Continuous Flow Sodiation of Substituted Acrylonitriles, Alkenyl Sulfides and Acrylates

Abstract

The sodiation of substituted acrylonitriles and alkenyl sulfides in a continuous flow set-up using NaDA (sodium diisopropylamide) in EtNMe₂ or NaTMP (sodium 2,2,6,6-tetramethylpiperidide)⋅TMEDA in n-hexane provides sodiated acrylonitriles and alkenyl sulfides, which are subsequently trapped in batch with various electrophiles such as aldehydes, ketones, disulfides and allylic bromides affording functionalized acrylonitriles and alkenyl sulfides. This flow-procedure was successfully extended to other acrylates by using Barbier-type conditions.

Keywords: Barbier-type reactions; acrylonitriles; alkenyl sulfides; flow chemistry; sodiation.

Scheme 1

Tentative mechanism for the stereoselective addition of sodiated phenylacrylonitrile 2a or 2 a′ to aldehydes or ketones.

Scheme 2

General set‐up for the sodiation of functionalized acrylonitriles with NaTMP⋅TMEDA in a microflow reactor and subsequent batch quench of the intermediate sodium organometallics with various electrophiles leading to functionalized acrylonitriles. [a] The diastereoselectivity was determined by crystal structure analyses, see Supporting Information. [b] The E‐ or Z‐ diastereoselectivity was assigned in analogy to related products, for which X‐ray data were obtained. [c] 10 mol % CuCN⋅2 LiCl.

Scheme 3

Sodiation of substituted acrylates of type 11 using a microflow reactor under standard‐flow conditions and Barbier conditions. In situ quench of the intermediate sodium organometallics of type 12 with adamantanone (3 o) afforded functionalized acrylates of type 13. [a] 0.20 m in THF, 1.0 equiv [b] 0.30 m in THF, 1.5 equiv.