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The Ni-catalyzed N-arylation of b-fluoroalkylamines with broad scope is reported for the first time. Use of the air-stable pre-catalyst (PAd2-DalPhos)Ni(o-tol)Cl allows for reactions to be conducted at room temperature (25 oC, NaOtBu), or by use of a commercially available dual-base system (100 oC, DBU/NaOTf), to circumvent decomposition of the N-(b-fluoroalkyl)aniline product. The mild protocols disclosed herein feature broad (hetero)aryl (pseudo)halide scope (X = Cl, Br, I, and for the first time phenol derived electrophiles), encompassing base sensitive substrates and enantioretentive transformations, in a manner that is unmatched by any previously reported catalyst system.

Base-metal catalysts capable of enabling the assembly of heteroatom-dense molecules by cross-coupling of primary heteroarylamines and (hetero)aryl chlorides, while sought-after given the ubiquity of unsymmetrical di(hetero)arylamino fragments in pharmacophores, are unknown. Herein, we disclose the new "double cage" bisphosphine PAd2-DalPhos (L2). The derived air-stable NiII pre-catalyst C2 functions well at low loadings in challenging test C-N cross-couplings with established substrates, and facilitates the first Ni-catalyzed C-N cross-couplings of primary five- or six-membered ring heteroarylamines and activated (hetero)aryl chlorides, with synthetically useful scope that is competitive with Pd catalysis.

The base metal-catalyzed C-N cross-coupling of bulky α,α,α-trisubstituted primary alkylamines with (hetero)aryl electrophiles represents a challenging and under-developed class of transformations that is of significant potential utility, including in the synthesis of lipophilic active pharmaceutical ingredients. Herein, we report that a new, air-stable Ni(II) pre-catalyst incorporating the optimized ancillary ligand PhPAd-DalPhos enables such transformations of (hetero)aryl chloride, bromide, and tosylate electrophiles to be carried out for the first time with substrate scope rivalling that achieved using state-of-the-art Pd catalysts, including room temperature cross-couplings of (hetero)aryl chlorides that are unprecedented for any catalyst (Pd, Ni, or other).

The influence of ancillary ligand and nickel oxidation state in the nickel-catalyzed C(sp2)–N cross-coupling of aryl chlorides is examined by use of experimental and DFT methods for the first time, focusing on (L)NiCl and (L)Ni(o-tolyl)Cl pre-catalysts (PAd-DalPhos, L1; dppf, L2). Whereas Ni(II) pre-catalysts generally out-performed Ni(I) species in our study, the viability and in some cases superiority of Ni(I) pre-catalysts in challenging aminations is established. Computational analyses support the viability of Ni(0)/Ni(II) cycles featuring rate-limiting C–N reductive elimination, as well as parallel Ni(I)/Ni(III) mechanisms involving rate-limiting C–Cl oxidative addition.

The first examples of stoichiometric dehydrogenative B-H/C(sp3 )-H benzylic borylation reactions, which are of relevance to catalytic methylarene (di)borylation, are reported. These unusual transformations involving a (κ2 -P,N)Pt(η3 -benzyl) complex, and either pinacolborane or catecholborane, proceed cleanly at room temperature. Density functional calculations suggest that borylation occurs via successive σ-bond metathesis steps, whereby a PtII -H intermediate engages in C(sp3 )-H bond activation-induced dehydrogenation.

The utility of RockPhos, Ad-BippyPhos, JosiPhos (CyPF-tBu), and Mor-DalPhos in palladium-catalyzed C–O cross-coupling reactions involving aliphatic alcohols and (hetero)aryl halides under analogous conditions was examined, both at room temperature and at elevated temperature (90 °C). In general, the RockPhos-based catalyst system proved superior, especially at room temperature, but catalysts based on the other ligands examined also proved effective across a range of C–O cross-couplings, in some cases providing better catalytic performance than RockPhos. New reactivity was established in terms of the scope of room temperature reactions. Proof-of-principle examples of such cross-couplings involving aryl mesylates were also demonstrated.

A crystallographically characterized three-coordinate, formally 14 electron Pt(II) complex 1 featuring terminal amido ligation is reported. Computational analysis revealed relatively weak π donation from the amide lone pair to platinum and supports a 14-electron assignment for 1. Stoichiometric reactivity studies confirmed the viability of net O-H and C-H addition across, as well as isonitrile insertion into, the terminal platinum-amido linkage of 1.

Structurally diverse (hetero)aryl chloride, bromide, and tosylate electrophiles were employed in the Ni-catalyzed monoarylation of ammonia, including chemoselective transformations. The employed JosiPhos/[Ni(cod)2] catalyst system enables the use of commercially available stock solutions of ammonia, or the use of ammonia gas in these reactions, thereby demonstrating the versatility and potential scalability of the reported protocol. Proof-of-principle experiments established that air-stable [(JosiPhos)NiCl2] precatalysts can be employed successfully in such transformations.

The application of a Mor-DalPhos/palladium catalyst system in the one-pot, multicomponent assembly of substituted indoles from ortho-chlorohaloarenes, alkyl ketones (including acetone), and primary amines is reported. The described protocols offer improved substrate scope in all three reaction components, under more mild conditions and without the need for an additional drying agent. Also reported are the first examples of such multicomponent reactions where all reactants are combined at the start of the reaction, without the need for inert atmosphere reaction conditions.

For the first time examples of enolate α-arylation employing aryl mesylate coupling partners and amination of inexpensive phenol derivatives with primary aliphatic amines are developed.

A mixture of tris(dibenzylideneacetone)dipalladium(0) (Pd2dba3) and 5-(di-tert-butylphosphino)-1′,3′,5′-triphenyl-1′H-[1,4′]bipyrazole (Bippyphos) is shown to be a robust and efficient catalyst system for the hydroxylation of structurally diverse (hetero)aryl halides under mild conditions and with broad substrate scope. Included in this reactivity survey is the successful synthesis of substituted benzofurans and related heteroatomic derivatives, which are formed via the hydroxylation of 2-haloalkynylarenes. Notably, a significant number of the reactions reported herein proceed at room temperature, and we have demonstrated that it is possible to conduct reactions on the benchtop under air using unpurified solvents with negligible loss in reactivity versus related transformations conducted under inert atmosphere conditions. We also report herein the first crystallographically characterized (Bippyphos)Pd(II) complex, which confirms the ability of this synthetically useful ligand to adopt a bidentate binding motif in a manner similar to Buchwald’s biarylphosphine ligand class.

An examination of the [{Pd(cinnamyl)Cl}(2)]/Mor-DalPhos (Mor-DalPhos = di(1-adamantyl)-2-morpholinophenylphosphine) catalyst system in Buchwald-Hartwig aminations employing ammonia was conducted to better understand the catalyst formation process and to guide the development of precatalysts for otherwise challenging room-temperature ammonia monoarylations. The combination of [{Pd(cinnamyl)Cl}(2)] and Mor-DalPhos afforded [(κ(2)-P,N-Mor-DalPhos)Pd(η(1)-cinnamyl)Cl] (2), which, in the presence of a base and chlorobenzene, generated [(κ(2)-P,N-Mor-DalPhos)Pd(Ph)Cl] (1 a). Halide abstraction from 1 a afforded [(κ(3)-P,N,O-Mor-DalPhos)Pd(Ph)]OTf (5), bringing to light a potential stabilizing interaction that is offered by Mor-DalPhos. An examination of [(κ(2)-P,N-Mor-DalPhos)Pd(aryl)Cl] (1 b-f) and related precatalysts for the coupling of ammonia and chlorobenzene at room temperature established the suitability of 1 a in such challenging applications. The scope of reactivity for the use of 1 a (5 mol %) encompassed a range of (hetero)aryl (pseudo)halides (X = Cl, Br, I, OTs) with diverse substituents (alkyl, aryl, ether, thioether, ketone, amine, fluoro, trifluoromethyl, and nitrile), including chemoselective arylations.

A mild and efficient protocol for the assembly of tetra-substituted 5-trifluoromethylpyrazoles is presented, involving halogenation at the 4-position of readily prepared tri-substituted 5-trifluoromethylpyrazoles to give 4-halo-1-phenyl-5-trifluoromethyl pyrazoles, and subsequent palladium-catalyzed Negishi or Buchwald–Hartwig cross-couplings to install carbon or nitrogen-based 4-substituents. Key to the success of these challenging cross-couplings is the use of XPhos and JosiPhos CyPF-tBu ligands, respectively.

N-Aryl derivatives of edaravone were identified as potentially effective small molecule inhibitors of tau and beta-amyloid aggregation in the context of developing disease-modifying therapeutics for Alzheimer's disease (AD). Palladium-catalyzed hydrazine monoarylation protocols were then employed as an expedient means of preparing a focused library of 21 edaravone derivatives featuring varied N-aryl substitution, thereby enabling structure-activity relationship (SAR) studies. On the basis of data obtained from two functional biochemical assays examining the effect of edaravone derivatives on both fibril and oligomer formation, it was determined that derivatives featuring an N-biaryl motif were four-fold more potent than edaravone.

Preparation of enols: when treated with [{Pd(cinnamyl)Cl}(2)]/cataCXium A (nBuPAd(2), Ad=adamantyl) under an atmosphere of CO, aryl ketones react with aryl halides in a carbonylative C-O coupling reaction to form (Z)-vinyl benzoates.

Variants of the DalPhos [2-aminophenylbisadamantyl)phosphine] ligand family were examined in a palladium-catalyzed carbonylative amination reaction using inexpensive carbon monoxide and ammonia as reagents. As a result of this survey, the Pyr-DalPhos ligand was identified as being effective for the selective aminocarbonylation of aryl bromides with ammonia, as well as primary and secondary alkylamines. A variety of primary aromatic, heteroaromatic and N-substituted benzamides were formed in moderate to good yields. As part of this study, a (Mor-DalPhos)Pd-benzoyl complex was prepared and crystallographically characterized, thereby showing the viability of the carbonyl insertion step.

We report the extension and optimization of the [Pd(cinnamyl)Cl]2/DalPhos catalyst system, previously found effective for the mono-α-arylation of acetone, to the mono-α-arylation of a variety of carbonyl-containing compounds with aryl halides and heteroaryl halides. Aryl methyl ketones, heteroaryl methyl ketones, propiophenones, malonates, and methoxyacetone can be α-arylated under relatively mild conditions and in good yields. We also report the limitations of the ligand/catalyst system towards other classes of carbonyl-containing compounds.

We report on the application of the [Pd(cinnamyl)Cl]2/Mor-DalPhos catalyst system in the Buchwald–Hartwig amination of (hetero)aryl chlorides with primary or secondary amines conducted either under aqueous conditions without the use of co-solvents and/or surfactants or under solvent-free conditions (52 examples). We have established that reactions of this type can be conducted without the rigorous exclusion of air, and in the case of the solvent-free reactions, we have demonstrated that appropriately selected liquid and solid reagents can be employed successfully.

The hydroamination of alkenes represents an atom-economical strategy for the synthesis of nitrogen-containing molecules from readily available components. In recent years, the application of Group 9 transition metal catalysts in this reaction has enabled significant progress to be made toward addressing several major challenges within the field of metal-mediated hydroamination. Using Rh- and Ir-based catalysts for the intermolecular hydroamination reaction, advances have been made in the regioselective addition of amines to olefins in an anti-Markovnikov fashion producing industrially relevant linear amine products, as well as the concise synthesis of chiral amines by asymmetric hydroamination. The intramolecular addition of a variety of amine groups to pendant alkenes has also been studied in the context of developing expedient routes to nitrogen-containing heterocycles; using simple Rh- and Ir-based catalysts, a wide range of substrates including those that contain functional groups that are poised for further synthetic elaboration are readily cyclized. Extension of these catalyst systems to include the asymmetric synthesis of a variety of functionalized 1-methylpyrrolidine compounds has recently been achieved. To complement these catalytic investigations, thorough stoichiometric and kinetic studies have unveiled diverse mechanistic pathways that originate from either initial amine or olefin activation. The understanding gained through these mechanistic investigations provides the framework for the design of increasingly effective alkene hydroamination catalysts.

The syntheses of 2-(di-tert-butylphosphino)-N,N-dimethylaniline (L1, 71%) and 2-(di-1-adamantylphosphino)-N,N-dimethylaniline (L2, 74 %), and their application in Buchwald-Hartwig amination, are reported. In combination with [Pd(allyl)Cl](2) or [Pd(cinnamyl)Cl](2), these structurally simple and air-stable P,N ligands enable the cross-coupling of aryl and heteroaryl chlorides, including those bearing as substituents enolizable ketones, ethers, esters, carboxylic acids, phenols, alcohols, olefins, amides, and halogens, to a diverse range of amine and related substrates that includes primary alkyl- and arylamines, cyclic and acyclic secondary amines, N-H imines, hydrazones, lithium amide, and ammonia. In many cases, the reactions can be performed at low catalyst loadings (0.5-0.02 mol % Pd) with excellent functional group tolerance and chemoselectivity. Examples of cross-coupling reactions involving 1,4-bromochlorobenzene and iodobenzene are also reported. Under similar conditions, inferior catalytic performance was achieved when using Pd(OAc)(2), PdCl(2), [PdCl(2)(cod)] (cod = 1,5-cyclooctadiene), [PdCl(2)(MeCN)(2)], or [Pd(2)(dba)(3)] (dba = dibenzylideneacetone) in combination with L1 or L2, or by use of [Pd(allyl)Cl](2) or [Pd(cinnamyl)Cl](2) with variants of L1 and L2 bearing less basic or less sterically demanding substituents on phosphorus or lacking an ortho-dimethylamino fragment. Given current limitations associated with established ligand classes with regard to maintaining high activity across the diverse possible range of C-N coupling applications, L1 and L2 represent unusually versatile ligand systems for the cross-coupling of aryl chlorides and amines.

Zwitterionische Komplexe von Platinmetallen, die sich durch eine formale Ladungstrennung zwischen einem kationischen Metallfragment und einem negativ geladenen Hilfsliganden auszeichnen, vereinigen das wunschenswerte Reaktivitatsprofil verwandter kationischer Komplexe mit der besseren Loslichkeit und Losungsmitteltoleranz neutraler Spezies. Daher sind zwitterionische Komplexe dieser Art interessante Kandidaten fur vielfaltige Anwendungen, insbesondere fur Reaktionen, in denen E-H- und E-C-σ-Bindungen zu Hauptgruppenelementen E gespalten und/oder gebildet werden. Hier werden Fortschritte bei der Entwicklung von Hilfsliganden vorgestellt, die die Synthese von Zwitterionen der Platinmetalle ermoglichten, und die Ergebnisse stochiometrischer und katalytischer Untersuchungen werden zusammengefasst, wobei die Reaktivitaten der Zwitterionen und ihrer ublicherweise eingesetzten kationischen Verwandten bei der σ-Bindungsaktivierung verglichen werden.

A catalyst system consisting of [Pd(cinnamyl)Cl]2 and JosiPhos is found to enable the first mono-α-arylation of acetone using a variety of aryl halides.

Substrates are mainly used as chlorides, but bromides or tosylates are also suitable in the chemoselective transformations which are promoted by the Ni/Josiphos system.

In addition cross couplings of arylchlorides and diamines as well as secondary aliphatic amines are described.

The complex [Rh(η3-benzyl)(dippe)] (1; dippe=bis(diisopropylphosphino)ethane=(ethane-1,2-diyl)bis[diisopropylphosphine]) reacted cleanly with Mes*PH2 (2; Mes*=2,4,6-tBu3C6H2) to provide a new Rh species [Rh(H)(dippe)(L)] (3), L being the 2,3-dihydro-3,3-dimethyl-1H-phosphindole ligand 4 (=tBu2C6H2(CMe2CH2PH)) (Scheme 1). Complex 3 was converted to the corresponding chloride [Rh(Cl)(dippe)(L)] (6) when treated with CH2Cl2, whereas the dimeric species [Rh2{μ-tBu2C6H2(CMe2CH2P)}(μ-H)(dippe)2] (7) was formed upon thermolysis in toluene (Scheme 2). The structures of 6 and 7⋅C7H8 were determined by X-ray crystallography. Complexes 1 and 3 served as catalyst precursors for the dehydrogenative coupling of C−H and P−H bonds in the conversion of 2 to 4 (Scheme 3). Deuteration studies with Mes*PD2 exposed a complex series of bond-activation pathways that appear to involve C−H activation of the dippe ligand by the Rh-atom (Schemes 4 and 5)

The stable 7-phosphanorbornadiene derivative, 2,3-benzo-1,4,5,6,7-pentaphenyl-7-phosphabicyclo[2.2.1]hepta-2,5-diene-7-oxide (1) was synthesized in 45% yield via the Diels-Alder reaction of pentaphenylphosphole oxide and benzyne. The reaction occurs specifically to give a single isomer, which was characterized by use of X-ray crystallography and 31P NMR spectroscopy. © 2000 John Wiley & Sons, Inc. Heteroatom Chem 11:182–186, 2000

Syntheses of title complexes (I) and (II) and their application in Buchwald—Hartwig amination reactions are reported.

For the first time examples of enolate α-arylation employing aryl mesylate coupling partners and amination of inexpensive phenol derivatives with primary aliphatic amines are developed.

An efficient catalytic system for the title reaction under mild reaction conditions is presented.

A wide range of aryl- and heteroaryl-chlorides and tosylates are converted to the corresponding amines.

Preparation of enols: when treated with [{Pd(cinnamyl)Cl}(2)]/cataCXium A (nBuPAd(2), Ad=adamantyl) under an atmosphere of CO, aryl ketones react with aryl halides in a carbonylative C-O coupling reaction to form (Z)-vinyl benzoates.

Aryl methyl ketones, heteroaryl methyl ketones, propiophenones, malonates, and methoxyacetone can be α-arylated with aryl halides or heteroaryl halides under relatively mild conditions.

Variants of the DalPhos [2-aminophenylbisadamantyl)phosphine] ligand family were examined in a palladium-catalyzed carbonylative amination reaction using inexpensive carbon monoxide and ammonia as reagents. As a result of this survey, the Pyr-DalPhos ligand was identified as being effective for the selective aminocarbonylation of aryl bromides with ammonia, as well as primary and secondary alkylamines. A variety of primary aromatic, heteroaromatic and N-substituted benzamides were formed in moderate to good yields. As part of this study, a (Mor-DalPhos)Pd-benzoyl complex was prepared and crystallographically characterized, thereby showing the viability of the carbonyl insertion step.

The new and easily prepared OTips-DalPhos ligand (L1) offers broad substrate scope at relatively low loadings in the palladium-catalyzed C–N cross-coupling/cyclization of o-alkynylhalo(hetero)arenes with primary amines, affording indoles and related heterocyclic derivatives in high yield.