Mechanistic Model for Enantioselective Intramolecular Alkene Cyanoamidation via Palladium-Catalyzed C–CN Bond Activation

Abstract

We studied key aspects of the mechanism of Pd-catalyzed C–CN bond activation and intramolecular enantioselective alkene cyanoamidation. An Abboud–Abraham–Kamlet–Taft (AAKT) linear solvation energy relationship (LSER) model for enantioselectivity was established. We investigated the impact of Lewis acid (BPh3), Lewis base (DMPU), and no additives. BPh3 additive led to diminished enantioselectivity and differing results in 13CN crossover experiments, initial rate kinetics, and natural abundance 12C/13C kinetic isotope effect measurements. We propose two catalytic mechanisms to account for our experimental results. We propose that the DMPU/nonadditive pathway passes through a κ2-phosphoramidite-stabilized Pd+ intermediate, resulting in high enantioselectivity. BPh3 prevents the dissociation of CN−, leading to a less rigid κ2-phosphoramidite-neutral Pd intermediate.

The roles of Lewis acidic additives in organotransition metal catalysis

“…Intramolecular versions in which alkenes are used as the coupling partner also have been reported, 15,16 including variants which include Pd catalysts. [17][18][19][20] The reaction of cyanoester 10, a more activated electrophile, with 5 to give alkenylnitrile 11 uses an electron-poor phosphine PAr…”

“…A clever manifestation of cooperative C(sp 3 )-CN bond activation is realized by the Morandi group, in which alkylnitriles are used as HCN group transfer reagents (Scheme 6), 26,27 utilizing the reversibility of the steps in the general alkene hydrocyanation mechanism to drive formation of the desired product without resorting to the use of hazardous HCN. For example, styrene (18) and isobutyrylnitrile (19) are converted to alkylnitrile 20 and isobutylene (21), using Ni(COD) 2 /DPE-Phos/ AlMe 2 Cl; isobutyrynitrile is selected as HCN transfer agent due to removal of gaseous isobutylene, driving selective formation of the desired product. A subsequent publication from the Morandi group uses a similar method to synthesize arylnitriles.…”

Studies towards the Total Synthesis of Drimentine C. Preparation of the AB and CDEF Ring Fragments

“…We initially envisioned the synthesis of drimentine C as a showcase of the cut‐and‐sew alkene cyanoamidation methodology studied by our lab and Takemoto . Retrosynthetically (Scheme ), we proposed accessing the natural product through late‐stage functionalization of lactam 6 via α‐aminonitrile and reductive condensation to form the E ring, hydrolysis of the nitrile to a carboxylic acid, and condensation with l ‐proline.…”

Metal-mediated C–CN Bond Activation in Organic Synthesis

“…123−127 The mechanism of the enantioselective cyanocarbamoylation has been studied in detail to reveal that a rigid bidentate phosphoramidite−Pd + intermediate generated through dissociation of CN − is key to achieve high enantioselectivity. 128 The alkene acceptors in these transformations are generally limited to 1,1-disubstituted ones that furnish alkylmetal intermediates that cannot undergo a β-H elimination. Some of these transformations have been successfully applied to the asymmetric synthesis of biologically active natural products that bear quaternary stereocenters.…”