O-containing heterocycles such as tetrahydrofuran (THF), tetrahydropyran (THP) and morpholine are prevalent moieties in natural products and drug molecules.1 Typically, such motifs are constructed by cyclisation of pre-functionalised linear precursors. In contrast, functionalisation at the α-position of cyclic structures offers the possibility to add complexity at a later stage of the synthesis. Recent advances in radical chemistry by using either oxidants or photocatalysis have offered methods to generate α-arylated or -alkylated THFs and THPs.2-6 However, metalation processes to achieve similar α-functionalisations have been unstudied since Schlosser’s pioneering work with n-BuK.7 Herein, we present a new route for the synthesis of α-substituted five- and six-membered O-containing heterocycles via an unprecedented lithiation-trapping protocol. Previous work by Bates et al. on the lithiation of THF using n-BuLi revealed a fast retro-[3+2] cycloaddition of the unstable lithiated species at r.t.8 We discovered that careful selection of reaction conditions allows selective C-H activation and minimal decomposition by using s-BuLi at low temperature (–60 °C). Other O-containing heterocycles such as THP and morpholine can be deprotonated at higher temperatures (0 °C) as the lithiated species are more stable. The so-generated nucleophiles can subsequently be trapped by a range of appropriate electrophiles including aldehydes, ketones, imines, alkyl halides and Weinreb amides giving access to products which are complementary to those obtained from the established radical-based methods. By employing optimised conditions for each system, products were obtained in high yields, chemo- and regioselectivity.

α-C-H activation of oxygen-containing heterocycles using organolithium reagents

2019 Fall National Meeting

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