Concise two-step solution phase syntheses of four novel dihydroquinazoline scaffolds

Abstract

Novel two-step solution phase protocols for the synthesis of dihydroquinazolines and fused dihydroquinazoline-benzodiazepine tetracycles are reported. The methodology employs the Ugi reaction to assemble desired diversity and acid treatment enables ring closing transformations. The protocols are further facilitated by the use of microwave irradiation and n-butyl isocyanide to control the rate of each ring forming transformation.

Synthesis of 3‐Substituted 2‐Indol­inones by a Multicomponent Coupling Isocyanide‐Dependent Microwave‐Assisted Intramolecular Transamidation Process

“…The characterization of 1h was verified using NMR and MS and unequivocally confirmed through X‐ray crystal structure analysis (Figure 1). Combined with previous data, these results indicate that the steric environment of the 2° amide is critical for product selectivity and we believe that the formation of methylamine gas is a driving force for the formation of 2‐indolinones via our intramolecular transamidation 37…”

Synthesis of dihydroquinazolines from 2-aminobenzylamine: N3-aryl derivatives with electron-withdrawing groups

“…Dihydroquinazolines can also be synthesized by heterocyclization of 2-aminobenzylamines (2-ABAs) with different C2 donors [ 3 , 16 – 17 29 – 36 ]. An alternative method is the ring closure of N- acyl-2-ABAs, but this strategy generally requires high temperatures and/or long reaction times [ 5 , 37 – 40 ].…”

Syntheses of 3,4- and 1,4-dihydroquinazolines from 2-aminobenzylamine

“…However, these reactions are frequently associated with long reaction times, poor yields and low selectivity [ 46 – 47 ]. The selective monofunctionalization of 2-ABA was achieved by using protective groups such as 9-BBN [ 48 ] or Boc [ 39 ], which require subsequent removal. Other alternative synthetic strategies use substrates like 2-nitrobenzoyl chloride, 2-nitrobenzaldehyde, 2-aminobenzamides, 2-aminobenzophenone, 2-nitrobenzyl bromide, among others, which require an additional reduction step [ 17 – 18 29 , 49 – 51 ].…”