Dearomatization of Pyridines: Photochemical Skeletal Enlargement for the Synthesis of 1,2-Diazepines

Abstract

In this report, we developed a unified and standardized one-pot sequence that converts pyridine derivatives into 1,2-diazepines by inserting a nitrogen atom. This skeletal transformation capitalizes on the in situ generation of 1-aminopyridinium ylides, which rearrange under UV light irradiation. A thorough evaluation of the key parameters (wavelength, reaction conditions, activating agent) allowed us to elaborate on a simple, mild, and user-friendly protocol. The model reaction was extrapolated to more than 40 examples, including drug derivatives, affording unique 7-membered structures. Mechanistic evidence supports the transient presence of a diazanorcaradiene species. Finally, pertinent transformations of the products, including ring contraction reactions to form pyrazoles, were conducted and paved the way to a broad application of the developed protocol.

Photochemical Skeletal Editing of Pyridines to Bicyclic Pyrazolines and Pyrazoles

“…For ring expansion, which is shown in Figure A, the reaction is initiated by the direct irradiation of pyridinium ylide reactant Int1 which then passes through a conical intersection (CI) point CI-1 to the ground state, generating bicyclic diazanorcaradiene Int2 or reverting to Int1 (see the PES scan in Figure S13). Int2 is a highly unstable intermediate, undergoing rapid 6π electrocyclization and ring expansion to yield the stable diazepine intermediate Int3 (Δ G ‡ = 3.6 kcal/mol) …”

“…Pyridine skeletal editing transformations can be categorized into two strategies: ring expansion and ring contraction (Figure D). Typically, the nucleophilicity of the nitrogen atom of pyridines is harnessed to prepare cationic pyridinium salts. − Pyridine expansion via N-functionalized pyridinium salt (imidopyridine ylide) has been widely employed in synthetic methodologies. − Additionally, ring contractions via carbon deletion under light or electricity have been documented, yielding pyrroles or pyrazolines as exclusive products. − …”

Precision single-atom editing: new frontiers in nitrogen insertion and substitution for the generation of N-heterocycles

“…Recently, Moreau and Ghiazza conducted a remarkable study on the synthesis of diazepines 125 through the insertion of a nitrogen atom into the carbon–nitrogen bond of pyridines 124 in Scheme 13. 58 The proposed mechanism demonstrates that the direct activation of the in situ formed 1-aminopyridinium ylide 127 exclusively generates the singlet excited state intermediate, which then rearranges to form the postulated diazanorcaradiene 128 . Subsequently, this intermediate rapidly opens, leading to the desired 1,2-diazepine 129 .…”

Photochemical dearomative skeletal modifications of heteroaromatics

“…Recently, Moreau and Ghiazza coworkers developed a one-pot procedure, converting diverse pyridine derivatives into 7-memberrd 1,2-diazepines including some pharmaceuticals derived analogues ( 376–378 ). 127 Notably, the diazanorcaradiene intermediate ( 380 ) is proved to be involved in the photochemical transformations. Mechanistically, the in situ formed pyridinium ylides 374 are directly activated by UV light, delivering singlet state intermediate 379 .…”