3.1.2. Synthesis of 5-vinyl-benzo[d]imidazole Derivatives
4-((4-isopropoxyphenyl)amino)-3-nitrobenzonitrile(3). 4-fluoro-3-nitrobenzonitrile 1 (20.00 g, 0.12 mol), 4-isopropoxyaniline 2 (22.76 g, 0.15 mol), and triethylamine (19.46 mL, 0.14 mol) were combined in acetonitrile (100 mL). The mixture was stirred at 90 °C for 24 h. The organic phase was dried with anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by slurrying with tert-butylmethylether and filtered to afford compound 3 (35.08 g, 98%) as a red solid. Mp 130–132 °C. 1H NMR (600 MHz, Chloroform-d): δ 9.71 (s, 1H), 8.52 (d, J = 2.1 Hz, 1H), 7.47 (dd, J = 9.1, 2.2 Hz, 1H), 7.16 (d, J = 8.9 Hz, 2H), 7.02 (d, J = 9.1 Hz, 1H), 6.96 (d, J = 8.9 Hz, 2H), 4.61–4.52 (m, 1H), 1.37 (d, J = 6.1 Hz, 6H). 13C NMR (151 MHz, Chloroform-d): δ 157.38, 146.91, 137.26, 132.12, 131.71, 129.01, 127.56, 117.94, 117.16, 116.93, 99.47, 70.43, 22.07. HRMS (ESI) m/z: (M + H)+ calcd for C16H15N3O3 298.1113; found 298.1187.
3-amino-4-((4-isopropoxyphenyl)amino)benzonitrile (4). A solution of compound 3 (24.00 g, 0.08 mol) in EtOAc (500 mL) was heated to 50 °C, and tin (II) chloride dihydrate (63.75 g 0.28 mol) was added in portions. The mixture was heated for 3 h at 60–62 °C. The reaction mixture was cooled to room temperature, and the pH was adjusted to alkaline by adding aqueous sodium bicarbonate, and this mixture was stirred for 1 h. The reaction mixture was filtered through a pad of Celite. The filtrate was washed with water and EtOAc. The organic phase was dried over anhydrous sodium sulfate overnight and concentrated; the residue product was purified using an automated chromatography system to afford compound 4 as a brownish-red solid (20.50, 95%). Mp 146−147 °C. 1H NMR (600 MHz, Chloroform-d): δ 7.05 (dd, J = 8.3, 2.0 Hz, 1H), 7.02 (s, 1H), 6.97 (d, J = 8.9 Hz, 2H), 6.93 (d, J = 8.3 Hz, 1H), 6.87 (d, J = 8.8 Hz, 2H), 5.53 (s, 1H), 4.55–4.45 (m, 1H), 4.07–3.28 (m, 2H), 1.34 (d, J = 6.1 Hz, 6H). 13C NMR (151 MHz, Chloroform-d): δ 154.50, 139.27, 135.21, 134.03, 125.78, 122.92, 120.11, 120.09, 117.32, 115.24, 102.85, 70.66, 22.24. HRMS (ESI) m/z: (M + H)+ calcd for C16H17N3O 268.1372; found 268.1446.
1-(4-isopropoxyphenyl)-1H-benzo[d]imidazole-5-carbonitrile (5). A mixture of compound 4 (20.00 g, 0.07 mol), formamidine acetate (10.13 g, 0.10 mol), and ethanol (500 mL) was stirred at 88 °C for 9 h. After the mixed solution was cooled to room temperature and stirred overnight, the solvent was removed under reduced pressure; the residue was diluted with water, stirred for 30 min, and filtered. Then, the residue was purified by slurrying with methanol and filtered to afford compound 5 (20.13 g, 97%) as an orange solid. Mp 193−195 °C. 1H NMR (600 MHz, Chloroform-d): δ 8.22 (s, 1H), 8.21 (d, J = 1.7 Hz, 1H), 7.57 (dd, J = 8.4, 1.5 Hz, 1H), 7.52 (d, J = 8.4 Hz, 1H), 7.39–7.35 (d, J = 8.9 Hz, 2H), 7.07 (d, J = 8.9 Hz, 2H), 4.67–4.60 (m, 1H), 1.40 (d, J = 6.1 Hz, 6H). 13C NMR (151 MHz, Chloroform-d): δ 158.59, 145.02, 143.02, 137.01, 127.53, 127.13, 126.10, 125.65, 119.71, 117.16, 111.84, 106.37, 70.67, 22.07. HRMS (ESI) m/z: (M + H)+ calcd for C17H15N3O 278.1215; found 278.1292.
1-(4-isopropoxyphenyl)-1H-benzo[d]imidazole-5-carbaldehyde (6). The mixture of compound 5 (8.40 g, 0.03 mol) and Raney Ni (8.40 g) in 75% formic acid (168 mL) was stirred at 100 °C for 1–2 h. The reaction mixture was filtered through a pad of Celite. The filtrate was washed with water and EtOAc. The organic phase was separated and dried over anhydrous sodium sulfate overnight. It was then filtered and concentrated; the residue was purified using an automated chromatography system to afford compound 6 (8.15 g, 96%) as a white solid. Mp 130–131 °C. 1H NMR (600 MHz, Chloroform-d): δ 10.09 (s, 1H), 8.34 (d, J = 1.5 Hz, 1H), 8.17 (s, 1H), 7.89 (dd, J = 8.4, 1.5 Hz, 1H), 7.54 (d, J = 8.4 Hz, 1H), 7.38 (d, J = 8.9 Hz, 2H), 7.06 (d, J = 8.9 Hz, 2H), 4.67–4.58 (m, 1H), 1.39 (d, J = 6.1 Hz, 6H). 13C NMR (151 MHz, Chloroform-d): δ 191.99, 158.39, 144.88, 143.75, 138.58, 132.26, 128.01, 126.03, 124.89, 123.99, 117.11, 111.27, 70.64, 22.07. HRMS (ESI) m/z: (M + H)+ calcd for C17H16N2O2 281.1212; found 281.1287.
3.1.3. General Procedure for Synthesis of Compounds 7a−7h(E/Z)
The corresponding Wittig reagents (1.00 eq.) were added to a stirring solution of tetrahydrofuran (5.00 mL) at −80 °C. Sodium butyllithium (2.50 M in hexanes, 1.05 eq.) was added and stirred for 1 h. Subsequently, compound 6 (1.00 eq.) was added, and the mixed solution was warmed to room temperature slowly. After 12 h, the reaction mixture was concentrated under reduced pressure and purified by flash column chromatography to obtain the products 7a−7h(E/Z).
(Z)-5-(4-(tert-butyl)styryl)-1-(4-isopropoxyphenyl)-1H-benzo[d]imidazole (7a−Z) [
41]. Compound
7a−Z was synthesized according to the general procedure, replacing the corresponding Wittig reagents with (4-(tert-butyl)benzyl)triphenylphosphonium. Compound
7a−Z was obtained as a light yellow solid in 45% yield. Mp 172–174 °C.
1H NMR (600 MHz, Chloroform-
d): δ 8.06 (s, 1H), 7.84 (s, 1H), 7.42 (d, J = 8.9 Hz, 2H), 7.35 (d, J = 8.4 Hz, 1H), 7.30 (d, J = 8.4 Hz, 1H), 7.28–7.23 (m, 4H), 7.07 (d, J = 8.9 Hz, 2H), 6.74 (d, J = 12.3 Hz, 1H), 6.60 (d, J = 12.2 Hz, 1H), 4.64 (p, J = 6.1 Hz, 1H), 1.43 (d, J = 6.1 Hz, 6H), 1.32 (s, 9H).
13C NMR (151 MHz, Chloroform-
d): δ 157.85, 150.64, 144.46, 143.28, 134.91, 133.96, 132.84, 128.88, 128.50, 127.62, 126.25, 125.73, 122.38, 118.52, 116.99, 110.63, 70.55, 34.74, 31.44, 22.12. HRMS (ESI) m/z: (M + H)
+ calcd for C
28H
30N
2O 411.2358; found 411.2422.
(E)-5-(4-(tert-butyl)styryl)-1-(4-isopropoxyphenyl)-1H-benzo[d]imidazole (7a−E) [
41]. Compound
7a−E was synthesized according to the general procedure, replacing the corresponding Wittig reagents with (4-(tert-butyl)benzyl)triphenylphosphonium. Compound
7a−E was obtained as a white solid in a yield of 23%. Mp 161–162 °C.
1H NMR (600 MHz, Chloroform-
d): δ 8.06 (s, 1H), 7.97 (s, 1H), 7.47 (ddd,
J = 59.1, 21.1, 8.9 Hz, 8H), 7.25 (d,
J = 16.1 Hz, 1H), 7.14 (d,
J = 16.2 Hz, 1H), 7.06 (d,
J = 8.5 Hz, 2H), 4.63 (p,
J = 6.5 Hz, 1H), 1.41 (d,
J = 6.3 Hz, 6H), 1.35 (s, 9H).
13C NMR (151 MHz, Chloroform-
d): δ 157.79, 150.14, 144.06, 143.01, 134.46, 133.43, 132.46, 129.92, 129.50, 128.94, 128.72, 125.70, 125.26, 125.04, 120.69, 116.96, 110.14, 70.54, 34.67, 31.42, 22.12. HRMS (ESI) m/z: (M + H)
+ calcd for C
28H
30N
2O 411.2358; found 411.2420.
(Z)-4-(2-(1-(4-isopropoxyphenyl)-1H-benzo[d]imidazol-5-yl) vinyl) benzonitrile (7b−Z) [
41]. Compound
7b−Z was synthesized according to the general procedure, replacing the corresponding Wittig reagents with (4-cyanobenzyl) triphenylphosphonium. Compound
7b−Z was obtained as a yellow solid in a yield of 36%. Mp 165–166 °C.
1H NMR (600 MHz, Chloroform-
d): δ 8.03 (s, 1H), 7.71 (s, 1H), 7.47 (d,
J = 8.4 Hz, 2H), 7.37 (d,
J = 8.8 Hz, 2H), 7.34 (d,
J = 8.2 Hz, 2H), 7.31 (d,
J = 8.4 Hz, 1H), 7.12 (dd,
J = 8.4, 1.7 Hz, 1H), 7.04 (d,
J = 8.9 Hz, 2H), 6.91 (d,
J = 12.2 Hz, 1H), 6.58 (d,
J = 12.1 Hz, 1H), 4.65–4.57 (m, 1H), 1.39 (d,
J = 6.1 Hz, 6H).
13C NMR (151 MHz, Chloroform-
d): δ 157.90, 144.12, 143.37, 142.47, 133.91, 133.76, 132.16, 130.97, 129.69, 128.62, 127.75, 125.69, 124.76, 120.92, 119.11, 116.97, 110.50, 110.40, 70.53, 22.07. HRMS (ESI) m/z: (M + H)
+ calcd for C
25H
21N
3O 380.1685; found 380.1747.
(E)-4-(2-(1-(4-isopropoxyphenyl)-1H-benzo[d]imidazol-5-yl) vinyl) benzonitrile (7b−E) [
41]. Compound
7b−E was synthesized according to the general procedure, replacing the corresponding Wittig reagents with (4-cyanobenzyl) triphenylphosphonium. Compound
7b−E was obtained as a yellow solid in a yield of 20%. Mp 161–162 °C.
1H NMR (600 MHz, Chloroform-
d): δ 8.07 (s, 1H), 7.99 (s, 1H), 7.63 (d,
J = 8.4 Hz, 2H), 7.60 (d,
J = 8.4 Hz, 2H), 7.53 (d,
J = 8.4 Hz, 1H), 7.45 (d,
J = 8.4 Hz, 1H), 7.41–7.34 (m, 3H), 7.11 (d,
J = 16.2 Hz, 1H), 7.05 (d,
J = 8.9 Hz, 2H), 4.68–4.59 (m, 1H), 1.40 (d,
J = 6.1 Hz, 6H).
13C NMR (151 MHz, Chloroform-
d): δ 157.97, 144.40, 143.66, 142.21, 134.70, 133.03, 132.59, 131.49, 128.59, 126.83, 125.74, 125.72, 122.67, 119.33, 119.26, 117.00, 110.91, 110.31, 70.55, 22.09. HRMS (ESI) m/z: (M + H)
+ calcd for C
25H
21N
3O 380.1685; found 380.1747.
(Z)-1-(4-isopropoxyphenyl)-5-(4-methylstyryl)-1H-benzo[d]imidazole (7c−Z). Compound 7c−Z was synthesized according to the general procedure, replacing the corresponding Wittig reagents with (4-methylbenzyl)triphenylphosphonium. Compound 7c−Z was obtained as a yellow solid in a yield of 25%. Mp 168–169 °C. 1H NMR (600 MHz, Chloroform-d): δ 8.01 (s, 1H), 7.77 (s, 1H), 7.37 (d, J = 8.5 Hz, 2H), 7.29 (d, J = 8.5 Hz, 1H), 7.23 (d, J = 8.5 Hz, 1H), 7.18 (d, J = 7.9 Hz, 2H), 7.07–6.94 (m, 4H), 6.71 (d, J = 12.2 Hz, 1H), 6.58 (d, J = 12.2 Hz, 1H), 4.66–4.57 (m, 1H), 2.30 (s, 3H), 1.39 (d, J = 6.2 Hz, 6H). 13C NMR (151 MHz, Chloroform-d): δ 157.75, 144.06, 142.97, 136.83, 134.54, 133.39, 132.30, 129.95, 129.59, 129.06, 128.90, 125.64, 125.04, 120.77, 116.93, 110.06, 70.51, 22.09, 21.34. HRMS (ESI) m/z: (M + H)+ calcd for C25H24N2O 369.1889; found 369.1955.
(E)-1-(4-isopropoxyphenyl)-5-(4-methylstyryl)-1H-benzo[d]imidazole (7c−E). Compound 7c−E was synthesized according to the general procedure, replacing the corresponding Wittig reagents with (4-methylbenzyl)triphenylphosphonium. Compound 7c−E was obtained as a yellow solid in a yield of 15%. Mp 168–170 °C. 1H NMR (600 MHz, Chloroform-d): δ 8.04 (s, 1H), 7.96 (s, 1H), 7.52 (d, J = 8.7 Hz, 1H), 7.49–7.36 (m, 5H), 7.23 (d, J = 16.3 Hz, 1H), 7.18 (d, J = 7.9 Hz, 2H), 7.12 (d, J = 16.3 Hz, 1H), 7.05 (d, J = 8.8 Hz, 2H), 4.67–4.57 (m, 1H), 2.37 (s, 3H), 1.40 (d, J = 6.1 Hz, 6H). 13C NMR (151 MHz, Chloroform-d): δ 157.84, 144.47, 143.26, 137.35, 134.88, 133.95, 132.80, 129.51, 128.87, 128.25, 127.72, 126.43, 125.70, 122.35, 118.50, 116.98, 110.63, 70.54, 22.11, 21.38. HRMS (ESI) m/z: (M + H)+ calcd for C25H24N2O 369.1889; found 369.1953.
(Z)-5-(4-ethoxystyryl)-1-(4-isopropoxyphenyl)-1H-benzo[d]imidazole (7d−Z). Compound 7d−Z was synthesized according to the general procedure, replacing the corresponding Wittig reagents with 4-ethoxybenzyl)triphenylphosphonium. Compound 7d−Z was obtained as a yellow solid in a yield of 50%. Mp 161–162 °C. 1H NMR (600 MHz, Chloroform-d): δ 8.05 (s, 1H), 7.82 (s, 1H), 7.41 (d, J = 8.9 Hz, 2H), 7.33 (d, J = 8.4 Hz, 1H), 7.27 (d, J = 8.5 Hz, 1H), 7.24 (d, J = 6.9 Hz, 2H), 7.06 (d, J = 6.9 Hz, 2H), 6.77 (d, J = 6.7 Hz, 2H), 6.69 (d, J = 12.1 Hz, 1H), 6.58 (d, J = 12.2 Hz, 1H), 4.64 (dtq, J = 9.2, 5.8, 3.2, 2.6 Hz, 1H), 4.02 (dt, J = 7.3, 2.4 Hz, 2H), 1.42 (dt, J = 5.0, 2.5 Hz, 9H). 13C NMR (151 MHz, Chloroform-d): δ 158.08, 157.72, 144.06, 142.92, 133.30, 132.45, 130.21, 129.75, 129.24, 129.04, 128.88, 125.60, 124.99, 120.66, 116.91, 114.25, 110.07, 70.48, 63.38, 22.07, 14.94. HRMS (ESI) m/z: (M + H)+ calcd for C26H26N2O2, 399.1994; found 399.2057.
(E)-5-(4-ethoxystyryl)-1-(4-isopropoxyphenyl)-1H-benzo[d]imidazole(7d−E). Compound 7d−E was synthesized according to the general procedure, replacing the corresponding Wittig reagents with 4-ethoxybenzyl)triphenylphosphonium. Compound 7d−E was obtained as a yellow solid in a yield of 30%. Mp 152–153 °C. 1H NMR (600 MHz, Chloroform-d): δ 8.04 (s, 1H), 7.94 (s, 1H), 7.59–7.36 (m, 6H), 7.18–7.00 (m, 4H), 6.89 (d, J = 6.2 Hz, 2H), 4.67–4.56 (m, 1H), 4.10–4.01 (m, 2H), 1.51–1.35 (m, 9H). 13C NMR (151 MHz, Chloroform-d): δ 158.62, 157.81, 144.44, 143.20, 133.79, 132.98, 130.33, 128.88, 127.69, 127.38, 127.05, 125.68, 122.26, 118.24, 116.97, 114.79, 110.60, 70.53, 63.60, 22.10, 14.98. HRMS (ESI) m/z: (M + H)+ calcd for C26H26N2O2 399.1994; found 399.2060.
(Z)-5-(4-(difluoromethoxy)styryl)-1-(4-isopropoxyphenyl)-1H-benzo[d]imidazole (7e−Z). Compound 7e−Z was synthesized according to the general procedure, replacing the corresponding Wittig reagents with (4-(difluoromethoxy)benzyl)triphenylphosphonium. Compound 7e−Z was obtained as a yellow solid in a yield of 30%. Mp 173–174 °C. 1H NMR (600 MHz, Chloroform-d): δ 8.02 (s, 1H), 7.74 (d, J = 1.6 Hz, 1H), 7.37 (d, J = 8.9 Hz, 2H), 7.31 (d, J = 8.4 Hz, 1H), 7.26 (d, J = 8.7 Hz, 2H), 7.18 (dd, J = 8.4, 1.7 Hz, 1H), 7.03 (d, J = 8.9 Hz, 2H), 6.94 (d, J = 8.6 Hz, 2H), 6.76 (d, J = 12.1 Hz, 1H), 6.56 (d, J = 12.1 Hz, 1H), 6.48 (t, J = 74.1 Hz, 1H), 4.65–4.56 (m, 1H), 1.39 (d, J = 6.1 Hz, 6H). 13C NMR (151 MHz, Chloroform-d): δ 157.83, 150.20 (t, J = 2.7 Hz), 144.09, 143.14, 134.75, 133.57, 131.75, 131.06, 130.50, 128.79, 128.31, 125.67, 124.90, 120.77, 119.20, 116.96, 116.08 (t, J = 259.0 Hz), 110.29, 70.53, 22.08. HRMS (ESI) m/z: (M + H)+ calcd for C25H22F2N2O2 421.1649; found 421.1712.
(E)-5-(4-(difluoromethoxy)styryl)-1-(4-isopropoxyphenyl)-1H-benzo[d]imidazole (7e−E). Compound 7e−E was synthesized according to the general procedure, replacing the corresponding Wittig reagents with (4-(difluoromethoxy)benzyl)triphenylphosphonium. Compound 7e−E was obtained as a yellow solid in a yield of 26%. Mp 173–174 °C. 1H NMR (600 MHz, Chloroform-d): δ 8.05 (s, 1H), 7.96 (s, 1H), 7.56–7.48 (m, 3H), 7.43 (d, J = 8.4 Hz, 1H), 7.38 (d, J = 8.8 Hz, 2H), 7.21 (d, J = 16.3 Hz, 1H), 7.14–7.07 (m, 3H), 7.05 (d, J = 8.8 Hz, 2H), 6.52 (t, J = 74.0 Hz, 1H), 4.67–4.58 (m, 1H), 1.40 (d, J = 6.1 Hz, 6H). 13C NMR (151 MHz, Chloroform-d): δ 157.87, 150.46 (t, J = 2.7 Hz), 144.48, 143.40, 135.12, 134.17, 132.29, 129.59, 128.78, 127.76, 126.37, 125.70, 122.39, 119.84, 118.70, 116.98, 116.08 (t, J = 260.0 Hz), 110.72, 70.54, 22.10. HRMS (ESI) m/z: (M + H)+ calcd for C25H22F2N2O2 421.1649; found 421.1713.
(Z)-1-(4-isopropoxyphenyl)-5-(4-(trifluoromethoxy)styryl)-1H-benzo[d]imidazole (7f−Z). Compound 7f−Z was synthesized according to the general procedure, replacing the corresponding Wittig reagents with triphenyl(4-(trifluoromethoxy)benzyl)phosphonium. Compound 7f−Z was obtained as a yellow solid in a yield of 30%. Mp 161–162 °C. 1H NMR (600 MHz, Chloroform-d): δ 8.03 (s, 1H), 7.75 (d, J = 1.7 Hz, 1H), 7.37 (d, J = 8.9 Hz, 2H), 7.31 (d, J = 8.4 Hz, 1H), 7.28 (d, J = 8.5 Hz, 2H), 7.18 (dd, J = 8.5, 1.7 Hz, 1H), 7.07–7.00 (m, 4H), 6.80 (d, J = 12.2 Hz, 1H), 6.56 (d, J = 12.1 Hz, 1H), 4.65–4.56 (m, 1H), 1.39 (d, J = 6.1 Hz, 6H). 13C NMR (151 MHz, Chloroform-d): δ 157.87, 148.10 (q, J = 1.5 Hz), 144.12, 143.20, 136.18, 133.66, 131.62, 131.57, 130.42, 128.79, 128.08, 125.70, 124.84, 120.85, 120.76, 120.57 (q, J = 257.2 Hz), 116.98, 110.35, 70.55, 22.10. HRMS (ESI) m/z: (M + H)+ calcd for C25H21F3N2O2 439.1555; found 439.1619.
(E)-1-(4-isopropoxyphenyl)-5-(4-(trifluoromethoxy)styryl)-1H-benzo[d]imidazole (7f−E). Compound 7f−E was synthesized according to the general procedure, replacing the corresponding Wittig reagents with triphenyl(4-(trifluoromethoxy)benzyl)phosphonium. Compound 7f−E was obtained as a yellow solid in a yield of 10%. Mp 160–162 °C. 1H NMR (600 MHz, Chloroform-d): δ 8.05 (s, 1H), 7.97 (d, J = 1.7 Hz, 1H), 7.55 (d, J = 8.8 Hz, 2H), 7.52 (dd, J = 8.5, 1.7 Hz, 1H), 7.44 (d, J = 8.4 Hz, 1H), 7.39 (d, J = 8.9 Hz, 2H), 7.25–7.19 (m, 3H), 7.11 (d, J = 16.2 Hz, 1H), 7.05 (d, J = 8.8 Hz, 2H), 4.66–4.57 (m, 1H), 1.40 (d, J = 6.1 Hz, 6H). 13C NMR (151 MHz, Chloroform-d): δ 157.93, 148.41, 144.44, 143.45, 136.49, 134.28, 132.17, 130.30, 128.76, 127.65, 126.17, 125.74, 122.47, 121.33, 120.63 (q, J = 257.2 Hz), 118.81, 117.01, 110.77, 70.56, 22.10. HRMS (ESI) m/z: (M + H)+ calcd for C25H21F3N2O2 439.1555; found 439.1619.
(Z)-1-(4-isopropoxyphenyl)-5-(4-(trifluoromethyl)styryl)-1H-benzo[d]imidazole (7g−Z). Compound 7g−Z was synthesized according to the general procedure, replacing the corresponding Wittig reagents with triphenyl(4-(trifluoromethyl)benzyl)phosphonium. Compound 7g−Z was obtained as a yellow solid in a yield of 35%. Mp 165–166 °C. 1H NMR (600 MHz, Chloroform-d): δ 8.03 (s, 1H), 7.74 (s, 1H), 7.45 (d, J = 8.3 Hz, 2H), 7.39–7.33 (m, 4H), 7.30 (dd, J = 8.5 Hz, 1H), 7.16 (d, J = 8.4 Hz, 1H), 7.06–7.00 (m, 2H), 6.86 (d, J = 12.2 Hz, 1H), 6.60 (d, J = 12.2 Hz, 1H), 4.66–4.55 (m, 1H), 1.41–1.35 (m, 6H). 13C NMR (151 MHz, Chloroform-d): δ 157.87, 144.10, 143.25, 141.25, 133.76, 132.72, 131.33, 129.27, 128.90 (q, J = 32.0 Hz), 128.72, 128.09, 125.68, 125.29 (q, J = 3.9 Hz), 124.85, 124.29 (q, J = 272.3 Hz), 120.89, 116.97, 110.39, 70.53, 22.07. HRMS (ESI) m/z: (M + H)+ calcd for C25H21F3N2O 423.1606; found 423.1667.
(E)-1-(4-isopropoxyphenyl)-5-(4-(trifluoromethyl)styryl)-1H-benzo[d]imidazole (7g−E). Compound 7g−E was synthesized according to the general procedure, replacing the corresponding Wittig reagents with tri-phenyl(4-(trifluoromethyl)benzyl)phosphonium. Compound 7g−E was obtained as a yellow solid in a yield of 20%. Mp 166–167 °C. 1H NMR (600 MHz, Chloroform-d): δ 8.06 (s, 1H), 7.99 (s, 1H), 7.69–7.57 (m, 4H), 7.53 (d, J = 8.5 Hz, 1H), 7.45 (d, J = 5.2 Hz, 1H), 7.39 (d, J = 5.2 Hz, 2H), 7.35 (d, J = 16.1 Hz, 1H), 7.15 (d, J = 16.2 Hz, 1H), 7.06 (d, J = 5.4 Hz, 2H), 4.66–4.57 (m, 1H), 1.44–1.35 (m, 6H). 13C NMR (151 MHz, Chloroform-d): δ 157.97, 144.44, 143.55, 141.18, 134.50, 131.89, 131.81, 129.08 (q, J = 32.0 Hz), 128.71, 126.57, 126.18, 125.76, 125.73, 124.41 (q, J = 271.5 Hz), 122.61, 119.10, 117.02, 110.84, 70.58, 22.11. HRMS (ESI) m/z: (M + H)+ calcd for C25H21F3N2O 423.1606; found 423.1668.
(Z)-1-(4-isopropoxyphenyl)-5-(2-(naphthalene-2-yl)vinyl)-1H-benzo[d]imidazole (7h−Z). Compound 7h−Z was synthesized according to the general procedure, replacing the corresponding Wittig reagents with (naphthalen-2-ylmethyl)triphenylphosphonium. Compound 7h−Z was obtained as a brown solid in a yield of 26%. Mp 170–171 °C. 1H NMR (600 MHz, Chloroform-d): δ 8.02 (s, 1H), 7.80 (s, 1H), 7.77 (s, 1H), 7.74–7.69 (m, 1H), 7.73–7.69 (m, 1H), 7.62 (d, J = 8.5 Hz, 1H), 7.43–7.40 (m, 2H), 7.39–7.35 (m, 3H), 7.28–7.22 (m, 2H), 7.02 (d, J = 8.9 Hz, 2H), 6.84 (d, J = 12.1 Hz, 1H), 6.78 (d, J = 12.2 Hz, 1H), 4.65–4.56 (m, 1H), 1.38 (d, J = 6.1 Hz, 6H). 13C NMR (151 MHz, Chloroform-d): δ 157.79, 143.99, 143.07, 135.23, 133.65, 133.53, 132.67, 132.16, 131.02, 129.56, 128.83, 128.11, 128.02, 127.73, 127.65, 127.10, 126.06, 125.91, 125.65, 125.12, 120.99, 116.95, 110.13, 70.52, 22.09. HRMS (ESI) m/z: (M + H)+ calcd for C28H24N2O 405.1889; found 405.1955.
(E)-1-(4-isopropoxyphenyl)-5-(2-(naphthalen-2-yl)vinyl)-1H-benzo[d]imidazole (7h−E). Compound 7h−Z was synthesized according to the general procedure, replacing the corresponding Wittig reagents with (naphthalen-2-ylmethyl)triphenylphosphonium. Compound 7h−E was obtained as a yellow solid in a yield of 15%. Mp 172–173 °C. 1H NMR (600 MHz, Chloroform-d): δ 8.06 (s, 1H), 8.03 (s, 1H), 7.88 (s, 1H), 7.85–7.80 (m, 3H), 7.79 (d, J = 8.5 Hz, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.48–7.38 (m, 6H), 7.31 (d, J = 16.2 Hz, 1H), 7.06 (d, J = 8.8 Hz, 2H), 4.68–4.59 (m, 1H), 1.41 (d, J = 6.1 Hz, 6H). 13C NMR (151 MHz, Chloroform-d): δ 157.86, 144.46, 143.34, 135.17, 134.12, 133.88, 133.05, 132.63, 129.60, 128.81, 128.40, 128.08, 127.84, 127.81, 126.49, 126.41, 125.88, 125.72, 123.65, 122.48, 118.69, 116.98, 110.73, 70.54, 22.11. HRMS (ESI) m/z: (M + H)+ calcd for C28H24N2O 405.1889; found 405.1951.
3.1.4. General Procedure for Synthesis of Compounds 13a−13j
To a mixture of compound 12 (1.00 eq.) and relatively aromatic aldehyde (R2-CHO, 1.00 eq.) in 1, 2-dichloroethane (3 mL) was added the Na(AcO)3BH (1.50 eq.) and stirred at room temperature for 6 h. After the mixture was stirred for 6 h, TLC monitors showed the complete consumption of compound 12. Following cooling, the mixture was divided between EtOAc and H2O, and the layers were separated, with the aqueous layer extracted with EtOAc and the organic layer washed with H2O. The organic phase was dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography to obtain the products 13a−13j.
2-methoxy-5-(((1-(4-methoxyphenyl)-1H-benzo[d]imidazol-5-yl)amino)methyl)phenol (13a). Compound 13a was synthesized according to the general procedure, replacing the corresponding aromatic aldehyde with isovanillin. Compound 13a was obtained as a white solid in a yield of 87%. Mp 182.1–183.3 °C. 1H NMR (600 MHz, Chloroform-d): δ 7.892 (s, 1H), 7.372 (t, 1H, J1 = 4.8, J2 = 1.8), 7.357 (t, 1H, J1 = 2.4, J2 = 3.0), 7.228 (d, 1H, J = 10.4) 7.034 (s, 2H), 7.019 (t, 1H, J1 = 2.4, J2 = 3.6), 6.978 (d, 1H, J = 1.8), 6.876 (m, 1H), 6.805 (dd, 1H, J = 10.4), 6.689 (dd, 1H) 5.666 (s, 1H), 4.274 (s, 2H), 3.852 (m, 6H). 13C NMR (151 MHz, DMSO-d6): δ 158.72, 146.89, 146.82, 145.65, 145.44, 142.60, 133.41, 129.78, 126.11, 125.15, 118.27, 115.52, 115.02, 112.92, 112.61, 110.91, 100.66, 56.13, 55.95, 47.28, 40.35, 40.21, 40.07, 39.94, 39.80, 39.66, 39.52. HRMS (ESI) m/z: (M + H)+ calcd for C22H21N3O3 376.1656; found 376.1654.
2-methoxy-4-(((1-(4-methoxyphenyl)-1H-benzo[d]imidazol-5-yl)amino)methyl)phenol (13b). Compound 13b was synthesized according to the general procedure, replacing the corresponding aromatic aldehyde with vanillin. Compound 13b was obtained as a yellow solid in a yield of 91%. Mp 157.6–159.0 °C. 1H NMR (600 MHz, Chloroform-d): δ7.908 (s, 1H), 7.374 (t, 1H, J1 = J2 = 2.4), 7.367 (t, 1H, J1 = 2.4, J2 = 3.6), 7.227 (d, 1H, J = 7.8), 7.066 (d, 1H), 7. 039 (t, 1H, J = 2.4), 7. 027 (t, 1H, J = 1.8), 6.932 (d, 1H, J = 1.8), 6.891 (dd, 1H, J = 8.4), 6.874 (d, 1H, J = 7.8), 6.703 (dd, 1H, J = 6.6), 5.598 (s, 1H), 4.283 (s, 2H), 3.868 (d, 6H, J = 3.0). 13C NMR (151 MHz, DMSO-d6): δ 158.71, 147.98, 145.74, 145.66, 145.44, 142.61, 131.50, 129.79, 126.16, 125.15, 120.12, 115.63, 115.53, 112.99, 112.05, 110.88, 100.78, 56.01, 55.96, 47.74. HRMS (ESI) m/z: (M + H)+ calcd for C22H21N3O3 376.1656; found 376.1652.
N-(2, 4-dimethoxybenzyl)-1-(4-methoxyphenyl)-1H-benzo[d]imidazol-5-amine (13c). Compound 13c was synthesized according to the general procedure, replacing the corresponding aromatic aldehyde with 2, 4-dimethoxybenzaldehyde. Compound 13c was obtained as a yellow solid in a yield of 88%. Mp 143.1–145.2 °C. 1H NMR (600 MHz, Chloroform-d): δ 8.517 (s, 1H), 7.385–7.412 (m, 3H), 7.112 (s, 1H), 7.097 (s, 1H), 7.063 (s, 1H), 6.924 (d, 1H, J = 7.8), 6.845 (s, 1H), 6.829 (s, 1H), 6.815 (s, 1H), 6.776 (d, 1H, J = 3.0), 4.377 (s, 2H), 3.908 (s, 3H), 3.897 (s, 3H), 3.733 (s, 3H). 13C NMR (151 MHz, DMSO-d6): δ 160.58, 141.36, 139.40, 131.50, 131.06, 129.73, 129.53, 127.99, 126.88, 126.87, 115.86, 115.68, 113.83, 56.48, 56.19, 45.82. HRMS (ESI) m/z: (M + H)+ calcd for C23H23N3O3 390.1812; found 390.1810.
1-(4-methoxyphenyl)-N-(2, 4,5-trimethoxybenzyl)-1H-benzo[d]imidazol-5-amine (13d). Compound 13d was synthesized according to the general procedure, replacing the corresponding aromatic aldehyde with 2, 4,5-trimethoxybenzaldehyde. Compound 13d was obtained as an orange solid in a yield of 88%. Mp 167.8–169.8 °C. 1H NMR (600 MHz, Chloroform-d): δ 7.894 (s, 1H), 7.374 (t, 1H, J1 = 3.6, J2 = 1.8), 7.360 (t, 1H, J1 = 1.8, J2 = 3.6), 7.226 (d, 1H, J = 8.4), 7.094 (d, 1H, J = 1.8), 7. 033 (t, 1H, J1 = 3.6, J2 = 1.8), 7. 019 (t, 1H, J1 = 1.8, J2 = 3.6), 6.920 (s, 1H), 6.716 (dd, 1H, J = 6.6), 6.536 (s, 1H), 4.304 (s, 2H), 3.870 (s, 3H), 3.860 (s, 3H), 3.839 (s, 3H), 3.779 (s, 3H). 13C NMR (151 MHz, DMSO-d6): δ 203.62, 158.72, 156.07, 151.76, 148.86, 145.73, 145.46, 142.98, 142.64, 125.15, 119.33, 115.53, 114.17, 112.89, 110.93, 100.64, 98.73, 56.92, 56.68, 56.34, 55.96, 42.08. HRMS (ESI) m/z: (M + H)+ calcd for C24H25N3O4 420.1918; found 420.1920.
2, 6-dimethoxy-4-(((1-(4-methoxyphenyl)-1H-benzo[d]imidazol-5-yl)amino)methyl)phenol (13e). Compound 13e was synthesized according to the general procedure, replacing the corresponding aromatic aldehyde with Syringaldehyde. Compound 13e was obtained as an orange solid in a yield of 95%. Mp 115.7–118.1 °C. 1H NMR (600 MHz, Chloroform-d): δ 7.917 (d, 1H, J = 3.6), 7.377 (t, 1H, J1 = J2 = 1.8), 7.366 (t, 1H, J1 = 1.8, J2 = 3.6), 7.244 (d, 1H, J = 6.0), 7.068 (d, 1H, J = 2.4), 7. 037 (t, 1H, J1 = 1.8, J2 = 1.2), 7. 025 (t, 1H, J1 = 2.4, J2 = 3.0), 6.708 (dd, 1H, J = 6.0), 6.651 (s, 2H), 6.482 (s, 1H),5.407 (d, 1H), 4.528 (s, 1H), 4.284 (s, 2H), 3.864 (s, 9H). 13C NMR (151 MHz, DMSO-d6): δ 158.72, 148.50, 148.41, 134.63, 125.79, 125.15, 115.62, 115.53, 113.03, 110.90, 105.28, 105.04, 100.85, 56.41, 55.96, 48.21. HRMS (ESI) m/z: (M + H)+ calcd for C23H23N3O4 406.1761; found 406.1762.
N-(4-(tert-butyl)benzyl)-1-(4-methoxyphenyl)-1H-benzo[d]imidazol-5-amine (13f). Compound 13f was synthesized according to the general procedure, replacing the corresponding aromatic aldehyde with p-t-butylbenzaldehyde. Compound 13f was obtained as a yellow solid in a yield of 95%. Mp 175.8–176.9 °C. 1H NMR (600 MHz, Chloroform-d): δ 7.897 (s, 1H), 7.326–7.3776 (m, 6H), 7.240 (d, 1H, J = 9.0), 7.054 (d, 1H, J = 2.4), 7. 036 (t, 1H, J = 2.4), 7. 025 (t, 1H, J = 2.4), 6.706 (dd, 1H, J = 6.6), 4.343 (s, 2H), 3.862 (s, 3H), 1.303 (s, 9H). 13C NMR (151 MHz, DMSO-d6): δ 158.73, 149.33, 145.61, 145.46, 142.63, 137.81, 129.78, 127.49, 126.17, 125.46, 125.16, 115.53, 112.94, 110.97, 100.62, 55.96, 47.34, 34.60, 31.67. HRMS (ESI) m/z: (M + H)+ calcd for C25H27N3O 386.2227; found 386.2330.
N-(4-methoxybenzyl)-1-(4-methoxyphenyl)-1H-benzo[d]imidazol-5-amine (13g). Compound 13g was synthesized according to the general procedure, replacing the corresponding aromatic aldehyde with 4-methoxybenzaldehyde. Compound 13g was obtained as a yellow solid in a yield of 90%. Mp 128.0–129.3 °C. 1H NMR (600 MHz, Chloroform-d): δ 7.897 (s, 1H), 7.374 (t, 1H, J1 = 3.0, J2 = 2.4), 7.359 (t, 1H, J1 = 2.4, J2 = 3.6), 7.325 (d, 1H, J = 3.0), 7.311 (d, 1H, J = 3.0), 7.235 (d, 1H, J = 8.4), 7. 054 (d, 1H, J = 2.4), 7.035 (t, 1H, J1 = 3.0, J2 = 2.4), 7.020 (t, 1H, J1 = 2.4, J2 = 3.6), 6.871 (t, 1H, J1 = 3.0, J2 = 1.8), 6.857 (t, 1H, J1 = 1.8, J2 = 3.0), 6.695 (dd, 1H, J = 6.6), 4.303 (s, 2H), 3.861 (s, 3H), 3.785 (s, 3H). 13C NMR (151 MHz, DMSO-d6): δ 158.73, 158.50, 145.57, 145.46, 142.62, 132.63, 129.78, 128.88, 126.18, 125.15, 115.53, 114.14, 112.98, 110.93, 100.76, 55.96, 55.47, 47.13. HRMS (ESI) m/z: (M + H)+ calcd for C22H21N3O2 360.1707; found 360.1705.
3-(((1-(4-methoxyphenyl)-1H-benzo[d]imidazol-5-yl)amino)methyl)phenol (13h). Compound 13h was synthesized according to the general procedure, replacing the corresponding aromatic aldehyde with 3-hydroxybenzaldehyde. Compound 13h was obtained as a yellow solid in a yield of 91%. Mp 182.9–184.3 °C. 1H NMR (600 MHz, Chloroform-d): 1H NMR (600 MHz, Chloroform-d): δ 7.926 (s, 1H), 7.365 (t, 1H, J1 = 3.6, J2 = 2.4), 7.350 (t, 1H, J1 = 2.4, J2 = 3.6), 7.226 (d, 1H, J = 8.4), 7.185 (t, 1H, J1 = J2 =7.8), 7. 035 (t, 1H, J1 = J2 = 2.4), 7. 020 (t, 1H, J1 = 3.6, J2 = 2.4), 6.928 (d, 1H, J = 7.2), 6.781 (dd, 1H, J = 6.0), 4.295 (s, 2H), 3.826 (s, 3H). 13C NMR (151 MHz, DMSO-d6): δ 158.73, 157.88, 145.60, 145.44, 142.64, 142.51, 129.77, 129.67, 126.16, 125.17, 118.23, 115.53, 114.34, 113.93, 112.86, 110.96, 100.62, 55.96, 47.62. HRMS (ESI) m/z: (M + H)+ calcd for C21H19N3O2 346.1550; found 346.1547.
N-(3, 4-dichlorobenzyl)-1-(4-methoxyphenyl)-1H-benzo[d]imidazol-5-amine (13i). Compound 13i was synthesized according to the general procedure, replacing the corresponding aromatic aldehyde with 3, 4-dichlorobenzaldehyde. Compound 13i was obtained as a yellow solid in a yield of 89%. Mp 134.1–135.8 °C. 1H NMR (600 MHz, Chloroform-d): δ 8.926 (s, 1H), 7.455 (t, 1H, J1 = 3.0, J2 = 1.8), 7.444 (d, 1H, J = 1.8), 7.435 (d, 1H, J = 1.2), 7.365 (d, 1H, J = 8.4), 7.265 (d, 1H, J = 9.0), 7. 220 (dd, 1H, J = 7.2), 7.096 (t, 1H, J1 = J2 = 3.6), 7.081 (t, 1H, J1 = 2.4, J2 = 3.0), 6.897 (d, 1H, J = 9.6), 4.356 (s, 2H), 3.878 (s, 3H). 13C NMR (151 MHz, DMSO-d6): δ 158.76, 146.23, 145.43, 145.11, 142.77, 129.72, 128.28, 127.82, 127.62, 126.38, 125.79, 125.59, 125.21, 115.53, 112.87, 111.14, 100.75, 55.96, 47.11. HRMS (ESI) m/z: (M + H)+ calcd for C21H17Cl2N3O 398.0821; found 398.0824.
1-(4-methoxyphenyl)-N-(4-(trifluoromethyl)benzyl)-1H-benzo[d]imidazol-5-amine (13j). Compound 13j was synthesized according to the general procedure, replacing the corresponding aromatic aldehyde with 4-(trifluoromethyl)benzaldehyde. Compound 13j was obtained as a white solid in a yield of 90%. Mp 198.3–200.5 °C. 1H NMR (600 MHz, Chloroform-d): δ 7.895 (s, 1H), 7.557 (d, 1H, J = 8.4), 7.518 (d, 1H, J = 7.8), 7.365 (t, 1H, J1 = J2 = 2.4), 7.350 (t, 1H, J1 = 2.4, J2 = 3.0), 7.245 (d, 1H, J = 8.4), 7.034 (t, 1H, J1 = 3.6, J2 = 1.8), 7.020 (t, 1H, J1 = 1.8, J2 = 3.6), 6.974 (d, 1H, J = 1.8), 6.695 (dd, 1H, J = 6.6), 4.463 (s, 2H), 4.160 (s, 1H), 3.860 (s, 3H). 13C NMR (151 MHz, DMSO-d6): δ 160.62, 153.55, 151.59, 133.35, 126.92, 126.84, 116.42, 115.69, 115.22, 113.81, 112.29, 112.05, 56.20, 55.74. HRMS (ESI) m/z: (M + H)+ calcd for C22H18F3N3O 398.1475; found 398.1480.