Three-component reaction: Synthesis, characterization, and biological study of some fused bridgehead nitrogen heterocyclic systems containing 4-methylthiophenyl moiety

Article abstract of DOI:10.1080/10426507.2010.506454

Several substituted thiazolo-[3,2-b]-1,2,4-triazole derivatives 4 were synthesized by a one-pot, three-component reaction of 3-(4-methylthiobenzyl)-1, 2,4-triazole-5-thiol 3, substituted 5-aryl-furan-2-carboxaldehydes/substituted aromatic aldehydes, and monochloroacetic acid in acetic acid using acetic anhydride and anhydrous sodium acetate. Compound 3 was obtained from 4-methylthiophenyl acetic acid by esterification followed by hydrazinolysis. All structures of the newly synthesized compounds were elucidated by elemental analysis and spectral data. The newly synthesized compounds were also screened for their antimicrobial and anti-inflammatory activities. 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. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/10426507.2010.506454

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Three-Component Reaction: Synthesis,
Characterization, and Biological Study
of Some Fused Bridgehead Nitrogen
Heterocyclic Systems Containing 4-
Methylthiophenyl Moiety
K. Manjunatha a , Boja Poojary a , Prajwal L. Lobo a , N. Suchetha
Kumari b & C. Anoop c
a Department of Chemistry, Mangalore University, Mangalagangothri,
Karnataka, India
b Department of Biochemistry, K. S. Hegde Medical Academy,
Deralakatte, Karnataka, India
c Clinigene International Ltd., Central Laboratory, A Biocon
Company, Bangalore, Karnataka, India
Version of record first published: 07 Mar 2011.
To cite this article: K. Manjunatha, Boja Poojary, Prajwal L. Lobo, N. Suchetha Kumari & C. Anoop
(2011): Three-Component Reaction: Synthesis, Characterization, and Biological Study of Some Fused
Bridgehead Nitrogen Heterocyclic Systems Containing 4-Methylthiophenyl Moiety, Phosphorus, Sulfur,
and Silicon and the Related Elements, 186:3, 526-532
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Phosphorus, Sulfur, and Silicon, 186:526–532, 2011
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2010.506454
THREE-COMPONENT REACTION: SYNTHESIS,
CHARACTERIZATION, AND BIOLOGICAL STUDY OF
SOME FUSED BRIDGEHEAD NITROGEN HETEROCYCLIC
SYSTEMS CONTAINING 4-METHYLTHIOPHENYL MOIETY
K. Manjunatha,1 Boja Poojary,1 Prajwal L. Lobo,1
N. Suchetha Kumari,2 and C. Anoop3
1Department of Chemistry, Mangalore University, Mangalagangothri,
Karnataka, India
2Department of Biochemistry, K. S. Hegde Medical Academy, Deralakatte,
Karnataka, India
3Clinigene International Ltd., Central Laboratory, A Biocon Company, Bangalore,
Karnataka, India
GRAPHICAL ABSTRACT
O
O
O
N
N
N
N
S
S
R1
N
N
R2
SCH3
SCH
3
Abstract Several substituted thiazolo-[3,2-b]-1,2,4-triazole derivatives 4 were synthesized by
a one-pot, three-component reaction of 3-(4-methylthiobenzyl)-1,2,4-triazole-5-thiol 3, substi-
tuted 5-aryl-furan-2-carboxaldehydes/substituted aromatic aldehydes, and monochloroacetic
acid in acetic acid using acetic anhydride and anhydrous sodium acetate. Compound 3 was
obtained from 4-methylthiophenyl acetic acid by esterification followed by hydrazinolysis. All
structures of the newly synthesized compounds were elucidated by elemental analysis and
spectral data. The newly synthesized compounds were also screened for their antimicrobial
and anti-inflammatory activities.
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 Anti-inflammatory activity; antimicrobial activity; 4-methylthiobenzyl; three com-
ponent reaction; 1,2,4-triazole-5-thiol
Received 20 May 2010; accepted 2 July 2010.
Address correspondence to Boja Poojary, Department of Chemistry, Mangalore University,
Mangalagangotri-574199, Karnataka State, India. E-mail: bojapoojary@gmail.com
526

FUSED BRIDGEHEAD NITROGEN HETEROCYCLIC SYSTEMS
527
INTRODUCTION
Multicomponent reactions (MCRs) are fundamentally different from two-component
reactions in several aspects. Convergent synthetic pathways generally show advantages
over linear or divergent approaches with respect to speed, time, yield, and reproducibility.
Among organic reactions, MCRs are highly convergent.1 MCRs with more than two starting
materials are assembled to afford a complex product. Therefore, they constitute a superior
tool for diversity-oriented, complexity-oriented, and complexity-generating synthesis for
drug discovery.2 MCRs being one-pot reactions, they are practically single-step conversions
and are easier to carry out compared to multistep synthesis.
Thiazoles are an important class of heterocyclic compounds, found in many potent
biologically active molecules such as fentiazac and meloxicam3,4 (both anti-inflammatory
agents), nizatidine5 (antiulcerative agent), and sulfathiazole (antibacterial agent). Thiazoles
represent an interesting class of compounds possessing a wide spectrum of biological activ-
ities such as anti-inflammatory, antimicrobial,6,7 antitumor,8 anticonvulsant,9 analgesic,10
and anticancer11 properties. It has been also reported that derivatives of 1,2,4-triazole and
their condensed nucleus systems exert diverse pharmacological activities such as antimi-
crobial, anti-inflammatory,12–14 anticancer,15 and antitubercular16 properties. Certain 1,2,4-
triazoles also find applications in the preparation of photographic plates and polymers, and
as analytical agents.17
A review of the literature revealed that the presence of 4-methylthiophenyl moiety18
is found to increase the biological activity of the molecules. A few heterocyclic analogues
containing N-bridged heterocycles bearing 4-methylthiophenyl moiety possess good anti-
inflammatory18,19 and antimicrobial20,21 activities.
Prompted by these chemical reactivities and broad spectrum of biological activ-
ity, we report in this article the synthesis of some fused bridgehead nitrogen hetero-
cyclic systems, viz., substituted thiazolo-[3,2-b]-1,2,4-triazole derivatives incorporating
4-methylthiophenyl moiety using a multicomponent synthesis, and we also screen them for
antimicrobial and anti-inflammatory activities.
RESULTS AND DISCUSSION
3-(4-Methylthiobenzyl)-1,2,4-triazole-5-thiol 3 was synthesized according to the pro-
cedure reported in the literature.22 The condensation of 3 with monochloroacetic acid and
5-aryl-furan-2-carbaldehydes/substituted benzaldehydes in the presence of acetic anhy-
dride, acetic acid, and anhydrous sodium acetate afforded substituted thiazolo-[3,2-b]-
1,2,4-triazole derivatives 4 (Scheme 1). Substituted 5-aryl-furan-2-carbaldehydes were
prepared through a Meerwein reaction.23
The structures of the newly synthesized compounds were confirmed by elemental
1
analysis, IR, H NMR, and mass spectrometry. Characterization data of all the newly
1
synthesized compounds are presented in Table 1. The H NMR spectrum of 3 showed a
down-field D2O exchangeable broad singlet at δ 13.30 ppm for its two tautomeric NH/SH
protons and a singlet at δ 2.41 ppm is assigned to the protons of SCH3 group. Also
a singlet at δ 3.83 ppm appeared for its benzylic CH2 group. The four protons of 4-
methylthiobenzyl moiety appeared as two distinct doublets centered at δ = 7.18 and δ =
7.20 ppm, respectively, with a coupling constant J = 7.2 Hz. Further, the LC-MS spectrum
of 3 showed the molecular ion peak at m/z 237, which corresponds to its molecular formula,
C10H11N3S2.

528
K. MANJUNATHA ET AL.
O
1) C2H5OH/H+
2) NH2NH2.H2O
O
H3C
HN
S
NH2
H3C
OH
S
2
1
1) KSCN/HCl/H2O
2) Aq. NaOH
O
N
N
Ar
N
N
Cl
SH
S
N
, Ar-CHO,
OH
N
O
H
3
4
Ac2O, NaOAc, AcOH
S
H3C
S
H3C
Ar = 5-(4-Cl-C6H4)furan-2-yl, 5-(4-NO2-C6H4)furan-2-yl, 2-(2-NO2-C6H4)furan-2-yl, 5-(4-Br-C6H4)furan-2-yl,
5-(2,4,5-Cl3-C6H2)furan-2-yl, 5-(3-Cl-4-F-C6H3)furan-2-yl, 5-(2-Me-6-NO2-C6H3)furan-2-yl,
5-(2-Me-4-NO2-C6H3)furan-2-yl, 5-(4-Cl-2-NO2-C6H3)furan-2-yl, 5-(2,4-Cl2-C6H3)furan-2-yl,
3,4-(OCH3)2-C6H3, 3,4-(OCH3)2-5-NO2-C6H2, 4-OH-C6H4, 3,5-F2-C6H3.
Scheme 1
In the IR spectra of 4a–n, all compounds displayed strong absorption bands in the
regions 1759–1724 cm−1 (C O) and 1628–1592 cm−1 (C N), respectively. The absorption
bands associated with other functional groups appeared in the expected regions. The absence
1
of signals due to two protons of tautomeric NH/SH in H NMR spectra of 4a–n and the
Table 1 Characterization data of compounds 4a–n
Compound
Ar
Molecular formula
Melting point (◦C)
Yield (%)
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
5-(4-Cl C6H4)furan-2-yl
5-(4-NO2 C6H4)furan-2-yl
5-(2-NO2 C6H4)furan-2-yl
5-(4-Br C6H4)furan-2-yl
5-(2,4,5-Cl3 C6H2)furan-2-yl
5-(3-Cl-4-F C6H3)furan-2-yl
5-(2-Me-6-NO2 C6H3)furan-2-yl
5-(2-Me-4-NO2 C6H3)furan-2-yl
5-(4-Cl-2-NO2 C6H3)furan-2-yl
5-(2,4-Cl2 C6H3)furan-2-yl
3,4-(OCH3)2 C6H3
C23H16ClN3O2S2
C23H16N4O4S2
C23H16N4O4S2
C23H16BrN3O2S2
C23H14Cl3N3O2S2
C23H15ClFN3O2S2
C24H18N4O4S2
C24H18N4O4S2
C23H15 ClN4O4S2
C23H15 Cl2N3O2S2
C21H19N3O3S2
C21H18N4O5S2
C19H15N3O2S2
C19H13F2N3OS2
196–198
250–252
150–152
173–175
208–210
200–202
224–226
168–170
215–217
144–146
158–160
167–169
120–124
161–163
71
75
69
72
76
80
69
78
70
64
67
72
70
65
3,4-(OCH3)2–5-NO2 C6H2
4-OH C6H4
3,5-F2 C6H3

FUSED BRIDGEHEAD NITROGEN HETEROCYCLIC SYSTEMS
529
presence of a new singlet in the region δ, 7.78–8.24 ppm for the exocyclic methyne proton of
the thiazolidinone ring confirmed the transformation of 3 into the corresponding substituted
thiazolo-[3,2-b]-1,2,4-triazole derivatives 4a–n. Two distinct doublets observed for 4a–j in
their 1H NMR spectra in the region δ, 6.92–7.00 ppm with a coupling constant value J =
3.6–4.2 Hz (β-protons of furan ring) also confirmed their structures. Furthermore in the
13C NMR spectra, 4a–n showed their characteristic -C O carbon signal in the region δ,
176–179.1 ppm in addition to other characteristic signals of the remaining carbon atoms.
BIOLOGICAL ACTIVITY
Anti-Inflammatory Activity
The anti-inflammatory activity of the 15 newly synthesized compounds was deter-
mined by the carrageenan induced paw edema method.24 The results of anti-inflammatory
activity are summarized in Table S1 (Supplemental Materials, available online).
Antimicrobial Activity
The newly synthesized compounds were screened for their antibacterial activity
against Staphylococcus aureus (ATTC-25923), Escherichia coli (ATTC-25922), Pseu-
domonas aeruginosa (ATTC-27853), and Klebsiella pneumoniae (recultured) bacterial
strains by a serial plate dilution method.25,26 The newly prepared compounds were also
screened for their antifungal activity against Aspergillus flavus (NCIM No. 524), As-
pergillus fumigatus (NCIM No. 902), Penicillium marneffei (recultured), and Trichophyton
mentagrophytes (recultured) in DMSO by a serial plate dilution method.27,28 The results of
antimicrobial activity are summarized in Tables S2 and S3 (Supplemental Materials).
CONCLUSION
We report the synthesis of substituted thiazolo-[3,2-b]-1,2,4-triazole derivatives by
making use of a three-component reaction protocol that resulted in good yields, and we
also report their pharmacological activities. Among the screened compounds for anti-
inflammatory activity, 4m, which contains a 4-hydroxyphenyl group as substituent, ex-
hibited the highest activity. Similarly, all the compounds tested for antimicrobial activity
showed moderate to good activity against the pathogenic strains. However, compounds 4a,
4c, and 4f showed good activity against all the bacterial strains. The good activity can
be attributed to the presence of pharmacologically active (4-chloro-phenyl)furyl, (2-nitro-
phenyl)furyl, and (3-chloro-4-fluro-phenyl)furyl groups. On the other hand, compound 4a
containing 4-chlorophenyl moiety attached to furyl ring showed good activity against all
the tested fungal strains.
EXPERIMENTAL
The melting points were determined by an open capillary method and are uncorrected.
The IR spectra (in KBr pellets) were recorded on a Shimadzu FT-IR 157 spectrophotometer.
The 1H NMR spectra were recorded (CDCl3/DMSO-d6 mixture) on a Bruker Avance II-400
(400 MHz) spectrometer using TMS as an internal standard. Mass spectra were recorded
on a Finnigan MAT8230 mass spectrometer. Elemental analysis (CHNS) was performed

530
K. MANJUNATHA ET AL.
on the CHNS Elementar Vario EL III. The progress of the reaction was monitored by TLC
on silica gel plates.
Procedure for the Preparation of 4-Methylthiophenyl-Acetic
Acid Hydrazide (2)
The mixture of ethyl ester of 4-methythiophenyl acetic acid 1 (0.1 mol) and hy-
drazine hydrate (0.2 mol) was refluxed in absolute alcohol (50 mL) for 8 h. The excess
solvent was then distilled off under reduced pressure, and the concentrated solution was
quenched with ice cold water. The solid that separated was filtered, washed, and dried.
The crude product was purified by recrystallization from ethanol to give 89% of 2 with
mp 136–138◦C (colorless). IR (KBr, cm−1): 3344 (NH, NH2), 3203 (NH2), 2963 (C H),
1622 (CO NH);1H NMR (400 MHz, CDCl3, δ): 2.49 (s, 3H, SCH3), 3.53 (s, 2H, CH2),
3.82 (br-s, 2H, NH2), 6.67 (br-s, 1H, NH), 7.18 (d, Ar-H, J = 8.4 Hz), 7.26 (d, Ar H, J =
8.4 Hz); LC-MS (m/z): 196 (M+), Anal. Calcd. (%) for C9H12N2OS: C55.09, H6.16,
N14.27. S 16.34, Found: C55.06, H6.15, N14.20, S16.26.
Procedure for the Preparation of 3-(4-Methylthiobenzyl)-1,2,4-
triazole-5-thiol (3)
4-Methylthiophenyl–acetic acid hydrazide (2) (0.1 mol) was dissolved in water
(100 mL) containing concentrated hydrochloric acid (10 mL). Potassium thiocyanate
(0.2 mol) was added, and the mixture was warmed on a water bath for 5 h. The reaction mix-
ture was cooled. The precipitated solid was filtered, dried, and recrystallized from ethanol to
get 4-methylthiophenylacetyl thiosemicarbazide. A mixture of resulting thiosemicarbazide
(0.01 mol) and sodium hydroxide (5%, 100 mL) was refluxed on a heating mantle for 3 h.
The reaction mixture was poured into crushed ice and acidified with dilute hydrochloric
acid. The precipitate thus obtained was filtered, dried, and recrystallized from ethanol to
obtain 85% of 3 with mp 195–197◦C (colorless solid). IR (KBr, cm−1): 3154 (NH), 1206
1
(C S); H-NMR(DMSO-d6, δ): 2.49 (s, 3H, SCH3), 3.53 (s, 2H, CH2), 7.18 (d, Ar-H,
J = 8.4 Hz), 7.26 (d, Ar-H, J = 8.4 Hz), 13.30 (brs, 2H, NH/SH); 13C NMR (100 MHz,
CDCl3, δ): 16.1, 32.1, 127.5, 128.5, 131.9, 139.2, 152.6, 167.1; LC-MS (m/z): 237 (M+);
Anal. Calcd. (%) for C10H11N3S2: C50.60, H4.67, N17.70, S27.02, Found: C50.56, H4.71,
N17.79, S27.05.
General Procedure for the Preparation of 2-(4-Methylthiobenzyl-7-
(5-aryl-2-furylidine/substituted benzylidene)-thiazolo[3,2-b]-
1,2,4-trizol-5(6H)-ones (4)
A
mixture of 3-(4-methylthiobenzyl)-1,2,4-triazole-5-thiol
3
(0.01 mol),
monochloroacetic acid (0.015 mol), 5-aryl-furan-2-carbaldehyde/substituted aro-
matic aldehydes (0.01 mol), acetic anhydride (15 mL), and anhydrous sodium acetate
(2 g) in glacial acetic acid (20 mL) was heated to reflux for 6–8 h. The reaction mixture
was cooled and poured onto crushed ice with vigorous stirring. The solid obtained was
filtered, washed with water, dried, and recrystallized from a mixture ethanol and dimethyl
formamide.
2-(4-Methylthiobenzyl-7-(4-chloro-phenyl-2-furylidine)-thiazolo[3,2-b]-1,
2,4-trizol-(6H)-one (4a). IR (KBr, cm−1): 3073 (Ar H), 2943 (C H), 1751 (C O),

FUSED BRIDGEHEAD NITROGEN HETEROCYCLIC SYSTEMS
531
1
1596 (C N); H NMR (DMSO-d6, δ): 2.44 (s, 3H, SCH3), 4.02 (s, 2H, CH2), 7.22 (d,
2H, 4-methylthiobenzyl, J = 8 Hz), 7.30 (d, 2H, 4-methylthiobenzyl, J = 8 Hz), 7.33
(d, 1H, furan H, J = 3.6 Hz), 7.48 (d, 1H, furan H, J = 3.6 Hz), 7.58–7.96 (m, 4H,
4-chlorophenyl), 7.96 (s, 1H, exocyclic methyne-H); LC-MS (m/z): 466 (M++1);13C
NMR (100 MHz, CDCl3, δ): 16.1, 32.1, 112.5, 116.1, 126.3, 126.9, 127.5, 128.2, 129.4,
130.4, 131.9, 139.2, 151.0, 152.6, 167.1, 177.6; Anal. Calcd. (%) for C23H16N3ClO2S2:
C59.28, H3.46, N9.02, S13.76, Found: C59.32, H3.42, N9.05, S13.80.
2-(4-Methylthiobenzyl-7-(4-nitro-phenyl-2-furylidine)-thiazolo[3,2-b]-1,
2,4-trizol-(6H)-one (4b). IR (KBr, cm−1): 3073 (Ar H), 2920 (C-H), 1734 (C O),
1
1612 (C N). H-NMR (DMSO-d6, δ): 2.45 (s, 3H, SCH3), 4.00 (s, 2H, CH2), 7.20 (d,
2H, 4-methylthiobenzyl, J = 8.4 Hz), 7.29 (d, 2H, 4-methylthiobenzyl, J = 8.0 Hz), 7.42
(d, 1H, furan H, J = 4 Hz), 7.53 (d, 1H, furan H, J = 4 Hz), 8.12 (d, 2H, 4-nitrophenyl,
J = 8.8 Hz), 8.35 (d, 2H, 4-nitrophenyl, J = 8.8 Hz), 8.13 (s, 1H, exocyclic methyne-H);
LC-MS (m/z): 477 (M++1); 13C NMR (100 MHz, CDCl3, δ): 16.1, 32.5, 114.2, 117.6,
126.7, 126.9, 127.3, 127.6, 129.8, 131.0, 132.4, 140.2, 151.4, 152.8, 168.2, 178.7; Anal.
Calcd. (%) for C23H16N4O4S2: C57.97, H3.38, N11.76, S13.46, Found: C57.94, H3.42,
N11.73, S13.49.
2-(4-Methylthiobenzyl-7-(4-bromo-phenyl-2-furylidine)-thiazolo[3,2-b]-
1,2,4-trizol-(6H)-one (4d). IR (KBr, cm−1): 3036 (Ar H), 2923 (C H), 1732 (C O),
1
1608 (C N), 853 (C-Br); H NMR (DMSO-d6, δ): 2.46 (s, 3H, SCH3), 3.98 (s, 2H,
CH2), 7.12 (d, 1H, furan H, J = 3.6 Hz), 7.26 (d, 1H, furan H, J = 3.6 Hz), 7.18 (d, 2H,
4-methylthiobenzyl, J = 8.4 Hz), 7.33 (d, 2H, 4-methylthiobenzyl, J = 8 Hz), 7.48 (d, 2H,
4-bromophenyl, J = 8 Hz), 7.64 (d, 2H, 4-nitrophenyl, J = 8 Hz), 8.05 (s, 1H, exocyclic
methyne-H); LC-MS (m/z): 509 (M++1); 13C NMR (100 MHz, CDCl3, δ): 16.9, 34.6,
111.5, 116.7, 126.1, 126.46, 127.4, 128.1, 129.8, 130.9, 131.5, 149.0, 151.1, 152.6, 169.2,
177.4; Anal. Calcd. (%) for C23H16N3BrO2S2: C54.12, H3.16, N7.86, S11.89, Found:
C54.20, H3.12, N7.78, S11.80.
2-(4-Methylthiobenzyl-7-(3,4-dimethoxy-benzylidine)-thiazolo[3,2-b]-1,
2,4-trizol-(6H)-one (4k). IR (KBr, cm−1): 3084 (Ar H), 2924 (C-H), 1732 (C O),
1587 (C N); 1H NMR (DMSO-d6, δ): 2.54 (s, 3H, SCH3), 3.86–3.87 (2s, 6H, 2xOCH3),
4.48 (s, 2H, CH2), 7.18 (d, 2H, 4-methylthiobenzyl, J = 8.4 Hz), 7.37 (d, 2H, 4-
methylthiobenzyl, J = 8.4 Hz), 7.47–7.68 (m, 3H, dimethoxyphenyl), 7.86 (s, 1H,
exocyclic methyne-H); LC-MS (m/z): 426 (M+); 13C NMR (100 MHz, CDCl3, δ): 16.8,
32.0, 57.6, 57.7, 124.8, 126.3, 126.0, 128.4, 128.5, 129. 4, 130.7, 131.8, 139.1, 151.0,
152.1, 167.0, 169.6, 178.2; Anal. Calcd. (%) for C21H19N3O3S2: C59.27, H4.50, N9.87,
S15.07, Found: C59.32, H4.55, N9.92, S15.02.
2-(4-Methylthiobenzyl-7-(3,5-difluoro-benzylidine)-thiazolo[3,2-b]-1,2,4-
trizol-(6H)-one (4n). IR (KBr, cm−1): 3045 (Ar H), 2961(C-H), 1724 (C O); 1H NMR
(DMSO-d6, δ): 2.49 (s, 3H, SCH3), 4.52 (s, 2H, CH2), 7.21 (d, 4-methylthiobenzyl, J =
7.8 Hz), 7.34 (d, 2H, 4-methylthiobenzyl, J = 7.6 Hz), 7.65–7.86 (m, 3H, difluorophenyl),
8.03 (s, 1H, exocyclic methyne-H); LC-MS (m/z): 402 (M+); 13C NMR (100 MHz, CDCl3,
δ): 16.2, 32.0, 126.2, 126.6, 127.8, 127.2, 129.3, 129.0, 130.1, 141.4, 149.5, 151.3, 152.6,
168.5, 169.4, 177.4; Anal.Calcd.(%) for C19H13N3OS2: C56.84, H3.26, N10.47, S15.97,
Found: C56.88, H3.22, N10.54, S15.92.
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