Mechanism and Selectivity in the Pd-Catalyzed Difunctionalization of Isoprene.

The three-component coupling of isoprene, an alkenyl triflate, and styrenylboronic acid catalyzed by a palladium pyrox complex affords access to skipped dienes from simple chemical feedstocks. Unfortunately, the transformation proceeds with only moderate selectivity and yields. The reaction mechanism and factors responsible for the resulting regioselectivity were elucidated using M06/SDD/6-311++G(d,p) + SMD calculations. Distortion of the palladium coordination sphere in the transition structure of the migratory insertion step is found to control the 4,1- vs 1,x-selectivity. The calculated ΔΔG⧧ of 1.0 kcal/mol for this step is in excellent agreement with the experimentally observed selectivity of 1:9.9 disfavoring the 4,1-product. The transmetalation was found to be the regioselectivity determining step for the formation of the 1,2- vs 1,4-addition products. Systematic conformational searches for the transmetalation transition structure revealed a series of steric interactions between the t-Bu substituent on the ligand and the substrates in the model system that are balanced by additional repulsive interactions between the substrates and the pyridyl portion of the ligand. The combination of these effects leads to the low to moderate 1,2- vs 1,4-selectivity in the experimentally studied system.

Hybrid enzymatic and organic electrocatalytic cascade for the complete oxidation of glycerol.

We demonstrate the complete electrochemical oxidation of the biofuel glycerol to CO2 using a hybrid enzymatic and small-molecule catalytic system. Combining an enzyme, oxalate oxidase, and an organic oxidation catalyst, 4-amino-TEMPO, we are able to electrochemically oxidize glycerol at a carbon electrode, while collecting up to as many as 16 electrons per molecule of fuel. Additionally, we investigate the anomalous electrocatalytic properties that allow 4-amino-TEMPO to be active under the acidic conditions that are required for oxalate oxidase to function.

Palladium-catalyzed 1,4-difunctionalization of butadiene to form skipped polyenes.

A palladium-catalyzed 1,4-addition across the commodity chemical 1,3-butadiene to afford skipped polyene products is reported. Through a palladium σ → π → σ allyl isomerization, two new carbon-carbon bonds are formed with high regioselectivity and trans stereoselectivity of the newly formed alkene. The utility of this method is highlighted by the successful synthesis of the ripostatin A skipped triene core.

Cu-Mediated C-H 18F-Fluorination of Electron-Rich (Hetero)arenes.

This communication describes a method for the nucleophilic radiofluorination of electron-rich arenes. The reaction involves the initial C(sp2)-H functionalization of an electron-rich arene with MesI(OH)OTs to form a (mesityl)(aryl)iodonium salt. This salt is then used in situ in a Cu-mediated radiofluorination with [18F]KF. This approach leverages the stability and availability of electron-rich arene starting materials to enable mild late-stage radiofluorination of toluene, anisole, aniline, pyrrole, and thiophene derivatives. The radiofluorination has been automated to access a 41 mCi dose of an 18F-labeled nimesulide derivative in high (2800 ± 700 Ci/mmol) specific activity.

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.

Development and Investigation of a Site Selective Palladium-Catalyzed 1,4-Difunctionalization of Isoprene using Pyridine-Oxazoline Ligands.

Palladium-catalyzed 1,4-difunctionalizations of isoprene that produce skipped polyenes are reported. Complex isomeric product mixtures are possible as a result of the difficult-to-control migratory insertion of isoprene into a Pd-alkenyl bond, but good site selectivity has been achieved using easily accessible Pyrox ligands. Mechanistic studies suggest that the control of insertion is the result of the unique electronic asymmetry and steric properties of the ligand.