Fast and scalable continuous flow synthesis of butenolides and coumarins

Author(s)

Ferreira, Lucas Coral ; Galaverna, Renan de Souza ; Mcbride, Tom ; Silva, Rodrigo Costa e ; Browne, Duncan L. ; Pastre, Julio Cezar

• Document type: Journal article
• Source: REACTION CHEMISTRY & ENGINEERING; v. N/A, p. 6-pg., 2025-02-10.

Abstract

Herein, we present a versatile and efficient continuous flow protocol for the synthesis of structurally diverse butenolides and coumarins through the in situ generation of acylketenes via the retro hetero-Diels-Alder reaction of dioxinones with alpha-hydroxy-ketones and salicylaldehydes, respectively. This protocol enabled the synthesis of 5 examples of butenolides with yields ranging from 30 to 91% and 16 examples of coumarins with yields ranging from 30 to 99%. The versatility and practicality of the protocol were demonstrated by the gram-scale synthesis of a biologically relevant gamma-spiro butenolide core, as well as the production of benzo-coumarins. Modern medicinal chemistry demands both scalability and the ability to synthesize structurally diverse compounds in a single synthetic platform, and our methodology effectively addresses these challenges in a fast and safer manner. (AU)

• FAPESP's process: 21/06661-5 - Enabling technologies for the sustainable chemical synthesis of platform molecules, new chemicals and bioactive compounds
• Grantee: Júlio Cezar Pastre
• Support Opportunities: Program for Research on Bioenergy (BIOEN) - Young Investigators Grants - Phase 2
• FAPESP's process: 23/07466-7 - Development of Self-Optimization Platforms for the Multi-Step Synthesis of APIs
• Grantee: Rodrigo Costa e Silva
• Support Opportunities: Scholarships in Brazil - Post-Doctoral