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

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.

Amino Alcohol Acrylonitriles as Activators of the Aryl Hydrocarbon Receptor Pathway: An Unexpected MTT Phenotypic Screening Outcome

“…To determine approach feasibility, a focused library was prepared and evaluated. Thus, the desired β‐amino alcohols were accessed via flow chemistry introduction of epi ‐chlorohydrin ( 7 ) to 4‐hydroxybenzaldehyde ( 8 ) which gave epoxide ( 9 ), Knoevenagel condensation with 3,4‐dichlorophenyl acetonitrile ( 10 ) in the basic ionic liquid benzyltrimethyl ammonium hydroxide gave the key epoxide ( 11 ) (64 % 2 steps; Scheme ). With intermediate 11 in hand, we next examined the synthesis of a pilot library of β‐amino alcohol acrylonitriles using amines 12 a‐ ‐ g , Library A .…”

“…6 Given our recent efforts with the phenyl acrylonitriles, we rationalized that enhanced breast cancer specificity and potency might result from increasing the number of amino moieties in these molecules. In turn, this allowed us to leverage against our in‐house facile access to β‐amino alcohols, thus we hypothesized that addition of this moiety may provide additional activation of the AhR pathway.…”

Flow Synthesis of Biologically-Relevant Compound Libraries

“…β-Amino alcohols are often key intermediates for the synthesis of biologically-active molecules; they are typically synthesized by amine-mediated ring-opening of epoxides. Following this strategy, McCluskey and co-workers studied the reaction of epichlorohydrin 9 with phenols 10 to yield the corresponding epoxides 11 (Scheme 4a) [27]. The flow procedure herein discussed is a further improvement of the batch synthesis proposed by the same authors [25].…”

“…β-Amino alcohols are often key intermediates for the synthesis of biologically-active molecules; they are typically synthesized by amine-mediated ring-opening of epoxides. Following this strategy, McCluskey and co-workers studied the reaction of epichlorohydrin 9 with phenols 10 to yield the corresponding epoxides 11 (Scheme 4a) [27]. Molecules 2020, 25, The optimal reaction conditions were found by pumping a 0.1 M solution of phenol 10 in DMF through an Omnifit ® column packed with a 1:1 mixture of Cs2CO3: acid-washed sand, to avoid the formation of the diol by-product, and then mixing such solution with epoxide 9 in DMF (5 M).…”

Continuous dimethyldioxirane generation for polymer epoxidation

“…18,19 The first use of DMDO continuous flow was reported in 2018 by McCluskey et al, who epoxidized a variety of alkenes in 60-98% yield. 20 However, the use of acetone as solvent limits the generality of this method for substrates such as higher olefin polymers that are insoluble in acetone. Methyl(trifluoromethyl)dioxirane (TFDO) has also been generated in continuous flow and used for aliphatic C-H oxidation.…”