Small-molecule H-bond donors in asymmetric catalysis.

Multicomponent reactions (MCRs) are one-pot reactions employing more than two starting materials, e.g. 3, 4, … 7, where most of the atoms of the starting materials are incorporated in the final product.1 Several descriptive tags are regularly attached to MCRs (Fig. 1): they are atom economic, e.g. the majority if not all of the atoms of the starting materials are incorporated in the product; they are efficient, e.g. they efficiently yield the product since the product is formed in one-step instead of multiple sequential steps; they are convergent, e.g. several starting materials combine in one reaction to form the product; they exhibit a very high bond-forming-index (BFI), e.g. several non-hydrogen atom bonds are formed in one synthetic transformation.2 Therefore MCRs are often a useful alternative to sequential multistep synthesis.






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Figure 1


Above: multistep syntheses can be divergent (sequential) or convergent; below: in analogy MCR reactions are convergent and one or two component reactions are divergent or less convergent.

Chemistry and Biology Of Multicomponent Reactions

The design and implementation of cascade reactions is a challenging facet of organic chemistry, yet one that can impart striking novelty, elegance, and efficiency to synthetic strategies. The application of cascade reactions to natural products synthesis represents a particularly demanding task, but the results can be both stunning and instructive. This Review highlights selected examples of cascade reactions in total synthesis, with particular emphasis on recent applications therein. The examples discussed herein illustrate the power of these processes in the construction of complex molecules and underscore their future potential in chemical synthesis.

Cascade reactions in total synthesis.

The preparation, structure, and chemistry of hypervalent iodine compounds are reviewed with emphasis on their synthetic application. Compounds of iodine possess reactivity similar to that of transition metals, but have the advantage of environmental sustainability and efficient utilization of natural resources. These compounds are widely used in organic synthesis as selective oxidants and environmentally friendly reagents. Synthetic uses of hypervalent iodine reagents in halogenation reactions, various oxidations, rearrangements, aminations, C–C bond-forming reactions, and transition metal-catalyzed reactions are summarized and discussed. Recent discovery of hypervalent catalytic systems and recyclable reagents, and the development of new enantioselective reactions using chiral hypervalent iodine compounds represent a particularly important achievement in the field of hypervalent iodine chemistry. One of the goals of this Review is to attract the attention of the scientific community as to the benefits of...

Advances in Synthetic Applications of Hypervalent Iodine Compounds

The chemistry of copper is extremely rich because it can easily access Cu0, CuI, CuII, and CuIII oxidation states allowing it to act through one-electron or two-electron processes. As a result, both radical pathways and powerful two-electron bond forming pathways via organmetallic intermediates, similar to those of palladium, can occur. In addition, the different oxidation states of copper associate well with a large number of different functional groups via Lewis acid interactions or π-coordination. In total, these feature confer a remarkably broad range of activities allowing copper to catalyze the oxidation and oxidative union of many substrates.

Oxygen is a highly atom economical, environmentally benign, and abundant oxidant, which makes it ideal in many ways.1 The high activation energies in the reactions of oxygen require that catalysts be employed.2 In combination with molecular oxygen, the chemistry of copper catalysis increases exponentially since oxygen can act as either a sink for electrons (oxidase activity) and/or as a source of oxygen atoms that are incorporated into the product (oxygenase activity). The oxidation of copper with oxygen is a facile process allowing catalytic turnover in net oxidative processes and ready access to the higher CuIII oxidation state, which enables a range of powerful transformations including two-electron reductive elimination to CuI. Molecular oxygen is also not hampered by toxic byproducts, being either reduced to water, occasionally via H2O2 (oxidase activity) or incorporated into the target structure with high atom economy (oxygenase activity). Such oxidations using oxygen or air (21% oxygen) have been employed safely in numerous commodity chemical continuous and batch processes.3

However, batch reactors employing volatile hydrocarbon solvents require that oxygen concentrations be kept low in the head space (typically <5–11%) to avoid flammable mixtures, which can limit the oxygen concentration in the reaction mixture.4,5,6 A number of alternate approaches have been developed allowing oxidation chemistry to be used safely across a broader array of conditions. For example, use of carbon dioxide instead of nitrogen as a diluent leads to reduced flammability.5 Alternately, water can be added to moderate the flammability allowing even pure oxygen to be employed.6 New reactor designs also allow pure oxygen to be used instead of diluted oxygen by maintaining gas bubbles in the solvent, which greatly improves reaction rates and prevents the build up of higher concentrations of oxygen in the head space.4a,7 Supercritical carbon dioxide has been found to be advantageous as a solvent due its chemical inertness towards oxidizing agents and its complete miscibility with oxygen or air over a wide range of temperatures.8 An number of flow technologies9 including flow reactors,10 capillary flow reactors,11 microchannel/microstructure structure reactors,12 and membrane reactors13 limit the amount of or afford separation of hydrocarbon/oxygen vapor phase thereby reducing the potential for explosions.

Enzymatic oxidizing systems based upon copper that exploit the many advantages and unique aspects of copper as a catalyst and oxygen as an oxidant as described in the preceding paragraphs are well known. They represent a powerful set of catalysts able to direct beautiful redox chemistry in a highly site-selective and stereoselective manner on simple as well as highly functionalized molecules. This ability has inspired organic chemists to discover small molecule catalysts that can emulate such processes. In addition, copper has been recognized as a powerful catalyst in several industrial processes (e.g. phenol polymerization, Glaser-Hay alkyne coupling) stimulating the study of the fundamental reaction steps and the organometallic copper intermediates. These studies have inspiried the development of nonenzymatic copper catalysts. For these reasons, the study of copper catalysis using molecular oxygen has undergone explosive growth, from 30 citations per year in the 1980s to over 300 citations per year in the 2000s.

A number of elegant reviews on the subject of catalytic copper oxidation chemistry have appeared. Most recently, reviews provide selected coverage of copper catalysts14 or a discussion of their use in the aerobic functionalization of C–H bonds.15 Other recent reviews cover copper and other metal catalysts with a range of oxidants, including oxygen, but several reaction types are not covered.16 Several other works provide a valuable overview of earlier efforts in the field.17 This review comprehensively covers copper catalyzed oxidation chemistry using oxygen as the oxidant up through 2011. Stoichiometric reactions with copper are discussed, as necessary, to put the development of the catalytic processes in context. Mixed metal systems utilizing copper, such as palladium catalyzed Wacker processes, are not included here. Decomposition reactions involving copper/oxygen and model systems of copper enzymes are not discussed exhaustively. To facilitate analysis of the reactions under discussion, the current mechanistic hypothesis is provided for each reaction. As our understanding of the basic chemical steps involving copper improve, it is expected that many of these mechanisms will evolve accordingly.

/pdf/aerobic-copper-catalyzed-organic-reactions-3ctljpvivz.pdf

Aerobic Copper-Catalyzed Organic Reactions

Organocatalytic C-H activation reactions have recently been developed besides the traditional metal-catalysed C-H activation reactions. The recent non-asymmetric and asymmetric C-H activation reactions mediated by organocatalysts are discussed in this review.

https://www.beilstein-journals.org/bjoc/content/pdf/1860-5397-8-159.pdf

Organocatalytic C–H activation reactions

Multicomponent reactions (MCRs) are one-pot processes that combine three or more substrates simultaneously. Such processes are of great interest in diversity-oriented synthesis, especially to generate compound libraries for screening purposes. The Ugi four-component reaction (Ugi 4CR) is one of the milestones in this field and great efforts have been devoted to the exploration of the potential of this transformation. A primary amine, a carbonyl compound, a carboxylic acid, and an isocyanide react to give a-amido amides in this remarkable reaction. In recent years several modifications of the classical Ugi 4CR have been described; these include variations of one of the components or the introduction of a linkage between two of them. In particular, the groups of Zhu and D/mling have contributed significantly to the advancement of this transformation. Mechanistically, the Ugi reaction is believed to proceed via a nitrilium ion intermediate (A), which results from the addition of the isocyanide to an in situ generated iminium ion (Scheme 1). Nucleophilc addition of the carboxylate ion followed by Mumm rearrangement leads to the final product and water as the only by-product (Scheme 1, path a). We reasoned that it should be possible to intercept the nitrilium ion A not with the carboxylate ion but rather with the water molecule generated in the course of imine formation. This would require using acids (HX) other than carboxylic acids and possibly result in a catalytic cycle (Scheme 1, path b). To the best of our knowledge such a three-component Ugi reaction, which transforms an aldehyde, a primary amine, and an isocyanide to an a-amino amide is unknown. Given the potential of these products for the synthesis of a-amino acids and their derivatives, we became interested in developing this new reaction. Here we report the first catalytic threecomponent Ugi reaction in which water acts as the internal nucleophile. We identified phenyl phosphinic acid (10) as the best catalyst for this perfectly atom-economic reaction, thus introducing a new motif for organocatalysis. The newly designed reaction does not proceed in the absence of catalyst. Stirring benzaldehyde (1a), p-anisidine (2a), and tert-butyl isocyanide (3a) at room temperature for three days in toluene resulted in no detectable quantities of the desired product (4a). Even heating the reaction mixture to 80 8C for 24 h did not result in the formation of product 4a. At this point we started to investigate different Brønsted acid catalysts for this reaction (Table 1). p-Toluenesulfonic acid (5) gave no conversion to the product either at room temperature or at 80 8C (Table 1, entry 1). The desired product was obtained in poor yields when phenyl boronic acid (6) or diphenyl phosphate (7) were used as the catalysts (Table 1, entries 2 and 3). Sc(OTf)3 (8) could also promote this reaction but with low conversion (Table 1, entry 4). Phenyl phosphonic acid (9) gave moderate conversion (Table 1, entry 5). Remarkably, we found phenyl phosphinic acid (10) to be a highly active catalyst for the reaction, giving the desired product in 95% conversion (Table 1, entry 6), whereas diphenyl phosphinic acid (11) and diphenyl phosphine oxide (12) were proved to be inactive (Table 1, entries 7 and 8). Decreasing the catalyst loading of 10 to 5 mol% resulted in considerably lower yield. Other solvents were also screened but toluene generally gave the best yields (see Supporting Information for details). Using phenyl phosphinic acid (10) as the catalyst and toluene as solvent, we initiated a study to explore the scope of this new three-component reaction. First, the reaction of a variety of different aldehydes 1 with p-anisidine (2a) as the Scheme 1. Ugi 4CR and new three-component reaction.

Catalytic Three-Component Ugi Reaction†

https://onlinelibrary.wiley.com/doi/pdf/10.1002/anie.200790071

Catalytic Asymmetric Acylcyanation of Imines

Catalytic asymmetric three-component acyl-Strecker reaction.

The first aminocatalyzed α-alkylation of α-branched aldehydes with benzyl bromides as alkylating agents has been developed. Using a sterically demanding proline derived catalyst, racemic α-branched aldehydes are reacted with alkylating agents in a DYKAT process to give the corresponding α-alkylated aldehydes with quaternary stereogenic centers in good yields and high enantioselectivities.

The catalytic asymmetric α-benzylation of aldehydes.

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