Sustainable synthesis of 3-substituted phthalides via a catalytic one-pot cascade strategy from 2-formylbenzoic acid with β-keto acids in glycerol

Lina Jia,Fuzhong Han

doi:10.3762/bjoc.13.139

Abstract

Background: Phthalides are privileged constituents of numerous pharmaceuticals, natural products and agrochemicals and exhibit several biological and therapeutic activities. Therefore, the development of new, facile, and sustainable strategies for the construction of these moieties is highly desired.Results: A broad substrate scope for β-keto acids was found to be strongly compatible with this catalytic process, affording a wide variety of 3-substituted phthalides in good to excellent yields.Conclusion: A concise and efficient synthesis strategy of 3-substituted phthalides from 2-formylbenzoic acid and β-keto acids via a catalytic one-pot cascade reaction in glycerol has been accomplished.

Highlights

The phthalides, known as isobenzofuran-1(3H)-ones, are an important class of heterocycles which are of continued interest for chemists [1,2]. 3-Substituted phthalides, which are recognized as versatile building blocks found in a large number of bioactive compounds [3-5], exhibit a broad spectrum of pharmacological activity, such as antibacterial, anti-HIV, antifungal, antibiotic, antitumor and immunosuppressive effects [6-10]
As part of our ongoing research interest in exploring novel and sustainable transformations of β-keto acids [41,42], we envisioned that the direct utilization of β-keto acids as nucleophilic species and glycerol as a solvent will allow the establishment of an efficient catalytic one-pot cascade aldol/cyclization reaction
The best result was achieved when 20 mol % of p-anisidine was used as the catalyst in glycerol at 65 °C for 0.5 h, providing 3a in 80% yield (Table 1, entry 9)

Summary

Introduction

The phthalides, known as isobenzofuran-1(3H)-ones, are an important class of heterocycles which are of continued interest for chemists [1,2]. 3-Substituted phthalides, which are recognized as versatile building blocks found in a large number of bioactive compounds [3-5], exhibit a broad spectrum of pharmacological activity, such as antibacterial, anti-HIV, antifungal, antibiotic, antitumor and immunosuppressive effects [6-10]. An efficient synthesis of 3-substituted phthalides via a one-pot cascade reaction is still in high demand. The importance of phthalides and the increasing awareness of the need for environmentally benign chemical production provide the demand and potential for the development of a green onepot cascade aldol/cyclization strategy for these compounds [22].

Results

Conclusion