Elusive Transmetalation Intermediate in Copper-Catalyzed Conjugate Additions: Direct NMR Detection of an Ethyl Group Attached to a Binuclear Phosphoramidite Copper Complex

Abstract

Copper-catalyzed asymmetric conjugate addition reactions are a very powerful and widely applied method for enantioselective carbon-carbon bond formation. However, structural and mechanistic insight into these famous reactions has been very limited so far. In this article, the first direct experimental detection of transmetalation intermediates in copper-catalyzed reactions is presented. Special combinations of (1)H,(31)P HMBC spectra allow for the identification of complexes with chemical bonds between the alkyl groups and the copper complexes. For the structural characterization of these transmetalation intermediates, a special approach is applied, in which samples using enantiopure ligands are compared with samples using enantiomeric mixtures of ligands. It is experimentally proven, for the first time, that the dimeric copper complex structure is retained upon transmetalation, providing an intermediate with mixed trigonal/tetrahedral coordination on the copper atoms. In addition, monomeric intermediates with one ligand, but no intermediates with two ligands, are detected. These experimental results, in combination with the well-known optimal ligand-to-copper ratio of 2:1 in synthetic applications, allow us to propose that a binuclear transmetalation intermediate is the reactive species in copper-catalyzed asymmetric conjugate addition reactions. This first direct experimental insight into the structure of the transmetalation intermediate is expected to support the mechanistic and theoretical understanding of this important class of reactions and to enable their further synthetic development. In addition, the special NMR approach presented here for the identification and characterization of intermediates below the detection limit of (1)H NMR spectra can be applied also to other classes of catalyses.

Catalytically Active Species in Copper/DiPPAM‐Catalyzed 1,6‐Asymmetric Conjugate Addition of Dialkylzinc to Dienones: A Computational Overview

“…[28] A similar intermediate was more recently described within the framework of the first direct experimental detection of transmetalation intermediates in copper-catalyzed addition reaction using the monodentate phosphoramidite ligand and diethylzinc as nucleophile. [29] Nevertheless, another bimetallic intermediate was detected in the latter study, this time exhibiting two Cu centers and three phosphine ligands. Two Cu centers are also present in the [Zn(μ-X)Cu(μ-X)CuR] trimetallic structure proposed as a catalytically active species (Figure 1, c) from a computational point of view by Calhorda et al In this case, inter-metallic bridge X can be a variety of suitable ligand, like an acetate (or thiophene carboxylate, triflate, …).…”

“…In this context, a halide‐bridged bimetallic monocopper is proposed for bidentate phosphine ligand (Josiphos) when resorting to a Grignard reagent (EtMgBr) as an alkyl source (Figure , b) . A similar intermediate was more recently described within the framework of the first direct experimental detection of transmetalation intermediates in copper‐catalyzed addition reaction using the monodentate phosphoramidite ligand and diethylzinc as nucleophile . Nevertheless, another bimetallic intermediate was detected in the latter study, this time exhibiting two Cu centers and three phosphine ligands.…”

Addition of Mixed (Alkenyl)dialkylzincates to Vicinal Diketo Esters

“…of LiCl in THF/dichloromethane as solvents were the optimal conditions (Scheme , Table ). ZnPh 2 was prepared from phenyllithium and ZnCl 2 …”

Crystal structure of [N,N-bis(diphenylphosphorothioyl)amidato-κ2 S,S′]bis(triphenylphosphane-κP)copper(I) dichloromethane monosolvate

“…Under an argon atmosphere, 5 ml anhydrous dichloromethane were added with stirring to a mixture of N,N-bis(diphenylphosphorothioyl)amine ( . Broadening of the 31 P signals of the phosphorus atoms directly coordinating to the copper atom, which has a large quadrupole moment, has frequently been observed (von Rekowski et al, 2014). Single crystals suitable for X-ray diffraction were obtained during the synthetic procedure.…”