Novel one-step synthesis of thiazolo[3,2-b]1,2,4-triazoles.

Article abstract of DOI:10.1021/ol990370w

[reaction: see text] Reactions of chalcones 3a-f with bis(1H-1,2,4-triazolyl) sulfoxide 4 formed the thiazolo[3,2-b]1,2,4-triazoles 5a-f, which resemble closely some previously prepared COX-2 inhibitors. The structure of 5a was confirmed by X-ray analysis

Full text of DOI:10.1021/ol990370w

ORGANIC
LETTERS
2000
Vol. 2, No. 4
429-431
Novel One-Step Synthesis of
Thiazolo[3,2-b]1,2,4-triazoles
Alan R. Katritzky,* Alfredo Pastor, and Michael Voronkov
Department of Chemistry, Center for Heterocyclic Compounds, UniVersity of Florida,
GainesVille, Florida 32611-7200
Peter J. Steel*
Department of Chemistry, UniVersity of Canterbury, Christchurch, New Zealand
katritzky@chem.ufl.edu
Received November 22, 1999
ABSTRACT
Reactions of chalcones 3a−f with bis(1H-1,2,4-triazolyl) sulfoxide 4 formed the thiazolo[3,2-b]1,2,4-triazoles 5a−f, which resemble closely some
previously prepared COX-2 inhibitors. The structure of 5a was confirmed by X-ray analysis.
A recent survey1 claims that side effects of nonsteroidal
antiinflammatory drugs, such as aspirin, cause as many
deaths each year as AIDS. The development of COX-2
inhibitor drugs, known to lack these harmful side effects
while providing pain relief, has broadened the range of
therapeutic options. Thiazolotriazoles possess a broad spec-
trum of biological activities: for example 1 and 2 (R3 )
Ar) are potent and selective COX-2 inhibitors;2 2 (R3 ) H)
also exhibits pronounced antiinflammatory and analgesic
activity3 (Figure 1).
(1) Wolfe, M. M.; Lichtenstein, D. R.; Singh, G. The New England
Journal of Medicine 1999, 340, 1888.
(2) Roy, P.; Leblanc, Y.; Ball, R. G.; Brideau, C.; Chan, C. C.; Chauret,
N.; Cromlish, W.; Ethier, D.; Gauthier, J. Y.; Gordon, R.; Greig, G.; Guay,
J.; Kargman, S.; Lau, C. K.; O’Neill, G.; Silva, J.; The´rien, M.; van Staden,
C.; Wong, E.; Xu, L.; Prasit, P. Bioorg. Med. Chem. Lett. 1997, 7, 57.
(3) Pignatello, R.; Mazzone, S.; Panico, A. M.; Mazzone, G.; Pennisi,
G.; Castana, R.; Matera, M.; Blandino, G. Eur. J. Med. Chem. 1991, 26,
929.
(4) (a) Dianov, V. M.; Chikaeva, I. G.; Timirkhanova, G. A.; Strokin,
Y. V.; Zarudiy, F. S.; Lifanov, V. A. Khim.-Farm. Zh. 1994, 28, 555. (b)
Houssin, R.; Helbecque, N.; Bernier, J.-L.; Henichart, J.-P. J. Biomol. Struct.
Dyn. 1986, 4, 219. (c) O¨ hler, E.; Kang, H.-S.; Zbiral, E. Chem. Ber. 1988,
121, 977. (d) Tamura, Y.; Hayashi, H.; Saeki, E.; Kim, J.-H.; Ikeda, M. J.
Heterocycl. Chem. 1974, 11, 459.
Figure 1.
Available methods for the preparation of the heterocyclic
core of 22,4 involve multistep procedures, and some are
specific to a given substituent pattern. The most straightfor-
ward approach to 2, from the corresponding triazole-2-thiones
and aryl R-bromobenzyl derivatives, provides only the
aromatic substituents R2 and R3.2 Other methods cyclize
triazole-2-thiones with epoxyphosphonates4b or utilize
2-formamidothiazoles4d or other procedures.4a,c
(5) Katritzky, A. R.; Pastor, A.; Voronkov, M. V. J. Heterocycl. Chem.,
submitted for publication.
(6) Shephard, M. C.; Sugavanam, B.; Worthington, P. A.; Collins, D.
J.; Griffin, D. U.S. Patent 4,113,465, 1978; Chem. Abstr. 1979, 90, 82144v.
We now report a one-step preparation of thiazolo[3,2-
10.1021/ol990370w CCC: $19.00 © 2000 American Chemical Society
Published on Web 02/02/2000

b]1,2,4-triazoles of the general formula 2, where R1 ) H
(Scheme 1). In the context of ongoing research on the 1,1-
Scheme 1
bis(1,2,4-triazolyl) derivative 4,5 we investigated the behavior
of 4 toward chalcones 3. When 3a-f were heated in the
presence of 1.3 equiv of 4, compounds 5a-f were isolated
by column chromatography in 11-30% yields. The highest
yields of 5a-f were achieved when toluene was employed,
while THF afforded no desired product.
Along with compounds 5a-f, the corresponding Michael
adducts 6a-f6 were isolated in 8-51% yield and, in one
case, a small amount of the corresponding 1,1-bis(1,2,4-
triazolyl) derivative 7b.5 When it was heated in xylene or
reacted neat, a mixture of 3a and 4 gave a detectable amount
of the side product 8 (Scheme 1). The experimental results
are summarized in Table 1.7
Figure 2. Perspective view of the crystal structure of 5a.
of the structure of 5a.8 The thiazolo[3,2-b]1,2,4-triazole ring
system is planar (maximum deviation 0.027 Å) and has a
geometry similar to that reported in two previous crystal
structures of compounds with this ring system,2,3 except for
a slight lengthening of the bond containing the two aryl
substituents (1.375 Å). This is presumably a result of the
polarization of this bond due to the very different electron
demands of the two substituents. The planes of the two aryl
rings are inclined to the plane of the thiazolotriazole system
at angles of 47.6 and 43.7°.
Table 1. Synthesis of Thiazolo[3,2-b]-1,2,4-triazoles 5a-f
entry
R1
R2
mp (°C)
yield (%)
5a
5b
5c
5d
5e
5f
6a
6b
6c
6d
6e
6f
p-MeC6H4
p-NO2C6H4
p-MeC6H4
C6H5
p-MeC6H4
p-ClC6H4
p-MeC6H4
p-NO2C6H4
p-MeC6H4
C6H5
p-MeOC6H4
C6H5
p-ClC6H4
C6H5
C4H3S
C6H5
p-MeOC6H4
C6H5
p-ClC6H4
C6H5
C4H3S
C6H5
140-141
151-152
162-163
148-149
oil
154-155
134-135
110-111
82-83
22
13
20
30
18
12
31
25
19
12
32
51
oil
103-105
89-90
p-MeC6H4
p-ClC6H4CO
While the mechanism of the conversion 3 f 5 is not clear,
7 is a possible intermediate. In fact, while 7b afforded
product 5b under the reaction conditions, similar treatment
of 6b gave no 5b (Scheme 1).
The structures of 5a and 8 were determined by single-
crystal X-ray diffraction. Figure 2 shows a perspective view
Figure 3. Perspective view of the crystal structure of 8.
Org. Lett., Vol. 2, No. 4, 2000
430

The structure of 89 is shown in Figure 3. This is only the
second crystal structure determination of this heterocyclic
ring system.10 Once again, the fused bicyclic ring system is
planar (maximum deviation 0.054 Å). The 4-methylphenyl
ring is approximately coplanar with the attached ring (2.1°),
while the 4-methoxyphenyl ring is nearly orthogonal to it
(71.2°).
(7) General Procedure for the Preparation of Thiazolo[3,2-b]-1,2,4-
triazoles 5a-f. 1-(Trimethylsilyl)-1H-1,2,4-triazole5 (11 mmol) was weighed
in a round-bottomed flask under argon, and thionyl chloride (6 mmol) was
then added neat via syringe dropwise at room temperature. A yellow solid
precipitated after the addition of the first drops. The mixture was stirred at
room temperature under argon for 15 min, and the resulting solid was dried
under vacuum. Dry toluene (10 mL) was then added, followed by addition
of the corresponding chalcone (5 mmol); the resulting mixture was heated
at 90 °C overnight. The reaction mixture was then cooled to room
temperature and concentrated in vacuo to afford a crude oil. Purification
was achieved by column chromatography on silica gel (with 1:1 hexanes/
ethyl acetate as eluent).
Acknowledgment. A.P. is grateful to the Ministerio de
Educacio´n y Cultura of Spain for the award of a fellowship
and its financial support.
Supporting Information Available: Full characterization
details, proton and carbon spectra, and elemental analysis
or HRMS data for compounds 5a-f, 6a-f, and 8. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(8) Crystal data for 5a: C19H15N3O2S, mol wt 349.4, monoclinic, C2/c,
a ) 23.266(6) Å, b ) 7.385(2) Å, c ) 20.466(5) Å, â ) 109.320(3)°, V )
3318.3(1) Å3, Z ) 8, T ) -105 °C, µ(Mo KR) ) 0.21 mm-1, Dcalcd
)
1.399 g cm-3, 2θmax ) 53° (CCD area detector), Rw(F2) ) 0.096 (all 3385
data), R ) 0.036 (2852 data with I > 2σ(I)).
(9) Crystal data for 8: C19H17N3OS, mol wt 335.4, triclinic, P1h, a )
6.333(3) Å, b ) 6.356(3) Å, c ) 21.935(9) Å, R ) 92.391(5)°, â ) 97.937-
(5)°, γ ) 105.777(6)°, V ) 838.6(1) Å3, Z ) 2, T ) -110 °C, µ(Mo KR)
) 0.20 mm-1, Dcalcd ) 1.328 g cm-3, 2θmax ) 45° (CCD area detector),
Rw(F2) ) 0.189 (all 2093 data), R ) 0.067 (1536 data with I > 2σ(I)).
OL990370W
(10) Clayton, J. P.; O’Hanlon, P. J.; King, T. J. J. Chem. Soc., Perkin
Trans. 1 1980, 1352.
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