One-Pot Synthesis of Functionalized Benzimidazoles and 1H-Pyrimidines via Cascade Reactions of o-Aminoanilines or Naphthalene-1,8-diamine with Alkynes and p-Tolylsulfonyl Azide

Abstract

A one-pot synthesis of functionalized benzimidazoles and 1H-pyrimidines via the cascade reactions of o-aminoanilines or naphthalene-1,8-diamine with terminal alkynes and p-tolylsulfonyl azide is reported. The protocol is efficient and general.

Key words

benzimidazole - 1H-pyrimidine - o-aminoanilines - naphthalene-1,8-diamine - alkynes

References and Notes

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13

General Procedure for the Synthesis of Benzimidazoles and Pyrimidines
To a solution of p-tolylsulfonyl azide (2.2 mmol), terminal alkyne (2.1 mmol), diamine (o-aminoaniline or naphthalene-1,8-diamine; 2 mmol), and CuI (0.2 mmol) in MeCN (10 mL), was added dropwise Et₃N (2 mmol). The reaction was stirred at r.t. under N₂ for 6 h, then concd. H₂SO₄ (98%,
0.4 mL) was added to the reaction mixture. The resulting solution was heated under reflux for 4 h. After cooling to r.t., the solution was poured into H₂O (20 mL), and neutralized with K₂CO₃. MeCN was removed in vacuum, and the resulting solution was extracted with EtOAc (3 × 5 mL). The organic layer was combined, dried over anhydrous sodium sulfate, and the solvent was removed under vacuum. The residue was purified by column chromatography on silica gel (petroleum ether-EtOAc, 2:1→1:2).
2-Benzyl-1H-benzo[d]imidazole (5a): White solid; mp 187-188 ˚C; ^¹H NMR (400 MHz, DMSO-d ₆): δ = 4.18 (2 H, s), 7.11-7.13 (2 H, m), 7.20-7.24 (1 H, m), 7.29-7.35 (4 H, m), 7.48 (2 H, br s), 12.32 (1 H, br s); ^¹³C NMR (100 MHz, DMSO-d ₆): δ = 35.4, 121.7, 126.9, 128.9, 129.1, 138.1, 153.9; IR (KBr): 3432, 3083, 3050, 3025, 2837, 2738, 2687, 2637, 1624, 1588, 1536, 1493, 1457, 1447, 1427, 1323, 1271, 1224, 1196, 1148, 1024, 1013, 1001, 926, 890, 848, 768, 749, 723, 695, 670, 619, 565 cm^-¹; MS (ESI): m/z = 209 [M + H]⁺; HRMS (ESI): m/z [M + H]⁺ calcd for C₁₄H₁₃N₂: 209.1073; found: 209.1073.
2-(4-Methoxybenzyl)-1H-benzo[d]imidazole (5b): Slightly yellow solid; mp 165-166 ˚C; ^¹H NMR (400 MHz, DMSO-d ₆): δ = 3.71 (3 H, s), 4.10 (2 H, s), 6.88 (2 H, d, J = 8.8 Hz), 7.10-7.13 (2 H, m), 7.25 (2 H, d, J = 8.4 Hz), 7.47 (2 H, br s), 12.24 (1 H, br s); ^¹³C NMR (125 MHz, DMSO-d ₆): δ = 34.5, 55.4, 114.3, 114.8, 121.5, 129.9, 130.1, 139.2, 154.3, 158.4; IR (KBr): 3436, 2999, 2937, 2901, 2841, 2759, 1611, 1584, 1537, 1512, 1456, 1442, 1412, 1326, 1305, 1271, 1244, 1184, 1105, 1029, 1000, 922, 838, 814, 769, 752, 729, 715, 573, 511 cm^-¹; MS (ESI): m/z = 239.0 [M + H]⁺; HRMS (ESI): m/z [M + H]⁺ calcd for C₁₅H₁₅N₂O: 239.1179; found: 239.1179.
2-(3-Chlorobenzyl)-1H-Pyrimidine (7a): Yellow solid; mp 171-173 ˚C; ^¹H NMR (400 MHz, DMSO-d ₆): δ = 3.59 (2 H, s), 6.34-6.50 (2 H, br), 6.97-7.09 (4 H, m), 7.32-7.39 (3 H, m), 7.46 (1 H, s), 10.64 (1 H, br s); ^¹³C NMR (125 MHz, DMSO-d ₆): δ = 40.9, 118.8, 121.8, 127.2, 128.0, 128.8, 129.1, 130.8, 133.5, 135.6, 139.7, 156.0; IR (KBr): 3404, 3047, 2813, 1639, 1609, 1597, 1542, 1479, 1445, 1433, 1416, 1369, 1341, 1300, 1241, 1174, 1094, 1078, 1052, 1032, 991, 866, 824, 786, 770, 759, 709, 682, 632 cm^-¹; MS (ESI): m/z = 291.1 [M - H]^-; HRMS (ESI): m/z [M + H]⁺ calcd for C₁₈H₁₄ClN₂: 293.0840; found: 293.0842.
2-(4-Chlorobenzyl)-1H-Pyrimidine (7b): Yellow solid; mp 183-185 ˚C; ^¹H NMR (400 MHz, DMSO-d ₆): δ = 3.57 (2 H, s), 6.30-6.53 (2 H, br), 6.98 (2 H, d, J = 8.0 Hz), 7.09 (2 H, br), 7.38-7.43 (4 H, m), 10.64 (1 H, br s); ^¹³C NMR (125 MHz, DMSO-d ₆): δ = 40.8, 108.4, 119.1, 121.9, 128.7, 129.0, 131.2, 132.2, 135.7, 136.3, 156.6; IR (KBr): 3398, 3047, 2927, 2823, 1918, 1635, 1594, 1535, 1491, 1476, 1442, 1425, 1413, 1373, 1342, 1309, 1291, 1238, 1182, 1165, 1092, 1051, 1030, 1017, 988, 825, 805, 793, 765, 713, 692, 616, 512 cm^-¹; MS (ESI): m/z = 291 [M - H]^-; HRMS (ESI): m/z [M + H]⁺ calcd for C₁₈H₁₄ClN₂: 293.0840; found: 293.0829.