Lithium Chloride-Mediated Stereoselective Synthesis of Cyclopropanecarboxamides from γ,δ-Epoxy Malonates through a Domino Cyclopropanation/Lactonization/Aminolysis Process

• Published in: Journal of organic chemistry Vol. 79; no. 10; pp. 4650 - 4658
• Main Authors: Marques, Marcelo V, Sá, Marcus M
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 16.05.2014; Amer Chemical Soc
• Subjects: Amides - chemical synthesis; Amides - chemistry; Amines - chemistry; Catalysis; Chemistry; Chemistry, Organic; Cyclopropanes - chemical synthesis; Cyclopropanes - chemistry; Lactones - chemical synthesis; Lactones - chemistry; Lewis Acids - chemistry; Lithium Chloride - chemistry; Malonates - chemistry; Molecular Structure; Physical Sciences; Science & Technology; Stereoisomerism; INTRAMOLECULAR CYCLOPROPANATION; ORGANIC-SYNTHESIS; CYCLOADDITION; ASYMMETRIC-SYNTHESIS; DIASTEREOSELECTIVE SYNTHESIS; INHIBITOR TMC435; 1,1-CYCLOPROPANEDIESTERS; AMINO-ACIDS; DERIVATIVES; RING-CLOSURE
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo500712t

The stereoselective synthesis of novel multifunctionalized cyclopropanes from γ,δ-epoxy malonates and amines mediated by LiCl under mild conditions was carried out. This domino reaction involves the initial cyclopropanation via intramolecular ring-opening of γ,δ-epoxy malonates through the cooperative catalysis of LiCl (acting as a Lewis acid) and a Brønsted base (a primary or, in selected cases, a secondary amine). The sequential events consisted of lactonization and aminolysis of the lactone ring, which ultimately furnished cyclopropanecarboxamides with different substitution patterns in good isolated yields. In all cases, a quaternary stereogenic center could be perfectly assembled, with a single diastereoisomer being obtained. This method proceeds with high atom economy, is remarkably modular and operationally simple, and tolerates a variety of functional groups. The involvement of readily available starting materials, the broad scope, and the use of a sustainable solvent (methanol or ethanol) at ambient temperature make this domino process highly effective. A reaction mechanism is proposed on the basis of the experimental observations involving the preparation and reactivity of cyclopropylidene lactones as possible intermediates of the domino process.