Supplementary material from "<i>In situ</i> epoxide generation by dimethyldioxirane oxidation and the use of epichlorohydrin in the flow synthesis of a library of β-amino alcohols"

Published on 2018-03-29T11:07:29Z (GMT) by
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 <b>1</b>, a potential antibiotic lead. The <i>in situ</i> (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 <b>1</b> were readily accessed either via (i) a flow/microwave hybrid approach, or (ii) a sequential flow approach. Key steps were the <i>in situ</i> 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 <b>1</b> and <b>10a</b>–<b>18 g</b>, resulting in modest (<b>11a</b>, 21%) to excellent (<b>12 g</b>, 80%) yields. Alternatively flow coupling of epichlorohydrin with phenols <b>4a</b>–<b>4 m</b> (22%–89%) and a Bi(OTf)<sub>3</sub> 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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Cossar, Peter J.; Baker, Jennifer R.; Cain, Nicholas; McCluskey, Adam (2018): Supplementary material from "In situ epoxide generation by dimethyldioxirane oxidation and the use of epichlorohydrin in the flow synthesis of a library of β-amino alcohols". The Royal Society. Collection.