1,3‐Dipolar Cycloaddition of 3‐Chromonyl‐Substituted Glycine Imino Esters with Arylidenes and in situ Diastereodivergent via Retrocycloaddition

Abstract

1,3-Dipolar cycloaddition through in situ generation of azomethine ylide provides a straightforward and critically important sustainable approach for access to diverse pyrrolidine chemical space. Herein, we developed a metal-free AcOH-activated 1,3-dipolar cycloaddition protocol that permits the synthesis of uncommon pyrrolidine cycloadducts with excellent diastereoselectivity. The challenging substrates of 3-formylchromone, glycine ester.HCl and arylidene dipolarophile were reacted in the presence of AcONa, which played a dual role as a base and AcOH source, to deliver firstly endocycloadduct. Under prolonged reaction time at room temperature or heating; the endo-adduct underwent diastereodiver-gent via a sequence of retro-cycloaddition, stereomutation of the generated syn-dipole into anti-dipole and recycloaddition; to furnish the scarcely known exo'-cycloadduct with high diastereodivergency. The reaction worked well with a broad range of substrates and the stereochemistry of the obtained cycloadducts was determined without ambiguity using NMR-and X-ray analysis. Experimental and theoretical DFT calculation studies were performed to support the proposed reaction mechanism and elucidate the key role of AcOH in the process which seems more beneficial than other transition metal-catalyzed processes.

Density Functional Theory Calculations: A Useful Tool to Investigate Mechanisms of 1,3-Dipolar Cycloaddition Reactions

“…On the contrary, using NPM the dipolarophile, the endo cycloadduct 146 was the only obtained product (86 (Scheme 39). Radwan et al [58] have studied the metal-free 1,3-dipolar cycloaddition of azomethine ylide 141, derived from 3-formylchromone 140, with glycine ester 139, and arylidenes 142a-e or phenylmaleimide 145 (NPM) in the presence of AcONa in toluene at room temperature. The cycloaddition process, in the case of arylidenes 142a-e as dipolarophiles, leads to a mixture of endo (143a-e) and exo' (144a-e) adducts in excellent yield (92-88%) and with an endo product as the major diastereomer.…”