Reactions of Isocyanide Dihalides and their Derivatives

The readily obtainable isocyanide dichlorides can be used as starting materials for the preparation of many types of substances. Exchange reactions yield numerous derivatives of formic and carbonic acids, while heterocyclic products have been obtained by reaction with bifunctional partners. The present article deals not only with reactions that are known from the literature but also with the author's own work, some of which has not been published before.     

Electrophilic Reagents—Recent Developments and Their Preparative Application

The most widely known electrophilic agents are protic acids and compounds with an electronsextet partial structure. Recent research has aimed at the development of new electrophilic reagents, with greater reactivity on the one hand and higher selectivity on the other, which would largely obviate the addition of Lewis acids (Friedel-Crafts catalysts), and also allow control of the isomer ratio in reactions with ambivalent substrates. Compounds with “super-leaving groups”, such as trifluoromethanesulfonate and fluorosulfate, have been demonstrated as most advantageous in this respect since they are sufficiently polarized or dissociated for reactions to take place even in the absence of Friedel-Crafts catalysts. Heterocycles such as pyridones or imidazole are likewise suitable leaving groups; they are employed for their high selectivity, and also because they allow working under non-aqueous conditions.     

Preparation,Structure, and Reactions of Halomalondialehdes

The present progress report provides a survey of the synthesis, structure, and reactions of halomalondialdehydes, including “cyanomalondialdehyde” (diformylacetonitrile), the only pseudohalogen compound so far known in this series. Halomalondialdehydes are reactive compounds, applicable in a variety of ways, and are characterized particularly by their cyclizations with bifunctional compounds. Many of the reactions discussed below can be applied to substituted malondialdehydes other than those specified.     

Carbene Complexes in Organic Synthesis [New Synthetic Methods (47)]

Transition metals are finding increasing use in organic synthesis on the borderline between “organic” and “inorganic” chemistry. Advantage is taken thereby of the fact that metal-induced CC bond formation often takes place with remarkable selectivity. The rapid development that has taken place in this area of chemistry is clearly demonstrated by the carbene complexes, examples of which are now known for almost all transition elements, and which have transformed from organometallic curiosities into synthetically useful reagents in less than two decades since the first studies of E. O. Fischer. They are not only suitable as carbene-transfer agents but also undergo interesting cycloadditions with other ligands in the co-ligand sphere. Their manipulation requires techniques no more complicated than those for Grignard reactions. Thus, carbene complexes can also be used in the synthesis of natural products such as vitamins or antibiotics.     

Ligand‐ and Solvent‐Controlled Regio‐ and Chemodivergent Carbonylative Reactions

The development of highly selective procedures is one of the core goals in organic chemistry. Among the known organic transformations, carbonylation reactions present an ideal choice for the preparation of carbonyl‐containing compounds. In this review, the recent achievements on the control of the selectivity for carbonylation reactions have been summarized. The effects of ligands, solvents, and bases on the selectivity are been discussed.     

Heuristic Chemistry—Elimination Reactions

Besides additions and substitutions, elimination reactions play a fundamental role in organic synthesis. However, conceptual reviews of known 1,x‐elimination patterns that go beyond the typical olefin‐forming 1,2‐eliminations are scarce. To develop a broader understanding of elimination reactions, we follow a heuristic approach and deduce recurrent reaction patterns from traditional and specific elimination reactions. Our work demonstrates that 1,x‐elimination reactions and their outcomes can be easily rationalized by defined mnemonic categories.     

Organomercury Compounds in Organic Synthesis

Organomercurials have been known since 1850 and many synthetic routes to these compounds presently exist. The ability of these compounds to accommodate a wide variety of functional groups and to tolerate quite diverse reaction conditions makes them attractive as synthetic intermediates. While the solvomercuration-demercuration and divalent carbon transfer reactions remain the most widely used of the organomercurial reactions, a number of new synthetic procedures employing organomercurials have been developed in recent years. Many of these involve transmetallation reactions with palladium salts.     

Carbon Suboxide in Preparative Organic Chemistry. New synthetic methods (1)

Although it has been known for nearly 70 years, carbon suboxide was used almost exclusively for the preparation of simple malonic acid derivatives until about 1960. Since then, however, the significance of this unusual “bisketene” has steadily increased in synthetic chemistry (especially that of heterocyclic compounds). This progress report surveys the possible applications of C₃O₂ in preparative organic chemistry, including photochemical reactions.     

Kinetic determinations of reactants utilizing uncatalyzed reactions

Kinetic-based determinations of reactants utilizing uncatalyzed chemical reactions do not match the polularity of catalytic methods for the determination of catalysts (particularly transition metal ions) or reactants (e.g., in enzymatic reactions) and this reflects on the scarcity of reviews on the topic. In some cases, however, advances in instrumentation and data manipulation provide competitive alternatives to nonkinetic-based methods for single as well as multispecies determinations. Such advances are reviewed here and applications illustrated.     

Cyclic Voltammetry—“Electrochemical Spectroscopy”. New Analytical Methods (25)

Polarography is still the best known classical measuring method in electroanalytical chemistry. However, in recent years its position has been challenged by cyclic voltammetry (CV). Simple diagnostic criteria and relatively easily acquired measuring techniques have hastened this development. Cyclic voltammetry has the further attraction of providing information not only on the thermodynamics of redox processes but also on the kinetics of heterogeneous electron-transfer reactions and coupled chemical reactions. The characteristic shapes of the voltammetric waves and their unequivocal position on the potential scale virtually fingerprint the individual electrochemical properties of redox systems. For this reason the method has been labeled “electrochemical spectroscopy”.     

Expanding the Scope of PNA‐Encoded Synthesis (PES): Mtt‐Protected PNA Fully Orthogonal to Fmoc Chemistry and a Broad Array of Robust Diversity‐Generating Reactions

Nucleic acid‐encoded libraries are emerging as an attractive and highly miniaturized format for the rapid identification of protein ligands. An important criterion in the synthesis of nucleic acid encoded libraries is the scope of reactions that can be used to introduce molecular diversity and devise divergent pathways for diversity‐oriented synthesis (DOS). To date, the protecting group strategies that have been used in peptide nucleic acid (PNA) encoded synthesis (PES) have limited the choice of reactions used in the library synthesis to just a few prototypes. Herein, we describe the preparation of PNA monomers with a protecting group combination (Mtt/Boc) that is orthogonal to Fmoc‐based synthesis and compatible with a large palette of reactions that have been productively used in DOS (palladium cross‐couplings, metathesis, reductive amination, amidation, heterocycle formation, nucleophilic addition, conjugate additions, Pictet–Spengler cyclization). We incorporate γ‐modifications in the PNA backbone that are known to enhance hybridization and solubility. We demonstrate the robustness of this strategy with a library synthesis that is characterized by MALDI MS analysis at every step.     

Regioselective Arene C−H Alkylation Enabled by Organic Photoredox Catalysis

Expanding the toolbox of C?H functionalization reactions applicable to the late‐stage modification of complex molecules is of interest in medicinal chemistry, wherein the preparation of structural variants of known pharmacophores is a key strategy for drug development. One manifold for the functionalization of aromatic molecules utilizes diazo compounds and a transition‐metal catalyst to generate a metallocarbene species, which is capable of direct insertion into an aromatic C?H bond. However, these high‐energy intermediates can often require directing groups or a large excess of substrate to achieve efficient and selective reactivity. Herein, we report that arene cation radicals generated by organic photoredox catalysis engage in formal C?H functionalization reactions with diazoacetate derivatives, furnishing sp²–sp³ coupled products with moderate‐to‐good regioselectivity. In contrast to previous methods utilizing metallocarbene intermediates, this transformation does not proceed via a carbene intermediate, nor does it require the presence of a transition‐metal catalyst.     

Nickel-Catalyzed Arylative Cyclizations of Alkyne- and Allene-Tethered Electrophiles using Arylboron Reagents

The use of arylboron reagents in metal-catalyzed domino addition–cyclization reactions is a well-established strategy for the preparation of diverse, highly functionalized carbo- and heterocyclic products. Although rhodium- and palladium-based catalysts have been commonly used for these reactions, more recent work has demonstrated nickel catalysis is also highly effective, in many cases offering unique reactivity and access to products that might otherwise not be readily available. This review gives an overview of nickel-catalyzed arylative cyclizations of alkyne- and allene-tethered electrophiles using arylboron reagents. The scope of the reactions is discussed in detail, and general mechanistic concepts underpinning the processes are described.     

Regio- and Stereoselective Syntheses with Organocopper Reagents

Of all of the organometallic reagents currently used to form carbon–carbon bonds, organocopper reagents rank amongst the most important. Interest in these reagents centers not only on their regioselectivity, but also increasingly on their application in stereoselective transformations (principally Michael additions and S_N2′ reactions); the use of suitable substrates or chirally modified cuprates can lead to highly diastereo- and enantioselective reactions. Simultaneously, extensions of methods for the preparation and application of these reagents (for example functionalized organocopper species and Lewis acid catalysis, respectively) have opened up new horizons for organocopper reagents. Mechanistically, the reactions are well-documented and understood, but this aspect of the subject has not kept pace with the many rapid developments in preparative chemistry. Organocopper ragents have proved to be indispensable in the synthesis of complex natural products and pharmaceuticals, chiral auxiliaries, and molecules with interesting structural features. In this review we will discuss some of the more recent important developments in this area; the organization will follow the type of selectivity (regio-, diastereo-, and enantioselectivity).     

New Reductive Transformations of Unsaturated Cyclic Hydrocarbons [New Synthetic Methods (66)]

The successive reduction of fully conjugated cyclic hydrocarbons leads to singly and multiply charged ions with unusual bonding. The charge distribution in these ions can be determined spectroscopically, and the information so obtained is then used in kinetically controlled trapping reactions for the regioselective introduction of electrophilic groups. When non-benzenoid substrates are used, syntheses become possible which can either not be carried out or can only be carried out with great difficulty in other ways. Examples of new preparative applications are cycloannelation and bridging reactions as well as polymerization reactions. The ion pair structure of the intermediate and the type of electrophile used are of paramount importance in controlling the mechanism of these reductive transformations.     

Azulenesulfonium Salts: Accessible,Stable, and Versatile Reagents for Cross‐Coupling

Azulenesulfonium salts may be readily prepared from the corresponding azulenes by an S_EAr reaction. These azulene sulfonium salts are bench‐stable species that may be employed as pseudohalides for cross‐coupling. Specifically, their application in Suzuki–Miyaura reactions has been demonstrated with a diverse selection of coupling partners. These azulenesulfonium salts possess significant advantages in comparison with the corresponding azulenyl halides, which are known to be unstable and difficult to prepare in pure form.     

Mass spectrometry for monitoring protease reactions

More than 560 genes are annotated as proteases in the human genome. About half of the genes are not or are only marginally characterized. Over the past decade, mass spectrometry has become the basis for proteomics, especially for protein identification, performed in a high-throughput manner. This development was also very fruitful for exploring the complex systems associated with protease functions, as briefly reviewed here. Mass spectrometry is an ideal tool for monitoring protease reactions, as will be highlighted in this review.     

Prescriptions and Ingredients for Controlled CC Bond Formation with Organometallic Reagents. New synthetic methods (5)

Merits and drawbacks of known carbon-carbon linking procedures are outlined. Two novel methods are discussed in some detail: the copper-catalyzed alkylation of Grignard reagents and reactions with allylpotassium compounds. Both methods provide a very efficient access to saturated, unsaturated, as well as functionally substituted hydrocarbons and moreover permit an astonishing degree of regio- and stereoselective control of olefin synthesis.     

IPy2BF4-mediated rearrangements of 1,2-difunctionalized compounds and olefins

Acetal derivatives are easily obtained from 1,2-difunctionalized compounds by a new reaction mediated by IPy2BF4 with a mechanism based on a 1,2-migration of aryl or alkyl groups. A new oxidative rearrangement reaction of olefins is also described. Moreover, when this metal-free protocol is applied to cyclic olefins, interesting ring-contraction reactions are observed. The new methodologies described here are a clean and efficient alternative to known strategies that make use of potentially toxic metallic complexes.     

Synthetic Approaches to Star‐Shaped Molecules with 1,3,5‐Trisubstituted Aromatic Cores

Herein, we summarize the synthetic approaches that have been developed for the synthesis of star‐shaped molecules. Typically, to design such highly functionalized molecules, simple building blocks are first assembled through trimerization reactions, starting from commercially available starting materials. Then, these building blocks are synthetically manipulated to generate extended star‐shaped molecules. We also discuss the syntheses of star‐shaped molecules that contain 2,4,6‐trisubstituted 1,3,5‐triazine or 1,3,5‐trisubstituted benzene rings as a central core and diverse substituted styrene, phenyl, and fluorene derivatives at their periphery, which endows these molecules with extended conjugation. A variety of metal‐catalyzed reactions, such as Suzuki, Buchwald–Hartwig, Sonogashira, Heck, and Negishi cross‐coupling reactions, as well as metathesis, have been employed to functionalize a range of star‐shaped molecules. The methods described herein will be helpful for designing a wide range of intricate compounds that are highly valuable in the fields of supramolecular chemistry and materials science. Owing to space limitations, we will not cover all of the publications on this topic. Instead, we will focus on examples that were reported by our research group and other relevant recent literature. Apart from the trimerization sequence, this Minireview has been structured based on the key reactions that were used to prepare the star‐shaped molecules and other higher analogues. Finally, some examples that do not fit into this classification are discussed.