A convenient synthesis of 4-substituted-4′-(2-thienyl)-2,2′-bithiazoles as potential phototoxic agents

Article abstract of DOI:10.1081/SCC-100108224

Alpha-tosyloxyacetylthiophene (3), obtained by the hypervalent iodine oxidation of 2-acetylthiophene (2) using [hydroxy(tosyloxy)iodo]benzene (HTIB), on treatment with rubeanic acid exclusively generates 4-(2-thienyl)thiazole-2-thiocarboxamide (4) which upon subsequent treatment with a variety of alpha-tosyloxyketones (5) affords the title compounds (6) in excellent yields.

Full text of DOI:10.1081/SCC-100108224

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A CONVENIENT SYNTHESIS OF 4-SUBSTITUTED-4′-
(2-THIENYL)- 2,2′-BITHIAZOLES AS POTENTIAL
PHOTOTOXIC AGENTS
Shiv P. Singh a , Rajesh Naithani a , Ranjana Aggarwal a & Om Prakash a
a Chemistry Department , Kurukshetra University , Kurukshetra, 136 119, India
Published online: 09 Nov 2006.
To cite this article: Shiv P. Singh , Rajesh Naithani , Ranjana Aggarwal & Om Prakash (2001) A CONVENIENT SYNTHESIS
OF 4-SUBSTITUTED-4′-(2-THIENYL)- 2,2′-BITHIAZOLES AS POTENTIAL PHOTOTOXIC AGENTS, Synthetic Communications:
An International Journal for Rapid Communication of Synthetic Organic Chemistry, 31:24, 3747-3751, DOI: 10.1081/
SCC-100108224
To link to this article: http://dx.doi.org/10.1081/SCC-100108224
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SYNTHETIC COMMUNICATIONS, 31(24), 3747–3751 (2001)
A CONVENIENT SYNTHESIS OF
4-SUBSTITUTED-40-(2-THIENYL)-
2,20-BITHIAZOLES AS POTENTIAL
PHOTOTOXIC AGENTS
Shiv P. Singh,* Rajesh Naithani, Ranjana Aggarwal,
and Om Prakash
Chemistry Department, Kurukshetra University,
Kurukshetra – 136 119, India
ABSTRACT
Alpha-tosyloxyacetylthiophene (3), obtained by the hyper-
valent iodine oxidation of 2-acetylthiophene (2) using [hydroxy-
(tosyloxy)iodo]benzene (HTIB), on treatment with rubeanic
acid exclusively generates 4-(2-thienyl)thiazole-2-thiocarbox-
amide (4) which upon subsequent treatment with a variety
of alpha-tosyloxyketones (5) affords the title compounds (6)
in excellent yields.
Alpha-terthienyl (1) derived from the roots of marigold plant (Tagetes
erecta) displays an impressive level of phototoxicity against various
organisms.1–3 In fact, the use of 1 as an insecticide and herbicide has been
patented because of its rapid photo-degradation, natural origin and high
level of activity.4 However, the phototoxicity of 1 towards non-targeted
*Corresponding author.
3747
Copyright & 2001 by Marcel Dekker, Inc.
www.dekker.com

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3748
SINGH ET AL.
aquatic organisms, coupled with the lack of specificity in its mode of action
suggests that the prospects of its safe and useful applications will remain
poor until suitable structural modifications are achieved. This very fact
underlines the significance of searching other molecules which may display
specific toxicity, particularly against the harmful ones without disturbing the
environmental balance.
As a part of our ongoing programme directed towards developing
newer phototoxic agents, we have reported the synthesis of a large
number of bithiazoles (6) with thiophene and aryl moieties. Many of them
have indeed shown significant phototoxic properties5–7 against the fourth
instar larvae of Culex tritaeneorhynchus. These compounds bear close
structural resemblance with 1. However, the procedure developed for
the synthesis of 6 suffered from a major drawback as the key intermediate
(4) could not be isolated in the pure form. There was invariably formation of
a mixture consisting of 4, rubeanic acid and the corresponding symmetrical
bithiazoles, thus limiting the usefulness of the procedure for the synthesis of
unsymmetrical bithiazoles such as 6b–f (Scheme-path a).
In continuation of our efforts to explore the utility of I (III) reagents
for the synthesis of a wide variety of compounds associated with various
biological activities,9–11 we now report a superior method for the synthesis
of 6 involving the intermediacy of alpha-tosyloxyacetylthiophene (3). The
procedure is facile and avoids the use of highly toxic, unstable, and lachry-
matory alpha-bromoacetylthiophene.
The key steps involved for the synthesis of bithiazoles (6) consist of
(i) Treating 2-acetylthiophene (2) with equimolar HTIB to obtain
alpha-tosyloxyacetylthiophene (3).
(ii) Reaction of 3 with rubeanic acid to form 4-(2-thienyl) thiazole-
2-thiocarboxamide (4).
(iii) Reaction between 4 and an appropriate alpha-tosyloxyketone
(5) affording 4-substituted-40-(2-thienyl)-2,20-bithiazoles (6a–f )
(Scheme-path b).
Finally, the present work is significant because of the following two
reasons.
1. Synthesis of several title compounds (6) which have photo-
toxic property can be achieved through an environmentally benign
procedure from 2 without using the toxic and lachrymatory alpha-halogen-
oketones.
2. Secondly, the method results in the exclusive formation of 4
instead of a mixture of 4 and symmetrical bithiazoles (6a) as reported
earlier.6

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4-SUBSTITUTED-40-(2-THIENYL)-2,20-BITHIAZOLES
3749
Scheme.
EXPERIMENTAL
Melting points were taken in open capillaries, and are uncorrected.
Synthesis of Substituted 4,40-bis-(2-Thienyl)-
2,20-bithiazoles
Alpha-Tosyloxyacetylthiophene (3)
To a stirred solution of 2-acetylthiophene (2) (1.26 g, 0.01 mol) in
acetonitrile was added HTIB (3.9 g, 0.01 mol) and the reaction mixture was

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SINGH ET AL.
Table.
Compound
No.
Molecular
Formula
M.P.
(ꢀC)
M.P. (ꢀC)
(Literature)
Yield
(%)*
6a
6b
6c
6d
6e
6f
C14H8N2S4
210
193
168
158
178
218
2126
1956
1706
1606
1796
2206
66 (50)
71 (45)
74 (45)
68 (55)
70 (44)
69 (44)
C16H10N2S3
C17H12N2OS3
C17H12N2S3
C16H9ClN2S3
C16H9N3O2S3
*Yields in bracket represent those obtained by the alpha-halogenoketone method.
refluxed for 4 h. Excess of solvent was distilled off and the residual mass was
crystallized from ethanol. The product (3) was further washed with
cold ethanol and dried, yield 70% (1.97 g) m.p. 95ꢀC (lit. 96ꢀC).12
All other alpha-tosyloxyphenylketones (5a–e) were prepared using this
standard procedure.5
4-(2-Thienyl)thiazole-2-thiocarboxamide (4)
Rubeanic acid (3.0 g, 0.025 mol) was dissolved in 50 mL ethanol and
an equimolar amount of alpha-tosyloxyacetylthiophene (6.8 g, 0.025 mol)
(3) was added, dropwise while maintaining the temperature at 50–60ꢀC
via a water bath. The mixture was stirred for 4 h. Excess of solvent was
distilled off to obtain a residue which was crystallized from ethanol to
afford 4-(2-thienyl)thiazole-2-thiocarboxamide (4). Yield 76% (4.10 g);
m.p. 139ꢀC, lit.6 m.p. 140ꢀC.
4,40-bis-(2-Thienyl)-2,20-bithiazole (6a)
4 (2.2 g, 0.01 mol) was dissolved in 50 mL ethanol and an equimolar
amount of 3 was added. The reaction mixture was refluxed for 4 h. Excess of
solvent was distilled off to afford a solid which on crystallization from
ethanol afforded the title compound. All other bithiazoles (6b–f ) were pre-
pared by treating 4 with alpha-tosyloxyphenylketones (5a–e) in similar
manner.
Melting points, literature melting points and yields of the bithiazoles
thus prepared are tabulated in the table.

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4-SUBSTITUTED-40-(2-THIENYL)-2,20-BITHIAZOLES
ACKNOWLEDGMENTS
3751
We are grateful to the University Grants Commission, New Delhi for
financial assistance.
REFERENCES
1. Gommers, F.G. Nematologica 1972, 18, 458.
2. Baker, J.; Gommers, F.G.; Nieuwenhius, I.; Wynberg, H. J. Biol.
Chem. 1979, 254, 1841.
3. Kagan, J.; Kagan, P.A.; Buhse, H.E. Jr. J. Chem. Ecol. 1984, 10, 1115.
4. Towers, G.H.N.; Arnason, J.T.; Wat, C.K.; Lambert, J.D. Canadian
Patent, 1173743; Chem. Abstr. 1985, 102, 41602r.
5. Prakash, O.; Ranjana. Singh, S.P. Indian J. Het. Chem. 1992, 1, 111.
6. Singh, S.P.; Ranjana. Indian J. Chem. 1992, 31B, 782.
7. Singh, S.P.; Ranjana. Indian J. Chem. 1993, 32B, 1130.
8. Prakash, O.; Moriarty, R.M. Adv. Het. Chem. 1998, 1, 69.
9. Prakash, O.; Singh, S.P. Aldrichimica Acta 1994, 27, 15.
10. Moriarty, R.M.; Prakash, O. Organic Reactions 1999, 000.
11. Prakash, O.; Goyal, S. Indian J. Het. Chem. 1991, 1, 103.
12. Moriarty, R.M.; Penmasta, R.; Awasthi, A.K.; Eqa, W.R.; Prakash, I.
J. Org. Chem. 1989, 54, 1101.
Received in the USA February 9, 2001

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