A Novel Dual Organocatalyst for the Asymmetric Pinder Reaction and a Mechanistic Proposal Consistent with the Isoinversion Effect Thereof.

Fotini Moschona,Athena Vagena,Gerasimos Rassias,Veroniki P Vidali

doi:10.3390/molecules26216398

Abstract

In general, the Pinder reaction concerns the reaction between an enolisable anhydride and an aldehyde proceeding initially through a Knoevenagel reaction followed by the ring closing process generating lactones with at least two chiral centers. These scaffolds are frequently present in natural products and synthetic bioactive molecules, hence it has attracted intense interest in organic synthesis and medicinal chemistry, particularly with respect to controlling the diastereo- and enantioselectivity. To the best of our knowledge, there has been only one attempt prior to this work towards the development of a catalytic enantioselective Pinder reaction. In our approach, we designed, synthesized, and tested dual chiral organocatalysts by combining BIMAH amines, (2-(α-(alkyl)methanamine)-1H-benzimidazoles, and a Lewis acid motif, such as squaramides, ureas and thioureas. The optimum catalyst was the derivative of isopropyl BIMAH bearing a bis(3,5-trifluoromethyl) thiourea, which afforded the Pinder products from various aromatic aldehydes with diastereomeric ratio >98:2 and enatioselectivity up to 92 ee%. Interestingly, the enantioselectivity of this catalyzed process is increased at higher concentrations and exhibits an isoinversion effect, namely an inverted "U" shaped dependency with respect to the temperature. Mechanistically, these features, point to a transition state involving an entropy-favored heterodimer interaction between a catalyst/anhydride and a catalyst/aldehyde complex when all other processes leading to this are much faster in comparison above the isoinversion temperature.

Highlights

The Pinder reaction has its roots in the Perkin reaction dating back to 1877, where an anhydride was first shown to defy its electrophilic nature and react as a nucleophile instead; at elevated temperatures, acetic anhydride reacted with aldehydes to give the aldol condensation product [1]
We used the reaction between homophthalic anhydride (1, 1 eq) and o-methyl benzaldehyde (5, 1.1 eq) as the model Pinder reaction to explore initially potential conditions and mediators for the generation of racemic 6 (Scheme 4)
The optimum organocatalyst from those examined consists of a thiourea Lewis acid component linked to a chiral aminomethyl-benzimidazole (BiMAH)

Summary

Introduction

The Pinder reaction has its roots in the Perkin reaction dating back to 1877, where an anhydride was first shown to defy its electrophilic nature and react as a nucleophile instead; at elevated temperatures, acetic anhydride reacted with aldehydes to give the aldol condensation product [1]. In the Perkin–Fittig development, it was demonstrated that with succinic anhydride, the initial aldol product could ring-close to afford the corresponding γ-lactone; when heated further, decarboxylation and dehydration occurred to yield the Perkin product [2]. 2-aryl substituted analogues exhibit enhanced enolization potential and have proved more productive substrates for the Perkin–Fittig reaction. In 1958, Pinder first reported the reaction of the more readily enolisable homophthalic anhydride (1, Scheme 1, pKa ~ 8.2)

Objectives

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Results

Conclusion