Synthesis of 3-arylamino-6-phenyl[1, 2, 4]triazolo[3,4-b][1, 3, 4]thiadiazine derivatives as potential bioactive molecules

Article abstract of DOI:10.1007/s10593-017-2098-5

[Figure not available: see fulltext.] 4-Amino-3-arylamino-5-mercapto-1,2,4-triazoles have been used as synthons for the synthesis of fused ring system of 3-arylamino-6-phenyl[1, 2, 4]triazolo[3,4-b][1, 3, 4]thiadiazines. The reaction in high yield produce

Full text of DOI:10.1007/s10593-017-2098-5

DOI 10.1007/s10593-017-2098-5
Chemistry of Heterocyclic Compounds 2017, 53(5), 604–607
Synthesis of 3-arylamino-6-phenyl[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine
derivatives as potential bioactive molecules
Suyog Marathe1, Anil V. Karnik1*
1 Department of Chemistry, University of Mumbai,
Vidyanagari, Kalina, Santacruz (E), Mumbai – 400 098, India;
е-mail: avkarnik@chem.mu.ac.in
Published in Khimiya Geterotsiklicheskikh Soedinenii,
2017, 53(5), 604–607
Submitted June 29, 2016
Accepted after revision April 1, 2017
N
N
H
HN
N
N
S
N
N
N
R
R
N
H2N
SH
4-Amino-3-arylamino-5-mercapto-1,2,4-triazoles have been used as synthons for the synthesis of fused ring system of 3-arylamino-
6-phenyl[1,2,4]triazolo[3,4-b][1,3,4]thiadiazines. The reaction in high yield produces compounds with bridgehead nitrogen and two
separate hydrazine units in the molecule making them potential candidates for possessing various biological activities.
Keywords: 4-amino-3-arylamino-5-mercapto-1,2,4-triazoles, 3-arylamino-6-phenyl[1,2,4]triazolo[3,4-b][1,3,4]thiadiazines, (2-arylamino-
1,3,4-thiadiazol-5-yl)(benzyl)sulfones.
In the last few decades, the chemistry of N-bridgehead
heterocycles and their fused derivatives have received
significant attention owing to their structural and biological
characteristics. The presence of thiol unit in such com-
pounds in general induces excellent bactericidal and anti-
inflammatory activity.1 In addition, hydrazine moiety has
been considered as an essential structural unit in many
pharmacophores.2 1,2,4-Triazole nucleus has been incor-
porated into diverse therapeutically vital drug candidates
possessing various types of biological activity including
H1/H2 histamine receptor blocking, cholinesterase
inhibitory, CNS stimulating, antianxiety, anti-inflam-
matory, sedative, antimicrobial,3,4 antileishmanial, anti-
tubercular,5 and antiviral6 activities. Drugs containing the
1,2,4-triazole moiety, e.g., triazolam,7 alprazolam,8
etizolam,9 and furacrylin10 have entered pharmaceutical
market. Due to the presence of both triazole and thiadiazine
rings, triazolothiadiazines are known to exhibit a wide
gamut of biological properties.11
5-mercapto-1,2,4-triazoles 2a–d were synthesized by the
hydrazinolysis of N-aryl-5-(benzylsulfonyl)-1,3,4-thiadiazol-
2-amines 1a–d. According to that report, hydrazinolysis of
compounds 1a–d could result in the formation of two
alternative products, namely, 4-amino-3-arylamino-4H-
1,2,4-triazole-5-thiols 2a–d and 4-aryl-3-hydrazinyl-4H-
1,2,4-triazole-3-thiols 3a–d (Scheme 1). Several com-
pounds having 5-substituted 4-amino-3-mercapto-1,2,4-
Scheme 1
H
N
N
O
NH2NH2H2O
N
R
S
1) 100°C, 1 h
2) 150°C, 4–5 h
Bn
S
O
H
N
1a d
–
N
N
R
N
O O
H2N
2a–d
H
5-Substituted 4-amino-3-mercapto-1,2,4-triazoles have
attracted the attention of many researchers due to the
presence of reactive groups at positions 3 and 4 of the
triazole ring, as they can serve as building blocks for
synthesis of large number of heterocyclic compounds
which have wide range of biological activities.12–14
SH
N
N N
S
53–64%
Bn
R
NH2
NH2
A
S–
+
N N
N
H2N
N
H
SH
R
4-Amino-3-anilino-4H-1,2,4-triazole-5-thiol (2a) was
a R = H, b R = 2-Me, c R = 4-OMe, d R = 4-Cl
reported in 1968 by Kurzer et al.15 4-Amino-3-arylamino-
3a–d
0009-3122/17/53(05)-0604©2017 Springer Science+Business Media New York
604

Chemistry of Heterocyclic Compounds 2017, 53(5), 604–607
triazole unit have been used as a building blocks for
Based on the earlier reported bioactivities of 1,2,4-tri-
azolo[3,4-b][1,3,4]thiadiazine derivatives, it is reasonable
to expect the new compounds of this class, reported in the
present work, to exhibit good bioactivities. The compounds
have been adequately characterized. Thus, this work has
resulted into establishing yet another route to 1,2,4-triazolo-
[3,4-b][1,3,4]thiadiazines with possibility to introduce
diverse heterocyclic substituents.
formation of [1,2,4]triazolo[3,4-b][1,3,4]thiadiazines deriva-
tives. Surprisingly, 4-aryl-3-hydrazinyl-4H-1,2,4-triazole-
3-thiols, though have similar structural features, have not
been used for preparation of triazolothiadiazine derivatives.
When the reaction of 5-(benzylsulfonyl)-N-phenyl-1,3,4-
thiadiazol-2-amine (1a) and hydrazine hydrate was carried
out as reported,15 we could isolate only one product
(Scheme 1), and the melting point of the compound
conformed to that which was reported for compound 2a by
Kurzer.15 Compound 3a was not formed in the reaction.
Kurzer has proposed an open-chain intermediate A
(Scheme 1), which further cyclizes to afford compounds 2a–d
and 3a–d. We support this hypothesis and are convinced
that the same intermediate must be responsible for the forma-
tion of compounds 2a–d in our experiments, too. From the
two possible nucleophilic nitrogens, NHNH2 and ArNH,
the hydrazine nitrogen, being the more nucleophilic one,
participates in the ring closure preferentially with elimina-
tion of BnSO2H which results in the formation of com-
pounds 2a–d. In difference to the literature method, we have
used a large excess of hydrazine for the reaction, which
appears to be the primary reason for the selective formation
of compounds 2a–d over isomeric compounds 3a–d.
Experimental
IR spectra were obtained in KBr pellets on a
1
PerkinElmer Frontier Optica FT-IR spectrophotometer. H
and 13C NMR spectra of compounds 2a–d, 4a–d were
recorded on a Bruker Avance II-300 spectrometer (300 and
75 MHz, respectively) in CDCl3+DMSO-d6 using TMS as
internal standard. 13C NMR and DEPT-135 spectra of
compound 4a were recorded on a Bruker Avance 200
spectrometer (50 MHz) and those of compounds 4b–d – on a
Jeol ECX 400 spectrometer (100 MHz) in CDCl3+DMSO-d6
using TMS as internal standard. The 13C NMR signals were
assigned using DEPT-135 experiment. Mass spectra were
recorded on a GC-MSQP-1000 spectrometer using electron
impact ionization with direct sample introduction (70 eV).
Elemental analyses were carried out on a Carlo Erba EA-
1108 elemental analyzer. Monitoring of the course of
reactions and purity of the compounds obtained was carried
out by TLC on silica gel plates (eluents petroleum ether –
CHCl3 or petroleum ether – AcOEt in various proportions).
Melting points were taken on a Lab-Hosp melting point
apparatus. Compounds 2a–d were synthesized according to
the literature procedure.15 Other chemicals were purchased
and used without any further purification.
The structures of compounds 2a–d were confirmed by
analytical and spectral data. Although these compounds
were reported earlier,15 their characterization was based on
IR spectra and elemental analysis. We have unambiguously
characterized compounds 2a–d. Apart from the satisfactory
1H and 13C NMR spectra, the electron impact mass
spectrum exhibited the expected [M]+ peaks, and a
significant daughter ion fragment at m/z 118 for compound
2a which indicated presence of the fragment Ph–NH–C=N
as a part of molecule 2a. Analogous peaks were observed
in the mass spectra of compounds 2b–d. The mass
spectrum of compound 2a also gave major ion peaks at m/z
161, 104, 92, 77, and 51. This combination of mass spectral
data confirmed that the compound isolated as the sole
product was 4-amino-5-anilino-4H-1,2,4-triazole-5-thiol (2a).
Compounds 2a–d were reacted further with α-bromo-
acetophenone for the synthesis of N-aryl-6-phenyl-
Synthesis of 4-amino-3-arylamino-4H-1,2,4-triazole-5-
thiols 2a–d (General method).15 A mixture of compound
1a–d (10.06 mmol) and hydrazine hydrate (80%, 20 ml,
320 mmol) was taken into 50-ml round-bottom flask. The
reaction mixture was refluxed initially for 1 h at 100°C.
Then the temperature was increased gradually up to 150°C,
and the refluxing continued for 4–5 h. The course of
reaction was monitored by TLC. On completion of
reaction, the mixture was poured onto crushed ice and
concd HCl was added dropwise until the pH of the mixture
reached 8. The colorless precipitate obtained was filtered
off and air-dried.
7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-3-amine
4a–d
(Scheme 2). All the reactions proceeded with satisfactory
1
yields. The products were characterized on the basis of H
and 13C NMR spectra, mass spectra, and elemental
analysis. 13C DEPT experiments confirmed the presence of
one methylene (7-CH2) group in compounds 4a–d by
means of a negative phase 13C signal at 61.2–64.4 ppm.
4-Amino-5-anilino-4H-1,2,4-triazole-5-thiol (2a). Yield
53%, mp 202–204°C (mp 203–205°C15). IR spectrum, ν, cm−1:
1
3339, 3317, 2957, 1621. H NMR spectrum, δ, ppm: 4.03
(2H, s, NH2); 6.82–7.50 (5H, m, H Ar); 8.12 (1H, s, NH);
12.82 (1H, s, SH). 13C NMR spectrum, δ, ppm: 117.3;
121.5; 128.8; 139.2; 148.2. Mass spectrum, m/z (Irel, %):
207 [M]+ (100), 161 (15), 135 (27), 118 [Ph–NH–C=N]+
(58), 104 (22), 92 (28), 77 [C6H5]+ (100), 51 (34). Found, %:
C 46.26; H 4.29; N 33.86; S 15.59. C8H9N5S. Calculated, %:
C 46.36; H 4.38; N 33.79; S 15.47.
Scheme 2
4-Amino-5-(2-methylphenyl)amino-4H-1,2,4-triazole-
5-thiol (2b). Yield 53%, mp 185–187°C. IR spectrum, ν, cm−1:
1
3376, 3341, 2949, 1637, 1599. H NMR spectrum, δ, ppm:
2.22 (3H, s, CH3); 5.18 (2H, s, NH2); 6.83–7.08 (4H, m, H Ar');
7.81 (1H, s, NH); 12.82 (1H, s, SH). 13C NMR spectrum,
605

Chemistry of Heterocyclic Compounds 2017, 53(5), 604–607
δ, ppm: 17.3 (CH3); 117.6; 122.2; 126.9; 130.3; 136.7;
δ, ppm: 2.41 (3H, s, CH3); 4.33 (2H, s, CH2); 7.10–7.41
(9H, m, H Ar); 8.92 (1H, s, NH). 13C NMR spectrum,
δ, ppm: 16.1 (CH3); 59.5 (CH2); 121.0; 124.0; 125.1;
125.3; 126.7; 127.0; 129.1; 129.2; 129.4; 136.4; 153.1;
170.1. 13C DEPT-135 spectrum, δ, ppm: 18.2 (CH3); 123.1
(CH Ar); 126.2 (CH Ar); 127.2 (CH Ar); 128.9 (2CH Ar);
129.2 (CH Ar); 131.3 (CH Ar); 131.6 (2CH Ar); and it
showed the negative signal of methylene group (C-7, CH2)
at 61.6 ppm. Mass spectrum, m/z (Irel, %): 321 [M]+ (90),
289 (18), 217 (42), 132 (40), 118 [C6H5NHCN]+ (20), 105
(100), 91 (32), 77 [C6H5]+ (90), 51 (28). Found, %: C 63.41;
H 4.79; N 21.90; S 9.90. C17H15N5S. Calculated, %: C 63.53;
H 4.70; N 21.79; S 9.98.
148.1; 164.0. Mass spectrum, m/z (Irel, %): 221 [M]+ (100),
190 (18), 175 (22), 149 (11), 132 [CH3C6H4–NH–C=N]+
(24), 118 (27), 91(57), 65 (22). Found, %: C 48.97; H 4.95;
N 31.53; S 14.55. C9H11N5S. Calculated, %: C 48.85;
H 5.01; N 31.65; S 14.49.
4-Amino-5-(4-methoxyphenyl)amino-4H-1,2,4-triazole-
5-thiol (2c). Yield 63%, mp 177–179°C. IR spectrum, ν, cm−1:
1
3320, 3129, 2963, 1626. H NMR spectrum, δ, ppm: 3.67
(3H, s, OCH3); 5.12 (2H, s, NH2); 6.71–7.40 (4H, m, H Ar);
7.78 (1H, s, NH); 12.73 (1H, s, SH). 13C NMR spectrum,
δ, ppm: 55.4 (OCH3); 114.1; 118.9; 134.1; 148.5; 154.5.
Mass spectrum, m/z (Irel, %): 237 [M]+ (100), 191 (8), 165
(12), 148 [CH3OC6H4–NH–C=N]+ (24), 134 (28), 107 (16),
92 (20), 60 (10). Found, %: C 46.68; H 4.72; N 29.58;
S 13.40. C9H11N5SO. Calculated, %: C 46.56; H 4.67;
N 29.51; S 13.51.
N-(4-Methoxyphenyl)-6-phenyl-7H-[1,2,4]triazolo[3,4-b]-
[1,3,4]thiadiazin-3-amine (4c). Yield 76%, mp 113–115°C.
IR spectrum (KBr), ν, cm−1: 3387, 3059, 2928, 1601.
1H NMR spectrum, δ, ppm: 3.69 (3H, s, OCH3); 4.27 (2H,
s, CH2); 6.74–7.36 (9H, m, H Ar); 9.76 (1H, s, NH).
13C NMR spectrum, δ, ppm: 53.7 (OCH3); 60.4 (CH2);
112.5; 117.8; 125.9; 126.9; 127.4; 132.4; 135.1; 149.5; 153.2;
164.4. 13C DEPT-135 spectrum, δ, ppm: 55.5 (OCH3);
114.4 (2CH Ar), 119.7 (2CH Ar); 127.8 (CH Ar); 128.7
(2CH Ar); 129.2 (2CH Ar); and it showed the negative
signal of methylene group (C-7, CH2) at 64.4 ppm. Mass
spectrum, m/z (Irel, %): 337 [M]+ (100), 318 (60), 305 (32),
233 (32), 148 (90), 133 (50), 105 (26), 77 [C6H5]+ (52), 51
(18). Found, %: C 60.61; H 4.35; N 20.70; S 9.60.
C17H15N5SO. Calculated, %: C 60.52; H 4.48; N 20.76;
S 9.50.
4-Amino-5-(4-chlorophenyl)amino-4H-1,2,4-triazole-
5-thiol (2d). Yield 64%, mp 201–203°C. IR spectrum, ν, cm−1:
1
3352, 3316, 3047, 1634. H NMR spectrum, δ, ppm: 4.13
(2H, s, NH2); 7.11–7.53 (4H, m, H Ar); 8.48 (1H, s, NH);
12.85 (1H, s, SH). 13C NMR spectrum, δ, ppm: 118.8;
125.8; 128.6; 138.2; 148.1. Mass spectrum, m/z (Irel, %): 241
[M]+ (100), 191 (14), 165 (28), 152 [ClC6H4–NH–C=N]+
(52), 134 (24), 105 (40), 92 (54), 60 (16). Found, %: C 39.60;
H 3.43; N 28.95; S 13.35. C8H8ClN5S. Calculated, %:
C 39.75; H 3.34; N 28.97; S 13.27.
Synthesis of N-aryl-6-phenyl-7H-[1,2,4]triazolo[3,4-b]-
[1,3,4]thiadiazin-3-amines 4a–d (General method).
A mixture of compound 2a–d (1.44 mmol) and K2CO3
(0.199 g, 1.44 mmol) was taken into 25-ml round-bottom
flask, and dry DMF (5 ml) was added to it. An equimolar
quantity of α-bromoacetophenone (0.286 g, 1.44 mmol)
was added to the reaction mixture. The flask was protected
with freshly prepared calcium chloride guard-tube. The
reaction mixture was kept on water bath at 95–100°C for
2 h, then a pinch of toluene-4-sulfonic acid was added, and
reaction mixture was stirred for another 1–1.5 h at the same
temperature. After the completion of the reaction, crushed ice
was added to it. On trituration, a solid precipitated which
was filtered, air-dried, and recrystallized from ethanol.
N,6-Diphenyl-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-
3-amine (4a). Yield 85%, mp 237–240°C. IR spectrum,
N-(4-Chlorophenyl)-6-phenyl-7H-[1,2,4]triazolo[3,4-b]-
[1,3,4]thiadiazin-3-amine (4d). Yield 78%, mp 125–127°C.
1
IR spectrum, ν, cm−1: 3395, 3059, 2924, 1598. H NMR
spectrum, δ, ppm: 4.67 (2H, s, CH2); 7.13–7.69 (9H, m,
H Ar); 10.80 (1H, s, NH). 13C NMR spectrum, δ, ppm: 59.7
(CH2); 117.7; 125.2; 126.9; 127.0; 127.2; 127.3; 128.9;
129.6; 154.2; 166.8. 13C DEPT-135 spectrum, δ, ppm:
120.0 (2CH Ar); 128.8 (CH Ar); 128.9 (2CH Ar); 129.1
(2CH Ar); 131.5 (2CH Ar); and it showed the negative
signal of methylene group (C-7, CH2) at 61.6 ppm. Mass
spectrum, m/z (Irel, %): 343 [M(37Cl)]+ (33), 341 [M(35Cl)]+
(100), 309 (20), 237 (30), 152 (20), 117 (12), 105 (22), 77
[C6H5]+ (32), 51 (12). Found, %: C 56.30; H 3.50; N 20.55;
S 9.28. C16H12ClN5S. Calculated, %: C 56.22; H 3.54;
N 20.49; S 9.38.
1
ν, cm−1: 3335, 2919, 2849, 1686. H NMR spectrum,
δ, ppm: 5.33 (2H, s, CH2); 6.88–7.39 (10H, m, H Ar); 9.75
(1H, s, NH). 13C NMR spectrum, δ, ppm: 60.2 (CH2);
117.1; 122.1; 125.4; 127.3; 127.6; 127.8; 129.8; 138.2; 153.8;
167.8. 13C DEPT-135 spectrum, δ, ppm: 118.1 (2CH Ar);
123.2 (CH Ar); 128.3 (2CH Ar); 128.6 (CH Ar); 128.8
(2CH Ar); 130.9 (2CH Ar); and it showed the negative
signal of methylene group (C-7, CH2) at 61.2 ppm. Mass
spectrum, m/z (Irel, %): 307 [M]+ (100), 275 (18), 230 (12),
203 (40), 118 [C6H5NHCN]+ (50), 104 (45), 91 (12), 77
[C6H5]+ (100), 51 (32). Found, % : C 62.63; H 4.22; N 22.85;
S 10.30. C16H13N5S. Calculated, %: C 62.52; H 4.26;
N 22.78; S 10.44.
References
1. (a) Maddila, S.; Pagadala, R.; Jonnalagadda, S. B. Lett. Org.
Chem. 2013, 10, 693. (b) Holla, B. S.; Poorjary, N. K.;
Rao, S. B.; Shivananda, M. K. Eur. J. Med. Chem. 2002,
37, 511.
2. Koçyiğit-Kaymakçıoğlu, B.; Oruç, E.; Unsalan, S.;
Kandemirli, F.; Shvets, N.; Rollas, S.; Dimoglo, A. Eur. J.
Med. Chem. 2006, 41, 1253.
3. (a) Birnkammer, T.; Spickenreither, A.; Brunskole, I.;
Lopuch, M.; Kagermeier, N.; Bernhardt, G.; Dove, S.; Seifert, R.;
Elz, S.; Buschauer, A. J. Med. Chem. 2012, 55, 1147.
(b) Heindel, N. D.; Reid, J. R. J. Heterocycl. Chem. 1980, 17,
1087.
4. (a) Demirbaş, N.; Uġuruoġlu, R.; Demirbaş, A. Bioorg. Med.
Chem. 2002, 10, 3717. (b) Shivarama Holla, B.;
N-(2-Methylphenyl)-6-phenyl-7H-[1,2,4]triazolo[3,4-b]-
[1,3,4]thiadiazin-3-amine (4b). Yield 71%, mp 83–85°C.
1
IR spectrum, ν, cm−1: 3375, 3059, 2920. H NMR spectrum,
606

Chemistry of Heterocyclic Compounds 2017, 53(5), 604–607
Sooryanayarana Rao, B.; Sarojini, B. K.; Akberali, P. M.;
Keshavayya, J.; Vaidya, V. P. Eur. J. Med. Chem. 2006,
Sucheta Kumari, N. Eur. J. Med. Chem. 2006, 41, 657.
5. Shiradkar, M. R.; Murahari, K. K.; Gangadasu, H. R.;
Suresh, T.; Kalyan, C. A.; Panchal, D.; Kaur, R.; Burange, P.;
Ghogare, J.; Mokale, V.; Raut, M. Bioorg. Med. Chem. 2007,
15, 3997.
41, 1048.
12. (a) Yanchenko, V. A.; Demchenko, A. M.; Lozinskii, M. O.
Chem. Heterocycl. Compd. 2004, 40, 516. [Khim. Geterotsikl.
Soedin. 2004, 614.] (b) Özil, M.; Bodur, O.; Ülker, S.;
Kahveci, B. Chem. Heterocycl. Compd. 2015, 51, 88. [Khim.
Geterotsikl. Soedin. 2015, 51, 88.] (c) Dilanyan, E. R.;
Hovsepyan, T. R.; Melik-Ohanjanyan, R. G. Chem.
Heterocycl. Compd. 2008, 44, 1395. [Khim. Geterotsikl.
Soedin. 2008, 1712.]
6. Al-Soud, Y. A.; Al-Dweri, M. N.; Al-Masoudi, N. A.
Farmaco 2004, 59, 775.
7. Brucato, A.; Coppola, A.; Gianguzza, S.; Provenzano, P. M.
Bull. Soc. Ital. Biol. Sper. 1978, 54, 1051.
8. Coffen, D. L.; Fryer, R. I. US Patent 3849434.
9. Shiroki, M.; Tahara, T.; Araki, K. JP Patent 50100096; Chem.
Abstr. 1976, 84, 59588k.
13. Elwahy, A. H.; Abbas, A. A.; Ibrahim, Y. A. J. Chem. Res.,
Synop. 1996, 182.
14. (a) Turan-Zitouni, G.; Kaplancikli, Z. A.; Erol, K.; Kiliç, F. S.
Farmaco 1999, 54, 218. (b) Kritsanida, M.; Mouroutsou, A.;
Marakos, P.; Pouli, N. Papakonstantinou-Garoufalias, S.;
Pannecouque, C.; Witvrouw, M.; De Clercq, E. Farmaco
2002, 57, 253.
10. Povelitsa, F. D.; Gural, A. G. Antibiotiki (Moscow) 1973, 18,
71; Chem. Abstr. 1973, 78, 93044.
11. (a) Nanjunda Swamy, S..; Basappa, B. S.; Prabhuswamy, B.;
Doreswamy, B. H.; Shashidhara Prasad, J.; Rangappa, K. S.
Eur. J. Med. Chem. 2006, 41, 531. (b) Mathew, V.;
15. Kurzer, F.; Wilkinson, M. J. Chem. Soc. C 1968, 2099.
607