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.

Synthesis of Collidine from Dinitrogen via a Tungsten Nitride

“…The presence of a 15 N nucleus was also observed in the corresponding 1 H and 13 C­{ 1 H} NMR spectra given that several signals appeared as 15 N-coupled doublets as comprehensively summarized in Figure . Mass spectrometric measurements further confirmed that the O atom within the starting material was replaced by an N atom via a skeletal editing process, whichin the present caseis referred to as O-for-N swapping reaction …”

“…In conclusion, collidine was prepared from N 2 via a tungsten nitride, which was shown to undergo an O-for-N swapping reaction upon treatment with 2,4,6-trimethylpyrylium triflate. Given that similar atom swapping reactions are scarce, the reaction sequence reported herein is considered particularly relevant, not only in the context of N 2 functionalization, but also in the context of skeletal editinga currently emerging field.…”

Leveraging Pyrazolium Ylide Reactivity to Access Indolizine and 1,2‐Dihydropyrimidine Derivatives

“…Possible reaction mechanisms to form the indolizine and 1,2-dihydropyrimidine products are proposed. Scheme 2A outlines a skeletal editing [9,36] N-deletion mechanism for the formation of indolizine products. Based on our isolation of the cyclobutene intermediate, we propose a stepwise 1,3-dipolar cycloaddition, followed by the addition of a second equivalent of alkyne to form the fused ring system 6 a.…”

N-Oxide-to-Carbon Transmutations of Azaarene N-Oxides

“…After examining the scope of this transformation, we recognized that the use of more complex sulfoxides could selectively introduce substituents at the newly introduced atom, thereby formally accomplishing an atom-swap/ ipso -functionalization. This type of tandem transformation has been described but is still underexplored. , Although attempts to use simple phenyl alkyl sulfoxides failed to furnish the desired benzene derivatives, possibly due to a deleterious steric effect that prevents ring closure, we found that symmetrical dialkyl sulfoxides can undergo the desired transformation (Scheme A). Linear alkyl groups were introduced to both pyridine and quinoline N -oxide substrates in preparatively useful yields ( 36 – 43 ).…”

“…There has been a substantial body of research directed toward selective peripheral functionalization of pyridines (e.g., metalations, C–H functionalizations, etc. ). , However, few reports demonstrate the transformation of pyridine scaffolds into other classes of aromatic compounds by ring atom substitution . In considering how this ring atom swap might be achieved, we drew inspiration from the Zincke aldehyde reaction wherein a nucleophilic addition to an activated pyridine ring is attended by ring-opening to a functionalized unsaturated iminium ion. , Morofuji and Kano recently reported a three-step protocol enabling the conversion of pyridines to functionalized benzene derivatives by reacting Zincke intermediates with carbon-based nucleophiles (Figure C) …”