meta-Selective C–H arylation of phenols via regiodiversion of electrophilic aromatic substitution

Abstract

Electrophilic aromatic substitution (EAS) is among the most widely used mechanistic manifolds in organic chemistry. Access to certain substitution patterns is, however, precluded by intrinsic and immutable substituent effects that ultimately restrict the diversity of benzenoid chemical space. Here we demonstrate that the established regioselectivity of EAS can be overcome simply by diverting the key σ-complex intermediate towards otherwise

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

“…While Jacobsen–Katsuki epoxidation did proceed quantitatively, as determined by 1 H NMR spectroscopy (Scheme D), epoxide 10 proved extremely sensitive to isolation and therefore could not be obtained pure. Notably, the opposite chemoselectivity is observed with m CPBA, which we have previously demonstrated oxidizes the bismuth center to Bi­(V) in preference to epoxidizing a pendant styrene or mediating Baeyer–Villiger rearrangement on a pendant formyl substituent …”

“…Notably, the opposite chemoselectivity is observed with mCPBA, which we have previously demonstrated oxidizes the bismuth center to Bi(V) in preference to epoxidizing a pendant styrene 38 or mediating Baeyer−Villiger rearrangement on a pendant formyl substituent. 41 Although styrenyl bismacycle 2d tolerates both oxidants (Scheme 4B) and reductants (Scheme 4C), not all redox processes were compatible. For example, only the unreacted starting material was recovered following attempted hydrogenation of 2d with H 2 and either Pd/C or Wilkinson′s catalyst (Scheme 4E), while complete decomposition was observed when using HBPin/Pd(OAc) 2 64 or hydrazine/ NiCl 2 .…”

“…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 .…”

“…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.…”

Water as an oxygen source in I2-mediated construction of highly functionalized maleimide-fused phenols

“…2 The common strategies rely on aromatic precursors including nucleophilic and electrophilic aromatic substitutions, 3 selective C–H hydroxylation of arenes, 4 decarboxylative hydroxylation of benzoic acids, 5 and transition-metal catalyzed cross-coupling reactions. 6 These approaches provide direct access to para - and ortho -substituted phenols. In the last decade, oxidative aromatization of cyclohexanones and cyclohexenones has emerged as a powerful alternative choice, 7 but most of these processes have been limited to the synthesis of simple substituted phenols.…”