Pd-Catalyzed Direct Arylation of Tautomerizable Heterocycles with Aryl Boronic Acids via C−OH Bond Activation Using Phosphonium Salts

Abstract

The first direct arylation via C-OH bond activation of tautomerizable heterocycles has been achieved using phosphonium salts, on the basis of a combination of the phosphonium coupling and Suzuki-Miyaura cross-coupling conditions. Optimal reaction condition is obtained through screening of phosphonium salts, Pd catalysts, and bases. The direct arylation via C-OH bond activation tolerates a variety of tautomerizable heterocycles and aryl boronic acids. The mechanism of the Pd-catalyzed phosphonium coupling is proposed to proceed via a domino seven-step process including the unprecedented heterocycle-Pd(II)-phosphonium species. Application of the Pd-catalyzed direct arylation via C-OH bond activation using PyBroP leads to the most efficient synthesis of the biologically important 6-arylpurine ribonucleoside in a single step from unactivated and unprotected inosine.

Nickel‐Catalyzed Cross‐Coupling of Phenols and Arylboronic Acids Through an In Situ Phenol Activation Mediated by PyBroP

“…The results showed that although these systems could react with phenols to form phenolic phosphonium salts [(ArOPR 3 ) + X À ], the subsequent metal-catalyzed cross-coupling with boronic acid was unsuccessful in the presence of various Pd or Ni catalysts. Further exploration eventually revealed that bromotripyrrolidinophosphonium hexafluorophosphate (PyBroP), which has been shown to be a mild and effective agent for the in situ activation of a-N-activated heterocyclic arenols, [10,11] was also a suitable agent for the activation of common phenols. However, here, a combination of Et 3 N and K 3 PO 4 (or K 2 CO 3 ) as the base coupled with an elevated reaction temperature (80-100 8C) is crucial for effective activation of phenols.…”

“…Very recently, the in situ activation of phenols through the formation of inorganic salts (e.g., ArOMgX) [9] and organic phenolic phosphonium salts, [10,11] or pivalate esters [6a] has emerged as an attractive approach for CÀC bond formation. These novel strategies provide an important advantage over the traditional ones; they merge the phenol activation and subsequent cross-coupling into a single operation and, therefore, make the transformation more practical in terms of efficiency, economy, and environmental impact.…”

Chemoselectivity and the Curious Reactivity Preferences of Functional Groups

“…[145] In 2008, Kang and co-workers reported that the bromophosphonium salt PyBroP can be employed as an in situ activating agent to allow the direct arylation of tautomerizable heterocycles by Suzuki-Miyaura coupling. [146] The broad functional-group tolerance and high-yielding procedure allowed for the preparation of a range of biaryls including 6-aryl purine ribonucleosides, which display cytostatic and anti-HCV (HCV = hepatitis C virus) properties.…”

State‐of‐the‐Art in Metal‐Catalyzed Cross‐Coupling Reactions of Organoboron Compounds with Organic Electrophiles

“…In 2008, a research group from Johnson & Johnson found that amide coupling reagents such as PyBroP could be employed to activate alcohols in situ toward the desired cross-coupling reactions (Eq. (21), Scheme 2.22) [77]. In this transformation, preactivation of alcohols toward cross-coupling reactions became unnecessary and activation of alcohols could be affected in a one-pot manner with the actual cross-coupling reactions.…”