Ligand-controlled cobalt-catalyzed regiodivergent hydroboration of aryl,alkyl-disubstituted internal allenes

We report a stereoselective regiodivergent hydroboration of aryl,alkyl-disubstituted internal allenes with pinacolborane (HBpin) in the presence of cobalt catalysts generated from bench-stable Co(acac)2 and bisphosphine ligands. An interesting correlation between the regioselectivity of this hydroboration and the bite angles of bisphosphine ligands was identified. When hydroboration was conducted with cobalt catalysts containing bisphosphines with medium bite angles (e.g. 98° for dppb and 96° for dppf), HBpin was selectively added to the alkyl-substituted double bond. However, HBpin was selectively added to the aryl-substituted double bond when the reactions were conducted with cobalt catalysts containing bisphosphines with large bite angles (e.g. 111° for xantphos and 114° for Nixantphos). A range of internal allenes underwent these Co-catalyzed hydroboration reactions in a regiodivergent manner to yield the corresponding (Z)-alkenylboronates in high isolated yields and with high regioselectivity. These reactions show good functional group compatibility and can be readily scaled up to gram scales without using a dry box. In addition, the comparison of regioselectivity between the Co-catalyzed hydrosilylation and hydroboration reactions of the same allene substrate suggests that this Co-catalyzed regiodivergent hydroboration of allenes proceeds through a Co-Bpin intermediate. Deuterium-labeling experiments suggest that the Co-Bpin intermediates react with allenes to form allylcobalt species which then react with HBpin to release (Z)-alkenylboronate products.


III. General Procedure for the Co-catalyzed Hydroboration of Internal Allene with Co(acac)2/xantphos
In an Argon-filled glovebox, Co(acac)2 (3.1 mg, 12.0 µmol), xantphos (6.9 mg,12.0 µmol), allene (0.400 mmol), HBpin (56.3 mg, 0.44 mmol), and toluene (1 mL) were added to a 4-mL screw-capped vial containing a magnetic stirring bar. The vial was sealed with a cap containing a PTFE septum and removed from the dry box. The reaction mixture was stirred at room temperature for 12 h, and the crude product was purified by column chromatography on silica gel with a mixture of hexane and ethyl acetate as eluent. The conditions for flash chromatography and data for characterization of the (Z)-alkenylboronate products are listed below.

IV. Procedures for Gram-Scale Reaction
(A) Co(acac)2 (20.6 mg, 80.0 µmol) and dppf (44.4 mg, 80.0 µmol) weighed in air and added to a 50 mL round Schlenk flask containing a stirring bar. The air in the flask was replaced with N2 by a sequential vacuum and N2-refill thrice. Then degassed toluene (12 mL) were added and the mixture was stirred for 5 minutes. Allene 1m (1.19 g, 8.00 mmol) and HBpin (1.13 g, 8.80 mmol) were injected successively into the mixture using a syringe. The reaction mixture was stirred at room temperature for 12 h. The crude mixture was purified by column chromatography silica gel with a mixture of hexane and ethyl acetate (80:1), yielding the product 2m (1.81 g, 82%) as a colorless oil.
(B) Co(acac)2 (20.6 mg, 80.0 µmol) and xantphos (46.3 mg, 80.0 µmol) weighed in air and added to a 50 mL round Schlenk flask containing a stirring bar. The air in the flask was replaced with N2 by a sequential vacuum and N2-refill thrice. Then degassed toluene (12 mL) were added and the mixture was stirred for 5 minutes. Allene 1f (1.27 g, 8.00 mmol) and HBpin (1.13 g, 8.80 mmol) were injected successively into the mixture using a syringe. The reaction mixture was stirred at room temperature for 12 h. The crude mixture was purified by column chromatography silica gel with a mixture of hexane and ethyl acetate (80:1), yielding the product 3f (1.81 g, 82%) as a colorless oil.

Procedure of Suzuki-Miyaura Coupling 1
To a 25 mL Schlenk flask charged with a magnetic stirring bar, were added the (Z)-alkenylboronate 2k (115 mg, 0.400 mmol), PhI (122 mg, 0.600 mmol), Pd(P t Bu3)2 (10.2 mg, 20.0 µmol), 2 mL of dry THF, and 0.4 mL of NaOH (3M, 1.2 mmol) aqueous solution. The flask was sealed with a PTFE septum, and allowed to react at 70 °C for 24 h. The crude residue of the reaction was purified by column chromatography on silica gel with a mixture of hexane and ethyl acetate (80:1), yielding the product 4 (87.7 mg, 92%) as a colorless oil. 1

Procedure of Deborohydrogenation 2
To a solution of 2k (115 mg, 0.400 mmol) in HOAc (5 mL) was added KHF2 (93.7 mg, 1.200 mmol) under air, the reaction mixture was stirred at room temperature for 6 h. Then the reaction was quenched with saturated K2CO3 solution, and resulting mixture was extracted with diethyl ether. The combined organic layers were washed with brine, and dried over anhydrous sodium sulfate. The volatiles were removed under reduced pressure and the residue was purified by column chromatography on silica gel with a mixture of hexane and ethyl acetate (80:1), yielding the product 5 (54.5 mg, 84%) as a colourless oil. 1 H NMR (400 MHz, CDCl3) δ 7.32-7.26 (m, 2H), 6.96-6.91 (m, 2H), 6.39 (dt, J = 11.5, 1.9 Hz, 1H), 5.63 (dt, J = 11.6, 7. mL of solution of I2 (2M, 0.800 mmol) in THF was added into the reaction mixture, and the resulting mixture was stirred for another 1 h. The mixture was then quenched with saturated aqueous Na2S2O4 (5.0 mL) and extracted with diethyl ether for three times. The combined organic layers were washed with saturated aqueous NHCO3 solution and brine, then dried over Na2SO4. The volatiles were removed under reduced pressure and the residue was purified by column chromatography on silica gel with a mixture of hexane and ethyl acetate (80:1), yielding the product 6 (88.7mg, 77%) as a colorless oil. 1

Reactions with Other Boron Source
The reaction of 1a with HBcat is not as selective as the reaction with HBpin. Because alkenylBcat products are too unstable to isolate, we converted alkenylBcat to Bpin esters for the convenience of isolation. As these reactions proceed through a Co-Boryl intermediate, the boryl group on the cobalt catalyst does influence the regioselectivity for these allene hydroboration reactions. Overall, the regioselectivity of these reactions are controlled by the synergy among the allene substrate, ligand, and the boryl group on the cobalt catalyst.
The reaction of 1a with 9-BBN is even less selective and this might be due to the un-catalyzed background reactions of allene 1a with active 9-BBN.
The reaction mixture was stirred at room temperature for 12 h, and the crude product was purified by column chromatography on silica gel with a mixture of hexane and ethyl acetate (10:1) as eluent, yielding product 3q-d1 (132 mg, 86%) as a colorless oil.

IX. General procedure of the Preparation of Allene Substrates 4
To a solution of triphenylphosphine (3.28g, 12.50 mmol) in THF at -15 °C was added 5.5 mL of diethyl azodicarboxylate solution (DEAD, 2.2 M in toluene, 12.00 mmol) dropwise over 1 minute. The reaction mixture was stirred at -15 °C for additional 10 minutes, then propargyl alcohol solution (10.00 mmol in THF) was added dropwise over 10 min. After 5 minutes, 2-nitrobenxylsulfonylhydrazine (NBSH) in THF (2.33g, 12.50 mmol) was added into the reaction mixture. The reaction was stirred at -15 °C for 40 minutes and then allowed to warm to room temperature for 6.5 h. After that, the reaction was quenched with saturated aqueous solution of NH4Cl, and extracted with diethyl ether thrice. The combined organic layers were washed with saturated aqueous NaHCO3 solution and brine, then dried over Na2SO4. All the volatiles were removed under reduced pressure and the residue was purified by column chromatography on silica gel.