A novel synthesis of thiazoles and thiazolopyridines using N-cyanoacetoarylsulfonylhydrazides

Article abstract of DOI:10.1081/SCC-120015806

A novel and efficient method for the synthesis of a new variety of 2-(N-acetoarylsulfonylhydrazide)-2-thiazolin-4-ones and their corresponding thiazolo [2,3-a] pyridines by the reaction of N-cyanoacetoarylsulphonylhydrazides with thioglycolic acid. The synthetic potential of the method is demonstrated.

Full text of DOI:10.1081/SCC-120015806

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A Novel Synthesis of Thiazoles and Thiazolopyridines
Using N -Cyanoacetoarylsulfonylhydrazides
Galal Hamza Elgemeie a & Shahinaz Hassan Sayed a
a Chemistry Department , Faculty of Science , Helwan University , Ain-Helwan, Cairo, Egypt
Published online: 16 Aug 2006.
To cite this article: Galal Hamza Elgemeie & Shahinaz Hassan Sayed (2003) A Novel Synthesis of Thiazoles and
Thiazolopyridines Using N -Cyanoacetoarylsulfonylhydrazides, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 33:4, 535-541, DOI: 10.1081/SCC-120015806
To link to this article: http://dx.doi.org/10.1081/SCC-120015806
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SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 4, pp. 535–541, 2003
A Novel Synthesis of Thiazoles and
Thiazolopyridines Using
N-Cyanoacetoarylsulfonylhydrazides
*
Galal Hamza Elgemeie and Shahinaz Hassan Sayed
Chemistry Department, Faculty of Science,
Helwan University, Ain-Helwan, Cairo, Egypt
ABSTRACT
A novel and efficient method for the synthesis of a new variety of
2-(N-acetoarylsulfonylhydrazide)-2-thiazolin-4-ones and their corre-
sponding thiazolo[2,3-a]pyridines by the reaction of N-cyanoaceto-
arylsulphonylhydrazides with thioglycolic acid. The synthetic
potential of the method is demonstrated.
We have previously reported several new approaches for the synthesis
of azolopyridines and azolopyrimidines utilizing the 2-substituted methyl
azolyl derivatives as starting materials.[1–7] In conjunction of this work
we report here on the utility of reactions of N-cyanoacetoarylsulphonyl-
*Correspondence: Galal Hamza Elgemeie, Chemistry Department, Faculty of
Science, Helwan University, Ain-Helwan, Cairo, Egypt; Fax: þ002 02 5870668;
E-mail: rughe@rusys.eg.net.
535
DOI: 10.1081/SCC-120015806
Copyright & 2003 by Marcel Dekker, Inc.
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536
Elgemeie and Sayed
hydrazides with thioglycolic acid for the synthesis of 2-(N-acetoaryl-
sulfonylhydrazide)-2-thiazolin-4-ones. Moreover, the scope and limitation
of our procedure for the synthesis of thiazoles are also reported. Thus,
ithas been found htatN
-cyanoacetoarylsulphonyl-hydrazides 2 react
with thioglycolic acid in refluxing pyridine for 3 h to give the condensa-
tion products 4 by water elimination. The analytical data for the product
4a revealed a molecular formula C11H11N3S2O4 (Mþ 313). Two
tautomeric structures were considered in solutions. The structure of the
2-functionally substituted methyl-2-thiazolin-4-one form was readily
ruled outbased on 1H NMR spectra, which revealed one proton signal
at ꢀ ¼ 5.49 ppm. This signal can be only interpreted in terms of the
2-substituted methylidine form. The formation of 4 by the reaction
of compound 2 with thioglycolic acid is assumed to proceed via the
intermediacy of 3, which formed by addition of thioglycolic acid to the
cyano group in compound 2. Compound 4 bearing latent functional
substituents were found useful to synthesize its fused ring derivatives.
Thus, compound 4 readily reacted with furan-2-al or thiophen-2-al in
refluxing ethanol containing a catalytic amount of piperidine in a 1:2
molar ratio to give the corresponding difuranylidene and dithiophenyl-
idene derivatives 7a–d. The structures of 7 were established on the basis
of elemental analysis and spectral data (MS, IR, 1H NMR). Compound 4
reacted with 2-b-cyanoethylenefuran derivatives 5a,b and 2-b-cyano-
ethylene-thiophene derivatives 5c,d to yield products for which the
5-amino-8-(N-formamidoarylsulfonylhydrazid)-7H-thiazolo[2,3-a]pyridine
structure 8 were assigned. Each structure of 8 was confirmed on the basis
of elemental analysis and spectral data (IR, MS, 1H NMR). Thus,
analytical data for compound 8a revealed a molecular formula
C24H17N5O6S2 (Mþ 535). The 1H NMR spectrum of 8a revealed a
signal at 5.00 ppm assignable to a pyridine H-4 and three broad signals
at ꢀ ¼ 6.33, 10.60 and 12.00 ppm assignable to the NH2 group and two
NH groups, respectively. Moreover, the IR spectrum revealed the
presence of two carbonyl groups at 1710 and 1680 cmꢀ1. The formation
of 8 by the reaction of 4 with 5 may be assumed to proceed via formation
of 1:2 Michael adduct intermediates 6, which cyclize with loss of
malononitrile or ethyl cyanoacetate to give compounds 8. Compounds
8 could also be obtained via direct reaction of 7 with malononitrile or
ethyl cyanoacetate in refluxing ethanol containing catalytic amounts of
piperidine.
In summary, we have achieved a regiospecific synthesis of interesting
2-(N-acetoarylsulfonylhydrazide)-2-thiazolin-4-ones and their corre-
sponding thiazolo[2,3-a]pyridine derivatives using the reaction of
N-cyanoacetosulphonylhydrazides with thioglycolic acid.

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Synthesis of Thiazoles and Thiazolopyridines
537
EXPERIMENTAL
All melting points are uncorrected. IR spectra were obtained
1
(KBr disk) on a Perkin Elmer 11650 FT-IR instrument. The H NMR
spectra were measured on a Varian 400 MHz spectrometer for
solutions in (CD3)2 SO using Si(CH3y)4 as an internal standard. Mass
spectra were recorded on a Varian MAT 112 spectrometer. Analytical
data were obtained from the Microanalytical Data Center at Cairo
Univerisity.

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538
Elgemeie and Sayed
2-(N-Acetoarylsulphonylhydrazide)-2-thiazolin-4-ones (4a,b)
General procedure
A mixture of an equimolar amounts of N-cyanoacetoaryl-sulphonyl-
hydrazides 2 and mercaptoacetic acid was refluxed in pyridine solution
for 3 h. The reaction mixture was then cooled, poured over ice-water
mixture and neutralized with dil. HCl solution. The formed solid product
was filtered off and recrystallized from ethanol.
4a: White (50%), m.p. 270ꢁC, ꢁmax/cmꢀ1 (KBr) 3454, 3055 (NH),
1
1736 (CO) and 1680 (CO); H NMR (DMSO) ꢀ ¼ 3.62 (s, 2H, CH2),
5.49 (s, 1H, CH), 7.55–7.80 (m, 5H, C6H5), 9.70 (s, br, 1H, NH), 9.80
(s, br, 1H, NH) and 11.37 (s, br, 1H, NH); 13C NMR (DMSO) ꢀ ¼ 31.98
(CH2), 89.07 (CH), 127.57–132.85 (C6H5), 140.00 (C-2), 165.51 (CO) and
174.07 (CO); m/z 313 (Calcd for C11H11N3S2O4: C, 42.17; H, 3.51;
N, 13.42; S, 20.45. Found: C, 41.7; H, 3.1; N, 13.6; S, 20.8%). 4b: Whit e
(55%), m.p. 240ꢁC, ꢁmax/cmꢀ1 (KBr) 3564, 3228 (NH), 1707 (CO) and
1
1655 (CO); H NMR (DMSO) ꢀ ¼ 2.38 (s, 3H, CH3), 3.63 (s, 2H, CH2),
5.49 (s, 1H, CH), 7.35–7.68 (m, 4H, C6H4), 9.60 (s, br, 1H, NH), 9.70
(s, br, 1H, NH) and 11.35 (s, br, 1H, NH); 13C NMR (DMSO) ꢀ ¼ 21.06
(CH3), 31.98 (CH2), 89.16 (CH), 127.63–129.30 (C6H4), 142.55 (C-2),
165.52 (CO), 174.06 (CO); m/z 327 (Calcd for C12H13N3S2O4: C, 44.04;
H, 3.98; N, 12.84; S, 19.57. Found: C, 43.8; H, 3.5; N, 13.1; S, 20.0%).
2,5-Difuranylidene- and
Dithiophenylidene-thiazolin-4-ones (7a–d)
General procedure
A mixture of 2-(N-acetoarylsulphonylhydrazid)-2-thiazoline-4-ones 4
(0.01 mole) and furan-2-al or thiophen-2-al (0.02 mole) was refluxed for
1 h in ethanol solution containing the catalytic amount of pipridine. The
reaction mixture was cooled and the formed solid product was filtered off
and recrystallized from the appropriate solvent.
7a: yellow, m.p. 160–162ꢁC (from EtOH) yield (80%); IR (KBr disc)
ꢁ
max/cmꢀ1 3330, 3200 (NH), 1705 (CO) and 1670 (CO); 1H NMR
(DMSO) ꢀ ¼ 7.61–8.52 (m, 13H, 2 ylidenic CH, 2 furan H-3,4,5 and
C6H5), 9.68 (s, br, 1H, NH) and 10.60 (s, br, 1H, NH); C21H15N3O6S2
(469), Calcd: C, 53.73; H, 3.20; N, 8.96; S, 13.65. Found: C, 53.6; H, 3.3;
N, 9.1; S, 13.2%. 7b: yellow, m.p. >290ꢁC (from EtOH) yield (78%);
IR (KBr disc) ꢁmax/cmꢀ1 3220, 3100 (NH), 1710 (CO) and 1670 (CO);

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Synthesis of Thiazoles and Thiazolopyridines
539
1H NMR (DMSO) ꢀ ¼ 2.38 (s, 3H, CH3), 7.65–8.42 (m, 12H, ylidenic
CH, 2 furan H-3,4,5 and C6H4), 9.60 (s, br, 1H, NH) and 11.30 (s, br,
1H, NH); C22H17N3O6S2 (483), Calcd: C, 54.66; H, 3.52; N, 8.70; S,
13.25. Found: C, 54.8; H, 3.4; N, 9.0; S, 13.0%. 7c: yellow, m.p
150–152ꢁC (from EtOH); yield (85%); IR (KBr disc) ꢁmax/cmꢀ1 3360,
3270 (NH), 1715 (CO) and 1690 (CO); 1H NMR (DMSO) ꢀ ¼
7.44–8.42 (m, 13H, 2 ylidenic CH, 2 thiophene H-3,4,5 and C6H5), 9.00
(s, br, 1H, NH), and 10.40 (s, br, 1H, NH); C21H15N3O4S4 (437),
Calcd: C, 57.67; H, 3.43; N, 9.61; S, 29.29. Found: C, 57.5; H, 3.4; N,
9.2; S, 29.0%. 7d: yellow, m.p 164–166ꢁC (from EtOH), yield (89%); IR
(KBr disc) ꢁmax/cmꢀ1 3380, 2780 (NH), 1700 (CO) and 1660 (CO);
1H NMR (DMSO) ꢀ ¼ 2.30 (s, 3H, CH3), 7.28–8.39 (m, 12H, 2 ylidenic
CH, 2 thiophene H-3,4,5 and C6H4), 9.00 (s, br, 1H, NH), and 10.40
(s, br, 1H, NH); C22H17N3O4S4 (515), Calcd: C, 51.26; H, 3.30; N, 8.16;
S, 24.85. Found: C, 51.5; H, 3.7; N, 8.0; S, 24.6%.
5-Amino-8-(N-formamidoarylsulfonylhydrazid)-3-oxo-2,3-
dihydro-7H-thiazolo[2,3-a]pyridines (8a–h)
General Procedure
Method (A): A mixture of 2-(N-acetoarylsulphonylhydrazid)-2-thia-
zolin-4-ones 4 (0.01 mol) and 2-b-cyanoethylenefuran derivatives 5a,b or
2-b-cyanoethylenethiophen derivatives 5c,d (0.02 mol) was refluxed in
ethanol solution containing a catalytic amount of pipridine for 1 h. The
reaction mixture was cooled and the solid product was filtered off and
recrystallized from the appropriate solvent.
Method (B): A mixture of 2,5-difuranylidene- or dithiophenylidene-
thiazolin-4-ones 7 (0.01 mol) and malononitril or ethyl cyanoacetate
(0.01 mol) was refluxed in ethanol solution containing the catalytic
amountof pipridine for 1 h. The reaciton mixutre was cooled and hte
solid product was filtered off and recrystallized from the appropriate
solvent.
8a: yellow, m.p. 228–230ꢁC (from EtOH) yield (73%); IR (KBr disc)
ꢁ
max/cmꢀ1 3320 (NH2), 2210 (CN), 1680 (CO), 1710 (CO); 1H NMR
(DMSO) ꢀ ¼ 5.00 (s, 1H, pyridine H-4), 6.33 (s, br, 2H, NH2),
7.19–7.62 (m, 12H, ylidenic CH, 2 furan H-3,4,5 and C6H5), 10.60
(s, br, 1H, NH) and 12.00 (s, br, 1H, NH); C24H17N5O6S2 (535),
Calcd: C, 53.83; H, 3.24; N, 13.08; S, 11.96. Found: C, 54.0; H, 3.5;
N, 13.3; S, 11.5%. 8b: yellow, m.p. 186–188ꢁC (from EtOH) yield

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540
Elgemeie and Sayed
(81%); IR (KBr disc) ꢁmax/cmꢀ1 3400, 3300 and 3200 (NH2), 2210 (CN),
1720 (CO) and 1680 (CO); 1H NMR (DMSO) ꢀ ¼ 3.32 (s, 3H, CH3), 4.89
(s, 1H, pyridine H-4), 6.55 (s, br, 2H, NH2), 7.19–7.62 (m, 11H, ylidenic
CH, 2 furan H-3,4,5 and C6H4), 10.82 (s, br, 1H, NH) and 12.2 (s, br, 1H,
NH); C25H19N5O6S2 (549), Calcd: C, 54.64; H, 3.46; N, 12.75. Found: C,
54.2; H, 3.4; N, 15.1%. 8c: yellow, m.p. >300ꢁC (from EtOH) yield
(75%); IR (KBr disc) ꢁmax/cmꢀ1 3400, 3320 and 3210 (NH2), 2205
1
(CN), 1730 (CO) and 1680 (CO); H NMR (DMSO) ꢀ ¼ 5.10 (s, 1H,
pyridine H-4), 6.45 (s, br, 2H, NH2), 7.39–7.49 (m, 12H, ylidenic CH, 2
thiophene H-3,4,5 and C6H5), 8.06 (m, 1H, NH), 10.87 (s, 1H, NH);
C24H17N5O4S4 (567), Calcd: C, 50.79; H, 3.00; N, 12.35; S, 22.57.
Found: C, 50.9; H, 2.9; N, 12.5; S, 22.4%. 8d: yellow, m.p. 180ꢁC
(from EtOH) yield (70%); IR (KBr disc) ꢁmax/cmꢀ1 3390, 3300 and
1
3200 (NH2), 2195 (CN), 1730 (CO) and 1650 (CO); H NMR (DMSO)
ꢀ ¼ 2.30 (s, 3H, CH3), 5.00 (s, 1H, pyridine H-4), 6.53 (s, br, 2H, NH2),
7.00–8.11 (m, 11H, ylidenic CH, 2 thiophene H-3,4,5 and C6H4), 8.88 (m,
1H, NH), 9.87 (s, 1H, NH); C25H19N5O4S4 (581), Calcd: C, 51.64; H,
3.27; N, 12.05; S, 22.03. Found: C, 51.5; H, 3.7; N, 12.2; S, 22.0%. 8e:
yellow, m.p. >300ꢁC (from EtOH) yield (85%); IR (KBr disc) ꢁmax/cmꢀ1
3410, 3320–3200 (NH2), 2195 (CN), 1730 (CO) and 1650 (CO); 1H NMR
(DMSO) ꢀ ¼ 1.09 (t, 3H, CH3), 3.48 (q, 2H, CH2), 5.20 (s, 1H, pyridine
H-4), 6.77 (s, br, 2H, NH2), 7.26-8.36 (m, 12H, ylidenic CH, 2 furan H-
3,4,5 and C6H5), 10.79 (s, br, 1H, NH) and 12.45 (s, br, 1H, NH);
C26H22N4O8S2 (582), Calcd: C, 53.61; H, 3.78; N, 9.62; S, 11.00.
Found: C, 53.9; H, 4.1; N, 10.0; S, 11.0%. 8f: yellow, m.p 198–200ꢁC
(from EtOH) yield (88%); IR (KBr disc) ꢁmax/cmꢀ1 3410, 3320 and 3200
(NH2), 2195 (CN), 1730 (CO) and 1650 (CO); 1H NMR (DMSO) ꢀ ¼ 1.09
(t, 3H, CH3), 2.28 (s, 3H, CH3), 3.48 (q, 2H, CH2), 5.18 (s, 1H, pyridine
H-4), 6.80 (s, br, 2H, NH2), 7.11–8.08 (m, 11H, ylidenic CH, 2 furan H-
3,4,5 and C6H4), 10.50 (s, br, 1H, NH) and 11.00 (s, br, 1H, NH);
C27H24N4O8S2 (596), Calcd: C, 54.36; H, 4.03; N, 9.40; S, 10.74.
Found: C, 53.9; H, 4.0; N, 9.5; S, 10.5%. 8g: yellow, m.p. 148ꢁC (from
EtOH) yield (66%); IR (KBr disc) ꢁmax/cmꢀ13370, 3300 and 3200 (NH2),
2210 (CN), 1720 (CO) and 1670 (CO); 1H NMR (DMSO) ꢀ ¼ 0.99 (t, 3H,
CH3), 3.88 (q, 2H, CH2), 4.99 (s, 1H, pyridine H-4), 6.78 (s, br, 2H,
NH2), 7.07–8.00 (m, 12H, ylidenic CH, 2 thiophene H-3,4,5 and C6H5),
10.77 (s, br, 1H, NH) and 11.08 (s, br, 1H, NH); C26H22N4O6S4 (614),
Calcd: C, 50.81; H, 3.58; N, 9.12; S, 20.85. Found: C, 50.9; H, 4.0; N, 9.4;
S, 20.5%. 8h: yellow, m.p 190–192ꢁC (from EtOH) yield (72%); IR (KBr
disc) ꢁmax/cmꢀ1 3380, 3310 and 3260 (NH2), 2195 (CN), 1730 (CO) and
1
1650 (CO); H NMR (DMSO) ꢀ ¼ 1.11 (t, 3H, CH3), 2.30 (s, 3H, CH3),
3.69 (q, 2H, CH2), 5.00 (s, 1H, pyridine H-4), 6.48 (s, br, 2H, NH2),

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Synthesis of Thiazoles and Thiazolopyridines
541
7.00–8.22 (m, 11H, ylidenic CH, 2 thiophene H-3,4,5 and C6H4), 10.98 (s,
br, 1H, NH) and 11.34 (s, br, 1H, NH); C27H24N4O6S4 (628), Calcd: C,
51.59; H, 3.82; N, 8.91; S, 20.38. Found: C, 51.6; H, 3.9; N, 8.5; S, 20.0%.
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1. Elgemeie, G.E.H.; Aal, A.F. Heterocycles 1986, 24, 349.
2. Fathy, N.M.; Elgemeie, G.E.H. Sulfur Letters 1988, 7, 189.
3. Mourad, A.E.; Elgemeie, G.E.H. Gazz. Chim. Italiana 1988, 118, 127.
4. Fathy, N.M.; Motti, F.M.; Elgemeie, G.E.H. Arch. Pharm.
(Weinheim) 1988, 321, 509.
5. Elgemeie, G.E.H.; Shams, H.Z.; Elkholy, Y.M.; Abbaas, N.
Heterocyclic Commun. 2000, 6, 363.
6. Arcadi, A.; Attansi, O.A.; Guidi, B.; Possi, E.; Santensanio, S. Chem.
Lett. 1999, 59.
7. Litvak, M.M. Khim-Farm, Zh. 1998, 32, 33.
Received in the UK July 23, 2001

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