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

Abstract

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.

Fig. 1

Enantioselective functionalization via ring-opening C−C bond cleavage. a Transition-metal-catalysis: normally strained rings. b Lewis acid-mediation or organocatalysis: strained rings only. c Radical-mediation: three-membered rings only. d This work: asymmetric radical transformations of four- and five-membered rings.

Fig. 2

Substrate scope of the cyclopentanone oxime esters 1. Reaction conditions: 1 (0.10 mmol), TMSCN (1.5 equiv), Cu(MeCN)₄PF₆ (2 mol%), L1 (3 mol%), Ir(ppy)₃ (0.5 mol%) in DMAc (1.0 mL) at RT for 36 h under the irradiation of 5 W blue LEDs. ^a1.0 mmol scale. ^bCu(MeCN)₄PF₆ (1.5 mol%), L1 (2.25 mol%). TMS Trimethylsilyl. Ts p-Methyl benzenesulfonyl.

Fig. 3

Substrate scope of the cyclobutanone oxime esters 3. Reaction conditions: 3 (0.10 mmol), TMSCN (1.5 equiv), CuSCN (3 mol%), L1 (3.6 mol%) in acetone (1.0 mL) at 10 °C for 24 h. ^aCuSCN (1 mol%), L1 (1.2 mol%). ^b48 h. ^c1.0 mmol scale. ^dCuSCN (5 mol%), L1 (6 mol%). ^eee of the crude product.

Fig. 4

Synthetic applications. a 2a or 4 h was converted to chiral diamides. b 2a or 4 h was converted to chiral diamines. Boc₂O Di-tert-butyl decarbonate.

Fig. 5

Preliminary mechanistic studies. a Radical trapping experiment with TEMPO. b Radical trapping experiment with O₂. TEMPO 2,2,6,6-Tetramethylpiperidinooxy.

Fig. 6

Proposed mechanisms. a copper catalysis. b a dual photoredox/copper catalysis.