Cyanide‐Free Cyanation of sp² and sp‐Carbon Atoms by an Oxazole‐Based Masked CN Source Using Flow Microreactors

Abstract

This work reports a cyanide-free continuous-flow process for cyanation of sp 2 and sp carbons to synthesize aryl, vinyl and acetylenic nitriles from (5-methyl-2-phenyloxazol-4yl) boronic acid [OxBA] reagent as a sole source of carbonbound masked À CN source. Non-toxic and stable OxBA reagent is generated by lithiation-borylation of bromooxazole, and the consecutive Suzuki-Miyaura cross-coupling with aryl, vinyl, or acetylenic halides and demasking [4 + 2]/ retro-[4 + 2] sequence were successfully accomplished to give the desired cyano compounds with reasonably good yields in a four-step flow manner. A unique feature of this cyanation protocol in flow enables to cyanate a variety of sp 2 and sp carbons to produce a broad spectrum of aryl acetonitrile. It is envisaged that the OxBA based cyanation would replace existing unstable and toxic approaches as well as non-toxic cyanation using two different sources of "C" and "N" to incorporate the À CN group.

A cyanide-free synthesis of nitriles exploiting flow chemistry

“…Various approaches have been taken to develop methodologies which circumvent this issue, including the use of masked nitrile transfer reagents, 9,15 biocatalysis 10,11 and continuous flow chemistry. [12][13][14][15] To date, none have been as attractive and robust as the van Leusen reaction, which was first reported in 1977, and is frequently used in the total synthesis of medicinal compounds. [16][17][18][19] The reaction relies on ketones reacting with TosMIC ( p-tosylmethyl isocyanide), 20 a nitrile transfer reagent, which prevents the inadvertent release of cyanide side products via a mechanistic sequence involving ring formation and subsequent ring-opening.…”

“…Various approaches have been taken to develop methodologies which circumvent this issue, including the use of masked nitrile transfer reagents, 9,15 biocatalysis 10,11 and continuous flow chemistry. 12–15 To date, none have been as attractive and robust as the van Leusen reaction, which was first reported in 1977, and is frequently used in the total synthesis of medicinal compounds.…”

“…14 A mechanistically insightful report by Sharma et al detailed a cyanide-free cyanation for the derivatisation of sp 2 and sp carbons via an oxazole-based masked nitrile source (Scheme 1B). 15 However, a cyanide-free continuous flow synthesis of nitriles via the van Leusen reaction is unreported in the literature despite its significant advantages.…”