Catalytic Strategies to Convert 2‐Halopyridines to 2‐Alkylpyridines

Abstract

Over the past decade, improvements in synthetic technologies have increased the feasibility and practicality of the preparation of 2-alkylpyridines from 2-halopyridines. Advances in iron-, nickel, and palladium-catalysis have increased efficiency in the access of 2-alkylpyridines with traditional cross-coupling approaches. Additionally, the emergence of cross-electrophile coupling reactions and photo-redox catalysis strategies have proven to be enabling technologies for the synthesis of 2-alkylpyridines. Nevertheless, these developments reveal remaining opportunities for more efficient, mild, and straightforward methods to access a broader range of 2-alkylpyridines from 2-halopyridines.[a] J.

Development and Execution of an Ni(II)-Catalyzed Reductive Cross-Coupling of Substituted 2-Chloropyridine and Ethyl 3-Chloropropanoate

“…In recent times, the cross-coupling of two electrophilic components has been accomplished using Ni, Co, or Pd catalysts. − Nickel-catalyzed reductive cross-coupling reactions using alkyl halides have emerged as powerful methods to construct C­(sp 2 )–C­(sp 3 ) bonds, ,− mainly because of their potential as viable alternatives to stoichiometric air- and moisture-sensitive organozinc and organoboron species used in Negishi and Suzuki couplings, respectively. − We were particularly intrigued by the Ni-catalyzed reductive cross-coupling of 2-chloropyridines with alkyl halides developed by Weix. , The ready commercial availability of the alkyl halide coupling partners was a significant advantage of this protocol, and therefore, we sought to apply this methodology to forge the key C–C bond in the large-scale synthesis of 2 (strategy d ). Our efforts toward the development of a robust process for the reductive coupling to prepare 2 on a multikilogram scale are described.…”

Photochemically-Mediated, Nickel-Catalyzed Synthesis of N-(Hetero)aryl Sulfamate Esters

“…Because of the prevalence of heteroaromatic motifs in biologically relevant small molecules, heteroaryl bromides were also investigated (Scheme ). Given our interest in functionalized pyridines, we were pleased to find that 2-, 3-, and 4-bromopyridines were all effective arylating agents using the disclosed protocol. Moreover, this procedure transforms a range of other six-membered heteroaryl bromides, including pyrimidine, quinoline, and azaindole substrates.…”

“…Using the disclosed conditions, topiramate undergoes arylation to furnish N -phenyl topiramate ( 2ad ). This approach represents a marked improvement in efficiency over the previously reported route and makes use of commercially available topiramate as a substrate.…”

Photochemically Mediated Nickel-Catalyzed Synthesis of N-(Hetero)aryl Sulfamides

“…The developed nickel-mediated transformations furnish these products with increased yields relative to those documented using a known palladium-mediated protocol, suggesting that this nickel-mediated approach is worthy of concurrent investigation in the course of synthetic campaigns. Given our interest in functionalized pyridines, we were pleased to find that bromopyridines were effective arylating agents using the disclosed protocol. Furthermore, this dual-catalytic reaction manifold can transform aryl bromides, without engaging either C­(sp 2 )–B ( 3e ) or C­(sp 2 )–Cl ( 3f and 3g ) bonds to afford products with useful synthetic handles for further functionalization.…”