Mild and efficient palladium/BrettPhos-catalyzed methoxylation and deuteriomethoxylation of activated aryl bromides

Palladium‐Catalyzed Rapid Methoxylation and Deuteriomethoxylation of Bromo–chalcones: Uncovering the Catalytic Activity of the Pd/tBuXPhos Catalyst System

“…This result, rapidness of coupling, substantiates an aryl halide bearing an electron‐withdrawing group at p ‐position or an aryl halide possesses an extent of conjugation prefers an electronic pathway of reductive elimination mechanism rather than steric pathway . Predictably, notwithstanding the strong hydride donor nature of methanol, its more nucleophilic nature than fluoroalcohols would allow the rapid coupling of methanol and methanol‐ d 4 with, aryl bromides with an extent of conjugation, bromo‐chalcones …”

“…Surprisingly, this catalyst system could couple 2‐fluoroethanol with 4‐bromoacetophenone and 4‐bromobenzonitrile in about 50 min., albeit 2‐fluoroethanol is relatively weak nucleophilic in nature . With methanol and methanol‐ d 4 , this catalyst system could also couple with deactivated aryl bromides even at low temperature (55 o C) . This result implies that the alcohols behave differently, for a given Pd/ L system, depending on the choice of reductive elimination pathway which in turn the property of the ligand and the aryl halides.…”

“…The recent advances in the development of various phosphine ligands led to a promising outcomes in the C−O cross‐coupling reactions . However, Pd‐catalyzed coupling of simple methanol and methanol‐ d 4 has been paid more attention only in recent years,–– albeit Pd‐ catalyzed coupling of methanol with aryl bromides (only two examples) has already been reported by Buchwald group …”

“…Predictably, incorporation of deuterimethoxy group in chalcones enhances their biological, pharmaceutical activities, and reduces their toxicological properties. However, as yet no general and efficient procedure for the rapid methoxylation and deuteriomethoxylation of bromo‐chalcones is described in the literature …”

Transition‐Metal‐Catalyzed Utilization of Methanol as a C1 Source in Organic Synthesis

“…However,t he applicability of this method is limited because of the drastic reaction conditions, low functional group tolerance,and the necessity to use toxic reagents.A lternatively,i n2 012, Beller and co-workers [39] reported the first synthetic method for the palladiumcatalyzed coupling of aryl halides with methanol to synthesize substituted anisoles in moderate to good yields (Scheme 15). [42] For the preparation of new pharmaceuticals,the use of deuterated methoxy compounds has become increasingly important.…”