Manganese-Catalyzed Ring Expansion of Cycloalkenes To Access Pyridines and Isoquinolines

Keywords

pyridine - isoquinolines - transition-metal catalysis - ring expansion

Significance

Pyridine and isoquinoline derivatives are prevalent in bioactive compounds as well as in natural products. Here, the authors report a Mn-catalyzed cycloalkene ring expansion transformation for the synthesis of azaheterocycles 3 and 5 in moderate to good yields. Azidyl radical addition to the cycloalkene as the initial step and resulting C-radical addition to O₂, followed by intramolecular rearrangement involving C–O, N–N, and C–C bond cleavage followed by C–N bond formation, together with aromatization, enable the creation of pyridine and isoquinoline derivatives. Various control experiments were carried out to establish a plausible reaction mechanism. Additionally, the synthetic utility of this ring-expansion strategy was exemplified by the synthesis of the FDA-approved drug vismodegib in good yield.

Comment

Ring-expansion reactions remain a powerful tool in organic synthesis to construct diverse molecules. Over 35 examples of pyridine derivatives were synthesized employing substituted cycloalkene 1. A lower yield was observed with vinyl-substituted cycloalkene, while higher yields were observed for electron-withdrawing para-substituted phenyl and halide-substituted cycloalkenes 1. For 1-naphthyl-substituted cycloalkene, a large decrease in product yield was observed. The replacement of phenyl with heterocyclic groups shows a varied effect on the yield. Similarly, differently substituted isoquinolines were obtained from indenes, in varying yields. 3-Phenyl-substituted indene gave a good yield, whereas para-substitution on the 3-phenyl group has a negative effect on the yield.

Publication History

Article published online:
25 February 2025