# TBACN-Promoted Regioselective Cyanofunctionalization and Benzannulation: Enabling Access to Cyanoindolizine Scaffolds via Alkyne Cyclization

## TL;DR

A new chemical method using TBACN efficiently creates cyanoindolizine structures, which are useful for making drug-like molecules.

## Contribution

The first TBACN-mediated benzannulation of propargyl units with regioselective cyanofunctionalization is reported.

## Key findings

- A cascade reaction using TBACN enables streamlined synthesis of cyanoindolizine derivatives.
- The reaction shows high regioselectivity and functional group tolerance.
- The cyano group can be transformed into other functional groups like amides.

## Abstract

A novel and regioselective
cyanofunctionalization–benzannulation
cascade reaction has been developed, utilizing tetrabutylammonium
cyanide (TBACN) as a practical and efficient cyanide source. This
transformation provides streamlined access to a structurally diverse
array of cyano-substituted indolizine scaffolds, which are valuable
intermediates in the synthesis of nitrogen-containing heterocycles
with potential pharmaceutical applications. The methodology employs
readily available N-propargyl pyrrole derivatives
as starting materials and proceeds under relatively mild reaction
conditions, enabling the synthesis of 20 structurally distinct cyanoindolizine
derivatives. The reaction exhibits remarkable regioselectivity in
the installation of the cyano group, a feature that was not initially
anticipated. This unexpected regioselective outcome was elucidated
through a combination of control experiments, by-product analysis,
and intermediate isolation, shedding light on the underlying mechanistic
pathway. Furthermore, the reaction displays a broad substrate scope,
demonstrating high functional group tolerance with respect to both
electronic and steric variations on the pyrrole ring and the propargyl
substituents. The versatility of the methodology is further highlighted
by the potential for downstream transformations of the cyano group
into other functional groups, such as amide moieties, which expand
the synthetic utility of the obtained scaffolds. Importantly, this
work represents the first reported example of a TBACN-mediated benzannulation
of propargyl units, marking a significant advancement in the field
of heterocyclic chemistry. The strategy not only provides a novel
route to access complex indolizine frameworks but also offers valuable
mechanistic insights and synthetic opportunities for the design and
development of biologically relevant heterocycles.