One-pot synthesis of GABA amides via the nucleophilic addition of amines to 3,3-disubstituted cyclopropenes

Abstract

A one-pot synthesis of various GABA amides has been demostrated, employing the nucleophilic addition of primary and secondary amines across the double bond of cyclopropene-3-carboxamides, followed by ring-opening of the resulting donor-acceptor cyclopropanes and subsequent in situ reduction of enamine (imine) intermediates.

Efficient one-pot synthesis of 1-arylcycloprop-2-ene-1-carboxamides

“…These reaction conditions seemed to be optimal, since our attempts to accelerate the process by raising the reaction temperature led to notable deterioration of the yield, due to a side reaction involving nucleophilic attack of excess secondary amine across the double bond of cyclopropene. 4 …”

“…3 The amide functionality could also serve as an efficient electron-pulling entity to trigger “push-pull” ring-opening in the nucleophilic addition of amines to cyclopropenes (path d , Scheme 1). 4 The application of amides in bioorthogonal transformations for installation of the cyclopropene moiety into biological probes has also been shown recently. 5 …”

Directed nucleophilic addition of phenoxides to cyclopropenes

“…Starting materials in these reactions rapidly decomposed upon heating, potentially due to oligomerization involving a base-assisted attack of N -nucleophiles generated in the reaction mixture. 14 Finally, we found a negligible effect on reactivity of the substituents in the aromatic ring alpha to carboxamide functionality. All such cyclopropenes ( 12j–12n ) provided the corresponding products in good yields (Table 2, entries 19–27).…”

“…Two conditions were probed, which previously proved best for the base-assisted additions of alkoxides 8,9 and nitrogen-based nucleophiles. 14 The first set of conditions employed a suspension of finely powdered KOH (1.50 equiv.) in anhydrous THF (Table 1, entry 1), and the second exploits a solution of t -BuOK (1.50 equiv.)…”

Metal-Templated Assembly of Cyclopropane-Fused Diazepanones and Diazecanones via exo-trig Nucleophilic Cyclization of Cyclopropenes with Tethered Carbamates

“…At higher temperature, it was possible to force a thermally induced intramolecular nucleophilic attack in substrate 9, but the resulting donor−acceptor cyclopropane 10 tended toward facile ring-cleavage 10,11 and subsequent decomposition of cyclic imine 11 (Scheme 2). 12…”