Coordinating activation strategy for C(sp3)–H/C(sp3)–H cross-coupling to access β-aromatic α-amino acids

The past decade has witnessed significant advances in C–H bond functionalizations with the discovery of new mechanisms. Non-precious transition-metal-catalysed radical oxidative coupling for C(sp3)–H bond transformations is an appealing strategy for C–C bond formations. The radical oxidative C(sp3)–H/C(sp3)–H cross-coupling reactions of α-C(sp3)–H bonds of amines with free radicals represent a conceptual and practical challenge. We herein develop the coordinating activation strategy to illustrate the nickel-catalysed radical oxidative cross-coupling between C(sp3)–H bonds and (hetero)arylmethyl free radicals. The protocol can tolerate a rich variety of α-amino acids and (hetero)arylmethanes as well as arylmethylenes and arylmethines, affording a large library of α-tertiary and α-quaternary β-aromatic α-amino acids. This process also features low-cost metal catalyst, readily handled and easily removable coordinating group, synthetic simplicity and gram-scale production, which would enable the potential for economical production at commercial scale in the future.

High-resolution mass spectra (HRMS) were obtained with a Waters-Q-TOF-Premier (ESI). Melting points were determined with XRC-1 and are uncorrected.
Unless otherwise noted, all reagents were obtained from commercial suppliers and used without further purification. Compounds 1a-1v were prepared according to the literature procedure [1][2] . All solvents were purified and dried according to standard methods prior to use.

II. General procedure for the oxidative cross-coupling of α-amino acid esters with arylmethanes
Reaction conditions A: An oven-dried Schlenk tube with a magnetic stir bar was charged with amino acid derivative 1 (0.25 mmol), arylmethane 2 (1.0 mL) and Ni(acac) 2 (12.8 mg, 0.05 mmol) under N 2 atmosphere. The reaction solution was stirred at room temperature for several minutes and DTBP (182.6 µL, 1.0 mmol) was then added. The tube was sealed with a teflon-coated cap and the mixture was stirred at 140 o C for 18 h. After being cooled to ambient temperature, the solution was diluted with 20 mL of CH 2 Cl 2 , filtered through a celite pad, and washed with 10-20 mL of CH 2 Cl 2 . The combined organic phases were concentrated and the residue was purified by column chromatography on silica gel to provide the desired product.

Reaction conditions B:
An oven-dried Schlenk tube with a magnetic stir bar was charged with amino acid derivative 1 (0.25 mmol), arylmethane 2 (2.5 mmol), Ni(acac) 2 (12.8 mg, 0.05 mmol) and benzene (0.5 mL) under an N 2 atmosphere. The reaction solution was stirred at room temperature for several minutes and DTBP (182.6 µL, 1.0 mmol) was then added. The tube was sealed with a teflon-coated cap and the mixture was stirred at 140 o C for 18 h. After being cooled to ambient temperature, the solution was diluted with 20 mL of CH 2 Cl 2 , filtered through a celite pad, and washed with 10-20 mL of CH 2 Cl 2 . The combined organic phases were concentrated and the residue was purified by column chromatography on silica gel to provide the desired product.

III. Procedure for the synthesis of 3a and 5c on gram scale a) Procedure for the synthesis of 3a on gram scale
An oven-dried Schlenk tube with a magnetic stir bar was charged with ethyl 3-phenyl-2-(picolinamido)propanoate 1a (1.4917 g, 5.0 mmol), toluene 2a (25.0 mL) and Ni(acac) 2 (128.0 mg, 0.5 mmol) under an N 2 atmosphere. The reaction solution was stirred at room temperature for several minutes and DTBP (3.65 mL, 20.0 mmol) was then added. The tube was sealed with a teflon-coated cap and the mixture was stirred at 140 o C for 18 h. After being cooled to ambient temperature, the solution was diluted with 40 mL of CH 2 Cl 2 , filtered through a celite pad, and washed with 20-30 mL of CH 2 Cl 2 . The combined organic phases were concentrated and the residue was purified by column chromatography on silica gel to provide the product 3a (1.5224 g, 78%).

b) Procedure for the synthesis of 5c on gram scale
An oven-dried Schlenk tube with a magnetic stir bar was charged with ethyl 2-(picolinamido)acetate 1t (1.041 g, 5.0 mmol), m-xylene 2c (25.0 mL) and Ni(acac) 2 (64.0 mg, 0.25 mmol) under an N 2 atmosphere. The reaction solution was stirred at room temperature for several minutes and DTBP (3.65 mL, 20.0 mmol) was then added. The tube was sealed with a teflon-coated cap and the mixture was stirred at 150 o C for 18 h. After being cooled to ambient temperature, the solution was diluted with 40 mL of CH 2 Cl 2 , filtered through a celite pad, and washed with 20-30 mL of CH 2 Cl 2 . The combined organic phases were concentrated and the residue was purified by column chromatography on silica gel to provide the product 5c (786.7 mg, 50%) and 1t was recovered in 36% yield.

IV. Removal of picolinic acid auxiliary. a) Procedure for the synthesis of 6a
An oven-dried Schlenk tube with a magnetic stir bar was charged with product 1a (1.49 g, 5.0 mmol, 1.0 equiv) and ethanol (30.0 mL) under an N 2 atmosphere. The reaction solution was stirred at room temperature and BF 3 ·Et 2 O (6.3 mL, 50.0 mmol, 10.0 equiv) was added dropwise to the stirred solution. The tube was sealed with a teflon-coated cap and the mixture was stirred at 140 o C for 32 h. After being cooled to ambient temperature, the mixture was quenched by slow addition of saturated Na 2 CO 3 solution. The aqueous phase was extracted with ethyl acetate (3 × 30 mL). The combined organic layers were next washed with brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo. The residue was dissolved in DCM (30.0 mL). Et 3 N (1.4 mL, 10.0 mmol, 2.0 equiv) and Boc 2 O (2.18 g, 10.0 mmol, 2.0 equiv) were then added. The solution was stirred overnight at room temperature. After concentration, the mixture was purified by column chromatography using petroleum ether/EtOAc (15/1) as the eluent, and the product 6a was obtained as colorless oil (1.13 g, 77%).

b) Procedure for the synthesis of 6b
An oven-dried Schlenk tube with a magnetic stir bar was charged with product 5c (786.7 mg, 2.5 mmol, 1.0 equiv) and ethanol (20.0 mL) under an N 2 atmosphere. The reaction solution was stirred at room temperature and BF 3 ·Et 2 O (3.2 mL, 25.0 mmol, 10.0 equiv) was added dropwise to the stirred solution. The tube was sealed with a teflon-coated cap and the mixture was stirred at 140 o C for 32 h. After being cooled to ambient temperature, the mixture was quenched by slow addition of saturated Na 2 CO 3 solution. The aqueous phase was extracted with ethyl acetate (3 × 30 mL). The combined organic layers were next washed with brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo. The residue was dissolved in DCM (30.0 mL). Et 3 N (0.7 mL, 5.0 mmol, 2.0 equiv) and Boc 2 O (1.09 g, 5.0 mmol, 2.0 equiv) were then added. The solution was stirred overnight at room temperature. After concentration, the mixture was purified by column chromatography using petroleum ether/EtOAc (15/1) as the eluent, and the product 6b was obtained as colorless oil (563.9 mg, 73%). solution was stirred at room temperature for several minutes and DTBP (182.6 µL, 1.0 mmol) was then added. The tube was sealed with a teflon-coated cap and the mixture was stirred at 140 o C for 18 h. After being cooled to ambient temperature, the solution was diluted with 20 mL of CH 2 Cl 2 , filtered through a celite pad, and washed with 10-20 mL of CH 2 Cl 2 . The combined organic phases were concentrated and the residue was purified by column chromatography on silica gel (ethyl acetate/petroleum ether = 1/4, v/v) to provide the desired product. The product was analysized by 1