Bismuth‐Mediated α‐Arylation of Acidic Diketones with ortho‐Substituted Boronic Acids

Abstract

The α-arylation of cyclic and fluoroalkyl 1,3diketones is made challenging by the highly stabilized nature of the corresponding enolates, and is especially difficult for sterically demanding aryl partners. As a general solution to this problem, we report the Bimediated oxidative coupling of acidic diones and orthosubstituted arylboronic acids. Starting from a benchstable bismacycle precursor, a sequence of B-to-Bi transmetallation, oxidation and CÀ C bond formation furnishes the arylated diones. Development of methodology that tolerates both sensitive functionality and steric demand is supported by interrogation of key reactive intermediates. Application of our strategy to cyclic diones enables the concise synthesis of important agrochemical intermediates which were previously prepared using toxic Pb reagents. This methodology also enables the first ever arylation of fluoroalkyl diones which, upon condensation with hydrazine, provides direct access to valuable fluoroalkyl pyrazoles.

Umpolung Synthesis of Pyridyl Ethers by BiV‐Mediated O‐Arylation of Pyridones

“…As anticipated, [35][46] a primary amine is not tolerated in the oxidation step (Scheme 3, entry b), and is also incompatible with the subsequent arylation. However, in contrast to our recentlyreported methodology for Bi(V)-mediated dione arylation, [35] a secondary benzylic alcohol is tolerated in the oxidation (entry c); this difference in reactivity may reflect the distinct speciation of the Bi(V) centres being formed in each case. Benzaldehydes, amides and nitriles are tolerated in both steps (entries d-f).…”

“…Given that both mCPBA and Selectfluor rapidly effect the oxidation of arylbismacycle 2, this observation suggests that the issue lies in either (1) formation of a key Bi(V)-pyridonate intermediate, or (2) the subsequent product-forming arylation process. Due to the greater thermal stability of the Bi(V) species formed with Selectfluorthe O,F-bridged dimer 3 (Scheme 1C), which was previously isolated and characterized crystallographically [35] we further explored the use of this fluoronium reagent in combination with isolated bismacycles bearing both ortho-substituted and ortho-unsubstituted aryl moieties (Table 1). While the yield of aryloxypyridines 4 and 5 increased with reaction temperature (Table 1, entries 1-4), the addition of base was detrimental (entry 5; see also Table S2).…”

“…We sought to develop a modular and convenient strategy in which a reactive Bi V arylating agent is prepared from bench-stable precursor 1 via sequential B-to-Bi transmetallation and oxidation (Scheme 1C). Having previously established the key transmetallation step, [34,35] our initial studies focused on the oxidation/arylation procedure. Disappointingly, conditions optimized for the arylation of phenols [34] and acidic diones [35] proved unsuitable for the arylation of pyridones: < 5 % of the desired aryloxypyridine was formed at room temperature using either mCPBA or Selectfluor as the oxidant (Figure S1).…”

“…Having previously established the key transmetallation step, [34,35] our initial studies focused on the oxidation/arylation procedure. Disappointingly, conditions optimized for the arylation of phenols [34] and acidic diones [35] proved unsuitable for the arylation of pyridones: < 5 % of the desired aryloxypyridine was formed at room temperature using either mCPBA or Selectfluor as the oxidant (Figure S1). Given that both mCPBA and Selectfluor rapidly effect the oxidation of arylbismacycle 2, this observation suggests that the issue lies in either (1) formation of a key Bi V -pyridonate intermediate, or (2) the subsequent product-forming arylation process.…”

Umpolung Synthesis of Pyridyl Ethers by BiV‐Mediated O‐Arylation of Pyridones

“…As anticipated, [35, 46] a primary amine is not tolerated in the oxidation step (Scheme 3, entry b), and is also incompatible with the subsequent arylation. However, in contrast to our recently‐reported methodology for Bi V ‐mediated dione arylation, [35] a secondary benzylic alcohol is tolerated in the oxidation (entry c); this difference in reactivity may reflect the distinct speciation of the Bi V centres being formed in each case. Benzaldehydes, amides and nitriles are tolerated in both steps (entries d–f).…”