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.

The metalation of unsaturated nitriles and sulfides is an important synthetic procedure. [1] After quenching with various electrophiles, highly functionalized unsaturated products are obtained, which may be useful building blocks for biologically active heterocycles and natural products. [2] The batch-metalation of alkenyl nitriles or sulfides with lithium bases is often complicated due to competitive allylic lithiations. [3] The use of stronger, more polar bases like sodium or potassium amides may avoid such limitations. However, the sodiation of such unsaturated compounds is much less explored. [4] Moreover, the use of sodium organometallics is of high interest due to the low price, high abundancy and low toxicity of sodium salts. [5] Recently, arylsodium compounds have been prepared by Collum using NaDA (sodium diisopropylamide) as deprotonating agent [4e,6] and by Asako and Takai, who have investigated the utility of arylsodiums in catalytic cross-couplings. [7] Yoshida, Ley, Organ and others have demonstrated a high functional group tolerance performing challenging metalations in a continuous flow set-up. [8] Based on these studies, we have extended the Collum procedure to the preparation of sodiated aryl and heteroaryl derivatives which are difficult to generate otherwise and decompose upon batch-sodiation. [9] KDA·TMEDA (potassium diisopropylamide·N,N,N',N'-tetramethylethylenediamine) in n-hexane was used in continuous flow for similar metalations. [10] Herein, we wish to report that NaDA and NaTMP (TMPH = 2,2,6,6-tetramethylpiperidine) were efficient bases for the regioselective flow-metalation of various substituted acrylonitriles and alkenyl sulfides. [11] In first experiments, we have optimized the sodiation of cinnamonitrile (1 a) and have found that metalation with NaDA (0.24 m in DMEA (dimethylethylamine), 1.2 equiv) at À78 8C using a combined flow-rate of 10 mL min À1 and a 0.02 mL reactor proceeded best with a residence time of 0.12 s affording organosodium 2 a. Subsequent trapping with electrophiles of type 3 such as aldehydes, ketones, disulfides and allylic bromides afforded 2-substituted cinnamonitriles of type 4 with usually high E/Z ratios ( Table 1, entries 1-10). Thus, for a quenching with aromatic aldehydes, we obtained the Zproduct of type 4 as major product, whereas for more sterically hindered ketones the E-product was formed.
The diastereoselectivity of products of type 4 obtained after the addition to a carbonyl electrophile was tentatively explained by assuming that the sodiated nitrile 2 a reacted fast with an aldehyde (RCHO) according to pathway A leading to the allylic alcohol Z-4. In contrast, by using ketones, an equilibration to the cummulene form 2 a' may occur and the cyclic transition state A would be disfavoured due to steric hindrance. E/Z isomerization of the cummulene structure 2 a' occurred affording the E-4 product via transition state B (Scheme 1).
We have then extended this flow procedure to various functionalized arylacrylonitriles of type 5. Electron-rich cinnamonitrile derivatives (5 a-5 d) were selectively metalated in 2-position using NaDA in a continuous flow set-up within 0.12 s at À78 8C. The resulting organosodiums (6 a-d) were trapped in batch with various carbonyl electrophiles, such as m-anisaldehyde (3 k), cyclohexanecarboxaldehyde (3 l) or cyclohexanone (3 m), and with 3-bromocyclohexene Scheme 1. Tentative mechanism for the stereoselective addition of sodiated phenylacrylonitrile 2a or 2 a' to aldehydes or ketones.
[c] The diastereoselectivity was determined by crystal structure analyses, see Supporting Information.
[c] The diastereoselectivity was determined by crystal structure analyses, see Supporting Information.
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.
in n-hexane. The resulting sodiated acrylonitriles and alkenyl sulfides were 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. Table 3: Sodiation of alkyl-and alkenyl-substituted acrylonitriles of type 8 using a microflow reactor and subsequent batch quench of the intermediate sodium organometallics of type 9 with various electrophiles of type 3 leading to functionalized alkyl-and alkenyl-substituted acrylonitriles of type 10. [a] Yield of analytically pure product. [b] 10 mol % CuCN·2 LiCl.