Chemoselective α,β‐Dehydrogenation of Saturated Amides

Abstract We report a method for the selective α,β‐dehydrogenation of amides in the presence of other carbonyl moieties under mild conditions. Our strategy relies on electrophilic activation coupled to in situ selective selenium‐mediated dehydrogenation. The α,β‐unsaturated products were obtained in moderate to excellent yields, and their synthetic versatility was demonstrated by a range of transformations. Mechanistic experiments suggest formation of an electrophilic SeIV species.


General Information
Unless otherwise stated, all glassware was flame-dried before use and all reactions were performed under an atmosphere of argon. All solvents were distilled from appropriate drying agents prior to use. Triflic anhydride was distilled over P4O10 prior to use. All other reagents were used as received from commercial suppliers unless otherwise stated. Reaction progress was monitored by thin layer chromatography (TLC) performed on aluminium plates coated with silica gel F254 with 0.2 mm thickness. Chromatograms were visualized by fluorescence quenching with UV light at 254 nm or by staining using potassium permanganate or phosphomolybdic acid. Flash column chromatography was performed using silica gel 60 (230-400 mesh, Merck and co.). Neat infra-red spectra were recorded using a Perkin-Elmer Spectrum 100 FT-IR spectrometer. Wavenumbers (νmax) are reported in cm -1 . Mass spectra were obtained using a Finnigan MAT 8200 or (70 eV) or an Agilent 5973 (70 eV) spectrometer, using electrospray ionization (ESI).
Splitting patterns that could not be interpreted or easily visualized were designated as multiplet (m) or broad (br). Selected 13 C NMR spectra were recorded using the attached proton test (APT) to facilitate the confirmation and assignment of the structure.

General Procedure A:
To a solution of the amine (1.00 eq.) and triethylamine (2.00 eq.) in dichloromethane (0.1 M) at 0°C, the corresponding acyl chloride (1.20 eq.) was added dropwise and the resulting reaction mixture was allowed to warm to room temperature while stirring overnight (14 h). After this time, a saturated aqueous solution of sodium bicarbonate was added and the biphasic system was separated. The aqueous phase was extracted with dichloromethane (1×) and the organic phases were combined and dried over anhydrous sodium sulfate. The dried solution was filtered and concentrated under reduced pressure. The resulting crude material was purified by flash column chromatography on silica gel to afford the desired compound.

General Procedure B:
To a solution of the amine (1.00 eq.), triethylamine (1.00 eq.), hydroxybenzotriazole (HOBt, 1.00 eq.) and Given the difficulty of separating the dehydrogenated products from the starting materials, we have reported Rf values in a solvent system which we found best provided some separation between the starting materials and products.

All reactions were run on a 0.2 mmol scale unless otherwise indicated.
To a solution of amide 1 (1.0 eq.) and 2-iodopyridine (2.2 eq.) in dichloromethane (2 mL, 0.1 M) at 0 °C was added trifluoromethanesulfonic anhydride (1.1 eq.) and the resulting mixture was stirred at 0 °C and colouration of the solution was observed. After 15 min, a previously prepared solution of A (1 mL, 0.2 M of PhSeO2H) was added and the reaction mixture was stirred at 0 °C for 5 min. The resulting mixture was allowed to warm to ambient temperature (25 °C) over the course of 5 minutes to 1 h, after which time a saturated aqueous solution of sodium carbonate (5 mL) was added. The biphasic mixture was separated and the aqueous phase was extracted with dichloromethane (2 × 5 mL). The combined organic phases were dried over anhydrous sodium sulfate, the dried solution was filtered and the filtrate was concentrated under reduced pressure. The crude residue was purified by flash column chromatography (SiO2, heptanes/ethyl acetate) to afford the compounds 4. In most cases, the dehydrogenated amide 4 was isolated with remnants of the corresponding starting material (typically 5 -10%). A further purification was necessary in most cases and was carried out on preparative TLC, typically using an acetone/heptanes system -to both determine the yield and for full characterization of the product -see individual compounds for details.

Preparation of solution A:
To a suspension of the seleninic acid (1 eq.) in dichloromethane (1 mL for 0.2 mmol of the seleninic acid) was added the triethylamine (3 eq.). Solubilisation of the suspension was observed and then Dess-Martin periodinane (2.2 eq.) was added at room temperature and stirred 2 hours. S18

N,N-Dimethylcinnamamide (4d)
The product was prepared according to General Procedure C on 0.2 mmol scale.

N,N-Diethylcinnamamide (4e)
The product was prepared according to General Procedure C on 0.2 mmol scale.
Following purification by silica gel flash chromatography (acetone/heptanes 1:5 to 2:3) and a further purification on preparative TLC (acetone/heptanes 1:1), the product was isolated as an off-white solid
Following purification by silica gel flash chromatography (acetone/heptanes 1:5 to 1:1), the product was isolated as a yellow oil (16.8

S28
The product was prepared according to General Procedure C on 0.2 mmol scale. Following purification by silica gel flash chromatography (EtOAc/heptanes 1:9 to 2:3) and a further purification on preparative TLC (acetone/heptanes 1:1), the product was isolated as a yellow oil (31. 6