Xianjie Fang

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.

General and Regioselective Synthesis of Pyrroles via Ruthenium-Catalyzed Multicomponent Reactions

A general and highly regioselective synthesis of pyrroles via ruthenium-catalyzed three-component reactions has been developed. A variety of ketones including less reactive aryl and alkyl substrates were efficiently converted in combination with different type of amines and vicinal diols into various substituted pyrroles in reasonable to excellent isolated yields. Additionally, α-functionalized ketones gave synthetically interesting amido-, alkoxy-, aryloxy-, and phosphate-substituted pyrroles in a straightforward manner. The synthetic protocol proceeds in the presence of a commercially available ruthenium catalyst system and catalytic amount of base. It proceeds with high atom-efficiency and shows a broad substrate scope and functional group tolerance, making it a highly practical approach for preparation of various pyrrole derivatives.

A General Catalytic Methylation of Amines Using Carbon Dioxide

Carbon dioxide is the most abundant carbon source responsible for the generation of all organic compounds in nature. Its use as an inexpensive and nontoxic C1 feedstock is of increasing interest for the production of value-added chemicals. Owing to its high stability, well designed activation of CO2 and a thermodynamic driving force are required for efficient transformations. In this respect, in recent years important developments in the conversion of carbon dioxide into formates, methanol (methoxides), and methane have been reported. For example, under hydrosilylation conditions CO2 is reduced to silyl formates in the presence of catalytic amounts of organic bases, Ru complexes, or Cu complexes; its reduction to silyl methoxides can be catalyzed by N-heterocyclic carbenes; and, when catalyzed by Zr/B(C6F5)3, frustrated Lewis pairs/B(C6F5)3, or Ir-pincer complexes, it can even be reduced to methane. Notably, using hydrogen, the reduction of CO2 to formic acid derivatives can be catalyzed by Rh, Ir, Ru, and Fe complexes. More recently, its reduction to methanol has been achieved using Ru-pincer complexes and multi-catalyst cascade catalysis. Though there exists numerous reactions between amines and CO2, to the best of our knowledge there is only one example known that describes the synthetically interesting methylation of amines by CO2. More specifically, Vaska and co-workers reported the formation of methylamine as a minor product using Ru or Os complexes. However, it was later suspected that an alkyl group exchange was (partially) responsible for the methylamine product. Hence, it remains that no general catalytic methylation reactions using carbon dioxide is known to date. Instead, activated methyl compounds, such as methyl iodide, dimethyl sulfate, MeOTf, diazomethane, and reductive amination systems (HCHO/ reductant), are often used for this purpose. However, the toxicity of most of these reagents and/or the limited substrate scope attract organic chemists to extend this research area. In this regard, it is interesting to note that the use of dimethyl carbonate or methanol as eco-friendly alternatives has been more recently reported as well. Herein, we describe for the first time a single Ru complex that is able to convert carbon dioxide and amines into various kinds of N-methylated products. Our initial design was motivated by previous reports on the dehydration of primary amides using silanes and the hydrosilylation of carboxylic acid derivatives by us and other groups. Hence, we started to investigate the reaction of carbon dioxide and N-methylaniline (1a) in the presence of silanes as a model system (Table 1). To identify active catalysts around 15 different metal precursors including Ru, Rh, Cu and Fe complexes and 12 phosphine and nitrogen ligands were tested using phenyl silane as reductant (Figure S1 and Table S2). As shown in Table 1, commercially available [RuCl2(dmso)4] (dmso = dimethylsulfoxide) proved to be the best catalyst precursor, giving dimethylaniline in 70% yield (Table 1, entry 3); no reaction occurred without the catalyst. To our delight, using nBuPAd2 (4 mol%; Ad = adamantyl) improved the yields up to 92 % (Table 1, entry 5; see also the Supporting Information, Figure S1). Using other types of metal complexes, hydrosilanes, or solvents led to much lower reactivity (2–63 % yield; Table 1, entries 6–9). However, when using highly polar acetonitrile as the solvent, the best reactivity was obtained (98 % yield; Table 1, entry 10). Methylation reactions of nitrogen compounds are of major importance in biology, for example, in epigenetics, embryonic development, and some cancer growth. Therefore, the methylation of different types of amines was studied in

Selective Palladium‐Catalyzed Aminocarbonylation of Olefins with Aromatic Amines and Nitroarenes

Molecular-defined catalysts allow for the refinement of readily available feedstocks to more complex functionalized products. Prime examples for such transformations are carbonylation processes, which make use of carbon monoxide—currently the most important C1 building block. In fact, carbonylations represent industrial core reactions for converting various bulk chemicals into a diverse set of useful products for our daily life. More specifically, the transitionmetal-catalyzed addition of carbon monoxide to olefins or alkynes in the presence of a suitable nucleophile, such as water, alcohols, and amines, leads to the formation of saturated or unsaturated carboxylic acid derivatives. Nowadays, palladium is one of the most commonly employed metals in these transformations. Compared with the reaction of olefins, carbon monoxide, and alcohols (hydroesterification) or water (hydrocarboxylation), related aminocarbonylations leading to amides have received much less attention. The same is also true compared to the well-studied aminocarbonylation of alkynes, intramolecular aminocarbonylation of alkenes, and aminocarbonylation of aryl and vinyl halides. This is somewhat surprising as the aminocarbonylation of olefins provides a 100% atom-efficient route for producing carboxamides, which represent versatile building blocks and intermediates for the chemical, pharmaceutical, and agrochemical industries. In early studies of aminocarbonylations, cobalt-carbonyl complexes or nickel cyanide were used as catalysts. Ironcarbonyl complexes and ruthenium chloride also showed some catalytic activity. However, all these reactions were carried out under very severe conditions (> 200 8C; > 150 atm). Since the 1980s, more effective catalysts, such as ruthenium-carbonyl complexes and cobalt on charcoal, have been developed. Nevertheless, the substrate scope was limited and the reaction conditions were still harsh (150 8C; 70 atm). Notably, the formation of the corresponding formamide by-products was hardly suppressed. Hence, so far there exists no general and selective intermolecular aminocarbonylation of different olefins under mild conditions. Herein, we present an efficient homogeneous palladiumbased catalyst system for the aminocarbonylation of olefins with a variety of (hetero)aromatic amines or nitro compounds under relatively mild conditions. Notably, the corresponding products were obtained in high yield with good regioselectivity, and unwanted formamides were not observed. In our initial investigations we examined the effect of a series of phosphine ligands on the model reaction of 1octene (1a) with aniline (2a) and carbon monoxide. When monodentate ligands were used, no conversion or just trace amounts of the desired products were observed (Table 1, entries 1–4). Commercially available bidentate ligands (e.g. BINAP, Dppp, L2, and L4) showed low activity in the formation of the desired product (Table 1, entries 5–14). Hence, some of our own developed N-phenylpyrrole-based bisphosphine ligands with different steric properties were tested (Table 1, entries 15–17). To our delight, L10 was identified as the most promising ligand and the reaction afforded the desired product 3aa with moderate conversion, albeit with good selectivity. To improve the reaction further, we evaluated the influence of reaction parameters such as the molar ratio of 1a to 2a, acid co-catalyst, and solvent in the presence of L10 as the ligand. As shown in Table 1, the yield of 3aa was strongly affected by the molar ratio of 1a to 2a as a consequence of some isomerization of the olefin. Consequently, as the molar ratio of 1 a to 2a increased to 2:1, the yield of 3aa increased to 86% (Table 1, entry 18). Moreover, no reaction occurred in the absence of para-toluenesulfonic acid monohydrate (p-TsOH), thus indicating the importance of the acid for the generation of the catalytically active palladium hydride species (Table 1, entry 19). Interestingly, changing the THF solvent to toluene resulted in full conversion of 2a and gave nearly quantitative yields of the corresponding amides, as determined by GC (Table 1, entry 20). No conversion was observed and the starting materials were recovered in the absence of [Pd(acac)2] (acac = acetylacetonate) or when using other catalysts such as [Rh(CO)2(acac)], [Co2(CO)8], [Ir(cod)(acac)] (cod = 1,5cyclooctadiene), [Ru3(CO)12], [Fe3(CO)12], and [Ni(acac)2] (Table 1, entry 21). With the optimized reaction conditions established (Table 1, entry 20), we examined the scope and limitations of this aminocarbonylation process with respect to various olefins (Table 2). Both shortand long-chain terminal olefins 1a–1e provided the corresponding amides in good to excellent yields and with good regioselectivities (Table 2, entries 1–4). The more challenging internal olefin 1e was transformed to C9-amides in 53 % yield. The linear amide is still formed preferentially because of isomerization of the olefin (66:34 n/i selectivity; Table 2, entry 5). Lower linear [*] X. Fang, Dr. R. Jackstell, Prof. Dr. M. Beller Leibniz-Institut f r Katalyse e. V. an der Universit t Rostock Albert-Einstein-Strasse 29a, 18059 Rostock (Germany) E-mail: matthias.beller@catalysis.de Homepage: http://www.catalysis.de

Selective Palladium-Catalyzed Aminocarbonylation of 1,3-Dienes: Atom-Efficient Synthesis of β,γ-Unsaturated Amides

Carbonylation reactions constitute important methodologies for the synthesis of all kinds of carboxylic acid derivatives. The development of novel and efficient catalysts for these transformations is of interest for both academic and industrial research. Here, the first palladium-based catalyst system for the aminocarbonylation of 1,3-dienes is described. This atom-efficient transformation proceeds under additive-free conditions and provides straightforward access to a variety of β,γ-unsaturated amides in good to excellent yields, often with high selectivities.

Selective Palladium‐Catalyzed Hydroformylation of Alkynes to α,β‐Unsaturated Aldehydes

Atom-efficient: A selective palladium catalyst system is used for the hydroformylation of alkynes (see picture). In this syngas reaction, various alkynes were smoothly transformed to synthetically interesting α,β-unsaturated aldehydes in good yields with high regio- and stereoselectivity.

Rh(I)-Catalyzed Hydroamidation of Olefins via Selective Activation of N–H Bonds in Aliphatic Amines

Hydroamidation of olefins constitutes an ideal, atom-efficient method to prepare carboxylic amides from easily available olefins, CO, and amines. So far, aliphatic amines are not suitable for these transformations. Here, we present a ligand- and additive-free Rh(I) catalyst as solution to this problem. Various amides are obtained in good yields and excellent regioselectivities. Notably, chemoselective amidation of aliphatic amines takes place in the presence of aromatic amines and alcohols. Mechanistic studies reveal the presence of Rh-acyl species as crucial intermediates for the selectivity and rate-limiting step in the proposed Rh(I)-catalytic cycle.

Highly active and efficient catalysts for alkoxycarbonylation of alkenes

Carbonylation reactions of alkenes constitute the most important industrial processes in homogeneous catalysis. Despite the tremendous progress in this transformation, the development of advanced catalyst systems to improve their activity and widen the range of feedstocks continues to be essential for new practical applications. Herein a palladium catalyst based on 1,2-bis((tert-butyl(pyridin-2-yl)phosphanyl)methyl)benzene L3 (pytbpx) is rationally designed and synthesized. Application of this system allows a general alkoxycarbonylation of sterically hindered and demanding olefins including all kinds of tetra-, tri- and 1,1-disubstituted alkenes as well as natural products and pharmaceuticals to the desired esters in excellent yield. Industrially relevant bulk ethylene is functionalized with high activity (TON: >1,425,000; TOF: 44,000 h−1 for initial 18 h) and selectivity (>99%). Given its generality and efficiency, we expect this catalytic system to immediately impact both the chemical industry and research laboratories by providing a practical synthetic tool for the transformation of nearly any alkene into a versatile ester product.

Domino‐Hydroformylation/Aldol Condensation Catalysis: Highly Selective Synthesis of α,β‐Unsaturated Aldehydes from Olefins

A general and highly chemo-, regio-, and stereoselective synthesis of α,β-unsaturated aldehydes by a domino hydroformylation/aldol condensation reaction has been developed. A variety of olefins and aromatic aldehydes were efficiently converted into various substituted α,β-unsaturated aldehydes in good to excellent yields in the presence of a rhodium phosphine/acid-base catalyst system. In view of the easy availability of the substrates, the high atom-efficiency, the excellent selectivity, and the mild conditions, this method is expected to complement current methodologies for the preparation of α,β-unsaturated aldehydes.

Palladium‐Catalyzed Alkoxycarbonylation of Conjugated Dienes under Acid‐Free Conditions: Atom‐Economic Synthesis of β,γ‐Unsaturated Esters

Carbonylation reactions constitute important methodologies for the synthesis of all kinds of carboxylic acid derivatives. The development of novel and better catalysts for these transformations is of interest for both academic and industrial research. Here, a benign palladium-based catalyst system for the alkoxycarbonylation of conjugated dienes under acid-free conditions has been developed. This atom-efficient transformation provides straightforward access to a variety of β,γ-unsaturated esters in good to excellent yields and often with high selectivities. As an industrially relevant example the (formal) synthesis of dimethyl adipate and ε-caprolactam from 1,3-butadiene is demonstrated.