Biobased dihydrolevoglucosenone (Cyrene) enables rapid and efficient synthesis of acylals under microwave irradiation

Abstract

The synthesis of asymmetric acylals starting from chloromethyl esters has been comprehensively documented in the extant literature. However, this process is typically associated with the use of toxic and environmentally hazardous solvents, such as N,N-dimethylformamide (DMF) or, less frequently, N-methylpyrrolidone (NMP), as well as an often protracted (up to several days) reaction time. In this study, we demonstrate that dihydrolevoglucosenone (Cyrene), a green solvent, in combination with microwave irradiation, leads to a substantial reduction in reaction time by several orders of magnitude (a few minutes instead of hours or days) with good to excellent yields. In certain instances, precipitation is a sufficient method for the removal of high boiling Cyrene, resulting in an approximate 70 fold improvement of molar efficiency (Mol E.%) compared to standard procedures. In case of more lavish purification, Dry Column Vacuum Chromatography (DCVC) has been demonstrated to be a suitable purification approach, characterised by its expeditious nature and its significantly reduced generation of organic waste in comparison with conventional column chromatography. Building on this and in addition to the green synthesis, an ultra-low cost and highly efficient chromatographic method, based on similar principles to the DCVC, has been developed, resulting in a 12 fold improvement in the E-factor versus column chromatography. The protocol is robust for acylal synthesis for a wide range of carboxylic acids up to relevant drugs and biochemically important reagents. It provides the opportunity to create large libraries of acylal compounds for medicinal chemistry or biochemistry approaches in a short time.

Graphical abstract: Biobased dihydrolevoglucosenone (Cyrene) enables rapid and efficient synthesis of acylals under microwave irradiation

Supplementary files

Article information

Article type
Paper
Submitted
05 May 2025
Accepted
12 Jun 2025
First published
16 Jun 2025
This article is Open Access
Creative Commons BY license

RSC Sustainability, 2025, Advance Article

Biobased dihydrolevoglucosenone (Cyrene) enables rapid and efficient synthesis of acylals under microwave irradiation

T. Keydel and A. Link, RSC Sustainability, 2025, Advance Article , DOI: 10.1039/D5SU00325C

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