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The applicability of C–H functionalization to medicinally important 2-pyridyl-based N-heterocycles suffers from severe challenges owing to the high Lewis basicity of the N-atom. This arrests catalytic activity and yields undesirable positional selectivity due to preferential chelate formation. In this regard, we report a novel palladium(II)-catalyzed arylation strategy on multiple-N-containing pyridazines by over-riding the functionalization due to a chelated palladacycle. We report a regioselective mono-arylation at the 8-position of diphenyl azolopyridazines without any ortho-C–H activation on the proximal phenyl groups. This methodology presents a broad arylation scope with uncompromised yield and positional selectivity, including the heteroarylation of N-heterocycles, which is an unprecedented feat for these types of molecules.

Site-selective C-H functionalization has emerged as an efficient tool in simplifying the synthesis of complex molecules. Most often, directing group (DG)-assisted metallacycle formation serves as an efficient strategy to ensure promising regioselectivity. A wide variety of ortho- and meta-C-H functionalizations stand as examples in this regard. Yet despite this significant progress, DG-assisted selective para-C-H functionalization in arenes has remained unexplored, mainly because it involves the formation of a geometrically constrained metallacyclic transition state. Here we report an easily recyclable, novel Si-containing biphenyl-based template that directs efficient functionalization of the distal p-C-H bond of toluene by forming a D-shaped assembly. This DG allows the required flexibility to support the formation of an oversized pre-transition state. By overcoming electronic and steric bias, para-olefination and acetoxylation were successfully performed while undermining o- and m-C-H activation. The applicability of this D-shaped biphenyl template-based strategy is demonstrated by synthesizing various complex molecules.

Non-heme iron(IV)–oxo species form iron(III) intermediates during hydrogen atom abstraction (HAA) from the C–H bond. While synthesizing a room temperature stable, electron rich, non-heme iron(IV)–oxo compound, we obtained iron(III)–hydroxide, iron(III)–alkoxide and hydroxylated-substrate-bound iron(II) as the detectable intermediates. The present study revealed that a radical rebound pathway was operative for benzylic C–H oxidation of ethylbenzene and cumene. A dissociative pathway for cyclohexane oxidation was established based on UV-vis and radical trap experiments. Interestingly, experimental evidence including O-18 labeling and mechanistic study suggested an electron transfer mechanism to be operative during C–H oxidation of alcohols (e.g. benzyl alcohol and cyclobutanol). The present report, therefore, unveils non-heme iron(IV)–oxo promoted substrate-dependent C–H oxidation pathways which are of synthetic as well as biological significance.