Pd-catalyzed cross-coupling reactions that form C–N bonds have become useful methods to synthesize anilines and aniline derivatives, an important class of compounds throughout chemical research. A ...key factor in the widespread adoption of these methods has been the continued development of reliable and versatile catalysts that function under operationally simple, user-friendly conditions. This review provides an overview of Pd-catalyzed N-arylation reactions found in both basic and applied chemical research from 2008 to the present. Selected examples of C–N cross-coupling reactions between nine classes of nitrogen-based coupling partners and (pseudo)aryl halides are described for the synthesis of heterocycles, medicinally relevant compounds, natural products, organic materials, and catalysts.
In organic synthesis, ligand-modified copper(I) hydride (CuH) complexes have become well-known reagents and catalysts for selective reduction, particularly toward Michael acceptors and carbonyl ...compounds. Recently, our group and others have found that these hydride complexes undergo migratory insertion (hydrocupration) with relatively unactivated and electronically unpolarized olefins, producing alkylcopper intermediates that can be leveraged to forge a variety of useful bonds. The resulting formal hydrofunctionalization reactions have formed the basis for a resurgence of research in CuH catalysis. This Account chronicles the development of this concept in our research group, highlighting its origin in the context of asymmetric hydroamination, evolution to more general C-X bond-forming reactions, and applications in the addition of olefin-derived nucleophiles to carbonyl derivatives.Hydroamination, the formal insertion of an olefin into the N-H bond of an amine, is a process of significant academic and industrial interest, due to its potential to transform widely available alkenes and alkynes into valuable complex amines. We developed a polarity-reversed strategy for catalytic enantioselective hydroamination relying on the reaction of olefins with CuH to generate chiral organocopper intermediates, which are intercepted by electrophilic amine reagents. By engineering the auxiliary ligand, amine electrophile, and reaction conditions, the scope of this method has since been extended to include many types of olefins, including challenging internal olefins. Further, the scope of amine reagents has been expanded to enable the synthesis of primary, secondary, and tertiary amines as well as amides, N-alkylated heterocycles, and anilines. All of these reactions exhibit high regio- and stereoselectivity and, due to the mild conditions required, excellent tolerance for heterocycles and polar functional groups.Though the generation of alkylcopper species from olefins was originally devised as a means to solve the hydroamination problem, we soon found that these intermediates could react efficiently with an unexpectedly broad range of electrophiles, including alkyl halides, silicon reagents, arylpalladium species, heterocycles, and carbonyl derivatives. The general ability of olefins to function as precursors for nucleophilic intermediates has proved particularly advantageous in carbonyl addition reactions because it overcomes many of the disadvantages associated with traditional organometallic reagents. By removing the need for pregeneration of the nucleophile in a separate operation, CuH-catalyzed addition reactions of olefin-derived nucleophiles feature improved step economy, enhanced functional group tolerance, and the potential for catalyst control over regio- and stereoselectivity. Following this paradigm, feedstock olefins such as allene, butadiene, and styrene have been employed as reagents for asymmetric alkylation of ketones, imines, and aldehydes.
Copper closes the ring: Benzimidazoles are synthesized from amidines through a copper‐catalyzed CH functionalization/CN bond‐forming process. The method tolerates a broad range of functional groups ...and provides the benzimidazoles in up to 89 % yield. Best results are obtained by using 15 mol % Cu(OAc)2, 2–5 equivalents of HOAc as additive, and oxygen as the stoichiometric reoxidant (see scheme).
A versatile method for the rapid synthesis of diverse enantiomerically enriched lactones has been developed based on Cu-catalyzed enantioselective radical oxyfunctionalization of alkenes. The scope ...of this strategy encompasses a series of enantioselective difunctionalization reactions: oxyazidation, oxysulfonylation, oxyarylation, diacyloxylation, and oxyalkylation. These reactions provide straightforward access to a wide range of useful chiral lactone building blocks containing tetrasubstituted stereogenic centers, which are hard to access traditionally.
Palladium‐catalyzed amination reactions of aryl halides have undergone rapid development in the last 12 years, largely driven by the implementation of new classes of ligands. Biaryl phosphanes have ...proven to provide especially active catalysts in this context. This Review discusses the application of these catalysts in CN cross‐coupling reactions in the synthesis of heterocycles and pharmaceuticals, in materials science, and in natural product synthesis.
Since the first description of dialkylbiaryl phosphane ligands in 1998, numerous uses in the synthesis of pharmaceuticals, functional materials, natural products, and heterocycles have been found. The applications of ligands of this class in palladium‐catalyzed amination reactions are reviewed.
The general enantioselective synthesis of axially chiral disubstituted allenes from prochiral starting materials remains a long-standing challenge in organic synthesis. Here, we report an efficient ...enantio- and chemoselective copper hydride catalyzed semireduction of conjugated enynes to furnish 1,3-disubstituted allenes using water as the proton source. This protocol is sufficiently mild to accommodate an assortment of functional groups including keto, ester, amino, halo, and hydroxyl groups. Additionally, applications of this method for the selective synthesis of monodeuterated allenes and chiral 2,5-dihydropyrroles are described.
Something radical: An efficient enantioselective oxytrifluoromethylation of alkenes has been developed using a copper catalyst system. Mechanistic studies are consistent with a metal‐catalyzed redox ...radical addition mechanism in which a CO bond is formed by the copper‐mediated enantioselective trapping of a prochiral alkyl radical intermediate derived from the initial trifluoromethyl radical addition.
A highly enantio- and regioselective copper-catalyzed hydroamination reaction of alkenes has been developed using diethoxymethylsilane and esters of hydroxylamines. The process tolerates a wide ...variety of substituted styrenes, including trans-, cis-, and β,β-disubstituted styrenes, to yield α-branched amines. In addition, aliphatic alkenes coupled to generate exclusively the anti-Markovnikov hydroamination products.
Over the past three decades, Pd-catalyzed cross-coupling reactions have become a mainstay of organic synthesis. In particular, catalysts derived from biaryl monophosphines have shown wide utility in ...forming C–N bonds under mild reaction conditions. This work summarizes a variety of C–N cross-coupling reactions using biaryl monophosphines as supporting ligands, with the goal of directing synthetic chemists towards the ligands and conditions best suited for a particular coupling.
When I learned that I had received the 2018 Tetrahedron Prize for Creativity in Organic Chemistry, jointly with Professor John F. Hartwig of UC Berkeley, I felt a sense of great accomplishment. Accomplishment not specifically for me, but by my research group (and that of John's) in developing new chemistry that was both intrinsically interesting and of practical utility. The latter aspect is the reason that we have chosen to write this review to help practitioners in the field utilize palladium-catalyzed C–N coupling reactions more broadly, efficiently, and predictively in their own research efforts. We note that while we have limited this review to reactions using biaryl phosphine ligands, that many other good alternatives exist.
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A mild, versatile, and convenient method for the efficient oxytrifluoromethylation of unactivated alkenes based on a copper-catalyzed oxidative difunctionalization strategy has been developed. This ...methodology provides access to a variety of classes of synthetically useful CF3-containing building blocks from simple starting materials.
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