A Copper-Catalyzed Synthesis of Functionalized Quinazolines from Isocyanides and Aniline Tri- and Dichloroacetonitrile Adducts through Intramolecular C–H Activation

Abstract

A novel class of substituted quinazolines were prepared in good yields by a one-pot three-component reaction of isocyanides with adducts of anilines and tri- or dichloroacetonitrile, followed by intramolecular C–H activation, catalyzed by copper(I) iodide with l-proline as a ligand in acetonitrile at room temperature.

Keywords

C–H activation - dichloroacetonitrile - trichloroacetonitrile - copper catalysis - quinazolines - isocyanides

• References and Notes

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• 14 N-Phenyl-2-(trichloromethyl)quinazolin-4-amine (5a); Typical Procedure A mixture of PhNH₂ (2a; 1 mmol) and Cl₃CCN (1a; 1 mmol) was stirred for 5 min, and then a mixture of PhNC (4a; 1.5 mmol), CuI (0.10 mmol), Cs₂CO₃ (2.0 mmol), and l-proline (20 mol%) in MeCN (2 mL) was slowly added. The mixture was stirred at r.t. for 5 h until the reaction was complete [TLC, EtOAc–hexane (1:4)]. The mixture was then diluted with CH₂Cl₂ (2 mL) and aq NH₄Cl (3 mL). The resulting mixture was stirred for 30 min, and then the phases were separated. The aqueous phase was extracted with CH₂Cl₂, and the combined organic fractions were dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The resulting solid was collected by filtration and washed with hexane to give a cream-colored powder; yield: 0.29 g (85%); mp 188–190 °C. IR (KBr): 3344, 1604, 1585, 1164, 759 cm⁻¹. ¹H NMR (500 MHz, CDCl₃): δ = 5.05 (s, 1 H, NH), 7.29–7.35 (m, 3 H, Ph), 7.48 (d, ³ J = 7.7, 2 H, Ar), 7.55 (t, ³ J = 8.1, 1 H, Ar), 7.62 (t, ³ J = 8.1, 1 H, Ar), 8.02 (d, ³ J = 8.1, 1 H, Ar), 8.26 (d, ³ J = 8.1, 1 H, Ar). ¹³C NMR (125.7 MHz, CDCl₃): δ = 90.6 (CCl₃), 127.2 (CH), 127.9 (2 CH), 128.1 (CH), 128.6 (2 CH), 129.4 (CH), 130.1 (CH), 131.4 (CH), 133.8 (C), 142.7 (C), 148.0 (C), 156.2 (C), 160.1 (C). MS: m/z (%) = 338 (11) [M + 1], 259 (12), 244 (18), 128 (24), 116 (100), 92 (56), 77 (60). Anal. Calcd for C₁₅H₁₀Cl₃N₃ (338.62): C, 53.20; H, 2.98; N, 12.41. Found: C, 53.18; H, 2.95; N, 12.49.
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