Torquoselectivity

Abstract: Before 1965, only a few examples of reactions of this type were known, and it was generally believed that steric effects determined the stereochemical course of such reactions. As anomalies were discovered, theories were developed to explain them. These theories led to predictions, which were tested by experiment and verified. Eventually, a comprehensive quantitative theory of stereoselectivity was developed, such that now the products of reactions of this type can be predicted with confidence. Cyclobutene was first prepared by Willstatter1 in 1905. Although its ready thermal conversion to 1,3butadiene was noted often in the early literature, it was not until the 1950s that mechanistic studies were undertaken. In 1958 Walters reported that the conversion of cyclobutene to butadiene was a wellbehaved unimolecular process occurring at 150 °C,2 a relatively low temperature compared to the 350 °C required for thermal cleavage of the almost equally strained cyclobutane. Walters reported an activation energy of 32.5 kcal/mol for the reaction along with a log A of 13.1. By that time initial reports of the stereochemistry of the ring-opening of 3-substituted and 3,4-disubstituted cyclobutenes had begun to appear, and by 1959 the substantial investigations of Vogel3,4 and particularly of Criegee and his co-workers5-7 had led to considerable mechanistic understanding of the reaction.

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.