康 · 学术 | Reaction of the Day No. 1295

转自：康龙化成

Palladium-Catalyzed Amination ofAryl Halides with Aqueous Ammonia and Hydroxide Base Enabled by LigandDevelopment

Kyoungmin Choi,# John N. Brunn,# Kailaskumar Borate, Rahul Kaduskar,Carlos Lizandara Pueyo,Harish Shinde, Roland Goetz, and John F. Hartwig*

Department of Chemistry, University ofCalifornia, Berkeley, California 94720, United States;

Therapeutics &Biotechnology Division, Korea Research Institute of Chemical Technology,Daejeon 34114, Republic of Korea; BASF Chemicals India Pvt. Ltd., Navi Mumbai400705, India;

BASFCorporation, Berkeley, California 94720, United States; BASF SE, Ludwigshafen 67056,Germany

—J.Am. Chem. Soc., 2024, 10.1021/jacs.4c05768

Recommended byXuemeiYao_ MC3

ABSTRACT:Theconversion of aryl halides to primary arylamines with a convenient andinexpensive source of ammonia has been a long-standing synthetic challenge.Aqueous ammonia would be the most convenient and least expensive form ofammonia, but such a palladium-catalyzed amination reaction with a highconcentration of water faces challenges concerning catalyst stability andcompeting hydroxylation, and palladium-catalyzed reactions with this practicalreagent are rare. Further, most reactions with ammonia to form primary aminesare conducted with tert-butoxide base, but reactions with ammonium hydroxidewould contain hydroxide as base. Thus, ammonia surrogates, ammonia in organicsolvents, and ammonium salts have been used under anhydrous conditions insteadwith varying levels of selectivity for the primary amine. We report thepalladium-catalyzed amination of aryl and heteroaryl chlorides and bromideswith aqueous ammonia and a hydroxide base to form the primary arylamine withhigh selectivity. The palladium catalyst containing a new dialkyl biheteroaryl phosphine ligand (KPhos)suppresses both the formation of aryl alcohol and diarylamine side products.Mechanistic studies with a soluble hydroxide base revealed turnover-limitingreductive elimination of the arylamine and an equilibrium between arylpalladium amido and hydroxo complexes prior to the turnover-limiting step.

Background: Transition-metal-catalyzedamination of aryl halides with ammonia or its surrogates

Summary and Comments

Prof.JohnF. Hartwig and co-worker havedeveloped acatalyst for highly selective and broadly applicable palladium-catalyzedamination of aryl chlorides and bromides with aqueous ammonia and a hydroxidebase. The selective formation of primary arylamines was achieved by developing KPhos, aligand that contains a methyl substituent on the AdBippyPhos ligand. This small modification to C4 ofthe bipyrazole adjacent to the C−P bond dramatically improved the selectivityfor monoarylation over diarylation, and the palladium catalyst containingbipyrazole ligands are selective for amination over hydroxylation with aqueousammonia. The reaction occurred with a broad range of aryl halides to providethe primary arylamines with at least 20:1 selectivity for the formation of the monoarylamine overthe diarylamine. Mechanistic investigations under the reaction conditions witha soluble hydroxide base or KOH base have demonstrated that reductiveelimination from the arylpalladium(II)amido complex, which is in equilibrium with the resting arylpalladium(II) hydroxo complex, is turnover-limiting. Studies exploring the applicability of the KPhosligand for other catalytic cross-coupling reactions, in which nucleophiles maybe delivered in aqueous solution and a hydroxide base may be used, are beingconducted in our laboratory.

（转自：康龙化成）