Novel method of 4,6-dimethyl-2-thioxo-1,2-dihydronicotinonitrile synthesis

Article abstract of DOI:10.1134/S1070363215080083

Condensation of acetaldehyde with cyanothioacetamide and 1-(prop-1-en-2-yl)pyrrolidine has afforded 4,6-dimethyl-2-thioxo-1,2-dihydronicotinonitrile. Alkylation of the latter with α-haloketones yields substituted 2-alkylsulfanyl-4,6-dimethylnicotinonitriles and thieno[2,3-b]pyridines.

Full text of DOI:10.1134/S1070363215080083

ISSN 1070-3632, Russian Journal of General Chemistry, 2015, Vol. 85, No. 8, pp. 1834–1837. © Pleiades Publishing, Ltd., 2015.
Original Russian Text © I.V. Dyachenko, 2015, published in Zhurnal Obshchei Khimii, 2015, Vol. 85, No. 8, pp. 1276–1279.
Novel Method of 4,6-Dimethyl-2-thioxo-1,2-dihydronicotinonitrile
Synthesis
I. V. Dyachenko
Shevchenko Lugansk University, ul. Oboronnyaya 2, Lugansk, 91011 Ukraine
e-mail: ivladya87@e-mail.ua
Received March 26, 2015
Abstract—Condensation of acetaldehyde with cyanothioacetamide and 1-(prop-1-en-2-yl)pyrrolidine has
afforded 4,6-dimethyl-2-thioxo-1,2-dihydronicotinonitrile. Alkylation of the latter with α-haloketones yields
substituted 2-alkylsulfanyl-4,6-dimethylnicotinonitriles and thieno[2,3-b]pyridines.
Keywords: acetaldehyde, cyanothioacetamide, 1-(prop-1-en-2-yl)pyrrolidine, 2-thioxo-1,2-dihydronicotinonitrile,
2-alkylsulfanylnicotinonitriles, thieno[2,3-b]pyridines
DOI: 10.1134/S1070363215080083
Alkyl-substituted 2-thioxo(oxo)-1,2-dihydronicotino-
nitriles are intermediates in the synthesis of anti-
inflammatory [1] and antineoplastic [2] drugs. They
are components of medicines for Alzheimer’s disease
treatment [3, 4], herbicides [5], and azo dyes [6, 7].
The known methods of their synthesis are based on
condensation of acetylacetone with cyanoacetamide or
cyanothioacetamide [8], nucleophilic substitution of
the chlorine atom in 2-thioureachloronicotinonitrile
[9], and the Michael reaction via the methylene com-
ponents exchange [10].
In this work, we propose a new method of 4,6-di-
methyl-2-thioxo-1,2-dihydronicotinonitrile I synthesis:
Scheme 1.
Me
Me
N
Me
N
CN
S
CN
S
CN
S
H
IV
Me
_H2O
CHO
H2N
H2N
H2N
Me
N
A
B
II
III
, _2[H]
N
H
Z
KOH/ Hlg
Me
Me
Me
NH2
O
CN
S
CN
S
Z
Vа_Vh
KОН
Z
_KHlg,
_H2O
S
O
Me
N
Me
N
H
Me
N
O
VIIа_VIIIh
VIа_VIh
I
V–VII, Hlg = Br, Z = 3,4-Cl2C6H3 (a); Br, 4-BuC6H4 (b); Br, 4-PhC6H4 (c); Cl, 4-BrC6H4NHCO (d); Br, 2,4-Me2C6H3 (e);
Br, 4-BrC6H4 (f); Br, 3-BrC6H4 (g); Cl, PhCH2O (h).
1834

NOVEL METHOD OF 4,6-DIMETHYL-2-THIOXO-1,2-DIHYDRONICOTINONITRILE
1835
Table 1. Yields, melting points, and elemental analysis data for 2-alkylsulfanyl-4,6-dimethylnicotinonitriles VIa–VIh and 3-
amino-4,6-dimethyl-2-Z-thieno[2,3-b]pyridines VIIa–VIIh
Found, %
H
Calculated, %
H
Comp. Yield,
mp, °С
Formula
no.
%
C
N
7.85
8.14
7.77
11.02
8.95
7.65
7.61
8.86
7.87
8.19
7.74
11.08
8.94
7.60
7.62
8.81
C
N
7.98
8.28
7.81
11.17
9.02
7.75
7.75
8.97
7.98
8.28
7.81
11.17
9.02
7.75
7.75
8.97
VIа
89
75
81
77
70
82
76
73
85
70
74
82
76
71
80
72
118–120 (АсОН)
80–81 (MeCN)
54.60
70.86
73.69
50.95
69.51
53.14
53.11
65.19
54.69
70.89
37.61
50.99
69.57
53.07
53.14
65.25
3.32
6.41
4.92
3.66
5.70
3.58
3.55
5.00
3.38
6.46
4.88
3.65
5.70
3.50
3.49
5.07
C16H12Cl2N2OS
C20H22N2OS
54.71
70.97
73.72
51.07
69.65
53.20
53.20
65.36
54.71
70.97
37.72
51.07
69.65
53.20
53.20
65.36
3.44
6.55
5.06
3.75
5.85
3.63
3.63
5.16
3.44
6.55
5.06
3.75
5.85
3.63
3.63
5.16
VIb
VIc
156–158 (BuОН)
199–201 (AcОН)
116–118 (MeOH)
125–127 (EtОН)
138–140 (AcОН)
81–83 (PrOH)
211–213а (BuOH)
113–114 (MeOH)
195–197 (PrОН)
230–232b (AcОН)
173–175 (AcОН)
180–182 (AcOH)
191–192 (AcOH)
113–115 (MeOH)
C22H18N2OS
VId
VIe
C16H14BrN3ОS
C18H18N2ОS
VIf
C16H13BrN2ОS
C16H13BrN2ОS
C17H16N2О2S
C16H12Cl2N2ОS
C20H22N2OS
VIg
VIh
VIIa
VIIb
VIIc
VIId
VIIe
VIIf
VIIg
VIIh
C22H18N2OS
C16H14BrN3OS
C18H18N2OS
C16H13BrN2OS
C16H13BrN2OS
C17H16N2O2S
a Sublimated at 170°С. b Sublimated at 200°С.
a three-component condensation of acetaldehyde II,
cyanothioacetamide III, and 1-(prop-1-en-2-yl)pyrro-
lidine IV in anhydrous ethanol at 20°C. The probable
reaction scheme included the Knöevenagel alkene A
formation that further alkylated the enamine IV via the
Stork reaction [11] to give the adduct B. The latter
underwent intramolecular transamination [12] and
oxidation (apparently with air oxygen) yielding the
nicotinonitrile I (Scheme 1).
synthesized compounds (Tables 1 and 2). Their IR
spectra contained characteristic absorption bands of
stretching vibrations at 2218–2225 (C≡N) and 1667–
1
1714 cm–1 (C=O). The H NMR spectra contained the
signals of methyl groups (2.14–2.79 ppm), pyridine H5
proton (7.00–7.09 ppm), and SCH2 fragment (for
compound VI, 4.15–4.84 ppm).
1H NMR spectra of compounds VIIa–VIIh
contained the signal of amino group (6.81–8.08 ppm)
instead of that of SCH2 protons, thus confirming the
occurred intramolecular cyclization [17–19]. In
addition, absorption bands at 3180–3385 and 1638–
1648 cm–1 appeared in the IR spectra of thieno-
pyridines VII, assigned to stretching and deformation
vibrations of the amino group; no absorption bands of
the nitrile group stretching was registered.
Alkylation of compound I with α-haloketones Va–
Vh in an alkaline DMF solution proceeded regio-
selectively at the sulfur atom to form the cor-
responding thioethers VIa–VIh. The latter underwent
intramolecular cyclization to give the substituted 3-
amino-4,6-dimethylthieno[2,3-b]pyridines VIIa–VIIh,
promising components of antidotes of hormonal action
herbicide [13, 14], sunflower growth promoters [15]
and inhibitors of the C-terminal hydrolase L1 (UCH-
L1) [16].
In summary, the three-component condensation of
acetaldehyde, cyanothioacetamide, and 1-(prop-1-en-
2-yl)pyrrolidine yields 4,6-dimethyl-2-thioxo-1,2-di-
hydronicotinonitrile that can be further converted into
potentially biologically active substituted 2-alkyl-
The determined physico-chemical and spectral
parameters confirmed the structures of all the
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 85 No. 8 2015

1836
DYACHENKO
Table 2. IR, 1Н NMR and gas chromatography–mass spectrometry data for 2-alkylsulfanyl-4,6-dimethylnicotinonitriles VIa–
VIh and 3-amino-4,6-dimethyl-2-Z-thieno[2,3-b]pyridines VIIa–VIIh
ν, cm–1
δ, ppm (J, Hz)
Comp.
no.
m/z
[M + 1]+
C≡N or
C=O,
SCH2 or
Ме
other signals
NH2
2219
δ(NH2)
NH2, Н5
VIа
1714
352
339
2.14, 2.38 4.78, 7.03 7.83 d (1H, НAr, J 7.5), 8.01 d (1H, НAr, J 7.5), 8.29 s
(1Н, НAr)
VIb
2222
2220
1703
1710
2.17, 2.38 4.80, 7.03 0.84 t (3H, Me, J 6.5), 1.11–1.72 m (4Н, 2SН2), 2.67
t (2Н, SН2, J 6.4), 7.36 d (2H, НAr, J 8.2), 7.98 d (2H,
НAr, J 8.2)
VIc
359
2.18, 2.37 4.84, 7.01 7.45 d (2H, НAr, J 6.6), 7.51 t (1Н, НAr, J 6.9), 7.72 t
(2H, НAr, J 7.0), 7.84 d (2H, НAr, J 8.4), 8.14 d (2H,
НAr, J 8.4)
VId
VIe
2224
2223
1699
1705
377
295
2.39 (2Ме) 4.15, 7.07 7.42 d (2H, НAr, J 7.1), 7.62 d (2H, НAr, J 7.1), 10.36
br. s (1Н, NH)
2.22, 2.35 4.63, 7.02 2.15 s (3Н, Mе), 2.18 s (3Н, Mе), 6.88–7.00 m (2Н,
НAr), 7.83 d (1H, НAr, J 7.6)
VIf
VIg
VIh
2220
2218
2225
1702
362
362
313
352
2.16, 2.38 4.78, 7.03 7.75 d (2H, НAr, J 7.5), 8.00 d (2H, НAr, J 7.5)
2.32, 2.39 4.15, 7.07 7.32 s (5H, Ph)
1714
1699
2.16, 2.39 4.82, 7.04 7.43–7.72 m (2Н, НAr), 8.04 d (2H, НAr, J 8.1)
2.56, 2.79 8.06, 7.05 7.68–7.79 m (2Н, НAr), 7.89 s (1Н, НAr)
VIIa 3322,
3211, 3190
1695, 1648
VIIb 3316,
3284, 3202
1699, 1645
1695, 1646
1667, 1642
1708, 1647
1690, 1638
1711, 1640
1693, 1646
339
359
377
295
362
362
313
2.52, 2.76 8.00, 7.09 0.91 t (3H, Me, J 6.4), 1.12–1.81 m (4Н, 2SН2), 7.34
d (2H, НAr, J 8.3), 7.69 d (2H, НAr, J 8.3)
VIIc 3315,
3294, 3202
2.51, 2.77 8.08, 7.09 7.45 d (2H, НAr, J 8.4), 7.72 d (2H, НAr, J 8.4), 7.84 s
(5Н, Ph)
VIId 3300,
3280, 3195
2.52, 2.73 7.00, 7.05 7.48 d (2H, НAr, J 7.8), 7.66 d (2H, НAr, J 7.8), 9.52
br. s (1Н, NH)
VIIe 3385,
3309, 3214
2.54, 2.72 7.20, 7.07 2.16 s (3Н, Mе), 2.22 s (3Н, Mе), 6.71–6.84 m (2H,
НAr), 7.88 d (1H, НAr, J 7.7)
VIIf 3322,
3277, 3180
2.52, 2.75 8.08, 7.09 7.65 d (2H, НAr, J 7.2), 7.78 d (2H, НAr, J 7.2)
VIIg 3319,
3295, 3200
2.48, 2.70 6.81, 7.01 5.30 s (2Н, ОSН2), 7.40 s (5Н, Ph)
VIIh 3333,
3298, 3213
2.44, 2.73 8.05, 7.04 7.45–7.61 m (2H, НAr), 7.68–7.82 m (2H, НAr)
sulfanyl-4,6-dimethylnicotinonitriles and thieno[2,3-b]-
pyridines.
(300.13 MHz) relative to internal TMS reference.
Elemental analysis was performed with a EuroVector
EA-3000 analyzer. Gas chromatography–mass spectra
(CF3COOH solution, CI) were obtained using a
Hewlett-Packard 5890/5972 Chrommass GC/MS
instrument equipped with an HP5-MS column. Melting
points were determined with a Kofler bench. The
reaction progress was monitored by TLC using Silufol
EXPERIMENTAL
IR spectra (KBr pellets) were recorded with an UR-
1
20 spectrometer. H NMR spectra (DMSO-d6) were
registered with
a
Bruker AM-300 instrument
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 85 No. 8 2015

NOVEL METHOD OF 4,6-DIMETHYL-2-THIOXO-1,2-DIHYDRONICOTINONITRILE
UV-254 plates, eluting with acetone–hexane (3 : 5)
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1837
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4,6-Dimethyl-2-thioxo-1,2-dihydronicotinonitrile
(I). 0.6 mL (10 mmol) of freshly distilled anhydrous
acetaldehyde and 2–3 drops of triethylamine were
added at 20°C to a stirred suspension of 1.0 g
(10 mmol) cyanothioacetamide in 20 mL of anhydrous
ethanol. The mixture was stirred during 15 min until
complete homogenization. 1.1 g (10 mmol) of enamine
IV was then added. The reaction mixture was stirred
during 1 h and then incubated during 24 h. Next, the
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aqueous KOH and the corresponding α-haloketone
Va–Vh were added to a stirred solution of 1.7 g
(10 mmol) of nicotinonitrile I in 10 mL of DMF; the
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3-Amino-4,6-dimethyl-2-Z-thieno[2,3-b]pyridines
(VIIa–VIIh) (general procedure). 5.6 mL (10 mmol)
of 10% aqueous KOH solution was added to a stirred
solution of 10 mmol of the appropriate sulfide VI in
15 mL of DMF; the mixture was stirred during 4 h and
then diluted with an equal volume of water. The
resulting precipitate was filtered off and washed with
water, ethanol, and hexane. Parameters of the products
VIIa–VIIh are given in Tables 1 and 2.
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RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 85 No. 8 2015