Palladium-catalyzed N-monoarylation of amidines and a one-pot synthesis of quinazoline derivatives

Abstract

A method for the Pd-catalyzed N-arylation of both aryl and alkyl amidines with a wide range of aryl bromides, chlorides, and triflates is described. The reactions proceed in short reaction times and with excellent selectivity for monoarylation. A one-pot synthesis of quinazoline derivatives, via addition of an aldehyde to the crude reaction mixture following Pd-catalyzed N-arylation, is also demonstrated.

Figure 1

Biaryl phosphine ligands utilized in the catalytic Pd-based C-N cross-coupling reactions with N-containing and potentially chelating substrates.

Scheme 1

N-Monoarylation of Aryl Amidines.^{a a}Reaction conditions: ArX (1.0 mmol), amidine hydrochloride (1.1 mmol), Pd₂dba₃ (n mol %), L2 (2n mol %), Cs₂CO₃ (2.6 mmol), t-BuOH (4 mL/mmol of ArX), 85 or 110 °C, 2 h; isolated yields, average of two runs.

Scheme 2

N-Monoarylation of Alkyl Amidines.^{a a}Reaction conditions: ArX (1.0 mmol), amidine hydrochloride (1.1 mmol), Pd₂dba₃ (n mol %), L2 (2n mol %), Cs₂CO₃ (2.6 mmol), t-BuOH (4 mL/mmol), 85 or 110 °C, 2 h; isolated yields, average of two runs.

Scheme 3

Optimization of Quinazoline Formation.^{a a}Conversion and yield were calculated by ¹H NMR using 1,3,5-trimethoxybenzene as an internal standard.

Scheme 4

One-Pot Synthesis of Quinazoline Derivatives.^{a a}Reaction conditions: (i) ArX (1.0 mmol), amidine hydrochloride (1.0 mmol), Pd₂dba₃ (n mol %), L2 (2n mol %), Cs₂CO₃ (3.4 mmol), t-BuOH (4 mL/mmol of ArX), 110 °C, 2 h; (ii) aldehyde (1.5 mmol), 130 °C, 16 h; (iii) DDQ (1 mmol), EtOAc/H₂O, rt, 1 h; isolated yields, average of two runs.