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. 2024 Jul 17;146(28):19414-19424.
doi: 10.1021/jacs.4c05768. Epub 2024 Jul 5.

Palladium-Catalyzed Amination of Aryl Halides with Aqueous Ammonia and Hydroxide Base Enabled by Ligand Development

Kyoungmin Choi  1 , John N Brunn  1 , Kailaskumar Borate  2 , Rahul Kaduskar  2 , Carlos Lizandara Pueyo  3 , Harish Shinde  2 , Roland Goetz  4 , John F Hartwig  1
Affiliations

Palladium-Catalyzed Amination of Aryl Halides with Aqueous Ammonia and Hydroxide Base Enabled by Ligand Development

Kyoungmin Choi et al. J Am Chem Soc. .

Abstract

The conversion of aryl halides to primary arylamines with a convenient and inexpensive source of ammonia has been a long-standing synthetic challenge. Aqueous ammonia would be the most convenient and least expensive form of ammonia, but such a palladium-catalyzed amination reaction with a high concentration of water faces challenges concerning catalyst stability and competing hydroxylation, and palladium-catalyzed reactions with this practical reagent are rare. Further, most reactions with ammonia to form primary amines are conducted with tert-butoxide base, but reactions with ammonium hydroxide would contain hydroxide as base. Thus, ammonia surrogates, ammonia in organic solvents, and ammonium salts have been used under anhydrous conditions instead with varying levels of selectivity for the primary amine. We report the palladium-catalyzed amination of aryl and heteroaryl chlorides and bromides with aqueous ammonia and a hydroxide base to form the primary arylamine with high 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-limiting reductive elimination of the arylamine and an equilibrium between arylpalladium amido and hydroxo complexes prior to the turnover-limiting step.

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Conflict of interest statement

The authors declare the following competing financial interest(s): A provisional patent based on this work has been filed.

Figures

Figure 1.
Figure 1.
Transition-metal-catalyzed amination of aryl halides with ammonia or its surrogates. (a) General scheme of the reaction. (b) Known sources of ammonia in Pd-catalyzed amination reactions and their limitations. (c) Challenge of employing aqueous ammonia in the Pd-catalyzed C−N coupling reactions: selective monoarylation of ammonia over diarylation and hydroxylation of aryl halides. (d) Development of the palladium catalyst for the selective amination of aryl halides with aqueous ammonia and a hydroxide base in this work.
Figure 2.
Figure 2.
(a) Evaluation of representative dialkyl aryl phosphine ligands and KPhos. Standard reaction conditions: 1a (0.1 mmol), Pd-precatalyst (0.5 μmol), ligand (2.0 μmol), aq NH3 (0.3 mmol), and KOH (0.3 mmol) in 1,4-dioxane (1.0 mL) at 100 °C for 24 h. aConversion of 1a and yields of products were determined by 19F NMR spectroscopy with 1-fluoronaphthalene as an internal standard. (b) Working hypotheses of how the Kphos ligand achieves higher product selectivity and turnover number. (c) Gram scale synthesis of KPhos without purification by column chromatography. (d) Observation of the progress of amination reactions with KPhos or AdBippyPhos ligand recorded by 19F NMR spectroscopy.
Figure 3.
Figure 3.
(a) Thermal ellipsoid plot of OA1 with 50% probability ellipsoids. (b) Selected distances between hydrogens of methyl at pyrazole and hydrogens of the adamantyl group at phosphorus. (c) Selected distances between ortho-hydrogens of the aryl group bound to palladium and hydrogens of the adamantyl group at phosphorus.
Figure 4.
Figure 4.
Resting state of the catalyst under the conditions with TBA(OH) (top) or KOH (bottom) determined by (a) 19F and (b) 31P{1H} NMR spectroscopy, and comparison with [(KPhos)Pd(4−F-C6H4)OH] independently generated in situ (middle).
Figure 5.
Figure 5.
(a) Reaction conditions for the kinetic studies. (b) Dependence of the initial rates on varied concentrations of the reagents, product, or catalyst. (c) Linear free energy relationship between the para-substituents of aryl chloride and the relative initial rates. Hammett plot (Left) and Swain–Lupton plot (Right). (d) Proposed mechanism of the palladium-catalyzed amination of aryl halides with aqueous ammonia and a hydroxide base.
Scheme 1.
Scheme 1.
Kinetic Isotope Effect of 4-Chlorobenzotrifluoride from Reaction in Separate Vessels
See this image and copyright information in PMC

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    1. Naghipour, A. et al. reported that Pd(PPh3)2Cl2 catalyzes amination of aryl iodides and bromides in aqueous ammonia but the catalyst is not working for 1-chloro-4-fluorobenzene 1a with KOH base. For details, see:

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