Four‐Component Reaction for the Synthesis of Indolizines by Copper‐Catalyzed Aerobic Oxidative Dehydrogenative Aromatization

Abstract

A one‐pot, four‐component reaction was developed for the synthesis of indolizines from pyridines, α‐halide carbonyl compounds, primary amines, and maleic anhydride. The key step in this reaction involved the copper‐catalyzed aerobic oxidative aromatization of a tetrahydrogen–indolizine intermediate. Oxygen gas was employed as a clean oxidant to facilitate the catalytic process. Notably, this transformation used readily available starting materials, exhibited broad substrate scope, was easy to handle, and required mild reaction conditions.

Synthesis of Pyrrole via a Silver-Catalyzed 1,3-Dipolar Cycloaddition/Oxidative Dehydrogenative Aromatization Tandem Reaction

“…Furthermore, DDQ is expensive and toxic, and its consumption during the course of these reactions results in the formation of toxic byproducts. We recently reported a series of synthetic methods for the construction of indolizines using a tandem one-pot 1,3-dipolar cycloaddition/​oxidative dehydrogenative aromatization reaction sequence . As part of our ongoing research toward the oxidative dehydrogenative aromatization reactions of nitrogen-containing heterocycles, we report herein the development of a practical synthetic method for the construction of pyrroles via a tandem reaction sequence starting from simple alkenes (Scheme ).…”

Copper‐Catalysed Multicomponent Syntheses of Heterocycles

“…A four‐component reaction has been reported for the synthesis of Indolizines via a Cu‐catalysed aerobic oxidative dehydrogenative aromatization (Scheme ) . The multicomponent reaction involved reaction between an amine (1.0 equiv.)…”

The regioselective annulation of N-methylpyridinium ylides with alkenes enabled by palladium catalysis: access to 3-unsubstituted indolizine derivatives

“…A large number of elegant works on the use of different alkynes as dipolarophiles to synthesize indolizines substituted at the C1, C2, or C3-site by divergent types of substituents were reported in detail (Scheme 1A, eqn (1)). 5 Compared with alkynes, relatively few studies, which also show promising results in the construction of multi-substituted indolizine derivatives, have been developed by utilizing other types of cyclization substrates such as O -phosphorylated hydroxyketeneimines, 6 ethyl bromodifluoroacetate, 7 and alkenes 8 (Scheme 1A, eqn (2)–(4)). It is worth mentioning that the previous reports exhibit a standard feature, namely, a variety of electron-withdrawing groups (EWG) linked to pyridinium ylides, which strongly facilitate the activation of the C–H bonds of methylene under strong alkaline conditions to form ylides, 9 are indispensable for the achievement of the annulation of the reaction (Scheme 1A).…”

“…It is worth mentioning that the previous reports exhibit a standard feature, namely, a variety of electron-withdrawing groups (EWG) linked to pyridinium ylides, which strongly facilitate the activation of the C–H bonds of methylene under strong alkaline conditions to form ylides, 9 are indispensable for the achievement of the annulation of the reaction (Scheme 1A). Despite these remarkable advances in constructing multi-substituted indolizine derivatives, 5–8 the synthesis of 3-unsubstituted indolizines with alkenes as dipolarophiles has only been sporadically reported thus far. However, these rare studies on the successful preparation of 3-unsubstituted indolizines are at the cost of releasing HBr or CO 2 , 8 which presents negative carbon neutrality, 10 terrible performances in terms of data, and limited substrate scope.…”

“…Despite these remarkable advances in constructing multi-substituted indolizine derivatives, 5–8 the synthesis of 3-unsubstituted indolizines with alkenes as dipolarophiles has only been sporadically reported thus far. However, these rare studies on the successful preparation of 3-unsubstituted indolizines are at the cost of releasing HBr or CO 2 , 8 which presents negative carbon neutrality, 10 terrible performances in terms of data, and limited substrate scope. 8 f However, the construction of 3-unsubstituted indolizines by using EWG-free substrates is of important synthetic value 3,18,20 and conquering weak activation sites remains a challenge.…”