Modular Synthesis of Cyclopropane‐Fused N‐Heterocycles Enabled by Underexplored Diazo Reagents

Abstract

Cyclopropane‐fused N‐heterocycles are featured in various biologically active compounds and represent attractive scaffolds in medicinal chemistry. However, synthesis routes to access structurally and functionally diverse cyclopropane‐fused N‐heterocycles remain underexplored. Leveraging novel α‐diazo acylating agents, we report a general approach for the direct and modular synthesis of cyclopropane‐fused lactams from unsaturated amines. The operationally simple transformation, which proceeds through successive acylation, (3+2) cycloaddition and fragmentation, tolerates a broad range of functional groups and yields a wide spectrum of complex molecular scaffolds, including fused, bridged and spiro ring systems. We demonstrate the utility of this transformation in the concise syntheses of therapeutic agents milnaciprane and amitifadine.

Photogenerated donor–donor diazo compounds enable facile access to spirocyclopropanes

“…We began our investigation with 4-phenylcyclohexanone derived tosylhydrazone (1a), methyl methacrylate (2a) and benzophenone (20 mol%) as triplet sensitizer known to facilitate the extrusion of nitrogen from D 1 -pyrazoline motifs. 29,30 Herein, CH 2 Cl 2 was identified to be the best solvent with caesium carbonate as the base (Table S1 and S2, ESI †). The reaction did not proceed without irradiation or in the absence of a base.…”

Dipole‐Transmissive 1,3‐Dipolar Cycloadditions for the Rapid Construction of Polycyclic N‐Heterocycles: Synthetic and Mechanistic Investigations

“…Similar results were obtained when the reaction was conducted in the dark, which excluded possible contributions from photochemical pathways (entry 2). While thermal diazo decomposition followed by [2+1]‐cycloaddition could lead to cyclopropane 15 , it seemed unlikely that such high diastereoselectivity could be achieved via a carbene pathway [14] . Furthermore, treatment of substrate 13 with Rh 2 (OAc) 4 [15] delivered a complex mixture and cyclopropane 15 was not detected (entry 3).…”

Photosensitized O 2 enables intermolecular alkene cyclopropanation by active methylene compounds

“…This method is profoundly dependent on reactive carbene and metal-carbenoid intermediates [[M]=CR 2 ], in particular the donor-acceptor Rh-carbenoids (9,10,12) derived from highly energetic diazoalkanes, which require stringent precautions for handling (13,14). The metal-carbenoids are typically generated from diazomethane (CH 2 N 2 ), TMSCHN 2 , PhCHN 2 , and a-diazocarbonyl compounds by decomposition in reaction with transition-metal [M] catalysts (8,15,16), and more recently under photoredox (17,18) and engineered enzymatic (19)(20)(21)(22) conditions. The classic Simmons-Smith and related reactions (23) also transform alkenes into cyclopropanes, yet, again, these reactions require a large excess of unstable, often difficult-to-access 1,1-and 1,2-dihaloalkanes and highly reactive Et 2 Zn or Zn/Cu reagents to generate an adequate quantity of zinc carbenoids for satisfactory reactivity.…”