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Direct Synthesis of Enamides via Electrophilic Activation of Amides

Philipp Spieß, Martin Berger, Daniel Kaiser and Nuno Maulide*

*Institute of Organic Chemistry, University of Vienna, Währinger Straße 38, 1090 Vienna, Austria, Email:

P. Spiess, M. Berger, D. Kaiser, N. Maulide, J. Am. Chem. Soc., 2021, 143, 10524-10529.

DOI: 10.1021/jacs.1c04363

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A dehydrogenation of amides to enamides employs the combination of LiHMDS and triflic anhydride, which serves as both the electrophilic activator and the oxidant. The reaction offers simple setup and broad substrate scope. The synthetic utility of the formed enamides was demonstrated in a range of transformations.

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Application of Enamides

General Procedure: Synthesis of Enamides

A flame-dried Schlenk flask was loaded with the corresponding amide (0.30 mmol, 1.00 eq.) which was dissolved in anhydrous Et2O (1.5 mL). The solution was cooled down to -94 °C (dry ice/acetone mixture). Then LiHMDS (1 M in THF, 1.44 mL, 1.44 mmol, 4.80 eq.) was added slowly (ca. 20 s). After the addition, the resulting mixture was stirred for 10 min. Following Tf2O (121 µL, 0.72 mmol, 2.40 eq.) was added dropwise over 1 min with vigorous stirring (very important). The reaction was stirred for 30 min before remaining reagents were quenched by the addition of a saturated solution of NH4Cl (10 mL). The solution was transferred into a separatory funnel and extracted with CH2Cl2 (3 x 10 mL). The combined organic phases were dried over anhydrous MgSO4 and the solvent was removed under reduced pressure. The crude material was purified by column chromatography (SiO2, heptanes/EtOAc). Importantly, a noticeable instability of enamides on silica gel has been observed. Therefore, the silica gel was treated with NEt3/Et2O (1:9), followed by drying in the air prior to use in the flash column chromatography.

Key Words


ID: J48-Y2021