Visible‐Light‐Mediated Decarboxylative Radical Additions to Vinyl Boronic Esters: Rapid Access to γ‐Amino Boronic Esters

Abstract The synthesis of alkyl boronic esters by direct decarboxylative radical addition of carboxylic acids to vinyl boronic esters is described. The reaction proceeds under mild photoredox catalysis and involves an unprecedented single‐electron reduction of an α‐boryl radical intermediate to the corresponding anion. The reaction is amenable to a diverse range of substrates, including α‐amino, α‐oxy, and alkyl carboxylic acids, thus providing a novel method to rapidly access boron‐containing molecules of potential biological importance.


Reaction Setup
The Kessil lamps were positioned 5 cm from the reaction vial. When 1 × lamp was used, a mirror was placed beneath the vial at an angle of 45º (see diagram A below). When 2 × lamps were used, the lamps were positioned on opposite sides of the reaction vial, each at a distance of 5 cm (see diagram B below).
Diagram A Diagram B

General Procedures
General Procedure A [For use with fully protected α-amino acids (Table 2, Conditions A and   Table 3)]: To a 7 mL vial equipped with a stir bar was added the amino acid (1.0 equiv.), Ir(ppy)2(dtbbpy)PF6 (1.0 mol%) and Cs2CO3 (1.1 equiv.). DMF (0.10 M) was then added followed by vinyl boronic ester pinacol ester (1.5 equiv.). The vial was sealed with a suba-seal and the reaction mixture degassed by sparging with nitrogen for 10 minutes. The nitrogen inlet was removed and the vial further sealed with parafilm. The reaction mixture was stirred at 800 rpm and irradiated with 40 W blue Kessil LED lamps for between 30 and 62 h. The reaction mixture was diluted with water (20 mL) and extracted into ethyl acetate (3 × 20 ml). The organic phase was washed with water (20 mL), brine (20 mL), dried (Na2SO4) and filtered before removal of the solvent in vacuo. The crude product was then purified by normal-phase flash column chromatography.
General Procedure B [For use with α-amino acids possessing free N-H groups (Table 2, Conditions B), and α-oxy acids (Table 4)]: To a 7 mL vial equipped with a stir bar was added the amino acid (1.0 equiv.), Ir[dF(CF3)ppy]2(dtbbpy)PF6 (2.0 mol%) and Cs2CO3 (1.0 equiv.). Anhydrous DMA (0.05 M or 0.10 M) was then added followed by vinyl boronic ester pinacol ester (1.5 equiv.). The vial was sealed with a suba-seal and the reaction mixture degassed by sparging with nitrogen for 10 minutes. The nitrogen inlet was removed and the vial further sealed with parafilm. The reaction mixture was stirred at 800 rpm and irradiated with 40 W blue Kessil LED lamps for between 30 and 62 h. The reaction mixture was diluted with water (20 mL) and extracted into ethyl acetate (3 × 20 ml). The organic phase was washed with water (20 mL), brine (20 mL), dried (Na2SO4) and filtered before removal of the solvent in vacuo. The crude product was then purified by normal-phase flash column chromatography.

Scheme S1: Generation of S2 by protodeboronation of 30
Studies to determine the origin of this protodeboronation process revealed that the protodeboronation likely occurred after initial formation of 30. Subjecting S3 to the photochemical conditions in the absence of 1 and with only 0.5 equivalents of S1 (to mimic the reaction conditions at full conversion) resulted in the formation of >99% of ethylbenzene (Scheme S2). The formation of ethylbenzene from S3 suggests that protodeboronation to generate S2 occurs after initial formation of the desired product 30. Furthermore, the observation that styrene was not formed under the reaction conditions disfavours the possibility of protodeboronation of S1 followed by reaction of 1 with styrene. 9 Scheme S2: Studies to determine the origin of protodeboronation product S2. Yields determined by GC using 1,2,4-trimethoxybenzene as an internal standard The mechanism of the protodeboronation reaction is believed to proceed through a radical mechanism. Recent work by Ley and co-workers has shown that benzylic pinacol boronic esters, in the presence of a Lewis base to generate the corresponding boronate complex, undergo single electron oxidation under photoredox catalysis to cleave the C-B bond. 10 The resulting benzylic radical can then be trapped by an appropriate acceptor.

Scheme S4: Deuterium incorporation studies with preformed cesium salt 51
Boc-Pro-OCs (51) was prepared by the slow addition of MeOH/H2O (2:1, 5.4 mL) to a mixture of Boc-Pro-OH (1)  The deuterium incorporation study was carried out as follows: In a N2-filled glovebox, Boc-Pro-OCs (51) (43 mg, 0.12 mmol) and Ir(ppy)2(dtbbpy)PF6 (1.1 mg, 0.0012 mmol, 1.0 mol%) were added to a dry 7 mL vial. The vial was sealed with a septum and removed from the glovebox before the sequential addition of anhydrous DMF (2.5 mL), vinyl boronic acid pinacol ester (32 µL, 0.19 mmol, 1.5 equiv.) and D2O (2.2 µL, 0.12 mmol, 1.0 equiv.). The reaction mixture degassed by sparging with nitrogen for 10 minutes. The nitrogen inlet was removed and the vial further sealed with parafilm. The reaction mixture was stirred at 800 rpm and irradiated with 1 × Kessil lamps for 20 h. D2O (1.0 mL) was added and the mixture stirred for 5 min. The reaction mixture was diluted with water (10 mL) and extracted into ethyl acetate (3 × 10 mL). The organic phase was washed with water (10 mL), brine (10 mL), dried (Na2SO4) and filtered before removal of the solvent in vacuo. Purification by flash column chromatography (10% EtOAc/pentane) gave the product 3 (12 mg, 0.037 mmol, 31%) as a colourless oil. The product was formed with 58% D-incorporation α to the boronic ester group, While the incorporation of deuterium into the product of the reaction shown in Scheme S4 confirms the formation of an intermediate α-boryl anion (50, Scheme 2), the lack of complete deuteration raises the possibility that alternative mechanisms may also be operating. The 42% the DMF, D2O, or the hydroscopic cesium salt 51) or via a hydrogen-atom-transfer process between the intermediate α-boryl radical (49, Scheme 2) and the solvent DMF. To investigate this further, the reaction between Boc-Pro-OH (1) and vinyl boronic ester 2 was performed in DMF-d7 (Scheme S5). The product 3 was formed in 63% yield without any observed deuterium incorporation, suggesting that the protonated product formed in Scheme S4 arises from H2O contamination.
Scheme S6: Reduction of iodide S5 to anion S7 via radical S6 Samples were prepared with 0.025 mmol of S5 in 4 mL of 5 mM tetra-n-butylammonium hexafluorophosphate in dry, degassed MeCN. A glassy carbon working electrode, platinum wire counter electrode, silver wire reference electrode were used. A scan rate over a range between 50 -200 mV s -1 was used and an average reduction potential was taken. The obtained value was referenced to Fc/Fc + and converted to SCE by adding 0.38 V.