Development of a General Method for the Hiyama-Denmark Cross-Coupling of Tetrasubstituted Vinyl Silanes.

General conditions for the Hiyama-Denmark cross-coupling of tetrasubstituted vinyl silanes and aryl halides are reported. Prior reports of Hiyama-Denmark reactions of tetrasubstituted vinyl silanes have required the use of vinyl silanols or silanolates, which are challenging to handle, or internally activated vinyl silanes, which lack structural generality. Now, unactivated tetrasubstituted vinyl silanes, bearing bench-stable tetraorganosilicon centers, and aryl halides can be coupled. The key to this discovery is the identification of dimethyl(5-methylfuryl)vinylsilanes as bench stable and easily prepared cross-coupling partners that are readily activated under mild conditions in Hiyama-Denmark couplings. These palladium-catalyzed cross-couplings proceed well with aryl chlorides, though aryl bromides and iodides are also tolerated, and the reactions display high stereospecificity in the formation of tetrasubstituted alkenes. In addition, only a mild base (KOSiMe3) and common solvents (THF/DMA) are required, and importantly toxic additives (such as 18-crown-6) are not needed. We also show that these conditions are equally applicable to Hiyama-Denamrk coupling of trisubstituted vinyl silanes.

Metal-Free C-C Coupling of an Allenyl Sulfone with Picolyl Amides to Access Vinyl Sulfones via Pyridine-Initiated In Situ Generation of Sulfinate Anion.

Vinyl sulfones are privileged motifs known for their biological activity and synthetic utility. Synthetic transformations to efficiently access high-value compounds with these motifs are desired and sought after. Herein, a new procedure is described to form vinyl sulfone-containing compounds by selective functionalization of the C(sp3)-H bond adjacent to the pyridine ring of pharmacologically prevalent picolyl amides with an allenyl sulfone, 1-methyl-4-(propa-1,2-dien-1-ylsulfonyl)benzene. The reaction conditions are mild with no metal catalyst or additives required and display good functional group tolerance. Mechanistic studies for this unusual transformation suggest that the reaction operates via a rare pyridine-initiated and p-toluenesulfinate anion-mediated activation of the allenyl sulfone analogous to phosphine-triggered reactions.

Computational Study of the Ni-Catalyzed C-H Oxidative Cycloaddition of Aromatic Amides with Alkynes.

The mechanism of Ni-catalyzed ortho C(sp2)-H oxidative cycloaddition of aromatic amides with internal alkynes containing 2-pyridinylmethylamine directing group was investigated using density functional theory (DFT) calculations. The C-H cleavage step proceeds via σ-complex-assisted metathesis (σ-CAM) with an alkenyl-Ni(II) complex. This is in contrast to the more common carboxylate/carbonate-assisted concerted metalation-deprotonation mechanism in related Ni-catalyzed C-H bond functionalization reactions with N,N-bidentate directing groups. In this reaction, the alkyne not only serves as the coupling partner, but also facilitates the σ-CAM C-H metalation both kinetically and thermodynamically. The subsequent functionalization of the five-membered nickelacycle proceeds via alkyne insertion into the Ni-C bond to form a seven-membered nickelacycle. This process proceeds with high levels of regioselectivity to form a C-C bond with sterically more encumbered alkyne terminus. This unusual regioselectivity is due to steric repulsions with the directing group that is coplanar with the alkyne in the migratory insertion transition state. The C-N bond reductive elimination to form the isoquinolone cycloadduct is promoted by PPh3 complexation to the Ni center and the use of flexible 2-pyridinylmethylamine directing group. The origin of the cis-trans isomerism of alkene byproduct was also explained by computations.

Ni-Catalyzed Arylboration of Unactivated Alkenes: Scope and Mechanistic Studies.

A method for the Ni-catalyzed arylboration of unactivated monosubstituted, 1,1-disubstituted, and trisubstituted alkenes is disclosed. The reaction is notable in that it converts highly substituted alkenes, aryl bromides, and diboron reagents to products that contain a quaternary carbon and a synthetically versatile carbon-boron bond with control of stereoselectivity and regioselectivity. In addition, the method is demonstrated to be useful for the synthesis of saturated nitrogen heterocycles, which are important motifs in pharmaceutical compounds. Finally, due to the unusual reactivity demonstrated, the mechanistic details of the reaction were studied with both computational and experimental techniques.

Computational Study of Ni-Catalyzed C-H Functionalization: Factors That Control the Competition of Oxidative Addition and Radical Pathways.

The mechanisms of Ni-catalyzed C-H arylation, alkylation, and sulfenylation with N,N-bidentate directing groups are investigated using density functional theory (DFT) calculations. While the C-H cleavage occurs via the concerted metalation-deprotonation (CMD) mechanism in all types of reactions, the subsequent C-C and C-X bond formation steps may occur via either oxidative addition to form a Ni(IV) intermediate or radical pathways involving Ni(III) complexes generated from homolytic dissociation of disulfides/peroxides or halide-atom transfer from alkyl halides. DFT calculations revealed that radical mechanisms are preferred in reactions with sterically hindered coupling partners with relatively low bond dissociation energies (BDE) such as dicumyl peroxide, heptafluoroisopropyl iodide and diphenyl disulfide. In contrast, these radical processes are highly disfavored when generating unstable phenyl and primary alkyl radicals. In such cases, the reaction proceeds via an oxidative addition/reductive elimination mechanism involving a Ni(IV) intermediate. These theoretical insights into the substrate-controlled mechanisms in the C-H functionalizations were employed to investigate a number of experimental phenomena including substituent effects on reactivity, chemo- and regioselectivity and the effects of oxidant in the intermolecular oxidative C-H/C-H coupling reactions.