Pd(0)-Catalyzed Bidentate Auxiliary Directed Enantioselective Benzylic C–H Arylation of 3-Arylpropanamides Using the BINOL Phosphoramidite Ligand

Abstract

Palladium-catalyzed enantioselective C(sp 3 )−H functionalization could provide valuable reactions for organic synthesis. While significant progress has been made on monodentate directing-group-mediated (DG-mediated) enantioselective C−H functionalization using amino acid or N-heterocyclebased chiral ligands, methods for enantioselective C(sp 3 )−H functionalization mediated by bidentate DGs have lagged far behind. For Pd-catalyzed C(sp 3 )−H functionalization reactions, 8aminoquinoline (AQ) is a powerful N,N-bidentate auxiliary. The bidentate binding mode of AQ can stabilize high-valent Pd intermediates, enabling challenging transformations through a Pd II/IV catalytic manifold. Recently, Duan reported an enantioselective Pd-catalyzed AQ-directed benzylic C−H arylation of 3arylpropanamides using Pd II catalyst and the BINOL phosphoramide (P V ) ligand. Herein, we report a protocol for Pd-catalyzed AQ-mediated enantioselective benzylic C−H arylation of 3-arylpropanamides using Pd 0 catalyst and the BINOLphosphoramidite (P III ) ligand. These reactions give good to high yield and improved enantioselectivity (up to 95% ee). Mechanistic studies indicate that the reactions proceed via a Pd 0/II catalytic cycle, unprecedented for AQ-directed reactions. DFT calculations suggest that both the phosphoramidite ligand and cesium carbonate base are involved in the enantiodetermining C−H palladation step, and that the AQ directing group converts between binding modes to accommodate the C−H palladation and reductive elimination steps.

Palladium-catalyzed direct asymmetric C–H bond functionalization enabled by the directing group strategy

“…Later, the same group introduced a novel protocol for AQmediated Pd(0)-catalyzed enantioselective b-C(sp 3 )-H arylation of 3-substituted propanamides in the presence of the BINOL phosphoramidite ligand L30 (Scheme 33). 49 Compared with Duan's work, this is the rst example of AQ-directed processes involving a Pd(0/II) catalytic cycle, providing the chiral desired products in good yields and enantioselectivities (up to 95% ee). Furthermore, the control reactions and DFT calculations showed that both the BINOL phosphoramidite ligand L30 and Cs 2 CO 3 were involved in the enantio-determining C(sp Very recently, the Chen group reported a Pd(II)-catalyzed enantioselective intramolecular b-C(sp 3 )-H amidation reaction of 3-substituted propanamides for the synthesis of chiral b-arylb-lactams.…”

Transition-Metal-Catalyzed, Coordination-Assisted Functionalization of Nonactivated C(sp3)–H Bonds

“…They proposed that an enantioenriched intermediate, 591 , is formed by cleaving one of the two enantiotopic β-C–H bonds of 592 with the assistance of chiral phosphoric amide ligand L70 . In 2018, the Chen group reported a Pd(0)-catalyzed enantioselective benzylic methylene C­(sp 3 )–H arylation of 3-arylpropanamides with the BINOL phosphoramidite (P III ) ligand L71 (Scheme b) . This represented the first Pd(0)-catalyzed enantioselective C­(sp 3 )–H arylation reaction employing bidentate DGs.…”

Chiral Catalysts for Pd0‐Catalyzed Enantioselective C−H Activation

“…Whereas intramolecular Pd 0 -catalyzed enantioselective CÀH activation is well developed and represented by at remendous number of examples, intermolecular versions are much less common.I n2 018, Chen and co-workers reported the first example of Pd 0 -catalyzed intermolecular enantioselective C(sp 3 )À Ha rylation. [52] To this purpose, they employed the well-established aminoquinoline (AQ) directing group [53] and (S)-MeMonophos as the chiral ligand (Scheme15). Generally,b identate directingg roups (DGs) exhibit superior reactivity to monodentate DGs in palladium-catalyzed CÀHa ctivation reactions.…”