Palladium-Catalyzed, Mild Dehydrogenation of 4-Alkylpyridines

Abstract

We report a mild palladium-catalyzed selective dehydrogenation of 4-alkylpyridines that exploits their soft enolization to alkylidene dihydropyridines using allyl chloroformate under metal-free conditions. Treatment of these intermediates with a palladium catalyst liberates an alkylpyridylic anion and an allylpalladium(II) intermediate, which combine and undergo βhydride elimination to install a double bond. Importantly, the formation of gas byproducts makes the process very practical. Furthermore, the reaction tolerates a broad range of functional groups, including many that can be dehydrogenated using similar palladium-catalyzed reactions, and is selective for 4-alkylpyridines even in substrates bearing multiple pyridylic positions.

Site-Selective Acceptorless Dehydrogenation of Aliphatics Enabled by Organophotoredox/Cobalt Dual Catalysis

“…Compared to aryl alkanes, methods for the dehydrogenation of heteroaryl analogues are much less explored. Very recently, Newhouse reported the first practical oxidative dehydrogenation of heteroaryl alkanes by nickel catalysis in the presence of a stoichiometric bromothiophene oxidant . Our system provides an oxidant-free alternative.…”

Direct Methenylation of 4-Alkylpyridines Using Eschenmoser’s Salt

“…8 Most existing syntheses of 4-alkenyl pyridines have targeted the preparation of 4-vinyl pyridine itself, as well as 1,2-disubstituted and tri-/tetrasubstituted alkenyl pyridines. 9 In contrast, synthetic strategies for accessing geminal 1,1-disubstituted 4-alkenyl pyridines are less common and generally involve reactions of 4-acyl pyridines (Wittig reaction, organometallic addition–dehydration). 10 Additionally, a Cu-promoted methenylation between 4-benzylpyridines and N , N -dimethylacetamide has been reported.…”

Rhodium-Catalyzed Chemodivergent Pyridylation of Alkynes with Pyridylboronic Acids

“…Encouraged by this result, we then wondered whether the rhodium catalytic system could be applied to addition of pyridylboronic acids to alkynes (Scheme A) . If successful, valuable alkenylpyridines, which are not only useful synthons for various types of transformations but also prevalent structural motifs in pharmaceutical drugs and natural products (selected examples are shown in Scheme B), could be readily accessed . To the best of our knowledge, only a few entries on the hydropyridylation of a carbon–carbon triple bond with 2-substituted pyridylboronic acids have been disclosed, mainly by Xie’s group in the Mn-catalyzed hydroarylation of 1,3-diynes and tert -propargyl alcohols. , Nonetheless, a general catalytic system that works for the pyridylation of simple alkynes with diverse pyridylboronic acids has not been developed.…”