Homologation of the Fischer Indolization: A Quinoline Synthesis via Homo-Diaza-Cope Rearrangement

Abstract

We disclose a new Brønsted acid promoted quinoline synthesis, proceeding via homo-diaza-Cope rearrangement of N-aryl-N'-cyclopropyl hydrazines. Our strategy can be considered a homologation of Fischer's classical indole synthesis and delivers 6-membered N-heterocycles, including previously inaccessible pyridine derivatives. This approach can also be used as a pyridannulation methodology toward constructing polycyclic polyheteroaromatics. A computational analysis has been employed to probe plausible activation modes and to interrogate the role of the catalyst.

Keywords: DFT calculations; Fischer indolization; annulation; cyclopropane; quinolines; rearrangements.

Figure 1

Outline of this study.

Scheme 1

The reactions were carried out on a 0.3 mmol scale at a concentration of 0.015 M using 10 equivalents of acid.

Figure 2

Proposed reaction pathway along with DFT computed activation energies (kcal mol⁻¹) for the key transition states at the B3LYP‐D3/def2‐TZVP//PBE‐D3/def2‐SVP level of theory.