S.P. Aytaç et al. / European Journal of Medicinal Chemistry 44 (2009) 4528–4538
4535
H-2, H-6), 13.41 (s, 1H, NH); MS (70 eV, EI): m/z (%): 250 (Mþ,
86.36%), 234 (Mþ –NH2, 2.61%), 134 (CH3OC6H4CHCH2, 50.44%), 121
(CH3OC6H4CH2, 100%), 91 (C7H7, 17.39%), 77 (C6H5, 20.87%). Anal.
Calcd. for C11H14N4OS: C, 52.78; H, 5.64; N, 22.38; S, 12.81. Found: C,
52.46; H, 5.57; N, 22.38; S, 12.71.
6.1.2.2. 3-(4-Methoxyphenylmethyl)-6-(4-chlorophenyl)-7H-1,2,4-
triazolo[3,4-b]-1,3,4-thiadiazine (1b). Yield 56%; m.p. 188–190 ꢀC (It
is precipitated with H2NOH sol.); IR (KBr): 1610 (C]N), 1301 (C–N),
1249 (C–O) cmꢁ1; 1H NMR
d (ppm): 3.72 (s, 3H, OCH3), 3.95 (s, 2H,
CH2), 4.30 (s, 2H, SCH2), 6.84 (d, 2H arom. H-3, H-5), 7.29 (d, 2H,
arom. H-2, H-6), 7.52 (d, 2H, arom. H0-2, H0-6), 7.81 (d, 2H, arom. H-
30, H-50); MS (70 eV, EI): m/z (%): 374 (Mþ þ4, 2.42%), 372 (Mþ þ2,
35.76%), 370 (Mþ, 100%), 355 (Mþ –CH3, 15.76%), 338 (Mþ –S,
12.73%), 337 (Mþ –SH, 10.30%), 335 (Mþ –Cl, 13.33%), 259 (Mþ
–C6H4Cl, 26.67%), 233 (Mþ –ClC6H4CN, 7.27%), 218 ([Mþ
–(ClC6H4CN þ CH3)], 27.88%), 147 (CH3OC6H4CH2CN, 75.44%), 132
([CH3OC6H4CH2CN-CH3], 48.49%), 121 (CH3OC6H4CH2, 79.39%), 111
($C6H4Cl, 30.45%). Anal. Calcd. for C18H15ClN40S: C, 58.30; H, 4.08;
N, 15.11; S, 8.64. Found: C, 57.98; H, 3.92; N, 14.99; S, 8.54.
6.1.1.3. 4-Amino-3-(3,4,5-trimethoxyphenylmethyl)-1,2,4-triazole-5-
thione (3). Yield 47%; mp 173–175 ꢀC (benzene-methanol); IR
(KBr): 3300, 3234 (N–H), 1591 (C]N), 1311 (C–N), 1244 (C–O), 1182
(C]S) cmꢁ1 1H NMR
; d (ppm): 3.83 (s, 3H, OCH3), 3.85 (s, 6H,
OCH3), 4.02 (s, 2H, CH2), 4.57 (s, 2H, NH2), 6.52 (s, 2H, arom. H-2, H-
6), 10.56 (s, 1H, NH); MS (70 eV, EI): m/z (%): 296 (Mþ, 100%), 281
(Mþ –CH3, 32,14%), 280 (Mþ –NH2, 57.86%), 264 (Mþ –S, 4.29%), 192
((H3CO)3C6H2CH2CN–CH3, 12.14%), 181 ((CH3O)3C6H2CH2, 8.57%).
Anal. Calcd. for C12H16N4O3S: C, 48.64; H, 5.44; N, 18.91; S, 10.82.
Found: C, 48.60; H, 5.44; N, 18.72; S, 10.80.
6.1.2.3. 3-(4-Methoxyphenylmethyl)-6-(4-fluorophenyl)-7H-1,2,4-tri-
azolo[3,4-b]-1,3,4-thiadiazine (1c). Yield 47%; m.p. 192–193 ꢀC
(ethanol); IR (KBr): 1600 (C]N), 1307 (C–N), 1249 (C–O) cmꢁ1 1H
;
6.1.1.4. 4-Amino-3-[2-(3,4,5-trimethoxyphenyl)ethyl]-1,2,4-triazole-
NMR
d (ppm): 3.78 (s, 3H, OCH3), 3.94 (s, 2H, CH2), 4.29 (s, 2H,
5-thione (4). Yield 70%; m.p. 139–140 ꢀC (chloroform); IR (KBr):
SCH2), 6.84 (d, 2H, arom. H-3, H-5), 7.20–7.22 (m, 2H, arom. H-30, H-
50), 7.29 (d, 2H, arom. H-2, H-6) 7.86–7.91 (m, 2H, arom. H-20, H-60);
MS (70 eV, EI): m/z (%): 356 (Mþ þ2, 6.88%), 354 (Mþ, 100%), 339
(Mþ –CH3, 15.63%), 322 (Mþ –S, 1.88%), 321 (Mþ –SH, 10.00%), 259
(Mþ –C6H4F, 10.00%), 233 (Mþ –C6H5CN, 8.13%), 218 ([Mþ
–(FC6H4CN þ CH3)], 21.88%), 147 (CH3OC6H4CH2CN, 63.13%), 132
(CH3OC6H4CH2CN–CH3, 28.75%), 121 (CH3OC6H4CH2, 72.50%), 95
(C6H4F, 23.75%). Anal. Calcd. for C18H15FN4OS: C, 61.00; H, 4.27; N,
15.81; S, 9.05. Found: C, 61.32; H, 4.30; N, 15.87; S, 9.08.
3294 (N–H), 1587 (C]N),1311 (C–N), 1242 (C–O), 1188 (C]S) cmꢁ1
;
1H NMR
d (ppm): 2.93 (t, 4H, CH2CH2), 3.62 (s, 3H, OCH3), 3.74 (s,
6H, OCH3), 5.52 (s, 2H, NH2), 6.52 (s, 2H, arom. H-2, H-6), 13.44 (s,
1H, NH); MS (70 eV, EI): m/z (%): 310 (Mþ, 50.87%), 181
((CH3O)3C6H2CH2, 100%). Anal. Calcd. for C13H18N4O3S: C, 50.31; H,
5.85; N, 18.05; S, 10.33. Found: C, 49.96; H, 5.81; N, 17.88; S, 10.34.
6.1.2. Synthesis of 3,6-disubstituted 7H-1,2,4-triazolo[3,4-b]-1,3,4-
thiadiazines (1a–4c) [8–10]
A mixture of the corresponding triazoles 1–4 (1 mmol) and
phenacyl halogenes (1 mmol) in anhydrous ethanol (20 mL) was
heated under reflux. Reactions were ended under control of TLC. The
mixture was then cooled to the room temperature and neutralized
with 20% ammonium hydroxide solution. The separated precipitate
was collected by filtration and purified with crystallization.
Compound 1a [38] has already been reported. Since there are
only NMR findings describing compound 1a in literature, all spectral
analysis was performed. Single crystal X-ray crystallographic and
spectral data of the compounds 2a and 4a have been submitted
elsewhere for publication. Compounds 1b (886949-15-1) and 1c
(933228-88-7) are seen as commercial products in ‘‘Science Finder.’’
Because there is no information in the literature for the preparation
and spectral characteristics, these two compounds have been
included in our researchprogram and characterized byspectral data.
Yields, melting points, spectral and analytical data of all
synthesized compounds are given below.
6.1.2.4. 3-[2-(4-Methoxyphenyl)ethyl]-6-phenyl-7H-1,2,4-triazolo[3,4-
b]-1,3,4-thiadiazine (2a). Yield 64%; m.p. 142–143 ꢀC (ethanol). All
spectral data have been submitted for publication.
6.1.2.5. 3-[2-(4-Methoxyphenyl)ethyl]-6-(4-chlorophenyl)-7H-1,2,4-
triazolo[3,4-b]-1,3,4-thiadiazine (2b). Yield 53%; m.p. 141–142 ꢀC
(ethanol); IR (KBr): 1616 (C]N), 1300 (C–N), 1249 (C–O) cmꢁ1 1H
;
NMR d (ppm): 3.12 (t, 2H, CH2CH2), 3.31 (t, 2H, CH2CH2), 3.70 (s, 3H,
OCH3), 3.91 (s, 2H, SCH2), 6.74 (d, 2H, arom. H-3, H-5), 7.09 (d, 2H,
arom. H-2, H-6), 7.52 (d, 2H, arom. H-20, H-60), 7.78 (d, 2H, arom. H-
30, H-50); MS (70 eV, EI): m/z (%): 388 (Mþ þ4, 0.97%), 386 (Mþ þ2,
17.10%), 384 (Mþ 45.81%), 369 (Mþ –CH3, 1.61%), 351 (Mþ –SH,
1.29%), 247 (Mþ, –ClC6H4CN, 2.58%), 232 ([Mþ –(ClC6H4CN þ CH3)],
36.13%), 134 (CH3OC6H4CHCH2, 9.68%), 121 (CH3OC6H4CH2, 100%),
111 (C6H4Cl, 6.45%). Anal. Calcd. for C19H17ClN40S: C, 59.29; H, 4.45;
N, 14.56; S, 8.33. Found: C, 59.13; H, 4.44; N, 14.70; S, 8.37.
6.1.2.6. 3-[2-(4-Methoxyphenyl)ethyl]-6-(4-fluorophenyl)-7H-1,2,4-
triazolo[3,4-b]-1,3,4-thiadiazine (2c). Yield 61%; m.p. 155–156 ꢀC
6.1.2.1. 3-(4-Methoxyphenylmethyl)-6-phenyl-7H-1,2,4-triazolo[3,4-
(ethanol); IR (KBr): 1598 (C]N), 1300 (C–N), 1247 (C–O) cmꢁ1 1H
;
b]-1,3,4-thiadiazine (1a) [38]. Yield 54%; m.p. 153–154 ꢀC (ethanol);
IR (KBr): 1610 (C]N), 1301 (C–N), 1246 (C–O) cmꢁ1 1H NMR
;
NMR d (ppm): 3.14 (t, 2H, CH2CH2), 3.35 (t, 2H, CH2CH2), 3.70 (s, 3H,
d
(ppm): 3.79 (s, 3H, OCH3), 3.95 (s, 2H, CH2), 4.25 (s, 2H, SCH2), 6.85
OCH3), 3.95 (s, 2H, SCH2), 6.74 (d, 2H, arom. H-3, H-5), 7.10 (d, 2H,
arom. H-2, H-6), 7.22–7.26 (m, 2H, arom. H-30, H-50), 7.85–7.88 (m,
2H, arom. H-20, H-60); MS (70 eV, EI): m/z (%): 370 (Mþ þ2, 6.00%),
368 (Mþ, 79.33%), 353 (Mþ –CH3, 3.00%), 335 (Mþ –SH, 1.67%), 247
(Mþ –FC6H4CN, 3.33%), 232 ([Mþ –(FC6H4CN þ CH3)], 41.33%), 134
(CH3OC6H4CHCH2, 10.67%), 121 (CH3OC6H4CH2, 100%), 95 (C6H4F,
12.00%). Anal. Calcd. for C19H17FN4OS: C, 61.94; H, 4.65; N, 15.21; S,
8.70. Found: C, 61.82; H, 4.74; N, 15.08; S, 8.80.
(d, 2H, arom. H-3, H-5), 7.32 (d, 2H, arom. H-2, H-6), 7.52–7.61 (m,
3H, arom. H-30, H-40, H-50), 7.87 (d, 2H, arom. H-20, H-60); 13C NMR
d
(ppm): 23.45 (–CH2–), 29.85 (-SCH2-), 55.71 (–OCH3), 114.60
(arom. C-3, C-5), 128.12 (arom. C-30, C-50), 128.61 (arom. C-40),
129.76 (arom. C-20, C-60), 130.54 (arom. C-2, C-6), 132.59 (arom. C-
1), 134.18 (arom. C-10), 140.93 (C-8a), 153.52 (arom. C-4), 155.36 (C-
3), 158.75 (C-6); MS (70 eV, EI): m/z (%): 338 (Mþ þ2, 7.90%), 336
(Mþ, 100%), 321 (Mþ –CH3, 14.91%), 304 (Mþ –S, 2.63%), 303 (Mþ
–SH, 11.40%), 259 (Mþ –C6H5, 18.42%), 233 (Mþ –C6H5CN, 10.53%),
218 (Mþ –[(C6H5CN) þ CH3], 20.18%), 147 (CH3OC6H4CH2CN,
75.44%), 132 ([CH3OC6H4CH2CN-CH3], 33.33%), 121 (CH3OC6H4CH2,
50.0%), 77 (C6H5, 61.40%). Anal. Calcd. for C18H16N4OS: C, 64.27; H,
4.79; N, 16.65; S, 9.53. Found: C, 64.12; H, 4.89; N, 16.75; S, 9.45.
6.1.2.7. 3-(3,4,5-Trimethoxyphenylmethyl)-6-phenyl-7H-1,2,4-triazolo-
[3,4-b]-1,3,4-thiadiazine (3a). Yield 70%; m.p. 170–171.5 ꢀC
(ethanol); IR (KBr): 1587 (C]N), 1330 (C–N), 1240 (C–O) cmꢁ1 1H
;
NMR
d (ppm): 3.77 (s, 6H, OCH3), 3.81 (s, 3H, OCH3), 3.98 (s, 2H,