Synthesis of Polyfunctional Diorganomagnesium and Diorganozinc Reagents through In Situ Trapping Halogen–Lithium Exchange of Highly Functionalized (Hetero)aryl Halides in Continuous Flow

Abstract

We report a halogen-lithium exchange performed in the presence of various metal salts (ZnCl , MgCl ⋅LiCl) on a broad range of sensitive bromo- or iodo(hetero)arenes using BuLi or PhLi as the exchange reagent and a commercially available continuous-flow setup. The resulting diarylmagnesium or diarylzinc species were trapped with various electrophiles, resulting in the formation of polyfunctional (hetero)arenes in high yields. This method enables the functionalization of (hetero)arenes containing highly sensitive groups such as an isothiocyanate, nitro, azide, or ester. A straightforward scale-up was possible without further optimization.

Continuous-Flow Reactions Mediated by Main Group Organometallics

“…This Barbier procedure in continuous flow is also very useful for performing Br/Li-exchange reactions of organozinc or diorganomagnesium reagents bearing azido or nitro groups, such as 33 and 34 (Scheme 11). 24 An extension to heterocyclic reagents such as the diquinolinylmagnesium species 35 is also possible. 25 The generation of lithiated heterocycles in continuous flow is of particular interest in the case of oxadiazoles, because these heterocycles have a tendency to fragment.…”

Flow Technology for the Genesis and Use of (Highly) Reactive Organometallic Reagents

“…The in situ trapping with metal salts has been recently extended to highly reactive lithiated intermediates generated by halogen–lithium exchange . In this work, bromo‐ or iodo(hetero)arenes bearing sensitive functional groups (i.e.…”

Synthesis of Organometallic Compounds in Flow

“…Organomagnesium compounds can be generated from transmetalation of lithiated species. Interestingly, Knochel reported the possibility of in situ trapping transmetalation of aromatic or heteroaromatic lithium derivatives prepared by metalation or halogen‐lithium exchange …”

“…Organozinc halides can be obtained by transmetalation of lithium derivatives in the same manner that has been described for Grignard reagents ( Figures , and ) …”

“…Interestingly, Knochel reported the possibility of in situ trapping transmetalation of aromatic or heteroaromatic lithium derivatives prepared by metalation [72 -74] or halogenlithium exchange. [75] They showed that acrylates could be deprotonated by lithium dicyclohexylamide (Cy 2 NLi) in presence of MgCl 2 to afford the corresponding magnesium derivative that could then be quenched by different aldehydes (Figure 21).…”