Enantioselective cyanation via radical-mediated C–C single bond cleavage for synthesis of chiral dinitriles

Ring-opening reaction via selective cleavage of C–C bond is known as a powerful strategy for construction of complex molecules. Complementary to the ionic process focusing on mostly small ring systems, radical-mediated C–C bond cleavage offers a solution for further diverse enantioselective functionalization benefited from its mild conditions, whereas such asymmetric transformations are still limited to three-membered rings so far. Herein, we describe radical-mediated ring-opening and enantioselective cyanation of four- and five-membered cycloketone oxime esters to access chiral 1,5- and 1,6-dinitriles. Employment of dual photoredox/copper catalysis is essential for the asymmetric ring-opening cyanation of cyclopentanone oxime esters. Both reactions proceed under mild conditions giving chiral dinitriles in high yields and enantioselectivity with low catalyst loading and broad substrate scope. The products dinitriles can be converted to valuable optically active diamides and diamines. Mechanistic studies indicate that the benzylic radical generated via C–C single bond cleavage is involved in the catalytic cycle.


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The 2-arylcyclopentan-1-ones were synthesized according to the reported procedure 3 .
MeOH (0.56 M) was added and the reaction was stirred for 12 h at 75 ºC. Then methanol was removed under vacuum and the resulting mixture was extracted with DCM. The organic layer was washed with water and dried over Na2SO4. The solvent was removed under reduced pressure and the crude material was subjected to column chromatography to afford oximes.
After 1 h, a saturated solution of aqueous NaHCO3 (10 mL) was added to the above solution, and the mixture was diluted with DCM. The organic layer was washed with brine (20 mL) and dried over Na2SO4. The solvent was removed under vacuum and the residue was subjected to column chromatography on silica gel with EtOAc-petroleum ether as an eluent to give the substrate.
A solution of KO t Bu ( To a mixture of hydroxylamine hydrochloride (1.2 equiv), sodium acetate (1.5 equiv), methanol (0.56 M) in a flask was added cyclobutanone (~5 mmol, 1.0 equiv) and the mixture was stirred at 75 °C for 12 h. The reaction mixture was cooled to room temperature and then methanol was removed under vacuum and the resulting mixture was extracted with DCM. The organic layer was washed with water and dried over Na2SO4. The solvent was removed under reduced pressure and the crude material was subjected to column chromatography to afford cyclobutanone oximes.
To a mixture of cyclobutanone oxime (~3 mmol, 1.0 equiv), triethylamine (1.5 equiv) and DCM (0.5 M) in a flask was added 4-(trifluoromethyl)benzoyl chlorides (1.1 equiv) slowly at 0 °C. After 1 h, a saturated solution of aqueous NaHCO3 (10 mL) was added to the above solution, and the mixture was diluted with DCM. The organic layer was washed with brine and dried over Na2SO4. The solvent was removed under vacuum and the residue was subjected to column chromatography on silica gel with EtOAc-
for C12H12N2  were sequentially added under N2 atmosphere. The tube was sealed with a Teflon-lined cap, and the mixture was stirred at a distance of ~5 cm from a 5 W blue LEDs at room temperature for 36 h .The reaction mixture was diluted with EA(10 mL). The organic layer was washed with brine (3×5 mL) and dried over anhydrous Na2SO4. After filtration and concentration, the residue was purified by silica gel chromatography to afford product 9 as a yellowish oil (58 %).
The tube was sealed with a Teflon-lined cap, then the mixture was stirred at room temperature for 0.5 h. The catalyst solution II was prepared firstly and used in the next step.
(2) Procedure of the radical trapping experiment with O2: To a 25 mL screw-cap sealed tube containing substrate 1a (0.1 mmol, 1.0 equiv), catalyst solution I(1 mL) and TMSCN (0.15 mmol, 1.5 equiv) were sequentially added under air atmosphere. The tube was sealed with a Teflon screw-cap, and the mixture was stirred at a distance of ~5 cm from a 5 W blue LEDs at room temperature for 36 h .The reaction mixture was diluted with EA(10 mL). The organic layer was washed with brine (3×5 mL) and dried over anhydrous Na2SO4. After filtration and concentration, the residue was purified by silica gel chromatography to afford product 11 as a white solid. (p, J = 6.9 Hz, 2H); 13 C NMR (101 MHz,CDCl3) δ 197.9,146.3,139.9,135.3,129.1,128.7,128.5,127.5,127.4,119.5,36.5,19.9,16.8 To a 25 mL screw-cap sealed tube containing substrate 3h(0.1 mmol, 1.0 equiv), 0.8 mL Acetone, catalyst solution II (200 uL) and TMSCN (0.15 mmol, 1.5 equiv) were sequentially added under air atmosphere. The tube was sealed with a Teflon screw-cap, and the mixture was stirred at 10 ºC for 24 h .Then Solvent was removed under vacuum and the crude product was purified by flash chromatography on silica gel directly to give the product 12 as a white solid.

Further transformations of the products
(1) Procedure for the synthesis of diamides 5 and 6. 10 To a stirred solution of 2a or 4h (1.0 equiv, 0.1 mmol) in tert-butyl acetate(0.4 mL) in a 25 mL screw-cap sealed tube was added slowly conc. H2SO4 (10 uL). The tube was sealed with a Teflon screw-cap, and the mixture was stirred at 42 ºC for 2 h. The reaction mixture was diluted with EA(10 mL). The organic layer was washed with sat. aq.