Photochemically Mediated Ring Expansion of Indoles and Pyrroles with Chlorodiazirines: Synthetic Methodology and Thermal Hazard Assessment

Abstract

We demonstrate that arylchlorodiazirines serve as photo-activated halocarbene precursors for the selective one-carbon ring expansion of N-substituted pyrroles and indoles to the corresponding pyridinium and quinolinium salts. Preliminary investigations indicate that the same strategy also enables the conversion of N-substituted pyrazoles to pyrimidinium salts. The N-substituent of the substrate plays an essential role in: (1) increasing substrate scope by preventing product degradation, (2) enhancing yields by suppressing co-product inhibition, and (3) activating the azinium products towards subsequent synthetic manipulations. This latter point is illustrated by subjecting the quinolinium salts to four complementary partial reductions, which provide concise access to ring-expanded products with different degrees of increased C(sp³ ) character. Thermal analysis of the diazirines by differential scanning calorimetry (DSC) provides detailed insight into their energetic properties, and highlights the safety benefits of photolyzing-rather than thermolyzing-these reagents.

Keywords: Diazirines; Differential Scanning Calorimetry; Photochemistry; Ring Expansion; Skeletal Editing.

Scheme 1

Carbon atom insertion into indoles via halocyclopropanation/fragmentation. a) evolution of halocarbene precursors; b) ring expansion of N‐substituted indoles as a direct route to azinium salts.

Scheme 2

Scope of the one‐carbon ring expansion of azoles and diazoles. a) application to indoles; b) investigation of diazirine partners; c) application to pyrroles; d) application to pyrazoles. Yields refer to isolated material.^[a] Using 5 equivalents of diazirine.^[b] Solvent is TBME; regioisomeric ratio determined by NMR spectroscopic analysis following precipitation.

Scheme 3

Robustness screen of indole ring expansion. Yields determined by ¹⁹F NMR spectroscopic analysis vs internal standard.^[a] Ar=4‐F₃C‐C₆H₄.

Scheme 4

Derivatization of quinolinium salts. Yields refer to material isolated following purification.^[a] Yield determined by ¹H NMR spectroscopic analysis vs internal standard.

Figure 1

Graphical depiction of thermal stability data. a) dependence of T _init, T _onset (left‐hand axis) and ΔH _d (right‐hand axis) on the electronic properties of arylchlorodiazirines; b) comparison of arylchlorodiazirines to common energetic laboratory reagents.[ ⁶² , ⁶⁴ , ⁶⁶ ]

Scheme 5

Applications of photolytic carbene generation at sub‐ambient temperatures. a) Synthesis of quinolinium salts; comparison to thermolytic methods for the synthesis of: b) quinolines, and c) pyrimidines. Yields refer to isolated material.^[a] “rt” refers to the internal temperature of the air‐cooled photoreactor (see Supporting Information), which did not rise more than 5 °C above ambient temperature over the course of a 16 h reaction.^[b] Yield determined by ¹H NMR spectroscopic analysis vs internal standard.