Relative reactivity of alkenyl alcohols in the palladium-catalyzed redox-relay Heck reaction

The relative rates of alkenyl alcohols in the Pd-catalyzed redox-relay Heck reaction were measured in order to examine the effect of their steric and electronic properties on the rate-determining step. Competition experiments between an allylic alkenyl alcohol and two substrates with differing chain lengths revealed that the allylic alcohol reacts 3–4 times faster in either case. Competition between di- and trisubstituted alkenyl alcohols provided an interesting scenario, in which the disubstituted alkene was consumed first followed by reaction of the trisubstituted alkene. Consistent with this observation, the transition structures for the migratory insertion of the aryl group into the di- and trisubstituted alkenes were calculated with a lower barrier for the former. An internal competition between a substrate containing two alcohols with differing chain lengths demonstrated the catalyst's preference for migrating toward the closest alcohol. Additionally, it was observed that increasing the electron-density in the arene boronic acid promotes a faster reaction, which correlates with Hammett [sigma-rho] values to give a [rho] of −0.87

Enantioselective Palladium-Catalyzed Alkenylation of Trisubstituted Alkenols To Form Allylic Quaternary Centers

In this report, we describe the generation of remote allylic quaternary stereocenters β, γ, and δ relative to a carbonyl in high enantioselectivity. We utilize a redox-relay Heck reaction between alkenyl triflates and acyclic trisubstituted alkenols of varying chain-lengths. A wide array of terminal (<i>E</i>)-alkenyl triflates are suitable for this process. The utility of this functionalization is validated further by conversion of the products, via simple organic processes to access remotely functionalized chiral tertiary acid, amine, and alcohol products

Palladium-Catalyzed Enantio­selective Heck Alkenylation of Acyclic Alkenols Using a Redox-Relay Strategy

We report a highly enantio­selective intermolecular Heck reaction of alkenyl triflates and acyclic primary or racemic secondary alkenols. The mild reaction conditions permit installation of a wide range of alkenyl groups at positions β, γ, or δ to a carbonyl group in high enantio­selectivity. The success of this reaction is attributed to the use of electron-withdrawing alkenyl triflates, which offer selective β-hydride elimination followed by migration of the catalyst through the alkyl chain to give the alkenylated carbonyl products. The synthetic utility of the process is demonstrated by a two-step modification of a reaction product to yield a tricyclic core structure, present in various natural products

Distinctive <i>Meta</i>-Directing Group Effect for Iridium-Catalyzed 1,1-Diarylalkene Enantioselective Hydrogenation

An iridium-catalyzed asymmetric hydrogenation of 1,1-diarylkenes is described. Employing a novel, modular phosphoramidite ligand, PhosPrOx, in this transformation affords biologically relevant 1,1-diarylmethine products in good enantiomeric ratios (96.5:3.5 to 71:29). We propose that a <i>meta</i>-directing group, 3,5-dimethoxyphenyl, is responsible for the observed enantioselection, the highest reported, to date, for iridium-catalyzed hydrogenation of 1,1-diarylalkenes lacking <i>ortho</i>-directing groups

Palladium-Catalyzed 1,3-Difunctionalization Using Terminal Alkenes with Alkenyl Nonaflates and Aryl Boronic Acids

A Pd-catalyzed 1,3-difunctionalization of terminal alkenes using 1,1-disubstituted alkenyl nonaflates and arylboronic acid coupling partners is reported. This transformation affords allylic arene products that are difficult to selectively access using traditional Heck cross-coupling methodologies. The evaluation of seldom employed 1,1-disubstituted alkenyl nonaflate coupling partners led to the elucidation of subtle mechanistic features of π-allyl stabilized Pd-intermediates. Good stereo- and regioselectivity for the formation of 1,3-addition products can be accessed through a minimization of steric interactions that emanate from alkenyl nonaflate substitution

Synthesis of Highly Functionalized Tri- and Tetrasubstituted Alkenes via Pd-Catalyzed 1,2-Hydrovinylation of Terminal 1,3-Dienes

An efficient method for the construction of Csp²–Csp³ bond in a regio- and stereoselective fashion involving 1,3-terminal dienes, enol triflates/nonaflates, and sodium formate under Pd(0)-catalysis is described. The three component assembly allows trapping of a π-allyl intermediate, after the initial migratory insertion of the diene, by a hydride source that leads to structurally complex and synthetically challenging tri- and tetrasubstituted alkene building blocks

Developing a Modern Approach To Account for Steric Effects in Hammett-Type Correlations

The effects of aryl ring <i>ortho</i>-, <i>meta</i>-, and <i>para</i>-substitution on site selectivity and enantioselectivity were investigated in the following reactions: (1) enantioselective Pd-catalyzed redox-relay Heck reaction of arylboronic acids, (2) Pd-catalyzed β-aryl elimination of triarylmethanols, and (3) benzoylformate decarboxylase-catalyzed enantioselective benzoin condensation of benzaldehydes. Through these studies, it is demonstrated that the electronic and steric effects of various substituents on selectivities obtained in these reactions can be described by NBO charges, the IR carbonyl stretching frequency, and Sterimol values of various substituted benzoic acids. An extended compilation of NBO charges and IR carbonyl stretching frequencies of various substituted benzoic acids was used as an alternative to Hammett values. These parameters provide a correlative tool that allows for the analysis of a much greater range of substituent effects because they can also account for proximal and remote steric effects

Prediction of Catalyst and Substrate Performance in the Enantioselective Propargylation of Aliphatic Ketones by a Multidimensional Model of Steric Effects

The effectiveness of a new asymmetric catalytic methodology is often weighed by the number of diverse substrates that undergo reaction with high enantio­selectivity. Here we report a study that correlates substrate and ligand steric effects to enantio­selectivity for the prop­argyl­ation of aliphatic ketones. The mathematical model is shown to be highly predictive when applied to substrate/catalyst combinations outside the training set

Palladium-Catalyzed Allylic Cross-Coupling Reactions of Primary and Secondary Homoallylic Electrophiles

The Pd(0)-catalyzed allylic cross-coupling of homoallylic tosylate substrates using boronic acids and pinacol esters is reported. The reaction uses 2-(4,5-dihydro-2-oxazolyl)­quinoline (quinox) as a ligand and is performed at ambient temperature. The scope of the reaction is broad in terms of both the boronate transmetalating reagent and the substrate and includes secondary tosylates. Mechanistic studies support an alkene-mediated S_N2-type stereoinvertive oxidative addition of unactivated primary and secondary alkyl tosylates

Palladium-Catalyzed Enantioselective Redox-Relay Heck Arylation of 1,1-Disubstituted Homoallylic Alcohols

An enantio­selective redox-relay oxidative Heck arylation of 1,1-disubstituted alkenes to construct β-stereo­centers was developed using a new pyridyl-oxazoline ligand. Various 1,2-diaryl carbonyl compounds were readily obtained in moderate yield and good to excellent enantio­selectivity. Additionally, analysis of the reaction outcomes using multi­dimensional correlations revealed that enantio­selectivity is tied to specific electronic features of the 1,1-disubstituted alkenol and the extent of polarizability of the ligand