C–H Functionalization of Pyridines via Oxazino Pyridine Intermediates: Switching to para-Selectivity under Acidic Conditions

Abstract

para-Selective C−H functionalization of pyridines holds a significant value but remains underdeveloped. Site-switchable C−H functionalization of pyridines under easily tunable conditions expedites drug development. We recently reported a redox-neutral dearomatization−rearomatization strategy for meta-C−H functionalization of pyridines via oxazino pyridine intermediates. Here, we demonstrate that these oxazino pyridine intermediates undergo highly para-selective functionalization simply by switching to acidic conditions. A broad scope of para-alkylated and arylated pyridines is prepared through radical as well as ionic pathways. These mild and catalyst-free methods are applied to the late-stage para-functionalization of drugs using pyridines as the limiting reagents. Consecutive meta,para-difunctionalization of pyridines is also achieved with complete regiocontrol relying on the pH-dependent reactivity of oxazino pyridines.

Catalyst-free visible light-promoted defunctionalization of alkyl isocyanides with a hydrosilane through C–N bond cleavage

“…On the basis of the above experimental results and previous reports, 15–17 we propose the following reaction pathway for the defunctionalization of alkyl isocyanides (Scheme 4). Tris(trimethylsilyl)silane has a low Si–H bond energy (79 kcal mol −1 ) and is amenable to homolytic cleavage under blue light irradiation to generate silicon-centered radical 3 .…”

“…In 1990, Kulicke and Giese reported a hydrosilylation reaction of alkenes with tris(trimethylsilyl)silane under photolysis via a radical mechanism. 15,16 Encouraged by this report, we envisioned that defunctionalization of alkyl isocyanides with tris(trimethylsilyl)silane, a radical-based reducing agent, 17 would take place under light irradiation in the absence of a radical initiator. To our delight, the defunctionalization reaction of alkyl isocyanide 1a with tris(trimethylsilyl)silane smoothly proceeded in benzene under blue light irradiation at room temperature, and the desired reduced product 2a was obtained in 99% yield (Table 1, entry 1).…”

“…Tris(trimethylsilyl)silane has a low Si–H bond energy (79 kcal mol −1 ) and is amenable to homolytic cleavage under blue light irradiation to generate silicon-centered radical 3 . 15,16 Radical 3 abstracts the isocyano group of alkyl isocyanide 1 to give alkyl radical 4 and (Me 3 Si) 3 SiCN. 19 Alkyl radical 4 undergoes hydrogen atom abstraction from tris(trimethylsilyl)silane, 17 delivering the reduced product 2 and regenerating radical 3 .…”

A dearomatization–rearomatization strategy for construction of 4H-quinolizin-4-ones via C–H bond functionalization of pyridines

“…1,2 Recently, the Studer group reported a novel dearomatization-rearomatization strategy for transition-metal-free C-H bond functionalization of pyridines by a one-pot sequence (Scheme 1A). 3,4 In 2022, Studer and coworkers developed an unprecedented radical/ ionic meta-C-H functionalization of pyridines via oxazino pyridine intermediates. 3 Afterwards, the same group also achieved para-C-H bond functionalization of pyridines by switching oxazino pyridine intermediates into pyridinium intermediates under acidic conditions.…”

“…3 Afterwards, the same group also achieved para-C-H bond functionalization of pyridines by switching oxazino pyridine intermediates into pyridinium intermediates under acidic conditions. 4 The dearomatization-rearomatization strategy could be expected to solve more problems in the construction and derivatization of (hetero)arenes. 5 Functionalized 4H-quinolizin-4-ones, which are special pyridine derivatives, have garnered more and more attention in the pharmaceutical industry because of their polar zwitterionic character.…”