Nucleophilic trifluoromethoxylation of alkyl halides without silver

The biological properties of molecules containing the trifluoromethoxy group have made these compounds important targets in pharmaceuticals and agrochemicals, yet their preparation is still a substantial challenge. Herein, we present a practical nucleophilic trifluoromethoxylation of alkyl halides with (E)-O-trifluoromethyl-benzaldoximes (TFBO) as a trifluoromethoxylation reagent in the absence of silver under mild reaction conditions. The trifluoromethoxylation reagent TFBO is easily prepared and thermally stable, and can release CF3O− species in the presence of a base. Furthermore, broad scope and good functional group compatibility are demonstrated by application of the method to the late-stage trifluoromethoxylation of alkyl halides in complex small molecules.

DMA, HMPA, MeCN and DCM etc. used in reactions were dried according to the purification handbook Purification of Laboratory Chemicals before using. H 2 O was distilled. Cs 2 CO 3 was purchased from J&K. CF 3 SO 2 Na and PhI(OAc) 2 were purchased from Bidepharm. TLC was performed on silica gel Huanghai HSGF254 plates and visualized by quenching of UV fluorescence (λ max = 254 nm). 200-300 mesh silica gel was purchased from Qingdao Haiyang Chemical Co., China. Unless otherwise noted, all other reagents and starting materials were purchased from commercial sources and used without further purification. The data for NMR spectra ( 1 H NMR, 13 C NMR and 19 F NMR) were recorded at 293 K on a Bruker AVANCE AV 400 (400MHz, 101MHz and 376MHz) and chemical shifts were recorded relative to the solvent resonance. Signal positions were recorded in ppm and the following abbreviations were used singularly or in combination to indicate the multiplicity of signals: s singlet, d doublet, t triplet, q quartet, m multiplet, Hz Hertz. For 1 H NMR: CDCl 3 = δ 7.26 ppm, DMSO = δ 2.50 ppm. For 13 C NMR: CDCl 3 = δ 77.16 ppm, DMSO = δ 39.52 ppm. Mass spectra were obtained on Agilent 6520 Q-TOF LC/MS and Aligent 7890/5975C-GS/MSD. HRMS were obtained on Varian 7.0T FTMS.

Supplementary Note:
The Trifluoromethoxylating reaction is sensitive to water, but is not sensitive to oxygen， which can be operated outside the glove box. And the yield was influenced by the sizes of sealed vial tube.
Please be careful of the fluorophosgene which is formed through the decomposition of trifluoromethoxy anio
The crude 5-chloropentyl 4-formylbenzoate (1.24 g, 4.87 mmol, 1.00 equiv.) was dissolved with acetone (8.0 mL), sodium iodide (2.19 g, 14.6 mmol, 3.00 equiv.) was added at room temperature. Subsequently, the reaction flask was wrapped in aluminum foil and refluxed at 75 °C for 24 h. Afterwards the solvent was removed in reduced pressure. The solid was dissolved in EtOAc and washed successively with water 2 times and a saturated solution of sodium chloride. The organic phase was dried over anhydrous MgSO 4 , filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel, eluting with n-hexane/EtOAc 12:1 (v/v) to afford 1.42 g 5-iodopentyl 4-formylbenzoate (S14) as a yellowish oil (84% yield).
The crude 5-chloropentyl 4-ethynylbenzoate (307 mg, 1.22 mmol, 1.00 equiv.) was dissolved with acetone (2.5 mL), sodium iodide (551 mg, 3.67 mmol, 3.00 equiv.) was added at room temperature. Subsequently, the reaction flask was wrapped in aluminum foil and refluxed at 75 °C for 24 h. Afterwards the solvent was removed in reduced pressure. The solid was dissolved in EtOAc and washed successively with water 2 times and a saturated solution of sodium chloride. The organic phase was dried over anhydrous MgSO 4 , filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel, eluting with n-hexane/EtOAc 15:1 (v/v) to afford 296 mg 5-iodopentyl 4-ethynylbenzoate (S15) as a white solid (71% yield).
The crude 5-chloropentyl picolinate (1.45 g, 6.35 mmol, 1.00 equiv.) was dissolved with acetone (10.0 mL), sodium iodide (2.86 g, 19.0 mmol, 3.00 equiv.) was added at room temperature. Subsequently, the reaction flask was wrapped in aluminum foil and refluxed at 75 °C for 24 h. Afterwards the solvent was removed in reduced pressure. The solid was dissolved in EtOAc (50.0 mL) and washed successively with water (30.0 mL) 2 times and a saturated solution of sodium chloride (30.0 mL). The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel, eluting with n-hexane/EtOAc 4:1 (v/v) to afford 732 mg 5-iodopentyl picolinate (S17) as a yellowish oil (46% yield).

1-Methyl-3-(3-iodopropyl)-1H-indole (S23)
To a solution of 3-indolepropionic acid (0.500 g, 2.64 mmol, 1.00 equiv.) in anhydrous DMF (5.00 mL) at 0 °C was added NaH (0.360 g, 7.93 mmol, 3.00 equiv.). After the addition, the mixture was allowed to stir for 10 mins and MeI (1.21 g, 7.93 mmol, 3.00 equiv.) was added. The reaction mixture was allowed to stir at room temperature for 1 h before the addition of 10.0 mL of ice water and 10.0 ml of EtOAc. After extraction with EtOAc (10.0 mL×2), the organic phase was dried over MgSO 4 , filtered and concentrated under reduced pressure to give a yellow oil (0.610 g). The crude product was used in the next step without further purification.
To a flask containing a stirring solution of the crude product (0.610 mg, 2.90 mmol, 1.00 equiv.) in dry THF (5.00 mL) was added LiAlH 4 (0.380 g, 10.0 mmol, 3.50 equiv.) at 0 °C. After 1 h, the reaction was quenched with 10.0 ml ice water, the reaction mixture was extracted with EtOAc (10.0 mL×2), the organic phase was dried over MgSO 4 , filtered and concentrated under reduced pressure to give a brown oil (0.410 g), The crude product was used in the next step without further purification.
In a round bottom flask, the brown crude product (0.210 g, 0.980 mmol, 1.00 equiv.), Ph 3 P (0.310 g, 1.18 mmol, 1.20 equiv.) and imidazole (86.0 mg, 1.18 mmol, 1.20 equiv.) were dissolved in THF (5.00 mL), and the reaction was stirred for 10 mins at room temperature before the addition of iodine (0.310 g, 1.18 mmol, 1.20 equiv.). The reaction was stirred at room temperature for 1 h, then filtered and concentrated under reduced pressure. The residue was purified by preparative TLC, eluting with n-hexane/EtOAc 20:
The reaction was quenched by the addition of a saturated solution of sodium thiosulfate and extracted three times with EtOAc (20.0 mL). The combined organic layer was washed with brine, dried over anhydrous MgSO 4 , filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel, eluting with n-hexane/EtOAc 20:1 (v/v) to afford N-Boc-3-(2-iodoethyl)azetidine (S25) as a colorless liquid (68% yield).

nesulfonamide (S40)
To a solution of celecoxib (0.510 g, 1.31 mmol, 1.00 equiv.) and K 2 CO 3 (0.970 g, 6.60 mmol, 5.00 equiv.) in anhydrous acetone (10.0 mL) at 0 °C was added MeI (0.960 g, 6.60 mmol, 5.00 equiv.). After the addition, the mixture was allowed to stir overnight at room temperature. The reaction mixture was concentrated in vacuo before the addition of 10.0 mL of water. After extraction with EtOAc (10.0 mL×2), the organic phase was dried over MgSO 4 , filtered and concentrated under reduced pressure to give a yellow solid (0.540 g). The crude product of celecoxib derivative was used in the next step without further purification.

Mycophenolic acid iodination derivative (S41)
To a solution of mycophenolic acid (500 mg, 1.56 mmol, 1.00 equiv.) and MeI (0.583 mL, 9.37 mmol, 6.00 equiv.) in acetone (10.0 mL) was added K 2 CO 3 (1.51 g, 1.09 mmol, 7.00 equiv.). Subsequently, the reaction mixture was warmed to reflux for 5 h. Afterwards the reaction mixture was concentrated in vacuo and the residue was dissolved in EtOAc. The organic phase was washed with water, dried over sodium sulphate, filtered and concentrated in vacuo. The residue and LiOH (224 mg, 9.36 mmol, 6.00 equiv.) were suspended in a mixture of H 2 O and THF (1:4, 20.0 mL) and stirred at 30 °C for 12 h. The solution was acidified with aqueous HCl (1 M). The mixture was extracted with EtOAc (80.0 mL×3), the combined organic layer was washed with brine and dried (MgSO 4 ), and the solvents were evaporated.
The crude product of the last step, ClCO 2 CH 2 CH(Me) 2 (634 mg, 4.68 mmol, 3.00 equiv.), Et 3 N (474 mg, 4.68 mmol, 3.00 equiv.) were dissolved in THF (10.0 mL), and the reaction was stirred at 0 °C. After 2 hours, the reaction was concentrated in vacuo. The intermediate was loaded into a round bottom flask, and dissolved in EtOH (10.0 mL). Sodium borohydride (354 mg, 9.36 mmol, 6.00 equiv.) was added and the reaction was stirred at 0 °C for 2 h. The reaction was quenched with water and saturated aqueous ammonium chloride, and the combined aqueous layers were extracted three times with EtOAc. The combined organic layer was washed with bring, dried over anhydrous MgSO 4 , filtered, and concentrated in vacuo. The residue was purified by chromatography on silica gel, eluting with n-hexane/EtOAc 2:1 (v/v) to afford 289 mg Mycophenolic acid deoxidized derivative (S41-1) as a colorless liquid (58% yield). Mycophenolic acid deoxidized derivative (S41-1) (289 mg, 0.902 mmol, 1.00 equiv.) was dissolved with dry THF (5.00 mL), to which was added sequentially PPh 3 (284 mg, 1.08 mmol, 1.20 equiv.), imidazole (79.8 mg, 1.17 mmol, 1.30 equiv.) and iodine (275 mg, 1.08 mmol, 1.20 equiv.) in three portions. The reaction was stirred 1 h at room temperature. The reaction was quenched by the addition of a saturated solution of sodium thiosulfate and extracted three times with EtOAc (20.0 mL). The combined organic layer was washed with brine, dried over anhydrous MgSO 4 , filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel, eluting with n-hexane/EtOAc 10:1 (v/v) to afford 320 mg Mycophenolic acid iodination derivative (S41) as a colorless liquid (82% yield).  13
A stirred solution of acetylcyclosporin A (S48-1) in CH 2 Cl 2 (120 mL) cooled to -78 °C was saturated with ozone. After 30 mins, MeOH (60.0 mL) and excess sodium borohydride (900 mg) were added, and the reaction was allowed to warm to room temperature. Additional sodium borohydride (900 mg, excess) was added at room temperature. After 2 hours, the reaction was quenched with sat. aq. NH 4 Cl (20.0 mL), and water (100 mL) was added. Organic solvents were removed by rotary evaporation and the crude product was extracted with EtOAc (50.0 mL×5 ). The combined organic extracts were dried (MgSO 4 ), filtered through a pad of silica gel and concentrated in vacuo to give 778 mg crude product (S48-2). The crude product was used without further purification. 5 To a solution of the crude S48-2 (778 mg, 630 mmol, 1.00 equiv.), DMAP (4-dimethylaminepyridine) (308 mg, 2.52 mmol, 4.00 equiv.) and EDCI (N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride) (483 mg, 2.52 mmol, 4.00 equiv.) in dry CH 2 Cl 2 (10.0 mL) at room temperature under N 2 were added 5-Bromovaleric acid (456 mg, 2.52 mmol, 4.00 equiv.). The reaction was stirred at room temperature for 12 h before diluted with CH 2 Cl 2 (20.0 mL) and quenched with H 2 O (20.0 mL). The aqueous layer was separated and extracted times with CH 2 Cl 2 (50.0 mL × 3). The combined organic layer was dried over anhydrous MgSO 4 , filtered through a pad of silica gel and concentrated in vacuo to give crude product (S48-3). The crude product was used for next step directly.
The crude S48-3 was dissolved with acetone (2.0 mL), sodium iodide (250 mg) was added at room temperature. Subsequently, the reaction flask was wrapped in aluminum foil and refluxed at 75 °C for 4 h. Afterwards the solvent was removed in reduced pressure. The solid was dissolved in EtOAc and washed successively with water 2 times and a saturated solution of sodium chloride. The organic phase was dried over anhydrous MgSO 4 , filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel, eluting with CH 2 Cl 2 /CH 3 OH 60:1 (v/v) to afford 440 mg 5-iodopentyl 4-ethynylbenzoate (S48) as a white solid (30% yield).

Comparision of TFBO with TFMT Supplementary
In a 2.00 mL sealed vial, equipped with a rubber septum and a magnetic stirrer, silver fluoride (42.3 mg, 0.333 mmol, 1.00 equiv.) was introduced. In a N 2 glovebox, anhydrous CH 3 CN (0.670 mL) were added and the heterogenous mixture was cooled to -30 °C , TFMT (0.100 mL) was then added, the vessel was tightly closed (autogenous pressure of COF 2 is needed to allow the reaction to proceed) and the reaction mixture was stirred for 2 h at -30 °C . After addition of the substrate (neat when liquid or dissolved in the minimum of CH 3 CN when solid) by the mean of a gas-tight syringe, stirring was continued at -30 °C for 30 mins then at RT for 24 h (in the dark). The yield was determined by comparing the integration of the 19 F NMR resonance of product with that of benzotrifluoride (-62.8 ppm).
The method of "nBu 4 NOCF 3 ": In a 2.00 mL sealed vial, equipped with a rubber septum and a magnetic stirrer, silver fluoride (42.3 mg, 0.333 mmol, 1.00 equiv.) and TBAI (123 mg, 0.333 mmol, 1.00 equiv.) was introduced. In a N 2 glovebox, anhydrous CH 3 CN (0.670 mL) were added and the heterogenous mixture was cooled to -30 °C , TFMT (0.100 mL) was then added, the vessel was tightly closed (autogenous pressure of COF 2 is needed to allow the reaction to proceed) and the reaction mixture was stirred for 2 h at -30 °C . After addition of the substrate (neat when liquid or dissolved in the minimum of CH 3 CN when solid) by the mean of a gas-tight syringe, stirring was continued at -30 °C for 30 mins then at RT for 24 h (in the dark). The yield was determined by comparing the integration of the 19 F NMR resonance of product with that of benzotrifluoride (-62.8 ppm).