Synthesis of 1,4-Dihydropyridines and Related Heterocycles by Iodine-Mediated Annulation Reactions of N-Cyclopropyl Enamines

Abstract

The annulation of N-cyclopropyl enamines to produce 1,4-dihydropyridine (1,4-DHP) derivatives is described. In the presence of molecular iodine (I 2 ), an N-cyclopropyl enamine substrate undergoes iodination, opening of the cyclopropyl ring, and annulation with a second molecule of the substrate to form the 1,4-DHP product. This reaction is amenable to gram-scale operations under mild reaction conditions with no transition metals being required. Further transformations of the 1,4-DHPs leads to related pyridine and bicyclic frameworks.

Synthesis of Quinazolinone-Fused Tetrahydroisoquinolines and Related Polycyclic Scaffolds by Iodine-Mediated sp3 C–H Amination

“…On the basis of these experimental results and our earlier work on I 2 -promoted C–H amination, tentative mechanisms are proposed for this sp 3 C–H amination reaction (Scheme ). Using the formation of product 2a as an example, iodination of the substrate ( 1a ) by molecular iodine under basic conditions gives an N-iodo intermediate ( B ) (path a ).…”

“…In 2020, Jia and co-workers described the synthesis of tetracyclic quinazolinones and Rutaecarpine by oxidative cyclization promoted by trifluoroacetic acid (TFA) and t -butyl hydroperoxide (TBHP) . Our interest in C–H amination reactions promoted by molecular iodine (I 2 ) led us to develop an I 2 -mediated intramolecular sp 3 C–H amination reaction for the synthesis of quinazolinone-fused tetrahydroisoquinolines and Rutaecarpine derivatives from readily accessible 2-aminobenzamide substrates, as is described in this paper.…”

Activation of aminocyclopropanes via radical intermediates

“…73 The Chang group described an iodine-mediated annulation reaction of N -cyclopropyl enamines for the synthesis of 1,4-dihydropyridines. 74 However, in these two examples a 2-electron, S N 2-like mechanism was proposed rather than a radical pathway, as the formation of a N–I bond was not observed by in situ NMR studies. However, this experiment cannot exclude a fast generation of the radical from the N–I bond, and the formed neutral nitrogen-centered radical is reported to undergo ring-opening faster than the corresponding nitrogen-centered radical cation.…”

I2-mediated coupling of quinazolinone enamines with 2-aminopyridines: a new strategy to access spiroquinazolinones

“…17 In contrast, using umpoled enamines as the reaction substrates directly has been investigated to a lesser extent. 18…”