Reaction Optimization, Scalability, and Mechanistic Insight on the Catalytic Enantioselective Desymmetrization of 1,1-Diborylalkanes via Suzuki-Miyaura Cross-Coupling.

A method for enantioselective desymmetrization of 1,1-diborylalkanes through a stereoselective Pd-catalyzed Suzuki-Miyaura cross-coupling has been thoroughly optimized. The most effective ligand was found to be a α,α,α,α-tetra-aryl-1,3-dioxolane-4,5-dimethanol (TADDOL)-derived phosphoramidite. Results show that in order to achieve high selectivity, a suitable balance between the sterics of the aryl groups and the amino group on the ligand must be achieved. While the base has been known to facilitate transmetallation in cross-coupling reactions, mechanistic studies on this desymmetrization process reveal that the base, in the presence of KHF2, likely plays an additional role in the hydrolysis of the pinacol boronates to the corresponding boronic acids. Through an in depth optimization of the chiral ligand and mechanistic studies, it was possible to obtain ee values over 90% for several aryl bromides and to develop a reliably scalable process (up to one gram of 1,1-diborylalkane substrate).

Optimization of Reaction and Substrate Activation in the Stereoselective Cross-Coupling of Chiral 3,3-Diboronyl Amides.

A method has been developed for the chemo- and stereoselective Suzuki-Miyaura cross-coupling of optically enriched gem-diboronyl compounds with various aryl bromides. Experimental evidence suggests that the Lewis acidity of the second boron group in these substrates plays a significant role in facilitating these otherwise challenging cross-coupling processes. ß-Diboronyl esters may be successfully cross-coupled in excellent yield and enantiomeric excess with prior conversion of the pinacol boronate to the corresponding trifluoroborate salt. In contrast, a substrate bearing a Weinreb amide can undergo direct coupling of the Bpin moiety, likely due to the stronger coordination of the more basic amide carbonyl group. The resulting optically enriched secondary boronate may be used in a second enantioselective cross-coupling to afford pharmaceutically relevant diarylmethane products. The use of a Weinreb amide substrate allows for facile postcoupling modification, as demonstrated by a transformation to the corresponding ketone.

Mechanistic analysis of azine N-oxide direct arylation: evidence for a critical role of acetate in the Pd(OAc)2 precatalyst.

Detailed mechanistic studies on the palladium-catalyzed direct arylation of pyridine N-oxides are presented. The order of each reaction component is determined to provide a general mechanistic picture. The C-H bond cleaving step is examined in further detail through computational studies, and the calculated results are in support of an inner-sphere concerted metalation-deprotonation (CMD) pathway. Competition experiments were conducted with N-oxides of varying electronic characters, and results revealed an enhancement of rate when using a more electron-deficient species, which is in support of a CMD transition state. The effect of base on reaction rate was also examined and it was found that a carboxylate base was required for the reaction to proceed. This led to the conclusion that Pd(OAc)(2) plays a pivotal role in the reaction mechanism as more than merely a precatalyst, but also as a source of acetate base required for the C-H bond cleavage step.

Palladium-catalyzed direct arylation of azine and azole N-oxides: reaction development, scope and applications in synthesis.

Palladium-catalyzed direct arylation reactions are described with a broad range of azine and azole N-oxides. In addition to aspects of functional group compatibility, issues of regioselectivity have been explored when nonsymmetrical azine N-oxides are used. In these cases, both the choice of ligand and the nature of the azine substituents play important roles in determining the regioisomeric distribution. When azole N-oxides are employed, preferential reaction is observed for arylation at C2 which occurs under very mild conditions. Subsequent reactions are observed to occur at C5 followed by arylation at C4. The potential utility of this methodology is illustrated by its use in the synthesis of a potent sodium channel inhibitor 1 and a Tie2 Tyrosine Kinase inhibitor 2.