SYNTHESIS OF HETEROCYCLIC KETENE N,S-ACETALS AND THEIR REACTIONS WIZH α,β-UNSATURATED NITRILES

Full text of DOI:10.1135/cccc19951065

New Compounds
1065
SYNTHESIS OF HETEROCYCLIC KETENE N,S-ACETALS AND THEIR
REACTIONS WITH α,β-UNSATURATED NITRILES
Ahmed K. EL-SHAFEI, Ahmed M. M. EL-SAGHIER and Ahmed M. SOLIMAN
Chemistry Department,
Faculty of Sciences, Sohag, Egypt
Received August 15, 1994
Accepted March 19, 1995
In an extention of our recent studies1–4 on the application of ketoketene or cyanoketene
S,S-acetals in heterocyclic synthesis we report here a simple procedure for the synthesis
of 1-amino-4-acetyl- 2-cyano-3-phenyl-3H-pyrido[2,1-b][1,3]benzothiazole (Va) or
benzoxazole derivative Vb from 2-(1-acetyl-2-oxopropylidene)benzothiazole5 IIIa or
benzoxazole derivative4 IIIb and benzylidenemalononitrile (cf. Scheme 1).
The reaction mechanism was assumed to follow a preliminary hydrolysis of one of
the acetyl groups followed by a nucleophilic addition of the ethylenic −CH hydrogen
atom at the ethylenic double bond of the benzylidenemalononitrile with subsequent
cyclization. This proposed mechanism was confirmed by a separate two-step reaction
where compound IIIa and IIIb were hydrolyzed by boiling either in ethanol in presence
of piperidine or in methanol in presence of sodium methoxide into the intermediate
product 2-(2-oxopropylidene)benzothiazole (IVa) or benzoxazole derivative4 IVb which
was reacted with benzylidenemalononitrile in boiling ethanol in the presence of a
catalytic amount of piperidine to afford compounds Va and Vb.
Compound IIIa was also allowed to react with a variety of α,β-unsaturated nitriles
including arylidenemalononitrile, arylidene ethylcyanoacetate, arylidenecyano-
acetamide and arylidenephenylacetonitrile in refluxing ethanol containing piperidine
base where in each case a preliminary hydrolysis of one of the two acetyl groups was
affected followed by a nucleophilic addition of the formed carbanion at the arylidene
double bond and cyclization into the desired 3H-pyrido-[2,1-b][1,3]benzothiazole
derivatives VIa–VIi, cf. Scheme 1.
EXPERIMENTAL
Melting points are uncorrected. IR spectra were obtained (KBr disc) on a Nicolet 710 FT-IR
.
spectrometer, wavenumbers are given in cm−1 1H NMR spectra were measured on a Varian EM
360A instrument (60 MHz) in CD3SOCD3 or CDCl3 with tetramethylsilane as internal standard.
Chemical shifts are given in ppm (δ-scale), coupling constants (J) in Hz.
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El-Shafei, El-Saghier, Soliman:
SCHEME 1
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New Compounds
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2-(1-Acetyl-2-oxopropylidene)benzothiazole (IIIa)
A solution of 2-[di(methylthio)methylene]pentan-2,4-dione4 (817 mg, 4.0 mmol) and 2-amino-
thiophenol (513 mg, 4.1 mmol) in absolute ethanol (25 ml) was refluxed for 24 h. After cooling the
precipitate was filtered off and recrystallized from ethanol. Yield 886 mg (95%) of IIIa, m.p. 155 °C.
IR spectrum: 3 430 (NH); 1 660 (C=O); 1 540 (C=C). 1H NMR spectrum (CDCl3): 10.70 br, 1 H
(NH); 7.90–7.40 m, 4 H (H-arom.); 2.30 s, 3 H (CH3); 2.15 s, 3 H (CH3). For C12H11NO2S (233.3)
calculated: 61.78% C, 4.75% H, 6.00% N, 13.74% S; found: 61.64% C, 4.68% H, 6.13% N, 13.71% S.
2-(2-Oxopropylidene)benzothiazole (IVa)
A) Compound IIIa (2.33 g, 10 mmol) was added to the solution of sodium (1 g) in methanol (30 ml)
and the mixture was refluxed for 4 h. Water (20 ml) was then added and the mixture was extracted
with chloroform (3 × 50 ml). The collected extracts were dried over anhydrous sodium sulfate, the
solvent was evaporated and the solid precipitate was recrystallized from ethanol. Yield 2.12 g (91%),
m.p. 110 °C. IR spectrum: 3 450 (NH); 1 650 (C=O). 1H NMR spectrum (CDCl3): 11.70 br, 1 H
(NH); 8.70–8.20 m, 4 H (H-arom.); 5.40 s, 1 H (=CH−); 3.10 s, 3 H (COCH3). For C10H9NOS
(191.3) calculated: 62.80% C, 4.70% H, 7.32% N, 16.77% S; found: 62.64% C, 4.81% H, 7.55% N,
16.87% S.
B) A mixture of compound IIIa (2.33 g, 10 mmol) and piperidine (1 ml) in ethanol (30 ml)
refluxed for 1 h, the reaction mixture was then concentrated to its half volume. After cooling, the
precipitate solid was filtered off and recrystallized from ethanol. Yield 1.98 g (85%) of compound
IVa identical with sample prepared by procedure A.
2-(2-Oxopropylidene)benzoxazole (IVb)
A) Compound IVb was prepared from compound IIIb (2.17 g, 10 mmol) according the above
mentioned procedure A. Yield 2.07 g (89%) of IVb, m.p. 70 °C, literature4 gives m.p. 70 °C.
B) Compound IVb was prepared from compound IIIb (2.17 g, 10 mmol) according the above
mentioned procedure B. Yield 1.96 g (84%) of IVb identical with sample prepared by procedure A.
4-Acetyl-1-amino-2-cyano-3-phenyl-3H-pyrido[2,1-b][1,3]benzothiazole (Va)
A) A mixture of compound IVa (1.91 g, 10 mmol) and benzylidenemalononitrile (1.54 g, 10 mmol)
in ethanol (30 ml) was refluxed for 30 min in presence of a catalytic amount of piperidine. On
cooling the solid precipitate was filtered off and recrystallized from ethanol into yellow crystals.
Yield 3.28 g (95%) of Va, m.p. 269 °C. IR spectrum: 3 400, 3 302 (NH2); 2 180 (CN); 1 654 (C=O).
1H NMR spectrum (CD3SOCD3): 7.90–7.10 br, 9 H (H-arom.); 6.30–6.10 br, 2 H (NH2); 4.70 s, 1 H
(CH-Ph); 2.00 s, 3 H (CH3). For C20H15N3OS (345.4) calculated: 69.55% C, 4.38% H, 12.17% N,
9.28% S; found: 69.32% C, 4.63% H, 11.87% N, 9.54% S.
B) Compound IIIa (2.33 g, 10 mmol) and piperidine (1 ml) are added to a stirred suspension of
benzylidenemalononitrile (1.54 g, 10 mmol) in ethanol (30 ml). The reaction mixture was refluxed
for 2 h, and then was left to cool. The precipitated solid was filtered off and recrystallized from
ethanol into yellow crystals. Yield 3.10 g (90%) of compound Va identical with sample prepared by
procedure A.
4-Acetyl-1-amino-2-cyano-3-phenyl-3H-pyrido[2,1-b][1,3]benzoxazole (Vb)
A) A mixture of compound IVb (1.75 g, 10 mmol) and benzylidenemalononitrile (1.54 g, 10 mmol)
in ethanol (30 ml) was heated at reflux temperature for 30 min in presence of a catalytic amount of
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piperidine. The solid product was filtered off and recrystallized from ethanol into orange crystals.
Yield 2.83 g (86%) of compound Vb, m.p. 200 °C. IR spectrum: 3 400, 3 320 (NH2); 2 184 (CN); 1 677
(C=O). 1H NMR (CD3SOCD3): 7.90 – 7.20 br, 9 H (H-arom.); 4.90 s, 1 H (CH-Ph); 4.70 s, 2 H
(NH2). For C20H15N3O2 (329.4) calculated: 72.93% C, 4.59% H, 12.76% N; found: 72.65% C, 4.76% H,
12.89% N.
B) Compound IIIb (2.17 g, 10 mmol) and piperidine (1 ml) are added to a stirred suspension of
benzylidenemalononitrile (1.54 g, 10 mmol) in ethanol (30 ml). The reaction mixture was refluxed
for 2 h and then was left to cool. The precipitated solid was filtered off and recrystallized from
ethanol into orange crystals. Yield 2.63 g (80%) of compound Vb identical with sample prepared by
procedure A.
General Procedure for Preparation of 3H-Pyrido[2,1-b][1,3]benzothiazole Derivatives VIa – VIi
Compound IIIa (2.33 g, 10 mmol) and piperidine (1 ml) was added to a stirred suspension of the
appropriate α,β-unsaturated nitrile (10 mmol) in ethanol (50 ml). The reaction mixture was refluxed
over different periods of time and then allowed to cool, the product was filtered off and recrystallized
from methanol (compounds VIc, VIf–VIh) or ethanol (compounds VIa, VIb, VIe, VIi).
4-Acetyl-1-amino-2-ethoxycarbonyl-3-phenyl-3H-pyrido[2,1b][1,3]benzothiazole (VIa). Reaction
1
time 3 h, yield 3.18 g (81%), m.p. 318 °C. IR spectrum: 3 436, 3 351 (NH2); 1 738 (C=O). H NMR
spectrum (CD3SOCD3): 7.70–7.20 m, 9 H (H-arom.); 6.30 s, 2 H (NH2); 4.25 q, 2 H, J = 7 (OCH2);
2.30 s, 3 H (COCH3); 1.30 t, 3 H, J = 7 (CH3). For C22H20N2O3S (392.5) calculated: 67.33% C,
5.14% H, 7.14% N, 8.17% S; found: 67.76% C, 5.09% H, 7.28% N, 8.34% S.
4-Acetyl-1-amino-2-carbamoyl-3-phenyl-3H-pyrido[2,1-b][1,3]benzothiazole (VIb). Reaction time
4 h, yield 2.58 g (71%), m.p. 217 °C. IR spectrum: 3 370, 3 260 (NH2); 1 632 (C=O). 1H NMR
(CD3SOCD3): 7.90–7.30 m, 9 H (H-arom.); 6.40–6.10 br, 2 H (NH2); 4.80 s, 1 H (CH-Ar); 4.30–4.00 br, 2 H
(CONH2); 2,60 s, 3 H (CH3). For C20H17N3O2S (363.4) calculated: 66.10% C, 4.71% H, 11.56% N,
8.82% S; found: 66.34% C, 4.53% H, 11.34% N, 8.54% S.
4-Acetyl-1-amino-2-cyano-3-(4-methoxyphenyl)-3H-pyrido[2,1-b][1,3]benzothiazole (VIc). Reaction
time 2.5 h, yield 3.08 g (82%), m.p. 262 °C. IR spectrum: 3 471, 3 372 (NH2); 2 182 (CN); 1 647
(C=O). 1H NMR (CD3SOCD3): 8.20–6.80 m, 8 H (H-arom.); 6.30–5.90 br, 2 H (NH2); 4.60 s, 1 H
(CH-Ar); 3.70 s, 3 H (OCH3); 2.20 s, 3 H (COCH3). For C21H17N3O2S (375.4) calculated: 67.19% C,
4.56% H, 11.19% N, 8.54% S; found: 67.54% C, 4.33% H, 11.56% N, 8.63% S.
4-Acetyl-1-amino-2-ethoxycarbonyl-3-(4-methoxyphenyl)-3H-pyrido[2,1-b][1,3]benzothiazole (VId).
Reaction time 3 h, yield 3.17 g (75%), m.p. 230 °C. IR spectrum: 3 408, 3 351 (NH2); 1 698 (C=O).
1H NMR (CD3SOCD3): 8.00–7.20 m, 8 H (H-arom.); 5.80 s, 2 H (NH2); 5.20 s, 1 H (CH-Ar); 4.25 q,
2 H, J = 7 (OCH2); 3.30 s, 3 H (OCH3); 2.20 s, 3 H (COCH3); 1.35 t, 3 H, J = 7 (CH3). For
C23H22N2O4S (422.5) calculated: 65.39% C, 5.25% H, 6.63% N, 7.59% S; found: 65.55% C, 5.60% H,
6.33% N, 7.19% S.
4-Acetyl-1-amino-2-carbamoyl-3-(4-methoxyphenyl)-3H-pyrido[2,1-b]-[1,3]benzothiazole (VIe). Reaction
time 6 h, yield 2.56 g (65%), m.p. 266 °C. IR spectrum: 3 400, 3 307, 3 290 (NH2, CONH2); 1 630
(C=O). 1H NMR (CDCl3): 7.90–7.10 m, 8 H (H-arom.); 6.70 s, 2 H (NH2); 5.20 s, 1 H (CH-Ar);
4.40–3.90 br, 2 H (CONH2); 3.40 s, 3 H (OCH3); 2.20 s, 3 H (COCH3). For C21H19N3O3S (393.5)
calculated: 64.10% C, 4.86% H, 10.68% N, 8.15% S; found: 64.46% C, 4.44% H, 10.98% N, 8.09% S.
4-Acetyl-1-amino-2-cyano-3-(4-nitrophenyl)-3H-pyrido[2,1-b][1,3]benzothiazole (VIf). Reaction
1
time 3 h, yield 3.24 g (83%), m.p. 257 °C. IR spectrum: 3 470, 3 370 (NH2); 1 665 (C=O). H NMR
(CD3SOCD3): 8.80–7.80 m, 8 H (H-arom.); 7.20 s, 2 H (NH2); 5.60 s, 1 H (CH-Ar); 2.60 s, 3 H
(COCH3). For C20H14N4O3S (390.4) calculated: 61.53% C, 3.61% H, 14.35% N, 8.21% S; found:
61.21% C, 3.43% H, 14.86% N, 8.08% S.
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New Compounds
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4-Acetyl-1-amino-2-ethoxycarboxycarbonyl-3-(4-nitrophenyl)-3H-pyrido[2,1-b][1,3]-benzothiazole
(VIg). Reaction time 3 h, yield 3.37 g (77%), m.p. 259 °C. IR spectrum: 3 422, 3 330 (NH2); 1 724
(C=O). 1H NMR (CD3SOCD3): 8.10–7.70 m, 8 H (H-arom.); 6.80 s, 2 H (NH2); 5.40 s, 1 H
(CH-Ar); 4.00 q, 2 H, J = 7 (OCH2); 2.60 s, 3 H (COCH3); 1.55 t, 3 H, J = 7 (CH3). For
C22H19N3O5S (437.5) calculated: 60.40% C, 4.38% H, 9.61% N, 7.33% S; found: 60.89% C, 4.76% H,
9.27% N, 7.64% S.
4-Acetyl-1-amino-2-carbamoyl-3-(4-nitrophenyl)-3H-pyrido[2,1-b][1,3]benzothiazole (VIh). Reaction
time 5 h, yield 2.74 g (67%), m.p. 247 °C. IR spectrum: 3 400, 3 300, 3 280 (NH2, CONH2); 1 650
(C=O). 1H NMR (CD3SOCD3): 8.00–7.10 m, 8 H (H-arom.); 6.80 s, 2 H (NH2); 5.40 s, 1 H
(CH-Ar); 4.40–4.00 br, 2 H (CONH2); 2.30 s, 3 H (COCH3). For C20H16N4O4S (408.4) calculated:
58.82% C, 3.95% H, 13.72% N, 7.85% S; found: 58.64% C, 3.91% H, 13.66% N, 7.53% S.
4-Acetyl-1-amino-2-phenyl-3-(4-nitrophenyl)-3H-pyrido[2,1-b][1,3]benzothiazole (VIi). Reaction
1
time 3 h, yield 2.46 g (62%), m.p. 130 °C. IR spectrum: 3 480, 3 400 (NH2), 1 703 (C=O). H NMR
(CD3SOCD3): 9.00–7.90 m, 13 H (H-arom.); 7.10 s, 2 H (NH2); 5.40 s, 1 H (CH-Ar); 2.50 s, 3 H
(COCH3). For C25H20N2OS (396.5) calculated: 75.73% C, 5.08% H, 7.07% N, 8.09% S; found:
75.35% C, 5.32% H, 7.41% N, 8.33% S.
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