Simple and convenient routes to new polyheterocycles incorporating pyrazole, thiazole, thiophene, and 1,3,4-thiadiazole moieties

Article abstract of DOI:10.1002/hc.10024

The synthesis of the polyheterocycles incorporating pyrazole, thiazole, thiophene, and 1,3,4- thiadiazole moieties was discussed. The cyanothioacetanilide derivative reacted readily with either α-halocarbonyl compounds or α-halodicarbonyl compounds to afford the same thiophene derivatives. The behavior of cyanothioacetanilide derivative towards a variety of hydrazonoyl chlorides was also discussed. The reaction of the thioacetanilide derivative with α-ketohydrazonoyl halides proceeds in the same manner regardless of the type of hydrazonoyl halide used.

Full text of DOI:10.1002/hc.10024

Heteroatom Chemistry
Volume 13, Number 3, 2002
Simple and Convenient Routes to
New Polyheterocycles Incorporating
Pyrazole, Thiazole, Thiophene, and
1,3,4-Thiadiazole Moieties
Zaghloul E. Kandeel, Kamal M. Dawood, Eman A. Ragab,
and Ahmad M. Farag
Department of Chemistry, Faculty of Science, Cairo University, Giza 12613, Egypt
Received 2 April 2001; revised 6 September 2001
hydroxide solution afforded the non-isolable in-
ABSTRACT: The cyanothioacetanilide derivative 3
reacted readily with either -halocarbonyl compounds
4 or -halodicarbonyl compounds 8 to afford the
same thiophene derivatives 6. Compound 3 also re-
acted with hydrazonoyl chlorides 12 and 16 and fur-
nished the new polyheterocyles 14 and 17, respec-
C
termediate 2, which was converted in situ into
2-cyano-2-N-[4-(1,2-dihydro-1,5-dimethyl-2-phenyl-
3-oxo-3H-pyrazol-4-yl)thiazol-2-yl]carboxamidothi-
oacetanilide (3) upon treatment with cold HCl
solution (Scheme 1). The 1H NMR spectrum of
compound 3 revealed the presence of signals due to
methyne and two NH protons at ␦ 4.43, 11.76, and
12.17, respectively. The reaction of the latter product
with a variety of ␣-halocarbonyl compounds, as a key
step for the synthesis of polysubstituted thiophene
derivatives, was investigated. Thus, compound 3
reacted with ethyl chloroacetate (4a) in refluxing
ethanol in the presence of triethylamine, to afford
a single product identified as the thiophene deriva-
tive 6a, rather than the expected dihydrothiazole
derivative 7a (Scheme 1) based on the elemental
and spectral analyses of the isolated product (see
Experimental).
When compound 3 was treated with ethyl
␣-chloroacetoacetate (8a) under the same reac-
tion conditions, it afforded a product identical
in all respects with 6a (Scheme 1). A reason-
able mechanism of the latter reaction is outlined
in Scheme 2. A similar behavior was observed
when compound 3 reacted with either chloroace-
tone (4b) or 3-chloropentan-2,4-dione (8b) un-
der the same experimental conditions, where it
afforded only one and the same product. The
structure of the isolated product was assigned
tively.
2002 Wiley Periodicals, Inc. Heteroatom Chem
13:248–251, 2002; Published online in Wiley Interscience
(www.interscience.wiley.com). DOI 10.1002/hc.10024
INTRODUCTION
Recently, our research program has utilized some
reactive-sulfur containing intermediates as versatile
building blocks for the synthesis of several thio-
phene, thiazole, and 1,3,4-thiadiazole derivatives
[1–3]. In this context, we report herein a conve-
nient route to a variety of polyheterocyclic ring sys-
tems incorporating an antipyrin moiety via the re-
action of the cyanothioacetanilide derivative 3 with
some ␣-halocarbonyl compounds and halohydra-
zone derivatives.
Thus, reaction of cyanoacetamide derivative 1
[4] with phenyl isothiocyanate in potassium
Correspondence to: Ahmad M. Farag; e-mail: afarag@main-scc.
cairo.eun.eg.
c
2002 Wiley Periodicals, Inc.
248

Simple and Convenient Routes to New Polyheterocycles 249
latter products were confirmed on the basis of their
elemental analyses and spectral data. For example,
the IR spectra of all products 6a–e were free from a
1
nitrile absorption band near 2200 cm .
It is noteworthy to report that all the products
6a–e were alternatively synthesized by the treatment
of the precursors of intermediate 2 with the corre-
sponding ␣-halocarbonyl compounds 4a–e, respec-
tively, (Scheme 1).
The behavior of compound 3 towards a variety
of hydrazonoyl chlorides was also examined.
Thus, treatment of compound 3 with (C-acetyl-,
C-acetanilido-, or C-ethoxycarbonyl)-N-arylhydra-
zonoyl chlorides 12a–i, in ethanolic triethylamine
solution under refluxing conditions, furnished, in
each case, only one isolable product. The structures
of the isolated products were assigned as the di-
hydrothiadiazole derivatives 14a–i (Scheme 3) on
the basis of their elemental analyses and spectral
1
data. For example, the H NMR spectrum of 14b
revealed four singlet signals at ␦ 2.58, 2.62, 3.18,
and 3.28 corresponding to four CH3 protons in
addition to a multiplet in the region ␦ 7.11–7.77
and a broad signal at ␦ 11.08 due to aromatic and
amide-NH protons, respectively. The IR spectra of
the products 14a–i exhibited, in all cases, the pres-
ence of nitrile, amide-NH, and carbonyl stretching
SCHEME 1
as 2-acetyl-3-amino-4-N-[4-(antipyrin-4-yl)thiazol-
2-yl]carboxamido-5-N-phenylaminothiophene (6b)
(Schemes 1 and 2). Both elemental analysis and spec-
troscopic data are in complete agreement with the
assigned structure.
In addition, compound 3 reacted with other ␣-
haloketones 4c–e under similar reaction conditions
to afford the polysubstituted thiophene derivatives
6c–e, respectively (Scheme 1). The structures of the
SCHEME 2
SCHEME 3

250 Kandeel et al.
1
The reaction mixture was refluxed for 1 h, then al-
lowed to cool. The formed solid product was filtered
off, washed with ethanol, and recrystallized from
DMF/water to afford the corresponding thiophene
derivatives 6a–e in 74–81% yield.
bands near 3390, 2200, and 1680 cm , respectively.
Formation of the 2,3-dihydrothiadiazole structures
14a–i is assumed to proceed via a mechanism anal-
ogous to that reported previously [3] (Scheme 3).
Although loss of an ethanol molecule from the
intermediates 13g–i leading to the formation of
compounds 15 would seem to be easier than the
loss of aniline leading to the formation of com-
pounds 14; however the obtained results showed
that reaction of the thioacetanilide derivative 3 with
␣-ketohydrazonoyl halides 12a–i proceeds in the
same manner, regardless of the type of hydrazonoyl
halide used. This finding was supported by the
reaction of C-phenyl-N-phenylmethanehydrazonoyl
chloride (16) with compound 3, where the reac-
tion product was assigned as 2-N-[4-(antipyrin-
4-yl)thiazol-2-ylcarboxamido]-cyanomethylene-3,4-
diphenyl-2,3-dihydro-1,3,4-thiadiazole (17) on the
basis of its elemental analysis and spectral data
(Scheme 3).
1
6a: (76%) mp 246–248 C; ␯max/cm (KBr) 3437
(broad), 3319 (2NH, NH2), 1641 (broad), 1620
(3C O), 1589 (C N); ␦H (CDCl3) 1.29 (t, 3H), 2.43
(s, 3H), 3.2 (s, 3H), 4.24 (g, 2H), 6.39 (br. s, 2H, NH2),
7.07–7.56 (m, 11H), 11.82 (br. s, 1H), 12.21 (br. s, 1H);
m/z 574 (M+) (Found: C, 58.7; H, 4.8; N, 14.9; S, 10.9.
C28H26N6O4S2 requires C, 58.52; H, 4.56; N, 14.62; S,
11.16%).
1
6b: (81%) mp 230–232 C ␯max/cm (KBr) 3383,
3267, 3222 (2NH, NH2), 1650 (broad), 1633 (3C O);
␦H (DMSO-d6), 2.44 (s, 3H), 2.47 (s, 3H), 3.27 (s, 3H),
7.37–7.61 (m, 11H), 8.45 (br. s, 2H, NH2), 11.80 (br. s,
1H, NH), 12.10 (br. s, 1H, NH); m/z 544 (M+) (Found:
C, 59.3; H, 4.5; N, 15.7; S, 11.9. C27H24N6O3S2 re-
quires C, 59.54; H, 4.44; N, 15.43; S, 11.77%).
1
6c: (74%) mp 241–242 C, ␯max/cm (KBr) 3406
(broad), 3296 (2NH, NH2), 1647 (broad), 1620
(3C O), 1589 (C N); ␦H (CDCl3) 2.45 (s, 3H), 3.23 (s,
3H), 6.37 (s, 1H, thiazole-5-CH), 7.12–7.70 (m, 15H,
ArH), 8.95 (br. s, 2H, NH2), 12.05 (s, 1H, NH), 12.38
(s, 1H, NH); m/z 606 (M+) (Found: C, 63.6; H, 4.0;
N, 14.0; S, 10.7. C32H26N6O3S2 requires C, 63.35; H,
4.32; N, 13.85; S, 10.57%).
EXPERIMENTAL
2-(Bromoacetyl)benzothiazole (4e) [5] and hydra-
zonoyl chlorides 12a–c [6], 12d–f [7], 12g–i [8], and
16 [9] were prepared according to the procedures
reported in the given references.
1
6d: (78%) mp 258–260 C; ␯max/cm (KBr) 3405,
2-Cyano-2-N-[4-(antipyrin-4-yl)thiazol-2-yl]-
carboxamidothioacetanilide (3)
3371, 3255, (2NH and NH2), 1656 (broad), 1630
(3C O), 1594 (C N); m/z 641 (M+) (Found: C, 60.2;
H, 3.7; N, 13.0; S, 9.8. C32H25ClN6O3S2 requires C,
59.94; H, 3.93; N, 13.11; S, 10.00%).
To a stirred solution of potassium hydroxide (0.11 g,
2 mmol) in dimethylformamide (DMF) (20 ml)
was added 2-cyano-N-[4-(antipyrin-4-yl)thiazol-2-
yl]acetamide (1) [4]. After the mixture had been
stirred for 30 min, phenyl isothiocyanate (0.27 g, 2
mmol) was added to the mixture. Stirring was con-
tinued for 6 h, then the mixture was poured over
crushed ice containing hydrochloric acid. The solid
product so formed was filtered off, washed with wa-
ter, dried, and finally recrystallized from DMF/water
1
6e: (79%) mp 260–262 C; ␯max/cm (KBr) 3405,
3367, 3251 (2NH and NH2), 1649 (broad), 1622
(3C O); ␦H (CDCl3) 2.47 (s, 3H), 3.28 (s, 3H), 6.97
(s, 1H thiazole-5-CH), 7.32–7.59 (m, 10H), 8.05–8.22
(m, 4H), 9.40 (br. s, 2H, NH2), 12.10 (br. s, 1H, NH),
13.15 (br. s, 1H, NH); (Found: C, 60.0; H, 3.7; N, 14.9;
S, 14.6. C33H25N7O3S3 requires C, 59.71; H, 3.80; N,
14.77; S, 14.49%).
1
to afford 3 in 90% yield, mp 201–202 C, ␯max/cm
(KBr) 3446 (NH), 2199 (C N), 1623, 1697 (2C O),
1610, 1589 (2C N); ␦H (CDC13) 2.43 (s, 3H), 3.47 (s,
3H), 4.43 (s, 1H), 7.28–7.86 (m, 11H), 11.76 (s, 1H),
12.17 (s, 1H); m/z 488 (M+) (Found: C, 58.8; H, 4.4;
N, 17.4; S, 12.9. C24H20N6S2O2 requires C, 59.00; H,
4.13; N, 17.20; S, 13.13%).
Reaction of 3 with -Chlorodicarbonyl
Compounds 8a,b
A mixture of the cyanothioacetanilide derivative 3
(0.7 g, 2 mmol) and the appropriate ␣-chlorodiketone
(8a) or ␣-chloroketoester (8b) (2 mmol) in absolute
ethanol (20 ml), in the presence of triethylamine
(0.2 ml), was refluxed for 2 h, then left to cool. The
resulting reaction mixture was poured into a cold
solution of 0.5 N HC1. The precipitated product was
filtered off, washed with water followed by ethanol,
dried, and finally recrystallized from DMF/water to
afford products identical in all respects with those
Reaction of 3 with -Halocarbonyl Compounds
4a–e. General Procedure
To a solution of 3 (0.976 g, 2 mmol) in ethanol (20 ml)
and the appropriate ␣-halocarbonyl compound
4a–e (2 mmol), 0.2 ml of triethylamine was added.

Simple and Convenient Routes to New Polyheterocycles 251
obtained from the reaction of 3 with chloroacetone
and with ethyl chloroacetate.
1603 (C N); ␦H (insoluble in the common NMR
solvents); (Found: C, 57.4; H, 3.6; N, 17.1; S, 9.5.
C32H23C1N8O3S2 requires C, 57.61; H, 3.47; N, 16.80;
S, 9.61%).
1
Reaction of 3 with Hydrazonoyl Chlorides 12a–i
and 16
14g: (80%) mp 270–271 C; ␯max/cm (KBr) 3440
(NH), 2187 (C N), 1709, 1640 (2C O), 1611, 1587
(2C N); ␦H (DMSO-d6) 1.45 (t, 3H), 2.71 (s, 3H), 3.19
(s, 3H), 4.53 (q, 2H), 7.42–7.67 (m, 11H), 9.15 (br. s,
1H); m/z 585 (M+) (Found: C, 57.1; H, 4.1; N, 16.5;
S, 11.2. C28H23N7O4S2 requires C, 57.42; H, 3.96; N,
These reactions were carried out by the same proce-
dure described above for the syntheses of thiophene
derivatives 6a–e using the appropriate hydrazonoyl
chloride 12a–i or 16 instead of the ␣-halocarbonyl
compounds 4a–e.
16.74; S, 10.95%).
1
14h: (80%) mp 242–243 C; ␯max/cm
(KBr)
1
14a: (82%) mp 209–210 C; ␯max/cm (KBr) 3387
3383(NH), 2189 (C N), 1719, 1645 (2C O); ␦H
(DMSO-d6) 1.35 (t, 3H), 2.72 (s, 3H), 2.90 (s, 3H),
3.17 (s, 3H), 4.49 (q, 2H), 7.37–7.58 (m, 10H), 12.4
(br. s, 1H); m/z 599 (M+) (Found: C, 58.2; H, 4.0; N,
16.6; S, 10.4. C29H25N7O4S2 requires C, 58.08; H, 4.20;
N, 16.35; S, 10.69%).
(NH), 2210 (C N), 1680, 1659, 1645 (3C O), 1602
(C N); ␦H(DMSO-d6) 2.61 (s, 3H), 3.18 (s, 3H), 3.26
(s, 3H), 7.12–7.74 (m, 11H, ArH and thiazole-5-CH),
11.15 (br. s, 1H); m/z 555 (M+) (Found: C, 58.6; H,
3.6; N, 17.2; S, 11.3. C27H21N7O3S2 requires C, 58.36;
H, 3.81; N, 17.65; S, 11.54%).
1
14i: (76%) mp 278–280 C; ␯max/cm (KBr) 3404
14b: (83%); mp 204–205 C; ␯max/cm 1 (KBr) 3393
(NH), 2189 (C N), 1697, 1640 (broad) (3C O), 1611,
1589 (2C N); ␦H (DMSO-d6) 2.58 (s, 3H), 2.62 (s,
3H), 3.18 (s, 3H), 3.28 (s, 3H), 7.12–7.77 (m, 10H),
11.08 (br. s, 1H); (Found: C, 59.1; H, 4.2; N, 17.5;
S, 11.3. C28H23N7O3S2 requires C, 59.04; H, 4.07; N,
17.21; S, 11.26%).
(NH), 2191 (C N), 1709, 1636 (2C O), 1589 (C N);
m/z 620 (M+) (Found: C, 54.0; H, 3.7; N, 15.6; S, 10.0.
C28H22N7O4S2Cl requires C, 54.23; H, 3.58; N, 15.81;
S, 10.34%).
1
17: (75%) mp 272–274 C; ␯max/cm (KBr) 3444
(NH), 2189 (C N), 1670, 1645 (2C O), 1610 (C N);
␦
(DMSO-d6) 2.74 (s, 3H), 3.16 (s, 3H), 7.38–7.98
1
H
14c: (88%) mp 220–222 C; ␯max/cm (KBr) 3393
(m, 16H), 11.08 (br. s, 1H); m/z 589 (M+) (Found: C,
63.4; H, 4.2; N, 16.8; S, 10.9. C31H23N7O2S2 requires
C, 63.14; H, 3.93; N, 16.63; S, 10.88%).
(NH), 2189 (C N), 1693, 1650 (broad) (3C O), 1610,
1590 (2C N) m/z 591 (M+ + 1), 590 (M+) (Found:
C, 55.2; H, 3.6; N, 16.5; S, 10.6. C27H20N7S2O3C1 re-
quires C, 54.96; H, 3.42; N, 16.62; S, 10.87%).
1
14d: (85%) mp 212–213 C; ␯max/cm
(KBr)
REFERENCES
3476, 3402 (2NH), 2190 (C N), 1650 (broad), 1630
(3C O), 1608, 1590 (2C N); ␦H (DMSO-d6) 2.61 (s,
3H), 3.18 (s, 3H), 7.10–7.81 (m, 16H), 11.05 (br. s,
1H), 12.40 (br. s, 1H); m/z 632 (M+) (Found: C, 60.9;
H, 3.6; N, 17.4; S, 10.0. C32H24N8O3S2 requires C,
60.74; H, 3.82; N, 17.71; S, 10.14%).
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14e: (87%) mp 289–291 C; ␯max/cm 1 (KBr) 3404,
3271 (2NH), 2207 (C N), 1679, 1658, 1645 (3C O),
1603 (C N); ␦H (DMSO-d6) 2.46 (s, 3H), 2.73 (s, 3H),
3.16 (s, 3H), 7.35–7.81 (m, 15H), 11.02 (br. s, 1H),
11.18 (br. s, 1H) (Found: C, 61.4; H, 3.8; N, 17.5;
S, 10.1. C33H26N8O3S2 requires C, 61.28, H, 4.05; N,
17.33; S, 9.92%).
1
14f: (90%) mp > 300 C; ␯max/cm (KBr) 3400,
3261 (2NH ), 2204 (C N), 1661, 1634, 1620 (3C O),
[9] Wolkoff, P. Can J Chem 1975, 53, 1333.