Barbier Continuous Flow Preparation and Reactions of Carbamoyllithiums for Nucleophilic Amidation.

An ambient temperature continuous flow method for nucleophilic amidation and thioamidation is described. Deprotonation of formamides by lithium diisopropylamine (LDA) affords carbamoyllithium intermediates that are quenched in situ with various electrophiles such as ketones, allyl bromides, Weinreb and morpholino amides. The nature of the reactive lithium intermediates and the thermodynamics of the metalation were further investigated by ab initio calculations and kinetic experiments.

High-Temperature Continuous-Flow Zincations of Functionalized Arenes and Heteroarenes Using (Cy2N)2Zn·2LiCl.

The treatment of sensitive arenes and heteroarenes with the zinc bis-amide (Cy2N)2Zn·2LiCl (0.55 equiv), prepared in quantitative yield by the reaction of Cy2NLi with ZnCl2, leads under flow conditions to a fast zincation within 10 min at temperatures between 25 and 100 °C. The resulting organozinc reagents can be trapped with various organic halides (allylic bromides, aryl iodides) in high yields.

Continuous Flow Magnesiation or Zincation of Acrylonitriles, Acrylates, and Nitroolefins. Application to the Synthesis of Butenolides.

Scalable continuous flow procedures are reported for the metalation and downstream functionalization of β-substituted acrylates. The flow conditions allow the metalation of acrylonitriles, acrylates, and nitroolefins at 0.25-2.

Practical and economic lithiations of functionalized arenes and heteroarenes using CyNLi in the presence of Mg, Zn or La halides in a continuous flow.

The economic amide base lithium dicyclohexylamide (CyNLi) allows fast and convenient (40 s, 0 °C) trapping flow metalations of a broad range of functionalized arenes, heteroarenes and acrylate derivatives in the presence of various metal salts (ZnCl·2LiCl, MgCl, LaCl·2LiCl). The resulting Zn-, Mg- or La-organometallic intermediates are trapped with various electrophiles in high yields. These flow metalations are easily scaled-up without further optimization.

Practical continuous-flow trapping metalations of functionalized arenes and heteroarenes using TMPLi in the presence of Mg, Zn, Cu, or La halides.

The flow metalation of various arenes and heteroarenes involving an in situ trapping with metal salts (ZnCl2 ⋅2 LiCl, MgCl2 , CuCN⋅2 LiCl, LaCl3 ⋅2 LiCl) under very convenient conditions (0 °C, 40 s) is reported. The resulting Mg, Zn, Cu, or La organic species are trapped with various electrophiles in high yields. In several cases, unusual kinetically controlled regioselectivities are obtained.

Continuous flow magnesiation of functionalized heterocycles and acrylates with TMPMgCl⋅LiCl.

A flow procedure for the metalation of functionalized heterocycles (pyridines, pyrimidines, thiophenes, and thiazoles) and various acrylates using the strong, non-nucleophilic base TMPMgCl⋅LiCl is reported. The flow conditions allow the magnesiations to be performed under more convenient conditions than the comparable batch reactions, which often require cryogenic temperatures and long reaction times. Moreover, the flow reactions are directly scalable without further optimization.