Metal-Free C–H Alkyliminylation and Acylation of Alkenes with Secondary Amides

Carbon–carbon bond formation by metal-free cross-coupling of two reactants with low reactivity represents a challenge in organic synthesis. Secondary amides and alkenes are two classes of bench-stable compounds. The low electrophilicity of the former and low nucleophilicity of the latter make the direct coupling of these two partners challenging yet highly desirable. We report herein an unprecedented intermolecular reaction of secondary amides with alkenes to afford α,β-unsaturated ketimines or enones, which are versatile intermediates for organic synthesis and are prevalent in bioactive compounds and functional materials. Our strategy relies on the chemoselective activation of the secondary amide with trifluoromethanesulfonic anhydride (Tf2O)/2-fluoropyridine to generate a highly reactive nitrilium intermediate, which reacts efficiently with alkenes. This metal-free synthesis is characterized by its mild reaction conditions, excellent functional group tolerance and chemoselectivity, allowing the preparation of multi-functionalized compounds without using protecting groups.

Dichloromethane was distilled over calcium hydride under Argon. All reactions were carried out under Argon.

General procedure for the direct C-H alkyliminylation of alkenes with secondary amides to
give ,-unsaturated ketimines 2 (General Procedure I).
Into a dry 10-mL round-bottom flask equipped with a magnetic stirring bar were added successively a secondary amide (0.5 mmol, 1.0 equiv), 2 mL of anhydrous CH 2 Cl 2 and 2-fluoropyridine (0.6 mmol, 1.2 equiv) under an argon atmosphere. After being cooled to 0 °C, trifluoromethanesulfonic anhydride (Tf 2 O) (155 mg, 93 μL, 0.55 mmol, 1.1 equiv) was added dropwise via a syringe and the reaction was stirred for 10 min. To the resulting mixture, alkenes (0.6 mmol, 1.2 equiv) was added dropwise at 0 °C. The mixture was allowed to warm-up to room temperature (or 40 °C) and stirred for 2 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by flash column chromatography (FC) on silica gel S57 (pre-neutralized with 2% Et 3 N in n-hexane) to afford the desired ,-unsaturated ketimine 2.
General procedure for the direct C-H acylation of alkenes with secondary amides to give enones 3 (General Procedure II).
Into a dry 10-mL round-bottom flask equipped with a stirring bar were added successively a secondary amide (0.5 mmol, 1.0 equiv), 2 mL of anhydrous CH 2 Cl 2 and 2xxx (0.6 mmol, 1.2 equiv) under an argon atmosphere. After being cooled to 0 °C, trifluoromethanesulfonic anhydride (Tf 2 O) (155 mg, 93 μL, 0.55 mmol, 1.1 equiv) was added dropwise via a syringe and the reaction was stirred for 10 min. To the resulting mixture, alkenes (0.6 mmol, 1.2 equiv) was added dropwise at 0 °C. The mixture was allowed to warm-up to room temperature (or 40 °C) and stirred for 2 h. The reaction mixture was concentrated under reduced pressure. To the resulting residue were added 5 mL of EtOH and 5 mL of an aqueous solution of HCl (3.0 M). The resulting mixture was heated to reflux until completion of the reaction as monitored by TLC analysis (2-12 h). After being cooled to rt, 10 mL of CH 2 Cl 2 was added, and the mixture extracted with CH 2 Cl 2 (3  10 mL). The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford the desired ,-unsaturated ketone (enone) 3.

Mechanistic studies
Investigation of the in suit formed intermediates by NMR Procedure: To a dry NMR tube were sequentially added amide 1p (25.3 mg, 0.1 mmol), CD 2 Cl 2 (0.75 mL) at 0 °C, The NMR tube was slightly shaken. At this point, 1 H NMR was taken giving spectrum A.
Then the NMR tube was kept in ice-water bath. To the mixture Tf 2 O (18.5 μL, 1.1 eq.) was added.
The NMR tube was slightly shaken. The mixture was allowed to warm to rt and kept for 10 min.
At this point, 1 H NMR was taken giving spectrum B.

Investigation of the in situ generated intermediates by in situ IR
ReactIR® 15 (Mettler Toledo) was used for the in situ IR measurement.