Month 2014
1-(5-(R-Amino)-1,2,4-thiadiazol-3-yl)propan-2-ones
N-[3-(5-methyl-1-phenyl-1 H-1,2,3-triazol-4-yl)-1,2,4-thiadiazol-
5-yl]benzamide (5c). Yield: 3.41 g (96%); white crystals; mp
bonded 1,2,4-thiadiazol-3-yl- 1,2,3-triazoles or 2-aminothio-
phenes by using low cost starting materials and mild experi-
mental conditions, providing a large variety of substituents
and allowing the discovery of new drug candidates.
1
>300ꢀС. H NMR (400 MHz, DMSO-d6): d = 2.70 (s, 3H, CH3),
7.41–7.46 (m, 3H, НPh-3,4,5), 7.63 (td, J=5.9, 3.9 Hz, 1H, НPh-4),
7.69–7.65 (m, 4H, НPh-2,3,5,6), 8.19 (dd, J=6.5, 2.8 Hz, 2H, НPh-
2,6). 13C NMR (100 MHz, Acetone-d6) d = 188.0, 173.5, 160.9,
142.1, 139.3, 136.2, 135.7, 130.8, 130.70 (2xC), 130.2 (2xC),
130.1, 128.2 (2xC), 126.4 (2xC), 10.7. MS (CI): m/z (%) = 363
(100%) [M + H+]. Anal. Calcd. for C18H14N6OS (362.41): C,
59.65; H, 3.89; N, 23.19. Found: C, 59.79: H, 3.72: N, 22.98.
N-{3-[5-methyl-1-(4-methylphenyl)-1 H-1,2,3-triazol-4-yl]-1,2,4-
EXPERIMENTAL
All melting points were determined in capillary tubes in a
Thiele apparatus and are uncorrected. 1H NMR spectra were
1
recorded on a Varian Mercury 400 instrument (400 MHz for H
1
100MHz for 13C) and Bruker 500 (500 MHz for H, 125 MHz
thiadiazol-5-yl}benzamide (5d).
Yield: 3.50 g (93%); white
for 13C) with TMS or deuterated solvent as an internal reference.
Mass spectra were run using Agilent 1100 series LC/MSD with
an API-ES/APCI ionization mode (Agilent Technologies, Sta.
Clara, CA). The evolution of the reactions and purity of the syn-
thesized compounds were monitored chromatographically on
Silufol UV-254 plates.
crystals; mp >300ꢀС. 1H NMR (400 MHz, DMSO-d6): d = 2.44 (s,
3H, CH3), 2.67 (s, 3H, CH3), 7.41–7.44 (m, 3H, НPh-3,4,5), 7.45
(d, J=8.40 Hz, 2H, НAr-3,5), 7.54 (d, J=8.28 Hz, 2H, НAr-2,6),
8.19 (dd, J = 6.58, 3.10 Hz, 2H, НPh-2,6). 13C NMR (100 MHz,
Acetone-d6) d = 188.1, 173.4, 160.7, 142.1, 139.8, 139.4,
135.6, 133.9, 130.9, 130.7 (2xC), 130.2 (2xC), 128.3 (2xC),
126.1 (2xC), 13.5, 10.6. MS (CI): m/z (%) = 377 (100%)
[M + H+]. Anal. Calcd. for C19H16N6OS (376.43): C, 60.62; H,
4.28; N, 22.33. Found: C, 60.47; H, 4.03; N, 22.49.
Starting 1-(5-(R-amino)-1,2,4-thiadiazol-3-yl)propan-2-ones
3a–c were prepared by the following procedure. Compound 3a:
The mixture of phenylisocyanate 1a (1.20 mL, 10 mmol) and 3-ami-
noisoxazole 2 (0.98 g, 10 mmol) in acetonitrile (10 mL) was heated
under reflux for 2 h, cooled to room temperature. The formed solid
was filtered off and used without further purification. Characteristic
data coincide with Vivona et al. [2c]. Compounds 3b,c: To the solu-
tion of acid chloride (1 mmol) in acetonitrile (10 mL) KSCN (0.11 g,
1.1 mmol) was added under vigorously stirring. The mixture
was stirred at 60ꢀC for 30 min and 3-aminoisoxazole 2 (0.098 g,
0.001 mol) was added. The mixture was left for stirring at 60ꢀC
for 1 h, then cooled to room temperature and diluted with
water (20 mL). The formed precipitate was filtered off and crystal-
lized. Characteristic data compounds 3b,c coincide with literature
data [2d,e].
N-{3-[1-(4-chlorophenyl)-5-methyl-1 H-1,2,3-triazol-4-yl]-1,2,4-
thiadiazol-5-yl}benzamide (5e).
Yield: 3.81 g (96%); white
crystals; mp >300ꢀС. 1H NMR (400 MHz, DMSO-d6): d =2.77 (s,
3
3Н, CH3), 7.36-7.40 (m, 3H, НPh-3,4,5), 7.64 (d, J=8.8Hz, 2H,
НAr-3,5), 7.68 (d, 3J= 8.8 Hz, 2H, НAr-2,6), 8.17-8.23 (m, 2H,
НPh-2,6). MS (CI): m/z (%) = 397 (100%) [M + H+]. 13C NMR
(100 MHz, Acetone-d6) d = 187.9, 173.8, 160.8, 141.9, 139.6,
135.8, 135.2, 134.3, 130.9, 130.7 (2xC), 129.3 (2xC), 128.7 (2xC),
128.0 (2xC), 11.0. Anal. Calcd. for C18H13ClN6OS (396.85): C,
54.48; H, 3.30; N, 21.18. Found: C, 54.31; H, 3.52; N, 21.00.
General procedure for 1-aryl-1 H-1,2,3-triazoles 5a,с one-pot
synthesis.
To the solution of isocyanates 1a or 1c (10 mmol)
Synthesis of 1-aryl-1H-1,2,3-triazoles (5a–e). To the solution
of sodium methoxide (540 mg, 10.0 mmol) in dry methanol (20 mL),
in acetonitrile (20 mL) 3-aminoisoxazole 2 (0.98g, 10mmol),
arylazide 4 (10 mmol) and Et3N (1.4 mL, 10 mmol) were added
under vigorously stirring. The mixture was stirred at 60ꢀC for 2h,
then cooled to room temperature and diluted with water (20 mL).
The formed precipitate was filtered off and crystallized.
Compounds 5a and 5c were isolated in 17 and 39% yields,
correspondingly.
appropriate 1-(5-(R-amino)-1,2,4-thiadiazol-3-yl)propan-2-one
3
(10.0 mmol) was added. To this solution, arylazide 4 (10.0 mmol)
in dry methanol (2 mL) was added dropwise. The mixture was
stirred till precipitate formation. The resulting suspension was
filtered, and the solid product was washed with water and methanol
to give the corresponding triazole 5.
3-(5-Methyl-1-phenyl-1 H-1,2,3-triazol-4-yl)-N-phenyl-1,2,4-
thiadiazol-5-amine (5a). Yield: 2.81 g (84%); white crystals;
mp 228–229ꢀС. 1H NMR (400 MHz, DMSO-d6): d = 2.71 (s,
General procedure for thiophene 7a-с synthesis. Morpholine
(0.76 g, 0.9 mL, 10.4 mmol) was added dropwise to the solution
containing 1-(5-(R-amino)-1,2,4-thiadiazol-3-yl)propan-2-one
3
3
3
(10.0 mmol), ethyl cyanoacetate 6 (1.47 g, 1.11 mL, 10.41 mmol)
and sulfur (0.35 g, 10.93 mmol) in ethanol (10 mL) with a few
drops of DMF. The mixture was stirred at 70ꢀC to complete sulfur
disappearance and precipitate formation. The resulting suspension
was cooled to room temperature and filtered. The solid product was
washed with methanol to give the corresponding thiophene 7.
Ethyl 2-amino-4-methyl-5-[5-(phenylamino)-1,2,4-thiadiazol-3-
3Н, CH3), 7.04 (t, J = 8.8 Hz, 1H, НPh-4), 7.36 (t, J = 8.8 Hz,
3
2H, НPh-3,5), 7.58 (d, J = 8.8 Hz, 2H, НPh-2,6), 7.59-7.65 (m,
5H, НPh), 11.21 (br.s, 1H, NH). 13C NMR (100 MHz, Acetone-
d6) d = 177.8, 165.3, 143.7, 138.9, 138.5, 136.6, 130.8, 130.7
(2xC), 130.4 (2xC), 126.4 (2xC), 123.9, 119.0 (2xC), 11.00.
MS (CI): m/z (%) = 335 (100%) [M + H+]. Anal. Calcd. for
C17H14N6S (334.40): C, 61.06; H, 4.22; N, 25.13. Found: C,
60.83; H, 4.04; N 25.01.
yl]thiophene-3-carboxylate (7a).
Yield: 2.45 g (68%); white
crystals; mp 175–176ꢀС. 1H NMR (500 MHz, DMSO-d6): d =1.32
(t, J=7.2 Hz, 3H, CH3), 2.78 (s, 3H, CH3), 4.25 (q, J=7.2 Hz, 2H,
CH2), 7.10 (t, J=7.4 Hz, 1H, НPh-4), 7.42 (t, J=7.8 Hz, 2H, НPh-
3,5), 7.60 (d, J=7.8 Hz, 2H, НPh-2,6), 7.72 (s, 2H, NH2), 10.96 (s,
1H, NH). 13C NMR (125 MHz, CDCl3) d 178.0, 165.9, 165.6,
165.1, 140.4, 138.7, 129.8 (2xC), 123.3, 118.1 (2xC), 112.1, 106.1,
59.6, 16.6, 14.8. MS (CI): m/z (%) = 361 (100%) [M + H+]. Anal.
Calcd. for C16H16N4O2S2 (360.45): C, 53.31; H, 4.47; N, 15.54.
Found: C, 53.18; H, 4.63; N, 15.70.
Ethyl [3-(5-methyl-1-phenyl-1 H-1,2,3-triazol-4-yl)-1,2,4-thiadiazol-
5-yl]carbamate (5b).
Yield: 2.65 g (80%); white crystals; mp
>300ꢀС. 1H NMR (400 MHz, DMSO-d6): d =1.23 (t, 3J=7.2Hz, 3Н,
CH3), 2.70 (s, 3Н, CH3), 4.05 (q, 3J= 7.2 Hz, 2H, CH2), 7.55–7.64 (m,
5H, НPh). 13C NMR (100 MHz, Acetone-d6) d = 187.8, 173.9, 155.1,
142.1, 138.9, 136.2, 130.4 (2xC), 130.0, 126.5 (2xC), 61.9, 14.3, 10.9.
MS (CI): m/z (%) = 331 (100%) [M + H+]. Anal. Calcd. for
C14H14N6O2S (330.36): C, 50.90; H, 4.27; N, 25.44. Found: C, 50.77;
H, 4.51; N, 25.26.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet