Synthesis of 3-aroylnicotinonitriles from aroylketene dithioacetals

Article abstract of DOI:10.1055/s-2006-958964

The Knoevenagel adducts of 2-aroyl-3,3-bis(alkylsulfanyl)acrylaldehydes and malononitrile were cyclized in the presence of diisopropylamine to afford 5-aroyl-2,6-bis(methylsulfanyl)nicotinonitriles. Cyclization in the presence of aqueous ammonia gave 2-am

Full text of DOI:10.1055/s-2006-958964

428
PAPER
Synthesis of 3-Aroylnicotinonitriles from Aroylketene Dithioacetals
S
ynthesis of 3-A
.
roylnicotino
R
nitriles . Anabha,a K. N. Nirmala,a Abraham Thomas,b C. V. Asokan*a
a
School of Chemical Sciences, Mahatma Gandhi University, Priyadarshini Hills P. O., Kottayam, Kerala 686 560, India
Fax +(91)4812731009; E-mail: asokancv@yahoo.com
Glenmark Pharmaceuticals Ltd, TTC Industrial Area, Navi Mumbai, 400 709, Maharashtra, India
b
Received 11 July 2006; revised 2 November 2006
group at the 2-position can be achieved by such cycliza-
tions. In this paper we report the cyclization of 2-aroyl-2-
[3,3-bis(methylsulfanyl)-2-propylidene]malononitriles 3
to give 5-aroyl-2,6-bis(methylsulfanyl)nicotinonitriles 5
Abstract: The Knoevenagel adducts of 2-aroyl-3,3-bis(alkylsulfa-
nyl)acrylaldehydes and malononitrile were cyclized in the presence
of diisopropylamine to afford 5-aroyl-2,6-bis(methylsulfanyl)nico-
tinonitriles. Cyclization in the presence of aqueous ammonia gave
2-amino-5-aroyl-6-(methylsulfanyl) nicotinonitriles. A multicom- and 2-amino-5-aroyl-6-(methylsulfanyl)nicotinonitriles
ponent reaction involving aroylketene dithioacetals, malononitrile
and Vilsmeier reagent gave 5-aroyl-2-chloro-6-(methylsulfa-
nyl)nicotinonitrile.
6. A one-pot three-component reaction involving aroyl
ketene dithioacetals, malononitrile and Vilsmeier reagent
to afford 5-aroyl-2-chloro-6-(methylsulfanyl)nicotinoni-
Key words: ketene dithioacetals, Knoevenagel condensation, Vils-
triles 7 has also been described. The pyridine moiety is
meier–Haack reaction, nicotinonitriles, multicomponent reaction
present in numerous biologically active compounds,
which have found applications as pharmaceuticals and
agrochemicals.12–14 Nicotinonitriles are valuable for their
synthetic applications as well as their medicinal impor-
tance and the development of new synthetic methods to
synthesize them continues to be important.
a-Oxoketene dithioacetals are highly versatile intermedi-
ates in organic synthesis.1–4 Recently we disclosed that the
reaction of aroyl ketene dithioacetals with Vilsmeier–
Haack reagent afford 2-aroyl-3,3-bis(alkylsulfanyl)acryl-
aldehydes in excellent yields.5 Rudorf et al. have explored
the synthetic utility of ketene dithioacetals, having an al-
dehyde functionality at the a-position, in the construction
of functionalized heterocycles.6,7 We have also reported
that the Knoevenagel adducts 3 derived from the a-formyl
ketene dithioacetals 2 undergo acid-catalyzed cyclization
to give 2-pyridone derivatives (Scheme 1).5
The attempted cyclization of propylidene malononitriles
3, in the presence of potassium carbonate and methane-
thiol in N,N-dimethylformamide at 110 °C under the con-
ditions reported by Peseke et al.8 gave only the
aroylketene dithioacetals 1 instead of the expected py-
ridines 5 apparently by a reaction involving an addition
elimination mechanism. We envisioned that the desired
cyclization might proceed in the presence of sterically-
hindered secondary amines.15 Thus 2-aroyl-2-[3,3-
bis(methylsulfanyl)-2-propylidene] malononitriles 3 were
treated with one equivalent of diisopropylamine at 70 °C
for five minutes in a closed vessel to give the 5-aroyl-2,6-
bis(methylsulfanyl) nicotinonitriles 5 in 30–60% yields
(Scheme 2, Table 1).
O
O
CHO
SMe
NCCH2CN
DMF/POCl3
Ar
MeS
Ar
MeS
NH4OAc,
AcOH, 70 °C
SMe
2
1
O
O
O
O
CN
CN
i-Pr2NH
Ar
MeS
Ar
MeS
CN
CN
CN
HCl
Ar
MeS
EtOH, 70 °C, 5 min
Ar
MeS
CN
SMe
N
SMe
t-BuOH
N
O
SMe
H
5
3
4
3
Scheme 2
Scheme 1
Table 1 Synthesis of 5-Aroyl-2,6-bis(methylsulfanyl)nicotinoni-
triles
The cyclization of 1,3-butadienes, with a cyano group at
one terminal and alkoxy, amino or alkylthio groups at the
other terminal, to pyridines is initiated by addition of a nu-
cleophile at the carbon of the nitrile group.8–11 Synthesis
of pyridine derivatives with a halo, amino or alkylthio
5
a
b
c
Ar
Yield (%)
Ph
40
34
42
60
4-MeOC6H4
4-MeC6H4
4-ClC6H4
SYNTHESIS 2007, No. 3, pp 0428–0432
x
x
.
x
x
.2
0
0
7
Advanced online publication: 21.12.2006
DOI: 10.1055/s-2006-958964; Art ID: T10306SS
d
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of 3-Aroylnicotinonitriles
429
Table 1 Synthesis of 5-Aroyl-2,6-bis(methylsulfanyl)nicotinoni-
triles
Cl
O
SMe
SMe
Me
NC
CN
H
N
Ar
Cl
5
e
Ar
Yield (%)
30
Me
1
2-naphthyl
O
SMe
N
DMF
r.t., 12 h then 90 °C, 1 h
The cyclization induced by addition of ammonia to the ni-
trile group of the push-pull diene 3 was examined next.
When 2-aroyl-2-[3,3-bis(methylsulfanyl)-2-propyl-
idene]malononitriles 3 were treated with an excess of
aqueous ammonia16,17 in ethanol at 70 °C in a closed ves-
sel for 5 min, 2-amino-5-aroyl-6-(methylsulfanyl)nicoti-
+
3
Ar
Cl
CN
7
nonitriles 6 were formed in 54–67% yields (Scheme 3, Scheme 4
Table 2).
Table 3 Synthesis of 5-Aroyl-2-chloro-6-methylsulfanylnicotino-
nitriles 7a–d
O
H
SMe
O
SMe
N
25% aq NH3
EtOH
Ar
SMe
CN
Ar
Ar
Yield (%)
NH2
7
3
CN
CN
3a, 7a
3b, 7b
3d, 7c
3f, 7d
Ph
47
27
21
76
15
52
45
–
3
6
4-MeOC6H4
4-ClC6H4
4-NO2C6H4
Scheme 3
Table 2 Synthesis of 2-Amino-5-aroyl-6-methylsulfanylnicotino-
nitriles
6
a
b
c
Ar
Yield (%)
In conclusion, we have shown that the Knoevenagel ad-
ducts of 2-aroyl-3,3-bis(alkylsulfanyl)arylaldehydes un-
dergo cyclization in the presence of diisopropyl amine to
give 5-aroyl-2,6-bis(methylsulfanyl)nicotinonitriles and
in the presence of aqueous ammonia to give 2-amino-5-
aroyl-6-(methylsulfanyl)nicotinoniriles. We have also
demonstrated that a multicomponent reaction involving
aroylketene dithioacetals, malononitrile and Vilsmeier re-
agent lead to the formation of 5-aroyl-2-chloro-6-(meth-
ylsulfanyl)nicotinonitriles.
Ph
63
59
56
67
4-MeOC6H4
4-MeC6H4
4-ClC6H4
d
The reaction of suitably substituted alkylidene malononi-
triles with Vilsmeier–Haack reagent leads to iminoalkyla-
tion followed by cyclization to give functionalized 2-
chloropyridines. We envisioned a multicomponent18–20
strategy in which a mixture of a-oxoketene dithioacetal
and malononitrile is treated with Vilsmeier reagent. Imi-
noalkylation at the a-position of the ketene dithioacetals
would be followed by condensation with malononitrile
and subsequent cyclization of the adduct to afford 2-chlo-
rosubstituted nicotinonitriles. The Vilsmeier–Haack re-
agent was prepared by the slow addition of phosphorus
oxychloride to N,N-dimethylformamide at 0 °C, followed
by stirring at room temperature for 15 minutes. To this a
mixture of malononitrile and benzoylketene dithioacetal
1a was added and stirred at room temperature for 12 hours
followed by heating at 90 °C for one hour. Usual work-up
using aqueous saturated potassium carbonate solution,
and purification by chromatography gave 5-benzoyl-2-
chloro-6-(methylsulfanyl) nicotinonitrile 7a in 47% yield
along with the adduct 3a in 15% yield. The reaction was
extended to other substituted ketene dithioacetals to ob-
tain substituted nicotinonitriles 7b–d in 21–76% overall
yields (Scheme 4, Table 3).
Melting points were determined on a Buchi-530 melting point ap-
paratus and are uncorrected. IR spectra were recorded on a Shimad-
zu IR-470 spectrometer. The 1H NMR spectra were recorded on a
Bruker WM 300 (300 MHz) using TMS as internal standard and
CDCl3 as solvent. The 13C NMR spectra were recorded on a Bruker
WM 300 (75.47 MHz) spectrometer using CDCl3 as solvent. Both
1H NMR and 13C NMR values are expressed as d (ppm). The Elec-
tron Impact Mass spectra were obtained on a Finnigan-Mat 312 in-
strument or Schimadzu GCMS 5050 model instrument. The CHN
analyses were done on an Elementar Vario EL III Carlo Erba 1108
instrument.
All reagents were commercially available and were purified before
use. The previously reported aroylketene dithioacetals were pre-
pared by the known procedure.21 The 2-[3,3-bis(methylsulfanyl)-2-
aroyl-2-propylidene] malononitriles 3 were prepared according to
our recently reported procedure.5 Anhydrous sodium sulfate was
used as the drying agent.
2-[3,3-Bis(methylsulfanyl)-2-(2-naphthoyl)-2-propylidene]mal-
ononitrile (3e)
Obtained by the Knoevenagel condensation reaction5 of 3,3-bis(me-
thylsulfanyl)-2-(2-naphthoyl)acrylaldehyde (1.51 g, 5 mmol) with
Synthesis 2007, No. 3, 428–432 © Thieme Stuttgart · New York

430
E. R. Anabha et al.
PAPER
malononitrile (495 mg, 7.5 mmol) in the presence of ammonium ac-
etate (1.5 g, 20 mmol) and AcOH (5 mL).
MS (EI): m/z (%) = 330 (22) [M+], 315 (18), 297 (15), 283 (24), 279
(7), 239 (8), 228 (11), 208 (12), 185 (26), 171 (14), 157 (22), 149
(81), 135 (100), 121 (53), 111 (58).
Deep yellow crystals; yield: 1.44 g (82%); mp 122–124 °C.
IR (KBr): 2214, 1657, 1532, 1451, 1288, 1162, 912, 812 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.46 (s, 6 H, SCH3), 7.26–7.64 (m,
2 H, ArH), 7.88–8.01 (m, 4 H, ArH), 8.17 (s, 1 H, ArH), 8.29 (s, 1
H, vinylic).
Anal. Calcd for C16H14N2O2S2: C, 58.16; H, 4.27; N, 8.48. Found:
C, 58.21; H, 4.25; N, 8.43.
2,6-Bis(methylsulfanyl)-5-(4-chlorobenzoyl)nicotinonitrile (5d)
Yellow crystals; yield: 340 mg (59%); mp 188–190 °C.
13C NMR (75.47 MHz, CDCl3): d = 18.82, 81.80, 111.31, 114.51,
124.19, 127.10, 128.02, 129.25, 129.80, 132.54, 133.89, 136.20,
136.31, 151.34, 166.32, 192.10.
MS (EI): m/z (%) = 350 (12) [M+], 335 (9), 155 (100), 127 (98), 115
(4), 77 (23).
IR (KBr): 2929, 2360, 2226, 1652, 1574, 1481, 1357, 1279, 1238,
1129, 1010 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.62 (s, 3 H, SCH3), 2.97 (s, 3 H,
SCH3), 7.49 (d, J = 9 Hz, 2 H, ArH), 7.64 (d, J = 9 Hz, 2 H, ArH),
7.90 (s, 1 H, H-4).
13C NMR (75.47 MHz, CDCl3): d = 13.53, 14.35, 100.10, 109.21,
115.19, 124.60, 129.16, 129.81, 130.94, 135.09, 139.86, 141.52,
165.59, 191.93.
MS (EI): m/z (%) = 336 (18) [M+ + 2], 334 (56) [M+], 319 (21), 301
(68), 286 (12), 273 (8), 257 (6), 237 (9), 223 (16), 209 (54), 179 (8),
141 (11), 139 (61), 113 (33), 111 (100), 97 (13), 75 (78).
Anal. Calcd for C19H14N2OS2: C, 65.12; H, 4.03; N, 7.99. Found: C,
65.31; H, 4.05; N, 7.04.
Synthesis of 5-Aroyl-2,6-bis(alkylsulfanyl)nicotinonitriles 5;
General Procedure
The appropriate 2-[2-aroyl-3,3-bis(methylsulfanyl)-2-propyl-
idene]malononitrile 2 (1.7 mmol) and diisopropylamine was taken
up in EtOH (10 mL), equipped with a reflux condenser, flushed with
nitrogen and closed with a nitrogen-filled balloon. The solution was
heated at 70 °C for 5 min and then cooled to r.t.. The EtOH was
evaporated and the residue was dissolved in CHCl3, washed with
H2O, dried over anhyd Na2SO4 and the solvent was evaporated. The
crude product obtained was purified by column chromatography
over silica gel using hexane–EtOAc (19:1) as the eluent.
Anal. Calcd for C15H11ClN2OS2: C, 53.80; H, 3.31; N, 8.37. Found:
C, 53.99; H, 3.33; N, 8.40.
2,6-Bis(methylsulfanyl)-5-(2-naphthoyl)nicotinonitrile (5e)
Yellow crystals; yield: 180 mg (30%); mp 188–190 °C.
IR (KBr): 3053, 2924, 2218, 1643, 1560, 1477, 1358, 1286, 1225,
1022 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.64 (s, 3 H, SCH3), 2.76 (s, 3 H,
SCH3), 7.63 (m, 3 H, ArH), 7.82 (s, 1 H, ArH), 7.85 (m, 3 H, ArH),
8.12 (s, 1 H, H-4).
MS (EI): m/z (%) = 350 (38) [M+], 335 (14), 317 (19), 257 (9), 209
(34), 183 (22), 155 (32), 127 (100), 97 (53), 84 (71), 69 (98).
5-Benzoyl-2,6-bis(methylsulfanyl)nicotinonitrile (5a)
Yellow crystals; yield: 200 mg (40%); mp 124–126 °C.
IR (KBr): 3052, 2919, 2217, 1646, 1560, 1481, 1288, 997 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.54 (s, 3 H, SCH3), 2.65 (s, 3 H,
SCH3), 7.43 (t, J = 8 Hz, 2 H, ArH), 7.55 (t, J = 8 Hz, 1 H, ArH),
7.59 (d, J = 8 Hz, 2 H, ArH), 7.69 (s, 1 H, H-4).
13C NMR (75.47 MHz, CDCl3): d = 13.99, 14.87, 100.35, 115.81,
125.195, 129.21, 129.98, 133.65, 137.26, 142.35, 165.76, 167.17,
193.63.
Anal. Calcd for C19H14N2OS2: C, 65.12; H, 4.03; N, 7.99. Found: C,
64.87; H, 3.99; N, 7.95.
Synthesis of 2-Amino-5-aroyl-6-(alkylsulfanyl)nicotinonitriles
6; General Procedure
MS (EI): m/z (%) = 300 (100) [M+], 288 (3.8), 286 (20.9), 268
(23.8), 253 (10.3), 224 (8.5), 210 (3.9), 105 (22), 91 (7), 77 (42).
Aqueous ammonia (25%, 1.5 mL) was added to 2-[2-aroyl-3,3-
bis(methylsulfanyl)-2-propylidene]malononitrile 2 (1.7 mmol) in
EtOH (10 mL), equipped with a reflux condenser and closed with a
nitrogen-filled balloon. The solution was heated at 70 °C for 5 min
and then cooled to r.t.. The EtOH was evaporated and the residue
was dissolved in CHCl3, washed with H2O, dried over anhyd
Na2SO4. The solvent was evaporated under vacuum and the crude
product was purified by column chromatography over silica gel us-
ing hexane–EtOAc (19:1) as the eluent.
Anal. Calcd for C15H12N2OS2: C, 59.97; H, 4.03; N, 9.33. Found: C,
59.23; H, 4.07; N, 9.41.
2,6-Bis(methylsulfanyl)-5-(4-methylbenzoyl)nicotinonitrile (5b)
Yellow crystals; yield: 170 mg (32%); mp 126–128 °C.
IR (KBr): 3427, 2922, 2365, 2216, 1647, 1566, 1481, 1285, 1050
cm–1.
1H NMR (300 MHz, CDCl3): d = 2.45 (s, 3 H, CH3), 2.62 (s, 3 H,
SCH3), 2.74 (s, 3 H, SCH3), 7.28 (d, J = 8 Hz, 2 H, ArH), 7.60 (d,
J = 8 Hz, 2 H, ArH), 7.79 (s, 1 H, H-4).
2-Amino-5-benzoyl-6-(methylsulfanyl)nicotinonitrile (6a)
Yellow crystals; yield: 290 mg (63%); mp 162–164 °C.
IR (KBr): 3496, 3383, 3052, 2919, 2210, 1640, 1580, 1514, 1302,
1262 cm–1.
MS (EI): m/z (%) = 314 (27) [M+], 281 (38), 149 (20), 119 (40), 105
1H NMR (300 MHz, CDCl3): d = 2.42 (s, 3 H, SCH3), 5.50 (s, 2 H,
NH2), 7.42 (t, J = 8 Hz, 2 H, ArH), 7.49–7.57 (m, 3 H, ArH), 7.74
(s, 1 H, H-4).
(22), 91 (54), 69 (100).
Anal. Calcd for C16H14N2OS2: C, 61.12; H, 4.49; N, 8.91. Found: C,
61.24; H, 4.51; N, 8.96.
13C NMR (75.47 MHz, CDCl3): d = 14.2, 84.0, 116.3, 122.0, 128.6,
2,6-Bis(methylsulfanyl)-5-(4-methoxybenzoyl)nicotinonitrile
(5c)
Yellow crystals; yield: 190 mg (34%); mp 110–112 °C.
129.3, 132.4, 137.8, 144.8, 146.0, 158.2, 169.3, 192.4.
MS (EI): m/z (%) = 269 (54) [M+], 254 (70), 236 (47), 192 (30), 178
(20), 105 (46), 77 (100).
IR (KBr): 2930, 2216, 1650, 1607, 1566, 1369, 1258, 1167, 1015
cm–1.
1H NMR (300 MHz, CDCl3): d = 2.17 (s, 3 H, SCH3), 2.54 (s, 3 H,
SCH3), 3.87 (s, 3 H, OCH3), 6.48 (d, J = 8 Hz, 2 H, ArH), 7.26 (d,
J = 8 Hz, 2 H, ArH), 7.31 (s, 1 H, H-4).
Anal. Calcd for C14H11N3OS: C, 62.43; H, 4.12; N, 15.60. Found:
C, 62.13; H, 4.26; N, 15.79.
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Synthesis of 3-Aroylnicotinonitriles
431
2-Amino-5-(4-methylbenzoyl)-6-(methylsulfanyl)nicotinoni-
trile (6b)
5-Benzoyl-2-chloro-6-(methylsuphanyl)nicotinonitrile (7a)
Yellow crystals; mp 158–160 °C mp; yield: 610 mg (47%).
Yellow crystals; yield: 270 mg (56%); mp 168–170 °C.
IR (KBr): 3425, 3306, 3200, 2230, 1637, 1585, 1518, 1304 cm–1.
IR (KBr): 2929, 2234, 1646, 1578, 1492, 1374, 1209, 1231, 1004
cm–1.
1H NMR (300 MHz, CDCl3): d = 2.44 (s, 3 H, CH3), 2.47 (s, 3 H,
SCH3), 5.52 (s, 2 H, NH2), 7.27 (d, J = 8 Hz, 2 H, ArH), 7.53 (d,
J = 8 Hz, 2 H, ArH), 7.77 (s, 1 H, H-4).
1H NMR (300 MHz, CDCl3): d = 2.47 (s, 3 H, SCH3), 7.54 (t, J = 8
Hz, 2 H, ArH), 7.64 (t, J = 8 Hz, 1 H, ArH), 7.68 (t, J = 8 Hz, 2 H,
ArH), 7.87 (s, 1 H, H-4).
13C NMR (75.47 MHz, CDCl3): d = 14.1 (SCH3), 21.9 (CH3), 83.8,
116.1 (CN), 120.6, 129.1, 129.7, 134.8, 143.3, 144.2, 158.0, 169.1,
192.1 (CO).
13C NMR (75.47 MHz, CDCl3): d = 14.38 (SCH3), 103.59, 114.54
(CN), 128.93, 129.19, 129.69, 133.98, 135.88, 142.24, 153.24,
167.49.
MS (EI): m/z (%) = 283 (43) [M+], 268 (100), 257 (4), 241 (6), 236
MS (EI): m/z (%) = 290 (6) [M+ + 2], 288 (21) [M+], 273 (23), 257
(12), 210 (4), 179 (11), 153 (18), 132 (5), 106 (9), 63 (32).
(11), 255 (35), 245 (9), 197 (15), 152 (8), 105 (48), 77 (100).
Anal. Calcd for C15H13N3OS: C, 63.58; H, 4.62; N, 14.83. Found:
C, 63.59; H, 4.65; N, 14.88.
Anal. Calcd for C14H9ClN2OS: C, 58.23; H, 3.14; N, 9.70. Found:
C, 58.52; H, 3.18; N, 9.77.
2-Amino-5-(4-methoxybenzoyl)-6-(methylsulfanyl)nicotinoni-
trile (6c)
Yellow crystals; yield: 300 mg (59%); mp 166–168 °C.
2-[3,3-Bis(methylsulfanyl)-2-(4-methoxybenzoyl)-2-propyl-
idene]malononitrile (3b)
Yellow crystals; yield: 770 mg (52%); mp 114–116 °C (Lit.5 114–
116 °C).
IR (KBr): 3451, 3351, 3230, 2221, 1635, 1567, 1525, 1247, 1160
cm–1.
1H NMR (300 MHz, CDCl3): d = 2.46 (s, 3 H, SCH3), 3.88 (s, 3 H,
OCH3), 5.46 (s, 2 H, NH2), 6.94 (d, J = 8 Hz, 2 H, ArH), 7.64 (d,
J = 8 Hz, 2 H, ArH), 7.73 (s, 1 H, H-4).
MS (EI): m/z (%) = 299 (46) [M+], 284 (100), 266 (42), 241 (24),
192 (26), 178 (34), 149 (18), 135 (65), 121 (19), 107 (36), 92 (52),
77 (66).
2-Chloro-5-(4-methoxybenzoyl)-6-(methylsulfanyl)nicotinoni-
trile (7b)
Yellow crystalline solid, yield: 380 mg (27%); mp 152–154 °C.
IR (KBr): 2926, 2232, 1601, 1573, 1379, 1275, 1120, 1011 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.58 (s, 3 H, SCH3), 3.90 (s, 3 H,
OCH3), 6.97 (d, J = 8 Hz, 2 H, ArH), 7.71 (d, J = 8 Hz, 2 H, ArH),
7.78 (s, 1 H, H-4).
MS (EI): m/z (%) = 318 (5) [M+], 305 (2), 303 (6), 287 (4), 285 (5),
199 (5), 165 (5), 135 (18), 121 (19), 107 (13), 97 (17), 81 (29), 69
(100).
Anal. Calcd for C15H13N3O2S: C, 60.18; H, 4.38; N, 14.04. Found:
C, 60.41; H, 4.39; N, 14.08.
2-Amino-5-(4-chlorobenzoyl)-6-(methylsulfanyl)nicotinonitrile
(6d)
Yellow crystals; yield: 340 mg (67%); mp 188–190 °C.
Anal. Calcd for C15H11ClN2O2S: C, 56.52; H, 3.48; N, 8.79. Found:
C, 56.73; H, 3.51; N, 8.85.
IR (KBr): 3514, 3467, 3054, 2219, 1648, 1567, 1483, 1366, 1283,
1239, 1008 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.62 (s, 3 H, SCH3), 5.56 (br s, 2
H, NH2), 7.41 (d, J = 8 Hz, 2 H, ArH), 7.54 (d, J = 8 Hz, 2 H, ArH),
8.39 (s, 1 H, H-4).
2-[3,3-Bis(methylsulfanyl)-2-(4-chlorobenzoyl)-2-propyl-
idene]malononitrile (3c)
Yellow crystals; yield: 315 mg (21%); mp 132–134 °C (Lit.5 132–
134 °C).
MS (EI): m/z (%) = 305 (27) [M+ + 2], 303 (83) [M+], 286 (16), 273
(14), 237 (19), 223 (22), 209 (71), 139 (56), 111 (100), 89 (11), 75
(73).
2-Chloro-5-(4-chlorobenzoyl)-6-(methylsulfanyl)nicotinoni-
trile (7c)
Yellow crystalline solid; yield: 660 mg (45%); mp 168–170 °C.
IR (KBr): 3049, 2220, 1653, 1576, 1489, 1382, 1286, 1234, 1010
cm–1.
Anal. Calcd for C14H10ClN3OS: C, 55.35; H, 3.32; N, 13.83. Found:
C, 55.10; H, 3.32; N, 13.89.
1H NMR (300 MHz, CDCl3): d = 2.59 (s, 3 H, SCH3), 7.48 (d, J = 8
Hz, 2 H, ArH), 7.65 (d, J = 8 Hz, 2 H, ArH), 7.81 (s, 1 H, H-4)
MS (EI): m/z (%) = 326 (5) [M+ + 4], 324 (16) [M+ + 2], 322 (23)
[M+], 309 (12), 307 (21), 291 (52), 289 (73), 197 (42), 141 (20), 139
(63), 113 (31), 111 (100), 85 (21), 75 (84).
5-Aroyl-2-chloro-6-(alkylsulfanyl)nicotinonitriles 7; General
Procedure
The Vilsmeier–Haack reagent was prepared by mixing DMF (15
mL, 200 mmol) and POCl3 (1.92 mL, 20 mmol) at 0 °C followed by
stirring at r.t. for 15 min. To the Vilsmeier–Haack reagent a mixture
of aroylketene dithioacetal 1 (4.5 mmol) and malononitrile (450 mg,
6.75 mmol) was added at r.t. and stirred well for 12 h. The reaction
mixture was then heated to 100 °C for 1 h, cooled, poured over ice-
cold K2CO3 solution and extracted with Et2O (3 × 50 mL). The or-
ganic layer was washed with H2O, dried over Na2SO4 and the sol-
vent was removed by evaporation. The crude reaction mixture was
purifed by column chromatography using hexane–EtOAc (97:3) as
the eluent to give 3 and 7 (see Table 3). We have recently reported
spectral data of 3.5
Anal. Calcd for C14H8Cl2N2OS: C, 52.03; H, 2.49; N, 8.67. Found:
C, 52.21; H, 2.51; N, 8.70.
2-Chloro-5-(4-nitrobenzoyl)-6-(methylsulfanyl)nicotinonitrile
(7d)
Yellow crystalline solid; yield: 1.1 g (76%); mp 200–202 °C.
IR (KBr): 2930, 2221, 1653, 1522, 1279, 1011 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.6 (s, 3 H, SCH3), 7.86 (m, 3 H,
ArH, H-4), 8.36 (d, J = 8 Hz, 2 H, ArH).
MS (EI): m/z (%) = 333 (14) [M+], 302 (12), 288 (16), 256 (14), 214
(15), 183 (35), 159 (10), 129 (18), 120 (29), 97 (83), 71 (87), 57
(100).
2-[2-Benzoyl-3,3-bis(methylsulfanyl)-2-propylidene]malononi-
trile (3a)
Yellow crystals; yield: 200 mg (15%); mp 112–114 °C (Lit.5 112–
114 °C).
Synthesis 2007, No. 3, 428–432 © Thieme Stuttgart · New York

432
E. R. Anabha et al.
PAPER
Anal. Calcd for C14H8ClN3O3S: C, 50.38; H, 2.42; N, 12.59. Found:
C, 50.11; H, 2.47; N, 12.63.
(9) Peseke, K.; Michalik, M.; Schonhusen, U.; Quincoces, J. J.
Prakt. Chem./Chem.-Ztg. 1987, 329, 877.
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(11) Peseke, K. Z. Chem. 1977, 17, 288.
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Chem. 1990, 27, 1437.
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Elem. 1993, 82, 91.
(14) Raghukumar, V.; Thirumalai, D.; Ramakrishnan, V. T.;
Karunakara, V.; Ramamurthy, P. Tetrahedron 2003, 59,
3761.
(15) Das, S.; George, M.; Mathew, T.; Asokan, C. V. J. Chem.
Soc., Perkin Trans. 2 1996, 731.
(16) Kambe, S.; Saito, K.; Sakurai, A.; Midorikawa, H. Synthesis
1980, 366.
(17) Rudolf, I.; Michalik, M.; Montero, A.; Peseke, K. Synthesis
2001, 1686.
(18) Domling, A.; Ugi, I. Angew. Chem. Int. Ed. 2000, 39, 3168.
(19) Nair, V.; Rajesh, C.; Vinod, A. U.; Bindu, S.; Sreekanth, A.
R.; Mathen, J. S.; Balagopal, L. Acc. Chem. Res. 2003, 36,
899.
Acknowledgement
This work was supported by Kerala State CSTE and CSIR New De-
lhi (project No. 01(1954)/04/EMR-II). We thank CDRI, Lucknow
and SIF, IISc, Bangalore for spectral and analytical data. ERA
thanks CSIR for a Senior Research Fellowship.
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Synthesis 2007, No. 3, 428–432 © Thieme Stuttgart · New York