Palladium-Catalyzed C–H Activation/Cross-Coupling of Pyridine N-Oxides with Nonactivated Secondary Alkyl Bromides

Abstract

An unexpected C-H activation/C-C cross-coupling reaction has been found to occur between pyridine N-oxides and general nonactivated secondary and even tertiary alkyl bromides. It provides a practically useful approach for the synthesis of alkylated pyridine derivatives. Experimental observations indicated that the C-Br cleavage step involves a radical-type process. Thus, the title reaction provides a rather extraordinary example of Pd-catalyzed cross-coupling of secondary and tertiary aliphatic electrophiles.

Halogen-Bonded Co-Crystals of Aromatic N-oxides: Polydentate Acceptors for Halogen and Hydrogen Bonds

“…The C−H···O contacts are attractive, and are rather site acidity-dependent. For example, the C2-proton acidity in pyridine N-oxides for ortho-C−H functionalization in organic synthesis [19][20][21][22][23][24][25], and in crystal engineering for C−H···O−N interactions is well studied [51][52][53][54]. However, to the best of our knowledge, the combination of C−H···O−N and C−I···O−N interactions through the N−O group, giving rise to supramolecular assemblies, has not been extensively studied.…”

“…Aromatic N-oxides have been long known in heterocyclic chemistry for functionalized pyridines syntheses [19][20][21][22][23][24][25]. Besides being valuable synthetic intermediates, the dipolar neutral N⁺−O − group exhibits a push-pull property towards aromatic rings, enabling it to undergo both electrophilic and nucleophilic substitution reactions, categorizing these compounds as promising building blocks in supramolecular chemistry [26,27].…”

Recent advances in the application of group-10 transition metal based catalysts in C–H activation and functionalization

“…Transition metal catalyzed intermolecular cross-coupling of inert C−H bonds has recently emerged as a powerful method for C−C bond formation [41]. The first example of Pd as C−H activator was reported for the synthesis of olefinated arenes from benzene using Pd(OAc)2 [42].…”

“…For the synthesis of alkylated pyridine derivatives, Fu et al [41] reported an extraordinary gram scale example of the Pd-catalyzed cross-coupling of secondary and tertiary aliphatic electrophiles with pyridine N-oxides (Scheme 29). They found application of this method in the alkylation of naturally occurring alkaloids such as quinine, cinchonine and in the coupling of steroids and alkyl pyridine derivatives.…”

Synthesis and Late-Stage Functionalization of Complex Molecules through C–H Fluorination and Nucleophilic Aromatic Substitution

“…7 However, these reactions are limited to the formation of C–C bonds, and the reaction conditions and scope suggest that these reactions are not suitable for complex substrates. 8 Other functionalizations of heteroaryl C–H bonds involve cross-coupling at the most acidic C–H bond; these methods occur most commonly with five-membered ring heteroarenes. 7a−7c …”