Recent Advances in the Transition-Metal-Free Synthesis of Quinazolines

Abstract

Quinazolines are a privileged class of nitrogen-containing heterocycles, widely present in a variety of natural products and synthetic chemicals with a broad spectrum of biological and medicinal activities. Owing to their pharmaceutical applications and promising biological value, a variety of synthetic methodologies have been reported for these scaffolds. From the perspective of green and sustainable chemistry, transition-metal-free synthesis provides an alternative method for accessing several biologically active heterocycles. In this review, we summarize the recent progress achieved in the transition-metal-free synthesis of quinazolines and we cover the literature from 2015 to 2022. This aspect is present alongside the advantages, limitations, mechanistic rationalization, and future perspectives associated with the synthetic methodologies.

Regioselective quinazoline C2 modifications through the azide–tetrazole tautomeric equilibrium

“…The regioselectivity and the structure of 4-azido-6,7-dimethoxy-2-sulfonylquinazoline derivatives 12 were proven by chemical synthesis of the regioisomers 15 (Scheme 7) and X-ray analysis of 12a (Scheme 6). 6,7-Dimethoxy-2,4-diazidoquinazoline (13) was synthesized from commercially available dichloroquinazoline 7 in 93% yield. Further, thioether substituents were installed in the presence of K 2 CO 3 .…”

“…A selective C2 modification can be achieved by using 2-chloroquinazolines IV , where the C4 position is blocked by an unreactive C–C or C–H bond ( Scheme 1 ). Cyclization reactions of substituted anilines VI , VII or N -arylamidines VIII are frequently employed for synthesizing C2-substituted quinazolines ( Scheme 1 ), thereby influencing the spatial arrangement of the desired substituents [ 13 – 14 ]. Moreover, there have been recent advancements in efficient C–H activation techniques employing transition-metal and photocatalysis [ 15 – 16 ].…”