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.
Highlights
We report a reaction that selectively generates 3-arylpyridine and quinoline motifs by inserting aryl carbynyl cation equivalents into pyrrole and indole cores, respectively
I n recent years, molecular editing has taken root as an approach to diversify the suite of complexity-building reactions available to the synthetic community.1−5 This paradigm has so far focused on C−H functionalization, which, while effective, does not harness the immense potential manifest in the underlying molecular skeleton
Though benzal halides have been employed toward this purpose, the procedures are typically low yielding.37 α-halo diazoalkanes have been reported, but their intrinsic instability has limited their use.38−40 Suero has recently reported the related α-iodonium diazo compounds as surprisingly stable, isolable carbynyl cation equivalents, though despite increased stability relative to the parent α-halo compounds, Suero reagents retain the requirement of a stabilizing electron-withdrawing group.41−44 the associated oxidizing capacity of iodine(III) limits their application to reducing substrates such as pyrroles and indoles
Summary
Dr Alexander Filatov and Dr Andrew McNeece are thanked for assistance with X-ray crystallography. The University of Chicago’s Research Computing Center is thanked for computational resources. Yiming Wang (University of Pittsburgh) and Prof. Zach Wickens (University of Wisconsin) for helpful discussions
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