Synthesis of difluoromethylated allenes through trifunctionalization of 1,3-enynes

Organofluorine compounds have shown their great value in many aspects. Moreover, allenes are also a class of important compounds. Fluorinated or fluoroalkylated allenes might provide an option as candidates for drug and material developments, as allenes allow a great number of valuable transformations. Herein, we report a metal-free synthesis of difluoromethylated allenes via regioselective trifunctionalization of 1,3-enynes. This method proceeds through double C–F bond formation with concomitant introduction of an amino group to the allene. Synthetic applications are conducted and preliminary mechanistic studies suggest that a two-step pathway is involved. DFT calculations revealed an unusual dibenzenesulfonimide-assisted fluorination/fluoroamination with NFSI. In addition, kinetic reaction study revealed the induction period of both major and side products to support the proposed reaction mechanism. This work offers a convenient approach for the synthesis of a range of difluoromethylated allenes and is also a rare example of trifunctionalization of 1,3-enynes.


Supplementary Methods
General Information. All reactions were carried out under an atmosphere of nitrogen in glassware with magnetic stirring unless otherwise indicated. Commercially obtained reagents were used as received. Solvents were dried by Inert PureSolv MD5. Liquids and solutions were transferred via syringe. All reactions were monitored by thin-layer chromatography. 1 H, 19 F, and 13 C NMR spectra were recorded on Bruker-BioSpin AVANCE III HD or JEOL ECZ600S. Data for 1 H NMR spectra are reported relative to CDCl3 as an internal standard (7.26 ppm) and are reported as follows: chemical shift (ppm), multiplicity, coupling constant (Hz), and integration. Data for 13 C NMR spectra are reported relative to CDCl3 as an internal standard (77.0 ppm) and are reported in terms of chemical shift (ppm). GC-MS data were recorded on Thermo ISQ QD. HRMS data were recorded on Bruker Impact II UHR-TOF.

Synthesis of 1,3-Enynes
To a 50 mL round bottomed flask was charged with compound S2 (5 mmol, 1 equiv) and 10 mL of THF. The solution was cooled to -78 °C and n-BuLi (2.5 M in THF, 2 mL, 5 mmol, 1 equiv) was added. The resulting solution was stirred for 20 minutes at room temperature and then cooled to -78 °C again. Ketone S1 (5 mmol, 1 equiv) was added dropwise. The reaction mixture was then allowed to warm to room temperature and was monitored by TLC for completion. On completion the reaction was quenched with saturated aqueous NH4Cl (40 mL). The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine (30 mL), dried over MgSO4 and filtered. Then concentrated under reduced pressure to afford the crude material S3. 1 The resulting crude propargyl alcohol S3 was dissolved in dry DCM (5 mL), and the mixture was cooled to 0 °C with a cooling bath. To this solution was added TEA (25 mmol, 5 equiv) and methylsulfonyl chloride (12.5 mmol, 2.5 equiv) sequentially. After 30 min the reaction was monitored by TLC for completion. Once completion the reaction was quenched with saturated aqueous NH4Cl (40 mL). The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine (30 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material was purified by flash chromatography to yield the 1,3-enyne.

General Procedure for Amino-Difluorination of 1,3-Enynes
General Procedure: In a flame-dried Schlenk tube, NFSI (1.5 mmol, 3.0 equiv) were dissolved in toluene (1 mL) under a nitrogen atmosphere. Then, 1,3-enyne (0.5 mmol, 1.0 equiv) was added. The reaction mixture was stirred at 80 o C for 12 h. After the reaction completion as detected by TLC, the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel (PE/EA or PE/DCM) to afford the allene product.

Characterization
Data for the

Difluoromethylated Allenes
Following the general procedure, compound 4a was obtained as a pale yellow oil (177 mg, 65% yield

Mechanism Studies
In a flame-dried Schlenk tube, NFSI (0.75 mmol, 3.0 equiv) were dissolved in toluene (0.5 mL) under a nitrogen atmosphere. Then, allene 3a (0.25 mmol, 1.0 equiv) was added. The reaction mixture was stirred at 80 o C for 12 h. After the reaction completion, the reaction mixture was detected by GC-MS analysis and no desired product 4a was detected.
In a flame-dried Schlenk tube, NFSI (3 mmol, 1.5 equiv) and 1,3-enyne 1a (2 mmol, 1.0 equiv) were dissolved in DCM (6 mL) under a nitrogen atmosphere. The reaction mixture was stirred at 70 o C. After the reaction completion as detected by TLC, the solvent was concentrated under vacuum. The crude residue was purified by flash column chromatography on silica gel to give the product 9a in 20% yield.
In a flame-dried Schlenk tube, NFSI (0.6 mmol, 3.0 equiv) were dissolved in toluene (0.5 mL) under a nitrogen atmosphere. Then, fluoro-1,3-enyne 9a (0.2 mmol, 1.0 equiv) was added. The reaction mixture was stirred at 80 o C for 12 h. After the reaction completion, the crude residue was purified by flash column chromatography on silica gel to give the product 4a in 74% yield.
In a flame-dried Seal tube, NFSI (0.6 mmol, 3.0 equiv), HNTs2 (0.6 mmol, 3 equiv) were dissolved in DCM (0.5 mL) under a nitrogen atmosphere. Then, 1,3-enyne 1a (0.2 mmol, 1.0 equiv) was added. The reaction mixture was stirred at 80 o C for 12 h. After the reaction completion, the crude residue was purified by flash column chromatography on silica gel to give the product 4a in 32% yield and crossover product In a flame-dried Seal tube, NFSI (1.5 mmol, 3.0 equiv) were dissolved in toluene (1 mL) under a nitrogen atmosphere. Then, 1,3-enyne 1a (0.5 mmol, 1.0 equiv) was added. The reaction mixture was stirred at 80 o C. After given time, the mixture was diluted by 2 mL of hexane and cooled by ice. After removal of solvents, the residue was detected by 19 F NMR with trifluoromethylbenzene as the internal standard, and the yield was given below (also see, Supplementary Figure 5).

Computational Method and Details
The