A Remarkable One-Pot Sequential Four-Component Synthesis of Tetrahydroquinazolines via an Isocyanide-Based Multicomponent Reaction

Abstract

A novel one-pot sequential four-component strategy has been developed for the synthesis of tetrahydroquinazolines using either an aliphatic or an acyl halide, an isocyanide, and a 1,3-diamine, in methanol at 60 °C, in good to moderate yields without using a catalyst.

Key words

quinazoline - multicomponent - isocyanide

• References and Notes

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• 41 N-Cyclohexyl-4-oxo-2-phenyl-1,2,3,4-tetrahydro-quinazoline-2-carboxamide (4a) – Typical Procedure To magnetically stirred benzoyl chloride (0.14 g, 1.00 mmol) was added cyclohexyl isocyanide (0.11 g, 1.00 mmol), and the reaction mixture was heated for 2 h at 60 °C. After cooling, MeOH (5 mL) and 2-aminobenzamide were added, and the reaction mixture was stirred for 24 h at 60 °C. After completion of the reaction (TLC), the solvent was removed under vacuum, the residue was crystallized from CH₂Cl₂–n-hexane (3:1), and the product 4a was obtained as a white solid (0.21 g, 60%); yield 0.21 g (60%); mp 222–225 °C. IR (KBr): 3381, 3324, 2932, 2844, 1649, 1612, 1492, 1461 cm^–1. ¹H NMR (300.13 MHz, DMSO-d ₆): δ = 1.08–1.59 (10 H, m, 5 CH₂ of c-Hex), 3.52 (1 H, br s, CH of c-Hex), 6.69 (1 H, br s, NH), 6.93 (1 H, br s, NH), 7.25–7.70 (9 H, m, CHAr), 8.41 (1 H, br s, CONH). ¹³C NMR (75.47 MHz, DMSO-d ₆): δ = 24.6, 25.5, 32.4, 48.8, 75.5, 114.7, 115.5, 118.2, 126.8, 127.6, 128.7, 129.0, 134.0, 141.4, 147.2, 163.9, 170.3. MS: m/z (%) = 350 (90) [M⁺ + 1], 223 (100), 297 (25), 145 (15), 119 (30), 92 (60), 55 (65). Anal. Calcd for C₂₁H₂₃N₃O₂: C, 72.18; H, 6.63; N, 12.03. Found: C, 72.10; H, 6.58; N, 12.17. 2-(4-Bromophenyl)-N-cyclohexyl-4-oxo-1,2,3,4-tetrahydroquinazoline-2-carboxamide (4b) Yellow powder; yield 0.23 g (54%); mp 242–245 °C. IR (KBr): 3371, 3326, 2922, 2830, 1659, 1622, 1483, 1454 cm^–1. ¹H NMR (300.13 MHz, DMSO-d ₆): δ = 1.14–1.60 (10 H, m, 5 CH₂ of c-Hex), 3.50 (1 H, br s, CH of c-Hex), 6.69 (1 H, br s, NH), 6.92 (1 H, br s, NH), 7.28–7.79 (8 H, m, CHAr), 8.53 (1 H, br, CONH). ¹³C NMR (75.47 MHz, DMSO-d ₆): δ = 24.7, 24.8, 32.3, 48.9, 75.1, 114.7, 115.6, 118.3, 122.4, 127.6, 129.1, 129.3, 131.6, 131.8, 134.1, 140.9, 147.0, 163.8, 169.8. Anal. Calcd for C₂₁H₂₂BrN₃O₂: C, 58.89; H, 5.18; Br, 18.66; N, 9.81. Found: C, 58.75; H, 5.24; N, 9.96. N-Cyclohexyl-2-methyl-4-oxo-1,2,3,4-tetrahydroquinazoline-2-carboxamide (4c) White powder; yield 0.18 g (63%); mp 232–235 °C. IR (KBr): 3413, 3321, 3002, 2923, 2852, 1624, 1580, 1525, 1455 cm^–1. ¹H NMR (300.13 MHz, DMSO-d ₆): δ = 1.07–1.70 (10 H, m, 5 CH₂ of c-Hex), 1.88 (3 H, s, CH₃), 2.89 (1 H, br s, CH of c-Hex), 7.21 (1 H, br s, NH), 7.38 (1 H, br s, NH), 7.55–7.90 (4 H, m, CHAr), 8.60 (1 H, br, CONH). ¹³C NMR (75.47 MHz, DMSO-d ₆): δ = 24.2, 25.0, 25.2, 30.7, 49.7, 78.1, 115.1, 122.3, 124.8, 126.3, 126.8, 128.1, 135.1, 147.4, 155.4, 164.3. Anal. Calcd for C₁₆H₂₁N₃O₂: C, 66.88; H, 7.37; N, 14.62. Found: C, 66.80; H, 7.43; N, 14.69. N-tert-Butyl-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinazoline-2-carboxamide (4d) White powder; yield 0.20 g (62%); mp 182–184 °C. IR (KBr): 3260, 3191, 2964, 2926, 2837, 1635, 1612, 1511 cm^–1. ¹H NMR (300.13 MHz, DMSO-d ₆): δ = 1.57 (9 H, s, 3 CH₃), 6.62 (1 H, br s, NH), 6.65 (1 H, br s, NH), 6.74–7.33 (9 H, m, Ar), 7.89 (1 H, br, CONH). ¹³C NMR (75.47 MHz, DMSO-d ₆): δ = 29.7, 45.7, 80.1, 114.7, 116.2, 118.7, 126.4, 127.3 128.3, 129.1, 133.9, 134.0, 141.0, 154.0, 164.5. Anal. Calcd for C₁₉H₂₁N₃O₂: C, 70.57; H, 6.55; N, 12.99. Found: C, 70.64; H, 6.61; N, 12.90. N-Cyclohexyl-2-ethyl-4-oxo-1,2,3,4-tetrahydroquinazoline-2-carboxamide (4e) White powder; yield 0.19 g (63%); mp 176–179 °C. IR (KBr): 2983, 2940, 2862, 2825, 1701, 1644, 1618, 1498, 1455 cm^–1. ¹H NMR (300.13 MHz, DMSO-d ₆): δ = 1.08–1.88 (13 H, m, 5 CH₂ of c-Hex and CH₃), 2.28 (2 H, br, CH ₂CH₃), 2.90 (1 H, br s, CH of c-Hex), 7.11 (1 H, br s, NH), 7.19 (1 H, br s, NH), 7.36–7.91 (4 H, m, CHAr), 8.55 (1 H, br, CONH). ¹³C NMR (62.83 MHz, DMSO-d ₆): δ = 23.2, 24.7, 25.4, 32.9, 35.2, 48.4, 76.4, 113.9, 114.1, 117.3, 126.9, 131.8, 148.5, 159.2, 167.1. Anal. Calcd for C₁₇H₂₃N₃O₂: C, 67.75; H, 7.69; N, 13.94. Found: C, 67.69; H, 7.62; N, 14.09. N-tert-Butyl-2-ethyl-4-oxo-1,2,3,4-tetrahydroquinazoline-2-carboxamide (4f) Brown powder; yield 0.18 g (65%); mp 157–159 °C. IR (KBr): 3259, 2968, 2895, 1634, 1613, 1515, 1492, 1385 cm^–1. ¹H NMR (300.13 MHz, DMSO-d ₆): δ = 1.22–1.33 (14 H, br s, 3 CH₃ of t-Bu, CH₂CH ₃ and CH ₂CH₃), 6.59 (1 H, br s, NH), 6.67 (1 H, br s, NH), 7.17–7.91 (4 H, m, CHAr), 8.10 (1 H, br, CONH). ¹³C NMR (75.47 MHz, DMSO-d ₆): δ = 27.5, 29.4, 51.4, 67.3, 78.4, 114.2, 114.7, 116.8, 127.6, 133.6, 147.6, 158.4, 168.4. MS: m/z (%) = 276 (25) [M⁺ + 1], 223 (80), 200 (15), 177 (15), 161 (100), 120 (25), 92 (25), 58 (75). Anal. Calcd for C₁₅H₂₁N₃O₂: C, 65.43; H, 7.69; N, 15.26. Found: C, 65.49; H, 7.74; N, 15.18. N-Cyclohexyl-2-phenyl-1,2,3,4-tetrahydroquinazoline-2-carboxamide (4g) White powder; yield 0.22 g (66%); mp 153–159 °C. IR (KBr): 2940, 2862, 2730, 1675, 1606, 1511, 1442 cm^–1. ¹H NMR (300.13 MHz, DMSO-d ₆): δ = 1.07–1.89 (10 H, m, 5 CH₂ of c-Hex), 2.88 (2 H, br, CH₂, ArCH₂), 3.40 (1 H, br s, CH of c-Hex), 6.63 (1 H, br s, NH), 6.72 (1 H, br s, NH), 7.14–7.24 (9 H, m, Ar), 8.35 (1 H, br, CONH). ¹³C NMR (75.47 MHz, DMSO-d ₆): δ = 24.2, 25.0, 30.6, 41.1, 49.7, 76.6, 117.2, 118.4, 127.4, 126.2, 127.5, 127.6, 128.5, 129.2, 131.3, 150.1, 151.2, 167.9. Anal. Calcd for C₂₁H₂₅N₃O: C, 75.19; H, 7.51; N, 12.53. Found: C, 75.12; H, 7.44; N, 12.62. N-Cyclohexyl-2-methyl-1,2,3,4-tetrahydroquinazoline-2-carboxamide (4h) White powder; yield 0.19 g (70%); mp 145–148 °C. IR (KBr): 3425, 3336, 3021, 2936, 1637, 1587, 1500, 1461 cm^–1. ¹H NMR (300.13 MHz, DMSO-d ₆): δ = 1.07–1.70 (10 H, m, 5 CH₂ of c-Hex), 1.89 (3 H, s, CH₃), 2.89 (1 H, br s, CH of c-Hex), 3.86 (2 H, br, CH₂, ArCH₂), 6.56 (1 H, br s, NH), 6.69 (1 H, br s, NH), 7.01–7.15 (4 H, m, CHAr), 8.26 (1 H, br, CONH). ¹³C NMR (75.47 MHz, DMSO-d ₆): δ = 24.2, 25.0, 30.7, 38.9, 40.9, 49.7, 82.2, 116.0, 116.6, 117.7, 129.8, 130.9, 147.5, 159.1, 165.2. Anal. Calcd for C₁₆H₂₃N₃O: C, 70.30; H, 8.48; N, 15.37. Found: C, 70.39; H, 8.57; N, 15.24. N-Cyclohexyl-2-ethyl-1,2,3,4-tetrahydroquinazoline-2-carboxamide (4i) White powder; yield 0.19 g (66%); mp 149–151 °C. IR (KBr): 3381, 3325, 3014, 2932, 2869, 1648, 1612, 1503 cm^–1. ¹H NMR (300.13 MHz, DMSO-d ₆): δ = 0.84–1.67 (13 H, m, 5 CH₂ of c-Hex and CH₃), 1.89 (2 H, br s, CH ₂CH₃), 2.88 (1 H, br s, CH of c-Hex), 3.39 (2 H, br, ArCH₂), 6.56 (1 H, br s, NH), 6.70 (1 H, br s, NH), 7.13–7.28 (4 H, m, CHAr), 8.20 (1 H, br, CONH₂). ¹³C NMR (75.47 MHz, DMSO-d ₆): δ = 15.6, 24.2, 25.0, 30.6, 40.7, 41.1, 49.7, 77.3, 117.2, 118.4, 127.4, 127.6, 129.3, 131.3, 150.1, 157.3, 164.5. Anal. Calcd for C₁₇H₂₅N₃O: C, 71.04; H, 8.77; N, 14.62. Found: C, 71.21; H, 8.64; N, 14.70. (2E,2′E)-2,2′-[Ethane-1,2-diylbis(azan-1-yl-1-ylidene)]bis[2-(4-bromophenyl)-N-cyclohexylacetamide] (8) White powder; yield 0.50 g (78%); mp 202–204 °C. IR (KBr): 3244, 3071, 2093, 2853, 1623, 1553, 1448 cm^–1. ¹H NMR (300.13 MHz, DMSO-d ₆): δ = 1.22–1.84 (20 H, m, 10 CH₂ of c-Hex), 2.15–2.21 (4 H, m, 2 CH₂), 3.10 (2 H, br s, 2 NH), 3.64–3.75 (2 H, m, 2 CH of c-Hex), 7.16–7.60 (10 H, m, CHAr), 7.74 (2 H, br, CONH). ¹³C NMR (75.47 MHz, DMSO-d ₆): δ = 24.8, 25.5, 32.8, 46.1, 84.6, 125.6, 128.2, 128.4, 141.8, 172.9. MS: m/z = 646 (10) [M⁺ + 2], 644 (20) [M⁺], 642 (10) [M⁺ – 2], 604 (15), 518 (50), 478 (25), 392 (15), 351 (20), 335 (30), 321 (10), 266 (20), 210 (25), 184 (60), 102 (15), 83 (70), 55 (100). Anal. Calcd for C₂₈H₃₈N₄, C, 78.10; H, 8.89; N, 13.01. Found: C, 78.01; H, 8.95; N, 13.05. (2E,2′E)-2,2′-[1,2-Phenylenebis(azan-1-yl-1-ylidene)]bis[2-(4-bromophenyl)-N-cyclohexylacetamide] (9) White powder; yield 0.49 g (71%); mp 162–163 °C. IR (KBr): 3338, 3297, 2933, 2878, 2854, 1644, 1514, 1485, 1455 cm^–1. ¹H NMR (300.13 MHz, DMSO-d ₆): δ = 1.24–1.83 (20 H, m, 10 CH₂ of c-Hex), 2.82 (4 H, br, 2 CH₂), 3.64 (2 H, br s, 2 CH of c-Hex), 7.49–7.66 (8 H, m, CHAr), 7.72 (2 H, br, CONH). ¹³C NMR (75.47 MHz, DMSO-d ₆): δ = 25.0, 25.5, 32.7, 46.6, 48.0, 84.5, 123.0, 128.8, 129.9, 131.0, 175.2. Anal. Calcd for C₂₈H₃₆Br₂N₄, C, 57.15; H, 6.17; Br, 27.16; N, 9.52. Found: C, 57.10; H, 6.09; N, 9.61.