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

Peter J Cossar,Adam Mccluskey,Nicholas Cain,Jennifer R Baker

doi:10.1098/rsos.171190

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.

Highlights

As part of our medicinal chemistry programme we identified β-amino alcohol 1 as a lead compound of interest
Method development commenced with the use of a flow instrument equipped with peristaltic pumps; passing two reagent streams, epichlorohydrin 3 and 4-nitrophenol 4 (0.1 M) in dimethylformamide (DMF), through an Omnifit® column packed with Cs2CO3 and acid washed sand (1 : 1) at 75°C, increasing in 10°C increments to 105°C, with the reaction monitored by ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS)
We have demonstrated that the flow coupling of phenols with epichlorohydrin provides a facile and highly scalable route to a wide variety of epoxides in moderate to excellent yields (22–89%)

Summary

Introduction

As part of our medicinal chemistry programme we identified β-amino alcohol 1 as a lead compound of interest. Analogues of this nature are known to be biologically active and have. Β-Amino alcohols are typically accessed through amine-mediated ring opening of epoxides, catalysed by Lewis acids [6,7,8,9]. In keeping with an epoxide ring opening strategy, 1 can be accessed via aminopyrimidine 2, racemic epichlorohydrin 3 and 4-nitrophenol 4, enabling robust focused library development (figure 1). Flow chemistry can be considered a mature technology with considerable progress in the use of flow chemistry approaches in multi-step synthesis [10,11,12,13,14,15,16,17,18,19,20], the synthesis of drug like molecules [21,22,23,24,25,26], selective hydrogenations [27] and in the use of unstable and/or dangerous reagents [16,17,18,27,28]

Methods

Results

Conclusion