Inexpensive multigram-scale synthesis of cyclic enamines and 3-N spirocyclopropyl systems

Abstract

Cyclic enamines are important synthons for many synthetic and pharmacological targets. Here, we report an inexpensive, catalyst-free, multigram-scale synthesis for cyclic enamines with exocyclic double bonds and four- to seven-membered rings. This strategy is more conducive to scale up, permissive of functionalization around the cyclic system, and less sensitive to the nature of the N-protecting group than previously-described methods for cyclic enamine synthesis. Further, we explore application of these enamines to the synthesis of highly-strained spirocyclic 3N-cyclopropyl scaffolds.

Selective Carbon–Carbon Bond Cleavage of Cyclopropylamine Derivatives

“…92 Under certain conditions, both halogen substituents may be eliminated to give a terminal alkyne. 93,94 For example, Laughlin and co-workers 94 observed that unstable fluorobromocyclopropyl derivative 112 is generated upon cyclopropanation of 111. This decomposes through a ring opening-elimination sequence to give 113 (Scheme 30).…”

Caged Cyclopropenes with Improved Tetrazine Ligation Kinetics

“…Having the C3-nitrogen atom in the spirocyclic cyclopropene system is key to the activation strategy as it serves as an anchor for linking photo- or enzyme-labile cages, thereby hindering IEEDA tetrazine–cyclopropene ligation . However, such C3-nitrogen-containing cyclopropenes are rare and difficult to synthesize and generally also require installation of an inductively electron-withdrawing group at the C3 position. For example, the nonactivatable spirocyclic cyclopropene scaffold in which a cyclopropene and a cyclobutane are fused together at the cyclopropene C3 is known, but our attempts to install a nitrogen atom at C3 resulted in ring-opening isomerization of cyclopropenes to form alkynes or allenes .…”

Synthesis and Characterization of Enaminone Derivatives of Barbituric Acid

“…Enaminones are a significant subclass of organic compounds which contain conjugated N-C=C-C=O fragment owing to fact that they include both nucleophilic and electrophilic moieties at same skeleton (Castro-Alvarez et al, 2017). These active sites help to synthesis of linear or cyclic hetero atom containing organic compounds (Negri et al, 2004;Kumar et al, 2018). Both enaminones and the organic compounds derived from them have biological activity against the most harmful microorganisms (Negri et al, 2004;Baldwin et al, 2018).…”