Mark Stradiotto

Rhodium- and Iridium-Catalyzed Hydroamination of Alkenes

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.

A Highly Versatile Catalyst System for the Cross-Coupling of Aryl Chlorides and Amines

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.

Stereo- and Regioselective Gold-Catalyzed Hydroamination of Internal Alkynes with Dialkylamines

We report the use of a P,N-ligand to support a gold complex as a state-of-the-art precatalyst for the stereoselective hydroamination of internal aryl alkynes with dialkylamines to afford E-enamine products. Substrates featuring a diverse range of functional groups on both the amine (ether, sulfide, N-Boc amine, fluoro, nitrile, nitro, alcohol, N-heterocycles, amide, ester, and carboxylic acid) and alkyne (ether, N-heterocycles, N-phthalimide amines, and silyl ethers) are accommodated with synthetically useful regioselectivity.

Addressing Challenges in Palladium-Catalyzed Cross-Coupling Reactions Through Ligand Design

The development of palladium-catalyzed cross-coupling reactions has revolutionized the synthesis of organic molecules on both bench-top and industrial scales. While significant research effort has been directed toward evaluating how modifying various reaction parameters can influence the outcome of a given cross-coupling reaction, the design and implementation of novel ancillary ligand frameworks has played a particularly important role in advancing the state-of-the-art. This Review seeks to highlight notable examples from the recent chemical literature, in which newly developed ancillary ligands have enabled more challenging substrate transformations to be addressed with greater selectivity and/or under increasingly mild conditions. Throughout, the importance and subtlety of ligand effects in palladium-catalyzed cross-coupling reactions are described, in an effort to inspire further development and understanding within the field of ancillary ligand design.

Palladium-catalyzed mono-α-arylation of acetone with aryl halides and tosylates.

We report the first example of selective Pd-catalyzed mono-α-arylation of acetone employing aryl chlorides, bromides, iodides, and tosylates. The use of appropriately designed P,N-ligands proved to be the key to controlling the reactivity and selectivity. The reaction affords good yields with substrates containing a range of functional groups at modest Pd loadings using Cs(2)CO(3) as the base and employing acetone as both a reagent and the solvent.

Palladium-Catalyzed Cross-Coupling of Aryl Chlorides and Tosylates with Hydrazine

Aryl hydrazines are highly valuable intermediates in the synthesis of a number of important nitrogen-containing heterocyclic frameworks such as indoles (through the Fischer indole synthesis), indazoles, aryl pyrazoles, and aryl triazoles. In some cases, hydrazine reacts with haloarenes directly in nucleophilic aromatic substitution reactions; however, such reactions typically occur at high temperatures, and/or only with highly electron-deficient haloarenes, or at selected positions of halogenated heterocycles. 4] The prevailing method for the preparation of aryl hydrazines relies on the stoichiometric oxidation of anilines to their corresponding diazonium salts and subsequent reduction. The transitionmetal-catalyzed cross-coupling of aryl halides and hydrazine represents an attractive alternative to the traditional synthesis of aryl hydrazines. However, despite the tremendous progress made in the field of Buchwald–Hartwig amination reactions over the past decade, no such reaction has been reported. Hydrazine presents a number of potential problems in palladium-catalyzed cross-coupling reactions. First, hydrazine is an aggressive reductant of both organic and inorganic substrates, and could reduce key PdAr(X) species, thereby promoting the generation of catalytically inactive Pd aggregates, as well as reducing aryl halide substrates by hydrodehalogenation. Second, aryl hydrazines can undergo metalmediated N N bond cleavage, thus resulting in the formation of undesired aniline by-products. Finally, and most importantly, the product aryl hydrazines still possess three reactive N H bonds that can undergo further C N crosscoupling, thus leading to polyarylated products. Some of these challenges have been circumvented by the use of hydrazine surrogates with attenuated reactivity such as benzophenone hydrazone or protected hydrazides, although such strategies are not ideal from efficiency or economic standpoints. In addition, arylor alkyl-substituted hydrazines, which are less prone to undergo some of the above described detrimental side reactions, have been employed as substrates. Herein, we report on a palladium catalyst system and reaction conditions that allow, for the first time, the cross-coupling of aryl chlorides and tosylates with hydrazine. The reactions proceed rapidly under relatively mild conditions with excellent monoarylation selectivity, thus providing direct access to aryl hydrazines. We began by screening a variety of ligands (Scheme 1) and reaction conditions (Table 1) in the hope of effecting the cross-coupling of 4-phenylchlorobenzene with readily avail-

Intramolecular hydroamination of unactivated alkenes with secondary alkyl- and arylamines employing [Ir(COD)Cl]2 as a catalyst precursor.

Commercially available [Ir(COD)Cl](2) is an effective precatalyst for the intramolecular hydroamination of a range of unactivated alkenes with pendant secondary alkyl- or arylamines, at relatively low loadings (typically 0.25-5.0 mol % Ir) and without the need for added ligands or other cocatalysts.

BippyPhos: A Single Ligand With Unprecedented Scope in the Buchwald–Hartwig Amination of (Hetero)aryl Chlorides

Over the past two decades, considerable attention has been given to the development of new ligands for the palladium-catalyzed arylation of amines and related NH-containing substrates (i.e., Buchwald-Hartwig amination). The generation of structurally diverse ligands, by research groups in both academia and industry, has facilitated the accommodation of sterically and electronically divergent substrates including ammonia, hydrazine, amines, amides, and NH heterocycles. Despite these achievements, problems with catalyst generality persist and access to multiple ligands is necessary to accommodate all of these NH-containing substrates. In our quest to address this significant limitation we identified the BippyPhos/[Pd(cinnamyl)Cl]2 catalyst system as being capable of catalyzing the amination of a variety of functionalized (hetero)aryl chlorides, as well as bromides and tosylates, at moderate to low catalyst loadings. The successful transformations described herein include primary and secondary amines, NH heterocycles, amides, ammonia and hydrazine, thus demonstrating the largest scope in the NH-containing coupling partner reported for a single Pd/ligand catalyst system. We also established BippyPhos/[Pd(cinnamyl)Cl]2 as exhibiting the broadest demonstrated substrate scope for metal-catalyzed cross-coupling of (hetero)aryl chlorides with NH indoles. Furthermore, the remarkable ability of BippyPhos/[Pd(cinnamyl)Cl]2 to catalyze both the selective monoarylation of ammonia and the N-arylation of indoles was exploited in the development of a new one-pot, two-step synthesis of N-aryl heterocycles from ammonia, ortho-alkynylhalo(hetero)arenes and (hetero) aryl halides through tandem N-arylation/hydroamination reactions. Although the scope in the NH-containing coupling partner is broad, BippyPhos/[Pd(cinnamyl)Cl]2 also displays a marked selectivity profile that was exploited in the chemoselective monoarylation of substrates featuring two chemically distinct NH-containing moieties.

Addressing Challenges in Palladium‐Catalyzed Cross‐Couplings of Aryl Mesylates: Monoarylation of Ketones and Primary Alkyl Amines

...................................................................................................................... x LIST OF ABBREVIATIONS AND SYMBOLS USED ............................................... xi ACKNOWLEDGEMENTS .......................................................................................... xiv CHAPTER

An Examination of the Palladium/Mor-DalPhos Catalyst System in the Context of Selective Ammonia Monoarylation at Room Temperature†

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.