Diverse reactivity of the gem-difluorovinyl iodonium salt for direct incorporation of the difluoroethylene group into N- and O-nucleophiles

The synthesis of gem-difluoroethylene compounds remains a difficult task in organic synthesis. Here, the direct difluoroethylation reactions of N- and O-nucleophiles including amides and acids were realized with a hypervalent iodine reagent: gem-difluorovinyl iodonium salt (DFVI). The reactions were accomplished via a neighbouring group rearrangement. The gem-difluorovinyl iodonium salt was found to display diverse reactivity due to its unique electronic effect and was applied to the incorporation of difluoroethylene group, including difluorovinylation of carboxylic acids, difluorovinylation and 1,3-cyclic fluorovinylation of amides and 1,1-cyclic difluoroethylation of amines.


Preparation of tributyl (2,2-difluorovinyl)stannane
A suspension of 2,2-difluorovinyl 4-methylbenzenesulfonate (10 mmol), Pd2(dba)2 (0.3 mmol), S-phos (0.6 mmol), LiBr (300 mmol) in 50 mL of propan-2-ol was degassed three times with freeze/pump/thaw technique in a flame-dried round bottom flask. 1.0 Equiv. of 1,1,1,2,2,2-hexabutyldistannane (10 mmol) was added using a syringe to the thawed solution under nitrogen. The reaction was allowed to react at 80 o C for 12 hours and solvent was removed in vacuo. Then 50 ml of EA was added and the organic layer was washed with a saturated solution of potassium fluoride. The precipitate was filtered through celite and washed with EA (2 × 30 mL). Then organic layer was dried over anhydrous Na2SO4. Solvent was removed in vacuo. The reaction mixture was purified by flash chromatography on silica gel (eluent: PE) to afford crude product. Pure product was obtained when crude product was distilled under high vacuum (b.p.: 46 o C (0.4 Pa)), the spectroscopy was consistent with those reported in the literature. [1]

2.2
Preparation of (2,2-difluorovinyl)(aryl)-λ 3 -iodaneyl trifluoromethanesulfonate Trimethylsilyltrifluoromethanesulfonate (1.4 mL, 7.8 mmol) was added to a stirred solution of bis(trifluoroacetoxy)iodo benzene (3.1 g, 7.2 mmol) in CH2Cl2 (25 mL) at -20 °C. The mixture was warmed to ambient temperature for 10 min until the color of the solution changed from colorless to yellow. The reaction mixture was re-cooled to -30 °C, and trimethylsilyl cyanide (1.0 mL, 7.8 mmol) was added via syringe resulting in the formation of a yellow-white salt 6a. Et2O was added to the reaction mixture and solvent was removed through catheter tied with filter paper below 0 o C. Wash the solid twice with ether to afford pure 6a. 6b-6c was synthesized according to the reported literature. [2] In a Schlenk tube (100 mL), a portion of the above salt (6 mmol) was suspended in CH2Cl2 (40 mL) and cooled to -40 °C. Tributyl(vinyl)tin (6 mmol) dissolved in CH2Cl2 (10 mL) was then added dropwise to the stirring solution. After the addition was complete, the cooling bath was removed and the reaction allowed to warm to ambient temperature. After 2 hours the slightly yellow solution was concentrated in vacuo leaving approx. 5 mL CH2Cl2 to which Et2O (20 mL) was added with vigorous stirring and -20 o C. The precipitate was filtered and washed with Et2O (3×10 mL), 1a -1c was obtained as a white solid (1a: 68% yield, 1b: 58 % yield, 1c: 65 %yield.).

Equivalent of starting materials and base
a Reaction conditions: 3,5-dichlorobenzoic acid, 1a, Ag2CO3 (0.1 mmol) in CH3CN (0.5 mL) at 25 o C for 12 h; b Yields were determined by 19 F NMR analysis of the crude reaction mixture with an internal standard p-fluoroiodobenzene. c isolated yield in parentheses; d 4 equivalent Ag2CO3 was used.

Equivalent of staring materials
a Reaction conditions: 1-naphthamide (0.05 mmol), 1a, Ag2CO3 in DCM (0.5 mL) at 25 o C for 12 h; b Yields were determined by 19 F NMR analysis of the crude reaction mixture with an internal standard p-fluoroiodobenzene; c isolated yield in parentheses; d CuO (0.10 mmol) was added; e PIDA (0.10 mmol) was added.

Optimization of difluoroethylation of amine with reagent 1
a Reaction conditions: p-bromoaniline (0.05 mmol), 1a (0.05 mmol), Base (0.10 mmol) in DCM (0.5 mL) at 25 o C for 12 h; b Yields were determined by 19 F NMR analysis of the crude reaction mixture with an internal standard p-fluoroiodobenzene; c isolated yield in parentheses; d 1a was replaced with 1b; e 1a was replaced with 1c; f 1a was replaced with 1c (1.2 eq., 0.06 mmol).

General procedure for gem-difluorovinylation of carboxylic acid with reagent 1a
Carboxylic acid (0.2 mmol 1.0 equiv.), Ag2CO3 (4.0 equivalent / 1.0 equivalent carboxyl group) and reagent 1a (4.0 equivalent / 1.0 equivalent carboxyl group) were placed into an oven-dried Schlenk tube that is equipped with a stirring bar under N2.
The tube was quickly sealed with a rubber stopper and 2 mL of freshly distilled CH3CN was added. The reaction was stirred at room temperature for 12 h. Then the reaction mixture was concentrated in vacuo and purified by flash chromatography on silica gel.

General procedure for gem-difluorovinylation of amide with reagent 1a
Amide (0.8 mmol 4.0 equiv.), Ag2CO3 (10% mol) and reagent 1a (0.2 mmol 1.0 equiv.) were placed into an oven-dried Schlenk tube that is equipped with a stirring bar under N2. The tube was quickly sealed with a rubber stopper and 2 mL of freshly distilled CH2Cl2 was added. The reaction was stirred at room temperature for 12 h. Then the reaction mixture was concentrated in vacuo and purified by flash chromatography on silica gel.

General procedure for fluorovinylation of amide with reagent 1a
Amide (0.2 mmol 1.0 equiv.), Ag2CO3 (0.4 mmol 2.0 equiv.) and reagent 1a (0.24 mmol 1.2 equiv.) were placed into an oven-dried Schlenk tube that is equipped with a stirring bar under N2. The tube was quickly sealed with a rubber stopper and 2 mL of freshly distilled CH2Cl2 was added. The reaction was stirred at room temperature for 12 h. Then the reaction mixture was concentrated in vacuo and purified by flash chromatography on silica gel.

General procedure for difluoroethylation of amine with reagent 1c
Amine (0.2 mmol 1.0 equiv.), Na2CO3 (0.4 mmol 2.0 equiv.) and reagent 1c (0.24 mmol 1.2 equiv.) were placed into an oven-dried Schlenk tube that is equipped with a stirring bar under N2. The tube was quickly sealed with a rubber stopper and 2 mL of freshly distilled CH2Cl2 was added. The reaction was stirred at room temperature for 12 h. Then the reaction mixture was concentrated in vacuo and purified by flash chromatography on silica gel.

Mechanism study 8.1 Reaction between silver benzoate and iodonium salt
Silver benzoate (0.05 mmol, 1.0 eq.), reagent 1a (0.05 mmol, 1.0 eq.) were placed into an oven-dried Schlenk tube that is equipped with a stirring bar under N2. The tube was quickly sealed with a rubber stopper and 0.5 mL of freshly distilled CH3CN was added. The reaction was stirred at room temperature for 12 h. Then the reaction mixture was added internal standard p-fluoroiodobenzene (4 μl) to calculate the NMR yield. Yield 63% (p-fluoroiodobenzene 19 FNMR (-115.14 --115.19))

Investigation on the interaction of 1a with amide
1-naphthamide (0.05 mmol), reagent 1a (0.05 mmol) were placed into an NMR tube in CD2Cl2, comparing the NMR of mixture with starting materials. A significant upfield shift (0.19 ppm) of the F resonance in iodonium salt 1a and simultaneously a downfield shift (0.34 ppm) of the active N proton signal in amide was observed.

X-Ray crystallographic data
The single crystal for compound 1a, 3a, 4j were prepared from a mixture solvent of CHCl3 and diethyl ether or pentane. The data were collected on a Rigaku Oxford Diffract instrument using Cu-Kα radiation (λ = 1.54178 Å) or Mo-Kα (λ = 0.71073 Å) at 173 K or 293 K. Data collection was controlled by CrysAlis Pro (Rigaku,2016). Computations were performed using the SHELXTL NT ver. 5.10 program package (Bruker, 1997) on an IBM PC 586 computer. All non-hydrogen atoms were subjected to anisotropic refinement. The hydrogen atoms were generated geometrically with C-H bonds of 0.93-0.97 Å according to criteria described in the SHELXTL manual (Bruker, 1997). The crystallographic data have already been deposited at the Cambridge Crystallographic Data Centre. CCDC numbers: 2141360 (1a), 2141361 (4j), 2141364 (3a).