Palladium-Catalyzed C(sp³)–H Arylation of Diarylmethanes at Room Temperature: Synthesis of Triarylmethanes via Deprotonative-Cross-Coupling Processes

Abstract

Although metal-catalyzed direct arylation reactions of non- or weakly acidic C-H bonds have recently received much attention, chemists have relied heavily on substrates with appropriately placed directing groups to steer reactivity. To date, examples of intermolecular arylation of unactivated C(sp(3))-H bonds in the absence of a directing group remain scarce. We report herein the first general, high-yielding, and scalable method for palladium-catalyzed C(sp(3))-H arylation of simple diarylmethane derivatives with aryl bromides at room temperature. This method facilitates access to a variety of sterically and electronically diverse hetero- and nonheteroaryl-containing triarylmethanes, a class of compounds with various applications and interesting biological activity. Key to the success of this approach is an in situ metalation of the substrate via C-H deprotonation under catalytic cross-coupling conditions, which is referred to as a deprotonative-cross-coupling process (DCCP). Base and catalyst identification were performed by high-throughput experimentation (HTE) and led to a unique base/catalyst combination [KN(SiMe(3))(2)/Pd-NiXantphos] that proved to efficiently promote the room-temperature DCCP of diarylmethanes. Additionally, the DCCP exhibits remarkable chemoselectivity in the presence of substrates that are known to undergo O-, N-, enolate-, and C(sp(2))-H arylation.

Alkylation of Pyridines at Their 4‐Positions with Styrenes plus Yttrium Reagent or Benzyl Grignard Reagents

“…The above mechanism and also the pharmaceutical utility of diarylmethane derivatives such as 4, which are becoming more and more important, [16,17] prompted us to investigate the possibility of direct addition of benzyl metal species to pyridines. As nucleophilic addition at the 2-position of pyridines is more common than that at 4-position, [1][2][3][4][5] the exclusive addition of benzylmetal species at the 4-position as shown in Scheme 2 should be synthetically quite useful.…”

Palladium‐Catalyzed Direct α‐Arylation of Benzyl Thioethers with Aryl Bromides

“…This study highlights the compatibility of the NiXantPhos-based palladium catalyst to highly reactive organolithium, -sodium, and -potassium intermediates that are structurally quite different than those employed in prior previously as coupling partners. [3, 18] …”

Palladium-Catalyzed Cross-Coupling of 2-Aryl-1,3-dithianes

“…8 Recently, Walsh and co-workers have even used the less activated diphenylmethane (pKa 32.3, DMSO 9 ) as a transmetalation reagent in Pd-catalyzed cross-coupling reactions. 10 …”