Novel and facile synthesis of thiophene, thiazole, 2H-pyran-2-one benzimidazo[1,2-a]pyridine and pyridine derivatives containing antipyrine moiety

Article abstract of DOI:10.1080/10426500490468083

Several new thiophene, thiazole, 2H-pyran-2-one, benzimidazo[1,2-a]- pyridine and pyridine derivatives were synthesised from active methylene reagents, 4-chloroacetylantipyrine and enaminones as starting materials.

Full text of DOI:10.1080/10426500490468083

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Phosphorus, Sulfur, and Silicon and the Related
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NOVEL AND FACILE SYNTHESIS OF THIOPHENE,
THIAZOLE, 2H-PYRAN-2-ONE BENZIMIDAZO[1,2-
a]PYRIDINE AND PYRIDINE DERIVATIVES CONTAINING
ANTIPYRINE MOIETY
F. M. A. El-Taweel a
a Chemistry Department, Faculty of Science, Mansoura University, New Damietta City, Egypt
Version of record first published: 16 Aug 2010.
To cite this article: F. M. A. El-Taweel (2004): NOVEL AND FACILE SYNTHESIS OF THIOPHENE, THIAZOLE, 2H-PYRAN-2-ONE
BENZIMIDAZO[1,2-a]PYRIDINE AND PYRIDINE DERIVATIVES CONTAINING ANTIPYRINE MOIETY, Phosphorus, Sulfur, and Silicon and
the Related Elements, 179:7, 1267-1277
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Phosphorus, Sulfur, and Silicon, 179:1267–1277, 2004
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Copyright Taylor & Francis Inc.
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500490468083
NOVEL AND FACILE SYNTHESIS OF THIOPHENE,
THIAZOLE, 2H-PYRAN-2-ONE
BENZIMIDAZO[1,2-a]PYRIDINE AND PYRIDINE
DERIVATIVES CONTAINING ANTIPYRINE MOIETY
F. M. A. El-Taweel
Chemistry Department, Faculty of Science, Mansoura
University, New Damietta City, Egypt
(Received August 1, 2003; accepted November 7, 2003)
Several new thiophene, thiazole, 2H-pyran-2-one, benzimidazo[1,2-a]-
pyridine and pyridine derivatives were synthesised from active methy-
lene reagents, 4-chloroacetylantipyrine and enaminones as starting
materials.
Keywords: 2H-Pyran-2-one; benzimidazopyridine; pyridine; thiazole;
thiophene
Thiophene and thiazole derivatives carrying antipyrinyl moiety pos-
sess diverse pharmacological properties.1−8 These pharmacological ac-
tivities have been attracted special attention to synthesize a new
class of thiophene and thiazole derivatives carrying antipyrinyl moi-
ety because of their applications in the field of pharmaceuticals1−8
and biodegradable agrochemicals.9,10 This article reports the synthesis
of thiophene and thiazole derivatives using readily available starting
materials.
RESULTS AND DISCUSSION
It has been found that, active methylene nitriles 1a–d were treated
with phenyl isothiocyanate in dimethylformamide (DMF) under basic
conditions in KOH/DMF to give the non-isolable intermediates 4. These
were reacted with 4-chloroacetyl-1-phenyl-2,3-dimethyl-3-pyrazolin-5-
one (2) to give the enamine derivatives 5a–d. Structures 5 were sup-
ported by their elemental analysis and spectral data.
Address correspondence to F. M. A. El-Taweel, Department of Chemistry, Faculty of
Science, New Damietta City, A. R. Egypt. E-mail: tasaid@hotmail.com
1267

1268
F. M. A. El-Taweel
Compounds 5a,c were converted into 3-aminothiophene derivatives
1
6a,c. H-NMR spectra of 6 clearly indicate the absence of signals at
δ ꢁ 4.0 ppm attributable to methylene groups which in good agreement
with the thiophene structures 6 (Scheme 1).
SCHEME 1
On the other hand, the enaminonitriles 5a–d can be converted into
thiazole derivatives 7a–d by stirring with concentrated sulphuric acid.
The elemental analysis and spectral data of the reaction products were
compatible only with the thiazole structures 7.
Treatment of thiazole 7a with hydrazine hydrate afforded the pyra-
zole derivative 9. IR spectra of 9 clearly indicate the absence of cyano
group and the presence of amino group. The same products 9 was

Derivatives Containing Antipyrine Moiety
1269
synthesized by an independent method via reacting the enaminonitrile
5a with hydrazine hydrate to give the pyrazole derivative 8 followed
by cyclization of the later by the effect of concentrated sulphuric acid
(Scheme 2).
SCHEME 2
Also, it has been found that, mixture of both acetylacetone (2a) or
acetoacetanilide (3b) and phenyl isothiocyanate in dimethylformamide
containing equivalent amount of potassium hydroxide give the inter-
mediates 10. These were alkylated with 4-chloroacetylantipyrine (2) to
yield products with water elimination. Structures 12 and 13 were con-
sidered for the reaction products. The thiazole structures 13 were ruled
out based on 1H-NMR spectra which clearly showed the absence of sig-
nals at δ ꢁ 6.5 ppm due to thiazole H-5. Thus, the thiophene structures
12 were assigned as reaction products. Compounds 12a,b were thought
to be formed via sequence demonstrated in (Scheme 3).

1270
F. M. A. El-Taweel
SCHEME 3
In addition, the chemical reactivity of active methylene nitrile 1e4
towards a variety of chemical reagents have been investigated. Thus,
compound 1e was allowed to react with the enaminones 14 in ethanol
and in the presence of acetic acid as catalyst to afford α-pyrones 17 or
the pyridines 18. Structures 17 were supported by IR spectra which
revealed the absence of cyano groups. Compounds 17 were assumed to
be formed via first addition of the active methylene in 1e to the activated
double bond in 14 and eliminate one molecule of dimethylamine to give
the intermediates 16 which readily cyclized to afford the α-pyrones 17.

Derivatives Containing Antipyrine Moiety
1271
In a similar manner, 1e was subjected to react with the enaminon-
itrile 15 to yield benzimidazo[1,2-a]pyridine 20. Compound 20 was
identified as a reaction product by its elemental and spectral analy-
sis (Scheme 4).
SCHEME 4
Compound 1e condensed with aromatic aldehydes to afford the aryli-
denes 21. Structures 21 were established as reaction products from
1H-NMR spectrum of 21a which displays the absence of a signal at-
tributable to the exocyclic methylene group and the presence of ylidenic
proton at δ = 8.3 ppm (see Tables I and II).
Refluxing thiazole 1e with arylidenemalononitriles 22 in ethanol
containing catalytic amount of piperidine resulted in the formation of
the pyridines 24 or the 4H-pyrans 25. Structures 24 were proposed as
reaction products based on their elemental and spectral data. If the re-
action product is 25, 1H-NMR spectrum would show signals at δ ꢁ 4.5–
5.0 ppm for pyran H-4. Moreover, compounds 24 were also synthesized

1272
F. M. A. El-Taweel
TABLE I Analytical Data and Physical Characteristics of Novel Compounds
Elemental analysis
(found)
Molecular
formula (M.wt)
Compd no.
m.p. (◦C)
Yield
80
C
H
N
5a
C23H19N5SO2
(429.5)
C34H30N6SO4
(618.73)
C28H24N4SO2
(480.59)
C29H24N6SO2
(520.62)
208–210
64.12
(64.14)
66.03
(66.34)
69.98
(69.79)
66.90
(66.84)
64.12
(64.45)
69.98
(70.03)
67.13
(67.26)
67.98
(67.89)
72.70
(72.64)
69.30
(69.61)
59.85
(60.03)
62.29
(62.11)
67.40
(67.60)
67.37
(67.53)
55.16
(55.44)
59.58
(59.64)
60.66
4.46
(5.20)
4.89
(5.03)
5.03
(5.35)
4.65
(4.73)
4.46
(4.51)
5.03
(5.14)
4.16
(4.38)
4.70
(4.83)
4.79
(5.03)
4.41
(4.81)
5.02
(5.13)
4.77
(4.81)
5.20
(5.40)
5.11
(5.31)
3.34
(3.57)
3.45
(3.37)
3.39
16.31
(16.36)
13.58
(13.41)
11.66
5b
5c
198–200
182–184
190–192
>300
78
70
65
70
60
70
70
65
63
60
60
70
62
63
60
62
70
63
62
65
60
(11.47)
16.14
5d
(16.27)
16.31
6a
C23H19N5SO2
(429.50)
28H24N4SO4
(16.24)
11.66
6c
C
240–242
520–252
230–232
220–222
232–234
250–252
>300
(480.59)
(11.56)
17.02
7a
C23H17N5SO
(411.49)
C34H28N6SO3
(600.70)
(17.11)
13.99
7b
(14.05)
12.11
7c
C28H22N4SO
(462.58)
(12.16)
16.72
7d
C29H22N6SO
(502.6)
(16.14)
21.24
8
C23H23N7SO2
(461.55)
(21.34)
22.11
9
C23H21N7SO
(443.53)
25H23N3SO3
(445.54)
31H28N4SO4
(552.65)
C24H18N4S3O4
(522.62)
29H20N4S2O6
(584.63)
27H18N8S2O
(534.62)
24H18BrS2N5O2
(552.48)
24H18CIS2N5O2
(508.02)
22H17N5S3O2
(479.60)
C27H18BrN7S2O2
(616.53)
C25H17N7S3O2
(543.65)
(22.24)
9.43
(9.50)
10.14
(10.22)
10.72
(10.36)
9.58
12a
12b
17a
17b
20
C
C
225–227
154–156
170–172
185–187
190–192
210–212
232–234
210–212
250–252
180–182
C
(9.45)
20.99
C
(60.51)
52.18
(52.37)
56.74
(56.67)
55.10
(55.33)
52.60
(3.52)
3.28
(3.24)
3.57
(3.38)
3.57
(3.67)
2.94
(20.83)
12.68
(12.53)
13.79
(13.63)
14.60
(14.57)
15.90
21a
21b
21c
24a
24b
C
C
C
(52.54)
55.23
(55.47)
(3.11)
3.15
(3.22)
(15.87)
18.04
(18.21)

Derivatives Containing Antipyrine Moiety
1273
TABLE II Spectral Data of Newly Synthesized Compounds
Compd no.
IR (cm−1
)
1H-NMR (δH)
5a
3100 (NH), 2205 (CN), 1680, 2.59 (s, 3H, CH3), 3.37 (s, 3H, N CH3),
1670 (CO) 4.6 (s, 2H, CH2), 7.0–7.6
(m, 10H, aromatic H), 8.3 (s, 1H, NH).
3570 (NH), 2210 (CN), 1680, 2.33, 2.5 (2S, 6H, 2CH3), 3.07.3.31 (2S, 6H,
5b
5c
5d
6a
6c
1670 (CO)
2N CH3), 4.21 (s, 2H, CH2),7.18–7.51
(m, 15H, aromatic H), 10.3 (s, 1H, NH).
3540 (NH), 2207 (CN), 1680, 2.61 (s, 3H, CH3), 3.36 (s, 3H, N CH3),
1665 (CO)
4.3 (s, 2H, CH2), 6.8–7.7 (m, 15H,
aromatic H), 9.2 (s, 1H, NH).
3560 (NH), 2205 (CN), 1680, 2.53 (s, 3H, CH3), 3.4 (s, 3H, N CH3),
1660 (CO)
4.4 (s, 2H, CH2). 6.9–7.8 (m, 14H,
aromatic H), 8.4, 9.8 (2S, 2H, 2NH).
2.38 (s, 3H, CH3), 3.33 (s, 3H, N CH3),
7.15–7.61 (m, 15H, aromatic H),
7.8, 10.2 (2S, NH, NH2).
3410, 3300 (NH2,NH), 2215
(CN), 1680, 1670 (CO).
3390, 3290, 3230 (NH2,NH),
2208 (CN), 1680, 1660 (CO).
2.36 (s, 3H, CH3), 3.36 (s, 3H, N CH3),
6.97.6 (m, 15H, aromatic H),
9.2, 10.1 (2S, NH, NH2).
7a
7b
7c
8
2190 (CN), 1665 (CO).
2.7 (s, 3H, CH3), 3.0 (s, 3H, N CH3),
7.0–7.6 (m, 11H, aromatic H).
2.3, 2.45 (2S, 6H, 2CH3), 3.2, 3.33 (2S, 6H,
2N CH3), 7.2–7.7 (m, 15H, aromatic H).
2.4 (s, 3H, CH3), 3.35 (s, 3H, N CH3),
6.7–7.7 (m, 11H, aromatic H).
2215 (CN), 1685,
1665 (CO)
2210 (CN), 1660 (CO)
3400, 3350 (NH2, NH), 1785, 2.51 (s, 3H, CH3), 3.2 (s, 3H, N CH3),
1660 (CO)
4.37 (s, 2H, CH2), 6.9–7.6 (m, 10H,
aromatic H), 7.8 (s, 2H, NH2),
8.6 (s, 2H, NH2). 9.3 (s, 1H, NH).
2.43 (s, 3H, CH3), 3.34 (s, 3H, N CH3),
6.65–7.67 (m, 11H, aromatic H).
8.7, 9.6 (2S, 4H, 2NH2).
9
3480, 3370 (NH2, NH),
1665 (CO)
12a
12b
17a
3460 (NH), 1685, 1675,
1660 (CO)
2.47, 2.5, 2.6 (3S, 9H, 3CH3), 3.33 (s, 3H,
N
CH3), 7.15–7.6 (m, 10H aromatic H),
11.7 (s, 1H, NH).
3510,3460 (NH),1680,1675
1665 (CO).
2.4, 2.48 (2S, 6H, 2CH3), 3.7 (s, 3H,
OCH3), 6.95–7.7 (m, 14H, aromatic H),
9.3, 10.2 (2S, 2H, 2NH).
3450 (NH), 1743 (CO),
1702 (CO), 1650 (CO).
2.35 (s, 3H, CH3), 3.33 (s, 3H,
N
CH3), 6.64 (s, 1H, thiazole H-5),
6.92 (d, J = 8Hz, 1H, pyrone, H-5), 7.2–8.0
(m, 8H, aromatic H), 8.2 (d, J = 8Hz, 1H,
pyrone H-4), 9.6 (s,1H, NH).
20
3460 (NH), 2227, 2218
(2CN), 1654 (CO)
2.35 (s,3H,CH3), 3.35 (s, 3H,
N
CH3), 7.41–8.01 (m, 11H,
aromatic H), 10.1 (s, 1H, NH).
2.4 (s, 3H, CH3), 3.2 (s, 3H, N CH3),
6.7 (s.1H, thiazole H-5), 7.3–7.52 (m, 9H,
aromatic H), 8.3 (s, 1H, CH),
9.7 (s, 1H, NH).
24a
3447 (NH), 2200 (CN),
1710 (CO), 1660 (CO)

1274
F. M. A. El-Taweel
TABLE II Spectral Data of Newly Synthesized Compounds (Continued)
Compd no.
IR (cm−1
)
1H-NMR (δH)
214a
3448, 3387 (NH2), 2216 (CN),
1730 (CO, 1670 (CO)
2.34 (s, 3H, CH3), 3.3 (s, 3H,
N
CH3), 7.1–7.74 (m, 10H,
aromatic H); 8.3 (s, 2H, NH2).
2.28 (s, 3H, CH3), 3.4 (s,
3H,N CH3), 7.35–7.98 (m, 9H,
aromatic H), 8.74 (s,2H, NH2).
24c
3460, 3390 (NH2), 2220 (CN),
1715 (CO), 1636 (CO)
via reacting the arylidenes 21 with malononitrile in ethanolic-pyridine.
Formation of 24 were suggested to take place via Michael type addition
of the active methylene group in 1e to the π-deficient centre in 22 to
give the Michael adduct 23, which cyclized and readily eliminate one
molecule of hydrogen to yield the pyridines 24 (Scheme 5).
SCHEME 5

Derivatives Containing Antipyrine Moiety
1275
EXPERIMENTAL
All melting points are uncorrected and measured on Griffin & George
MBF 010T (London) apparatus. Recorded yields correspond to the pure
products. IR(KBr) spectra were recorded on a Perkin Elmer SP-880
1
spectrophotometer and H-NMR spectra were measured on a Varian
270 MHz spectrometer in DMSO-d6 as solvent and TMS as an internal
standard (chemical shifts are reported in δ units ppm. Microanalysis
were performed on LECOCHN-932.
Preparation of the Enaminonitriles 5a--d
A solution of 1a–d (0.01 mmol) in dimethylformamide (30 ml), phenyl
isothiocyanate (0.01 mmol) and potassium hydroxide (0.01 mmol) in
water (10 ml) were added. The reaction mixture was stirred for 6 h
at room temperature then (0.01 mmol) of 2 was added. The reaction
was then stirred over night, poured on cold water and neutralized with
dil. HCl. The solid products were collected by filtration and crystallized
from ethanol to give 5a–d.
FIGURE 1

1276
F. M. A. El-Taweel
Preparation of Thiophene Derivative 6a,c
A solution of (0.01 mmol) of 5a,b in ethanol (50 ml) containing few
drops of piperidine was refluxed for 4 h then left to cool. The solid de-
posited were collected by filtration and crystallized from ethanol to give
6a,c.
Preparation of 3-Phenyl-1,3-thiazolines 7
A solution of 5 (0.01 mmol) in conc. sulphuric acid (10 ml) was stirred
for 3 h at room temperature then poured into ice. The precipitates
were collected by filtration and crystallized from ethanol-dioxane to
give 7.
Reaction of 5 and 7 with Hydrazine Hydrate: General
Procedure for Preparation of 8 and 9
A solution of 5 to 7 (0.01 mmol) in ethanol (50 ml) were treated with
hydrazine hydrate were refluxed for 1 h and then left to cool. The solid
products were collected by filtration and crystallized from ethanol-DMF
to give compounds 8 and 9 respectively.
Compound 9 were prepared by stirring 0.01 mmol of 8 with conc.
H2SO4.
Formation of Thiophenes 12a,b
A solution of (0.01 mmol) of 3a,b in dimethylformamide (30 ml) con-
taining potassium hydroxide (0.01 mmol) and (0.01 mmol) of phenyl
isothiocyanate was stirred overnight. To this solution (0.01 mmol) of
2 was added, then stirred again overnight, poured on ice. The precipi-
tates formed were collected by filtration and crystallized from ethanol
to give 12a,b.
Reaction of 1e with the Enamines 14 and 15:
Formation of 17 and 20
A solution of 1e (0.01 mmol) and (0.01 mmol) of 14 or 15 in ethanol
(50 ml) containing acetic acid (1 ml) was refluxed for 6 h. The sol-
vent was removed by distillation under reduced pressure and the re-
sulting solutions were left to cool. The solid precipitates were col-
lected by filtration and recrystallized from ethanol to give 17 and 20
respectively.

Derivatives Containing Antipyrine Moiety
1277
Condensation of 1e with Aromatic Aldehydes:
Formation of 21
A solution of 1e (0.01 mmol) and the appropriate amounts of aromatic
aldehydes (0.01 mmol) in ethanol (50 ml) with (0.1 ml) of piperidene
was refluxed for 3 h then left to cool. The resulting solids obtained on
standing were collected by filtration and crystallized from ethanol to
give 21a–c.
Formation of Pyridines 24a,c
Method A
A solution of 1e (0.01 mmol) in ethanol (50 ml) was treated with 4
(0.01 mmol) and few drops of piperidine were heated under reflux for 3 h.
The resulting solid products were collected by filtration, recrystallized
from ethanol/DMF and then identified as 24a,c.
Method B
A suspension of 21a,c (0.01 mmol) in ethanol (50 ml) was treated
with malononitrile (0.01 mmol) and dry pyridine (1 ml). The mixture
was refluxed for 5 h and the solvent was concentrated in vacuo and
crystallized (m.p. and mixed m.p.s as 24a,c).
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