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

Abstract

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.

Correction to “Skeletal Editing of Pyrimidines to Pyrazoles by Formal Carbon Deletion”

“…20 Similarly, Levin and coworkers recently disclosed an analogous carbene insertion into pyrazole N−N bonds to generate 2-aryl pyrimidines. 21 Here, we report a reverse of the latter process�a method for the conversion of pyrimidines into pyrazoles by a formal carbon deletion (Figure 1B).…”

Skeletal Editing of Pyrimidines to Pyrazoles by Formal Carbon Deletion

“…Recently, Morandi and coworkers reported a nitrogen insertion into indole C–C bonds to generate quinazolines . Similarly, Levin and coworkers recently disclosed an analogous carbene insertion into pyrazole N–N bonds to generate 2-aryl pyrimidines . Here, we report a reverse of the latter processa method for the conversion of pyrimidines into pyrazoles by a formal carbon deletion (Figure B).…”

Skeletal Editing: Interconversion of Arenes and Heteroarenes

“…[43] F) C-Atom insertion into indazoles mediated by chlorodiazirines. [44] esp = α,α,α',α'-tetramethyl-1,3-benzenedipropionic acid.…”

“…In addition to the ring expansion of indoles, Levin demonstrated that the ring expansion of pyrazoles and indazoles could also be achieved using chlorodiazirines (Scheme 2,F). [44] This reaction is proposed to proceed through formation of an ylide intermediate which then fragments with NÀ N cleavage through an electrocyclic ring-opening (Scheme 2,F-i). The resulting diazahexatriene undergoes ring closure with loss of HCl to afford the desired pyrimidine or quinazoline.…”