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.

One-Carbon Insertion and Polarity Inversion Enabled a Pyrrole Strategy to the Total Syntheses of Pyridine-Containing Lycopodium Alkaloids: Complanadine A and Lycodine

“…It goes through a dihalocarbene cycloaddition on a pyrrole double bond followed by ring expansion to provide a 3-halopyridine. Despite its discovery in 1881, the development of the Ciamician–Dennstedt rearrangement has been very limited, and it has not yet been used in total synthesis. The pyridine-to-pyrrole retrosynthetic analysis led us to key intermediate 24 , which could be converted to chloropyridine 26 via the Ciamician–Dennstedt rearrangement, then to lycodine and complanadine A.…”

Late-stage diversification of indole skeletons through nitrogen atom insertion

“…Formal single atom insertion reactions to modify aromatic moieties have proven to be especially challenging given the inherent inertness of aromatic carbon-based skeleton towards cleavage of a carbon-carbon bond (12). Despite this formidable challenge, a limited number of carbon (13)(14)(15)(16) or oxygen (17)(18)(19) insertion or deletion reactions to reshape molecular architectures has been developed. Given the prevalence of nitrogen atoms in biologically active molecules, the direct modification of valuable core structures through single nitrogen atom manipulation is of particular significance (20) and especially interesting in the context of evaluating structure-activity relationships in medicinal chemistry settings.…”

“…In our design, a stepwise (2+1) cycloaddition would initially provide an aziridine intermediate. Subsequent elimination of iodobenzene, followed by aromatization of the reaction intermediate, would facilitate the desired ring expansion reactions towards the quinazoline product (15).…”

Stereoselective Synthesis of Cyclobutanes by Contraction of Pyrrolidines

“…In 2021, Levin’s group disclosed the nitrogen deletion of secondary amines using an N -anomeric amide, 24 postulating the concept of skeletal editing of organic molecules. 25 , 26 An N -anomeric amide acts as a nitrogen transfer reagent to a secondary amine to produce a 1,1-diazene, which generates a biradical via nitrogen extrusion, affording cyclobutane. Another nitrogen-deletion protocol of secondary amines featuring a Curtius-type rearrangement/nitrogen extrusion was reported by Lu’s group very recently.…”

“…Replacing the β-ester group of 24 with nitrile group delivered 25 and 26 in comparable yields from the corresponding exo-and endo-pyrrolidines. Remarkably, the diastereoselective formation of cyclobutanes is not affected by the stereochemistry at the β-position of the corresponding pyrrolidines, allowing efficient selective access to the corresponding diastereomers (25,26).…”