Efficient Copper-Catalyzed Synthesis of 4-Aminoquinazoline and 2,4-Diaminoquinazoline Derivatives

Abstract

We have developed an efficient copper-catalyzed method for the synthesis of 4-aminoquinazoline and 2,4-diaminoquinazoline derivatives via reactions of substituted 2-bromo-benzonitriles with amidines or guanidine, and the method is of economical and practical advantage.

Key words

copper - Ullmann-type reaction - cross-coupling - quinazoline - synthetic method

References and Notes

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27

General Procedure for the Synthesis of Compounds 3a-m A 25 mL round-bottom flask was charged with a magnetic stirrer and DMF (3 mL), substituted 2-bromobenzonitrile (1, 1 mmol), amidine hydrochloride (2, 1.2 mmol), DMEDA (0.2 mmol, 18 mg), and K₂CO₃ (2 mmol, 138 mg) [2 mmol (656 mg) of Cs₂CO₃ were used for acetamidine hydro-chloride] after stirring of the mixture for 15 min under nitrogen atmosphere, and CuI (0.1 mmol, 19 mg) was added to the flask. The mixture was stirred at 80 ˚C for the time indicated in Table  [²] . The resulting mixture was cooled to r.t. and filtered. The solid was washed with DMF (2 × 3 mL), and the combined filtrate was concentrated by the rotary evaporator, and the residue was purified by column chromatography on silica gel using CHCl₃-MeOH (40:1 to 5:1) as eluent to give the desired product.
Cyclopropyl-4-aminoquinazoline (3c)
Eluent CHCl₃-MeOH (40:1). Yield 134 mg (72%). White solid; mp 198-200 ˚C. ^¹H NMR (300 MHz, DMSO-d ₆): δ = 8.12 (d, 1 H, J = 7.9 Hz), 7.58 (m, 4 H), 7.34 (t, 1 H, J = 7.4 Hz), 1.99 (m, 1 H, J = 7.5 Hz), 1.05-0.87 (m, 4 H). ^¹³C NMR (75 MHz, DMSO-d ₆): δ = 167.6, 162.3, 150.5, 133.2, 126.9, 124.5, 124.0, 113.4, 18.4, 9.4. HRMS: m/z calcd for C₁₁H₁₁N₃ [M + H]⁺: 186.1031; found: 186.1037.