8.2, 3J = 7.6 Hz, CHN), 4.48 (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);
1H NMR of the minor isomer (300.13 MHz, DMSO-d6) δ: 8.65 (1H, br s, NHNH2), 8.12 (1H, br d, 3J =
8.5 Hz, NHCH), 7.32–7.47 (3H, m, ArH), 5.64 (2H, br s, NH2N=C), 5.42 (1H, ddd, 3J = 8.5, 3J = 7.5,
3J = 6.9 Hz, CHN), 4.46 (2H, br s, NH2NH), 2.97 (1H, dd, 2J = 14.6, 3J = 7.5 Hz, HA in CH2), 2.93 (1H,
dd, 2J = 14.6, 3J = 6.9 Hz, HB in CH2), 2.26 (3H, s, CH3), signals of six aromatic protons overlap with
signals of aromatic protons of the major isomer; 13C NMR of the major isomer (75.48 MHz, DMSO-d6)
δ: 180.5 (C=S), 141.7 (C=N), 139.1 (C), 139.0 (C), 136.0 (C), 128.7 (2CH), 127.8 (2CH), 126.7 (3CH),
125.0 (2CH), 53.8 (CHN), 31.5 (CH2), 20.7 (CH3). Anal. Calcd for C17H21N5S: C, 62.36; H, 6.46; N,
21.39. Found: C, 62.22; H, 6.64; N, 21.44.
4.3.3. Hydrazone of 4-{[1-(4-methoxyphenyl)-3-oxo-3-phenyl]prop-1-yl}thiosemicarbazide (7c).
Compound 7c (0.793 g, 94%) as a 84:16 mixture of geometric isomers was prepared from
isothiocyanatoketone 4c (0.730 g, 2.46 mmol) and N2H4·H2O (2.48 g, 49.5 mmol) in EtOH (12 mL)
(reflux, 3 h) as described for 7a. Crystallization of the crude product from EtOH afforded a 97:3
mixture of isomers, and crystallization from MeCN gave the only major isomer. Mp 90.5−93 °C (dec,
EtOH); mp 93−95 °C (dec, MeCN); IR (Nujol) ν, cm–1: 3388 (br m), 3304 (m), 3258 (m), 3195 (br s),
3171 (sh) (ν NH), 3064 (w), 3050 (w), 3033 (w) (ν CHarom), 1651 (m), 1638 (sh) (ν C=N, δ NH2), 1613
(m), 1586 (w) (ν CCarom), 1542 (s) (thioamide-II), 1516 (s), 1500 (w) (ν CCarom), 1254 (s), 1034 (m) (ν
C–O), 828 (m), 766 (m), 702 (m) (δ CHarom); 1H NMR of the major isomer (300.13 MHz, DMSO-d6) δ:
8.75 (1H, br s, NHNH2), 8.19 (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), 6.66 (2H, br s, NH2N=C), 5.64 (1H, ddd, 3J = 8.4, 3J = 7.9, 3J = 7.3
Hz, CHN), 4.48 (2H, br s, NH2NH), 3.69 (3H, s, OCH3), 3.25 (1H, dd, 2J = 14.2, 3J = 7.3 Hz, HA in
CH2), 3.10 (1H, dd, 2J = 14.2, 3J = 8.4 Hz, HB in CH2); 1H NMR of the minor isomer (300.13 MHz,
DMSO-d6) δ: 8.59 (1H, br s, NHNH2), 8.07 (1H, br d, 3J = 8.5 Hz, NHCH), 7.39–7.46 (2H, m, ArH),
21

3
3
ACCEPTED MANUSCRIP3T
7.32–7.39 (1H, m, ArH), 5.62 (2H, br s, NH2N=C), 5.42 (1H, ddd, J = 8.5, J = 7.5, J = 7.1 Hz,
CHN), 4.43 (2H, br s, NH2NH), 3.72 (3H, s, OCH3), 2.99 (1H, dd, 2J = 14.6, 3J = 7.5 Hz, HA in CH2),
2.93 (1H, dd, 2J = 14.6, 3J = 7.1 Hz, HB in CH2), signals of other protons overlap with proton signals of
the major isomer; 13C NMR of the major isomer (75.48 MHz, DMSO-d6) δ: 180.4 (C=S), 158.3 (C),
141.7 (C=N), 139.0 (C), 134.0 (C), 128.0 (2CH), 127.8 (2CH), 126.7 (CH), 125.0 (2CH), 113.5 (2CH),
55.0 (OCH3), 53.5 (CHN), 31.5 (CH2). Anal. Calcd for C17H21N5OS: C, 59.45; H, 6.16; N, 20.39.
Found: C, 59.27; H, 6.30; N, 20.36.
4.3.4. Hydrazone of 4-{[1-(3,4-dimethoxyphenyl)-3-oxo-3-phenyl]prop-1-yl}thiosemicarbazide (7d).
Compound 7d (0.964 g, 89%) as a 84:16 mixture of geometric isomers was prepared from
isothiocyanatoketone 4d (0.946 g, 2.89 mmol) and N2H4·H2O (2.48 g, 57.9 mmol) in EtOH (14 mL)
(reflux, 3 h) as described for 7a. After crystallization from MeCN the isomeric ratio changed to 95:5,
respectively. Mp 177.5−178 °C (dec, MeCN); IR (Nujol) ν, cm–1: 3326 (s), 3303 (s), 3193 (br s), 3131
(w) (ν NH), 3085 (w), 3044 (w) (ν CHarom), 1649 (m) (ν C=N, δ NH2), 1593 (m) (ν CCarom), 1536 (s)
(thioamide-II), 1514 (s), 1496 (m) (ν CCarom), 1260 (s), 1020 (s) (ν C–O), 833 (m), 768 (w), 696 (m) (δ
CHarom); 1H NMR of the major isomer (300.13 MHz, DMSO-d6) δ: 8.71 (1H, br s, NHNH2), 8.15 (1H,
br d, 3J = 7.5 Hz, NHCH), 7.50–7.56 (2H, m, ArH), 7.12–7.26 (3H, m, ArH), 6.94–6.99 (1H, m, ArH),
6.75–6.84 (2H, m, ArH), 6.64 (2H, br s, NH2N=C), 5.64 (1H, ddd, 3J = 8.7, 3J = 7.5, 3J = 7.1 Hz,
CHN), 4.47 (2H, br s, NH2NH), 3.68 (3H, s, OCH3), 3.67 (3H, s, OCH3), 3.24 (1H, dd, 2J = 14.2, 3J =
7.1 Hz, HA in CH2), 3.17 (1H, dd, 2J = 14.2, 3J = 8.7 Hz, HB in CH2); 1H NMR of the minor isomer
(300.13 MHz, DMSO-d6) δ: 8.58 (1H, br s, NHNH2), 8.07 (1H, br d, 3J = 8.9 Hz, NHCH), 7.32–7.46
(3H, m, ArH), 6.82–6.88 (2H, m, ArH), 5.63 (2H, br s, NH2N=C), 5.42 (1H, ddd, 3J = 8.9, 3J = 7.4, 3J =
7.0 Hz, CHN), 4.42 (2H, br s, NH2NH), 3.71 (3H, s, OCH3), 3.70 (3H, s, OCH3), 3.02 (1H, dd, 2J =
14.4, 3J = 7.4 Hz, HA in CH2), 2.94 (1H, dd, 2J = 14.4, 3J = 7.0 Hz, HB in CH2), signals of other
aromatic protons overlap with signals of aromatic protons of the major isomer; 13C NMR of the major
isomer (75.48 MHz, DMSO-d6) δ: 180.3 (C=S), 148.4 (C), 147.9 (C), 141.8 (C=N), 139.1 (C), 134.2
(C), 127.8 (2CH), 126.6 (CH), 125.1 (2CH), 119.2 (CH), 111.4 (CH), 110.9 (CH), 55.48 (OCH3), 55.46
(OCH3), 53.8 (CHN), 31.3 (CH2). Anal. Calcd for C18H23N5O2S: C, 57.89; H, 6.21; N, 18.75. Found: C,
57.90; H, 6.42; N, 19.08.
4.3.5. Hydrazone 4-{[1-(4-tert-butylphenyl)-3-oxo-3-phenyl]prop-1-yl}thiosemicarbazide (7e).
Compound 7e (1.89 g, 89%) as a 90:10 mixture of geometric isomers was prepared from
isothiocyanatoketone 4e (1.86 g, 5.75 mmol) and N2H4·H2O (5.76 g, 115.1 mmol) in EtOH (28 mL)
(reflux, 3 h) as described for 7a. After crystallization from EtOH the isomeric ratio changed to 95:5,
respectively. Mp 157.5−158.5 °C (dec, EtOH); IR (Nujol) ν, cm–1: 3378 (m), 3301 (s), 3199 (br s),
22

ACCEPTED MANUSCRIPT
3159 (s) (ν NH), 3089 (w), 3054 (w), 3027 (w) (ν CHarom), 1626 (m) (ν C=N, δ NH2), 1587 (w) (ν
CCarom), 1535 (s) (thioamide-II), 1503 (m) (ν CCarom), 819 (m), 754 (m), 693 (m) (δ CHarom); 1H NMR
of the major isomer (300.13 MHz, DMSO-d6) δ: 8.70 (1H, br s, NHNH2), 8.23 (1H, br d, 3J = 8.1 Hz,
NHCH), 7.45–7.50 (2H, m, ArH), 7.24–7.31 (4H, m, ArH), 7.10–7.24 (3H, m, ArH), 6.67 (2H, br s,
NH2N=C), 5.67 (1H, ddd, 3J = 8.1, 3J = 7.8, 3J = 7.7 Hz, CHN), 4.45 (2H, br s, NH2NH), 3.31 (1H, dd,
2J = 14.2, 3J = 7.7 Hz, HA in CH2), 3.04 (1H, dd, 2J = 14.2, 3J = 7.8 Hz, HB in CH2), 1.24 (9H, s, 3×CH3
in t-Bu); 1H NMR of the minor isomer (300.13 MHz, DMSO-d6) δ: 8.61 (1H, br s, NHNH2), 8.12 (1H,
br d, 3J = 8.6 Hz, NHCH), 7.31–7.45 (3H, m, ArH), 5.64 (2H, br s, NH2N=C), 5.47 (1H, ddd, 3J = 8.6,
3J = 7.6, 3J = 6.7 Hz, CHN), 2.97 (1H, dd, 2J = 14.6, 3J = 7.6 Hz, HA in CH2), 2.93 (1H, dd, 2J = 14.6,
3J = 6.7 Hz, HB in CH2), 1.26 (9H, s, 3×CH3 in t-Bu), signals of other protons overlap with proton
signals of the major isomer; 13C NMR of the major isomer (75.48 MHz, DMSO-d6) δ: 180.6 (C=S),
149.3 (C), 141.9 (C=N), 139.2 (C), 139.0 (C), 127.6 (2CH), 126.5 (CH), 126.4 (2CH), 125.0 (2CH),
124.8 (2CH), 53.7 (CHN), 34.1 (CMe3), 31.7 (CH2), 31.1 (3×CH3 in t-Bu). Anal. Calcd for C20H27N5S:
C, 65.01; H, 7.36; N, 18.95. Found: C, 65.02; H, 7.43; N, 19.20.
4.3.6. Hydrazone of 4-{[3-(4-methylphenyl)-3-oxo-1-phenyl]prop-1-yl}thiosemicarbazide (7f).
Compound 7f (2.97 g, 93%) as a 97:3 mixture of geometric isomers was prepared from
isothiocyanatoketone 4f (2.76 g, 9.79 mmol) and N2H4·H2O (9.82 g, 196.2 mmol) in EtOH (55 mL)
(reflux, 3 h) as described for 7a. After crystallization from EtOH the isomeric ratio changed to 98:2,
respectively. Mp 156.5−157 °C (dec, EtOH); IR (Nujol) ν, cm–1: 3402 (m), 3349 (m), 3305 (m), 3276
(m), 3191 (br s) (ν NH), 3086 (w), 3061 (w), 3032 (w) (ν CHarom), 1637 (sh), 1608 (m) (ν C=N, δ NH2),
1583 (w), 1559 (w) (ν CCarom), 1523 (s) (thioamide-II), 1495 (m) (ν CCarom), 815 (m), 755 (m), 702 (m)
(δ CHarom); 1H NMR of the major isomer (300.13 MHz, DMSO-d6) δ: 8.71 (1H, br s, NHNH2), 8.27
(1H, br d, 3J = 8.4 Hz, NHCH), 7.39–7.45 (2H, m, ArH), 7.31–7.37 (2H, m, ArH), 7.22–7.29 (2H, m,
ArH), 7.15–7.22 (1H, m, ArH), 7.01–7.06 (2H, m, ArH), 6.52 (2H, br s, NH2N=C), 5.71 (1H, ddd, 3J =
8.4, 3J = 8.1, 3J = 7.6 Hz, CHN), 4.47 (2H, br s, NH2NH), 3.26 (1H, dd, 2J = 14.2, 3J = 7.6 Hz, HA in
CH2), 3.09 (1H, dd, 2J = 14.2, 3J = 8.1 Hz, HB in CH2), 2.25 (3H, s, CH3); 1H NMR of the minor isomer
(300.13 MHz, DMSO-d6) δ: 8.63 (1H, br s, NHNH2), 8.17 (1H, br d, 3J = 8.5 Hz, NHCH), 5.62 (2H, br
s, NH2N=C), 5.47 (1H, ddd, 3J = 8.5, 3J = 7.3, 3J = 6.8 Hz, CHN), 2.96 (1H, dd, 2J = 14.4, 3J = 7.3 Hz,
HA in CH2), 2.93 (1H, dd, 2J = 14.4, 3J = 6.8 Hz, HB in CH2), 2.32 (3H, s, CH3), signals of other
protons overlap with proton signals of the major isomer; 13C NMR of the major isomer (75.48 MHz,
DMSO-d6) δ: 180.6 (C=S), 142.2 (C), 142.0 (C=N), 136.2 (C), 135.8 (C), 128.4 (2CH), 128.0 (2CH),
126.9 (CH), 126.7 (2CH), 124.9 (2CH), 54.0 (CHN), 31.5 (CH2), 20.6 (CH3). Anal. Calcd for
C17H21N5S: C, 62.36; H, 6.46; N, 21.39. Found: C, 62.24; H, 6.66; N, 21.48.
23

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4.3.7. Hydrazone of 4-{[1,3-di(4-methylphenyl)-3-oxo]prop-1-yl}thiosemicarbazide (7g). Compound
7g (1.30 g, 89%) as a 83:17 mixture of geometric isomers was prepared from isothiocyanatoketone 4g
(1.26 g, 4.27 mmol) and N2H4·H2O (4.30 g, 85.9 mmol) in EtOH (21 mL) (reflux, 3 h) as described for
7a. After crystallization from EtOH the isomeric ratio changed to 96:4, respectively. Mp 149−149.5 °C
(dec, EtOH); IR (Nujol) ν, cm–1: 3408 (m), 3325 (s), 3195 (br s), 3119 (w) (ν NH), 3050 (w), 3027 (w)
(ν CHarom), 1628 (s) (ν C=N, δ NH2), 1586 (m) (ν CCarom), 1543 (s) (thioamide-II), 1514 (s) (ν CCarom),
818 (s), 797 (s) (δ CHarom); 1H NMR of the major isomer (300.13 MHz, DMSO-d6) δ: 8.73 (1H, br s,
NHNH2), 8.22 (1H, br d, 3J = 8.5 Hz, NHCH), 7.41–7.47 (2H, m, ArH), 7.19–7.24 (2H, m, ArH), 7.02–
7.09 (4H, m, ArH), 6.52 (2H, br s, NH2N=C), 5.65 (1H, ddd, 3J = 8.5, 3J = 8.1, 3J = 7.6 Hz, CHN), 4.48
(2H, br s, NH2NH), 3.23 (1H, dd, 2J = 14.2, 3J = 7.6 Hz, HA in CH2), 3.07 (1H, dd, 2J = 14.2, 3J = 8.1
Hz, HB in CH2), 2.25 (3H, s, CH3), 2.24 (3H, s, CH3); 1H NMR of the minor isomer (300.13 MHz,
DMSO-d6) δ: 8.65 (1H, br s, NHNH2), 8.11 (1H, br d, 3J = 8.5 Hz, NHCH), 5.61 (2H, br s, NH2N=C),
5.39 (1H, ddd, 3J = 8.5, 3J = 7.4, 3J = 7.0 Hz, CHN), 2.95 (1H, dd, 2J = 14.6, 3J = 7.4 Hz, HA in CH2),
2.91 (1H, dd, 2J = 14.6, 3J = 7.0 Hz, HB in CH2), 2.32 (3H, s, CH3), signals of other protons overlap
with proton signals of the major isomer; 13C NMR of the major isomer (75.48 MHz, DMSO-d6) δ:
180.5 (C=S), 142.0 (C=N), 139.2 (C), 136.2 (C), 136.0 (C), 135.8 (C), 128.7 (2CH), 128.5 (2CH),
126.7 (2CH), 125.0 (2CH), 53.8 (CHN), 31.5 (CH2), 20.67 (CH3), 20.66 (CH3). Anal. Calcd for
C18H23N5S: C, 63.31; H, 6.79; N, 20.51. Found: C, 63.07; H, 7.13; N, 20.45.
4.3.8. Hydrazone of 4-{[1-(4-methoxyphenyl)-3-(4-methylphenyl)-3-oxo]prop-1-yl}thiosemicarbazide
(7h). Compound 7h (0.582 g, 89%) as a 88:12 mixture of geometric isomers was prepared from
isothiocyanatoketone 4h (0.571 g, 1.83 mmol) and N2H4·H2O (1.84 g, 36.8 mmol) in EtOH (8 mL)
(reflux, 3 h) as described for 7a. Two crystallization of the crude product from EtOH afforded a 97:3
mixture of isomers, and single crystallization from MeCN gave the only major isomer. Mp 100−103 °C
(dec, EtOH); mp 99.5−102.5 °C (dec, MeCN); IR (Nujol) ν, cm–1: 3375 (br m), 3310 (m), 3276 (m),
3197 (br s) (ν NH), 3081 (w), 3065 (w) (ν CHarom), 1650 (m), 1631 (w) (ν C=N, δ NH2), 1612 (s), 1587
(m) (ν CCarom), 1541 (s) (thioamide-II), 1514 (s) (ν CCarom), 1254 (s), 1034 (s) (ν C–O), 824 (s) (δ
CHarom); 1H NMR of the major isomer (300.13 MHz, DMSO-d6) δ: 8.68 (1H, br s, NHNH2), 8.18 (1H,
br d, 3J = 8.4 Hz, NHCH), 7.40–7.45 (2H, m, ArH), 7.22–7.28 (2H, m, ArH), 7.01–7.06 (2H, m, ArH),
6.78–6.84 (2H, m, ArH), 6.50 (2H, br s, NH2N=C), 5.64 (1H, ddd, 3J = 8.4, 3J = 8.4, 3J = 7.3 Hz,
CHN), 4.46 (2H, br s, NH2NH), 3.70 (3H, s, OCH3), 3.23 (1H, dd, 2J = 14.2, 3J = 7.3 Hz, HA in CH2),
3.08 (1H, dd, 2J = 14.2, 3J = 8.4 Hz, HB in CH2), 2.25 (3H, s, CH3); 1H NMR of the minor isomer
(300.13 MHz, DMSO-d6) δ: 8.58 (1H, br s, NHNH2), 8.06 (1H, br d, 3J = 8.5 Hz, NHCH), 7.14–7.20
(2H, m, ArH), 7.05–7.10 (2H, m, ArH), 5.59 (2H, br s, NH2N=C), 5.39 (1H, ddd, 3J = 8.5, 3J = 7.4, 3J =
7.1 Hz, CHN), 3.72 (3H, s, OCH3), 2.97 (1H, dd, 2J = 14.5, 3J = 7.4 Hz, HA in CH2), 2.90 (1H, dd, 2J =
24

3
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14.5, J = 7.1 Hz, HB in CH2), 2.32 (3H, s, CH3), signals of other protons overlap with proton signals of
the major isomer; 13C NMR of the major isomer (75.48 MHz, DMSO-d6) δ: 180.4 (C=S), 158.2 (C),
142.1 (C=N), 136.2 (C), 135.8 (C), 134.0 (C), 128.4 (2CH), 127.9 (2CH), 125.0 (2CH), 113.4 (2CH),
55.0 (OCH3), 53.5 (CHN), 31.6 (CH2), 20.6 (CH3). Anal. Calcd for C18H23N5OS·0.15C2H5OH: C,
60.32; H, 6.61; N, 19.22. Found: C, 59.92; H, 6.67; N, 19.35.35
4.3.9. Hydrazone of 4-{[1-(3,4-dimethoxyphenyl)-3-(4-methylphenyl)-3-oxo]prop-1-
yl}thiosemicarbazide (7i). Compound 7i (1.66 g, 92%) as a 83:17 mixture of geometric isomers was
prepared from isothiocyanatoketone 4i (1.59 g, 4.65 mmol) and N2H4·H2O (4.69 g, 93.7 mmol) in
EtOH (24 mL) (reflux, 3 h) as described for 7a. After crystallization from EtOH the isomeric ratio
changed to 88:12, respectively. Mp 131−133 °C (dec, EtOH); IR (Nujol) ν, cm–1: 3332 (s), 3309 (s),
3199 (br s), 3133 (w) (ν NH), 3024 (w) (ν CHarom), 1650 (m), 1626 (w) (ν C=N, δ NH2), 1604 (w),
1591 (m) (ν CCarom), 1534 (s) (thioamide-II), 1513 (s), 1496 (m) (ν CCarom), 1257 (s), 1021 (s) (ν C–O),
854 (m), 819 (m) (δ CHarom); 1H NMR of the major isomer (300.13 MHz, DMSO-d6) δ: 8.76 (1H, br s,
NHNH2), 8.18 (1H, br d, 3J = 8.5 Hz, NHCH), 7.41–7.47 (2H, m, ArH), 7.01–7.07 (2H, m, ArH), 6.98–
7.01 (1H, m, ArH), 6.75–6.82 (2H, m, ArH), 6.55 (2H, br s, NH2N=C), 5.62 (1H, ddd, 3J = 8.6, 3J =
8.5, 3J = 7.2 Hz, CHN), 4.49 (2H, br s, NH2NH), 3.683 (3H, s, OCH3), 3.680 (3H, s, OCH3), 3.21 (1H,
dd, 2J = 14.2, 3J = 7.2 Hz, HA in CH2), 3.14 (1H, dd, 2J = 14.2, 3J = 8.6 Hz, HB in CH2), 2.25 (3H, s,
CH3); 1H NMR of the minor isomer (300.13 MHz, DMSO-d6) δ: 8.64 (1H, br s, NHNH2), 8.09 (1H, br
d, 3J = 8.5 Hz, NHCH), 7.21–7.26 (2H, m, ArH), 7.06–7.11 (2H, m, ArH), 6.85–6.87 (1H, m, ArH),
6.81–6.85 (1H, m, ArH), 6.73–6.77 (1H, m, ArH, signals partly overlap with signals of aromatic
protons of the major isomer), 5.62 (2H, br s, NH2N=C), 5.38 (1H, ddd, 3J = 8.5, 3J = 7.4, 3J = 7.2 Hz,
CHN), 4.46 (2H, br s, NH2NH), 3.71 (3H, s, OCH3), 3.69 (3H, s, OCH3), 2.99 (1H, dd, 2J = 14.2, 3J =
7.4 Hz, HA in CH2), 2.91 (1H, dd, 2J = 14.2, 3J = 7.2 Hz, HB in CH2), 2.32 (3H, s, CH3); 13C NMR of
the major isomer (75.48 MHz, DMSO-d6) δ: 180.4 (C=S), 148.4 (C), 147.9 (C), 142.1 (C=N), 136.3
(C), 135.7 (C), 134.3 (C), 128.4 (2CH), 125.0 (2CH), 119.1 (CH), 111.5 (CH), 110.9 (CH), 55.48
(OCH3), 55.46 (OCH3), 53.8 (CHN), 31.4 (CH2), 20.6 (CH3). Anal. Calcd for C19H25N5O2S: C, 58.89;
H, 6.50; N, 18.07. Found: C, 58.78; H, 6.62; N, 18.19.
4.3.10. Hydrazone of 2-methyl-4-[(3-oxo-1,3-diphenyl)prop-1-yl]thiosemicarbazide (7j). A solution of
thiosemicarbazide 5c (0.716 g, 2.28 mmol) and N2H4·H2O (2.31 g, 46.2 mmol) in EtOH (18 mL) was
stirred under reflux for 3 h, and the liquids were removed in vacuum (temperature of bath about 50–55
°C). The residue was co-evaporated with toluene (4 × 10 mL), the resulting oily solid was triturated
upon cooling with H2O (10 mL) and petroleum ether (10 mL) until crystallization was completed. The
suspension was cooled. The precipitate was filtered, and washed with ice-cold H2O, petroleum ether,
25

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and dried to give product (0.698 g, 94%) as a 95:5 mixture of hydrazone 7j (two geometric isomers in a
ratio of 78:22) and hydrazone 7a. Crystallization of the crude product from EtOH afforded practically
pure hydrazone 7j (two isomers, 98:2) containing only 1 mol% of hydrazone 7a as an admixture. Mp
142−143.5 °C (dec, EtOH); IR (Nujol) ν, cm–1: 3415 (m), 3279 (br s), 3171 (m) (ν NH), 3086 (w), 3062
(w), 3033 (w) (ν CHarom), 1626 (s) (ν C=N, δ NH2), 1584 (w), 1561 (w) (ν CCarom), 1528 (s)
(thioamide-II), 1495 (w) (ν CCarom), 764 (m), 754 (m), 691 (s) (δ CHarom); 1H NMR of the major isomer
(300.13 MHz, DMSO-d6) δ: 8.66 (1H, br d, 3J = 8.5 Hz, NHCH), 7.48–7.54 (2H, m, ArH), 7.29–7.35
(2H, m, ArH), 7.12–7.28 (6H, m, ArH), 6.67 (2H, br s, NH2N=C), 5.62 (1H, ddd, 3J = 8.5, 3J = 8.0, 3J =
7.7 Hz, CHN), 4.89 (2H, br s, NH2N), 3.40 (3H, s, NCH3), 3.27 (1H, dd, 2J = 14.3, 3J = 7.7 Hz, HA in
CH2), 3.08 (1H, dd, 2J = 14.3, 3J = 8.0 Hz, HB in CH2); 1H NMR of the minor isomer (300.13 MHz,
DMSO-d6) δ: 8.57 (1H, br d, 3J = 8.5 Hz, NHCH), 7.39–7.47 (2H, m, ArH), 5.67 (2H, br s, NH2N=C),
5.38 (1H, ddd, 3J = 8.5, 3J = 7.6, 3J = 6.8 Hz, CHN), 4.88 (2H, br s, NH2N), 3.41 (3H, s, NCH3), 2.96
(1H, dd, 2J = 14.7, 3J = 7.6 Hz, HA in CH2), 2.93 (1H, dd, 2J = 14.7, 3J = 6.8 Hz, HB in CH2), signals of
other protons overlap with proton signals of the major isomer; 13C NMR of the major isomer (75.48
MHz, DMSO-d6) δ: 180.1 (C=S), 142.4 (C), 141.7 (C=N), 139.0 (C), 128.1 (2CH), 127.8 (2CH), 126.9
(CH), 126.74 (2CH), 126.69 (CH), 125.0 (2CH), 55.3 (CHN), 42.4 (NCH3), 31.6 (CH2). Anal. Calcd
for C17H21N5S: C, 62.36; H, 6.46; N, 21.39. Found: C, 62.56; H, 6.60; N, 21.55.
4.3.11. Hydrazone of 2-methyl-4-{[1-(4-methylphenyl)-3-oxo-3-phenyl]prop-1-yl}thiosemicarbazide
(7k). The reaction of thiosemicarbazide 5d (1.10 g, 3.37 mmol) with N2H4·H2O (3.41 g, 68.1 mmol) in
EtOH (25 mL) (reflux, 3 h) to give product (1.11 g, 97%) as a 95:5 mixture of hydrazone 7k (two
geometric isomers in a ratio of 78:22) and hydrazone 7b was performed as described for the synthesis
of 7j. Crystallization of the crude product from EtOH afforded practically pure hydrazone 7k (two
isomers, 99:1) containing only 2 mol% of hydrazone 7b as an admixture. Mp 147.5−149.5 °C (dec,
EtOH); IR (Nujol) ν, cm–1: 3420 (m), 3284 (br s), 3175 (m), 3131 (w) (ν NH), 3088 (w), 3060 (w),
3021 (w) (ν CHarom), 1625 (s) (ν C=N, δ NH2), 1583 (m), 1560 (w) (ν CCarom), 1526 (s) (thioamide-II),
1496 (w) (ν CCarom), 826 (m), 762 (s), 694 (s) (δ CHarom); 1H NMR of the major isomer (300.13 MHz,
DMSO-d6) δ: 8.59 (1H, br d, 3J = 8.5 Hz, NHCH), 7.50–7.56 (2H, m, ArH), 7.13–7.27 (5H, m, ArH),
7.02–7.08 (2H, m, ArH), 6.65 (2H, br s, NH2N=C), 5.57 (1H, ddd, 3J = 8.5, 3J = 8.2, 3J = 7.6 Hz,
CHN), 4.88 (2H, br s, NH2N), 3.40 (3H, s, NCH3), 3.25 (1H, dd, 2J = 14.2, 3J = 7.6 Hz, HA in CH2),
3.07 (1H, dd, 2J = 14.2, 3J = 8.2 Hz, HB in CH2), 2.23 (3H, s, CH3); 1H NMR of the minor isomer
(300.13 MHz, DMSO-d6) δ: 8.48 (1H, br d, 3J = 8.5 Hz, NHCH), 7.39–7.47 (2H, m, ArH), 7.32–7.39
(1H, m, ArH), 5.64 (2H, br s, NH2N=C), 5.32 (1H, ddd, 3J = 8.5, 3J = 7.7, 3J = 6.8 Hz, CHN), 4.85 (2H,
br s, NH2N), 3.40 (3H, s, NCH3), 2.95 (1H, dd, 2J = 14.6, 3J = 7.7 Hz, HA in CH2), 2.90 (1H, dd, 2J =
14.6, 3J = 6.8 Hz, HB in CH2), 2.25 (3H, s, CH3), signals of other protons overlap with proton signals of
26

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the major isomer; C NMR of the major isomer (75.48 MHz, DMSO-d6) δ: 180.1 (C=S), 141.7 (C=N),
139.3 (C), 139.0 (C), 136.0 (C), 128.6 (2CH), 127.8 (2CH), 126.69 (CH), 126.65 (2CH), 125.0 (2CH),
55.1 (CHN), 42.4 (NCH3), 31.5 (CH2), 20.7 (CH3). Anal. Calcd for C18H23N5S: C, 63.31; H, 6.79; N,
20.51. Found: C, 63.28; H, 7.05; N, 20.80.
4.4. Synthesis of 2,4,5,6-tetrahydro-3H-1,2,4-triazepine-3-thiones 8a-l
4.4.1. 5,7-Diphenyl-2,4,5,6-tetrahydro-3H-1,2,4-triazepine-3-thione (8a). Method A: A solution of
hydrazone 7a (1.18 g, 3.77 mmol) and TsOH·H2O (0.794 g, 4.17 mmol) in EtOH (39 mL) was stirred
under reflux for 1.5 h, and the solvent was removed in vacuum. The residue was triturated with
saturated aqueous NaHCO3 (10 mL) upon cooling until crystallization was completed, and the obtained
suspension was cooled. The precipitate was filtered, washed with ice-cold H2O, petroleum ether, and
dried. The crude product was purified using column chromatography on aluminium oxide (20.49 g)
eluting with petroleum ether–CHCl3 (from 3:1 to 1:3). The main fraction was concentrated. The residue
was dried in vacuum (water pump) until the stable foam formed. The resulting foam was triturated with
H2O, the obtained precipitate was filtered, washed with H2O, petroleum ether, and dried to give
triazepine 8a (0.807 g, 76%) as a very light yellow solid. Analytically pure sample (white crystals) was
obtained by crystallization from MeCN. Mp 168.5−170 °C (dec, MeCN) (lit.8c 166−168 °C); IR (Nujol)
ν, cm–1: 3361 (w), 3181 (br vs), 3089 (m) (ν NH), 3060 (w) (ν CHarom), 1627 (m) (ν C=N), 1555 (s)
(thioamide-II), 1180 (vs) (δ NH + ν CN), 766 (s), 697 (s) (δ CHarom); 1H NMR (300.13 MHz, DMSO-
d6) δ: 10.86 (1H, br d, 4J = 2.0 Hz, N(2)H), 9.05 (1H, br dd, 3J = 4.9, 4J = 2.0 Hz, N(4)H), 7.35–7.41 (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: 177.1 (C-3), 158.3 (C-7), 142.0 (C), 137.2 (C), 129.2 (CH), 128.1 (2CH), 128.0 (2CH),
127.2 (CH), 125.8 (4CH), 59.0 (C-5), 36.8 (C-6). Anal. Calcd for C16H15N3S: C, 68.30; H, 5.37; N,
14.93. Found: C, 67.97; H, 5.60; N, 15.08.
Method B: A solution of thiosemicarbazide 5a (0.594 g, 1.98 mmol) and AcOH (0.47 mL, 8.12
mmol) in EtOH (20 mL) was stirred under reflux for 3 h, and the solvent was removed in vacuum. The
residue was triturated with saturated aqueous NaHCO3 (5 mL) upon cooling until crystallization was
completed, and the obtained suspension was cooled. The precipitate was filtered, washed with ice-cold
H2O, petroleum ether, and dried. The crude product was purified using column chromatography on
silica gel (17.06 g) eluting with petroleum ether–CHCl3 (from 3:2 to 2:3). The main fraction was
concentrated. The residue was dried in vacuum (water pump) until the stable foam formed. The
resulting foam was triturated with ether, the obtained suspension was cooled (–15 °C), the precipitate
was filtered on cold (–15 °C) filter , washed with cold (–15 °C) ether (3 × 5 mL), and dried to give
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triazepine 8a (0.461 g, 83%) as a very light yellow solid. Analytically pure sample (white crystals) was
obtained by crystallization from MeCN.
4.4.2. 5-(4-Methylphenyl)-7-phenyl-2,4,5,6-tetrahydro-3H-1,2,4-triazepine-3-thione (8b). Compound
8b (0.837 g, 76%, very light yellow solid) was obtained from hydrazone 7b (1.22 g, 3.72 mmol) and
TsOH·H2O (0.781 g, 4.11 mmol) in EtOH (39 mL) (reflux, 1.5 h) as described for 8a in Method A. The
crude product was purified using column chromatography on aluminium oxide (20.03 g) eluting with
petroleum ether–CHCl3 (from 3:1 to 1:4). The main fraction was concentrated. The residue was dried in
vacuum (water pump) until the stable foam formed. The resulting foam was triturated with H2O, the
obtained precipitate was filtered, washed with H2O, petroleum ether, and dried to give triazepine 8b.
The analytically pure sample (very light yellow solid) was obtained by crystallization from MeCN. Mp
200.5−202 °C (dec, MeCN); IR (Nujol) ν, cm–1: 3195 (br vs), 3104 (m) (ν NH), 3057 (w), 3022 (w) (ν
CHarom), 1619 (m) (ν C=N), 1573 (m) (ν CCarom), 1548 (s) (thioamide-II), 1513 (m) (ν CCarom), 1178
(vs) (δ NH + ν CN), 816 (m), 766 (s), 702 (m) (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: 177.0 (C-3), 158.0 (C-7), 139.1 (C), 137.3 (C),
136.3 (C), 129.3 (CH), 128.7 (2CH), 128.2 (2CH), 125.9 (2CH), 125.8 (2CH), 58.7 (C-5), 36.9 (C-6),
20.6 (CH3). Anal. Calcd for C17H17N3S: C, 69.12; H, 5.80; N, 14.22. Found: C, 69.20; H, 6.13; N,
14.52.
4.4.3. 5-(4-Methoxyphenyl)-7-phenyl-2,4,5,6-tetrahydro-3H-1,2,4-triazepine-3-thione (8c). Compound
8c (0.855 g, 75%, very light yellow solid) was obtained from hydrazone 7b (1.26 g, 3.67 mmol) and
TsOH·H2O (0.770 g, 4.05 mmol) in EtOH (37 mL) (reflux, 1.5 h) as described for 8a in Method A. The
crude product was purified using column chromatography on aluminium oxide (33.26 g) eluting with
petroleum ether–CHCl3 (from 3:1 to 1:3). The main fraction was concentrated. The residue was dried in
vacuum (water pump) until the stable foam formed. The resulting foam was triturated with H2O, the
obtained precipitate was filtered, washed with H2O, petroleum ether, and dried to give triazepine 8c.
The analytically pure sample (white solid) was obtained by crystallization from EtOAc. Mp 166−167
°C (dec, AcOEt); IR (Nujol) ν, cm–1: 3183 (br vs), 3101 (m) (ν NH), 1613 (m) (ν C=N), 1578 (s)
(thioamide-II), 1511 (s), 1487 (m) (ν CCarom), 1254 (s) (ν C–O), 1177 (s) (δ NH + ν CN), 1034 (m) (ν
C–O), 828 (m), 768 (s), 699 (m) (δ CHarom); 1H NMR (300.13 MHz, DMSO-d6) δ: 10.87 (1H, br d, 4J =
2.0 Hz, N(2)H), 9.04 (1H, br dd, 3J = 5.0, 4J = 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
28

2
3
4
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ACCEPTED MANUSCRIPT
Hz, H-5), 3.66 (3H, s, OCH3), 3.50 (1H, ddd, J = 14.7, J = 6.3, J = 0.9 Hz, HA-6), 3.20 (1H, dd, J =
14.7, 3J = 2.6 Hz, HB-6); 13C NMR (75.48 MHz, DMSO-d6) δ: 176.9 (C-3), 158.4 (C), 158.2 (C-7),
137.3 (C), 134.2 (C), 129.3 (CH), 128.2 (2CH), 127.1 (2CH), 126.0 (2CH), 113.6 (2CH), 58.5 (C-5),
55.0 (OCH3), 37.0 (C-6). Anal. Calcd for C17H17N3OS: C, 65.57; H, 5.50; N, 13.49. Found: C, 65.58;
H, 5.77; N, 13.43.
4.4.4. 5-(3,4-Dimethoxyphenyl)-7-phenyl-2,4,5,6-tetrahydro-3H-1,2,4-triazepine-3-thione (8d).
Compound 8d (0.455 g, 73%, very light yellow solid) was obtained from hydrazone 7d (0.689 g, 1.82
mmol) and TsOH·H2O (0.399 g, 2.10 mmol) in EtOH (20 mL) (reflux, 1.5 h) as described for 8a in
Method A. The crude product was purified using column chromatography on aluminium oxide (20.38
g) eluting with petroleum ether–CHCl3 (from 3:1 to 1:2). The main fraction was concentrated. The
residue was dried in vacuum (water pump) until the stable foam formed. The resulting foam was
triturated with H2O, the obtained precipitate was filtered, washed with H2O, petroleum ether, and dried
to give triazepine 8d. The analytically pure sample (white solid) as a strong solvate with benzene
(8d/C6H6 = 2:1) was obtained after crystallization from C6H6.36 To remove benzene the solid was co-
evaporated with CHCl3 (3 × 5 mL), the obtained foam was triturated with H2O, the obtained precipitate
was filtered, washed with H2O, petroleum ether, and dried in high vacuum. Mp 90−91.5 °C; IR (Nujol)
ν, cm–1: 3182 (br vs) (ν NH), 3084 (w), 3061 (w) (ν CHarom), 1624 (m) (ν C=N), 1594 (m) (CCarom),
1550 (s) (thioamide-II), 1516 (s) (ν CCarom), 1263 (s) (ν C–O), 1178 (s) (δ NH + ν CN), 1024 (s) (ν C–
O), 807 (m), 764 (s), 694 (s) (δ CHarom); 1H NMR (300.13 MHz, DMSO-d6) δ: 10.86 (1H, br d, 4J = 2.0
Hz, N(2)H), 9.04 (1H, br dd, 3J = 5.0, 4J = 2.0 Hz, N(4)H), 7.43–7.50 (2H, m, ArH), 7.24–7.35 (3H, m,
ArH), 6.81–6.87 (2H, m, ArH), 6.65–6.70 (1H, m, ArH), 4.87 (1H, ddd, 3J = 6.4, 3J = 5.0, 3J = 2.6 Hz,
H-5), 3.65 (3H, s, OCH3), 3.61 (3H, s, OCH3), 3.61 (1H, dd, 2J = 14.7, 3J = 6.4 Hz, HA-6, signals partly
overlap with signals of the OCH3 groups), 3.18 (1H, dd, 2J = 14.7, 3J = 2.6 Hz, HB-6); 13C NMR (75.48
MHz, DMSO-d6) δ: 177.0 (C-3), 158.2 (C-7), 148.4 (C), 147.9 (C), 137.3 (C), 134.4 (C), 129.3 (CH),
128.1 (2CH), 125.9 (2CH), 118.1 (CH), 111.5 (CH), 110.2 (CH), 58.6 (C-5), 55.5 (OCH3), 55.4
(OCH3), 36.6 (C-6). Anal. Calcd for C18H19N3O2S·0.05CHCl3: C, 62.41; H, 5.53; N, 12.10. Found: C,
62.18; H, 5.74; N, 12.21.37
4.4.5. 5-(4-tert-Butylphenyl)-7-phenyl-2,4,5,6-tetrahydro-3H-1,2,4-triazepine-3-thione (8e). Compound
8e (0.882 g, 78%) was obtained from hydrazone 7e (1.24 g, 3.35 mmol) and TsOH·H2O (0.711 g, 3.74
mmol) in EtOH (35 mL) (reflux, 1.5 h) as described for 8a in Method A. The crude product was
purified using column chromatography on aluminium oxide (34.85 g) eluting with petroleum ether–
CHCl3 (from 3:1 to 0:1). The main fraction was concentrated. The residue was dried in vacuum (water
pump), triturated with H2O, the obtained precipitate was filtered, washed with H2O, petroleum ether,
29