Microwave-mediated InCl3-catalyzed three-component annelation of thiadiazine ring onto 4-Amino-4H-[1,2,4]triazole-3-thiol

Article abstract of DOI:10.1007/s10593-014-1509-0

A novel efficient three-component annelation of the thiadiazinyl ring onto 4-amino-4H-[1,2,4]triazole-3-thiol, catalyzed by nontoxic, recyclable InCl3 under microwave activation, has been developed. The transformation of 4-amino-5-aryl-4H-[1,2,4]triazole-3-thiol into triazolothiadiazine involves chemoselective successive double addition reaction consisting of an InCl3-catalyzed dehydrative nucleophilic addition of amino group to an aromatic aldehyde followed by addition of the resulting Schiff base to cyclohexyl isocyanide. The intramolecular cyclization of the adduct results in 3,6-diaryl-5H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine. The reaction proceeds smoothly with good yields.

Full text of DOI:10.1007/s10593-014-1509-0

Chemistry of Heterocyclic Compounds, Vol. 50, No. 4, July, 2014 (Russian Original Vol. 50, No. 4, April, 2014)
MICROWAVE-MEDIATED InCl3-CATALYZED
THREE-COMPONENT ANNELATION OF THIADIAZINЕ
RING ONTO 4-AMINO-4H-[1,2,4]TRIAZOLE-3-THIOL
1
2
3
*
V. Srivastava , P. K. Singh , and P. P. Singh
A novel efficient three-component annelation of the thiadiazinyl ring onto 4-amino-4H-[1,2,4]triazole-
3-thiol, catalyzed by nontoxic, recyclable InCl3 under microwave activation, has been developed. The
transformation of 4-amino-5-aryl-4H-[1,2,4]triazole-3-thiol into triazolothiadiazine involves
chemoselective successive double addition reaction consisting of an InCl3-catalyzed dehydrative
nucleophilic addition of amino group to an aromatic aldehyde followed by addition of the resulting
Schiff base to cyclohexyl isocyanide. The intramolecular cyclization of the adduct results in 3,6-diaryl-
5H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine. The reaction proceeds smoothly with good yields.
Keywords: indium trichloride, triazolothiadiazine, annelation, microwave synthesis, three-component
reaction.
The 1,2,4-triazole moiety is present in anastrozole [1], estazolam [2], triazolam [3], ribavirin [4],
dapiprazole [5], and cefatrizine [6], which are in clinical use as antineoplastic, sedative, hypnotic, antiviral,
antiglaucoma, and antibacterial drugs and as ultraviolet screen. In addition, 1,2,4-triazoles also exhibit various
biological activities like analgesic, antiasthmatic, diuretic, antihypertensive, anticholinergic, antibacterial,
antifungal, and anti-inflammatory activity [7-10].
Similarly, the thiadiazine nucleus is also a versatile pharmacophore, which exhibits a wide variety of
biological activity. Chlorothiazide and diazoxide, which are widely used as diuretic and antihypertensive drugs,
respectively, possess the thiadiazine moiety [11, 12]. Several s-triazolothiadiazines have found potential
application as antibacterial, antifungal, and anti-inflammatory agents [13-15]. A number of triazoles fused to
thiadiazines are incorporated into a wide variety of therapeutically important compounds possessing a broad
spectrum of biological activities [16-18]. Therefore, triazolothiadiazines appear to be attractive scaffolds that
provide a chemical with diverse drug-like library.
_______
*To whom correspondence should be addressed, e-mail: ppsingh23@gmail.com.
1Laboratory of Green Synthesis, Department of Chemistry, University of Allahabad, Allahabad – 211002, U.P.,
India; e-mail: vishalgreenchem@gmail.com.
2Food Analysis and Research Laboratory, Center of Food Technology, University of Allahabad, Allahabad –
211002, U.P., India; e-mail: dr.pks@rediffmail.com.
3Department of Chemistry, United College of Engineering & Research, Naini, Allahabad - 211010, U.P., India.
_________________________________________________________________________________________
Published in Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 625-630, April, 2014. Original article
submitted February 11, 2014.
0009-3122/14/5004-0573©2014 Springer Science+Business Media New York
573

Some 7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazines, as well as 7-unsubstituted, 7-bromo-, and 7-piperazinyl-
substituted 5H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazines synthesized by a conventional method, as well as some
1,2,4-triazoles and 1,2,4-triazolo[3,4-b][1,3,4]thiadiazines derived from 4-amino-3-mercapto-1,2,4-triazoles, are
associated with diverse pharmacological activities [19-20]. The conventional methods may suffer from any one
of the following problems – low yield, long reaction time, use of hazardous chemicals.
Recent years have witnessed a phenomenal growth in the application of microwave irradiation [21-23]
and the use of recyclable, less expensive metal halide catalysts in organic transformations. The application of
microwave irradiation in conjunction with metal halide catalyst provides an environmentally benign process
with additional advantages, such as enhanced reaction rates, higher yields of products, easier work-up, and
considerable reduction in reaction time, all of which are eco-friendly attributes in the context of green chemistry
[24-26].
As a part of our program to develop new, simple, selective, eco-friendly methodologies for the synthesis
of biodynamic heterocyclic compounds and their nucleoside analogs [27-30], we devised an original InCl3-
catalyzed microwave-activated synthesis of some novel triazolothiadiazines via site-selective double addition
reactions. The synthesis involves dehydrative nucleophilic addition of the NH2 group of triazole to an aromatic
aldehyde, yielding Schiff base that on addition of cyclohexyl isocyanide in ethanol followed by cyclocondensation
is transformed into triazolo-fused thiadiazine, the whole process being carried out in a one-pot procedure.
The strategy of the synthesis is outlined in the scheme below. A mixture of 4-amino-5-aryl-
4H-[1,2,4]triazole-3-thiol 1a-c, aromatic aldehyde 2a-d, cyclohexyl cyanide 3, and InCl3 at 60°C in ethanol was
subjected to intermittent microwave irradiation for 2 min in a microwave (MW) oven at 600 W, followed by
thorough mixing in ethanol outside the oven and irradiating again for another 2 min. This intermittent
irradiation/mixing cycle was repeated for a total irradiation time specified in Table 1 to afford triazolothia-
diazines 4a-l in 75-85% yield.
All aromatic aldehydes containing both electron-withdrawing as well as electron-donating groups
reacted well under these reaction conditions to give the corresponding products in good yields. It was found that
the reactions did not proceed when aliphatic aldehydes were used.
TABLE 1. InCl3-catalyzed Synthesis of Triazolothiadiazine under MW
and Conventional Heating
Time
Yield
Product
Ar1
Ar2
MW, min Conventional, h
MW, % Conventional, %
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-H2NC6H4 4-O2NC6H4
4-H2NC6H4 4-ClC6H4
4-H2NC6H4 4-MeC6H4
4-H2NC6H4 4-MeOC6H4
4-HOC6H4
4-HOC6H4
4-HOC6H4
4-HOC6H4
4-O2NC6H4
4-ClC6H4
4-MeC6H4
4-MeOC6H4
6
7
8
5
6
8
9
10
10
5
8
9
9
7
8
9
9
10
10
7
80
78
77
82
83
77
78
75
76
85
75
77
37
36
35
38
39
34
33
30
32
40
33
40
4a
4b
4c
4d
4e
4f
4g
4h
4i
4-O2NC6H4
4-ClC6H4
4-MeC6H4
4-MeOC6H4
4j
4k
4l
6
9
6
8
574

For comparison purpose, the reactions were also carried using a thermostated oil-bath using InCl3
catalyst at the same temperature (60°C) as for the MW-activated process for a longer (optimized) period of time
(Table 1) to ascertain whether the MW activation improved the yield or simply increased the conversion rate. It
was found that significantly lower yields (30-40%) were obtained and much higher reaction times were needed
under conventional heating. All the products 4a-l were characterized by spectral analysis. The 1H and 13C NMR
data indicated the presence of the cyclohexyl group and two aryl groups, and the mass spectra and elemental
analysis data were fully consistent with the assigned molecular formula.
The proposed mechanism for the synthesis of 5H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine
In conclusion, we have described an environmentally benign, one-pot cyclization procedure for the
synthesis of 3,6-diaryl-5H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazines by means of a three-component condensation
using a recyclable and nontoxic InCl3 catalyst under microwave irradiation conditions. The InCl3-catalyzed
procedure provides an important, novel, and facile route for the synthesis of triazolothiadiazines and may find
application in the library synthesis of related biologically active heterocyclic compounds.
EXPERIMENTAL
IR spectra were recorded on a Shimadzu FTIR-420 spectrophotometer in KBr. 1H and 13C NMR spectra
were recorded on a Bruker Avance DPX-400 FT spectrometer (400 and 100 MHz, respectively) in CDCl3 using
TMS as the internal standard. Mass spectra were recorded on a JEOL SX-102 (FAB) mass spectrometer at 6 kV
and 10 mA with an accelerating voltage of 10 kV. Elemental analyses were carried out using a Coleman
automatic CHN-analyzer. A BP 310/50 laboratory microwave oven operating at 2450 MHz and power output of
600 W was used for all the experiments. All chemicals used were of reagent grade and were used as received
without further purification.
Synthesis of Triazolothiadiazines 4a-l (General Method: Conventional Heating). A mixture of
4-amino-4H-[1,2,4]triazole-3-thiol 1a-c (1.00 mmol), aromatic aldehyde 2a-d (1.00 mmol), cyclohexyl
isocyanide 3 (0.11 g, 1.00 mmol), and InCl3 (6.64 mg, 0.03 mmol) in EtOH (25 ml) was placed in a flame-dried
50 ml round-bottom flask. The reaction mixture was stirred at 60°C. After the completion of the reaction (TLC,
n-hexane–AcOEt, 7:3), the solvent was evaporated, and the product was extracted by diethyl ether and purified
by flash column chromatography on silica gel (eluent n-hexane–AcOEt, 4:1).
(General Method: MW Activation). The reaction mixture prepared as above was subjected to MW
irradiation for 2 min at 600 W. Then the reaction mixture was thoroughly mixed outside the MW oven. The
reaction mixture was again irradiated for another 2 min and this irradiation and mixing cycle was repeated until
575

the reaction was complete (TLC, n-hexane–AcOEt, 7:3). The solvent was evaporated, and the product was
worked up as indicated above.
3-(4-Chlorophenyl)-N-cyclohexyl-6-(4-nitrophenyl)-5H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-7-amine
(4a). Mp 150-151°C. IR spectrum, ν, cm-1: 1450 (NO2), 1645 (C=N), 1670 (C=C), 2920 (cyclohexyl C–H),
3070 (Ar C–H), 3310 (N–H). 1H NMR spectrum, δ, ppm (J, Hz): 1.44-1.66 (10H, m, 5CH2); 2.56-2.58 (1H, m,
CHN); 5.10 (2H, s, 2NH); 7.55 (2H, dd, J = 7.9, J = 2.0, H Ar); 8.04 (2H, dd, J = 8.5, J = 2.1, H Ar); 8.12 (2H,
dd, J = 7.9, J = 2.0, H Ar); 8.20 (2H, dd, J = 8.5, J = 2.1, H Ar). 13C NMR spectrum, δ, ppm: 22.4; 27.1; 33.4;
48.2; 111.3; 121.3; 123.5; 127.1; 128.4; 129.4; 133.8; 134.6; 141.0; 147.6; 148.0. Mass spectrum, m/z: 468
[M]+. Found, %: C 56.15; H 4.48; N 17.90. C22H21ClN6O2S. Calculated, %: C 56.35; H 4.51; N 17.92.
3,6-Bis(4-chlorophenyl)-N-cyclohexyl-5H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-7-amine
(4b).
Mp 157-158°C. IR spectrum, ν, cm-1: 1642 (C=N), 1665 (C=C), 2918 (cyclohexyl C–H), 3065 (Ar C–H), 3305
1
(N–H). H NMR spectrum, δ, ppm (J, Hz): 1.44-1.66 (10H, m, 5CH2); 2.56-2.58 (1H, m, CHN); 5.08 (2H, s,
2NH); 7.38 (4H, dd, J = 7.9, J = 2.0, H Ar); 7.83 (4H, dd, J = 7.9, J = 2.0, H Ar). 13C NMR spectrum, δ, ppm:
22.4; 27.1; 33.4; 48.2; 111.3; 121.3; 127.6; 128.4; 128.8; 129.4; 133.0; 133.8; 134.6; 148.0. Mass spectrum, m/z:
457 [M]+. Found, %: C 57.60; H 4.60; N 15.24. C22H21Cl2N5S. Calculated, %: C 57.64; H 4.62; N 15.28.
3-(4-Chlorophenyl)-N-cyclohexyl-6-(p-tolyl)-5H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-7-amine (4c).
Mp 159-160°C. IR spectrum, ν, cm-1: 1630 (C=N), 1658 (C=C), 2912 (cyclohexyl C–H), 3050 (Ar C–H), 3300
(N–H). 1H NMR spectrum, δ, ppm (J, Hz): 1.44-1.66 (10H, m, 5CH2); 2.35 (3H, s, CH3); 2.56-2.58 (1H, m, CHN);
5.06 (2H, s, 2NH); 7.18 (2H, dd, J = 7.4, J = 1.6, H Ar); 7.25 (2H, dd, J = 7.4, J = 1.6, H Ar); 7.55 (2H, dd,
13
J = 7.9, J = 2.0, H Ar); 8.12 (2H, dd, J = 7.9, J = 2.0, H Ar). C NMR spectrum, δ, ppm (J, Hz): 20.9; 22.4;
27.1; 33.4; 48.2; 111.3; 121.3; 126.1; 128.4; 129.1; 129.4; 131.9; 133.8; 134.6; 136.9; 148.0. Mass spectrum,
m/z: 437 [M]+. Found, %: C 63.03; H 5.46; N 15.66. C23H24ClN5S. Calculated, %: C 63.07; H 5.52; N 15.99.
3-(4-Chlorophenyl)-N-cyclohexyl-6-(4-methoxyphenyl)-5H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-
7-amine (4d). Mp 154-155°C. IR spectrum, ν, cm-1: 1638 (C=N), 1662 (C=C), 2916 (cyclohexyl C–H), 3055
1
(Ar C–H), 3303 (N–H). H NMR spectrum, δ, ppm (J, Hz): 1.44-1.66 (10H, m, 5CH2); 2.56-2.58 (1H, m,
CHN); 3.73 (3H, s, OCH3); 5.07 (2H, s, 2NH); 6.94 (2H, dd, J = 7.6, J = 1.8, H Ar); 7.55 (2H, dd, J = 7.6,
J = 1.8, H Ar); 7.57 (2H, dd, J = 7.9, J = 2.0, H Ar); 8.12 (2H, dd, J = 7.9, J = 2.0, H Ar). 13C NMR spectrum,
δ, ppm: 22.4; 27.1; 33.4; 48.2; 56.0; 111.3; 114.0; 121.3; 127.2; 128.4; 129.4; 133.8; 134.6; 148.0. Mass
spectrum, m/z: 453 [M]+. Found, %: C 60.65; H 5.30; N 15.30. C23H24ClN5OS. Calculated, %: C 60.85; H 5.33;
N 15.43.
3-(4-Aminophenyl)-N-cyclohexyl-6-(4-nitrophenyl)-5H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-7-amine
(4e). Mp 144-145°C. IR spectrum, ν, cm-1: 1448 (NO2), 1643 (C=N), 1666 (C=C), 2917 (cyclohexyl C–H), 3066
1
(Ar C–H), 3306 (N–H), 3490 (NH2). H NMR spectrum, δ, ppm (J, Hz): 1.44-1.66 (10H, m, 5CH2); 2.56-2.58
(1H, m, CHN); 4.00 (2H, s, NH2); 5.06 (2H, s, 2NH); 6.56-6.59 (2H, dd, J = 7.5, J = 1.7, H Ar); 7.90 (2H, dd,
13
J = 7.5, J = 1.7, H Ar); 8.04 (2H, dd, J = 8.5, J = 2.1, H Ar); 8.21 (2H, dd, J = 8.5, J = 2.1, H Ar). C NMR
spectrum, δ, ppm: 22.4; 27.1; 33.4; 48.2; 111.3; 115.6; 121.3; 123.5; 126.5; 127.1; 127.8; 141.0; 146.7; 147.6;
148.0. Mass spectrum, m/z: 449 [M]+. Found, %: C 58.68; H 5.10; N 21.71. C22H23N7O2S. Calculated, %:
C 58.78; H 5.16; N 21.81.
3-(4-Aminophenyl)-6-(4-chlorophenyl)-N-cyclohexyl-5H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-7-amine
(4f). Mp 151-152°C. IR spectrum, ν, cm-1: 1638 (C=N), 1662 (C=C), 2915 (cyclohexyl C–H), 3061 (Ar C–H),
1
3301 (N–H), 3482 (NH2). H NMR spectrum, δ, ppm (J, Hz): 1.44-1.66 (10H, m, 5CH2); 2.56-2.58 (1H, m,
CHN); 4.00 (2H, s, NH2); 5.08 (2H, s, 2NH); 6.58 (2H, dd, J = 7.5, J = 1.7, H Ar); 7.31 (2H, dd, J = 7.9,
J = 2.0, H Ar); 7.44 (2H, dd, J = 7.9, J = 2.0, H Ar); 7.89 (2H, dd, J = 7.5, J = 1.7, H Ar). 13C NMR spectrum,
δ, ppm: 22.4; 27.1; 33.4; 48.2; 111.3; 115.6; 121.3; 126.5; 127.6; 127.8; 128.8; 133.0; 146.7; 148.0. Mass
spectrum, m/z: 438 [M]+. Found, %: C 60.10; H 5.26; N 19.12. C22H23ClN6S. Calculated, %: C 60.19; H 5.28;
N 19.14.
3-(4-Aminophenyl)-N-cyclohexyl-6-(p-tolyl)-5H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-7-amine (4g).
Mp 150-151°C. IR spectrum, ν, cm−1: 1625 (C=N), 1654 (C=C), 2908 (cyclohexyl C–H), 3045 (Ar C–H), 3300
576

1
(N–H), 3484 (NH2). H NMR spectrum, δ, ppm (J, Hz): 1.44-1.66 (10H, m, 5CH2); 2.35 (3H, s, CH3); 2.56-2.58
(1H, m, CHN); 4.00 (2H, s, NH2); 5.02 (2H, s, 2NH); 6.58 (2H, dd, J = 7.5, J = 1.7, H Ar); 7.17 (2H, dd, J = 7.9,
J = 2.0, H Ar); 7.26 (2H, dd, J = 7.9, J = 2.0, H Ar); 7.89 (2H, dd, J = 7.5, J = 1.7, H Ar). 13C NMR spectrum,
δ, ppm: 20.9; 22.4; 27.1; 33.4; 48.2; 111.3; 115.6; 121.3; 126.1; 126.5; 127.8; 129.1; 131.9; 136.9; 146.7;
148.0. Mass spectrum, m/z: 418 [M]+. Found, %: C 65.98; H 6.16; N 20.02. C23H26N6S. Calculated, %: C 66.00;
H 6.26; N 20.08.
3-(4-Aminophenyl)-N-cyclohexyl-6-(4-methoxyphenyl)-5H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-
7-amine (4h). Mp 156-157°C. IR spectrum, ν, cm-1: 1635 (C=N), 1660 (C=C), 2912 (cyclohexyl C–H), 3050
(Ar C–H), 3301 (N–H), 3488 (NH2). 1H NMR spectrum, δ, ppm (J, Hz): 1.44-1.66 (10H, m, 5CH2); 2.56–2.58 (1H,
m, CHN); 3.73 (3H, s, OCH3); 4.00 (2H, s, NH2); 5.02 (2H, s, 2NH); 6.58 (2H, dd, J = 7.5, J = 1.7, H Ar); 6.94 (2H,
dd, J = 7.6, J = 1.8, H Ar); 7.55 (2H, dd, J = 7.6, J = 1.8, H Ar); 7.89 (2H, dd, J = 7.5, J = 1.7, H Ar). 13C NMR
spectrum, δ, ppm: 22.4; 27.1; 33.4; 48.2; 56.0; 111.3; 114.0; 115.6; 121.3; 126.5; 127.2; 127.8; 146.7; 148.0; 161.2.
Mass spectrum, m/z: 434 [M]+. Found, %: C 63.47; H 6.01; N 19.32. C23H26N6OS. Calculated, %: C 63.57; H 6.03;
N 19.34.
4-[7-Cyclohexylamino-6-(4-nitrophenyl)-5H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-3-yl]phenol (4i).
Mp 150-151°C. IR spectrum, ν, cm-1: 1452 (NO2), 1644 (C=N), 1668 (C=C), 2919 (cyclohexyl C–H), 3068 (Ar
1
C–H), 3308 (N–H), 3505 (OH). H NMR spectrum, δ, ppm (J, Hz): 1.44-1.66 (10H, m, 5CH2); 2.56-2.58 (1H,
m, CHN); 5.00 (1H, s, ArOH); 5.11 (2H, s, 2NH); 6.86 (2H, dd, J = 7.7, J = 1.9, H Ar); 7.91 (2H, dd, J = 7.7,
J = 1.9, H Ar); 8.04 (2H, dd, J = 8.5, J = 2.1, H Ar); 8.21 (2H, dd, J = 8.5, J = 2.1, H Ar). 13C NMR spectrum,
δ, ppm: 22.4; 27.1; 33.4; 48.2; 111.3; 116.2; 121.3; 123.5; 127.1; 128.4; 129.1; 147.6; 148.0; 157.3. Mass
spectrum, m/z: 450. Found, %: C 58.55; H 4.82; N 18.62. C22H22N6O3S. Calculated, %: C 58.65; H 4.92;
N 18.65.
4-[6-(4-Chlorophenyl)-7-cyclohexylamino-5H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-3-yl]phenol (4j).
Mp 153-154°C. IR spectrum, ν, cm-1: 1663 (C=C), 1640 (C=N), 2917 (cyclohexyl C–H), 3063 (Ar C–H), 3303
(N–H), 3500 (OH). 1H NMR spectrum, δ, ppm (J, Hz): 1.44-1.66 (10H, m, CH2); 2.56–2.58 (1H, m, CHN); 5.00
(1H, s, ArOH); 5.09 (2H, s, NH); 6.86 (2H, dd, J = 7.7, J = 1.9, H Ar); 7.32 (2H, dd, J = 7.9, J = 2.0, H Ar);
13
7.34 (2H, dd, J = 7.9, J = 2.0, H Ar); 7.91 (2H, dd, J = 7.7, J = 1.9, H Ar). C NMR spectrum, δ, ppm: 22.4;
27.1; 33.4; 48.2; 111.3; 116.2; 121.3; 127.6; 128.4; 128.8; 129.1; 148.0; 157.3. Mass spectrum, m/z: 439 [M]+.
Found, %: C 60.02; H 5.02; N 15.90. C22H22ClN5OS. Calculated, %: C 60.06; H 5.04; N 15.92.
4-[7-Cyclohexylamino-6-(p-tolyl)-5H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-3-yl]-phenol (4k). Mp
155-156°C. IR spectrum, ν, cm-1: 1656 (C=C); 1628 (C=N); 2910 (cyclohexyl C–H); 3047 (Ar C–H); 3300 (N–H);
1
3501 (OH). H NMR specrum, δ, ppm (J, Hz): 1.44-1.66 (10H, m, CH2); 2.35 (3H, s, CH3); 2.56-2.58 (1H, m,
CHN); 5.00 (1H, s, ArOH); 5.15 (2H, s, NH); 6.86 (2H, dd, J = 7.7, J = 1.9, H Ar); 7.18 (2H, dd, J = 7.4,
J = 1.6, H Ar); 7.26 (2H, dd, J = 7.4, J = 1.6, H Ar); 7.91 (2H, dd, J = 7.7, J = 1.9, H Ar). 13C NMR spectrum,
δ, ppm: 20.9; 22.4; 27.1; 33.4; 48.2; 111.3; 116.2; 121.3; 126.1; 128.4; 129.1; 131.9; 136.9; 148.0; 157.3. Mass
spectrum, m/z: 419 [M]+. Found, %: C 65.82; H 5.98; N 16.59. C23H25N5OS. Calculated, %: C 65.84; H 6.01;
N 16.69.
4-[7-Cyclohexylamino-6-(4-methoxyphenyl)-5H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-3-yl]phenol
(4l). Mp 158-159°C. IR spectrum, ν, cm-1: 1661 (C=C), 1637 (C=N), 2914 (cyclohexyl C–H), 3053 (Ar C–H),
1
3302 (N–H), 3503 (OH). H NMR spectrum, δ, ppm (J, Hz): 1.44-1.66 (10H, m, CH2); 2.56-2.58 (1H, m,
CHN); 3.73 (3H, s, OCH3); 5.00 (1H, s, ArOH); 5.09 (2H, s, NH); 6.86 (2H, dd, J = 7.7, J = 1.9, H Ar); 6.94
(2H, dd, J = 7.6, J = 1.8, H Ar); 7.55 (2H, dd, J = 7.6, J = 1.8, H Ar); 7.91 (2H, dd, J = 7.7, J = 1.9, H Ar).
13C NMR spectrum, δ, ppm: 22.4; 27.1; 33.4; 48.2; 56.0; 111.3; 114.0; 116.2; 121.3; 127.2; 128.4; 129.1; 148.0;
157.3; 161.2. Mass spectrum, m/z: 435 [M]+. Found, %: C 63.40; H 5.72; N 16.02. C23H25N5O2S. Calculated, %:
C 63.43; H 5.79; N 16.08.
We sincerely thank SAIF, CDRI, Lucknow, and IISc Banglaore for providing microanalyses and
spectra.
577

REFERENCES
1.
2.
3.
4.
5.
6.
7.
8.
P. N. Edwards and M. S. Large, EP Pat. Appl. 0296749.
J. B. Hester, US Pat. Appl. 3701782.
J. B. Hester, A. D. Rudzik, and B. V. Kamdar, J. Med. Chem., 14, 1078 (1971).
Y. Ito, Y. Nii, S. Kobayashi, and M. Ohno, Tetrahedron Lett., 20, 2521 (1979).
B. Silvestrini and L. Baiocchi, DE Pat. Appl. 2915318.
G. L. Dunn and J. R. E. John, DE Pat. Appl. 2316866.
B. N. Goswami, J. C. S. Kataky, and J. N. Baruah, J. Heterocycl. Chem., 21, 1225 (1984).
P. J. Kothari, M. A. Mehlhoff, S. P. Singh, S. S. Parmar, and V. I. Stenberg, J. Heterocycl. Chem., 17,
1369 (1980).
9.
10.
11.
12.
13.
14.
A. K. Sengupta and H. K. Misra, J. Indian Chem. Soc., 8, 508 (1981).
S. C. Sarmah and S. C. Bahel, J. Indian Chem. Soc., 59, 877 (1982).
D. W. Robertson and M. I. Steinberg, J. Med. Chem., 33, 1529 (1990).
S. D. Longman and T. C. Hamilton, Med. Res. Rev., 12, 73 (1992).
M. Bhalla, A. Hitkari, V. R. Gujrati, T. N. Bhalla, and K. Shanker, Eur. J. Med. Chem., 29, 713 (1994).
G. Mazzone, F. Bonina, R. Pignattello, A. M. Panico, A. Caruso, M. G. Leone, M. Amico-Roxas, and
G. Blandino, Farmaco, 44, 933 (1989); Chem. Abstr., 112, 191380n (1990).
A.-R. Lee, US Pat. Appl. 5498720.
V. V. Dabholkar, P. Naik, A. Karekar, and N. Shinde, Pharma Chem., 5, № 4, 161 (2013).
G. Turan-Zitouni, Z. A. Kaplancikli, K. Erol, and F. S. Kiliç, Farmaco, 54, 218 (1999).
B. S. Holla, R. Gonsalves, and S. Shenoy, Il Farmaco, 53, 574 (1998).
A. R. Prasad, T. Ramalingam, A. B. Rao, P. W. Diwan, and P. B. Sattur, Eur. J. Med. Chem., 24, 199
(1989).
15.
16.
17.
18.
19.
20.
21.
22.
23.
S. Giri, H. Singh, L. D. S. Yadav, and R. K. Khare, J. Indian Chem. Soc., 55, 168 (1978).
B. K. Banik,M. S. Manhas, S. N. Newas, and A. K. Bose, Bioorg. Med. Chem. Lett., 3, 2363 (1993).
Q. Cheng, W. Zhang, Y. Tagami, and T. Oritani, J. Chem. Soc., Perkin Trans. 1, 452 (2001).
K. V. G. C. Sekhar, V. S. Rao, A. S. Reddy, R. Sunandini, and V. S. A. K. Satuluri, Bull. Korean Chem.
Soc., 31, 1219 (2010).
24.
25.
26.
27.
28.
29.
T. Zeigler, H.-J. Kaisers, and R. Schlömer, and C. Koch, Tetrahedron, 55, 8397 (1999).
S. Caddick, Tetrahedron, 51, 10403, (1995).
H. M. Meshram, K. C. Sekhar, Y. S. S. Ganesh, and J. S. Yadav, Synlett, 1273 (2000).
I. R. Siddiqui, P. K. Singh, J. Singh, and J. Singh, J. Agric. Food Chem., 51, 7062 (2003).
I. R. Siddiqui, P. K. Singh, J. Singh, and J. Singh, J. Chem. Res., 554 (2004).
I. R. Siddiqui, P. K. Singh, J. Singh, and J. Singh, Indian J. Chem., Sect. B: Org. Chem. Incl. Med.
Chem., 44B, 2102 (2005).
30.
P. K. Singh, V. Srivastava, J. Singh, and I. R. Siddiqui, Indian J. Chem., Sect. B: Org. Chem. Incl. Med.
Chem., 44B, 2178 (2005).
578