Intermolecular Stetter Reactions on Morita‐Baylis‐Hillman Adducts: an Approach to Highly Functionalized 1,4‐Dicarbonyl Compounds

Abstract

We reported herein an N‐heterocyclic carbene (NHC)‐mediated intermolecular Stetter reaction between oxidized Morita‐Baylis‐Hillman (MBH) adducts and a variety of aldehydes. This protocol allows the synthesis of highly functionalized 1,4‐dicarbonyl compounds. The reaction is an alternative approach to these compounds using commercially available starting materials. This metal‐free process exhibits a wide substrate scope, excellent atom economy, compatibility with functionalized substrates and mild reaction conditions. The 1,4‐dicarbonyl compounds were prepared in two steps via MBH reactions with overall yields up to 99 %. This protocol is easily scalable. The synthetic usefulness of this method was demonstrated in a high yield synthesis of a tri‐substituted pyrrole used as an advanced intermediate in the total synthesis of kinase inhibitors as well as in the synthesis of another heterocycles.

Computational insights on the origin of enantioselectivity in reactions with diarylprolinol silyl ether catalysts via a radical pathway

“…An existing approach to access 1,4-dicarbonyls is Stetter reactions with thiamine catalysts via Breslow intermediates. 2,3 Recently, Melchiorre et al have proposed photocatalytic routes to synthesise 1,4-dicarbonyl compounds with stereochemical control using 1,4-dihydropyridine (DHP) and diarylprolinol silyl ether catalysts (the 'amine catalysts' below, Scheme 1). 4 In the optimised trial, a high yield of 88% has been achieved with a reasonable enantiomeric excess (ee) of 76%.…”

Recent Advances in Stetter Reaction and Related Chemistry: An update

“…Coelho et al ., developed and reported a NHC‐catalyzed intermolecular Stetter reaction of oxidized Morita‐Baylis Hillman (MBH) adducts 38 and various aldehydes 2 [30] . Based on approach, various substituted 1,4‐dicarbonyl products 40 were synthesized successfully.…”

“…In addition, various aromatic aldehydes having electron-withdrawing groups on 3,4-position in the aromatic ring provided the respective products in excellent yields ( (MBH) adducts 38 and various aldehydes 2. [30] Based on approach, various substituted 1,4-dicarbonyl products 40 were synthesized successfully. This reaction was performed using 2iodoxybenzoic acid (IBX) with subsequent addition of thiazolium salt 39, and cesium carbonate under nitrogen atmosphere in dichloromethane at room temperature.…”