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139
CF3-C2, J = 271.8 Hz), 120.85 (C-6), 124.61 (q, CF3-C5,
J = 271.8 Hz), 124.62 (q, C-5, J = 32.2 Hz), 138.32 (C-3a),
139.06 (C-7a), 142.61 (q, C-2, J = 40.3 Hz) ppm; MS: m/z
(% relative intensity) 254 (M+, 100), 234 (60), 215 (22), 204
(5), 184 (15); HRMS: calc. for C9H4F6N2: 254.0278, found:
254.0278.
dark purple–colored liquid, which was used immediately in a
subsequent step without purification.
5.4. Synthesis of precursors 14–16, 19–23
5.4.1. N-[2-Nitro-4-(trifluoromethyl)phenyl]acetamide (14)
A
stirred mixture of 4-(trifluoromethyl)-2-nitroaniline
5.2.5. 5(6)-Cyano-2-(trifluoromethyl)-1H-benzimidazole (5)
Eluted with hexane and recrystallized from cyclohexane-
CH2Cl2. Yield 7.98 g (93%) of white solid. M.p. 183–184 °C.
1H NMR (300 MHz, DMSO-d6) δ 7.48 (dd, 1H, H-6, J6,7
= 9.0, J6,4 = 0.9 Hz), 7.86 (d, 1H, H-7, J7,6 = 9.0 Hz), 8.34
(d, 1H, H-4, J4,6 = 0.9 Hz), 14.4 (bs, 1H, N-H) ppm; 13C
NMR (75.5 MHz, DMSO-d6) δ 106.3 (C-5), 118.6 (q, CF3,
J = 271.8 Hz), 117 (C-7), 119.2 (CN), 126.7 (C-4), 127.3
(C-6), 142.9 (q, C-2, J = 39.1 Hz); MS: m/z (% relative inten-
sity) 211 (M+, 100), 191 (68); HRMS: calc. for C9H4F3N3:
211.1436, found: 211.1438.
(12.2 g, 0.0591 mol), acetic anhydride (9.78 g, 9.06 ml,
0.0882 mol, 1.5 eq) and three drops of H2SO4 was heated at
80 °C for 1 h. The mixture was cooled, worked up by addition
of cold water and filtered by suction. The crude product was
recrystallized from hexane. Yield 14.2 g (97%) of white crys-
1
tals. M.p. 112–113 °C. H NMR (300 MHz, CDCl3) δ 2.38 (s,
3H, CO-CH3), 7.87 (dd, 1H, H-5, J5,3 = 3.1, J5,6 = 9.0 Hz),
8.51 (d, 1H, H-3, J3,5 = 3.1 Hz), 9.06 (d, 1H, H-6, J6,5
= 9.0 Hz) ppm; MS: m/z (% relative intensity) 248 (M+,10),
206 (100), 176 (20).
5.4.2. N-methyl-N-[2-nitro-4-(trifluoromethyl)phenyl]
acetamide (15)
5.2.6. 1-Methyl-2,5-bis(trifluoromethyl)-1H-benzimidazole (6)
Eluted with hexane and recrystallized from ethanol. Yield
10 g (71%) of white solid. M.p. 56–58 °C. 1H NMR
(300 MHz, CDCl3) δ 4.00 (s, 3H, CH3), 7.55 (d, 1H, H-7,
J7,6 = 8.7 Hz), 7.69 (dd, 1H, H-6, J6,4 = 1.5, J6,7 = 8.7 Hz),
8.16 (d, 1H, H-4, J4,6 = 1.5 Hz) ppm; 13C NMR (75.5 MHz,
CDCl3) δ 31.12 (d, N-CH3, J = 2.0 Hz), 110.83 (C-7), 118.74
(q, CF3-C2, J = 271.9 Hz), 119.50 (q, C-4, J = 4.0 Hz), 122.14
(q, C-6, J = 4.1 Hz), 124.34 (q, CF3-C5, J = 275.9 Hz), 126.39
(q, C-5, J = 33.2 Hz), 137.83 (C-3a), 140.38 (C-7a), 142.77 (q,
C-2, J = 38.3 Hz) ppm; MS: m/z (% relative intensity) 268
(M+, 100), 249 (30), 218 (10), 197 (5); HRMS: calc. for
C10H6F6N2 (M+) m/z: 268.0435, found 268.0440.
Into a stirred mixture of 9 (14.1 g, 0.0572 mol) in dimethyl
sulfate (10.82 g, 8.11 ml, 0.0858 mol, 1.5 eq) and monoglyme
(14 ml) was added a solution of KOH 50% m/v (4.81 g,
0.0858 mol, 1.5 eq) at 32–35 °C. The mixture was cooled,
worked up by addition of cold water and extracted with
EtOAc. The combined organic extracts were washed with
brine, dried with anhydrous Na2SO4 and concentrated in vacuo
to give an orange liquid (14.78 g, 98.6%), which was immedi-
ately hydrolyzed in the next step.
5.4.3. N-methyl-2-nitro-4-(trifluoromethyl)aniline (16)
A solution of 15 (14 g, 0.0533 mol) in concentrated sulfuric
acid (15 ml) and water (1 ml) was heated at 80–90 °C for
15 min, and then cooled to room temperature. Ice (250 g)
was added and the precipitated solid was removed by filtration
and washed several times with water until neutral pH. It was
recrystallized from ethanol to give yellow pale needles
5.2.7. 1-Methyl-2,6-bis(trifluoromethyl)-1H-benzimidazole (7)
Eluted with hexane and recrystallized from ethanol. Yield
2.4 g (64%) of white solid. M.p. 122–124 °C. 1H NMR
(300 MHz, CDCl3) δ 4.05 (s, 3H, CH3), 7.66 (dd, 1H, H-5,
J5,7 = 1.7, J5,4 = 8.7 Hz), 8.01 (d, 1H, H-4, J4,5 = 8.7 Hz),
8.31 (d, 1H, H-7, J7,5 = 1.7 Hz) ppm; 13C NMR (75.5 MHz,
CDCl3) δ 31.44 (d, N-CH3, J = 2.1 Hz), 110.36 (q, C-7,
J = 4.9 Hz), 118.71 (q, CF3-C2, J = 272.2 Hz), 119.89 (q, C-
5, J = 3.5 Hz), 122.82 (C-4), 124.57 (q, CF3-C6,
J = 272.9 Hz), 125.61 (q, C-6, J = 31.7 Hz), 126.38 (C-7a),
135.68 (C-3a), 142.65 (q, C-2, J = 25.4 Hz) ppm; MS: m/z
(% relative intensity) 268 (M+, 100), 249 (30), 218 (20), 197
(20), 145 (10); HRMS: calc. for C10H6F6N2 (M+) m/z:
268.0435, found 268.0431.
1
(11.72 g, 98%). M.p. 73–75 °C. H NMR (300 MHz, CDCl3)
δ 3.05 (s, 3H, N-CH3), 6.94 (d, 1H, H-6, J6,5 = 8.8 Hz), 7.65
(dd, 1H, H-5, J5,6 = 8.8, J5,3 = 1.8 Hz), 8.48 (d, 1H, H-3, J3,5
= 1.8 Hz) ppm; MS: m/z (% relative intensity) 220 (M+,60),
201 (10), 145 (30), 127 (30), 105 (100).
5.4.4. 2,2,2-Trifluoro-N-[2-nitro-5-(trifluoromethyl)phenyl]
acetamide (19)
Into a cooled solution of compound 18 (6 g, 0.0372 mol) in
trifluoroacetic anhydride (10 ml) was added potassium nitrate
(3.75 g, 0.0372 mol, 1 eq) and the resulting solution was stir-
red at 0 °C for 3 h at 25 °C, then, all volatiles were removed in
vacuo, and the solid residue was purified by flash chromato-
graphy eluted with petroleum ether to give a single yellow pro-
duct (3.7 g, 33%). M.p. 87–89 °C. 1H NMR (300 MHz,
CDCl3) δ 11.47 (sa, 1H, N-H), 7.78 (dd, 1H, H-4, J4,6 = 1.9,
J4,3 = 9.2 Hz), 8.31 (d, 1H, H-3, J3,4 = 9.2 Hz), 9.00 (d, 1H,
H-6, J6,4 = 1.9 Hz) ppm; MS: m/z (% relative intensity) 302
(M+, 10), 283 (10), 233 (100), 205 (80).
5.3. General method of synthesis of 1,2-phenylenediamines 11–
13, 17 and 24
A mixture of adequate substituted 2-nitroaniline (6.37 g,
0.0282 mol), EtOH (100 ml) and 10% Ni-Raney (300 mg)
was hydrogenated at 25 °C until cessation of H2 uptake. The
catalyst was filtered off on a Whatman paper number 2,
washed with EtOH, and the filtrate concentrated to provide a