In situ epoxide generation by dimethyldioxirane oxidation and the use of epichlorohydrin in the flow synthesis of a library of β-amino alcohols

Royal Society Open Science
Peter J CossarAdam McCluskey

Abstract

The flow coupling of epichlorohydrin with substituted phenols, while efficient, limits the nature of the epoxide available for the development of focused libraries of β-amino alcohols. This limitation was encountered in the production of analogues of 1-(4-nitrophenoxy)-3-((2-((4-(trifluoromethyl)pyrimidin-2-yl)amino)ethyl)amino)propan-2-ol 1, a potential antibiotic lead. The in situ (flow) generation of dimethyldoxirane (DMDO) and subsequent flow olefin epoxidation abrogates this limitation and afforded facile access to structurally diverse β-amino alcohols. Analogues of 1 were readily accessed either via (i) a flow/microwave hybrid approach, or (ii) a sequential flow approach. Key steps were the in situ generation of DMDO, with olefin epoxidation in typically good yields and a flow-mediated ring opening aminolysis to form an expanded library of β-amino alcohols 1 and 10a-18g, resulting in modest (11a, 21%) to excellent (12g, 80%) yields. Alternatively flow coupling of epichlorohydrin with phenols 4a-4m (22%-89%) and a Bi(OTf)3 catalysed microwave ring opening with amines afforded a select range of β-amino alcohols, but with lower levels of aminolysis regiocontrol than the sequential flow approach.

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Citations

Feb 23, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Pilar María Luque Navarro, Daniela Lanari
Jun 18, 2021·Beilstein Journal of Organic Chemistry·Guido GambacortaIan R Baxendale
Jul 16, 2021·RSC Medicinal Chemistry·Jennifer R BakerJennette A Sakoff
Aug 21, 2021·The Journal of Organic Chemistry·Tanawat PhumjanPoonsakdi Ploypradith

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Methods Mentioned

BETA
NMR
column chromatography

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