Substitution of dichloromethane with greener solvents for the preparation of thioglycosides and glycosyl azides, and for a glycosylation reaction. Deacetylation in ethanol-ethyl acetate.

Authors

Ashis Dhara, Claire Breslin, Kayleigh Moran, Paul V Murphy

Published in

Carbohydrate research. Volume 568. Pages 110027. Jul 03, 2026. Epub Jul 03, 2026.

Abstract

The US environmental protection agency has recently prohibited most industrial and commercial uses of dichloromethane (DCM), due to its hazardous nature, requiring alternatives to be identified. The azide group is widely used in click chemistry or as a precursor to amines or for other reactions, with wide ranging applications. Glycosyl azides are prepared from Lewis acid catalysed reactions involving azidotrimethylsilane (TMSN₃) in DCM. Thioglycosides are widely used as donors in glycosylation or synthesised in glycomimetic research and similarly prepared using Lewis acids and thiols in DCM. Here, we replace DCM in the preparation of glycosyl azides and thioglycosides with ethyl acetate (EtOAc) or cyclopentyl methyl ether (CPME). We show EtOAc or CPME can replace DCM in an O-glycosylation reaction from thioglycoside donors. The yields and stereoselectivities of products were comparable from reactions in EtOAc or CPME or DCM of building blocks with participating or non-participating protecting groups. The reactivity is lower, in some cases, in EtOAc and CPME when compared with DCM, with the consequence that higher temperatures may be required. In addition, we used EtOH-EtOAc mixtures for global deacetylation reactions; this provides an alternative to MeOH, which is significantly more toxic than EtOH. We also describe oxidation of diacetone-d-glucose to its ketone derivative using Dess-Martin periodinane (DMP) in EtOAc, rather than in DCM, where the yield is comparable on a 25 g scale. A deterrent to using green solvents may be that they are more costly than traditional solvents, with CPME, for example, being currently >3-fold more expensive than DCM. However, researchers can minimise the quantity of CPME required and add EtOAc for subsequent extractions. An added and potentially important benefit is that the use of EtOAc or CPME rather than DCM for glycosyl azide formation removes the risk of potential formation of hazardous diazidomethane from reactions of TMSN₃ with DCM. Hazardous hydrazoic acid (HN₃) may form in reactions involving inorganic azides or TMSN₃ in solvents generally, and therefore appropriate precautions for minimising HN₃ and handling azides are always needed, irrespective of the solvent chosen.

PMID:
42418916
Bibliographic data and abstract were imported from PubMed on 09 Jul 2026.

Read full publication at:
Please sign in to see all details.

Stats

1-terrible, 9-excellent. How would you rate this publication? Sign in in to submit your rating.

Post a comment

You need to be signed in to post comments. You can sign in here.

Comments

There are no comments yet.