Carbon Atom Insertion into Pyrroles and Indoles Promoted by Chlorodiazirines

Abstract

Herein, we report a reaction that selectively generates 3-arylpyridine and quinoline motifs by inserting aryl carbynyl cation equivalents into pyrrole and indole cores, respectively. By employing α-chlorodiazirines as thermal precursors to the corresponding chlorocarbenes, the traditional haloform-based protocol central to the parent Ciamician-Dennstedt rearrangement can be modified to directly afford 3-(hetero)arylpyridines and quinolines. Chlorodiazirines are conveniently prepared in a single step by oxidation of commercially available amidinium salts. Selectivity as a function of pyrrole substitution pattern was examined, and a predictive model based on steric effects is put forward, with DFT calculations supporting a selectivity-determining cyclopropanation step. Computations surprisingly indicate that the stereochemistry of cyclopropanation is of little consequence to the subsequent electrocyclic ring opening that forges the pyridine core, due to a compensatory homoaromatic stabilization that counterbalances orbital-controlled torquoselectivity effects. The utility of this skeletal transform is further demonstrated through the preparation of quinolinophanes and the skeletal editing of pharmaceutically relevant pyrroles.

Figure 1

Introduction. (A) selected recent examples of peripheral editing of pyrroles and indoles; (B) the classical Ciamician–Dennstedt Rearrangement; (C) skeletal editing logic for heterocycle diversification (this work).

Figure 2

Scope of the indole-to-quinoline ring expansion. Conditions: 2 (1 equiv), 1 (3 equiv), Na₂CO₃ (3 equiv), CH₃CN (0.1 M), 50 °C, 12 h. Isolated yields, 0.1–0.3 mmol scale. ^a5 equiv of 1. ^b48 h.

Figure 3

Scope and selectivity of the pyrrole-to-pyridine ring expansion. Conditions: 4 (1 equiv), 1 (3 equiv), Na₂CO₃ (3 equiv), CH₃CN (0.1 M), 50 °C, 12 h. Isolated yields, 0.1–0.3 mmol scale. ^a48 h. Regioisomer assignments supported by ¹H-NOE. Selectivity model based on the difference between the Boltzmann averaged buried volume in a 3.75 Å sphere at C3 vs C4.

Figure 4

Unusual ortho and para isomers and computational investigation of their mechanism of formation. Conditions: 4 (1 equiv), 1 (3 equiv), Na₂CO₃ (3 equiv), CH₃CN (0.1 M), 50 °C, 12 h. Isolated yields, 0.1–0.3 mmol scale. ^aUnassigned minor isomer detected. ^bCarbene-C2 bond was frozen at length from B3LYP-D3/6-31g(d) optimization.