Synthesis of 2,5-dihydroisothiazole derivatives. 2*. 3-aryl(hetaryl)-substituted 2-alkyl-5-arylimino-2,5-dihydroisothiazoles

Article abstract of DOI:10.1007/s10593-014-1451-1

A series of new 2-alkyl-5-arylimino-2,5-dihydroisothiazoles, substituted at position 3 with aryl and hetaryl groups and not substituted at position 4 was prepared by oxidative cyclization of N-arylamides of 3-alkylaminoprop-2- enethioic acids. The formation of the starting thioanilides was investigated by reacting the respective N-alkylimines of acetophenones with isothiocyanates. The main by-products were identified and characterized.

Full text of DOI:10.1007/s10593-014-1451-1

Chemistry of Heterocyclic Compounds, Vol. 50, No. 1, April, 2014 (Russian Original Vol. 50, No. 1, January, 2014)
SYNTHESIS OF 2,5-DIHYDROISOTHIAZOLE
DERIVATIVES. 2*. 3-ARYL(HETARYL)-SUBSTITUTED
2-ALKYL-5-ARYLIMINO-2,5-DIHYDROISOTHIAZOLES
I. Skrastiņa1**, A. Baran1, D. Muceniece1, and J. Popelis1
A series of new 2-alkyl-5-arylimino-2,5-dihydroisothiazoles, substituted at position 3 with aryl and
hetaryl groups and not substituted at position 4 was prepared by oxidative cyclization of N-arylamides
of 3-alkylaminoprop-2-enethioic acids. The formation of the starting thioanilides was investigated by
reacting the respective N-alkylimines of acetophenones with isothiocyanates. The main by-products
were identified and characterized.
Keywords: 2-alkyl-3-aryl(hetaryl)-5-arylimino-2,5-dihydroisothiazole, N-arylamides of 3-alkylamino-
3-aryl(hetaryl)prop-2-enethioic acid, oxidative cyclization.
N-Arylanilides of 3-amino-2-ene- and 3-oxocarboxylic and thiocarboxylic acids are convenient
precursors for the synthesis of various biologically active heterocyclic systems, including derivatives of
pyrrolidine [2, 3], pyridine [4], benzothiazole [5], dithiolane [6], dithiazole, and isothiazole (1,2-thiazole) [2, 7].
For instance, the oxidative cyclization of 3-aminoprop-2-enethioic acid amides leads to the formation of
isothiazole-5(2H)-imines [8-11]. Despite the apparent simplicity of the method and the availability of the
starting compounds, the reaction often gives variable results, producing many by-products besides the target
isothiazoles [8, 9, 12, 13]. Probably due to this reason, partially hydrogenated isothiazoles remain a little known
class of compounds (see, for example, the reviews [14, 15]). Our literature search for these compounds
identified only approximately thirty publications, of which only a few appeared after the year 1990 [16-19].
We have previously obtained 2-alkyl-5-arylimino-2,5-dihydroisothiazole derivatives containing a methyl
group at position 3, as well as a benzoyl or ester group at position 4 [1]. In a continuation of investigations
towards the synthesis and the study of biological activity of 2-alkyl-5-arylimino-2,5-dihydroisothiazole
derivatives, we synthesized a range of new compounds of this class, containing aryl and hetaryl substituents at
position 3, and having no substituents at position 4.
We planned to prepare the target compounds from acetophenones or the acetylpyridines 1а-е by converting
them to the respective imines A through reactions with primary alkylamines [20, 21]. The obtained imines
reacted with the isothiocyanates 2a-i forming the thioamides 3a-u that could be converted to the target
dihydroisothiazoles 4a-u by oxidative cyclization according to known methods [9, 22-24].
_______
*For Communication 1, see [1].
**To whom correspondence should be addressed, e-mail: ingrida@osi.lv.
1Latvian Institute of Organic Synthesis, 21 Aizkraukles St., Riga LV-1006, Latvia.
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 96-113, January, 2014. Original
article submitted January 10, 2014.
0009-3122/14/5001-0087©2014 Springer Science+Business Media New York
87

SCN
Ar
Me
Ar
O
AlkNH2
TiCl4
R
N
Me
Alk
room temp.
1a–e
MeCN
2a–i
A
72 h
Ar
H
N
2
3
1) CHCl3, Py
0–5°C
2) I2, EtOH
0–5°C, 4 h
3
R
4
5
1
Ar
2 N
R
NH
S
N
Alk
S
Alk
1
3a–u
4a–u
1 a Ar = Ph, b Ar = 4-MeOC6H4, c Ar = 4-ClC6H4, d Ar = 4-Py, e Ar = 3-Py; 2 a R = H, b R = 4-Me,
c R = 3-Me, d R = 4-MeO, e R = 4-Me2N, f R = 4-Cl, g R = 4-F, h R = 3-F, i R = 3,4-Cl2;
3,4 a–f,l–u Alk = n-Pr; g,h,j Alk = n-Bu; i,k Alk = i-Bu; a Ar = Ph, R = 4-Cl; b Ar = Ph, R = 4-F;
c Ar = 4-MeOC6H4, R = 4-Me; d Ar = 4-MeOC6H4, R = 4-MeO; e Ar = 4-MeOC6H4, R = 4-F;
f Ar = 4-MeOC6H4, R = 3-F; g Ar = 4-ClC6H4, R = H; h Ar = 4-ClC6H4, R = 4-Me;
i Ar = 4-ClC6H4, R = 4-MeO; j Ar = 4-ClC6H4, R = 4-Cl; k Ar = 4-ClC6H4, R = 3-F;
l Ar = 4-ClC6H4, R = 3,4-Cl2; m Ar = 4-Py, R = 4-Me; n Ar = 4-Py, R = 4-MeO;
o Ar = 4-Py, R = 4-Me2N; p Ar = 4-Py, R = 4-Cl; q Ar = 4-Py, R = 3-F; r Ar = 4-Py, R = 3,4-Cl2;
s Ar = 3-Py, R = 3-F; t Ar = 3-Py, R = 3-Me; u Ar = 3-Py, R = 4-MeO
The first attempts of "traditional" synthesis of the imines A showed that this process was slow and did
not go to completion even after 1 week at room temperature, according to the TLC and LC/MS data [20]. Using
the obtained reaction mixture (with 60-70% imine content according to chromatography) in the further stages of
synthesis resulted in the formation of not only the target compounds 3 and 4, but also a range of minor products
5-8, which were isolated and characterized by NMR spectroscopy and X-ray structural analysis (Fig. 1 and 2).
2d,h
room temp.
Et2O
N
F
72 h
H
N
H
N
Bu-i
i-BuNH2
(from 2h)
Bu
i-
S
N
R
Me
ClC6H4
2 equiv.
[1c + i-BuNH2]
S
C6H4Cl
5d,h
6k
(a 1:1 mixture of
diastereomers)
Alk
HN
0.5 equiv.
Alk
N
Ar
S
H
H
N
N
Ar
Me
R
R
S
B
H2O, O2
H
N
HO
Ar
C6H4Cl
i-Bu
N
N
N
N
+
S
S
S
S
R
R
MeO
OMe
7i,k
8i,n (from 2d)
5 d R = 4-MeO, h R = 3-F; 7 i R = 4-MeO, k R = 3-F; 8 i Ar = 4-ClC6H4, n Ar = 4-Py
88

TABLE 1. The Reaction Conditions and Yields of 4-Methoxyaceto-
phenone Propylimine
Amount of amine,
equiv.
Imine yield*2,
%
Solvent, condensing agent*
Reaction duration, h
2.0
5.0
PhH, cat. AcOH
340
48
72
48
72
24
72
24
48
24
48
72
24
48
24
48
13
34
54
67
75
3
13
68
91
46
84
87
<1
<1
<1
<1
PhH, cat. AcOH
PhH, cat. AcOH
10.0
2.0
PhH, mol. sieves 4 Å, activated at
120°С
CHCl3, TiCl4 (2.0 equiv.)
2.0
2.0
CHCl3, Ti(O-i-Pr)4 (2.0 equiv.)
2.0
2.0
CHCl3, polyphosphoric acid
(2.0 equiv.)
CHCl3, POCl3 (2.0 equiv.)
_______
*All reactions were performed at room temperature.
*2The yield of the imine was determined by LC/MS without isolation from
the reaction mixture.
A review of the available literature about the synthesis of imines identified a multitude of predominantly
acidic reagents that acted as scavengers of water [25]. The most common of these reagents were used in the
synthesis of imines for this project, as presented in the Table 1. The propylimine of 4-methoxy-acetophenone
was selected as the model compound.
The Table 1 shows that titanium(IV) reagents were superior for achieving the condensation reaction
producing the target imine: the product yield reached ~90% after 48-72 h. The imine content in the reaction
mixture was nearly as high after 72 h at room temperature when a large excess of the amine (≥10 equiv.) was
used. Heating the reaction mixture to 40-50°С did not significantly accelerate the process.
The further experiments of imine synthesis for this project were performed with TiCl4 (2.0 equiv.) with
subsequent quenching of the excess condensing agent with a 10% aqueous NaOH solution by analogy to the
methods [21, 26]. The product isolated under these conditions contained about 90% of the target derivative and
10% of the starting acetophenone, the presence of which did not interfere with the subsequent stages.
The interaction of the obtained imines А with the isothiocyanates 2a-i proceeded without forming the
previously observed N-alkyl-N'-arylthioureas 5. The appearance of the latter in the preliminary experiments was
probably caused by the presence of significant quantities of unreacted primary amine in the reaction mixture,
which then easily reacted with isothiocyanates. The combined content of the by-products 6 and B was
unchanged according to LC/MS data, and was not higher than 15% of the amount of the target thioamides 3a-u,
which were isolated in moderate yields (62-78%, Table 2).
The formation of the thiazines analogous to compound 6 occurred by interaction of one isothiocyanate
molecule with two imine molecules as a formal [4+2] cycloaddition [27] of isothiocyanate (dienophile) to the
imine dimerization product (azabutadiene), or as a pericyclic process [28]. Compound 6k was obtained as a 1:1
mixture of diastereomers according to NMR and X-ray structural analysis data (Table 3, Fig. 1a), and the unit
cell consisted of two adjacent molecules of the opposite diastereomers. The derivatives 7i,k and 8i,n were
formed by the interaction of two isocyanate molecules with one imine molecule. The intermediate dithiol B
89

(not isolated, but detected by LC/MS) underwent oxidative cyclization into the 1,2-dithiolane [6, 29] upon
contact with air. The structures of compounds 7k and 8n were also confirmed by NMR spectroscopy and X-ray
structural analysis (Table 3, Fig. 1b,c).
Fig. 1. The structures of compounds (a) 6k, (b) 7k, and (c) 8n with atoms represented by thermal vibration
ellipsoids of 50% probability.
Remarkably, the cyclization of the thioanilides 3a-u into the dihydroisothiazoles 4a-u proceded
relatively smoothly. The sulfur atom of the starting compounds was oxidized under mild conditions by the
action of molecular iodine or bromine, after which the mixture was treated with a saturated Na2CO3 solution
according to the methods [9, 12]. The target compounds were obtained in 82-96% yields.
The structures of the obtained 3-amino-3-arylprop-2-enethioamides 3a-u were confirmed by NMR
spectroscopy (Table 3) and X-ray structural analysis. All of the obtained derivatives without an exception
90

existed only in the cis-enamine form due to the strong NH···S=C hydrogen bonding between the enamine and
thioamide groups. The proton of the enamine fragment gave an NMR signal in the downfield region at
11.68-11.98 ppm.
Fig. 2. The structures of compounds (a) 3k, (b) 4p, and (c) 4r with atoms represented by thermal vibration
ellipsoids of 50% probability.
1
The structures of the dihydroisothiazoles 4a-u were also in agreement with the Н and 13C NMR
1
spectroscopy data (Table 3). The Н NMR signals due to the protons at position 4 of the isothiazole ring
appeared at 6.04-6.10 ppm in the case of the aryl derivatives, and 6.10-6.21 ppm in the case of the hetaryl
derivatives. The 13С NMR signals of the isothiazole С-3, С-4, and С-5 atoms were observed at 159.5-163.7,
107.3-110.6, and 163.8-167.7 ppm, respectively. The structures of the products 4p,r were also confirmed by
X-ray structural analysis (Fig. 2). It was established that the imine double bond had a (Z)-configuration, the
aromatic rings were at sterically favored positions, and were rotated at an angle relative to the isothiazole ring
plane.
91

TABLE 2. The Physicochemical Characteristics of the Synthesized Compounds
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
Mp*, °C Yield, %
Color
C
3
H
4
N
5
1
3а
3b
3c
3d
3e
3f
2
6
7
8
C18H19ClN2S
C18H19FN2S
C20H24N2OS
C20H24N2O2S
C19H21FN2OS
C19H21FN2OS
C19H21ClN2S
C20H23ClN2S
C20H23ClN2OS
C19H20Cl2N2S
C19H20FClN2S
C18H17Cl3N2S
C18H21N3S
65.02
65.34
5.51
5.79
8.41
8.47
142-145
99-101
73
78
62
72
64
73
66
65
63
71
68
70
67
71
62
63
67
74
65
69
64
90
83
86
89
88
82
88
87
84
90
Light-yellow
Light-yellow
Light-yellow
Light-yellow
Light-yellow
Light-yellow
Light-yellow
Light-yellow
Yellow
68.71
5.97
8.79
68.76
6.09
8.91
70.25
70.55
7.08
7.10
8.22
8.23
173-176
176-179
173-175
110-112
143-145
96-98
67.33
6.83
7.81
67.39
6.79
7.86
66.15
66.25
6.08
6.15
8.02
8.13
66.38
6.29
8.06
66.25
6.15
8.13
3g
3h
3i
66.08
66.17
6.16
6.14
8.04
8.12
66.69
6.22
7.74
66.93
6.46
7.80
64.02
64.07
6.16
6.18
7.51
7.47
139-141
159-160
149-151
159-161
189-191
151-154
172-174
179-181
137-139
152-155
117-119
122-124
156-158
87-89
3j
60.10
5.23
7.37
Light-yellow
Light-yellow
Light-yellow
Yellow
60.16
5.31
7.38
3k
3l
62.90
62.89
5.66
5.56
7.66
7.72
54.25
4.22
6.94
54.08
4.29
7.01
3m
3n
3o
3p
3q
3r
3s
69.31
69.42
6.98
6.80
13.07
13.49
C18H21N3OS
C19H24N4S
65.69
6.54
12.59
Light-yellow
Yellow
66.03
6.46
12.83
67.16
67.02
7.12
7.11
16.38
16.45
C17H18ClN3S
C17H18FN3S
C17H17Cl2N3S
C17H18FN3S
C18H21N3S
61.13
5.46
12.57
Light-yellow
Light-yellow
Yellow
61.53
5.47
12.66
64.74
64.74
5.70
5.75
13.19
13.32
55.70
4.63
11.36
55.74
4.68
11.47
65.04
64.74
5.81
5.75
13.30
13.32
Light-yellow
Yellow
3t
69.46
6.76
13.44
69.42
6.80
13.49
3u
4a
4b
4c
4d
4e
4f
C18H21N3OS
C18H17ClN2S
C18H17FN2S
C20H22N2OS
C20H22N2O2S
C19H19FN2OS
C19H19FN2OS
C19H19ClN2S
C20H21ClN2S
C20H21ClN2OS
C19H18Cl2N2S
65.84
66.03
6.57
6.46
12.71
12.83
Light-yellow
Yellow
65.75
5.20
8.53
65.73
5.21
8.51
68.74
69.20
5.37
5.49
8.87
8.97
124-126
105-107
116-119
106-108
89-91
Yellow
70.79
6.50
8.25
Yellow
70.97
6.55
8.28
67.64
67.77
6.29
6.26
7.80
7.90
Orange
66.55
5.56
8.12
Light-yellow
Yellow
66.64
5.59
8.18
66.78
66.64
5.63
5.59
8.14
8.18
4g
4h
4i
66.41
5.49
8.18
111-114
99-100
Orange
66.55
5.59
8.17
67.25
67.30
5.88
5.93
7.81
7.85
Light-yellow
Light-yellow
Light-yellow
64.39
5.61
7.50
124-126
125-126
64.41
5.67
7.51
4j
60.58
60.48
4.79
4.81
7.40
7.42
92

TABLE 2 (continued)
1
4k
4l
2
3
4
5
6
7
8
C19H18ClFN2S
C18H15Cl3N2S
C18H19N3S
63.20
63.24
4.97
5.03
7.72
7.76
115-118
138-141
144-146
130-132
132-135
127-129
104-106
150-152
105-107
60-62
87
94
87
84
82
89
90
89
82
85
86
20
23
14
1
Orange
54.37
3.75
6.92
Light-yellow
Yellow
54.35
3.80
7.04
4m
4n
4o
4p
4q
4r
4s
69.81
69.87
5.99
6.19
13.46
13.58
C18H19N3OS
C19H22N4S
66.49
5.67
12.86
Yellowish brown
Orange
66.43
5.89
12.91
67.50
67.42
6.69
6.55
16.63
16.55
C17H16ClN3S
C17H16FN3S
C17H15Cl2N3S
C17H16FN3S
C18H19N3S
61.90
4.73
12.66
Yellow
61.90
4.89
12.74
54.91
55.15
5.03
5.15
13.28
13.41
Orange
56.06
3.89
11.46
Light-yellow
Light-yellow
Light-yellow
Yellow
56.05
4.15
11.53
65.37
65.15
5.29
5.15
13.33
13.41
4t
69.76
6.24
13.50
69.87
6.19
13.58
4u
5d
5h
6k
7i
C18H19N3OS
C12H18N2OS
C11H15FN2S
C27H25Cl2FN2S
66.43
66.43
5.91
5.89
12.87
12.91
63-65
60.49
7.79
11.68
119-121
66-68
White
60.47
7.61
11.75
58.43
58.38
6.65
6.68
12.26
12.28
White
65.13
4.97
6.57
107-109
218-220
147-149
172-174
201-203
White
64.93
5.05
5.61
C28H28ClN3O2S2 62.54
62.50
C26H22ClF2N3S2 65.90
5.33
5.24
7.57
7.81
Light-yellow
Light-yellow
Yellow
7k
8i
4.30
8.11
4
60.75
4.31
8.17
C24H19ClN2O3S2 59.81
59.68
C23H19N3O3S2
4.13
3.97
5.66
5.80
3
8n
61.32
4.30
9.26
6
Yellow
61.45
4.26
9.35
_______
*Solvents for recrystallization: Et2O (compounds 3s-u, 5d), H2O (compound
5h), hexane (compounds 6k, 7k), CH2Cl2 (compound 8n), MTBE (the rest of
the compounds)
Thus, we have described the preparation of a series of new 3-aryl(hetaryl)-substituted 2-alkyl-5-aryl-
imino-2,5-dihydroisothiazoles by oxidative cyclization of the respective 3-substituted anilides of 3-alkyl-
aminoprop-2-enethioic acids. The reaction leading to the formation of the starting thioamides was investigated,
and the most significant by-products were isolated and characterized. A study of the cytotoxic properties of the
obtained isothiazoles is planned.
EXPERIMENTAL
1H and 13C NMR spectra were acquired on a Varian 400-MR instrument (400 and 100 MHz, respectively)
1
13
in CDCl3, the residual solvent protons were used as internal standard (7.27 ppm for Н nuclei, 77.0 ppm for С
nuclei). The signals in certain cases were assigned by using homo- and heteronuclear 2D NMR experiments:
COSY, NOESY, HMBC, and HSQC. Mass spectra were recorded using an HPLC-MS equipment that consisted of
an Acquity UPLC system (Waters)-Q-TOF (Micromass) with a Waters Xbridge C18 column (3.5 μm, 2.1×50 mm),
0.6 ml/min flow rate, gradient elution with MeCN–HCOOH (0.1%) in water, electrospray ionization,
93

94

95

96

97

98

99

water, electrospray ionization, positive ion current recording. Elemental analysis was performed on an EA 1106
equipment (Carlo Erba Instruments). Melting points were recorded on a Kofler bench. The purity of the obtained
compounds was controlled by TLC on 60Å F254 silica gel plates (Merck). The reagents and solvents were purchased
from Acros and Alfa Aesar and were used without additional purification.
Preparation of N-Alkylimines of Acetophenones and Acetylpyridines (Intermediates А) (General
Method). The interaction of the ketones 1а-е with primary amines in the presence of TiCl4 required 48 h
according to the literature method [21]. After the reaction was complete, the mixture was filtered through Celite
and the solvent was removed by evaporation at reduced pressure. The imines that formed were further isolated
according to the method [26]. The obtained product contained ~90% of the target imine and up to 10% of the
1
starting acetophenone (according to the H NMR spectrum and LC/MS), and could be used in the next stage
without additional purification.
1
4-Methoxyacetophenone N-Propylimine. Light-yellow oil. H NMR spectrum, δ, ppm (J, Hz): 1.04
(3H, t, J = 6.6, CH2CH3); 1.97 (2H, sext, J = 6.2, CH2CH2Ме); 2.79 (3H, s, N=CCH3); 3.10-3.24 (1H, m) and
3.60-3.74 (1H, m, NCH2); 3.90 (3H, s, OCH3); 7.10 (2H, d, J = 7.2, H Ar); 8.20 (2H, d, J = 7.3, H Ar). Mass
spectrum, m/z (Irel, %): 192 [M+H]+ (100).
N-(4-Chlorophenyl)amide of (Z)-3-Phenyl-3-propylaminoprop-2-enethioic Acid (3a). A mixture of
acetophenone N-propylimine (7.74 g, 48 mmol) and 4-chlorophenylisothiocyanate (8.25 g, 49 mmol) in
anhydrous MeCN (10 ml) was stirred for 72 h at room temperature, and the crystalline precipitate 3a was
filtered off, recrystallized from MTBE, and air-dried. Yield 11.59 g (73%).
The thioamides 3b-u were obtained similarly.
The mother liquors obtained after collecting the crystalline compound 3n were evaporated and separated
by silica gel chromatography (elution with a petroleum ether–CH2Cl2 system, gradient from 1:1 to 1:10, with
added Et3N (0.5%)). The product was 3,5-bis(4-methoxyphenylimino)-4-(4-pyridoyl)-1,2-di-thiolane (8n).
Yield 0.4 g (6%).
Reaction of 3-Fluorophenylisothiocyanate with 4-Chloroacetophenone N-Isobutylimine. A mixture
of 4-chloroacetophenone N-isobutylimine (6.62 g, 31.6 mmol) obtained by the method [20] and
3-fluorophenylisothiocyanate (4.37 g, 28.5 mmol) in anhydrous Et2O (10 ml) was stirred at room temperature
for 72 h, then the crystalline precipitate of compound 3k was filtered off. Yield 2.97 g, 29%. The filtrate was
evaporated and separated by chromatography on silica gel (eluting with petroleum ether–Et2O, gradient from
10:0 to 5:2, with added Et3N (0.5%)). The elution sequence was: compound 7k (0.31 g, 4%), 4-chloro-
acetophenone (1.4 g, 29%), compound 6k (1.12 g, 14%), an additional crop of compound 3k (0.58 g), for a total
yield of 3.55 g, 34%, and the thiourea 5h (1.48 g, 23%).
Similarly, the reaction of 4-chloroacetophenone N-isobutylimine (6.15 g, 29.3 mmol) with
4-methoxyphenylisothiocyanate (4.63 g, 28.0 mmol), followed by silica gel column chromatography (elution
with petroleum ether MTBE, gradient from 10:0 to 5:2, with added Et3N (0.5%)) yielded the target thioamide 3i
(4.84 g, 46%), the thiourea 5d (1.33 g, 20%), and also the 1,2-dithiolanes 7i (0.10 g, 1%) and 8i (0.17 g, 3%).
5-(4-Chlorophenylimino)-3-phenyl-2-propyl-2,5-dihydroisothiazole (4a). Pyridine (2.9 ml, 37 mmol)
was added to a solution of the thioanilide 3a (11.58 g, 35 mmol) in anhydrous CHCl3 (35.0 ml). The reaction
mixture was cooled to 0-5°C, followed by a dropwise addition of iodine solution (8.88 g, 35 mmol) in EtOH
(60.0 ml) over 3 h and stirring at the same temperature for another 1 h. After the reaction was complete, the
solvent was evaporated, the residue was treated with Et2O (50 ml), the precipitated crystals were filtered off,
redissolved in CHCl3 (40 ml), extracted with saturated aqueous Na2CO3 (60 ml) and Н2О (60 ml), the solvent
was removed at reduced pressure, the residue was recrystallized from MTBE and air-dried.
Compounds 4b-u were obtained by an analogous method.
The X-ray structural analysis of compounds 3k, 4p, 4r, 6k, 7k, 8n was performed on a Nonius
KappaCDD automated diffractometer to 2θmax 55° (λ(Mo) 0.71073 Å). Compound 3k (C19H20FClN2S) formed
monoclinic crystals, at 293 K: a 9.7096(6), b 19.7188(14), c 10.3650(8) Å; β 108.648(4)°; V 1880.3(2) Å3;
space group P21/n; Z 4; dcalc 1.278 g/cm3; μ 0.326 mm-1; F(000) 756. Compound 4p (C17H16N3ClS) formed
100

triclinic crystals, at 173 K: a 6.7490(3), b 9.6460(3), c 13.4060(7) Å; α 95.996(1), β 98.8560(1), γ 107.861(1)°;
–
V 810.15(4) Å3; space group
; Z 2; dcalc 1.352 g/cm3; μ 0.364 mm-1; F(000) 344. Compound 4r
P1
(C17H15N3Cl2S) formed triclinic crystals, at 173 K: a 6.8560(2), b 9.6910(3), c 13.2340(5) Å; α 95.975(2),
–
β 93.839(2), γ 108.382(2)°; V 825.24(5) Å ; space group ; Z 2; dcalc 1.466 g/cm3; μ 0.521 mm-1; F(000) 376.
Compound 6k (C27H25Cl2FN2S) formed monoclinic crystals, at 293 K: a 10.7328(3), b 23.6570(9), c 11.0874
(4) Å; β 155.219(3)°; V 2546.8(1) Å3; space group P21; Z 4; dcalc 1.303 g/cm3; μ 0.363 mm-1; F(000) 1040.
3
P1
Compound 7k (C26H22ClF2N3S2) formed triclinic crystals, at 190 K: a 11.1036(3), b 12.0797(3), c 19.9825(7) Å;
–
α 99.112(1), β 103.434(1),  106.634(2)°; V 2423.98(12) Å3; space group
; Z 4 (Z' 2); dcalc 1.409 g/cm3,
P1
μ 0.366 mm-1; F(000) 1064. Compound 8n (C23H19N3O3S2) formed monoclinic crystals, at 183 K: a 13.9793(6),
b 7.3442(2), c 19.6917(12) Å; β 90.5430(10)°; V 2021.59(16) Å3; space group P21/c; Z 4; dcalc 1.477 g/cm3;
μ 0.296 mm-1; F(000) 936.
The unit cell parameters and the intensities of 7132 reflections for compound 3k, 5687 reflections (3669
independent, Rint 0.0176) for compound 4p, 5692 reflections (3749 independent, Rint 0.0308) for compound 4r,
9764 reflections for compound 6k, 15878 reflections (10923 independent, Rint 0.040) for compound 7k, 7826
reflections (4248 independent, Rint 0.1007) for compound 8n were measured on a Bruker-Nonius KappaCCD
automated X-ray diffractometer (λMoKα radiation,  0.71073 Å, graphite monochromator). The structures of
the compounds were solved by the direct method with SIR2004 software [30] and were refined with SHELXL
software package [31] in anisotropic approximation for non-hydrogen atoms. The hydrogen atom positions were
calculated geometrically, taking into account the differential synthesis of electron density and were refined with
the "rider" model at Uiso = 1.5Ueq for the methyl group and Uiso = 1.2Ueq for the rest of the hydrogen atoms. The
final probability factors for the structures 3k, 4p, 4r, 6k, 7k, and 8n were respectively R1 0.0785, wR2 0.1965;
R1 0.0373, wR2 0.0919; R1 0.0459, wR2 0.1154; R1 0.0817, wR2 0.2429; R1 0.095, wR2 0.301; and R1 0.0581, wR2
0.0993. The complete crystallographic data sets for compounds 3k, 4p, 4r, 6k, 7k, and 8n were deposited at the
Cambridge Crystallographic Data Center (deposits CCDC 976565, CCDC 956666, CCDC 956665, CCDC
976566, CCDC 979541, and CCDC 957328, respectively).
The authors would like to express their gratitude to A. Mishnev and D. Stepanov for the X-ray structural
investigations.
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