Palladium-catalyzed intramolecular Heck dearomative gem-difluorovinylation of indoles

A palladium-catalyzed dearomative reaction of indoles has been developed through a domino Heck/gem-difluorovinylation sequence. By taking advantage of a difluorocarbene precursor (ClCF2COONa), the palladium difluorocarbene ([Pd] 
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Created by potrace 1.16, written by Peter Selinger 2001-2019
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 CF2) species was formed smoothly. Then, a migratory insertion/β-H elimination process enabled access to polycyclic indolines containing 1,1-difluoroethylene units in acceptable yields with a broad substrate scope, which also showed dearomative gem-difluorovinylation for the first time. Remarkably, the superb diversified transformations allowed the product to install various functional groups.

The HRMS analysis was obtained on an Agilent6540 UHD Q-TOF mass spectrometer.
The melting point was recorded on BÜCHI (M-560) and uncorrected. The X-ray single crystal diffraction data were collected on a Bruker D8 VENTURE. Analytical thin layer chromatography (TLC) was performed on 0.25 mm silica gel 60 F254 plates and viewed by UV light (254 nm). Column chromatographic purification was performed using 200-300 mesh silica gel.

Materials.
All the chemical reagents were purchased from commercial sources and used as received unless otherwise indicated. Substrates 1 were prepared according to the known method. 1

General procedure for synthesis of products (taking 3a as an example)
To a Schlenk tube was added Pd(OAc)2 (10 mol%), DPEphos (12 mol%), 1a (0.2 mmol), K2CO3 (0.6 mmol), 4Å MS (100 mg), and 2a (0.4 mmol) under N2, after which 3.0 mL DCE was added into the reaction mixture by a syringe and the tube was sealed with Teflon cap. The mixture was stirred at 120 ℃ for 12 hours. When the reaction was completed, the solvent was removed under vacuum and the residue was purified by column chromatography on silica gel to afford the product 3a in 79% yield.

Gram-scale reaction
To a Schlenk tube was added Pd(OAc)2 (10 mol%), DPEphos (12 mol%), 1a (8 mmol), K2CO3 (24 mmol), 4Å MS (4000 mg), and 2a (16 mmol) under N2, after which 40 mL DCE was added into the reaction mixture by a syringe and the tube was sealed with Teflon cap. The mixture was stirred at 120 ℃ for 15 hours. When the reaction was completed, the solvent was removed under vacuum and the residue was purified by column chromatography on silica gel to afford the product 3a in 45% yield.

Synthetic transformations of product 3a 2.3.1 Procedure for synthesis of 4a
The synthesis of 4a was conducted according to a reported procedure. 2 To a 25 mL Schlenk flask was charged with gem-difluoroalkene 3a (0.2 mmol, 1.0 equiv.), 4methylbenzenethiol (0.4 mmol, 2.0 equiv.), and EtOH/H2O (2.0 mL, v/v = 2:1). The flask was then evacuated and backfilled with O2 three times and sealed with a Teflon cap. The resulting solution was stirred at room temperature for 12 h. Upon competition of the reaction, CH2Cl2 (10 mL) was added. The organic layer was washed with H2O (10 mL × 2) and brine (10 mL × 1 ), and the combined aqueous layers was extracted with CH2Cl2 (10 mL × 2) twice. The combine organic layers were dried over anhydrous Na2SO4. Then the solvents were removed via rotary evaporator and the residue was purified by column chromatography on silica gel to afford alcohol product 4a in 66% S4 yield.

Procedure for synthesis of 4b
The synthesis of 4b was conducted according to a reported procedure. 3 To a 10 mL Schlenk tube was charged with gem-difluoroalkene 3a (0.2 mmol, 1.0 equiv.), 4methylbenzenethiol (0.24 mmol, 1.2 equiv.), and dry DCE (40 μL). The reaction mixture was placed in a preheated metal block and stirred at 80 o C for 15 min. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel to afford product 4b in 85% yield.

Procedure for synthesis of 4c
The synthesis of 4c was conducted according to a reported procedure. 4 An ovendried 10 mL Schlenk tube was charged with Cs2CO3 (0.03 mmol), TMSCN (0.9 mmol, 3 equiv.), 3a (0.3 mmol, 1.0 equiv.), and dry MeCN (1.0 mL). The reaction mixture was stirred at room temperature for 2 h. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel to afford product 4c in 83% yield.
After completion of the reaction, the mixture was quenched with H2O (20 mL). The aqueous phase was extracted with CH2Cl2 (3 × 10 mL). The organic layer was dried over MgSO4 and filtered, and the filtrate was concentrated in vacuo. The crude product was purified by column chromatography on silica gel to afford product 4d in 85% yield.

Procedure for synthesis of 4e
The reduction was conducted according to a reported procedure. 6 A 25 mL of dried round-bottom flask was charged with gem-difluoroalkene 3a (0.2 mmol, 1.0 equiv.), benzoyl hydrazide (0.24 mmol, 1.2 equiv.), Cs2CO3 (0.4 mmol, 2 equiv.), and dry DMSO (1 mL) under N2 atmosphere. The mixture was stirred at 80 °C for 6 h (monitored by TLC). After the reaction completed, the reaction mixture was quenched with H2O (20 mL) and extracted with EtOAc (3×10 mL). The combined organic layer was washed with brine (3×10 mL), dried 3 over Na2SO4, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel to afford product 4e in 79% yield.

Procedure for synthesis of 4f
The reduction was conducted according to a reported procedure. 7 Selectfluor (0.3 S6 mmol, 1.5 equiv.), and gem-difluoroalkene 3a (0.2 mmol, 1 equiv.) were added in turn to an oven-dried 10 mL Schlenk tube equipped with a stir bar under a nitrogen atmosphere. The reactants were dissolved in dry CH3CN (0.8 mL), followed by the addition of dry MeOH (1 mmol, 5 equiv.). The reaction mixture was stirred at 40 o C for 4 h. The reaction mixture was diluted with ethyl acetate (20.0 mL) and transferred to a flask. The solvent was evaporated under vacuum. The residue was purified by column chromatography on silica gel to afford product 4f in 77% yield.

Procedure for synthesis of 4g
The reduction was conducted according to a reported procedure. 7 Selectfluor (0.3 mmol, 1.5 equiv.), and gem-difluoroalkene 3a (0.2 mmol, 1 equiv.) were added in turn to an oven-dried 10 mL Schlenk tube equipped with a stir bar under a nitrogen atmosphere. The reactants were dissolved in dry CH3CN (0.8 mL), followed by the addition of H2O (1.6 mmol, 8 equiv.). The reaction mixture was stirred at 40 o C for 4 h.
The reaction mixture was diluted with ethyl acetate (20.0 mL) and transferred to a flask.
The solvent was evaporated under vacuum. The residue was purified by column chromatography on silica gel to afford product 4g in 95% yield.

Procedure for synthesis of 4h
The reduction was conducted according to a reported procedure. 8 A solution of 4. Crystallographic data and molecular structure of compounds 3a, 3t, and 4h Figure S1. X-ray crystal structure of 3a Table S1. Crystal data and structure refinement details for 3a.