Umpolung Synthesis of Pyridyl Ethers by Bi^V‐Mediated O‐Arylation of Pyridones

Abstract

We report that O-selective arylation of 2-and 4-pyridones with arylboronic acids is affected by a modular, bismacycle-based system. The utility of this umpolung approach to pyridyl ethers, which is complementary to conventional methods based on SNAr or crosscoupling, is demonstrated through the concise synthesis of Ki6783 and picolinafen, and the formal synthesis of cabozantib and golvatinib. Computational investigations reveal that arylation proceeds in a concerted fashion via a 5-membered transition state. The kineticallycontrolled regioselectivity for O-arylationwhich is reversed relative to previous Bi(V)-mediated pyridone arylationsis attributed primarily to the geometric constraints imposed by the bismacyclic scaffold.

Synthesis of Highly Functionalized Bismacycles via Post-Transmetallation Modification of Arylboronic Acids

“…To showcase the broader utility of post-transmetallation functionalization in synthesis, we applied TBS-protected hydroxyphenyl bismacycle 17 to the electrophilic arylations developed previously in our laboratory (Scheme ). ,− Thus, the products from O -selective arylation of pyridones ( 23 ), ortho -selective arylation of naphthols ( 25 ), meta -selective arylation of phenols ( 28 ), and α-selective arylation of cyclic 1,3-diketones ( 29 ) were obtained in good yields. Due to the silyl protecting group in 17 , the arylations, and selected subsequent manipulations ( 25 → 26 , 29 → 30 ), all proceeded without the chemoselectivity issues that would accompany the direct use of parent hydroxyphenyl bismacycle 2g .…”

“…We have subsequently adapted our methodology to the meta-selective C−H arylation of phenols, 41 the α-arylation of cyclic and polyfluoroalkyl diones, 42 and the O-selective arylation of 2-and 4-pyridones. 43 Contemporaneously with our initial report, Cornella demonstrated the use of a structurally related sulfoximine-bridged bismacycle for catalytic C Ar −F formation 44 and subsequently used substituted sulfone-bridged bismacycles in catalytic C Ar -OTf formation 45 and sulfonyl fluoride synthesis. 46 The utility of our bismuth-mediated arylation strategy hinges on the B-to-Bi transmetallation process (1-X → 2, Scheme 1B), which we have so far demonstrated with over 65 distinct examples spanning a sterically and electronically diverse range of arylboronic acids.…”

“…acyclic heteroleptic bismuthanes), ,− and the resulting bismacycle co-product can be recovered and reused in excellent yield. We have subsequently adapted our methodology to the meta -selective C–H arylation of phenols, the α-arylation of cyclic and polyfluoroalkyl diones, and the O -selective arylation of 2- and 4-pyridones . Contemporaneously with our initial report, Cornella demonstrated the use of a structurally related sulfoximine-bridged bismacycle for catalytic C Ar –F formation and subsequently used substituted sulfone-bridged bismacycles in catalytic C Ar -OTf formation and sulfonyl fluoride synthesis …”

“…The utility of our bismuth-mediated arylation strategy hinges on the B-to-Bi transmetallation process ( 1-X → 2 , Scheme B), which we have so far demonstrated with over 65 distinct examples spanning a sterically and electronically diverse range of arylboronic acids. ,− However, while extremely enabling, the transmetallation comes with an implicit limitation: the requisite boronic acid must be accessible, either commercially or by de novo synthesis.…”

“…We anticipated that functional group interconversions (FGIs) at the exocyclic aryl group after its installation on bismuth ( 2 → 2′ , Scheme C) would provide a convenient solution to this issue. Furthermore, as a general strategy, “post-transmetallation modification” would also enable (1) the rapid structural diversification of a common aryl bismacycle precursor for library synthesis, and (2) installation of aryl moieties for which direct B-to-Bi transmetallation is slow, such as from electron-poor and sterically hindered boronic acids. , Given that the B-to-Bi transmetallation is compatible with numerous synthetically versatile functional groups, including halides, alkenes, and carbonyls, there is a huge scope for the transformations that could potentially be achieved. However, the overall success of the strategy requires not only that the desired transformation proceeds efficiently, but also that the weak Bi–C bonds remain intact during the reaction and any subsequent purifications.…”