Recent Approaches for the Synthesis of Tetrahydro-6H-isoquinolino[2,1-a] quinazolines

The fusion of the 1,2,3,4-tetrahydroquinazoline ring at the α-edge with 1,2,3,4- tetrahydroisoquinoline results in the formation of two distinct structural isomers: 4b,5,12,13- tetrahydro-6H-isoquinolino[2,1-a]quinazoline (THIQ[2,1-a]Qz) and 6,6a,7,12-tetrahydro-5Hisoquinolino[ 2,3-a]quinazoline (THIQ[2,3-a] Qz). Among these, THIQ[2,1-a] Qz is particularly significant, as it is found in natural products and biologically active alkaloids, and it exhibits a wide range of pharmacological activities. The synthesis of THIQ[2,1-a] Qz and its related derivatives can be achieved through various strategies. These include: i) Cyclization of 2-(3,4-dihydro-2(1H)- isoquinolinyl) benzaldehydes or 2-(2-haloethyl) benzaldehydes with nitrogen-containing substrates. ii) Reactions of 2-(2-azidoethyl) benzaldehyde with benzamides. iii) Copper- or palladium-catalyzed one-pot transformations of 2-halobenzamides or 2-haloarylhydrazides with tetrahydroisoquinolines. iv) Oxidative cross-dehydrogenative coupling (CDC) amidation of N-substituted tetrahydroisoquinolines using reagents such as PIFA, PhI(OAc)2, BINOL-derived phosphoric acids, or iridium catalysts. v) Gold(I)-catalyzed one-pot reactions of 2-(2-ethynylphenyl)-1,2,3,4-tetrahydroisoquinoline or 2-(2-ethynyl-phenyl) acetic acid with anilines, among other approaches.