Skeletal editing of pyridines through atom-pair swap from CN to CC

Abstract

Skeletal editing is a straightforward synthetic strategy for precise substitution or rearrangement of atoms in core ring structures of complex molecules; it enables quick diversification of compounds that is not possible by applying peripheral editing strategies. Previously reported skeletal editing of common arenes mainly relies on carbene- or nitrene-type insertion reactions or rearrangements. Although powerful, efficient and applicable to late-stage heteroarene core structure modification, these strategies cannot be used for skeletal editing of pyridines. Here we report the direct skeletal editing of pyridines through atom-pair swap from CN to CC to generate benzenes and naphthalenes in a modular fashion. Specifically, we use sequential dearomatization, cycloaddition and rearomatizing retrocycloaddition reactions in a one-pot sequence to transform the parent pyridines into benzenes and naphthalenes bearing diversified substituents at specific sites, as defined by the cycloaddition reaction components. Applications to late-stage skeletal diversification of pyridine cores in several drugs are demonstrated.

Fig. 1. Various strategies for skeletal editing of arenes and heteroarenes.

a, Heteroarene skeletal editing through single-atom insertion and deletion that can be used at a late-stage, yet not reported for pyridines. b, Atom swap in arenes is challenging, with existing methods showing limited substrate scope and therefore application to late-stage modification is not possible. c, Our developed strategy through sequential dearomatization, cycloaddition and rearomatizing retrocyclization enabling an atom-pair swap from CN to CC in pyridines. The method is a one-pot modular approach for pyridine editing with a broad substrate scope that is applicable to late-stage modification.

Fig. 2. Application of the skeletal editing strategy.

a, Skeletal editing of pyridine cores in drugs and drug derivatives. Compounds 42, 46, 48, 51, 52, 54 are obtained under condition A, whereas others are synthesized under condition B. All yields are isolated yields based on pyridine in a one-pot process unless stated otherwise. ^aThe gram-scale yield (in parenthesis) by using condition A. ^bThe gram-scale yield (in parenthesis) by using condition B under air. ^cApplying condition B with probenecid-derived alkyne (1.2 equiv.); the yield is based on the pyridine. ^dWith condition A using (+)-δ-tocopherol derived aryne precursor (1 equiv.), 4-phenylpyridine (1.5 equiv.), DMAD (1.5 equiv.), MP (1.5 equiv.) and caesium fluoride (1.5 equiv.); the yield is based on the aryne precursor. ^eCombined yield of the two constitutional isomers. b, Application of aryne formation from aryl thianthrenium salt in pyridine editing.

Fig. 3. Reaction of the 4-phenylpyridine-derived oxazino pyridine with 2-phenylethinylsulfonylfluoride to give 36.

Calculated transition states for the cycloaddition and retrocycloaddition, as well as the structures of the intermediate cycloadducts. The numbers in brackets represent the free energies ΔG_s(353 K), including solvation (PW6B95-D3//TPSS-D3+COSMO-RS/1,4-dioxane), in kilocalories per mole. The calculation is in agreement with the experimental results, which indicates the origin of the regioselectivity and the thermaldynamically favoured rearomatization process.