Unified Access to Pyrimidines and Quinazolines Enabled by N-N Cleaving Carbon Atom Insertion.

Given the ubiquity of heterocycles in biologically active molecules, transformations with the capacity to modify such molecular skeletons with modularity remain highly desirable. Ring expansions that enable interconversion of privileged heterocyclic motifs are especially interesting in this regard. As such, the known mechanisms for ring expansion and contraction determine the classes of heterocycle amenable to skeletal editing. Herein, we report a reaction that selectively cleaves the N-N bond of pyrazole and indazole cores to afford pyrimidines and quinazolines, respectively. This chlorodiazirine-mediated reaction provides a unified route to a related pair of heterocycles that are otherwise typically prepared by divergent approaches. Mechanistic experiments and DFT calculations support a pathway involving pyrazolium ylide fragmentation followed by cyclization of the ring-opened diazahexatriene intermediate to yield the new diazine core. Beyond enabling access to valuable heteroarenes from easily prepared starting materials, we demonstrate the synthetic utility of skeletal editing in the synthesis of a Rosuvastatin analog as well as in an aryl vector-adjusting direct scaffold hop.

A Synthetic Cycle for Heteroarene Synthesis by Nitride Insertion.

Recent interest in skeletal editing necessitates the continued development of reagent classes with the ability to transfer single atoms. Terminal transition metal nitrides hold immense promise for single-atom transfer, though their use in organic synthesis has so far been limited. Here we demonstrate a synthetic cycle with associated detailed mechanistic studies that primes the development of terminal transition metal nitrides as valuable single-atom transfer reagents. Specifically, we show [cis-terpyOsNCl2 ]PF6 inserts nitrogen into indenes to afford isoquinolines. Mechanistic studies for each step (insertion, aromatization, product release, and nitride regeneration) are reported, including crystallographic characterization of diverted intermediates, kinetics, and computational studies. The mechanistic foundation set by this synthetic cycle opens the door to the further development of nitrogen insertion heteroarene syntheses promoted by late transition metal nitrides.

Carbon Atom Insertion into Pyrroles and Indoles Promoted by Chlorodiazirines.

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.