Mechanistic study of the selectivity of olefin versus cyclobutene formation by palladium(0)-catalyzed intramolecular C(sp3)-H activation.

This study describes the mechanism and selectivity pattern of the Pd(0)-catalyzed C(sp(3))-H activation of a prototypical substrate bearing two linear alkyl groups. Experimentally, the use of the Pd/P(t-Bu)3 catalytic system leads to a ca. 7:3 mixture of olefin and benzocyclobutene (BCB) products. The C-H activation step was computed to be favored for the secondary position α to the benzylic carbon over the primary position ß to the benzylic carbon by more than 4 kcal mol(-1), in line with previous selectivity trends on analogous substrates. The five-membered palladacycle obtained through this activation step may then follow two different pathways, which were computationally characterized: (1) decoordination of the protonated base and reductive elimination to give the BCB product and (2) proton transfer to the aryl ligand and base-mediated ß-H elimination to give the olefin product. Experiments conducted with deuterated substrates were in accordance with this mechanism. The difference between the highest activation barriers in the two pathways was computed to be 1.2 kcal mol(-1) in favor of BCB formation. However, the use of a kinetic model revealed the critical influence of the kinetics of dissociation of HCO3(-) formed after the C-H activation step in actually directing the reaction toward either of the two pathways.

Diastereo- and enantioselective intramolecular C(sp3)-H arylation for the synthesis of fused cyclopentanes.

All C-H bonds are not equal: The intramolecular arylation of unactivated C(sp(3))-H bonds in the presence of a chiral Pd/binepine catalyst allows the synthesis of fused cyclopentanes efficiently and in an diastereo- and enantioselective manner (see scheme).

Intramolecular palladium-catalyzed alkane C-H arylation from aryl chlorides.

The first examples of efficient and general palladium-catalyzed intramolecular C(sp(3))-H arylation of (hetero)aryl chlorides, giving rise to a variety of valuable cyclobutarenes, indanes, indolines, dihydrobenzofurans, and indanones, are described. The use of aryl and heteroaryl chlorides significantly improves the scope of C(sp(3))-H arylation by facilitating the preparation of reaction substrates. Careful optimization studies have shown that the palladium ligand and the base/solvent combination are crucial to obtaining the desired class of product in high yields. Overall, three sets of reaction conditions employing P(t)Bu(3), PCyp(3), or PCy(3) as the palladium ligand and K(2)CO(3)/DMF or Cs(2)CO(3)/pivalic acid/mesitylene as the base/solvent combination allowed five different classes of products to be accessed using this methodology. In total, more than 40 examples of C-H arylation have been performed successfully. When several types of C(sp(3))-H bond were present in the substrate, the arylation was found to occur regioselectively at primary C-H bonds vs secondary or tertiary positions. In addition, in the presence of several primary C-H bonds, selectivity trends correlate with the size of the palladacyclic intermediate, with five-membered rings being favored over six- and seven-membered rings. Regio- and diastereoselectivity issues were studied computationally in the prototypal case of indane formation. DFT(B3PW91) calculations demonstrated that C-H activation is the rate-determining step and that the creation of a C-H agostic interaction, increasing the acidity of a geminal C-H bond, is a critical factor for the regiochemistry control.

Copper-catalyzed tandem oxidation-olefination process.

A novel catalytic sequence aerobic oxidation-olefination has been developed. A single and inexpensive copper catalyst provides a large range of olefins from alcohols in good to excellent yields. The reaction exhibits excellent functional group compatibility, and the nonbasic reaction conditions allow the transformation of chiral substrates without racemization.

One-pot approach for the synthesis of trans-cyclopropyl compounds from aldehydes. Application to the synthesis of GPR40 receptor agonists.

A novel multicatalytic one-pot process providing trans-cyclopropyl compounds from corresponding aldehydes has been developed and applied to the synthesis of GPR40 small molecule agonists.

Transition-metal-catalyzed chemoselective methylenation of dicarbonyl substrates.

Rhodium- and copper-catalyzed methylenation reactions with trimethylsilyldiazomethane, triphenylphosphine, and 2-propanol were used to react chemoselectively with aldehydes, alkoxymethylketones, and trifluoromethylketones in substrates also containing a less reactive carbonyl group. Terminal alkenes were obtained in high yields, and no protecting group was necessary in the methylenation process.

Copper-carbene complexes as catalysts in the synthesis of functionalized styrenes and aliphatic alkenes.

(NHC)-Cu (NHC = N-heterocyclic carbene) complexes efficiently catalyzed the methylenation of a variety of aliphatic and aromatic aldehydes and ketones in the presence of trimethylsilyldiazomethane, triphenylphosphine, and 2-propanol. The copper catalysts are not only inexpensive compared to rhodium complexes, but they also exhibit better functional group compatibility with aromatic aldehydes and ketones. Indeed very high yields were obtained for the formation of styrenes containing nitro, trifluoromethyl, amino, and ester groups, as well as for pyridine-, pyrrole-, and indole-substituted alkenes.