Palladium-Catalyzed Ortho C–H Arylation of Unprotected Anilines: Chemo- and Regioselectivity Enabled by the Cooperating Ligand [2,2′-Bipyridin]-6(1H)-one

Abstract

Metal-catalyzed C−H functionalizations on the aryl ring of anilines usually need cumbersome N-protection−deprotection strategies to ensure chemoselectivity. We describe here the Pd-catalyzed direct C−H arylation of unprotected anilines with no competition of the N-arylation product. The ligand [2,2′-bipyridin]-6(1H)-one drives the chemoselectivity by kinetic differentiation in the product-forming step, while playing a cooperating role in the C−H cleavage step. The latter is favored in an anionic intermediate where the NH moiety is deprotonated, driving the regioselectivity of the reaction toward ortho substitution.

Palladium mono-N-protected amino acid complexes: experimental validation of the ligand cooperation model in C–H activation

“…This strategy has proved useful in our former studies on the role of cooperating bipyridone ligands in C–H activation. 19 The presence of a fluorinated tag is also very useful in the characterization of the species formed. Pyridine, a ligand of moderate coordination ability, completes the coordination sphere of palladium and imparts enough stability to the complexes without blocking further reactivity by ligand substitution.…”

Direct Arylation of C(sp2)–H Bonds in Anilines

“…The Albéniz group recently managed to develop the direct ortho-arylation of primary and secondary anilines by means of palladium catalysis (Scheme 14). 32 The authors identified a This article is protected by copyright. All rights reserved.…”

“…The Albéniz group recently managed to develop the direct ortho -arylation of primary and secondary anilines by means of palladium catalysis (Scheme 14 ). 32 The authors identified a specific [(2,2′-bipyridin]-6(1 H )-one ligand as a crucial feature to obtain good regioselectivities in favor of the ortho position, as well as excellent chemoselectivities by circumventing the competitive Buchwald–Hartwig N -arylation reaction, most likely to happen in the case of N–H-containing anilines. This process proved efficient with primary and secondary anilines, however, a loss of regioselectivity was observed with N , N -dialkylated anilines.…”

Palladium catalyzed remote-meta-C–H functionalization of aniline scaffolds

“…There are a plethora of reports on achieving functionalization at the ortho-position of anilines via electrophilic and auxiliary assisted ortho-C-H activation. [38][39][40][41][42][43][44][45][46] On the other hand, it is important to note that meta-C-H functionalization is challenging and limited [47][48][49][50] due to the intrinsic electron donating nature of nitrogen in aniline systems. In this context, as far as we are aware, only three reports are known towards the meta-C-H alkenylation of anilines: namely, Yu's lab has disclosed the meta-C-H activation of anilines with the aid of a terminalnitrile containing directing template via an amide linkage 51 and later, Li et al, in 2017, revealed the meta-C-H functionalization of anilines by employing a carbamate-based linkage with the assistance of another aromatic-nitrile based directing template (Scheme 1a).…”