Visible-light photoredox-catalyzed umpolung carboxylation of carbonyl compounds with CO2

Photoredox-mediated umpolung strategy provides an alternative pattern for functionalization of carbonyl compounds. However, general approaches towards carboxylation of carbonyl compounds with CO2 remain scarce. Herein, we report a strategy for visible-light photoredox-catalyzed umpolung carboxylation of diverse carbonyl compounds with CO2 by using Lewis acidic chlorosilanes as activating/protecting groups. This strategy is general and practical to generate valuable α-hydroxycarboxylic acids. It works well for challenging alkyl aryl ketones and aryl aldehydes, as well as for α-ketoamides and α-ketoesters, the latter two of which have never been successfully applied in umpolung carboxylations with CO2 (to the best of our knowledge). This reaction features high selectivity, broad substrate scope, good functional group tolerance, mild reaction conditions and facile derivations of products to bioactive compounds, including oxypheonium, mepenzolate bromide, benactyzine, and tiotropium. Moreover, the formation of carbon radicals and carbanions as well as the key role of chlorosilanes are supported by control experiments.


2-(4-fluorophenyl)-2-hydroxy-2-phenylacetic (4f)
40. 1             Following general procedure for the carboxylation of alkyl aryl ketones, we observed a complicated mixture of products due to intense side reactions, including pinacol coupling and disproportionation, which might arise from the lower steric hindrance of aldehydes and the strong base.         The possibility of alcohol and silylether of alcohol as intermediate.

Figure S-7
Considering that the formation of carbanion could alternatively take a different mechanism: deprotonation of the reduced alcohol or silylether of alcohol. The 2a'' and 1C were performed in standard conditions, no desired -hydroxycarboxylic acids were detected, corresponding alcohols were remained along with little dehydroxycarboxylative products were detected. These results indicated this pathway was unlikely.  The control experiments without CO2, we found that the TON of formate was 4 using DMA as solvent. However, when using DMSO as solvent, no formate was detected by 1 H NMR. Moreover, no formate was detected in the absence of t BuOK. These results indicate that the formation of trace formate might arise from the use of DMA in the presence of t BuOK. The oven-dried Schlenk tube (10 mL) containing a stirring bar was charged with 1a and Ir(ppy)2(dtbbpy)PF6, then added t BuOK in glovebox. The tube was taken out, evacuated and backfilled with N2 for 3 times. Subsequently, i Pr2NEt, TMSCl and DMA was added via syringe under N2

C-Labeling Experiments
atmosphere. The resulting mixture was degassed by using a "freeze-pump-thaw" procedure and then injected 13 CO2 through controlling cylinder. Then The reaction was stirred in water bath and irradiated with a 30 W blue LED lamp (3 cm away, with cooling fan to keep the reaction temperature at 25~30 °C) for 12 h. After completion, 0.5 mL n Bu4NF (1.0 N in THF) was carefully added to quench the reaction, the mixture was allowed to stir for 30 min at room temperature. The reaction was quenched by 2 mL HCl (2 N), stirred for 10 min, and diluted with 2.5 mL EtOAc. The reaction mixture was extracted by EtOAc and the combined organic phases were concentrated in vacuo. The residue was purified by silica gel flash column chromatography to give the pure desired product in 37% yield. The 13C-content was determined to be 99% by HRMS (ESI-  150  160  170  180  190  200  210  220  230  240  250  260  270  280  290  300  310  320  330   The luminescence of Ir(ppy)2(dtbbpy)PF6 at max = 570 nm was readily quenched with i Pr2NEt with a slope of 266.4, while 1a and TMSCl just with a quenching slope of -2.3 and 51.2. These results suggested that the reaction proceed with reductive quenching to give reduced Ir II -catalyst.

Cyclic voltammetry test
Electrochemical studies were carried out with a CHI600E electrochemical workstation. All

The gram-scale reaction and synthetic application
The gram-scale synthesis of 6a

Synthesis of 11
To a stirred solution of 1-phenylethylene-

Synthesis of 13
The oven-dried Schlenk tube (10 mL) containing a stirring bar was charged with 2-cyclohexyl-2-hydroxy-2-phenylethanoic acid 2i (117 mg, 0.5 mmol), Na2CO3 (105 mg, 1 mmol), diethylamine (0.2 mL, 5 mmol) in DCE (2 mL) was heated at 80 C overnight. The reaction mixture was diluted with water, basified with 2 M NaOH to pH 12 and extracted with DCM. The solvent was removed under vacuum and the residue was purified by column chromatography to give the desired product 13 as a thick oil (141.7 mg, 85%).
The combined organic extracts were concentrated under vacuum. The residue was purified by column chromatography to give a white solid 15 (45.2 mg, 66% yield).