Mechanistic investigations on asymmetric N-H insertion of amines catalyzed by palladium-chiral guanidine complex

The mechanism and stereoselectivity of the asymmetric N-H insertion reactions between alpha-diazocarbonyl compounds and amines mediated by palladium-chiral guanidine complexes were investigated at the BP86-D3(BJ)/def2TZVP (SMD, CH2Cl2)//BP86-D3(BJ)/def2SVP (SMD, CH2Cl2) level at 303 K. The non-catalytic reaction occurred through a stepwise mechanism, with a high activation barrier of 56.4 kcal mol(-1). Good linear correlations between the global nucleophilicity index (N) of amine, Hammett substituent constants (sigma(p)), and the activation energy barriers (Delta G(not equal)) were found. The Pd(0)-guanidinecat-alyzed reaction consisted of three continuous steps, including: (i) generation of Pd-carbene intermediate by dinitrogen loss from alpha-diazoesters substrate, (ii) formation of C-N bond, and (iii) 1,2-H transfer by metal-associated ylide, accompanying with the regeneration of catalyst. A water molecule accelerated the final H-transfer by constructing hydrogen bonding network. The cyclohexyl group in ligand provided sufficient steric shielding around Pd-carbene intermediate from the re-face attack by amines. The combination of the hydrogen bonding orientation of amide moiety of guanidine ligand, as well as the steric repulsion between the ester group of alpha-diazoester substrate and bulky -CH(Ph)(2) group in ligand played an important role in controlling the stereoselectivity, affording the predominant S-configuration product observed in experiment. Introducing one aromatic ring to chiral backbone of the guanidine ligand enhanced the enantiodifferentiation of products by increasing the difference of strain energy (Delta Delta E-strain) of Pd-carbene moiety along two competing pathways. Different fromPd(0)-catalyst, the Pd (II)-chiral guanidine complex accelerated N-H insertion reaction via Lewis acid catalysis. In this process, the formation of free ylide in the reaction led to low ee. These results were in good agreement with experimental observations. (C) 2018 Elsevier Inc. All rights reserved.