Catalytic asymmetric radical aminoperfluoroalkylation and aminodifluoromethylation of alkenes to versatile enantioenriched-fluoroalkyl amines

Although great success has been achieved in asymmetric fluoroalkylation reactions via nucleophilic or electrophilic processes, the development of asymmetric radical versions of this type of reactions remains a formidable challenge because of the involvement of highly reactive radical species. Here we report a catalytic asymmetric radical aminoperfluoroalkylation and aminodifluoromethylation of alkenes with commercially available fluoroalkylsulfonyl chlorides as the radical sources, providing a versatile platform to access four types of enantioenriched α-tertiary pyrrolidines bearing β-perfluorobutanyl, trifluoromethyl, difluoroacetyl and even difluoromethyl groups in excellent yields and with excellent enantioselectivity. The key to success is not only the introduction of the CuBr/chiral phosphoric acid dual-catalytic system but also the use of silver carbonate to suppress strong background and side hydroamination reactions caused by a stoichiometric amount of the in situ generated HCl. Broad substrate scope, excellent functional group tolerance and versatile functionalization of the products make this approach very practical and attractive.


Supplementary Methods
All reactions were carried out under argon atmosphere using Schlenk techniques. Reagents were purchased at the highest commercial quality and used without further purification, unless otherwise stated. CuBr and Ag2CO3 were purchased from Sigma-Aldrich. Chiral phosphoric acid (CPA) was purchased from Daicel Chiral Technologies (China). Difluoromethylsulfonyl chloride and methyl 2-(chlorosulfonyl) -2,2-difluoroacetate were purchased from 9dingchem (China). Ethyl isobutyrate (i-PrCO2Et) was purchased from Adamas-beta® (Product Code: 91931B) and transferred under an argon atmosphere. Analytical thin layer chromatography (TLC) was performed on precoated silica gel 60 GF254 plates. Flash column chromatography was performed using Tsingdao silica gel (60, particle size 0.040-0.063 mm). Visualization on TLC was achieved by use of UV light (254 nm) or iodine. NMR spectra were recorded on Bruker DRX-500 and DPX 400 spectrometer at 400 or 500 MHz for 1 H NMR, 100 or 126 MHz for 13 C NMR and 376 MHz for 19 F NMR in CDCl3, Acetone-d6 with tetramethylsilane (TMS) as internal standard. The chemical shifts are expressed in ppm and coupling constants are given in Hz. Data for 1 H NMR are recorded as follows: chemical shift (ppm), multiplicity (s, singlet; d, doublet; t, triplet; q, quarter; p, pentet, m, multiplet; br, broad), coupling constant (Hz), integration. Data for 13 C NMR are reported in terms of chemical shift (δ, ppm). Mass spectrometric data were obtained using Bruker Apex IV RTMS. Enantiomeric excess (ee) was determined using Agilent high-performance liquid chromatography (HPLC) with a Hatachi detector (λ = 254, 242, 230 or 214 nm). Column conditions are reported in the experimental section below. Absolute configuration of a product was determined by X-ray analysis.
General procedure for the synthesis of substrates: Substrates 1 with N-aryl urea groups was synthesized according to the procedures previously reported. 1 1 1

Procedure for synthetic application:
Synthesis of 7: Sodium borohydride (9.5 mg, 0.25 mmol) was added to a solution of 4A (27.6 mg, 0.05 mmol) in THF (2 mL) in a sealed flask. The resulting mixture was stirred at 60 o C for 15 min. Methanol (2 mL) was then added by syringe and stirring was maintained for a further period of 15 min at the same temperature. After that, the solvent was removed in vacuo, and the residue was purified by a silica gel column chromatography (eluent: petroleum ether/EtOAc = 8/1) to give 7 (24.9 mg, 95%). After stirring at −78 °C for 1 h, the reaction mixture was allowed to warm to room temperature over a period of 11 h, quenched with saturated NH4Cl solution and stirred for 15 min. The mixture was extracted three times with ethyl acetate, dried over Na2SO4, and concentrated in vacuo. The crude product was purified by flash column chromatography on S161 silica gel (eluent: EtOAc/MeOH = 20/1) to give 8 (12.1 mg, 90%). and THF (0.5 mL) under argon. The reaction mixture was refluxed for 12 h, then cooled to room temperature, quenched with CH3OH (0.5 mL) at 0 o C (carefully addition), and stirred for an additional 60 min. The solvent was removed in vacuo, and the residue was purified by a silica gel column chromatography (eluent: petroleum ether/EtOAc = 50/1) to afford 10 (5.4 mg, 43%).

b) Radical clock
Procedure for synthesis of substrate 11 According to the procedures previously reported 2 , styrene (5.2 g, 50.0 mmol), CHBr3 (50.5 g, 200.0 mmol) and triethylbenzylammonium chloride (TEBA, 1.1 g, 5.0 mmol) were added to a 250 mL flask under nitrogen atmosphere. A solution of sodium hydroxide (6.0 g in 6.0 mL of H2O) was added dropwise to the mixture at 0 o C. After addition, the reaction mixture was stirred for 2 hours at 60 °C. The resulting mixture was diluted by 50 mL of water and extracted with dichloromethane (3 × 50 mL). The combined organic layers were washed with brine, and dried with anhydrous Na2SO4.

S165
The solvent was removed in vacuo, and distillation (120 o C (12 mmHg)) of the residue afforded (2,2-dibromocyclopropyl)benzene (s-1) (11.5 g, 83%) as a colorless liquid. According to the procedures previously reported, 3 to a solution of s-1 (2.75 g, 10.0 mmol) and titanium isopropoxide (0.14 g, 0.5 mmol) in dry THF (50 mL), ethylmagnesium bromide (5.4 mL, 2.4 M in 2-Methyltetrahydrofuran, 13.0 mmol) was slowly added by syringe at 0 o C. The reaction mixture was stirred at 0 °C for 20 min and then at room temperature for 20 min. Then the reaction was quenched by saturated NH4Cl solution (10 mL), and extracted with EtOAc (3 × 30 mL). The combined organic layers were brined, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by a silica gel chromatography (eluent: petroleum ether) to afford the desired product s-2 (0.89 g, 45%). To a solution of s-2 (1.97 g, 10.0 mmol) in dry Et2O (20 mL) was added t-BuLi (17.0 mL, 1.3 M in n-pentane, 22.0 mmol) at -78 o C. The reaction mixture was stirred at -78 o C for 30 min. 2,2-Dimethyl-4-oxobutanenitrile (1.11 g, 10.0 mmol) in dry Et2O (5 mL) was slowly added, and the reaction mixture was stirred for 2 h. Saturated NH4Cl solution was added and the solution was extracted with EtOAc (3 × 20 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford the crude product s-3. To a stirred suspension of Dess-Martin periodinane (5.09 g, 12.0 mmol) and NaHCO3 (1.00 g, 12.0 mmol) in CH2Cl2 (40 mL) was added a solution of s-3 in CH2Cl2 (10 mL) at 0 o C. The reaction mixture was stirred at room temperature for 2 h. The resulting solution was washed with saturated aqueous NaHCO3 (2 × 30 mL) and saturated aqueous NaS2O3 (2 × 30 mL), dried over anhydrous Na2SO4, and concentrated in vacuo to afford crude product, which was purified by a silica gel chromatography (eluent: petroleum ether/EtOAc = 10/1-4/1) to afford s-4 (0.52 g, 23% over two steps). Sodium bis(trimethylsilyl)amide (2.6 mL, 2.0 M in THF) was added to a solution of methyltriphenylphosphonium bromide (1.86 g, 5.2 mmol) in dry THF (10 mL) at 0 ºC. After stirring for 30 min, a solution of s-4 (0.91 g, 4 mmol) in THF (5 mL) was added and the reaction mixture was gradually warmed up to room temperature and stirred for an additional 8 h. The mixture was filtered through silica-pad (Et2O was used as an eluent). The eluate was concentrated in vacuo then purified by a silica gel chromatography (eluent: petroleum ether/EtOAc = 40/1-20/1) to afford s-5 (0.78 g, 87%). To a suspension of LiAlH4 (228 mg, 6.0 mmol) in Et2O (5 mL) at 0 °C was slowly added a solution of s-5 (676 mg, 3.0 mmol) in Et2O (3.0 mL), then the mixture was warmed to room temperature, stirred for an additional 2 h. The reaction mixture was quenched by slow, sequential addition of water (0.1 mL) in Na2SO4 (1.0 g) at 0 °C. The reaction mixture was warmed to room temperature, stirred for an additional 30 min, filtered and concentrated in vacuo to afford s-6, which was used in the next reaction without further purification. 1-Isocyanato-3-(trifluoromethyl)benzene (2.0 mmol) was slowly added to a stirred solution of s-6 (2.0 mmol) and ethyldiisopropylamine (iPr2NEt, 2.0 mmol) in dry CH2Cl2 (5.0 mL) at 0 o C. The reaction mixture was stirred for an additional 30 min at S166 0 o C. After complete conversion (monitored by TLC), the crude mixture was directly purified by silica gel column chromatography (eluent: petroleum ether/CH2Cl2 = 100:1-1:5, using petroleum ether (100%) to remove CH2Cl2 and iPr2NEt at first) to give urea substrate 11.