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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.

Ammonia is an abundant and inexpensive nitrogen source that represents an ideal reagent for amine synthesis. Despite its tremendous potential to provide more direct and economical routes to nitrogen-containing molecules, the use of ammonia in transition-metal-catalyzed reactions has only very recently begun to be realized.[1] The copper-or palladium-catalyzed cross-coupling of aryl halides and amines is a well-established and important method for the synthesis of arylamines in both academic and industrial settings, [2] and recent advances in catalyst design have enabled the use of ammonia as a coupling partner to generate primary arylamines. [3][4][5][6][7] Despite the success of these initial reports, a number of serious limitations regarding the scope and utility of metal-catalyzed cross-couplings of aryl halides and ammonia still exist and must be addressed before this method can be considered a viable alternative to more traditional aniline syntheses. In the case of copper, high loadings of metal and ligand are typically required (10-50 mol %) and less reactive but more economically attractive aryl chlorides, [8] or more readily accessible pseudohalides derived from phenols, are poor reaction partners.[3] Limitations regarding the palladium-catalyzed cross-coupling of ammonia [4][5][6][7] include the coupling of electron-rich, sterically unbiased aryl chlorides as well as the selective coupling of ammonia in the presence of additional amine functionality (chemoselectivity).[9] In addition, currently known systems require catalyst loading of 0.5-5 mol % of palladium as well as elevated temperatures (70-120 8C) to maintain reasonable activity for even simple aryl chloride substrates. The slow rate of oxidative addition of electron-rich aryl chlorides, combined with a lower tendency for such species lacking ortho-substitution to undergo reductive elimination [10] from the requisite [L n Pd(Ar)amido] species, can provide a rationale for the difficulties posed by such reaction partners and the elevated reaction temperatures required for catalyst turnover. Herein, we report the preparation of a suitably designed P,N-ligand that addresses several of the above-described challenges in ammonia cross-coupling, including highly chemoselective transformations and the first report of aryl chloride and aryl tosylate coupling with ammonia at room temperature.Recently, we initiated a research program employing P,Nligands as alternatives to more traditional archetypes in C À N coupling reactions. We envisioned that easily prepared and tunable ligands of this type might provide a useful middle ground in Buchwald-Hartwig aminations between strongly chelating bisphosphanes [2a] and biarylmonophosphanes [2b] that feature only weak secondary metal-ligand interactions.We have found L1 (Me-DalPhos) to be a broadly useful ligand for the palladium-catalyzed cross-coupling of aryl chlorides and amines (including ammonia); however, modestly electron-rich substrates lacking ortho-substitution gave very poor results, requiring harsh re...

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.

N‐alkylations of carbazoles with a variety of secondary and hindered primary alkyl iodides can be achieved by using a simple precatalyst (CuI) under mild conditions (0 °C) in the presence of a Brønsted base; at higher temperature (30 °C), secondary alkyl bromides also serve as suitable coupling partners. A Li[Cu(carbazolide)2] complex has been crystallographically characterized, and it may serve as an intermediate in the catalytic cycle.

Many classical and emerging methodologies in organic chemistry rely on CO2 extrusion to generate reactive intermediates for bond-forming events. Synthetic reactions that involve the microscopic reverse, the carboxylation of reactive intermediates, have conventionally been undertaken using very different conditions. We report that chemically stable C(sp3) carboxylates, such as arylacetic acids and malonate half-esters, undergo uncatalyzed reversible decarboxylation in dimethylformamide solution. Decarboxylation/carboxylation occurs with substrates resistant to protodecarboxylation by Brønsted acids under otherwise identical conditions. Isotopically labeled carboxylic acids can be prepared in high chemical and isotopic yield by simply supplying an atmosphere of 13CO2 to carboxylate salts in polar aprotic solvents. An understanding of carboxylate reactivity in solution enables conditions for the trapping of aldehydes, ketones, and α,β-unsaturated esters.

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.

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