Synthesis of 2,3-Bis[amino(benzylsulfanyl)methylidene]butanedinitrile and 2-(Benzylsulfanyl)pyridine-3-carbonitrile derivatives

Article abstract of DOI:10.1134/S1070428018120072

The alkylation of cyanothioacetamide with benzyl chloride in DMF in the presence of 10% aqueous potassium hydroxide afforded 2,3-bis[amino(benzylsulfanyl)methylidene]butanedinitrile. Analogous reaction with addition of acetylacetone or its 3-methyl derivative led to the formation of 2-benzylsulfanyl-4,6-dimethylor -4,5,6-trimethylpyridine-3-carbonitrile.

Full text of DOI:10.1134/S1070428018120072

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2018, Vol. 54, No. 12, pp. 1785–1789. © Pleiades Publishing, Ltd., 2018.
Original Russian Text © I.V. Dyachenko, V.D. Dyachenko, P.V. Dorovatovskii, V.N. Khrustalev, V.N. Torocheshnikov, V.G. Nenajdenko, 2018, published in
Zhurnal Organicheskoi Khimii, 2018, Vol. 54, No. 12, pp. 1771–1775.
Synthesis of 2,3-Bis[amino(benzylsulfanyl)methylidene]butane-
dinitrile and 2-(Benzylsulfanyl)pyridine-3-carbonitrile
derivatives
I. V. Dyachenkoa, V. D. Dyachenkoa, P. V. Dorovatovskiib, V. N. Khrustalevb, c,
V. N. Torocheshnikovd, and V. G. Nenajdenkod*
a Taras Shevchenko Lugansk National University, ul Oboronnaya 2, Lugansk, 92703 Ukraine
b National Research Center “Kurchatov Institute,” pl. Akademika Kurchatova 1, Moscow, 123182 Russia
c Peoples’Friendship University of Russia, ul. Miklukho-Maklaya 6, Moscow, 117198 Russia
d Faculty of Chemistry, Moscow State University, Leninskie gory 1, Moscow, 119991 Russia
*e-mail: nenajdenko@gmail.com
Received September 5, 2018; revised September 5, 2018; accepted September 7, 2018
Abstract—The alkylation of cyanothioacetamide with benzyl chloride in DMF in the presence of 10% aqueous
potassium hydroxide afforded 2,3-bis[amino(benzylsulfanyl)methylidene]butanedinitrile. Analogous reaction
with addition of acetylacetone or its 3-methyl derivative led to the formation of 2-benzylsulfanyl-4,6-dimethyl-
or -4,5,6-trimethylpyridine-3-carbonitrile.
DOI: 10.1134/S1070428018120072
respectively. The reaction is likely to proceed through
the same intermediate imidothioate A whose condensa-
tion with 1,3-dicarbonyl component 4 gives interme-
diate D (Guareschi–Torpe reaction), and intramolec-
ular cyclization of the latter yields stable final structure
5. Compounds 5a and 5b attract interest as interme-
diate products for the synthesis of compounds posses-
sing anti-inflammatory [5], antitumor [6], and growth-
regulating activity [7].
Cyanothioacetamide (1) is widely used in organic
synthesis as an active methylene compound for the
preparation of 2-thioxo-3-cyanopyridine derivatives
[1]. There are a few published data on the alkylation of
cyanothioacetamide. In particular, we previously
studied its alkylation with allyl bromide, which led to
the formation of 2,3-bis[allylsulfanyl(amino)methyli-
dene]butanedinitrile [2].
Herein we report the alkylation of 1 with benzyl
chloride (2) in DMF in the presence of 10% aqueous
potassium hydroxide at 20°C. The reaction afforded
2,3-bis[amino(benzylsulfanyl)methylidene]butanedi-
nitrile (3) (Scheme 1). Presumably, the reaction in-
volves intermediate formation of imidothioate A which
tautomerizes to enamino nitrile B, and the subsequent
Michael addition gives adduct C which is stabilized
via tautomerization to substituted buta-1,3-diene 3.
The latter is a promising building block for various
heterocyclizations [3, 4].
The structures of condensation products 5a and 5b
were unambiguously determined by X-ray analysis
(Fig. 1). The polymethylpyridinecarbonitrile fragments
of molecules 5a and 5b are almost planar. Deviations
of non-hydrogen atoms from the mean-square planes
do not exceed 0.022 (5a) or 0.020 Å (5b). However,
the conformations of 2-benzylsulfanyl substituents in
5a and 5b are different. In particular, the torsion angles
C2S1C7C8 are –86.30(12) and –79.63(17)°, the angles
S1C7C8C9 are –76.65(13) and –59.36(17)°, and the
dihedral angles between the pyridine and benzene ring
planes are 79.07(6) and 83.36(6)°, respectively.
When a third component, acetylacetone 4a or its
3-methyl derivative 4b, was added to the reaction
mixture, we isolated 2-(benzylsulfanyl)-4,6-dimethyl-
and -4,5,6-trimethylpyridine-3-carbonitriles 5a and 5b,
Molecules of both compounds in crystal form
double stacks along the a crystallographic axis. In
1785

DYACHENKO et al.
1786
Scheme 1.
NH2
NC
+
PhCH2Cl
S
1
2
O
O
Me
Me
Me
Me
N
R
R
4a, 4b
CN
S
NH
R
CN
S
KOH
NC
Me
–H2O
–H2O
S
Ph
HN
Ph
O
Me
Ph
A
D
5a, 5b
CN
CN
Ph
S
CN
S
Ph
S
CN
S
NH2
Ph
A
NC
NH
H2N
NH2
H2N
S
Ph
Ph
B
C
3
R = H (a), Me (b).
these stacks, molecules are displaced alternately in
parallel planes passing through the pyridine rings by
~1.4 (5a) and ~1.6 Å (5b) (Fig. 2).
In the crystal structure of 5a, molecules in the
stacks are oriented at a dihedral angle of 21.3(3)° with
respect to the 0YZ plane and are linked to each other
through π–π stacking interactions [the distance
between the pyridine ring planes is 3.396(5) Å, and the
shortest distance between the C2 and C4 (–x, 1 – y,
1 – z) or C4 and C2 atoms (–x, 1 – y, 1 – z) is
3.392(2) Å]. The presence of an additional methyl
group in position 5 of the pyridine ring of 5b not only
leads to greater displacement of molecules in the
double stacks relative to each other but also increases
the distance between the pyridine rings of the neigh-
boring molecules to 3.574(5) Å. Furthermore, mole-
C15
C4
C15
C4
N2
N2
C14
C14
C16
C5
C5
C3
C2
C3
C2
C6
C6
S1
C7
S1
N1
N1
C17
C16
C7
C8
C9
C8
C13
C9
C13
C10
C10
C12
C11
C12
5b
C11
5a
Fig. 1. Molecular structures of 2-(benzylsulfanyl)-4,6-dimethylpyridine-3-carbonitrile (5a) and 2-(benzylsulfanyl)-4,5,6-trimethyl-
pyridine-3-carbonitrile (5b) according to the X-ray diffraction data. Non-hydrogen atoms are shown as anisotropic displacement
ellipsoids with a probability of 50%.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 54 No. 12 2018

SYNTHESIS OF 2,3-BIS[AMINO(BENZYLSULFANYL)METHYLIDENE]BUTANEDINITRILE
1787
a
c
a
c
0
0
b
b
5a
5b
Fig. 2. Crystal packings of 2-(benzylsulfanyl)-4,6-dimethylpyridine-3-carbonitrile (5a) and 2-(benzylsulfanyl)-4,5,6-trimethyl-
pyridine-3-carbonitrile (5b).
cules 5b in the stacks are oriented at a smaller angle
with respect to the 0YZ plane [12.9(3)°] than in the
crystal structure of 5a. Thus, molecules 5b in crystal
are located at van der Waals distances from each other.
The IR spectra were recorded on an IKS-40 spec-
trometer from samples dispersed in mineral oil. The
1H and 13C NMR spectra were measured on a Varian
VXR-400 instrument at 399.97 and 100 MHz, respec-
tively, using DMSO-d6 as solvent and tetramethyl-
silane as internal standard. The high-resolution mass
spectra of 5a and 5b were recorded on an Orbitrap
Elite instrument; samples were dissolved in 1 mL of
DMSO, and the solutions were diluted by a factor of
100 with 1% formic acid in acetonitrile and introduced
into the ESI source at a flow rate of 40 μL/min using
a syringe pump with the gas supply being turned off;
capillary voltage 3.5 kV, capillary temperature 275°C;
positive and negative ion detection using an orbital
trap with a resolution of 480000; internal calibration
against [2DMSO + H]+ (m/z 157.03515, positive ions)
and dodecyl sulfate anion (m/z 265.14789; negative
ions). The mass spectrum of 3 (electron impact, 70 eV)
was obtained on an Agilent 1100 Series LC/MSD
instrument (a sample was introduced as a solution in
AcOH). Elemental analysis was performed on a Perkin
Elmer CHN analyzer. The melting points were meas-
ured on a Kofler hot stage. The progress of reactions
and the purity of the isolated compounds were moni-
tored by TLC on Silufol UV-254 plates using acetone–
hexane (3:5) as eluent; spots were visualized by treat-
ment with iodine vapor and under UV light.
EXPERIMENTAL
The X-ray diffraction data for compounds 5a and
5b were obtained on a BELOK synchrotron station
(National Research Center “Kurchatov Institute”) with
a Rayonix SX165 CCD two-coordinate detector (tem-
perature 100 K, λ 0.96990 Å, φ-scanning with a step of
1.0°). The data were processed by iMOSFLM program
implemented in CCP4 package [8]. A correction for
absorption was applied using SCALA program [9].
The principal crystallographic data and structure
refinement parameters are given in Table 1. The struc-
tures were solved by the direct method and were
refined against F2 by the full-matrix least-squares
method in anisotropic approximation for non-hydrogen
atoms. Hydrogen atoms were placed in geometrically
calculated positions and were refined with fixed
positional parameters (riding model) and isotropic dis-
placement parameters [Uiso(H) = 1.5Ueq(C) for methyl
groups, Uiso(H) = 1.2Ueq(C) for the other hydrogens].
All calculations were performed using SHELXTL [10].
The tabulated coordinates of atoms, bond lengths,
bond and torsion angles, and anisotropic displacement
parameters for compounds 5a and 5b were deposited
to the Cambridge Crystallographic Data Centre; CCDC
entry nos. 1868569 (5a) and 1868570 (5b).
2,3-Bis[amino(benzylsulfanyl)methylidene]-
butanedinitrile (3). Cyanothioacetamide (1), 1.0 g
(10 mmol), was dissolved in 15 mL of DMF, and
5.6 mL (10 mmol) of 10% aqueous potassium hydrox-
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 54 No. 12 2018

DYACHENKO et al.
1788
Table 1. X-Ray diffraction data for compounds 5a and 5b
120.7 (2C), 127.9 (2C), 129.2 (4C), 129.4 (4C), 134.0
(2C), 156.6 (2C). Mass spectrum: m/z 379.0 (Irel 100%)
[M + 1]+. Found, %: C 63.35; H 4.68; N 14.72.
C20H18N4S2. Calculated, %: C 63.46; H 4.79; N 14.80.
M 378.5.
Parameter
Formula
5a
5b
C15H14N2S
254.34
C16H16N2S
268.37
Molecular weight
0.05×0.05×0.20 0.15×0.15×0.20
Single crystal
dimensions, mm
2-(Benzylsulfanyl)-4,6-dimethylpyridine-
3-carbonitrile (5a). Cyanothioacetamide (1), 1.0 g
(10 mmol), was dissolved in 15 mL of DMF, and
5.6 mL (10 mmol) of 10% aqueous potassium hydrox-
ide and 1.2 mL (10 mmol) of benzyl chloride (2) were
added in succession with stirring at 20°C. The mixture
was stirred for 2 h, 1.23 mL (10 mmol) of acetylace-
tone (4a) was added, and the mixture was heated to
50°C, left to stand for 2 days, and diluted with an equal
volume of water. The precipitate was filtered off and
washed with water, ethanol, and hexane. Yield 1.7 g
(68%), colorless needles, mp 80–82°C (from AcOH)
[11]. 13C NMR spectrum, δC, ppm: 20.1, 24.7, 33.7,
104.2, 115.4, 120.9, 127.6, 128.8 (2C), 129.5 (2C),
138.1, 152.9, 160.7, 161.8. Found: m/z 255.0951
[M + H]+. C15H14N2S. Calculated: M + H 255.0878.
Monoclinic
P21/c
Triclinic
P-1
Crystal system
Space group
a, A
0007.1803(14)
10.040(2)
18.690(4)
90.00(0)
98.68(3)
90.00(0)
1331.9(5)
4
007.2950(15)
009.1851(18)
10.815(2)0
85.13(3)
81.63(3)
77.31(3)
698.4(3)
2
b, A
c, A
α, deg
β, deg
γ, deg
V, A3
Z
dcalc, g/cm3
F(000)
μ, mm–1
2θmax, deg
1.268
1.276
536
284
0.522
0.505
2-(Benzylsulfanyl)-4,5,6-trimethylpyridine-
3-carbonitrile (5b) was synthesized in a similar way
using 1.2 mL (10 mmol) of 3-methylpentane-2,4-dione
(4b). Yield 1.9 g (71%), colorless crystals, mp 120–
122°C (from EtOH) [12]. 13C NMR spectrum, δC, ppm:
14.6, 18.6, 24.0, 33.6, 105.0, 116.0, 125.5 (2C), 127.3,
127.5, 128.8 (2C), 138.4, 150.7, 156.9, 160.4. Found:
m/z 269.1108 [M + H]+. C16H16N2S. Calculated: M + H
269.1034.
76.92
76.58
23735
12066
Total number of
reflections
2756 (0.088)
2351
2497 (0.089)
2244
Number of indepen-
dent reflections (Rint)
Number of reflections
with I >2σ(I)
166
176
Number of variables
0.048, 0.120
0.056, 0.153
R1, wR2 [reflections
with I > 2σ(I)]
This study was performed under financial support
by the Russian Foundation for Basic Research (project
nos. 18-53-06006 Az_a, 16-29-10669 ofi_m) and by
the Ministry of Education and Science of the Russian
Federation (program “5-100” for increasing the rating
of the People’s Friendship University of Russia). The
X-ray diffraction study was performed using the
unique scientific setup Kurchatov synchrotron radia-
tion source under financial support by the Ministry of
Education and Science of the Russian Federation
(project ID RFMEFI61917X0007).
0.056, 0.126
0.062, 0.161
R1, wR2 (independent
reflections)
Goodness of fit (F2)
Extinction coefficient
Tmin, Tmax
1.080
0.993
0.011(1)
0.035(5)
0.890, 0.970
0.890, 0.920
ide and 1.2 mL (10 mmol) of benzyl chloride (2) were
added in succession with stirring at 20°C. The mixture
was stirred for 2 h and left to stand for 3 days. The
mixture was then slowly diluted with an equal volume
of water under stirring and was left to stand for 3 days
at room temperature. The precipitate was filtered off
and washed with water and methanol. Yield 1.6 g
(43%), white powder, mp 179–180°C (from EtOH).
IR spectrum, ν, cm–1: 3280–3450 (NH2), 2200 (C≡N),
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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 54 No. 12 2018

SYNTHESIS OF 2,3-BIS[AMINO(BENZYLSULFANYL)METHYLIDENE]BUTANEDINITRILE
1789
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