4
Tetrahedron
G60 (70 - 230 mesh) and using hexane/ethyl acetate 10:2 v/v, as the
eluent.
26. Data
of
4-trichloroacetyl-1-(4-methoxybenzyl)-5-methyl-1H-1,2,3-
triazole (7b): Yield 41%, yellow oil. 1H NMR (400.13 MHz, DMSO-d6):
δ 7.28 (d, J = 8.4 Hz, 2H, H-8, H-12), 6.95 (d, J = 8.5 Hz, 2H, H-9, H-
11), 5.63 (s, 2H, H-6), 3.74 (s, 3H, OCH3), 2.61 (s, 3H, CH3). 13C NMR
(100.61 MHz, DMSO-d6) δ 174.9 (CO), 159.1 (C-10), 143.3 (C-5), 135.3
(C-4), 129.3 (C-8, C-12), 126.4 (C-7), 114.2 (C-9, C-11), 94.7 (CCl3),
55.1 (OCH3), 50.4 (C-6), 9.4 (CH3). Anal. Calc. for C13H12Cl3N3O2
(348.61) C, 44.79, H, 3.47, N, 12.05 %. Found: C, 44.91, H, 3.58, N,
12.20%.
11
3
N
2
2
H3CO
F
12
7
O
NN
10
9
1
N
44
8
55
CCCll3
66
R1
R
F
5 - 7
27. Synthesis of 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxamides
(8a-c). General procedure: To a mixture of 4-trichloroacetyl-1-(2,6-
difluorobenzyl)-1H-1,2,3-triazoles (5a-c) (1 mmol) in methanol (3 ml)
was added ammonium hydroxide aqueous solution 28 – 30 % NH3 basis
(1.5 ml) and Et3N (0.5 ml) at 25 °C for 0.4 to 24 h. During this time, the
product 8a precipitated immediately, while the products 8b-c precipitate
during the reaction, as a white solids and were isolated by filtration,
washed with cold methanol, and drying under reduced pressure,
furnishing 8a-c in high degree of purity.
20. Data of 4-trichloroacetyl-1-(2,6-difluorobenzyl)-1H-1,2,3-triazole (5a):
Yield 70%, mp. 139 – 140 ºC. 1H NMR (200.13 MHz, CDCl3): δ 8.37 (s,
1H, H-5), 7.43 (tt, J = 8.4 Hz e J = 6.9 Hz, 1H, H-10), 7.06-6.98 (m, 2H;
H-9, H-11), 5.73 (s, 2H, H-6). 13C NMR (100.61 MHz, CDCl3): δ 173.9
1
3
(CO), 161.3 (dd, JC-F = 251.8 Hz, JC-F = 6.7 Hz, C-8, C-12), 139.9 (C-
3
2
4), 132.0 (t, JC-F = 10.3 Hz, C-10), 130.2 (C-5), 112.0 (dd, JC-F = 19.1
Hz, 4JC-F = 5.7 Hz, C-9, C-11), 109.7 (t, 2JC-F = 18.8 Hz, C-7), 94.4 (CCl3),
3
41.8 (t, JC-F = 4.0 Hz, C-6). Anal. Calc. for C11H6Cl3F2N3O (338.95): C,
38.80, H, 1.78, N, 12.34%. Found: C, 39.03, H, 1.79, N, 12.37%.
21. Data of 4-trichloroacetyl-1-(2,6-difluorobenzyl)-5-methyl-1H-1,2,3-
triazole (5b): Yield 60 %, mp. 109 – 110 ºC. 1H NMR (200.13 MHz,
CDCl3): δ 7.38 (tt, J = 8.3 Hz, J = 6.4 Hz, 1H, H-10), 6.99-6.95 (m, 2H,
H-9, H-11), 5.57 (s, 2H, CH2), 2.71 (s, 3H, CH3). 13C NMR (100.61
1
3
MHz, CDCl3): δ 175.5 (CO), 161.2 (dd, JC-F = 251.7 Hz, JC-F = 7.3 Hz,
3
C-8, C-12), 142.6 (C-4), 136 (C-5), 131.5 (t, JC-F = 10.2 Hz, C-10),
111.7 (dd, 2JC-F = 19.0 Hz, 4JC-F = 5.8 Hz, C-9, C-11), 109.7 (t, 2JC-F = 18.3
Hz, C-7), 94.8 (CCl3), 39.4 (t, 3JC-F = 3.6 Hz, C-6), 9.3 (CH3). Anal. Calc.
for C12H8Cl3F2N3O (352.97): C, 40.65, H, 2.27, N, 11.85%. Found: C,
40.62, H, 2.35, N, 11.83%.
28. Synthesis one-pot of Rufinamide (8a). General procedure: 2,6-
Difluorobenzyl azide (2) (1 mmol, 0.169g) and (E)-1,1,1-trichloro-4-
ethoxybut-3-en-2-one (1a) (1 mmol, 0.215g) were heated, in absence of
solvent to 130 °C for 48 h. Subsequently, methanol (3 ml) was added to
reactional mixture, followed by the addition of ammonium hydroxide
aqueous solution 28 – 30 % NH3 basis (1,5 ml) at 25 °C for 30 min.
During this time, the Rufinamide precipitated immediately as a white
solid and was isolated by filtration, washed with cold methanol, and
drying under reduced pressure, furnishing 8a in high degree of purity.
22. Data of 4-trichloroacetyl-5-phenyl-1-(2,6-difluorobenzyl)-1H-1,2,3-
triazole (5c): Yield 60 %, mp. 113 – 115 ºC. 1H NMR (200.13 MHz,
CDCl3): δ 7.54-7.51 (m, 3H, Ph), 7.36-7.25 (m, 3H, H-10 and Ph), 6.84
(t, J = 7.9 Hz, H-9, H-11), 5.46 (s, 2H, H-6). 13C NMR (100.61 MHz,
CDCl3): δ 174.4 (CO), 161.3 (dd, 1JC-F = 251.8 Hz, 3JC-F = 6.8 Hz, C-8, C-
12), 144.7 (C-4), 136.3 (C-5), 131.3 (t, 3JC-F = 10.4 Hz, C-10), 130.5 (Ph),
29. Data
of
1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxamide
2
4
(Rufinamide) (8a): Yield 50 – 60 %, mp. 240 – 241 ºC. Lit. 240 – 241
ºC.4 1H NMR (400.13 MHz, DMSO-d6): δ 8.53 (s, 1H, H-5), 7.74 (br s,
1H, NH), 7.52 (tt, J = 8.3 Hz, J = 6.8 Hz, 1H, H-10), 7.38 (br s, 1H, NH),
7.18 (t, J = 8.0 Hz, 2H, H-9, H-11), 5.72 (s, 2H, CH2). 13C NMR (100.61
129.2 (Ph), 128.8 (Ph), 125.1 (Ph), 111.4 (dd, JC-F = 19.1 Hz, JC-F = 5.7
Hz, C-9, C-11), 109.9 (t, 2JC-F = 18.3 Hz, C-7), 95.0 (CCl3), 40.4 (t, 3JC-F
3.7 Hz, C-6). HRMS (ESI): m/z calc. 415.9930 (M+H+). Found
=
415.9930.
1
3
MHz, DMSO-d6): δ 161.2 (dd, JC-F = 249.4 Hz, JC-F = 7.3 Hz, C-8, C-
23. Data of 1-benzyl-4-trichloroacetyl-1H-1,2,3-triazole (6a): Yield 48 %,
mp. 85 – 86 ºC. 1H NMR (400.13 MHz, DMSO-d6): δ 9.34 (s, 1H, H-5),
7.41-7.34 (m, 5H, H-8 to H-12), 5.74 (s, 1H, H-6). 13C NMR (100.61
MHz, DMSO-d6): δ 173.8 (CO), 137.9 (C-4), 134.8 (C-7), 132.2 (C-5),
128.6 (C-9, C-11), 128.2 (C-10), 127.9 (C-8, C-12), 94.2 (CCl3), 53.1 (C-
6). Anal. Calc. for C11H8Cl3N3O (304.56) C, 43.38, H, 2.65, N, 13.80%.
Found: C, 43.41, H, 2.67, N, 13.82%.
3
12), 161.7 (CO), 143.3 (C-4), 132.3 (t, JC-F = 10.4 Hz, C-10), 127.2 (C-
5), 112.4 (dd, 2JC-F = 18.7 Hz, 4JC-F = 5.4 Hz, C-9, C-11), 111.5 (t, 2JC-F
19.0 Hz, C-7), 41.6 (t, 3JC- F = 3.6 Hz, C-6).
=
30. Data
of
1-(2,6-difluorobenzyl)-5-methyl-1H-1,2,3-triazole-4-
carboxamide (8b): Yield 42 %, mp. 212 – 213 ºC. Lit. 208 – 210 ºC.32
1H NMR (400.13 MHz, DMSO-d6): δ 7.63 (br s, 1H, NH), 7.49 (tt, J =
8.1 Hz e J = 7.1 Hz, 1H, H-10), 7.31 (br s, 1H, NH), 7.15 (t, J = 8.0 Hz,
2H, H-9, H-11), 5.58 (s, 2H, CH2), 2.54 (s, 3H, CH3). 13C NMR (100.61
MHz, DMSO-d6): δ 163.2 (CO), δ 161.2 (dd, 1JC-F = 249.1 Hz, 3JC-F = 7.4
Hz, C-8, C-12), 138.2 (C-4), 136.7 (C-5), 132.1 (t, 3JC-F = 10.4 Hz, C-10),
24. Data of 1-benzyl-4-trichloroacetyl-5-methyl-1H-1,2,3-triazole (6b):
1
Yield 40 %, mp. 100 – 102 °C. H NMR (400.13 MHz, DMSO-d6): δ
7.42-7.35 (m, 3H, H-9 to H-11), 7.30 (d, J = 6.7 Hz, 2H, H-8, H-12),
5.72 (s, 2H, H-6), 2.61 (s, 3H, CH3). 13C NMR (100.61 MHz, DMSO-d6):
δ 174.9 (CO), 143.6 (C-5), 135.3 (C-4), 134.5 (C-7), 128.8 (C-9, C-11),
128.2 (C-10), 127.6 (C-8, C-12), 94.7 (CCl3), 50.8 (C-6), 9.4 (CH3).
Anal. Calc. for C12H10Cl3N3O (318.57) C, 45.24, H, 3.16, N, 13.19%.
Found: C, 45.29, H, 3.19, N, 13.25%.
4
112.3 (dd, 2JC-F = 18.7 Hz, JC-F = 5.9 Hz, C-9, C-11), 111.2 (t, 2JC-F = 18.8
Hz, C-7), 39.1 (C-6), 8.4 (CH3).
31. Data
of
1-(2,6-difluorobenzyl)-5-phenyl-1H-1,2,3-triazole-4-
carboxamide (8c): Yield 52 %, mp. 172 – 174 ºC. 1H NMR (400.13
MHz, DMSO-d6): δ 7.72 (br s, 1H, NH), 7.49-7.37 (m, 5H, Ph), 7.34 (br
s, 1H, NH), 7.02 (t, J = 8.1 Hz, 2H, H-9, H-11), 5.53 (s, 2H, CH2). 13C
25. Data of 4-trichloroacetyl-1-(4-methoxybenzyl)-1H-1,2,3-triazole (7a):
1
Yield 45 %, mp. 92 – 93 ºC. H NMR (400.13 MHz, DMSO-d6): δ 9.32
1
NMR (100.61 MHz, DMSO-d6): δ 162.1 (CO), 161.1 (dd, JC-F = 249.4
(s, 1H, H-5), 7.41 (d, J = 7.6 Hz, 2H, H-8, H-12), 6.97 (d, J = 7.5 Hz, 2H,
H-9, H-11), 5.68 (s, 2H, H-6), 3.75 (s, 3H, OCH3). 13C NMR (100.61
MHz, DMSO-d6): δ 174.5 (CO), 159.9 (C-10), 138.6 (C-4), 132.7 (C-5),
130.4 (C-8, C-12), 127.4 (C-7), 114.7 (C-9, C-11), 94.8 (CCl3), 55.6
(OCH3), 53.4 (C-6). Anal. Calc. for C12H10Cl3N3O2 (334.59) C, 43.08, H,
3.01, N, 12.56%. Found: C, 43.09, H, 3.01, N, 12.59%.
3
3
Hz, JC-F = 7.3 Hz, C-8, C-12), 139.2 (C-5), 139 (C-4), 131.8 (t, JC-F
=
10.5 Hz, C-10), 130.3 (Ph), 129.9 (Ph), 128.6 (Ph), 126.5 (Ph), 112.0 (dd,
2JC-F = 18.8 Hz, 4JC-F = 5.7 Hz, C-9, C-11), 111.3 (t, 2JC-F = 18.7 Hz, C-7),
3
40.6 (t, JC-F = 3.7 Hz, C-6). HRMS (ESI): m/z calc. 315.1052 (M+H+).
Found 315.1039.
32. Meier, R. EP Patent 0 199 262 A2, 1986.