2,6-Bis(pyrazol-1-yl)pyridine (1-bpp) as a General Ligand for the Negishi Alkylation of Alkylpyridinium Salts.

A Ni/1-bpp catalyst was demonstrated to be effective in the Negishi alkylation with multiple classes of alkylpyridinium salts, including α-primary and α-secondary. These conditions are also effective for benzylic pyridinium salts, demonstrating the successful Negishi alkylation of benzylic pyridinium salts for the first time. Further, 14 derivatives of 1-bpp were prepared with a variety of steric and electronic properties to study how these changes impact the success of the Negishi alkylation.

Design, Synthesis, and Physicochemical Studies of Configurationally Stable ß-Carboline Atropisomers.

Axially chiral atropisomers have energetic barriers to rotation, ΔGrot, that prevent racemization of the respective enantiomers. We used computational modeling to develop a suite of 10 bio-inspired 1-aryl-ß-carbolines with varying ΔGrot, from which a strong structure-activity relationship was observed for 2-substituted-1-naphthyl substituents. We then synthesized two of these atropisomers, 1d and 1f, by a four-step racemic synthesis and resolved the enantiomers via chiral chromatography. Racemization studies revealed experimental ΔGrot values of 39.5 and 33.0 kcal/mol for 1d and 1f, respectively, which were consistent with our computational results. These atropisomers exhibited long half-lives, which allowed for their physicochemical characterization and stereochemical assignment via UV-vis spectroscopy, fluorescence spectroscopy, electronic circular dichroism, and vibrational circular dichroism.

α-Chiral Amines via Thermally Promoted Deaminative Addition of Alkylpyridinium Salts to Sulfinimines.

A deaminative reaction of Katritzky alkylpyridinium salts and sulfinimines has been developed to deliver enantiopure α-chiral amines. The success of this method relied on the discovery of a thermally promoted deamination via single-electron transfer of an anion-π complex of the alkylpyridinium cation with potassium carbonate. This method boasts excellent diastereoselectivity over the α-stereocenter as well as broad functional group and heterocycle tolerance.

Engaging Alkenes and Alkynes in Deaminative Alkyl-Alkyl and Alkyl-Vinyl Cross-Couplings of Alkylpyridinium Salts.

An alkyl-alkyl cross-coupling of Katritzky alkylpyridinium salts and organoboranes, formed in situ via hydroboration of alkenes, has been developed. This method utilizes the abundance of both alkyl amine precursors and alkenes to form C(sp3)-C(sp3) bonds. This strategy is also effective with alkynes, enabling a C(sp3)-C(sp2) cross-coupling. Under these mild conditions, a broad range of functional groups, including protic groups, is tolerated. As seen with previous alkylpyridinium cross-couplings, mechanistic studies support an alkyl radical intermediate.

Deaminative Arylation of Amino Acid-derived Pyridinium Salts.

A Suzuki-Miyaura cross-coupling of α-pyridinium esters and arylboroxines has been developed. Combined with formation of the pyridinium salts from amino acid derivatives, this method enables amino acid derivatives to be efficiently transformed into α-aryl esters and amides. Under the mild conditions, broad functional group tolerance on both the amino acid derivatives and the arylboroxine are observed, including protic functional groups. Mechanistic studies support an alkyl radical intermediate, similar to other cross-couplings of alkylpyridinium salts.