Xiao-Feng Wu

From Noble Metal to Nobel Prize: Palladium‐Catalyzed Coupling Reactions as Key Methods in Organic Synthesis

Palladium is known to a broad audience as a beautiful, but expensive jewellery metal. In addition, it is nowadays found in nearly every car as part of the automotive catalysts, where palladium is used to eliminate harmful emissions produced by internal combustion engines. On the other hand, and not known to the general public, is the essential role of palladium catalysts in contemporary organic chemistry, a topic which has now been recognized with the Nobel Prize for Chemistry 2010. Have a look at any recent issue of a chemical journal devoted to organic synthesis and you will discover the broad utility of palladium-based catalysts. Among these different palladium-catalyzed reactions, the so-called cross-coupling reactions have become very powerful methods for the creation of new C C bonds. In general, bond formation takes place here between less-reactive organic electrophiles, typically aryl halides, and different carbon nucleophiles with the help of palladium. Remember the situation 50 years ago, when palladium began to make its way into organic chemistry. At that time C C bond formation in organic synthesis was typically achieved by stoichiometric reactions of reactive nucleophiles with electrophiles or by pericyclic reactions. Ironically, however, oxidation catalysis was the start of today s carbon–carbon bond-forming methods: The oxidation of olefins to carbonyl compounds, specifically the synthesis of acetaldehyde from ethylene (Wacker process) by applying palladium(II) catalysts, was an important inspiration for further applications. Probably also for Richard Heck, who worked in the 1960s as an industrial chemist with Hercules Corporation. There, in the late 1960s, he developed several coupling reactions of arylmercury compounds in the presence of either stoichiometric or catalytic amounts of palladium(II). Some of this work was published in 1968 in a remarkable series of seven consecutive articles, with Heck as the sole author! Based on the reaction of phenylmercuric acetate and lithium tetrachloropalladate under an atmosphere of ethylene, which afforded styrene in 80% yield and 10% trans-stilbene, he described in 1972 a protocol for the coupling of iodobenzene with styrene, which today is known as the “Heck reaction”. A very similar reaction had already been published by Tsutomo Mizoroki in 1971. However, Mizoroki didn t follow up on the reaction and died too young from cancer. The coupling protocol for aryl halides with olefins can be considered as a milestone for the development and application of organometallic catalysis in organic synthesis and set the stage for numerous further applications. Hence, palladium-catalyzed coupling reactions were disclosed continuously during the 1970s (Scheme 1). One of the related reactions is the Sonogashira coupling of aryl halides with alkynes, typically in the presence of catalytic amounts of palladium and copper salts.

Recent developments on the trifluoromethylation of (hetero)arenes.

Aryl-CF(3) as an extremely important family of fluorinated organic compounds holds wide applications in pharmaceuticals, agrochemicals, and advanced materials. Traditionally, such trifluoromethylated compounds have been synthesized from the corresponding aryl trichlorides via Cl exchange reactions (Scheme 1). This Focus review gives an overview over the recent development of trifluoromethylation of (hetero)arenes.

Palladium-Catalyzed Oxidative Carbonylation Reactions

Palladium-catalyzed coupling reactions have become a powerful tool for advanced organic synthesis. This type of reaction is of significant value for the preparation of pharmaceuticals, agrochemicals, as well as advanced materials. Both, academic as well as industrial laboratories continuously investigate new applications of the different methodologies. Clearly, this area constitutes one of the major topics in homogeneous catalysis and organic synthesis. Among the different palladium-catalyzed coupling reactions, several carbonylations have been developed and widely used in organic syntheses and are even applied in the pharmaceutical industry on ton-scale. Furthermore, methodologies such as the carbonylative Suzuki and Sonogashira reactions allow for the preparation of interesting building blocks, which can be easily refined further on. Although carbonylative coupling reactions of aryl halides have been well established, palladium-catalyzed oxidative carbonylation reactions are also interesting. Compared with the reactions of aryl halides, oxidative carbonylation reactions offer an interesting pathway. The oxidative addition step could be potentially avoided in oxidative reactions, but only few reviews exist in this area. In this Minireview, we summarize the recent development in the oxidative carbonylation reactions.

Transition-metal-catalyzed carbonylation reactions of olefins and alkynes: a personal account.

Carbon monoxide was discovered and identified in the 18th century. Since the first applications in industry 80 years ago, academic and industrial laboratories have broadly explored COs use in chemical reactions. Today organic chemists routinely employ CO in organic chemistry to synthesize all kinds of carbonyl compounds. Despite all these achievements and a century of carbonylation catalysis, many important research questions and challenges remain. Notably, apart from academic developments, industry applies carbonylation reactions with CO on bulk scale. In fact, today the largest applications of homogeneous catalysis (regarding scale) are carbonylation reactions, especially hydroformylations. In addition, the vast majority of acetic acid is produced via carbonylation of methanol (Monsanto or Cativa process). The carbonylation of olefins/alkynes with nucleophiles, such as alcohols and amines, represent another important type of such reactions. In this Account, we discuss our work on various carbonylations of unsaturated compounds and related reactions. Rhodium-catalyzed isomerization and hydroformylation reactions of internal olefins provide straightforward access to higher value aldehydes. Catalytic hydroaminomethylations offer an ideal way to synthesize substituted amines and even heterocycles directly. More recently, our group has also developed so-called alternative metal catalysts based on iridium, ruthenium, and iron. What about the future of carbonylation reactions? CO is already one of the most versatile C1 building blocks for organic synthesis and is widely used in industry. However, because of COs high toxicity and gaseous nature, organic chemists are often reluctant to apply carbonylations more frequently. In addition, new regulations have recently made the transportation of carbon monoxide more difficult. Hence, researchers will need to develop and more frequently use practical and benign CO-generating reagents. Apart from formates, alcohols, and metal carbonyls, carbon dioxide also offers interesting options. Industrial chemists seek easy to prepare catalysts and patent-free ligands/complexes. In addition, non-noble metal complexes will interest both academic and industrial researchers. The novel Lucite process for methyl methacrylate is an important example of an improved catalyst. This reaction makes use of a specific palladium/bisphosphine catalyst, which led to the successful implementation of the technology. More active and productive catalysts for related carbonylations of less reactive olefins would allow for other large scale applications of this methodology. From an academic point of view, researchers continue to look for selective reactions with more functionalized olefins. Finally, because of the volatility of simple metal carbonyl complexes, carbonylation reactions today remain a domain of homogeneous catalysis. The invention of more stable and recyclable heterogeneous catalysts or metal-free carbonylations (radical carbonylations) will be difficult, but could offer interesting challenges for young chemists.

Development of a General Palladium-Catalyzed Carbonylative Heck Reaction of Aryl Halides

The first general palladium-catalyzed carbonylative vinylation of aryl halides with olefins in the presence of CO has been developed. Applying a catalyst system consisting of [(cinnamyl)PdCl](2) and bulky imidazolyl-phosphine ligand L1 allows for the efficient and selective synthesis of α,β-unsaturated ketones under mild reaction conditions. Starting from easily available aryl halides and olefins, versatile building blocks can be prepared in a straightforward manner. The generality and functional group tolerance of this novel protocol is demonstrated.

Palladium-catalyzed carbonylative C-H activation of heteroarenes.

Transition metal catalyzed C H functionalization reactions of arenes and heteroarenes are finding increasing application in the preparation of organic building blocks and therapeutically important scaffolds. Notably, these methods can avoid the use of stoichiometric amounts of organometallic reagents along with any problems associated with their synthesis, stability, and/or functional group compatibility. Recent prominent examples include: transition metal (Rh, Pd, Ru, Ni, Cu) catalyzed arylation, alkylation, alkynylation, alkenylation, and benzylation of (hetero)arenes. In this context, the related carbonylative coupling reactions of (hetero)arenes using C H functionalization to afford carboxylic acid derivatives have been scarcely studied, and previous systems have been limited to chelation-assisted intramolecular reactions. In particular, the apparently simply synthesis of (hetero)aryl ketones from nonchelating substrates through an intermolecular carbonylative coupling reaction has not yet been reported. Among the various ways for the synthesis of (hetero)aryl ketones that have been developed, the palladium-catalyzed carbonylative coupling reactions of aryl halides with organometallic reagents has gained recent interest in modern organic synthesis (Scheme 1). 6] Typical organometallic

Ruthenium and Rhodium‐Catalyzed Carbonylation Reactions

Over the last few decades, carbonylation reactions have been accepted as important chemical transformations for both academic and industrial research. Carboxylic acid derivatives are the main product of carbonylation and are widely used in organic synthesis and fine chemicals preparation. Carbonylation reactions can increase the carbon chain of parent molecules, while introducing a carbonyl group. Herein, the main developments on ruthenium‐ and rhodium‐catalyzed carbonylation are summarized. Compared with palladium catalysts, ruthenium and rhodium catalyzed reactions are a powerful method for activating CH bonds under mild and phosphine free conditions.

Acylation of (Hetero)Arenes through CH Activation with Aroyl Surrogates

In this Minireview, the major achievements in the acylation of arenes and heteroarenes by C-H activation with aroyl groups are summarized and discussed. As the products are carbonyl-containing compounds that are typical products from carbonylation chemistry, the possible inspirations for these reactions are also discussed, as are mechanistic issues and possible problems for carbonylative diaryl ketone synthesis by C-H activation.

Development of a Second Generation Palladium Catalyst System for the Aminocarbonylation of Aryl Halides with CO and Ammonia

Primary aromatic and heteroaromatic amides constitute an important class of carboxylic acid derivatives. Owing to their facile further functionalization, for example, their reduction into primary amines, dehydration into nitriles, the formation of heterocycles and amino acid derivatives, as well as because of their inherent bio-activity, the selective synthesis of benzoic acid amides continues to attract significant attention in synthetic organic chemistry. (Scheme 1 and 2).

A general palladium-catalyzed carbonylative sonogashira coupling of aryl triflates.

Trifling with triflates: A new protocol for the carbonylative Sonogashira reactions of aryl triflates (see scheme) that provides a significant extension of this interesting methodology is described.