Enantiospecific Trifluoromethyl‐Radical‐Induced Three‐Component Coupling of Boronic Esters with Furans

Abstract In the presence of trifluoromethylsulfonium reagents, boronate complexes derived from 2‐lithio furan and non‐racemic secondary and tertiary alkyl or aryl boronic esters undergo deborylative three‐component coupling to give the corresponding 2,5‐disubstituted furans with excellent levels of enantiospecificity. The process proceeds via the reaction of boronate complexes with a trifluoromethyl radical, which triggers 1,2‐metallate rearrangement upon single‐electron oxidation. Alternative electrophiles can also be used in place of trifluoromethylsulfonium reagents to effect similar three‐component coupling reactions.


Reaction Optimization
To a stirred solution of furan (0. 40 M in THF,1.0 ml,0.40 mmol) under N2 at -78 °C was added nBuLi (1.6 M in hexane, 244 µL, 0.39 mmol) dropwise. The resulting solution was stirred for 1 h at r.t. (23 °C) before the addition of a solution of Cy-Bpin 1a (0.30 mmol) in THF (0.5 mL) at -78 °C. The reaction was stirred for 10 min at -78 °C before removing the solvent under vacuum. Solvent (2 mL) was added at 23 °C followed by trifluoromethylating reagent 9 (0.40 mmol). The solution was stirred at T °C for 1 h. PhCF3 (0.30 mmol) was added into this solution as an internal standard for 19 F NMR. A sample was removed and analysed by GC-MS.

General Procedures
To a stirred solution of furan (0.40 M in THF, 1.0 ml, 0.40 mmol) under N2 at -78 °C was added nBuLi (1.6 M in hexane, 244 µL, 0.390 mmol) dropwise. The resulting solution was stirred for 1 h at r.t. (23 °C) before the addition of a solution of boronic ester (0.30 mmol) in THF (0.5 mL) at -78 °C. The reaction was stirred for 10 min at -78 °C before removing the solvent under vacuum. MeOH (1 mL) and CH3CN (1 mL) were added at 23 °C followed by Umemoto reagent (161 mg, 0.400 mmol). The solution was stirred at r.t.
The resulting solution was stirred for 1 h at 23 °C before the addition of a solution of HCl (3 M in water, 1 mL) and stirring continued for a further 5 min. Water (10 mL) was added and the product extracted with Et2O (2 × 15 mL). The organic phases were washed with sat. aq. NaHCO3 then 20% aq. Na2S2O3, dried over MgSO4, filtered and concentrated in vacuo. The crude product purified by flash column chromatography on silica gel.
Note: The role of HCl prior to work up is to convert the methanol adduct, often observed after oxidation of the dihydrofuran intermediate, into the final product:

Trimethyl(4-(5-(trifluoromethyl)furan-2-yl)phenyl)silane (3u)
The title compound was synthesized with a modified General Procedure as shown below: To a stirred solution of (4-bromophenyl)trimethylsilane (92 mg, 0.40 mmol) in 1.5 mL THF at -78 °C under N2 was added nBuLi (1.6 M in hexane, 244 µL, 0.390 mmol) dropwise. The resulting solution was stirred for 0.5 h before the addition of a solution of furan-2-boronic acid pinacol ester 1u (58 mg, 0.30 mmol) in THF (0.5 mL) at -78 °C. The reaction was stirred for 10 min at -78 °C before removing the solvent under vacuum. MeOH (1 mL) and CH3CN (1 mL) were added at 23 °C followed by Umemoto reagent (161 mg, S24 0.400 mmol). The solution was stirred at 23 °C for 3 h before the sequential addition of K2CO3 (124 mg, 0.900 mmol) and I2 (102 mg, 0.400 mmol). The resulting solution was stirred for 1 h at 23 °C before the addition of a solution of HCl (3 M in water, 1 mL) and stirring continued for a further 5 min. Water (10 mL) was added and the product extracted with Et2O (2 × 15 mL). The organic phases were washed with sat. aq.
NaHCO3 then 20% aq. Na2S2O3, dried over MgSO4, filtered and concentrated in vacuo. The crude product purified by preparative TLC (petroleum ether) to afford the title compound as a colourless oil in 43% yield (37 mg).

2-(2-Methoxyphenyl)-5-(trifluoromethyl)furan (3v)
The title compound was synthesized with a modified General Procedure as shown below: To a stirred solution of 1-bromo-2-methoxybenzene (75 mg, 0.40 mmol) in 1.5 mL THF at -78 °C under N2 was added nBuLi (1.6 M in hexane, 244 µL, 0.390 mmol) dropwise. The resulting solution was stirred for 0.5 h before the addition of a solution of furan-2-boronic acid pinacol ester 1u (58 mg, 0.30 mmol) in THF (0.5 mL) at -78 °C. The reaction was stirred for 10 min at -78 °C before removing the solvent under vacuum. MeOH (1 mL) and CH3CN (1 mL) were added at 23 °C followed by Umemoto reagent (161 mg, 0.400 mmol). The solution was stirred at 23 °C for 3 h before the sequential addition of K2CO3 (124 mg, 0.900 mmol) and I2 (102 mg, 0.400 mmol). The resulting solution was stirred for 1 h at 23 °C before the addition of a solution of HCl (3 M in water, 1 mL) and stirring continued for a further 5 min. Water (10 mL)