Scope and mechanism in palladium-catalyzed isomerizations of highly substituted allylic, homoallylic, and alkenyl alcohols.

Herein we report the palladium-catalyzed isomerization of highly substituted allylic alcohols and alkenyl alcohols by means of a single catalytic system. The operationally simple reaction protocol is applicable to a broad range of substrates and displays a wide functional group tolerance, and the products are usually isolated in high chemical yield. Experimental and computational mechanistic investigations provide complementary and converging evidence for a chain-walking process consisting of repeated migratory insertion/ß-H elimination sequences. Interestingly, the catalyst does not dissociate from the substrate in the isomerization of allylic alcohols, whereas it disengages during the isomerization of alkenyl alcohols when additional substituents are present on the alkyl chain.

Palladium-N-heterocyclic carbene (NHC)-catalyzed asymmetric synthesis of indolines through regiodivergent C(sp3)-H activation: scope and DFT study.

Two bulky, chiral, monodentate N-heterocyclic carbene ligands were applied to palladium-catalyzed asymmetric C-H arylation to incorporate C(sp(3))-H bond activation. Racemic mixtures of the carbamate starting materials underwent regiodivergent reactions to afford different trans-2,3-substituted indolines. Although this CAr-Calkyl coupling requires high temperatures (140-160 °C), chiral induction is high. This regiodivergent reaction, when carried out with enantiopure starting materials, can lead to single structurally different enantiopure products, depending on the catalyst chirality. The C-H activation at a tertiary center was realized only in the case of a cyclopropyl group. No C-H activation takes place alpha to a tertiary center. A detailed DFT study is included and analyses of methyl versus methylene versus methine C-H activation is used to rationalize experimentally observed regio- and enantioselectivities.

Well-defined transition metal hydrides in catalytic isomerizations.

This Feature Article intends to provide an overview of a variety of catalytic isomerization reactions that have been performed using well-defined transition metal hydride precatalysts. A particular emphasis is placed on the underlying mechanistic features of the transformations discussed. These have been categorized depending upon the nature of the substrate and in most cases discussed following a chronological order.

Cobalt-catalyzed methoxycarbonylation of substituted dichlorobenzenes as an example of a facile radical anion nucleophilic substitution in chloroarenes.

A thorough mechanistic study on cobalt-catalysed direct methoxycarbonylation reactions of chlorobenzenes in the presence of methyl oxirane on a wide range of substrates, including poly- and monochloro derivatives with multiple substituents, is reported. The results demonstrate that the reaction is potentially useful as it proceeds under very mild conditions (t = 62 °C, PCO = 1 bar) and converts aryl chlorides to far more valuable products (especially ortho-substituted benzoic acids and esters) in high yields. This transformation also offers another opportunity for the utilization of environmentally harmful polychlorinated benzenes and biphenyls (PCBs). This study is the first to discover an unexpected universal positive ortho-effect: the proximity of any substituent (including Me, Ph, and MeO groups and halogen atoms) to the reaction centre accelerates the methoxycarbonylation in chlorobenzenes. The effect of the ortho-substituents is discussed in detail and explained in terms of a radical anion reaction mechanism. The advantages of the methoxycarbonylation as a model for the mechanistic study of radical anion reactions are also illustrated.

Highly modular C(1) -symmetric chiral (P,N) ligands with a stereolabile P center: experimental and theoretical studies.

An improved synthesis of a novel class of bidentate (P,N) ligands is presented, the structures of which are characterized by three distinct elements of chirality. The stereoselective installation of the elements of central chirality (at the benzylic carbon and the phosphorus atom) depends on the size of the phosphorus substituent. Thermal inversion of the phosphorus center has been studied experimentally and further correlated by DFT calculations. The potential of these ligands and the role of the phosphorus atom in the asymmetric α-arylation of aldehydes (Pd) and hydrogenation of allylic alcohols (Ir) have also been investigated.

Copper(ii) chloride mediated (aza)oxindole synthesis by oxidative coupling of Csp(2)-H and Csp(3)-H centers: substrate scope and DFT study.

A CuCl2 mediated direct intramolecular oxidative coupling of Csp(2)-H and Csp(3)-H centers gives access to 3,3-disubstituted oxindoles containing aromatic, heteroaromatic and alkyl substituents as well as a heteroatom at the quaternary center in good to excellent yields. The reaction is carried out in the presence of NaOtBu and CuCl2 in DMF at 110 °C. The key step of this reaction is the formation of an amidyl radical by one electron oxidation of amide enolate followed by an intramolecular radical cyclization reaction (homolytic aromatic substitution reaction). A detailed DFT study shows that the cyclization of the amidyl radical is the rate-limiting step in the oxindole synthesis, whereas the second single electron transfer (SET) becomes the rate-determining step in the aza-oxindole formation. Computational data are in agreement with the experimentally observed relative reactivity and regioselectivity.

Isomerization of terminal epoxides by a [Pd-H] catalyst: a combined experimental and theoretical mechanistic study.

An unusual palladium hydride complex has been shown to be a competent catalyst in the isomerization of a variety of terminal and internal epoxides. The reaction displayed broad scope and synthetic utility. Experimental and theoretical evidence are provided for an unprecedented hydride mechanism characterized by two distinct enantio-determining steps. These results hold promise for the development of an enantioselective variant of the reaction.

Cation affinity numbers of Lewis bases.

Using selected theoretical methods the affinity of a large range of Lewis bases towards model cations has been quantified. The range of model cations includes the methyl cation as the smallest carbon-centered electrophile, the benzhydryl and trityl cations as models for electrophilic substrates encountered in Lewis base-catalyzed synthetic procedures, and the acetyl cation as a substrate model for acyl-transfer reactions. Affinities towards these cationic electrophiles are complemented by data for Lewis-base addition to Michael acceptors as prototypical neutral electrophiles.

Theoretical prediction of selectivity in kinetic resolution of secondary alcohols catalyzed by chiral DMAP derivatives.

The mechanism of esterification of the secondary alcohol 1-(1-naphthyl)ethanol 9 by isobutyric anhydride catalyzed by 4-pyrrolidinopyridine (PPY, 11) and a series of single enantiomer atropisomeric 4-dialkylaminopyridines 8a-g has been studied computationally at the B3LYP/6-311+G(d,p)//B3LYP/6-31G(d) level. Comparison of the levels of enantioselectivity predicted computationally with the results obtained experimentally allowed the method to be validated. The value of the approach is demonstrated by the successful prediction that a structural modification of an aryl group within the catalyst from phenyl to 3,5-dimethylphenyl would lead to improved levels of selectivity in this type of kinetic resolution (KR) reaction, as was subsequently verified following synthesis and evaluation of this catalyst (8d). Experimentally, the selectivity of this type of KR is found to exhibit a significant deuterium isotope effect (for 9 vs d(1)-9).