High-Pressure Promoted Nazarov-like Electrocyclization Enables Access to trans-4,5-Diamino-cyclopent-2-enones Bearing Electron-Poor Anilines

Abstract

Unlike secondary alkyl amines and electron-rich anilines, secondary electron-poor anilines are challenging amine sources to explore the chemical space of Lewis acid-catalyzed condensation-based transformations with furfural. In this work, we report the efficient synthesis of trans-4,5-diamino cyclopentenones (DCP) using a high-pressure promoted Nazarov-like electrocyclization of Stenhouse salts arising from the Sc(III)-catalyzed condensation of furfural with secondary electron-poor anilines. The reaction enables access to otherwise difficult-to-access DCP and compatibility with a large scope of alkyl and aryl secondary amines. A 2- to 18-fold increase in yields for electron-poor anilines was highlighted using this approach in the synthesis of a pharmacologically active compound.

Scheme 1. Lewis Acid-Catalyzed Condensation of Furfural with Secondary Amines Bearing Electron-Poor Anilines under Atmospheric Pressure or High-Pressure Conditions

Scheme 2. Free Energy Profiles for the Complete DFT Study

DFT calculations were performed at the B3LYP-D3/def2TZVPP/SMD(ACN) level of theory using geometries optimized by B3LYP/6-31G(d). The distances shown are in Å, energies are in kcal mol^–1, and volumes are in cm³ mol^–1.

Scheme 3. Scope of DCP Obtained under Atmospheric vs High-Pressure Conditions

Scheme 4. Synthesis of 3-NO₂-Substituted Dehydro-benzoxazine α-Enaminone Derivative—ATP-Sensitive Potassium Channel Agonist