Gregory C. Fu

Palladium‐Catalyzed Coupling Reactions of Aryl Chlorides

Collectively, palladium-catalyzed coupling reactions represent some of the most powerful and versatile tools available to synthetic organic chemists. Their widespread popularity stems in part from the fact that they are generally tolerant to a large number of functional groups, which allows them to be employed in a wide range of applications. However, for many years a major limitation of palladium-catalyzed coupling processes has been the poor reactivity of aryl chlorides, which from the standpoints of cost and availability are more attractive substrates than the corresponding bromides, iodides, and triflates. Traditional palladium/triarylphosphane catalysts are only effective for the coupling of certain activated aryl chlorides (for example, heteroaryl chlorides and substrates that bear electron-withdrawing groups), but not for aryl chlorides in general. Since 1998, major advances have been described by a number of research groups addressing this challenge; catalysts based on bulky, electron-rich phosphanes and carbenes have proved to be particularly mild and versatile. This review summarizes both the seminal early work and the exciting recent developments in the area of palladium-catalyzed couplings of aryl chlorides.

The Development of Versatile Methods for Palladium-Catalyzed Coupling Reactions of Aryl Electrophiles through the Use of P(t-Bu)3 and PCy3 as Ligands

Metal-catalyzed coupling reactions of aryl electrophiles with organometallics and with olefins serve as unusually effective tools for forming new carbon-carbon bonds. By 1998, researchers had developed catalysts that achieved reactions of aryl iodides, bromides, and triflates. Nevertheless, many noteworthy challenges remained; among them were couplings of aryl iodides, bromides, and triflates under mild conditions (at room temperature, for example), couplings of hindered reaction partners, and couplings of inexpensive aryl chlorides. This Account highlights some of the progress that has been made in our laboratory over the past decade, largely through the appropriate choice of ligand, in achieving these synthetic objectives. In particular, we have established that palladium in combination with a bulky trialkylphosphine accomplishes a broad spectrum of coupling processes, including Suzuki, Stille, Negishi, and Heck reactions. These methods have been applied in a wide array of settings, such as natural-product synthesis, materials science, and bioorganic chemistry.

A Convenient and General Method for Pd-Catalyzed Suzuki Cross-Couplings of Aryl Chlorides and Arylboronic Acids

From only commercially available reagents a wide array of Suzuki cross-couplings of aryl chlorides with arylboronic acids can be effected in excellent yield [Eq. (a)]. This development provides a general solution to a long-standing limitation of this extremely powerful process-the poor reactivity of inexpensive and readily accessible aryl chlorides. dba=dibenzylideneacetone.

Palladiumkatalysierte Kupplungen von Arylchloriden

Palladiumkatalysierte Kupplungen gehoren zu den leistungsfahigsten und vielseitigsten Reaktionen, die dem organischen Chemiker fur die Synthese zur Verfugung stehen. Ihre grose Beliebtheit ruhrt teilweise daher, dass sie bei den Umsetzungen gewohnlich viele funktionelle Gruppen tolerieren, was ihre breite Verwendung in vielen Bereichen ermoglicht. Allerdings unterlagen die palladiumkatalysierten Kupplungen jahrelang grosen Einschrankungen durch die geringe Reaktivitat der Arylchloride; diese Verbindungen sind in Bezug auf Kosten und Verfugbarkeit attraktivere Substrate als die entsprechenden Bromide, Iodide und Triflate. Herkommliche Palladium/Triarylphosphan-Katalysatoren setzten nur bestimmte aktivierte Arylchloride um (z. B. Heteroarylchloride und Substrate mit elektronenanziehenden Gruppen), nicht aber Arylchloride generell. Seit 1998 haben mehrere Forschungsgruppen bedeutende Fortschritte hinsichtlich dieser Herausforderung beschrieben; Katalysatoren mit voluminosen, elektronenreichen Phosphanen und Carbenen erwiesen sich als sehr vielseitig und ermoglichen besonders milde Reaktionsbedingungen. Dieser Aufsatz fasst die fruhen, wegweisenden Arbeiten und die spannenden neuartigen Entwicklungen auf dem Gebiet der palladiumkatalysierten Kupplungen von Arylchloriden zusammen.

Photoinduced Ullmann C–N Coupling: Demonstrating the Viability of a Radical Pathway

Ullman Upgrade Precious metals may dominate contemporary catalysis, but the early development of synthetic organic chemistry relied on more abundant elements—a strategy that chemists are returning to now for the sake of sustainability. Copper-mediated coupling of aryl halides with amines was reported by Ullman more than a century ago and remains in use today for the synthesis of certain organic compounds. However, the reaction generally requires high temperature to proceed efficiently. Creutz et al. (p. 647) have developed a photochemical variant that uses copper and reacts at room temperature or below, apparently by a radical mechanism. A century-old carbon–nitrogen coupling method can be by accelerated by light. Carbon–nitrogen (C–N) bond-forming reactions of amines with aryl halides to generate arylamines (anilines), mediated by a stoichiometric copper reagent at elevated temperature (>180°C), were first described by Ullmann in 1903. In the intervening century, this and related C–N bond-forming processes have emerged as powerful tools for organic synthesis. Here, we report that Ullmann C–N coupling can be photoinduced by using a stoichiometric or a catalytic amount of copper, which enables the reaction to proceed under unusually mild conditions (room temperature or even –40°C). An array of data are consistent with a single-electron transfer mechanism, representing the most substantial experimental support to date for the viability of this pathway for Ullmann C–N couplings.

Catalytic Asymmetric Hiyama Cross-Couplings of Racemic α-Bromo Esters

The first catalytic asymmetric cross-coupling of α-halo carbonyl compounds with aryl metal reagents has been developed, thereby generating synthetically useful α-aryl carboxylic acid derivatives in good enantiomeric excess. The method can also be applied to enantioselective alkenylation reactions.

Enantioselective Alkyl−Alkyl Suzuki Cross-Couplings of Unactivated Homobenzylic Halides

The first effective method for asymmetric cross-couplings of unactivated alkyl electrophiles has been developed, specifically, a nickel-based catalyst for stereoconvergent Suzuki reactions of homobenzylic bromides with alkylboranes. To the best of our knowledge, there are no previous examples of enantioselective Suzuki couplings of alkyl electrophiles (activated or unactivated). Both of the catalyst components are commercially available.

Nickel-catalyzed asymmetric negishi cross-couplings of secondary allylic chlorides with alkylzincs.

Complementing previous advances in allylation chemistry, an effective nickel/Pybox catalyst for regioselective asymmetric Negishi cross-couplings of racemic secondary allylic chlorides with readily available organozinc halides has been developed. The method has been applied in two key steps of a formal total synthesis of fluvirucinine A1.

Application of a new chiral phosphepine to the catalytic asymmetric synthesis of highly functionalized cyclopentenes that bear an array of heteroatom-substituted quaternary stereocenters.

Through the design and synthesis of a new chiral phosphepine, the first catalytic asymmetric method for the [3 + 2] cycloaddition of allenes with olefins has been developed that generates cyclopentenes that bear nitrogen-, phosphorus-, oxygen-, and sulfur-substituted quaternary stereocenters. A wide array of racemic γ-substituted allenes can be employed in this stereoconvergent process, which occurs with good enantioselectivity, diastereoselectivity, regioselectivity, and yield. Mechanistic studies, including a unique observation of a (modest) kinetic resolution of a racemic allene, are consistent with addition of the phosphepine to the allene being the turnover-limiting step of the catalytic cycle.

Asymmetric copper-catalyzed C-N cross-couplings induced by visible light

Coppers light touch forges C-N bonds Organic photochemistry has traditionally relied on excitation in the ultraviolet, where carbon-based compounds tend to absorb. Over the past decade, the field has undergone a renaissance as compounds that absorb visible light have proven to be versatile catalysts for organic reactions. For the most part, however, these catalysts have contained rare metals such as ruthenium or iridium. Kainz et al. now report a blue light-driven C-N bond-forming reaction catalyzed by Earth-abundant copper (see the Perspective by Greaney). Through coordination to a chiral ligand, the copper center couples alkyl chlorides to indoles and carbazoles with a high degree of enantioselectivity. Science, this issue p. 681; see also p. 666 A copper complex harnesses light to form quaternary chiral centers with one nitrogen and three carbon substituents. [Also see Perspective by Greaney] Despite a well-developed and growing body of work in copper catalysis, the potential of copper to serve as a photocatalyst remains underexplored. Here we describe a photoinduced copper-catalyzed method for coupling readily available racemic tertiary alkyl chloride electrophiles with amines to generate fully substituted stereocenters with high enantioselectivity. The reaction proceeds at –40°C under excitation by a blue light-emitting diode and benefits from the use of a single, Earth-abundant transition metal acting as both the photocatalyst and the source of asymmetric induction. An enantioconvergent mechanism transforms the racemic starting material into a single product enantiomer.