The Role of Fluorine Substituents in the Regioselectivity of Intramolecular C–H Bond Functionalization of Benzylamines at Palladium(II)

Abstract

The effect of fluorine substituents on the regio­selectivity of intramolecular reactions of mono- and difluorinated N,N-dimethylbenzylamines (1a–f) at palladium, to form palladacycles di-μ-acetato­bis­[o-dimethylaminomethyl-n-fluorophenyl-C,N)­dipalladium­(II) (2a–f) and di-μ-chloro­bis­[o-dimethylaminomethyl-n-fluorophenyl-C,N)­dipalladium­(II) (3a–e), has been investigated. When fluorinated substrates with two sites available for the C–H functionalization (1c and 1e) undergo cyclopalladation via a CMD mechanism (acetate-bridged palladacycles), they do not exhibit regioselectivity. In contrast, the same substrates exhibit complete regioselectivity for the C–H functionalization para to fluorine in cyclopalladation reactions that proceed via an SEAr mechanism (involving chloride-bridged palladacycles). X-ray crystal structures were obtained for all the palladacycles synthesized, and a structural analysis showed that the number and the position of the fluorine atoms on the aromatic ring have a marked effect on the “clamshell” structure of the acetate-bridged palladacycles. By contrast, there is no great variation in the structures of the planar chloride-bridged palladacycles.

Di-Palladium Complexes are Active Catalysts for Mono-N-Protected Amino Acid Accelerated Enantioselective C-H Functionalization

“…At the same temperature and concentration used in catalysis, complex 7accounts for approximately half of the total palladium loading as assessed by 1 H NMR spectroscopy (SI Figure 10 -11). The stoichiometry of the bridge splitting complex was confirmed with MCV and is consistent with the bridge splitting equilibria observed with isolated dimers 64,65 and in systems with bimetallic 36,66 active catalysts (SI Figure 13).…”

The Importance of Kinetic and Thermodynamic Control when Assessing Mechanisms of Carboxylate-Assisted C–H Activation

“…With meta-substituted ligands L2-R most reactions proceed with para selectivity, and it is only with L2-F that the ortho isomer is favored both kinetically and thermodynamically. The formation of a mixture of ortho- and para-cyclometalated products in the reactions of fluorinated dimethylbenzylamines at [Pd­(OAc) 2 ] has previously been taken as evidence for an AMLA mechanism rather than S E Ar . The para-selectivity is predominantly steric in origin; however, the observation of ortho-H/D exchange with some L2-R ligands reveals an unexpectedly accessible C–H activation ortho to the substituent R. Indeed, ortho-C–H activation can even be faster than para-C–H activation, as seen in the greater amount of ortho-deuteration observed for L2-NMe 2 at Ir and L2-OMe at Rh.…”

“…33 In contrast, Fairlamb et al have recently shown that the regioselectivity of the cyclometalations of fluorinated dimethylbenzylamines at Pd is dependent on the Pd precursor used. 34 Thus, with [Pd(OAc) 2 ] roughly equal amounts of the ortho and para products are formed, whereas Li 2 PdCl 4 gave exclusively the para isomer. Both reactions were proposed to be under kinetic control, with the former suggested to proceed via an AMLA/ CMD mechanism and the latter more likely via S E Ar.…”

“…A later study by Ess suggested that the selectivity determining factor is the relative strength of the Pd–C bond being formed, the product with the stronger Pd–C bond being favored both kinetically and thermodynamically . In contrast, Fairlamb et al have recently shown that the regioselectivity of the cyclometalations of fluorinated dimethylbenzylamines at Pd is dependent on the Pd precursor used . Thus, with [Pd­(OAc) 2 ] roughly equal amounts of the ortho and para products are formed, whereas Li 2 PdCl 4 gave exclusively the para isomer.…”

Bi and trinuclear complexes in palladium carboxylate-assisted C–H activation reactions

“…Can C-H activation involving polynuclear complexes lead to different regioselectivities in comparison with the mononuclear pathway? 19 How are reactivity and nuclearity influenced by the addition of carboxylates of different metals? 20 What is the role of polynuclear complexes in the ongoing catalytic cycles of C-H functionalization reactions, where their formation is less probable?…”