Visible light photoredox-catalyzed deoxygenation of alcohols

Summary Carbon–oxygen single bonds are ubiquitous in natural products whereas efficient methods for their reductive defunctionalization are rare. In this work an environmentally benign protocol for the activation of carbon–oxygen single bonds of alcohols towards a reductive bond cleavage under visible light photocatalysis was developed. Alcohols were activated as 3,5-bis(trifluoromethyl)-substituted benzoates and irradiation with blue light in the presence of [Ir(ppy)2(dtb-bpy)](PF6) as visible light photocatalyst and Hünig’s base as sacrificial electron donor in an acetonitrile/water mixture generally gave good to excellent yields of the desired defunctionalized compounds. Functional group tolerance is high but the protocol developed is limited to benzylic, α-carbonyl, and α-cyanoalcohols; with other alcohols a slow partial C–F bond reduction in the 3,5-bis(trifluoromethyl)benzoate moiety occurs.


General procedure for the synthesis of benzoate esters via the acid chloride (GPI)
A 50 mL Schlenk flask equipped with a magnetic stir bar was charged with an alcohol (5.00 mmol, 1.00 equiv.), 4-DMAP (31 mg, 0.25 mmol, 0.05 equiv.), Et 3 N (5.0 ml, 3.5 g, 35 mmol, 7.0 equiv.), and DCM (50 mL). The mixture was cooled to 0 °C, then (trifluoromethyl)benzoyl chloride 45 (5.50 mmol, 1.10 equiv.) was added dropwise. The reaction mixture was allowed to warm to room temperature, solvent was evaporated under reduced pressure and the residue was purified by flash chromatography.

Synthesis of 3,5-bis(trifluoromethyl)benzoic anhydride 3,5-Bis(trifluoromethyl)benzoic anhydride (9):
A 50 mL three-neck round-bottom flask was equipped with a gas inlet, a dropping funnel, and a 20 cm Vigreux column with a Claisen bridge and a 10 mL round-bottom flask. The flask was charged with 3,5-bis(trifluoromethyl)benzoic acid (12.0 g, 46.5 mmol, 1.00 equiv.) and phosphoric acid (20 mg, 0.20 mmol, 0.43 mol%) and the dropping funnel was charged with acetic anhydride (8.8 mL, 9.5 g, 93 mmol, 2.0 equiv.). The flask was heated to 150 °C in an oil bath and about 6.5 mL of acetic anhydride was added via the dropping funnel. The mixture was slowly heated to 190 °C till no more acetic anhydride distilled. About half of the remaining acetic anhydride was added to the reaction mixture via the dropping funnel and the mixture was stirred till no more acetic anhydride distilled. The remainder of acetic anhydride was added and again till no more acetic anhydride distilled. Vaccum (20 mbar) was applied and distillation was continued at 190 °C till no more distillate could be collected.
The reaction mixture was allowed to cool to 100 °C after which the Vigreux column and the Claisen bridge were replaced with a distillation arch. The crude product was subsequently distilled at 170 °C / 1 mbar into a 50 mL Schlenk flask. Pure product was obtained after recrystallization from toluene / petrol ether as white crystals (9.07 g, 18.2 mmol, 78%

General procedure for the synthesis of benzoate esters via the acid anhydride (GPII)
A 50 mL Schlenk flask equipped with a magnetic stir bar was charged with an alcohol (2.00 mmol, 1.00 equiv.), 3,5-bis(trifluoromethyl)benzoic anhydride (9, 1.20 g, 2.40 mmol, 1.20 equiv.), Et 3 N (0.56 ml, 0.41 g, 4.0 mmol, 2.0 equiv.), and DCM (20 mL). The mixture was stirred at room temperature for 2 h. The solvent was evaporated under reduced pressure and the residue was redissolved in 20 mL EtOAc and extracted with 20 mL Na 2 CO 3 (aq, 10%) and 20 mL H 2 O. The united aqueous phases were acidified with 6 M HCl to give 3,5bis(trifluoromethyl)benzoic acid (5) as a white solid which was filtered and dried in vacuo.
The organic phase was evaporated and purified by flash chromatography.

Selective synthesis of monoacylated tartrate 6e
The preparation of mono-benzoate 6e was not straight-forward (Table 1). Reaction of (+)-DET (8) with 1.05 equiv. of 3,5-bis(trifluoromethyl)benzoic acid chloride gave only 5% of mono-benzoate 6 alongside with 45% of bis-benzoate 9 (entry 1). Modification of the reaction temperature gave almost identical results (entry 2 -4). Omission of DMAP on the other hand and performance of the reaction at -78 °C was found to give a high ratio of monobenzoylation over bis-benzoylation (entry 5 to 8).  Despite the efforts to increase the amount of mono-benzoylation product 6e the selectivity remained low with the acid chloride as acylation agent. Using 3,5-bis(trifluoromethyl)benzoic acid anhydride (9) in the presence of a Lewis acid catalyst largely increased the selectivity of S16 the benzoylation in favor of 6e (Table 2). Without Lewis acid additive the reaction already favors mono-benzoylation product 6e (entry 1). YbCl 3 increases the reaction speed as well as the selectivity (entry 2). While several other Lewis acids even slow down the reaction (entry 3 to 7), CuCl 2 again leads to high selectivity and even higher conversions (entry 8) compared to YbCl 3 . Lowering the amount of YbCl 3 leads to longer reaction times, slightly higher conversion rates, and diminished selectivity (entry 9 and 10) while in contrast lowering the amount of CuCl 2 leads to decreased conversions but increased selectivities (entry 11).
The assumption that at lower conversions the selectivity is higher is self-evidentnevertheless the conversion reaches its final point at the time indicated and no further rise was observed after prolonged times. Due to the considerably lower cost of CuCl 2 in comparison to YbCl 3 , CuCl 2 was ultimately used for a reaction in a larger scale (entry 12).
Surprisingly the large scale reaction took much longer than the reaction on small scale to  week and refluxed for another week. The reaction mixture was transferred to a separation funnel with 150 mL EtOAc, washed twice with 50 mL 10% Na 2 CO 3 (aq.), 50 mL water, and 50 mL brine. The combined aqueous phased were boiled up, cooled back to room temperature and acidified with conc. HCl (aq.) upon which the white precipitate was filtered and washed with 50 mL water to give 1.31 g (5.08 mmol, 67% based on benzoate that was employed and not incorporated in the product) 3,5-bis(trifluoromethyl)benzoic acid. The organic phases were dried over Na 2 SO 4 , evaporated and the resulting solid was purified on SiO 2 (petrol ether / EtOAc, 6:1 to 2:1) to give 2.07 g (4.63 mmol, 76.5%) (2R,3R)-diethyl 2-