Synthesis, characterization, and antiproliferative activity of 2-(2-Bromo-5-methoxyphenyl)-6-aryl-1,3-thiazolo[3,2b][1,2,4]triazoles

Article abstract of DOI:10.1080/10426500902775646

Eight new 2-(2-bromo-5-methoxyphenyl)-6-aryl-1,3-thiazolo[3,2-b][1,2,4] triazoles were synthesized by treating 5-(2-bromo-5-methoxyphenyl)-4H-1,2,4- triazole-3-thiol with phenacyl bromides. The new products were characterized by spectroscopic and analytic

Full text of DOI:10.1080/10426500902775646

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Phosphorus, Sulfur, and Silicon and the
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Synthesis, Characterization, and
Antiproliferative Activity of 2-(2-
Bromo-5-methoxyphenyl)-6-aryl-1,3-
thiazolo[3,2b][1,2,4]triazoles
B. Narayana a , K. K. Vijaya Raj a & B. K. Sarojini b
a Department of Post-Graduate Studies and Research in Chemistry ,
Mangalore University , Mangalagangotri, India
b Department of Chemistry , P. A. College of Engineering ,
Nadupadavu, Mangalore, India
Published online: 03 Feb 2010.
To cite this article: B. Narayana , K. K. Vijaya Raj & B. K. Sarojini (2010) Synthesis, Characterization,
and Antiproliferative Activity of 2-(2-Bromo-5-methoxyphenyl)-6-aryl-1,3-thiazolo[3,2b]
[1,2,4]triazoles, Phosphorus, Sulfur, and Silicon and the Related Elements, 185:2, 306-312
To link to this article: http://dx.doi.org/10.1080/10426500902775646
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Phosphorus, Sulfur, and Silicon, 185:306–312, 2010
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500902775646
SYNTHESIS, CHARACTERIZATION,
AND ANTIPROLIFERATIVE ACTIVITY OF 2-(2-BROMO-5-
METHOXYPHENYL)-6-ARYL-1,3-THIAZOLO[3,2b]
[1,2,4]TRIAZOLES
B. Narayana,1 K. K. Vijaya Raj,1 and B. K. Sarojini2
1Department of Post-Graduate Studies and Research in Chemistry, Mangalore
University, Mangalagangotri, India
2Department of Chemistry, P. A. College of Engineering, Nadupadavu, Mangalore,
India
Eight new 2-(2-bromo-5-methoxyphenyl)-6-aryl-1,3-thiazolo[3,2-b][1,2,4]triazoles were
synthesized by treating 5-(2-bromo-5-methoxyphenyl)-4H-1,2,4-triazole-3-thiol with
phenacyl bromides. The new products were characterized by spectroscopic and analytical
methods. Five of the new compounds were evaluated for their antiproliferative activity.
2-(2-Bromo-5-methoxyphenyl)-6-(3,4-dihydroxyphenyl)-1,3-thiazolo[3,2-b] [1,2,4]triazole
exhibited promising activity.
Supplemental materials are available for this article. Go to the publisher’s online edition of
Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental
file.
Keywords Antiproliferative activities; N-bridged heterocycles; characterization; synthesis;
thiazolotriazoles
INTRODUCTION
The synthesis of heterocyclic systems containing bridgehead nitrogen atom gained
considerable attention due to their wide range of biological activities. Many of the
thiazolo[3,2-b]-1,2,4-triazoles have been reported as anthelmintics,1 bactericides,2 medic-
inal fungicides,3 cardiotonics, and bronchodilators.4 In continuation of our research
work on thiazolotriazoles5 and compounds containing a 2-bromo-5-methoxyphenyl moi-
ety,6 we aimed to synthesize new 2-(2-bromo-5-methoxyphenyl)-6-aryl-1,3-thiazolo[3,2-
b][1,2,4]triazoles and investigate their antiproliferative activity.
Received 20 August 2008; accepted 26 January 2009.
The present affiliation for K. K. Vijaya Raj is GE India Technology Center Pvt Ltd, Bangalore, India.
The authors are thankful to The Head, SAIF, CDRI, Lucknow, and The Director, SAIF, Punjab University for
spectral analysis. Authors are also thankful to Dr. V. L. Narayanan, National Institute of Health (NIH), Bethesda,
MD, USA, for arranging the antiproliferative activity screening studies reported in this article.
Address correspondence to B. Narayana, Department of Post-Graduate Studies and Research in Chemistry,
Mangalore University, Mangalagangotri, 574 199, India. E-mail: nbadiadka@yahoo.co.uk
306

2,6-DIARYL-1,3-THIAZOLO[3,2-b][1,2,4]TRIAZOLES
307
The reaction of α-haloketones (2) with 2-substituted 5-mercapto-1,2,4-triazoles (1)
is expected to result in the formation of either 2,5-disubstituted thiazolo[3,2-b]-1,2,4-
triazoles (3) or 3,5-disubstituted thiazolo[2,3-c]-1,2,4-triazoles (4), or both,7–10 as given in
Scheme 1. Jag Mohan11 reported that the reaction of 3-(4-tolyl)-5-mercapto-1,2,4-triazole
with 4-substituted phenacyl bromides in dry methanol gives thiazolo[3,2-b][1,2,4]triazoles
in one step and not the isomeric thiazolo[2,3-c]-1,2,4-triazoles. This was also supported
by the synthesis of thiazolo[3,2-b]-1,2,4-triazoles reported by Narayana et al.12 Reaction
of mercaptotriazole (5) (R H) with bromoketones (6) in ethanol followed by cyclization
in polyphosphoric acid yielded the thiazolo[3,2-b]-1,2,4-triazoles (7) and not the isomeric
thiazolo[2,3-c]-1,2,4-triazoles (8), which was established by comparison with an authentic
sample of 8 (R1 = 4-MeC6H4) obtained by cyclization of 2-(4-bromobenzoyl)hydrazino-4-
(4-tolyl)thiazole-hydrobromide (9) (Scheme 2).11 The melting point, IR spectrum, and thin-
layer chromatographic behavior were used to identify this product. The reaction of 5 (R H)
with 6 in methanol led, however, directly to the cyclized products 7 (Scheme 3). In view of
these observations, we decided to synthesize further new 2-(2-bromo-5-methoxyphenyl)-
6-aryl-1,3-thiazolo[3,2-b][1,2,4]triazoles by treating 5-(2-bromo-5-methoxyphenyl)-4H-
1,2,4-triazole-3-thiol with phenacyl bromides in methanol. With the help of a single crys-
tal X-ray study,13 we have established that the cyclization resulted in the formation of
2-(2-bromo-5-methoxyphenyl)-6-aryl-1,3-thiazolo[3,2-b][1,2,4]triazoles only, and not the
isomeric thiazolo[2,3-c][1,2,4]triazoles.
O
N
Br
N
Ar
+
N
H
SH
Ar
(1)
(2)
Ar
N
N
N
N
N
Ar
Ar
N
S
S
Ar
(3)
(4)
Scheme 1
RESULTS AND DISCUSSION
Chemistry
The compound 5-(2-bromo-5-methoxyphenyl)-4H-1,2,4-triazole-3-thiol (10) was
synthesized by the reaction of 2-bromo-5-methoxybenzhydrazide with potassium thio-
cyanate and concentrated aqueous hydrogen chloride, followed by cyclization of the
resulting 1-(2-bromo-5-methoxybenzoyl)thiosemicarbazide with sodium hydroxide.5 The

308
B. NARAYANA ET AL.
O
Br
O
NH
NH
S
.HBr
N
O
NH NH
H2N
+
S
H3C
H3C
(9)
R
R
POCl3
R
S
R= CH3
N
CH3
N
N
(8)
Scheme 2
structure of the starting compound (10) was confirmed by recording 1H NMR in DMSO-d6
and mass spectra. A singlet at δ = 3.82 was due to three protons of the OCH3 group. A
doublet of doublet observed at δ = 7.07 (J = 3.1, 8.8 Hz), a doublet at δ = 7.23 (J = 2.9
Hz), and another doublet at δ = 7.68 (J = 8.8 Hz) accounts for the three aromatic protons.
The SH and NH protons appeared as two downfield singlets at δ = 13.66 and δ = 13.75,
respectively. The mass spectrum displayed the molecular ion peaks at m/z = 286 (80%
79Br-10) and 288 (90% 81Br-10). Further fragment peaks appeared at m/z = 254 (10%,
M+—SH), m/z = 176 (45%, phenyl mercaptotriazole radical cation), and m/z = 136 (70%,
MeOC6H4CNH+).
The 1,2,4-triazole (10) was then refluxed in ethanol with the phenacyl bromides
(11a–h) to get 2-(2-bromo-5-methoxyphenyl)-6-aryl-1,3-thiazolo[3,2-b][1,2,4]triazoles
(12a–h) (Scheme 4).
O
N
Br
N
+
R
N
H
SH
R1
(6)
(5)
PPA
x
N
N
R1
N
R
N
N
S
R
N
S
R1
(7)
(8)
Scheme 3

2,6-DIARYL-1,3-THIAZOLO[3,2-b][1,2,4]TRIAZOLES
309
CH3
O
H
N
SH
Ar
Br
+
N
O
N
( 10)
( 11a-h)
Br
Ethanol, Reflux
CH3
O
N
N
S
N
Br
Ar
( 12a-h)
Scheme 4
The isomeric thiazolo[2,3-c][1,2,4]triazoles were not formedinthis reaction. This was
confirmed by the synthesis of 3-(2-bromo-5-methoxyphenyl)-5-phenyl-1,3-thiazolo[2,3-
c]-1,2,4-triazole (13) by the cyclization of 2-bromo-5-methoxy-Nꢁ-[4-phenyl-1,3-thiazol-
2-yl]benzohydrazide (9) (Scheme 5).
H3C
O
CH3
O
O
Br
NH
N
NH
POCl3 / CH3CN
N
N
S
N
S
Br
9
( )
(13)
Scheme 5
The melting point, IR spectrum, and thin-layer chromatographic behavior were
used to differentiate this product from 2-(2-bromo-5-methoxyphenyl)-6-phenyl-1,3-
thiazolo[3,2-b]-1,2,4-triazole (12a). A single crystal X-ray study13 of (12a), formed
according to Scheme 4, unequivocally revealed its structure. In a few cases, acyclic
products were isolated and identified by IR and mass spectra. These acyclic compounds
were then cyclized by refluxing in methanol.
The new 2-(2-bromo-5-methoxyphenyl)-6-aryl-1,3-thiazolo[3,2-b]1,2,4-triazoles
(12a–h) were also well characterized by analytical and spectroscopic analyses to prove
their assigned structure. Characterization data are given in Table I.

310

2,6-DIARYL-1,3-THIAZOLO[3,2-b][1,2,4]TRIAZOLES
311
Antiproliferative Activity
Five of the new compounds (12b–d, 12g, and 12h) were screened for their antipro-
liferative activity at The National Institutes of Health (NIH), Bethesda, Maryland, USA,
under the Drug Discovery Programme of NCI as per the procedure suggested by Boyd and
Paull14 in a primary, three-cell, line-one dose antitumor assay against NCI-H (lung), MCF-7
(breast), and SF 268 (CNS). Further experimental details and Table II-S are available in the
Supplemental Materials online.
CONCLUSION
Nine new 2-(2-bromo-5-methoxyphenyl)-6-aryl-1,3-thiazolo[3,2-b][1,2,4]triazoles
were synthesized and evaluated for their antiproliferative activity. The compound
2-(2-bromo-5-methoxyphenyl)-6-(3,4-dihydroxyphenyl)-1,3-thiazolo[3,2-b][1,2,4]triazole
(12c) emerged as the most active one and can be recommended for further studies. As
the selection of the compound was done by NCI, the prediction of structure–activity
relationship is difficult to determine at this point of time.
EXPERIMENTAL
Melting points were taken in open capillary tubes and are uncorrected. The purity
of the compounds was confirmed by thin layer chromatography using Merck silica gel 60
F254 coated aluminum plates. IR spectra were recorded on a Shimadzu-FTIR spectrometer
1
in KBr (ν in cm−1). H NMR spectra were recorded in CDCl3 and in DMSO-d6 on a
Varian (300 MHz) spectrometer using TMS as internal standard, and 13C NMR spectra
were recorded in CDCl3 and in DMSO-d6 on a Varian (75 MHz) spectrometer. FABMS
spectra were recorded on a JEOL SX 102/DA-6000 mass spectrometer (6 kV, 10mA) using
argon/xenon as the FAB gas.
5-(2-Bromo-5-methoxyphenyl)-4H-1,2,4-triazole-3-thiol (10)
1-(2-Bromo-5-methoxybenzoyl)thiosemicarbazide (50 g, 0.164 mol) was refluxed
with 500 mL of 5% sodium hydroxide solution for 4 h and was cooled and filtered. The
clear solution was acidified with conc. HCl to pH 5–6. The solid obtained was filtered and
recrystallized (MeOH) to give white crystals; yield, 42 g (89%), mp >250◦C
2-(2-Bromo-5-methoxyphenyl)-6-aryl-1,3-thiazolo[3,2-b][1,2,4]triazoles
(12a–h)
5-(2-Bromo-5-methoxyphenyl)-4H-1,2,4-triazole-3-thiol (10) (0.01 mol) and the ap-
propriate phenacyl bromide (11) (0.01 mol) were refluxed in ethanol for 4 h. The progress
of the reaction was monitored by TLC. After the completion of the reaction, the reaction
mixture was cooled and the precipitated solid was filtered off. The solid was recrystallized
from MeOH/DMF. The compounds were obtained in 40–88% yield (see Table I).

312
B. NARAYANA ET AL.
Spectroscopic Data
2-(2-Bromo-5-methoxyphenyl)-6-phenyl-1,3-thiazolo[3,2-b][1,2,4]triazole
(12a)13. IR: 3118, 3070 (CH), 1560 (C N), 734 (C Br); 1H NMR (DMSO-d6): δ 3.8 (s,
3H, OCH3), 7.03 (dd, J = 3.3, 8.7 Hz, 1H, ArH), 7.44 (s, 1H, ArH), 7.55 (m, 3H, ArH),
7.67 (d, J = 8.7 Hz, 1H, ArH), 8.01 (s, 1H, ArH), 8.27 (d, J = 7.8 Hz, 1H, NH); 13C NMR
(DMSO-d6): δ 55.62, 111.14, 111.47, 116.96, 117.31, 126.27, 127.57, 129.00, 129.69,
131.52, 132.57, 134.66, 158.43; DEPT: 55.64, 111.16, 116.98, 117.34, 126.29, 129.04,
129.73, 134.68. FABMS: m/z 388 (95%, M+ + 1), 387 (20%, M+ + 1), 386 (100%, M+
+ 1), 307 (12%, M+—Br), 136 (40%, MeOC6H4CNH+).
2-(2-Bromo-5-methoxyphenyl)-6-(3,4-dihydroxyphenyl)-1,3-thiazolo[3,2-
1
b][1,2,4]triazole (12c). IR: 3400 (OH), 3109 (CH), 1562 (C N), 734 (C Br); H
NMR (CDCl3): δ 3.85 (s, 3H, OCH3), 6.87 (dd, J = 2.9, 8.7 Hz, 1H, ArH), 7.02 (s, 2H,
ArH), 7.26 (s, 5H, 2-OH + H2O), 7.45 (d, J = 3.0 Hz, 1H, ArH), 7.61 (d, J = 8.7 Hz,
2H, ArH), 7.82 (s, 1H, ArH). FABMS: m/z 420 (75%, M+ + 1), 419 (45%, M+ + 1), 418
(73%, M+ + 1), 136 (98%, MeOC6H4CNH+).
2-(2-Bromo-5-methoxyphenyl)-6-(3-carbamoyl-4-hydroxyphenyl)-1,3-
thiazolo-[3,2-b][1,2,4]triazole (12d). IR: 3411 (OH), 3336 (NH2), 1595 (C N), 821
(C Br); FABMS: m/z 447 (80%, M+ + 1) 446 (60%, M+), 445 (70%, M+ + 1), 136
(90%, MeOC6H4CNH+).
2-(2-Bromo-5-methoxyphenyl)-6-(4-methoxyphenyl)-1,3-thiazolo[3,2-b]
[1,2,4]-triazole (12h). IR: 3114, 2898 (CH), 1560 (C N), 1022, 812 (C Br); 1H NMR
(CDCl3): δ 3.83 (s, 3H, OCH3), 3.85 (s, 3H, OCH3), 6.86 (dd, J = 3.4, 8.8 Hz, 1H, ArH),
6.99 (s, 1H, ArH), 7.00 (dd, J = 1.8, 6.9 Hz, 2H, ArH), 7.49 (d, J = 3.0 Hz, 1H, ArH),
7.60 (d, J = 8.8 Hz, 1H, ArH), 8.11 (dd, J = 2.04, 8.7 Hz, 2H, ArH); FABMS: m/z 418
(100%, M+ + 1), 417 (60%, M+ + 1), 416 (98%, M+ + 1), 136 (60%, MeOC6H4CNH+).
3-(2-Bromo-5-methoxyphenyl)-5-phenyl-1,3-thiazolo[2,3-c][1,2,4]triazole
1
(13). IR: 3114, 2898 (CH), 1560 (C N), 1022, 812 (C Br); H NMR (CDCl3): δ 3.85
(s, 3H, OCH3), 6.99 (dd, J = 3.6, 9.0 Hz, 1H, ArH), 7.37–7.48 (m, 4H, ArH), 7.63 (d, J =
8.7 Hz, 1H, ArH), 7.79 (s, 1H, ArH), 8.0 (d J = 7.2 Hz, 2H, ArH).
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