New example of acyl cleavage of benzoyl-1,1,1-trifluoroacetone in a three-component synthesis of 4-aryl-2-thioxo-6-phenyl-1,2-dihydropyridine-3- carbonitriles

Article abstract of DOI:10.1134/S1070363212050180

A three-component condensation of aromatic aldehydes, cyanothioacetamide, and benzoyl-1,1,1-trifluoroacetone, involving the acyl cleavage of the latter, results in 4-aryl-2-thioxo-6-phenyl-1,2-dihydro-pyridine-3-carbonitriles. Their alkylation was studied.

Full text of DOI:10.1134/S1070363212050180

ISSN 1070-3632, Russian Journal of General Chemistry, 2012, Vol. 82, No. 5, pp. 906–910. © Pleiades Publishing, Ltd., 2012.
Original Russian Text © V.D. Dyachenko, 2012, published in Zhurnal Obshchei Khimii, 2012, Vol. 82, No. 5, pp. 828–832.
New Example of Acyl Cleavage of Benzoyl-1,1,1-trifluoroacetone
in a Three-Component Synthesis of 4-Aryl-2-thioxo-6-phenyl-1,2-
dihydropyridine-3-carbonitriles
V. D. Dyachenko
Taras Shevchenko Lugansk National University, ul. Oboronnaya, 2, Lugansk, 91011 Ukraine
e-mail: dvd_lug@online.lg.ua
Received February 28, 2011
Abstract—A three-component condensation of aromatic aldehydes, cyanothioacetamide, and benzoyl-1,1,1-
trifluoroacetone, involving the acyl cleavage of the latter, results in 4-aryl-2-thioxo-6-phenyl-1,2-dihydro-
pyridine-3-carbonitriles. Their alkylation was studied.
DOI: 10.1134/S1070363212050180
Previously, we found that arylmethylene cyanothio-
acetamides react with benzoyl-1,1,1-trifluoroacetone
under the Michael reaction conditions to form 4-aryl-
2-thioxo-6-phenyl-1,2-dihydropyridine-3-carbonitriles
rather than the expected substituted 5-trifluoroacetyl-
pyridine-2(1H)-thiones. This is due to the acyl cleavage
of benzoyl-1,1,1-trifluoracetone during the reaction [1].
XI and their regioselective alkylation involving the
sulfur atom, which is typical for such systems [4].
Further treating of thioethers Xa–Xn with alkali in
DMF affords substituted thieno[2,3-b]pyridines XIIa–
XIIg (method a), which can be obtained also by the
one-pot reaction of pyridine thiones IVa and IVb with
alkylating agents IXa–IXh in an alkaline medium
(method b). Thus, the thiophene ring closure in this
reaction indicates the vicinal location of cyano and
alkylsulfanyl groups. Compounds XII are promising
for designing products with antienzymatic [5, 6],
antidepressant [7], neurotropic [8], and antitumor [9,
10] actions. The yields, elemental analysis data, and
melting points of the synthesized compounds X, XII
are given in Table 1.
In the present work we show that the three-com-
ponent condensation of aromatic aldehydes I with cyano-
thioacetamide II and benzoyl-1,1,1-trifluoracetone III
occurs in ethanol at 20°C in the presence of two-fold
excess of N-methylmorpholine to give 4-aryl-2-thioxo-
6-phenyl-1,2-dihydropyridine-3-carbonitriles
IV
(method a). The reaction proceeds apparently through
the Knoevenagel condensation to form the products V
followed by the Michael addition of CH-acid III. The
corresponding obtained adducts VI undergo the acyl
cleavage [2] through intermediates VII formation
followed by the intramolecular cyclization to yield the
substituted pyridine-2(1H)-thiones IV by eliminating
water and trifluoroacetic acid.
The IR spectra of the obtained compounds X
contain the characteristic absorption bands of the
stretching vibrations of the conjugated cyano group in
the range of 2220–2230 cm–1. In the spectra of
thienopyridines XII these signals are absent, and there
are absorption bands of the stretching and bending
vibrations of amino group at ν 3211–3348 and 1640–
1649 cm–1, respectively.
The structure of compounds IV was confirmed by
the spectroscopic studies, authentic synthesis from
chalcone VIII and cyanothioacetamide II in the
presence of piperidine (method b) [3], as well as by the
chemical transformations.
1
In the H NMR spectra of compounds X there are
the signals of aromatic protons, C5H pyridine ring
proton, the protons of Z fragment with the cor-
responding chemical shifts δ (Table 2), and the SCH2
1
Thus, the treating of compounds IVa and IVb with
alkali in a DMF solution followed by reacting with
alkyl halides IXa–IXl gives rise to thioethers Xa–Xn.
The reaction occurs probably via the formation of salts
proton signals at δ 3.28–5.07 ppm. The H NMR
spectra of compounds XII contain a broad singlet of
the NH2 protons at δ 5.41–6.83 ppm instead of SCH2
protons, which is typical for such systems [11].
906

NEW EXAMPLE OF ACYL CLEAVAGE
O
907
Ar
O
NMe , EtOH
CN
CN
S
F3C
ArCHO
_H2O
H2N
S
Ph
III
O
H2N
а
Iа, Ib
II
V
III
Ar
Ar
O
F3C
HO
OH
O
CN
CN
S
H2O
F3C
H2N
S
H2N
VII
Ph
O
Ph
VI
_2[H],
_H2O,
_CF3COOH
Ar
Ar
S
Ar
NH
CN
CN
II,
KОН/DMF
_H2O
_H2O, _2[H]
Ph
N
S K
H2N
Ph
N
S
b
H
VIIIа, VIIIb
IVа, IVb
XI
IXа_IXh/KOH
_KHlg
Hlg
Z
b
IXa_IXl
Ar
Ar
NH2
CN
KОН/DMF
Z
а
S
Ph
N
H
S
Z
Ph
N
XIIа_XIIg, XIIo
Xа_Xn
I, IV, VIII, Ar = 2-MeOC6H4 (a), 4-BrC6H4 (b); IX, Hlg = Br, Z = PhCO (a); Cl, COOMe (b); Br, 4-MeOC6H4CO (c); Br,
4-ClC6H4CO (d); Br, 4-PhC6H4CO (e); Cl, 4-BrC6H4NHCO (f); Cl, COOCH2Ph (g); Cl, CN (h); Br, 2-MeC6H4 (i); I, Me
(CH2)4 (j); I, Me (k); Cl, Ph (l); X, XII, Ar = 4-BrC6H4, Z = COOCH2Ph (a); 2-MeOC6H4, PhCO (b); 2-MeOC6H4, COOMe
(c); 2-MeOC6H4, 4-MeOC6H4CO (d); 2-MeOC6H4, 4-ClC6H4CO (e); 2-MeOC6H4, 4-PhC6H4CO (f); 2-MeOC6H4, 4-
BrC6H4NHCO (g); 2-MeOC6H4, COOCH2Ph (h); 2-MeOC6H4, CN (i); 2-MeOC6H4, 2-MeC6H4 (j); 2-MeOC6H4, Me(CH2)4
(k); 2-MeOC6H4, Me (l), 4-BrC6H4, Ph (m); 4-BrC6H4, 4-BrC6H4NHCO (n); 4-BrC6H4, CN (o).
EXPERIMENTAL
monitored by TLC on Silufol UV 254 plates eluting
with an acetone–hexane mixture (3:5) and detecting
with iodine vapor and UV irradiation.
The IR spectra were recorded on an IKS-40
instrument (mulls in mineral oil). The 1H NMR spectra
were registered on a Bruker WP-100SY instrument
(100 MHz) in DMSO-d6 relative to internal TMS. The
mass spectra were taken on a Crommas GC/MS-
Hewlett-Packard 5890/5972 spectrometer, column HP-
5 MS (70 eV) in a CH2Cl2 solution. The melting points
were determined on a Koeffler block. The reaction
progress and purity of the obtained compounds were
4-(2-Methoxyphenyl)-2-thioxo-6-phenyl-1,2-di-
hydropyridine-3-carbonitrile (IVa). a. A mixture of
1.21 ml (10 mmol) of o-anisaldehyde Ia, 1.0 g (10 mmol)
of cyanothioacetamide II, and 1 drop of N-methyl-
morpholine in 20 ml of ethanol was stirred at 20°C for
15 min, after which was added 1.54 ml (10 mmol) of
benzoyl-1,1,1-trifluoroacetone III and 2.2 ml (20 mmol)
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 82 No. 5 2012

908
DYACHENKO
Table 1. Yields, melting points, and elemental analysis data of 4-aryl-2-Z-methylsulfanyl-6-phenylpyridine-3-carbonitriles
Ха–Xn and 3-amino-4-aeyl-6-phenyl-2-Z-thieno[2,3-b]pyridines ХIIа–XIIg, XIIo
Found, %
Н
Calculated, %
Yield, %
(а/b)
Comp. no.
mp, °С
Formula
С
N
С
Н
N
5.44
6.42
7.17
6.22
5.95
74
66
70
73
78
181–182 (АсОН)
141–143 (BuОН)
135–137 (MeCN)
205–207 (BuОН)
140–142 (BuОН)
62.88
74.13
67.58
74.52
68.70
3.65
4.50
4.49
4.81
3.95
5.33
6.33
7.02
6.13
5.84
C27H19BrN2O2S
C27H20N2O2S
C22H18N2O3S
C28H22N2O2S
C27H19ClN2O2S
62.92
74.29
67.68
74.64
68.86
3.72
4.62
4.65
4.92
4.07
Xа
Xb
Xc
Xd
Xe
74
78
210–212 (BuОН)
211–213 (АсОН)
165–166 (BuОН)
157–159 (АсОН)
103–105 (BuОН)
63–64 (MeOH)
77.14
60.98
71.95
70.40
76.62
74.48
72.71
65.49
53.85
62.80
74.03
67.61
74.54
68.77
77.25
61.02
59.01
4.68
3.72
4.68
4.15
5.19
6.37
5.13
3.67
2.81
3.61
4.58
4.48
4.88
3.96
4.60
3.71
2.85
5.31
7.78
5.81
11.69
6.47
6.85
7.94
5.95
7.14
5.32
6.34
6.99
6.18
5.79
5.33
7.84
10.22
C33H24N2O2S
C27H20BrN3O2S
C28H22N2O3S
C21H15N3OS
77.32
61.14
72.08
70.57
76.75
74.59
72.81
65.65
53.91
62.92
74.29
67.68
74.64
68.86
77.32
61.14
59.12
4.72
3.80
4.75
5.46
7.92
6.00
Xf
Xg
82
Xh
68
4.23 11.76
Xi
75
C27H22N2OS
5.25
6.51
5.24
3.75
2.96
3.72
4.62
4.65
4.92
4.07
4.72
3.80
6.63
6.96
8.09
6.12
7.25
5.44
6.42
7.17
6.22
5.95
5.46
7.92
Xj
69
C25H26N2OS
Xk
73
81–83 (EtOH)
C21H18N2OS
Xl
70
180–181 (АсОН)
227–229 (DMF)
183–185 (АсОН)
220–222 (АсОН)
198–200 (АсОН)
182–184 (АсОН)
181–183 (АсОН)
229–231 (DMF)
195–196 (BuОН)
245–247a (АсОН)
C25H17BrN2S
C26H17Br2N3OS
C27H19BrN2O2S
C27H20N2O2S
C22H18N2O3S
C28H22N2O2S
C27H19ClN2O2S
C33H24N2O2S
C27H20BrN3O2S
C20H12BrN3S
Xm
Xn
78
75/69
81/78
74/80
69/75
72/81
66/78
84/77
–/70
XIIа
XIIb
XIIc
XIId
XIIe
XIIf
XIIh
XIIo
2.98 10.34
а At 210°С sublimation occurs.
of N-methylmorpholine. The mixture was stirred for 4 h
and left standing for 48 h. Then the reaction mixture
was diluted with 10% hydrochloric acid to pH 5 and
kept for 1 day. The precipitate formed was filtered off,
washed with water, ethanol and hexane. Yield 2.2 g
(69%), yellow powder, mp 138–140°C (AcOH). IR
2-Alkylsulfanyl-4-aryl-6-phenylpyridine-3-car-
bonitriles Xa–Xn were prepared by the method of [12].
GC–MS spectrum of compound Xh, m/z (Irel, %):
467 (100) [M +1]+.
3-Amino-4-aryl-6-phenyl-2-Z-thieno[2,3-b]pyri-
dines (XIIa–XIIg, XIIo). a. To a solution of 10 mmol
of thioether X in 15 ml of DMF was added with stir-
ring 5.6 ml (10 mmol) of 10% aqueous solution of
KOH. The reaction mixture was stirred for 6 h, and
then diluted with an equal volume of water. The result-
ing precipitate was filtered off, washed with water,
ethanol, and hexane.
1
spectrum, ν, cm–1: 3380 (NH), 2228 (C≡N). H NMR
spectrum, δ, ppm: 3.84 s (3H, Me), 7.08 s (1H, C5N,
pyridine), 7.12 t (1H, HAr, J 8.1 Hz), 7.23 d (1H, HAr,
J 8.7 Hz), 7.39–7.63 m (5H, HAr), 7.84 d (1H, HAr, J
8.1 Hz), 8.03 m (1H, HAr), 14.23 br. s (1H, NH).
Found, %: C 71.52; H 4.29; N 8.71. C19H14N2OS.
Calculated, %: C 71.68; H 4.43; N 8.80.
GC–MS spectrum of compound XIIh, m/z (Irel, %):
467 (100) [M +1]+.
4-(4-Bromophenyl)-2-thioxo-6-phenyl-1,2-dihyd-
ropyridine-3-carbonitrile (IVb) was prepared similarly
to compound IVa using 1.85 g (10 mmol) of 4-bromo-
benzaldehyde Ib. Yield 2.64 g (72%), mp 219–221°C
(AcOH) (216–218°C [3]).
b. To a stirred solution of 10 mmol of pyri-
dinethione IV in 20 ml of DMF was sequentially
added 5.6 ml (10 mmol) of 10% aqueous solution of
KOH and 10 mmol of the alkylating agent IX. The
mixture was stirred for 4 h, and then the same amount
The method b used was described in [3]. The yield
of compound IVa was 75%, of IVb, 77%.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 82 No. 5 2012

NEW EXAMPLE OF ACYL CLEAVAGE
909
1
Table 2. The IR and H NMR spectral data of 4-aryl-2-Z-methylsulfanyl-6-phenylpyridine-3-carbonitriles Ха–Xn and 3-
amino-4-aeyl-6-phenyl-2-Z-thieno[2,3-b]pyridines ХIIа–XIIg, XIIo
IR spectrum, ν, cm–1
1Н NMR spectrum, δ, ppm (3J, Hz)
Comp.
no.
C≡N
С=О,
SCH2 (s) or
NH2 (br.s)
other signals
or NH2
δ NH2
2226
1710
4.36
5.14 s (2H, OCH2), 7.28 s (5H, Ph), 7.49 m (3H, Ph), 7.62 d and 7.84 d (4H, C6H4,
Xа
J 7.52), 7.92 s (1H, C5HPy), 8.20 m (2H, Ph)
2224
2225
1714
1702
5.06
4.27
3.82 s (3H, Ме), 7.11–7.92 m (13H, HAr), 8.15 d (2H, HAr, J 8.84)
Xb
Xc
3.67 s (3H, СООМе), 3.82 s (3H, Ме), 7.11–7.37 m (2H, HAr), 7.42–7.73 m (5H,
Ph), 7.88 s (1H, C5HPy), 8.19 m (2H, HAr)
2230
2228
2222
1715
1718
1703
1667
1717
–
5.01
5.04
5.07
4.31
4.37
4.53
4.73
2.44 s (3H, Ме), 3.82 s (3H, МеО), 7.02–7.61 m (9H, HAr), 7.72 s (1H, C5HPy), 7.85
d (2H, HAr, J 7.72), 8.05 d (2H, HAr, J 8.85)
Xd
3.83 s (3H, Ме), 7.02–7.55 m (7H, HAr), 7.64 d and 8.16 d (4Н, 4-ClС6Н4, J 8.58),
7.79 s (1H, C5HPy), 7.88 d (2H, HAr, J 8.75)
3.84 s (3H, Ме), 7.02–7.61 m (12H, HAr), 7.72 s (1H, C5HPy), 7.87–7.99 m (4H,
HAr), 8.21 d (2H, HAr, J 8.14)
Xe
Xf
2220
3211
3.82 s (3H, Ме), 7.09–7.49 m (7H, HAr), 7.61 d (4H, HAr, J 7.52), 7.81 s (1H,
C5HPy), 8.15 d (2H, HAr, J 8.79), 10.62 br. s (1H, NH)
Xg
2225
3.81 s (3H, Ме), 5.14 s (2H, OCH2), 7.13 t (2H, HAr, J 7.02), 7.26 s (5H, Ph), 7.31–
7.62 m (5H, HAr), 7.84 s (1H, C5HPy), 8.17 d (2H, HAr, J 8.66)
Xh
2227
2248
3.83 s (3H, Ме), 7.26 t (2H, HAr, J 7.11), 7.39–7.68 m (5H, HAr), 7.98 s (1H, HAr),
8.34 m (2H, HAr)
Xi
2221
2228
2226
2227
2229
–
2.42 s (3H, Ме), 3.81 s (3H, МеО), 7.02–7.29 m (5H, HAr), 7.34–7.65 m (6H, HAr),
Xj
7.84 s (1H, C5HPy), 8.27 m (2H, HAr)
–
3.28 t
(J 7.11)
0.85 t (3H, Ме, J 7.19), 1.12–1.56 m (6H, 3CH2), 1.69–1.87 m (2H, CH2), 3.83 s
(3H, МеО), 7.04–7.65 m (6H, HAr), 7.81 s, 8.23 m (2H, HAr)
Xk
–
3.47 q
(J 7.23)
1.42 t (3H, Ме, J 7.23), 3.81 s (3H, МеО), 7.01–7.32 m (3H, HAr), 7.44–7.69 m (4H,
Xl
HAr), 7.81 s (1H, C5HPy), 8.22 m (2H, HAr)
–
4.71
4.31
5.41
6.83
5.71
6.79
6.77
6.80
5.97
5.68
7.16–7.39 m (2H, HAr), 7.41–7.65 m (6H, HAr), 7.70–7.81 m (4H, HAr) 7.92 s (1H,
C5HPy), 8.28 m (2H, HAr)
7.22–7.81 m (11H, HAr), 7.92 s (1H, C5HPy), 8.18 d (2H, HAr, J 8.59),
10.62 br. s (1H, NH)
5.31 s (2H, CH2), 7.31–7.62 m (10H, HAr), 7.71 s (1H, C5HPy), 7.74–7.91 m (2H,
HAr), 8.19 m (2H, HAr)
Xm
Xn
1677
3190
3342
1702
1646
XIIа
XIIb
XIIc
XIId
XIIe
XIIf
XIIh
XIIo
3214
3348
1714
1647
3.77 s (3H, Ме), 7.11–7.85 m (13H, HAr), 8.23 m (2H, HAr)
3228
3332
1710
1640
3.79 br. s (6H, 2МеО), 7.12–7.83 m (8H, HAr), 8.19 m (2H, HAr)
3197
3324
1715
1646
2.41 s (3H, Ме), 3.76 s (3H, МеО), 7.12–7.62 m (9H, HAr), 7.75 d (2H, HAr, J 7.71),
7.81 s (1H, C5HPy), 8.21 m (2H, HAr)
3211
3330
1718
1648
3.78 s (3H, Ме), 7.13–7.65 m (9H, HAr), 7.74 d (2H, HAr, J 8.56), 7.89 s (1H,
C5HPy), 8.18 m (2H, HAr)
3225
3319
1717
1647
3.80 s (3H, Ме), 7.19–7.98 m (17H, HAr), 8.20 m (2H, HAr)
3244
3335
1670
3.76 s (3H, Ме), 7.12–7.83 m (12H, HAr), 8.23 m (2H, HAr), 9.66 br. s (1H, NH)
7.23–7.68 m (6H, HAr), 7.79 d (2H, HAr, J 7.51), 8.22 m (2H, HAr)
2208
3212
3345
1649
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DYACHENKO
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of alkali was added. The reaction mixture was stirred
again for 4 h and diluted with an equal volume of
water. The resulting precipitate was filtered off, washed
with water, ethanol, and hexane. The melting points
and chromatographic characteristics of compounds
XIIa–XIIg, XIIo are similar to those obtained by the
method a (Tables 1 and 2).
no. 220647x.
7. US Patent no. 856335, 1999; Ref. Zh. Khim., 1999,
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