Novel three component synthesis of 1,2,4-triazolo[3,4-b]thiazoles and their antimicrobial activity

Article abstract of DOI:10.1080/10426500490459641

1,2,4-Triazolo[3,4-b]thiazole derivatives 5a-j have been synthesized by novel multi-component reaction of 2,4-dichloro-5-fluorophenacyl bromide (1), thiosemicarbazide (2), and aromatic carboxylic acids (4) using phosphorous oxychloride as the cyclizing ag

Full text of DOI:10.1080/10426500490459641

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NOVEL THREE COMPONENT SYNTHESIS OF 1,2,4-
TRIAZOLO[3,4-b]THIAZOLES AND THEIR ANTIMICROBIAL
ACTIVITY
K. Subrahmanya Bhat a & B. Shivarama Holla a
a Mangalore University, Mangalagangotri, India
Version of record first published: 16 Aug 2010.
To cite this article: K. Subrahmanya Bhat & B. Shivarama Holla (2004): NOVEL THREE COMPONENT SYNTHESIS OF 1,2,4-
TRIAZOLO[3,4-b]THIAZOLES AND THEIR ANTIMICROBIAL ACTIVITY, Phosphorus, Sulfur, and Silicon and the Related Elements,
179:6, 1019-1026
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Phosphorus, Sulfur, and Silicon, 179:1019–1026, 2004
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Copyright Taylor & Francis Inc.
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500490459641
NOVEL THREE COMPONENT SYNTHESIS OF
1,2,4-TRIAZOLO[3,4-b]THIAZOLES AND THEIR
ANTIMICROBIAL ACTIVITY
K. Subrahmanya Bhat and B. Shivarama Holla
Mangalore University, Mangalagangotri, India
(Received June 30, 2003; accepted September 30, 2003)
1,2,4-Triazolo[3,4-b]thiazole derivatives 5a–j have been synthesized by
novel multi-component reaction of 2,4-dichloro-5-fluorophenacyl bro-
mide (1), thiosemicarbazide (2), and aromatic carboxylic acids (4) using
phosphorous oxychloride as the cyclizing agent. This reaction protocol
is simple, efficient, and requires shorter reaction times in comparison
to the conventional multi-step synthesis. The products were identified
to be same by an alternate synthesis. All the compounds were screened
for their antimicrobial activity against some of bacterial and fungal
strains.
Keywords: 1,2,4-Triazolo[3,4-b]thiazoles; antimicrobial activity; mul-
ticomponent reaction
1,2,4-Triazole derivatives have been of great interest in the medicinal
and agricultural fields due to their profound antibacterial, herbicidal,
insecticidal, and fungicidal activities.1−5 Similarly, thiazole derivatives
are reported to possess diverse pharmacological activities.6−7 It is there-
fore thought of interest to combine these two potential biologically ac-
tive units to give fused derivatives. Further, it is reported to increase
the biological activity profile of a molecule by substitution of hydrogen
by fluorine or trifluromethyl group.8 In this point of view, 2,4-dichloro-
5-fluoro moiety is interesting due to its influence over the activity of
ciprofloxacin, a broad spectrum antibacterial agent.9 Recently, multi-
component reactions (MCRs) are employed over conventional synthesis
We would like to thank RSIC, Punjab University, Chandigarh for spectral data. KSB
is thankful to CSIR, New Delhi for the award of Junior Research Fellowship. We are also
thankful to K. Roy of Nicolas Piramal India (L), Mumbai for antimicrobial screening of
the compounds reported herein.
Address correspondence to B. Shivarama Holla, Department of Chemistry, Mangalore
University, Mangalagangotri-574199, India. E-mail: hollabs@rediffmail.com
1019

1020
K. S. Bhat and B. S. Holla
for generating molecules for combinatorial libraries.10−12 In MCRs the
sequence of irreversible reactions all proceeds toward the product.13
In this article, we report the novel three component reaction of 2,4-
dichloro-5-fluoro phenacyl bromide (1), thiosemicarbazide (2), and aryl
carboxylic acid (4) to yield triazolothiazoles (5) in good to excellent yields
(Scheme 1). All the compounds were screened for their antimicrobial ac-
tivities against bacterial and fungal strains.
RESULTS AND DISCUSSION
2,4-Dichloro-5-fluoroacetophenone obtained from a commercial source
was brominated in the presence of dry aluminium chloride and di-
ethyl ether to give 2,4-dichloro-5-fluoro phenacyl bromide (1). The com-
pound (1) in acetonitrile was added slowly into thiosemicarbazide (2). To
this aryl carboxylic acids (4) and phosphorous oxychloride were added
in drops (Scheme 1). The formation of triazolothiazoles (5) was con-
firmed on the basis of elemental analysis and spectroscopic studies.
It is believed that the reaction proceeds through the initial forma-
tion of hydrazinothiazoles by nucleophilic attack of thiosemicarbazide
on phenacyl bromide. Hydrazinothiazole then undergoes cyclization
with carboxylic acids to give triazolthiazoles (5). The syntheses of the
same compounds were carried out by an alternate two-step reaction
(Scheme 2). In the 1H NMR spectrum of compound 3, showed a doublet
at δ 7.63 due to ortho H-F coupling with J value of 8Hz. Two sharp
singlets observed at δ 7.3 & 7.2 were assigned to protons of the 2,4-
dichloro-5-fluorophenyl moiety and that of thiazole ring. The hydrazino
protons appeared at δ 2.5 to 3. In the IR spectrum of compound 5b
peaks for NH and NH2 were absent indicating the formation of cyclized
1
product. The H NMR spectrum of compound 5b, showed a doublet at

Triazolothiazoles
1021
SCHEME 1 Synthesis of triazothiazoles.
δ 8.06 due to ortho H-F coupling with J value of 8.2 Hz. Two sharp
singlets observed at δ 8.05 & 7.15 were assigned to protons of the 2,4-
dichloro-5-fluorophenyl moiety and that of thiazole ring. Two distinct
doublet of doublets observed at δ 7.0–6.9 was due to the presence of
protons 4-methoxyphenyl moiety. Methoxy protons appeared as singlet
at δ 4. The mass spectrum of compound 5b did not show molecular ion
peak. The major fragmentations in the mass spectra were indicated in
Table II. The physical data of these compounds are given in Table I.
Spectral data for some of the compounds are given in Table II.
ANTIMICROBIAL ACTIVITY
All the newly synthesized compounds were screened for their in vitro
antibacterial activity against Escherichia coli ESS 2231 and Staphy-
lococcus aureus 209p. Antifungal activity studies were carried out
against Aspergillus fumigatus, Candida albicans, Candida albicans

1022
K. S. Bhat and B. S. Holla
SCHEME 2 Alternate synthesis of triazothiazoles.

Triazolothiazoles
1023
TABLE I Characterization Data of 1,2,4-Triazolo[3,2-a]thiazoles (3, 5a–j)
Comp. No.
R
m.p (◦C)
Yield (%)a,b
Mol. formulac
3
—
H
194–196
174–175
202–203
146–148
166
178–180
204–205
138–139
188
95
65
60
68
72
78
60
55
66
63
68
C9H6Cl2FN3S
5a
5b
5c
5d
5e
5f
5g
5h
5i
C16H8Cl2FN3S
C17H10Cl2FN3OS
C16H7Cl3FN3S
C16H7Cl3FN3S
C16H6Cl4FN3S
C16H5Cl4F2N3S
C22H11Cl2F2N3OS
C16H7Cl2FN4O2S
C16H7Cl2FN4O2S
C16H6Cl2FN5O4S
OCH3
-2 Cl
Cl
4
2,4 Cl2
2,4 Cl2
4
2
4
5
F
F 3 (OC6H5)
NO2
NO2
198–200
225–227
5j
3,5 (NO2)
aReported yields are after recrystallization.
bThe compounds were crystallized from ethanol + dioxan mixture.
cCompounds showed satisfactory microanalysis.
ATCC 10231, Candida krusei GO3, and Candida glabrata HO5 ac-
cording to literature method.14 Fluconazole, an antifungal drug was
used as the standard for comparison. It is interesting to note that all
the compounds are moderately active against Candida albicans and
Candida albicans ATCC 10231 (Table III). None of the compounds is
active against Candida krusei GO3 and Candida glabrata HO5. How-
ever, with respect to antibacterial activity only compound 5c containing
2-chlorophenyl moiety is active.
TABLE II Spectral Characterization Data of the Compounds (3, 5b, and 5f)
Comp.
No.
IR (υ cm−1
)
1H NMR (δ, ppm)
Mass (EIMS, m/z)
3
3250(NH str.),
7.63(d, 1H, JH
=
—
F
3025(Ar CH str.),
1580(C N str.),
1180(C F str.),
890(C Cl str.)
3050(Ar CH str.),
2980(OCH3 str.),
1585(C N str.),
1210(C F str.),
895(C Cl str.)
8 Hz), 7.3 (s, 1H,
thiazole H), 7.2(s,
1H, Ar H), 3(s, b,
NH), .6(s, b, NH2)
8.06(d, 1H, Ar H, J =
8.2 Hz), 8.04(s, 1H,
Ar H), 7.15(s, 1H,
thiazole H), 7.0
-6.9(dd, 4H, Ar H, J
= 8.6 Hz), 3.9(s, 3H,
OCH3)
8.0-7.5(m, 4H, ArHs),
7.3(s, 1H, thiazole
H)
5b
5f
393(M+, not observed),
342, 256, 206(4%),
135(100%), 107(9%)
3075(Ar CH str.),
1590(C N str.),
1178(C F str.),
890(C Cl str.)
453(M+, 6%), 418(2%),
261(12%), 204(58%),
191(100%), 163(45%)

1024
K. S. Bhat and B. S. Holla
TABLE III Antimicrobial Activity Data of Triazolothiazole Derivatives
(MIC in µg/ml) (3 and 5a---j)
Fungal strains tested
Bacterial strains tested
C. albicans
Comp. No.
E. coli 2231 S. aureus 209p A. fumigatus C. albicans ATCC 10231
3
5a
5b
5c
5d
5e
5f
5g
—
—
—
40
—
—
—
—
—
—
—
—
—
—
—
40
—
—
—
—
—
—
—
—
50
—
50
—
—
—
—
—
—
—
—
—
20
15
20
20
20
15
15
15
25
20
15
20
20
20
15
15
15
25
5h
5i
5j
25
20
<10
25
20
<10
Fluconazole
(standard drug)
MIC: Minimum inhibitory concentration.
— indicates the compounds are inactive.
EXPERIMENTAL
Melting points were taken in open capillary tubes and are uncorrected.
The IR spectra in KBr disc were recorded on a Shimadzu FT IR spec-
1
trophotometer. H NMR spectra were recorded in CDCl3/DMSO-d6 on
a Bruker AC-300F (300 MHz) NMR spectrometer using TMS as an
internal standard. The mass spectra were recorded on a JEOL-JMS
D-300 mass spectrometer operating at 70eV. Purity of the compounds
was checked by thin layer chromatography (TLC) on silica gel plates
using a hexane: chloroform (4:1) solvent system. Iodine was used as the
visualizing agent.
General Procedure for the Preparation of
2,4-Dichloro-5-fluorophenacyl Bromide (1)
2,4-dichloro-5-fluoro acetophenone (0.01 mmol) was dissolved in mini-
mum amount of dry diethyl ether. To it catalytic amount of aluminum
chloride was added (about 50 mg). The reaction mixture was cooled to 0–
5◦C. Pure bromine (0.01 mmol) was added drop wise with stirring. The
mixture was stirred for 2 h. The ether was removed by distillation. The
yield of 2,4-dichloro-5-fluorophenacyl bromide was nearly quantitative
and proceeded to next step without purification.

Triazolothiazoles
1025
General Procedure for the Synthesis
of 1,2,4-Triazolo[3,4-b]thiazoles (5)
A mixture of 2,4-dichloro-5-fluorophenacyl bromide (1 mmol) (1),
thiosemicarbazide (1 mmol) (2), and aryl carboxylic acid (1.2 mmol) (4)
were taken in 20 ml of dry acetonitrile/toluene. To it was added 5 ml of
phosphorous oxychloride dropwise, with stirring. The reaction mixture
was refluxed on an oil bath for 4 h. Excess of solvent and phosphorous
oxychloride were removed by distillation under reduced pressure. The
reaction mixture was cooled and poured onto crushed ice. The result-
ing solid product was filtered, washed with sodium bicarbonate solution
(2%), followed by cold water. It was dried and recrystallized from dioxan
and ethanol mixture. The yield and characterization data of triazoloth-
iazoles (5) prepared according to this method are given in Table I.
Synthesis of 4-(2,4-Dichloro-5-fluorophenyl)-
2-hydrazinothiazole (3)
2,4-Dichloro-5-fluorophenacyl bromide (1) (1 mmol) and thiosemicar-
bazide (2) in ethanol were refluxed on a waterbath for 30 min. The ex-
cess of solvent was distilled off. The solid product obtained was purified
by recrystallization from ethanol. m.p: 194-96; Yield: 86%.
Synthesis of 1,2,4-Triazolo[3,4-b]thiazoles (5)
A
mixture of 4-(2,4-dichloro-5-fluorophenyl)-2-hydrazinothiazole
(1 mmol) (3) and aryl carboxylic acid (1.2 mmol) (4) were refluxed with
5 mL of phosphorous oxychloride for 4 h (Scheme 2). The reaction
mixture was cooled, distilled off excess of phosphorous oxychloride, and
poured onto crushed ice. The solid product separated was filtered out
and purified by repeated crystallization. The products were identified
to be same as that of prepared by three component reaction.
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