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.
Original language | English |
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Article number | 171190 |
Number of pages | 22 |
Journal | Royal Society Open Science |
Volume | 5 |
Issue number | 4 |
DOIs | |
Publication status | Published - 4 Apr 2018 |
Keywords
- Dimethyl dioxirane
- Epoxide
- Flow chemistry
- Microwave
- β-amino alcohols
ASJC Scopus subject areas
- General