Facile TICl4-catalyzed synthesis of novel 1,2,4-triazoles appended to thiazoles

Article abstract of DOI:10.1007/s10593-011-0849-2

The reaction of sydnone-derived 3-aryl-5-methyl-1,3,4-oxadiazol-2(3H)-ones with thiourea and α-bromoacetophenone derivatives in the presence of a catalytic amount of TiCl₄ produces 2-aryl-4-(4-aryl-1,3-thiazol-2-yl) -5-methyl-2,4-dihydro-3H-1,2,4-triazol-3-ones. The title compounds were screened for their antibacterial and antifungal activity. The toxicity of the compounds was evaluated in terms of mutagenicity, tumorigenicity, and reproductive effects. The drug-relevant properties (ClogP, drug-likeness, and drug score) were calculated, and the structure-activity relationship was discussed.

Full text of DOI:10.1007/s10593-011-0849-2

Chemistry of Heterocyclic Compounds, Vol. 47, No. 7, October 2011 (Russian original Vol. 47, No. 7, July, 2011)
FACILE TICl4-CATALYZED SYNTHESIS OF NOVEL
1,2,4-TRIAZOLES APPENDED TO THIAZOLES
T. Gireesh1, R. R. Kamble1*, R. K. Hunnur1,
T. Taj1, and M. Y. Kariduraganavar1
The reaction of sydnone-derived 3-aryl-5-methyl-1,3,4-oxadiazol-2(3H)-ones with thiourea and
α-bromoacetophenone derivatives in the presence of a catalytic amount of TiCl4 produces 2-aryl-4-(4-
aryl-1,3-thiazol-2-yl)-5-methyl-2,4-dihydro-3H-1,2,4-triazol-3-ones. The title compounds were screened
for their antibacterial and antifungal activity. The toxicity of the compounds was evaluated in terms of
mutagenicity, tumorigenicity, and reproductive effects. The drug-relevant properties (ClogP, drug-
likeness, and drug score) were calculated, and the structure–activity relationship was discussed.
Keywords: mesoionic compounds, sydnones, TiCl4, 1,3-dipolar cycloaddition.
Sydnone is a typical mesoionic compound which has been investigated extensively because of its unique
electronic structure and biological activity. Sydnone has also recently gained importance as it readily undergoes
ring transformation into various heterocycles by 1,3-dipolar cycloaddition [1–3].
The importance of 1,2,4-triazoles in organic synthesis is due to the wide range of their biological proper-
ties, such as antibacterial, antimycobacterial, antimycotic, antidepressant, cardiotonic, analgesic, and anti-
inflammatory activities [4–13]. Thiazole derivatives are known to possess anti-inflammatory, anticancer,
antibacterial, antifungal, and antiallergic activities [14–19].
Many procedures for the synthesis of 4-substituted 1,2,4-triazoles have been described, such as the reac-
tion of ethyl formate or formic acid with hydrazine hydrate [20, 21], and the reaction of carbon monoxide with
hydrazine hydrate under high pressure [22], and the reaction of an appropriate aliphatic, aromatic, or
heterocyclic primary amine with diformohydrazide [23]. Another approach reported involves the reaction of
diphenylformamidine with formohydrazide [24]. As an example of recyclization, 2-phenyl-4-phenyl-
azooxazolin-5-one upon treatment with alcoholic potassium hydroxide gave 1,5-diphenyl-1H-1,2,4-triazol-
3-ylcarboxylic acid in quantitative yield [25]. 1,2-Dihydro-1,2,4,5-tetrazines undergo isomerization to
1,2,4-triazole derivatives [26]. We were interested to find mild conditions for 1,2,4-triazole synthesis, possibly
facilitated by a catalyst. The use of titanium(IV) chloride, an acidic catalyst, has been explored for various
_______
*To whom correspondence should be addressed,e-mail: kamchem9@gmail.com.
1PG Department of Studies in Chemistry, Karnatak University, Dharwad 580003, India.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 1069–1078, July, 2011. Original
article received August 10, 2010. With revisions March 31, 2011
0009-3122/11/4707-0877©2011 Springer Science+Business Media, Inc.
877

organic transformations, such as synthesis of α-aminophosphonates [27], Biginelli reaction [28], olefination of
aldehydes [29], and synthesis of imidazo[1,2-a]pyridine derivatives [30]. In this communication, we wish to
report the use of TiCl4 as a mild, efficient, and commercially available catalyst for the synthesis of 2-aryl-4-(4-
aryl-1,3-thiazol-2-yl)-5-methyl-2,4-dihydro-3H-1,2,4-triazol-3-ones 1a–q (Scheme 1).
Scheme 1
10 mol% TiCl4,
H2NCSNH2,
EtOH, DMF, reflux
H
+
O
1) Br2 in Ac2O,
0°C
R
O
S
R
N
N
O
2) 60°C
N
O
N
Me
2a–f
3a–f
O
O
S
R1COCH2Br
R
R
R1
N
N
5–7
N
N
N
NH2
N
N
Me
Me
1a–q
4a–f
1 a R = Ph, R1 = Ph, b R = p-MeC6H4, R1 = Ph, c R = m-MeC6H4, R1 = Ph, d R = p-ClC6H4, R1 = Ph, e R = m-ClC6H4, R1 = Ph,
f R = Ph, R1 = p-O2NC6H4, g R = p-MeC6H4, R1 = p-O2NC6H4, h R = m-MeC6H4, R1 = p-O2NC6H4, i R = p-anisyl, R1 = p-O2NC6H4,
j R = p-ClC6H4, R1 = p-O2NC6H4, k R = m-ClC6H4, R1 = p-O2NC6H4, l R = Ph, R1 = p-BrC6H4, m R = p-MeC6H4, R1 = p-BrC6H4,
n R = m-MeC6H4, R1 = p-BrC6H4, o R = p-anisyl, R1 = p-BrC6H4, p R = p-ClC6H4, R1 = p-BrC6H4, q R = m-ClC6H4, R1 = p-BrC6H4;
2–4 a R = Ph, b R = p-MeC6H4, c R = m-MeC6H4, d R = p-ClC6H4, e R = m-ClC6H4, f R = p-anisyl;
5 R1 = Ph; 6 R1 = p-O2NC6H4; 7 R1 = p-BrC6H4
The strategy of the present investigation was based on the literature precedents where a combination of
ring systems with pharmacologically active heterocycles results in molecules with better drug potential. In the
light of these observations we have designed and synthesized molecules 1a–q containing heterocycles of these
classes.
The 3-arylsydnones 2a–f were the synthetic precursors which reacted with bromine in acetic anhydride
[31] to form 1,3,4-oxadiazoles 3a–f. Initially, allowing compound 3a to react with thiourea in ethanol in the
absence of the catalyst produced only 20% of compound 4a after 24 h under reflux conditions. When a catalytic
amount of TiCl4 (5 mol %) was added, 60% conversion of compound 3a to 4a was observed after 5 h of reflux.
Increasing the amount of TiCl4 from 5 to 10 mol% resulted in 89% conversion after 2 h of reflux. Compound 1a
was obtained by cyclization of compound 4a with α-bromoacetophenone (5) in a good yield. We tried to use
also other Lewis acid catalysts like MgBr2, ZnCl2, I2, VCl3, sulfamic acid, and p-toluenesulfonic acid (PTSA)
for the above conversion and observed lower yields than with TiCl4 (Table 1).
TABLE 1. Comparison of Efficiency of Various Lewis Acid Catalysts on
the Conversion of Compound 3a into 1a via Intermediate 4a
Lewis acid catalyst
Time, h
Yield, %
Lewis acid catalyst
Time, h
Yield, %
TiCl4
MgBr2
ZnCl2
I2
1
10
8
91
50
55
53
VCl3
Sulfamic acid
PTSA
5
10
6
65
40
50
7
878

Having thus demonstrated TiCl4 to be the most effective catalyst for the above conversion, we applied it
to the reaction of compound 3a with thiourea in the presence of (10 mol% TiCl4, 2 h reflux). After completion
of the reaction (monitored by TLC) and without the isolation of the intermediate 4a, bromoacetophenone 5 was
added to the reaction mixture. As a result, the title compound 1a was produced in 87% yield. The plausible
reaction mechanism is presented in Scheme 2. As the reaction is carried out in ethanol–DMF, TiCl4 is likely
converted into Ti(OEt)4 that may also act as Lewis acid catalyst.
Scheme 2
Ti(IV)
H2N
S
Ti(IV)
S
O
S
O
O
S
H
NH2
R
O
N
N
R
NH2
N
H
N
N
R
N
N
NH2
N
O
4a–f
R
NH2
O
N
O
N
N
O
H
Me
Ti(IV)
Me
Me
Me
Ti(IV)
3a–f
Having established the best reaction conditions, we applied them to the reaction of compounds 3b–f
with thiourea in the presence of TiCl4 followed by addition of substituted bromoacetophenones 5–7 in situ,
furnishing the corresponding products 1b–q in excellent yields.
The intermediate 4a was isolated and characterized by IR, 1H and 13C NMR spectra. Its precursor 3a has
1
the C=O absorption band at 1770–1775 cm in its IR spectrum [31]. The low-frequency shift of this band to
1
1707 cm in compound 4a indicates the replacement of oxygen atom by nitrogen in the heterocyclic ring. The
presence of an NH2 group in the compound 4a is indicated by two IR absorption bands around 3327 and
1
1
3444 cm and by a broad singlet at 2.03 ppm, suppressed by D2O, in its H NMR spectrum. Aromatic protons
appeared in the range of 7.27–8.03 ppm as a multiplet.
1
The IR spectra of the title compounds 1a–q showed a sharp band around 1710–1715 cm due to the
1
carbonyl group of the 1,2,4-triazole ring. In the H NMR spectra, the closure of another heterocyclic ring was
indicated by a singlet in the range of 6.5–6.7 ppm, ascribed to the thiazole proton at position 5. The 13C NMR
and mass spectra of compounds 1a–q were consistent with the expected number of carbon atoms and molecular
mass, respectively.
The antibacterial screening (Table 2) shows that compound 1a without any substituent on the two
phenyl rings and compounds with methyl (at the meta position, 1c), as well as chloro and bromo (1d,e,l, and 1p)
substituents are active against Escherichia coli and Bacillus cereus, their activity being equal to or more than
that of the reference drug Norfloxacin. This activity was found to vary with the substitution at the phenyl rings
attached to the triazole and thiazole ring. The compounds having nitro group on the phenyl ring attached to the
thiazole moiety show weak to moderate activity.
In the case of antifungal activity studies, compounds with m-tolyl (1c), p-bromophenyl (1l), and both
p-chloro- and -bromophenyl substituents show activity higher than the reference drug Griseofulvin against the
fungus Candida albicans. Also the assay against Rhizoctonia bataticola indicated that the compounds with the
same set of substituents (1a–c,l,o,p) are more active than the reference drug. Interestingly, compounds 1f,g,j
with the nitro substituent show weak to moderate activity.
In view of the need to rapidly improve the lead structures into drug candidates, drug-likeness and toxi-
cology parameters based on topological descriptors have gained considerable attention. For a compound to
qualify as a drug candidate, certain parameters are to be analyzed according to Lipinski’s rule of five [32]. The
prediction of toxicity, drug-likeness, and drug score of the compounds was done using the on-line OSIRIS
Property Explorer and the occurrence frequency of each fragment is determined within the collection of
879

880

approved drugs and within the supposedly non-drug like collection of commercially available chemicals. A
positive drug-likeness value (0.1–10) means that the molecule contains predominantly fragments which are
frequently present in traded drugs. The OSIRIS calculations allow us to predict the toxicity risks in terms of
mutagenicity, tumorigenicity, irritating, and reproductive effects. The Clog P is an important physicochemical
property which indicates the lipophilicity and the ability of a molecule to cross biological membranes.
According to Lipinski’s rule of five, a Clog P value below 5 is feasible for a compound to be a future drug.
The synthesized compounds can be divided into three categories depending upon this evaluation: 1a–e
(no substituent on the phenyl group at the C(4) of the thiazole ring), 1f–k (nitro group at the para position of the
phenyl group on the C(4) of the thiazole ring), and 1l–q (bromine atom at the para position of the phenyl group
at the C(4) of the thiazole ring). Compounds 1a–k show marginal lipophilicity within the range 4.0–5.0, and
compounds 1l–q have Clog P above 5. Compounds 1a–f exhibit a drug score greater than 0.30, with 1l scoring
just below that value. With regard to their antibacterial properties, compounds 1a–e and 1l show good activity
against both bacterial strains. Compounds 1a–d and 1l effectively inhibit the growth of both fungal strains.
Hence, the drug score obtained by the OSIRIS Property Explorer can be at least tentatively correlated with the
antimicrobial assay results. It is interesting to observe that compounds 1o and 1p, in spite of their lower drug
score, have exhibited excellent activity against R. bataticola and 1p against A. candida.
Drug toxicity is a factor of great importance for a potential commercial drug, since a significant number
of drugs are disapproved in clinical trials based on their high toxicity profile. The toxicity of the compounds was
calculated in terms of mutagenic, tumorigenic, reproductive, and irritant effect. Only compounds 1i and 1o
exhibit mutagenic effect, and all the other compounds show very mild tumorigenic behavior, whereas none of
the compounds show either reproductive effect or irritating effect. Hence, these compounds (except 1i and 1o)
may be proposed as biologically safe for intake.
In summary, we have developed a simple, novel, and efficient protocol for the synthesis of a series of
triazoles appended to thiazoles using catalytic amounts of TiCl4 and studied their in vitro antibacterial and
antifungal activity. The advantages of the present method are milder reaction conditions with better yields. The
compounds were also tested for their toxicity, and their drug score was evaluated by property prediction
software. The structure–activity relationship suggests that the compounds without any substituent on the phenyl
ring attached to the thiazole are potent lead compounds for drug discovery with negligible toxicity.
EXPERIMENTAL
1
IR (KBr) spectra were recorded on a Nicolet-5700 FT-IR spectrometer. H and 13C NMR spectra were
recorded on a Bruker Avance 300 (300 and 75 MHz, respectinely) FT-NMR spectrometer in CDCl3 with TMS
as internal standard. Mass spectra were recorded on a Shimadzu Japan QP2010 GCMS instrument. Elemental
analyses were carried out using a Heraeus CHN Rapid Analyzer. Melting points were determined in open
capillaries. Purity of the compounds was checked by TLC (ethyl acetate–hexane, 7:3).
Compounds 3a–f were prepared according to the literature method [31].
3-Methyl-5-oxo-1-phenyl-1,5-dihydro-4H-1,2,4-triazole-4-carbothioamide (4a). A mixture of 5-methyl-
3-phenyl-1,3,4-oxadiazol-2(3H)-one 3a (0.01 mol), TiCl4 (10 mol %), and thiourea (0.01 mol) in absolute
ethanol (10 ml) was refluxed for about 2 h. The reaction mixture was cooled and poured into ice. The obtained
solid was filtered off and recrystallized from ethanol to give yellow needles, yield 87%; mp 146°C. IR spectrum,
ν, cm1: 3444 (NH), 3327 (NH), 1707 (C=O), 1641 (C=N), 1424 (C=S). 1H NMR spectrum, δ, ppm: 2.03 (2H, s,
NH2, D2O exch.); 2.33 (3H, s, 5-CH3); 7.24–7.79 (5H, m, H Ar). 13C NMR spectrum, δ, ppm: 22.0 (5-CH3);
121.3; 121.6; 124.5; 129.0; 129.2; 137.7; 155.5; 157.5; 183.0. Mass spectrum, m/z (Irel, %): 234 [M]+ (13), 174
(10), 133 (100), 105 (20), 77 (65). Found, %: C 51.27; H 4.30; N 23.91. C10H10N4OS. Calculated, %: C 51.20;
H 4.37; N 23.85.
881

2-Aryl-4-(4-aryl-1,3-thiazol-2-yl)-5-methyl-2,4-dihydro-3H-1,2,4-triazol-3-ones 1a–q (General
Method). A mixture of compound 3a–e (0.001 mol), thiourea (0.001 mol), and TiCl4 (10 mol%) in absolute
ethanol (10 ml) and DMF (10 ml) was heated under reflux. After completion of the ring insertion of the nitrogen
of thiourea (monitored by TLC), the corresponding bromoacetophenone 5–7 (0.001 mol) was added, and the
mixture was stirred for 1.5–3 h at room temperature. The solid product was filtered and crystallized from ethanol
to get pale-yellow needles of compounds 1a–q.
5-Methyl-2-phenyl-4-(4-phenylthiazol-2-yl)-2,4-dihydro-3H-1,2,4-triazol-3-one (1a), yield 87%
1
(2.91 g); mp 130–131°C. IR spectrum, ν, cm1: 3018 (C–H), 1703 (C=O), 1640 (C=N). H NMR spectrum, δ,
ppm: 2.50 (3H, s, 5-CH3); 6.60 (1H, s, H-5'); 7.00–7.65 (10H, m, H Ar). 13C NMR spectrum, δ, ppm: 24.5
(CH3); 99.4; 121.0; 121.5; 124.0; 128.0; 128.2; 128.8; 129.0; 129.1; 129.5; 133.0; 134.5; 138; 148.5; 150.0;
152.0; 172.0. Mass spectrum, m/z (Irel, %): 334 [M]+ (14), 200 (100), 173 (12), 132 (34), 104 (50), 77 (62).
Found, %: C 64.40; H 4.10; N 16.50. C18H14N4OS. Calculated, %: C 64.65; H 4.22; N 16.75.
5-Methyl-4-(4-phenylthiazol-2-yl)-2-(p-tolyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (1b), yield 92%
1
(3.19 g); mp 175–176°C. IR spectrum, ν, cm1: 3026 (C–H), 1708 (C=O), 1644 (C=N). H NMR spectrum, δ,
ppm: 2.30 (3H, s, CH3 Ar); 2.55 (3H, s, 5-CH3); 6.62 (1H, s, H-5'); 7.02–7.44 (9H, m, H Ar). 13C NMR
spectrum, δ, ppm: 22.0 (CH3); 23.5 (CH3 Ar); 99.0; 120.0; 120.2; 125.0; 128.0; 128.2; 129.0; 130.2; 130.5;
131.0; 132.0; 133.1; 134.0; 137.4; 147.0; 149.0; 165.0. Mass spectrum, m/z (Irel, %): 348 [M]+ (8), 214 (24), 187
(100), 146 (16), 118 (43), 89 (65). Found, %: C 65.51; H 4.62; N 16.06. C19H16N4OS. Calculated, %: C 65.50;
H 4.63; N 16.08.
5-Methyl-4-(4-phenylthiazol-2-yl)-2-(m-tolyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (1c), yield 92%
1
(3.21 g); mp 112–113°C. IR spectrum, ν, cm1: 3039 (C–H), 1710 (C=O), 1642 (C=N). H NMR spectrum, δ,
ppm: 2.35 (3H, s, CH3 Ar); 2.45 (3H, s, 5-CH3); 6.61 (1H, s, H-5'); 6.80–7.45 (9H, m, H Ar). 13C NMR
spectrum, δ, ppm: 20.0; 24.0 (CH3 Ar); 101.0; 118.5; 121.2; 121.4; 121.6; 124.5; 127.2; 127.4; 129.0; 129.3;
133.2; 137.0; 138.5; 145.0; 148.0; 162.0. Mass spectrum, m/z (Irel, %): 348 [M]+ (12), 218 (18), 177 (70), 159
(100), 151 (40). Found, %: C 65.35; H 4.45; N 16.02. C19H16N4OS. Calculated, %: C 65.50; H 4.63; N 16.08.
2-(p-Chlorophenyl)-5-methyl-4-(4-phenylthiazol-2-yl)-2,4-dihydro-3H-1,2,4-triazol-3-one
(1d),
1
yield 89% (3.28 g); mp 126–127°C. IR spectrum, ν, cm1: 3042 (C–H), 1707 (C=O), 1639 (C=N). H NMR
spectrum, δ, ppm (J, Hz): 2.35 (3H, s, 5-CH3); 6.58 (1H, s, H-5'); 7.19–7.30 (5H, m, H Ar); 7.50 (2H, d, J = 7.2,
13
H Ar), 7.64 (2H, d, J = 7.2, H Ar). C NMR spectrum, δ, ppm: 20.0; 100.0; 127.4; 127.6; 129.1; 129.5; 129.9;
130.0; 130.2; 130.5; 131.0; 132.0; 135.5; 136.0; 148.5; 150.0; 154.8; 166.0. Mass spectrum, m/z (Irel, %): 370
[M+2]+ (17), 368 [M]+ (48), 236 (11), 234 (29), 209 (08), 207 (20), 182 (100), 168 (7), 166 (18), 140 (9), 138
(20), 112 (10), 110 (31). Found, %: C 58.50; H 3.42; N 15.00. C18H13ClN4OS. Calculated, %: C 58.61; H 3.55;
N 15.19.
2-(m-Chlorophenyl)-5-methyl-4-(4-phenylthiazol-2-yl)-2,4-dihydro-3H-1,2,4-triazol-3-one
(1e),
1
yield 90% (3.34 g); mp 165–166°C. IR spectrum, ν, cm1: 3048 (C–H), 1704 (C=O), 1637 (C=N). H NMR
spectrum, δ, ppm: 2.48 (3H, s, 5-CH3); 6.59 (1H, s, H-5'); 7.04–7.65 (9H, m, H Ar). 13C NMR spectrum, δ, ppm:
25.8; 90.5; 119.5; 122.0; 124.5; 127.5; 128.0; 129.0; 129.5; 129.8; 130.4; 133.0; 134.5; 139.2; 148.2; 152.0;
155.0; 173.2. Mass spectrum, m/z (Irel, %): 370 [M+2]+ (9), 368 (25), 236 (22), 234 (20), 209 (29), 181 (100),
183 (19). Found, %: C 58.52; H 3.48; N 15.08. C18H13ClN4OS. Calculated, %: C 58.61; H 3.55; N, 15.19.
5-Methyl-4-[4-(p-nitrophenyl)thiazol-2-yl]-2-phenyl-2,4-dihydro-3H-1,2,4-triazol-3-one (1f), yield
90% (3.42 g); mp 128–129°C. IR spectrum, ν, cm1: 3026 (C–H), 1708 (C=O), 1645 (C=N). 1H NMR spectrum,
δ, ppm (J, Hz): 2.47 (3H, s, 5-CH3); 6.56 (1H, s, H-5'); 7.10–7.65 (5H, m, H Ar); 7.74 (2H, d, J = 8.4, H Ar);
8.25 (2H, d, J = 8.5, H Ar). 13C NMR spectrum, δ, ppm: 24.0; 89.4; 122.0; 122.5; 123.0; 123.5; 124.4; 128.5;
128.7; 129.0; 129.4; 137.6; 140.2; 148.0; 148.6; 152.0; 155.0; 170.5. Mass spectrum, m/z (Irel, %): 379 [M]+
(11), 200 (43), 173 (100), 132 (51), 104 (8), 77 (62). Found, %: C 56.88; H 3.43; N 18.39. C18H13N5O3S.
Calculated, %: C 56.98; H 3.45; N 18.46.
882

5-Methyl-4-[4-(p-nitrophenyl)thiazol-2-yl]-2-(p-tolyl)-2,4-dihydro-3H-1,2,4-triazol-3-one
(1g),
yield 89% (3.53 g); mp 145–146°C. IR spectrum, ν, cm1: 3048 (C–H), 1702 (C=O), 1648 (C=N). H NMR
spectrum, δ, ppm (J, Hz): 2.55 (3H, s, 5-CH3); 2.35 (3H, s, CH3 Ar); 6.58 (1H, s, H-5'); 7.05 (2H, d, J = 7.4,
H Ar); 7.48 (2H, d, J = 7.4, H Ar); 7.78 (2H, d, J = 8.0, H Ar); 8.28 (2H, d, J = 8.2, H Ar). 13C NMR spectrum,
δ, ppm: 20.0 (CH3); 25.0 (CH3 Ar ); 105.0; 121.6; 122.0; 130.5; 130.8; 134.0; 134.6; 135.0; 140.2; 148.0; 148.6;
128.4; 128.6; 149.0; 153.0; 155.0; 168.0. Mass spectrum, m/z (Irel, %): 393 [M]+ (16) 214 (36), 187 (62), 146
(43), 118 (100), 89 (62). Found, %: C 57.96; H 3.80; N 17.75. C19H15N5O3S. Calculated, %: C 58.01; H 3.84;
N 17.80.
1
5-Methyl-4-[4-(p-nitrophenyl)thiazol-2-yl]-2-(m-tolyl)-2,4-dihydro-3H-1,2,4-triazol-3-one
(1h),
yield 86% (3.39 g); mp 152–153°C. IR spectrum, ν, cm1: 3052 (C–H), 1706 (C=O), 1642 (C=N). H NMR
spectrum, δ, ppm (J, Hz): 2.32 (3H, s, CH3); 2.48 (3H, s, 5-CH3); 6.64 (1H, s, H-5'); 7.10–7.49 (4H, m, H Ar);
7.74 (2H, d, J = 7.0, H Ar); 8.30 (2H, d, J = 7.2, H Ar). 13C NMR spectrum, δ, ppm: 22.5 (CH3); 23.4 (CH3);
95.0; 115.0; 120.8; 122.0; 122.7; 124.5; 127.0; 128.5; 128.9; 137.5; 138.6; 139.2; 148.0; 149.0; 155.0; 157.0;
175.0. Mass spectrum, m/z (Irel, %): 393 [M]+ (22), 214 (30), 173 (40), 132 (46), 104 (74), 77 (100). Found, %:
C 57.90; H 3.82; N 17.78. C19H15N5O3S. Calculated, %: C 58.01; H 3.84; N 17.80.
1
2-(p-Anisyl)-5-methyl-4-[4-(p-nitrophenyl)thiazol-2-yl]-2,4-dihydro-3H-1,2,4-triazol-3-one (1i), yield
87% (3.58 g); mp 180–181°C. IR spectrum, ν, cm1: 3064 (C–H), 1713 (C=O), 1646 (C=N). 1H NMR spectrum, δ,
ppm (J, Hz): 2.45 (3H, s, 5-CH3); 3.60 (3H, s, OCH3); 6.64 (1H, s, H-5'); 7.42 (2H, d, J = 6.9, H Ar); 7.50 (2H, d,
J = 7.0, H Ar); 7.70 (2H, d, J = 8.4, H Ar); 8.21 (2H, d, J = 8.5, H Ar). 13C NMR spectrum, δ, ppm: 22.5 (CH3); 42.0
(OCH3); 99.0; 114.5; 114.8; 121.5; 121.7; 122.0; 122.2; 124.7; 130.8; 137.7; 139.2; 146.0; 148.4; 152.0; 155.0; 156.9;
173.0. Mass spectrum, m/z (Irel, %): 409 [M]+ (14), 230 (100), 203 (40), 162 (60), 134 (40), 106 (36). Found, %:
C 55.70; H 3.65; N 17.10. C19H15N5O4S. Calculated, %: C 55.74; H 3.69; N 17.11.
2-(p-Chlorophenyl)-5-methyl-4-[4-(p-nitrophenyl)thiazol-2-yl]-2,4-dihydro-1,2,4-triazole (1j), yield
92% (3.81 g); mp 137–138°C. IR spectrum, ν, cm1: 3058 (C–H), 1711 (C=O), 1640 (C=N). 1H NMR spectrum,
δ, ppm (J, Hz): 2.41 (3H, s, 5-CH3); 6.53 (1H, s, H-5'); 7.20 (2H, d, J = 7.2, H Ar); 7.55 (2H, d, J = 7.4, H Ar);
7.67 (2H, d, J = 8.0, H Ar); 8.19 (2H, d, J = 8.5, H Ar). 13C NMR spectrum, δ, ppm: 25.8; 86.0; 119.8; 120.0;
123.0; 123.5; 129.0; 129.2; 130.0; 130.4; 131.3; 136.0; 139.4; 150.0; 151.0; 154.0; 156.0; 162.0. Mass spectrum,
m/z (Irel, %): 415 [M+2]+ (10), 413 [M]+ (33), 234 (18), 236 (5), 209 (15), 207 (46), 166 (100), 168 (6), 140 (9),
138 (23), 114 (15), 112 (54). Found, %: C 52.20; H 2.88; N 16.90. C18H12ClN5O3S. Calculated, %: C 52.24;
H 2.92; N 16.92.
2-(m-Chlorophenyl)-5-methyl-4[4-(p-nitrophenyl)thiazol-2-yl]-2,4-dihydro-3H-1,2,4-triazol-3-one
(1k), yield 92% (3.84 g); mp 165–166°C. IR spectrum, ν, cm1: 3046 (C–H), 1709 (C=O), 1637 (C=N).
1H NMR spectrum, δ, ppm (J, Hz): 2.52 (3H, s, 5-CH3); 6.57 (1H, s, H-5'); 7.11–7.69 (4H, m, H Ar); 7.75 (2H,
d, J = 7.0, H Ar); 8.10 (2H, d, J = 7.0, H Ar). 13C NMR spectrum, δ, ppm: 24.6; 92.0; 119.7; 120.8; 121.0;
122.0; 122.2; 122.8; 124.5; 134.5; 139.0; 139.8; 139.6; 146.0; 148; 155; 159; 168. Mass spectrum, m/z (Irel, %):
415 [M+2]+ (16), 413 [M]+ (50), 236 (9), 234 (30), 209 (100), 207 (34), 168 (12), 166 (40), 114 (17), 112 (50).
Found, %: C 52.18; H 2.90; N 16.89. C18H12ClN5O3S. Calculated, %: C 52.24; H 2.92; N 16.92.
4-[4-(p-Bromophenyl)thiazol-2-yl]-5-methyl-2-phenyl-2,4-dihydro-3H-1,2,4-triazol-3-one (1l), yield
91% (3.75 g); mp 187–188°C. IR spectrum, ν, cm1: 3036 (C–H), 1703 (C=O), 1648 (C=N). 1H NMR spectrum,
δ, ppm (J, Hz): 2.45 (3H, s, 5-CH3); 6.50 (1H, s, H-5'); 7.37–7.80 (9H, m, H Ar). 13C NMR spectrum, δ, ppm:
21.5; 100.8; 120.6; 120.8; 124.5; 128.5; 128.8; 129.4; 129.7; 123.5; 132.0; 132.2; 132.5; 137.9; 148.5; 155.0;
159; 170.3. Mass spectrum, m/z (Irel, %): 414 [M+2]+ (24), 412 [M]+ (21), 205 (100), 178 (40), 137 (60), 109
(46), 81 (54). Found, %: C 52.30; H 3.15; N 13.50. C18H13BrN4OS. Calculated, %: C 52.31; H 3.17; N 13.56.
4-[4-(p-Bromophenyl)thiazol-2-yl]-5-methyl-2-(p-tolyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (1m),
1
yield 88% (3.78 g); mp 151–152°C. IR spectrum, ν, cm1: 3037 (C–H), 1707 (C=O), 1641 (C=N). H NMR
spectrum, δ, ppm (J, Hz): 2.32 (3H, s, CH3 Ar); 2.48 (3H, s, 5-CH3); 6.57 (1H, s, H-5'); 7.27 (2H, d, J = 7.7,
H Ar); 7.37 (2H, d, J = 8.2, H Ar); 7.49 (2H, d, J = 8.0, H Ar); 7.50 (2H, d, J = 8.2, H Ar). 13C NMR spectrum,
883

δ, ppm: 20.0 (CH3); 27.00 (CH3 Ar); 97.5; 121.5; 121.8; 124.0; 124.5; 129.0; 129.4; 130.0; 130.2; 131.9; 132.2;
132.4; 134.0; 134.5; 155.0; 157.0; 175.0. Mass spectrum, m/z (Irel, %): 428 [M+2]+ (31), 426 [M]+ (29), 221
(90), 194 (100), 166 (42), 138 (65), 110 (14). Found, %: C 53.40; H 3.50; N 13.07. C19H15BrN4OS. Calculated,
%: C 53.40; H 3.54; N 13.11.
4-[4-(p-Bromophenyl)thiazol-2-yl]-5-methyl-2-(m-tolyl)-2,4-dihydro-3H-1,2,4-triazol-3-one
(1n),
1
yield 91% (3.89 g); mp 109–110°C. IR spectrum, ν, cm1: 3061 (C–H), 1706 (C=O), 1639 (C=N). H NMR
spectrum, δ, ppm (J, Hz): 2.30 (3H, s, CH3 Ar); 2.42 (3H, s, 5-CH3); 6.62 (1H, s, H-5'); 6.84–7.35 (4H, m, H Ar);
13
7.60 (2H, d, J = 6.8, H Ar); 8.50 (2H, d, J = 6.9, H Ar). C NMR spectrum, δ, ppm: 22.2 (CH3); 23.0 (CH3 Ar);
98.0; 115.5; 121.3; 122.0; 124.5; 126.4; 129.8; 130.0; 132.6; 133.4; 133.6; 137.7; 138.4; 148.0; 150.0; 154.0;
169.0. Mass spectrum, m/z (Irel, %): 428 [M+2]+ (25), 426 [M]+ (21), 236 (9), 221 (40), 205 (100), 194 (62), 166
(35), 138 (40). Found, %: C 53.35; H 3.48; N 13.00. C19H15BrN4OS. Calculated, %: C 53.40; H 3.54; N 13.11.
2-(p-Anisyl)-4-[4-(p-bromophenyl)thiazol-2-yl]-5-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one (1o),
1
yield 86% (3.84 g); mp 210–211°C. IR spectrum, ν, cm1: 3043 (C–H), 1701 (C=O), 1645 (C=N). H NMR
spectrum, δ, ppm (J, Hz): 2.42 (3H, s, 5-CH3); 3.70 (3H, s, OCH3); 6.48 (1H, s, H-5'); 7.20 (2H, d, J = 6.5,
H Ar); 7.32 (2H, d, J = 6.6, H Ar); 7.40 (2H, d, J = 8.0, H Ar); 7.53 (2H, d, J = 8.5, H Ar). 13C NMR spectrum,
δ, ppm: 23.0 (CH3); 45.0 (OCH3); 80.0; 110.0; 110.4; 122.4; 122.7; 123.0; 125.0; 128.8; 129.0; 130.1; 131.3;
132.4; 134.6; 150.0; 151.0; 156.0; 163.0. Mass spectrum, m/z (Irel, %): 444 [M+2]+ (18), 442 [M]+ (15), 237
(100), 210 (9), 169 (67), 141 (50), 113 (69). Found, %: C 51.20; H 3.38; N 12.60. C19H15BrN4O2S. Calcu-
lated, %: C 51.48; H 3.41; N 12.64.
4-[4-(p-Bromophenyl)thiazol-2-yl]-2-(p-chlorophenyl)-5-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one
(1p), yield 89% (3.98 g); mp 159–160°C. IR spectrum, ν, cm1: 3077 (C–H), 1717 (C=O), 1641 (C=N). 1H NMR
spectrum, δ, ppm (J, Hz): 2.44 (3H, s, 5-CH3); 6.60 (1H, s, H-5'); 7.17 (2H, d, J = 7.4, H Ar); 7.46 (2H, d,
13
J = 7.6, H Ar); 7.40 (2H, d, J = 8.0, H Ar); 7.50 (2H, d, J = 8.2, H Ar). C NMR spectrum, δ, ppm: 23.0 (CH3);
94.0; 121.0; 123.0; 123.5; 128.8; 129.0; 130.2; 130.5; 131.0; 132.6; 132.9; 135.9; 143.0; 150.0; 153.0; 154.0; 168.0.
Mass spectrum, m/z (Irel, %): 449 [M+4]+ (16), 447 [M+2]+ (7), 445 [M]+ (13), 243 (100), 216 (42), 175 (11), 147
(40), 119 (65). Found, %: C 48.26; H 2.68; N 12.50. C18H12BrClN4OS. Calculated, %: C 48.29; H 2.70; N 12.51.
4-[4-(p-Bromophenyl)thiazol-2-yl]-2-(m-chlorophenyl)-5-methyl-2,4-dihydro-3H-1,2,4-triazol-
3-one (1q), yield 87% (3.92 g); mp 196–197°C. IR spectrum, ν, cm1: 3072 (C–H), 1718 (C=O), 1640 (C=N).
1H NMR spectrum, δ, ppm (J, Hz): 2.32 (3H, s, 5-CH3); 6.64 (1H, s, H-5'); 7.13–7.68 (8H, m, H Ar). 13C NMR
spectrum, δ, ppm: 24.5 (CH3); 101.0; 119.2; 120.0; 121.2; 121.4; 123.0; 123.5; 124.0; 128.4; 138.0; 138.9;
139.2; 143.4; 148.0; 151.0; 157.0; 174.0. Mass spectrum, m/z (Irel, %): 449 [M+4]+ (21), 447 [M+2]+ (16), 445
(8), 243 (75), 216 (100), 175 (60), 147 (40). Found, %: C 48.20; H 2.65; N 12.47. C18H12BrClN4OS. Calculated,
%: C 48.29; H 2.70; N 12.51.
Antimicrobial Activity Assay [31]. Compounds 1a–q were screened for their in vitro antibacterial ac-
tivity against E. coli and C. bacillus and antifungal activity against A. candida and R. bataticola. The reference
drugs used were Norfloxacin and Griseofulvin, respectively. The tests were carried out with the title compounds
and the reference drugs under identical conditions by the cup-plate method with 20 µg of the substance in 0.1 ml
of DMF. The relative percentage inhibition was calculated by the zone of inhibition in comparison with the
reference drug as follows:
Relative inhibition, % = 100 × (X – Y)/(Z – Y),
where X – total area of inhibition in test plate, Y – total area of inhibition in solvent (DMF) plate,
Z – total area of inhibition in reference plate.
The authors are grateful to Prof. (Mrs) B.V. Badami for support. The authors are also thankful to the
1
staff of USIC, K. U. Dharwad for IR, H, 13C NMR, and mass-spectral analysis. One of the authors (TMG)
acknowledges K. U. Dharwad for a University Research Studentship, and another (RRK) thanks the UGC, New
Delhi for providing financial assistance vide order No. 37-248/2009(SR).
884

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