Access to hexahydroazepinone heterocycles via palladium-catalysed C(sp3)-H alkenylation/ring-opening of cyclopropanes.

In this communication, we describe the synthesis of novel hexahydroazepinone derivatives starting from two simple building blocks in presence of a readily available palladium catalyst. The reaction proceeds through a selective C(sp3)-H alkenylation/ring-opening process to obtain the seven-membered ring products in good to excellent yields on a wide variety of substrates under batch, microwave, and continuous flow conditions.

Utilization of BozPhos as an Effective Ligand in Enantioselective C-H Functionalization of Cyclopropanes: Synthesis of Dihydroisoquinolones and Dihydroquinolones.

The bisphosphine monoxide ( R, R)-BozPhos enables enantioselective C-H functionalization of cyclopropanes in a palladium-catalyzed cyclization. The synthesis of a broad spectrum of dihydroisoquinolones and dihydroquinolones in good yields and high enantiomeric excess was achieved through the use of this hemilabile ligand. Furthermore, the isolation of an intermediary palladium(II)-BozPhos complex after oxidative addition was successful and a second complex provided further insight into bond length and angles through a crystal structure.

Access to Cyclopropyl-Fused Azacycles via a Palladium-Catalyzed Direct Alkenylation Strategy.

Palladium-catalyzed direct alkenylation of cyclopropyl C-H bonds proceeds in high efficiency. This transformation provides access to novel cyclopropyl-fused azacycles. Ligand studies suggest that bisphosphine monoxide analogues of dppf and rac-BINAP are the active ligand species. Preliminary results support that both BozPhos and IPrMonophos ligands can achieve high enantioinduction for this novel direct alkenylation reaction. To date, this represents the first example of enantioselective C-H functionalization employing a bisphosphine monoxide ligand.

Intramolecular sp(3) Functionalization of Cyclopropyl α-Amino Acid-Derived Benzamides.

Intramolecular Pd-catalyzed functionalization of cyclopropyl α-amino acid-derived benzamides proceeds without silver or pivalate additives. Both electronically and sterically diverse ethyl 1,2,3,4-tetrahydroisoquinolone-3-carboxylates were accessible in good to excellent yields.

Silver-promoted, palladium-catalyzed direct arylation of cyclopropanes: facile access to spiro 3,3'-cyclopropyl oxindoles.

The Pd-catalyzed, Ag(I)-mediated intramolecular direct arylation of cyclopropane C-H bonds is described. Various spiro 3,3'-cyclopropyl oxindoles can be obtained in good to excellent yields from easily accessible 2-bromoanilides. The kinetic isotope effect was determined and epimerization studies were conducted, suggesting that the formation of a putative Pd-enolate is not operative and that the reaction proceeds via a C-H arylation pathway.

Synthesis of 2- and 2,3-substituted pyrazolo[1,5-a]pyridines: scope and mechanistic considerations of a domino direct alkynylation and cyclization of N-iminopyridinium ylides using alkenyl bromides, alkenyl iodides, and alkynes.

Direct functionalization and tandem processes have both received considerable recent interest due to their cost and time efficiency. Herein we report the synthesis of difficult to obtain 2-substituted pyrazolo[1,5-a]pyridines through a tandem palladium-catalyzed/silver-mediated elimination/direct functionalization/cyclization reaction involving N-benzoyliminopyridinium ylides. As such, these biologically important molecules are prepared in an efficient, high-yielding manner, only requiring a two-step sequence from pyridine. Aryl-substituted alkenyl bromides and iodides are effective ylide coupling partners. Mechanistic studies led to the use of terminal alkynes, which extended the scope of the reaction to include alkyl substitution on the unsaturated reactive site. The optimization, scope, and mechanistic considerations of the process are discussed.