Synthesis of Quinazolin-4(3H)-ones via Amidine N-Arylation

Abstract

Pyrido[4,3-d]pyrimidin-4(3H)-one (1) was prepared by reacting 2-trifluoromethyl-4-iodo-nicotinic acid (2) with amidine 9a catalyzed by Pd(2)(dba)(3) and Xantphos, followed by cyclization effected with HBTU and subsequent demethylation using PhBCl(2). The amidine arylation method was found applicable for the syntheses of quinazolin-4(3H)-ones. Thus, reaction of 2-bromo or 2-iodo benzoate esters with amdidines afforded substituted quinazolin-4(3H)-ones in 44-89% yields.

Rapid assembly of quinazolinone scaffold via copper-catalyzed tandem reaction of 2-bromobenzamides with aldehydes and aqueous ammonia: application to the synthesis of the alkaloid tryptanthrin

“…In addition, both alkenyl-and alkyl-substituted aldehydes were well compatible with the reaction conditions to generate the desired products 3m and 3n in moderate yields (entries [13][14]. Next, 2-bromobenzamides 1 with different substitution patterns were investigated under our optimized reaction conditions, and it was observed that the tandem reactions of amides 1b-d with different aldehydes 2 and aqueous ammonia proceeded smoothly to afford 2-substituted quinazolinones 3o-w in yields ranging from 30-79% (entries [15][16][17][18][19][20][21][22][23].…”

Applications of Palladium-Catalyzed C–N Cross-Coupling Reactions

“…Li and co-workers (Pfizer) developed a procedure for the large-scale synthesis of quinazolin-4(3 H )-ones. 373 Targeting quinazoline 436 ( Scheme 108 b), the research group initially examined a Cu-catalyzed approach to access intermediate 435 . However, they only observed low conversion to the desired product.…”

Modern advances in heterocyclic chemistry in drug discovery

“…56 The route highlights the formation of a pyridopyrimidin-4(3H)-one using a palladium-catalyzed amidine N-arylation reaction. 56 The route highlights the formation of a pyridopyrimidin-4(3H)-one using a palladium-catalyzed amidine N-arylation reaction.…”