Abstract The Chan–Lam reaction is a copper‐mediated or ‐catalyzed formation of a wide variety of carbon–heteroatom bonds from an organoboron compound and a heteroatom nucleophile. In its broadest sense, the reaction allows arylation, vinylation, and alkylation of a wide range of heteroatom‐based functional groups including amines, amides, sulfonamides, N ‐heterocycles, alcohols, phenols, and thiols. The coupling partner is usually a boronic acid, although boronic esters have also been successful. An inexpensive copper mediator or catalyst, such as copper(II) acetate, is employed in the reaction. The typically mild, user‐friendly reaction conditions often involve an atmosphere of air, ambient temperature, and no ligand. This chapter presents a thorough overview of the Chan–Lam reaction with N ‐, O ‐, and S ‐based nucleophiles. The current understanding of the reaction mechanism is discussed along with a detailed overview of the scope and limitations of the process, and representative reaction conditions. Applications in the context of complex molecule synthesis are provided, as are comparisons to complementary metal‐catalyzed heteroatom‐functionalization methods using copper and palladium.
The traditional Nazarov reaction is the conrotatory 4π electrocyclization of conjugated pentadienyl cations, which are derived from Lewis or Brønsted acid activation of 1,4‐pentadien‐3‐ones. This reaction provides an expedient way to assemble carbocyclic products from simple, acyclic starting materials; however, reaction conditions often require at least one equivalent of a strong acid to facilitate cyclization, and the regioselectivity of the standard eliminative termination step is difficult to control. This chapter describes advances in Nazarov methodology since it was last reviewed in Organic Reactions in 1994. The discussion is focused on the preparation and use of alternative substrates to access the requisite pentadienyl cation as well as methods to induce cyclization with new and asymmetric catalytic systems. Also presented is a discussion of the interrupted Nazarov reaction, which utilizes both cationic and enolate intermediates to form new bonds or to initiate cascade or tandem reaction sequences. Both inter‐ and intramolecular interrupted Nazarov reactions generate highly functionalized products, some of which may possess four contiguous stereogenic centers. Trapping events can involve heteronucleophiles, π‐systems, or structural rearrangements, which occur in a stereocontrolled fashion.
Atropisomeric biaryl compounds are prepared by coupling two aryl partners in the presence of a chiral catalyst. When these biaryl products contain three or more substituents adjacent to the new aryl–aryl bond, the barrier to bond rotation becomes sufficiently high to enable the isolation of single enantiomers. This structural feature is found in numerous natural products and chiral ligand frameworks. The asymmetric catalytic construction of a carbon–carbon bond between two sp 2 ‐hybridized aryl fragments can be achieved with redox‐neutral cross‐couplings, reductive homo‐couplings, couplings through C–H activation, oxidative couplings, and couplings by nucleophilic addition to oxidized partners. Although considerable emphasis has been placed on traditional palladium‐catalyzed cross‐coupling reactions, including asymmetric Suzuki coupling, there have been significant advances in both reductive and oxidative approaches. Functional‐group tolerance on the coupling partners is varied and often dependent on the choice of chiral catalyst and ligand. Where appropriate, mechanisms and proposed stereochemical models are used to explain the observed axial chirality. These transformations are showcased in the syntheses of natural products and novel chiral ligands. The goal of this chapter is to demonstrate the significance of catalytic atroposelective aryl–aryl bond‐forming reactions, including the continued development of catalytic systems to achieve excellent yields and enantioselectivities. Additionally, some less‐common approaches towards catalytic atroposelective aryl–aryl bond formation are discussed.
The regioselective C−H functionalization of arenes is an ideal method for preparing substituted aromatic compounds, which are ubiquitous scaffolds in natural products, pharmaceuticals, and advanced materials. Palladium(0)‐catalyzed, norbornene‐mediated C−H functionalization—now known as the Catellani reaction—is a particularly efficient and modular means to access densely substituted aromatic compounds. Inspired by the Catellani reaction, many palladium(II)‐catalyzed variants have been developed, further expanding the synthetic utility of this chemistry. The Catellani reaction functionalizes both the ortho and ipso positions of the starting haloarene. Products are obtained with excellent regioselectivity, and enantioenriched norbornene derivatives may be used to render the reaction enantioselective. This method enables ortho ‐alkylation, ‐arylation, and ‐amination of various arene substrates, and can be combined with other palladium‐catalyzed processes. The mechanism, development, and applications of Catellani‐type reactions are discussed in this chapter.
Conjugated alkynes are valuable intermediates in the synthesis of natural products, agrochemicals, pharmaceuticals, fine chemicals, and organic molecular materials. Since its introduction in 1975, the palladium‐catalyzed Sonogashira reaction has become the primary choice for the construction of sp–sp 2 carbon–carbon bonds in aryl‐, heteroaryl‐, and alkenyl‐substituted alkynes. A vast range of reaction conditions have been explored to expand and optimize the scope of the Sonogashira reaction, including sustainable variants, microwave‐assisted cross couplings, and cross couplings performed in water. Research efforts also target the development of improved catalytic systems for the Sonogashira reaction, such as solid‐supported palladium catalysts and nanoparticles, the use of N ‐heterocyclic carbenes (NHCs) as ligands, as well as copper‐free variants of the reaction. This Chapter reviews the application of the palladium‐catalyzed Sonogashira cross coupling of terminal alkynes with aryl or alkenyl halides and triflates. Coupling reactions that form conjugated alkynes via alternative methods, or use different electrophiles, catalysts, or alkynes, are also briefly described.
The Meyer–Schuster rearrangement corresponds to a formal 1,3‐shift of a propargylic alcohol to afford the corresponding α,β‐unsaturated carbonyl compound via tautomerization of an allenol intermediate. The original acidic and harsh conditions have been replaced with mild and selective conditions that are compatible with a variety of functional and protecting groups. Commonly employed strategies include the activation of propargylic alcohols as esters, transition‐metal catalysis (e.g., gold complexes and oxometal complexes), and the C–H bond activation of terminal propargylic alcohols by transition‐metal insertion. The Meyer–Schuster rearrangement has been extended to all classes of propargylic alcohols and esters, including C sp ‐heteroatom‐substituted alkynols, as well as to propargylic amine derivatives (i.e., the aza‐Meyer–Schuster rearrangement). Moreover, the rearrangement can be employed in inter‐ and intramolecular one‐pot consecutive reactions, wherein multiple carbon–carbon and/or carbon–heteroatom bonds are formed. The Meyer–Schuster reaction exhibits a high atom economy, simple experimental procedures, and good‐to‐excellent product yields and stereoselectivities. Moreover, starting materials are easily accessible, and any toxic metals are employed in substoichiometric amounts. As such, the Meyer–Schuster rearrangement compares favorably with other standard protocols, such as the Wittig reaction, for the preparation of α,β‐unsaturated carbonyl compounds and derivatives. This review covers the literature since the identification of the reaction up to the end of 2020 and includes relevant references through November 2023. Both the mechanistic features and the regio‐ and stereoselectivity issues are discussed as they relate to the reaction conditions. The scope and limitations of the reaction are presented, as are a selection of synthetic applications, several general experimental procedures, and a comparison of the Meyer–Schuster rearrangement with other known methods. Finally, the tabular survey highlights the broad range of starting materials and products possible with the Meyer–Schuster rearrangement.
The reaction of allylic cations with 1,3‐dienes is formally equivalent to the Diels–Alder reaction but leads to seven‐membered rings. An allylic cation contains 2 pi electrons, and is thus precisely analogous to an alkene and, like the latter, can function as a dienophile. The substituent at the central carbon of the allylic cation serves to terminate the reaction. Most often, this substituent is an oxyanion or a silyl ether, but other groups have been used. These (4+3) cycloadditions can proceed via mechanisms that range from stepwise to concerted. Diastereoselectivity, regioselectivity, and enantioselectivity have all been achieved, though there are still opportunities for the development of new reactions in this area. Asymmetric catalysis and enzymatic catalysis of such reactions is in its infancy. More recent advances center on cations that are related to benzylic cations but involve electron rich heterocycles such as furans, indoles, thiophenes and related structures. This chapter covers advances in (4+3) cycloadditions of allylic and related cations from 1997 to 2017, with supplemental references added to bring the work up to date through 2023. It illustrates both the growth in technical progress and theoretical understanding of this reaction during that time.
Enantioselective Pictet–Spengler reactions are promoted or catalyzed by small chiral molecules, including Brønsted acids, Lewis acids, and hydrogen‐bond donors (e.g., thiourea compounds). While tryptamines and β‐phenethylamines are commonly used in these reactions, a variety of other aryl‐group‐containing amines are also viable substrates. Achiral starting materials can participate in cascade reaction sequences that include an enantioselective Pictet–Spengler step. Mechanistic insights for these transformations are provided whenever possible. The Pictet–Spengler reaction allows access to heterocyclic products that are otherwise assembled via less direct methodologies. These products are employed as key intermediates in the synthesis of natural products such as yohimbine, arboricine, corynantheidine, mitragynine, harmicine, peganumine A, deplancheine, arborescidine C, and crispine A. The literature coverage for this Chapter extends to December 2019.
The Cloke–Wilson rearrangement is a reaction that converts cyclopropanes bearing a carbonyl, thiocarbonyl, or imino group into dihydrofurans, dihydrothiophenes, or dihydropyrroles, respectively, in a transformation that is generally driven by the release of ring strain leading to the formation of significantly less‐strained five‐membered heterocyclic compounds. Although the Cloke–Wilson rearrangement has typically been carried out through thermal activation of the substrate (and very often requires harsh reaction conditions), more recent research has shown that this reaction can also be carried out using Brønsted acids, Lewis acids, Lewis bases, or organometallic complexes as catalysts or promoters. These advances have contributed to broadening the functional‐group tolerance of this transformation, and have allowed the Cloke–Wilson rearrangement to be used in the synthesis of densely functionalized heterocyclic scaffolds. This chapter covers all the examples reported in the literature in which a Cloke–Wilson rearrangement has been observed, including the standard reaction that involves formyl‐ or acyl‐substituted cyclopropanes that lead to dihydrofurans, and the heteroatom variants such as the aza‐ and sulfa‐Cloke–Wilson rearrangements. In addition, a detailed mechanistic explanation of the different general modes of substrate activation operating with each type of catalyst/promoter has also been included, together with representative examples of practical experimental protocols and some reports in which this reaction has been applied to total synthesis.
Kinugasa reaction O. Crosby, O. CrosbySearch for more papers by this author O. Crosby, O. CrosbySearch for more papers by this author First published: 17 April 2020 https://doi.org/10.1002/9783527809080.cataz09448 Read the full textAbout ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article. Catalysis from A to Z: A Concise EncyclopediaBrowse other articles of this reference work:BROWSE A-Z RelatedInformation
Extrusion reactions may be defined as chemical reactions in which an atom or small molecular fragment Y connected to two other atoms W and Z is lost from a molecule, leading to a product in which W becomes directly bonded to Z. Cheletropic reactions that afford aromatic or conjugated π systems by loss of a stable atomic or molecular fragment have also been classified as extrusion reactions. Typically, the fragments liberated in these reactions are small, stable inorganic molecules or atoms such as carbon monoxide, carbon dioxide, sulfur, sulfur monoxide, sulfur dioxide, selenium, tellurium, oxygen and nitrogen. This chapter primarily deals with the synthesis of arenes, heterocycles, 1,3‐dienes and polyenes using such extrusion processes. The utility of these reactions in the synthesis of sterically hindered molecules, dendrimers, pheromones, and other natural products are highlighted. The use of extrusion reactions for the “Click and Release” approach in drug development is also introduced.
The cross‐coupling reaction of alkyl halides with alkyl metal reagents is a straightforward synthetic method to construct saturated carbon frameworks. Although the development of alkyl–alkyl cross‐coupling reactions has lagged behind advances made in the cross‐coupling of unsaturated compounds, various catalysts for alkyl–alkyl coupling are now available. The construction of challenging saturated carbon frameworks, such as those incorporating a quaternary carbon or chiral carbon center(s), is accomplished with the appropriate combination of catalyst and coupling partners. This chapter outlines the current understanding and efficient application of alkyl–alkyl cross‐coupling reactions. The mechanism of the process is presented for representative catalysts and the scope and limitations of the coupling reaction are discussed for each catalytic system. Successful applications of alkyl–alkyl cross‐coupling processes are also described for the stereoselective formation of saturated hydrocarbon frameworks and the synthesis of natural products.
The classic Ugi reaction is a four‐component coupling process involving a carboxylic acid, a carbonyl compound, an amine, and an isocyanide, resulting in an N ‐acylamino acid amide product. Modified Ugi reactions employ special, often multifunctional, reaction components, and can involve fewer than or more than four components. This reaction exhibits broad scope and can be used to prepare complex heterocycles. As a result, this method has been employed to prepare diverse libraries of structurally related products, and in addition, is often applied to the synthesis of drugs, drug‐like molecules, and natural products. Applications in target‐directed synthesis are presented, as are comparisons to other related multicomponent reactions and heterocycle syntheses; modifications leading to achiral heteroaromatic ring systems are not included. This chapter covers the literature from the early days of the Ugi reaction in 1961 through the end of 2012.
Since the first preparation of organozirconocenes from alkenes and alkynes in 1972, hydrozirconation has become one of the most commonly used stoichiometric methods to convert readily available starting materials into reactive but stable organometallic intermediates. A broad range of subsequent transformations may be employed to convert organozirconocenes in situ into high‐value functionalized products, often with the strategic formation of one (or several) new carbon–carbon bonds. This chapter focuses on the hydrozirconation of terminal and internal alkynes, and the subsequent synthetic transformations of the resulting alkenylzirconocenes. Zirconocene hydrochloride, Cp 2 Zr(H)Cl, is most frequently employed for the hydrozirconation step and can be used as a reagent or prepared in situ. Subsequent reactions of alkenylzirconocenes include additions to inorganic electrophiles such as halogens, as well as in situ ligand transfers to other metals, such as palladium and zinc, that further expand the range of accessible bond formations. The initial discussion focuses on the mechanism and stereochemical considerations, and on the steric and electronic factors that determine the regiochemistry of the either kinetically or thermodynamically controlled hydrozirconation. The “Scope and Limitations” section presents information on functional group compatibilities and is organized by the type of synthetic transformation of alkenylzirconocenes. Representative applications of the hydrozirconation of alkynes are showcased in syntheses of natural products, comparisons to alternative methods for the hydrometallation of alkynes. The goal of this chapter is to demonstrate the significance of hydrozirconation in organic synthesis, including the utility of the stoichiometric zirconium organometallics obtained from alkyne substrates, and to provide inspiration for the future development of new synthetic methods and strategies.
The classic Ugi reaction is a four‐component coupling process that involves a carboxylic acid, a carbonyl compound, an amine, and an isocyanide. All reaction components are in a dynamic equilibrium with several intermediates, until an irreversible intramolecular 1,4‐ O → N acyl transfer leads to the formation of an N ‐acylamino acid amide. If chiral components are used in this reaction, a mixture of diastereomers is generally formed with moderate‐to‐low stereoselectivity. The broad scope of substrates that can be used in the Ugi reaction allows for the straightforward synthesis of libraries of structurally related amino acid and peptide derivatives. Therefore, this methodology is often applied to the synthesis of drugs, drug‐like molecules, and natural products. This chapter describes different variations of classic Ugi reactions, including the use of functionalized and cleavable reaction components to illustrate the broad scope of the reaction. In addition, applications in target‐directed synthesis and comparisons to other related multicomponent reactions are presented. Tabular surveys are organized according to the isocyanides used. The literature is discussed from the first disclosure of an Ugi reaction in 1961 through to the end of 2012.
This chapter presents a comprehensive review of reductive cyclizations of 2‐nitro‐ and β‐nitrostyrenes, 2‐nitrobiphenyls, and 1‐nitro‐1,3‐dienes to furnish indoles, carbazoles, and pyrroles, respectively, as well as heteroatom analogs thereof. Two variations of the reductive cyclization are discussed: the Cadogan–Sundberg reaction, which is mediated by ternary phosphorus compounds, and the Watanabe–Cenini–Söderberg reaction, which employs a palladium catalyst in the presence of carbon monoxide. A few closely related reductive cyclizations are also presented, as are comparisons with other cyclizations that form the nitrogen–carbon bond of indoles and derivatives.
This chapter describes the use of allyl‐ and vinylstannane reagents for a variety of radical‐based transformations. The processes discussed include direct addition of radicals to allyl‐ and vinylstannanes, multicomponent or multistep cascade reactions that terminate with an intermolecular allylation or vinylation, cyclizations onto allyl‐ or vinylstannane moieties, and allylstannylation reactions. Allylation reactions have provided a framework for the exploration of stereoselective radical reactions, and models for explaining the stereoselectivity obtained by a number of approaches are presented. Examples are provided to illustrate the scope of applications of allyl‐ and vinylstannane radical reactions in synthesis, as well as the ways that the newly introduced allyl and vinyl groups have been subsequently manipulated. A comparison is made to radical allylation and vinylation reactions that employ non‐tin‐based reagents.
Hydroformylation is powerful catalytic reaction capable of converting alkenes directly into aldehydes by addition of a formyl group and hydrogen across the double bond. Installation of the formyl group at an internal carbon establishes a chiral center, and a variety of chiral ligands may be employed to direct the enantioselectivity of the reaction. The alkene substrates are easily accessed, and the resultant aldehydes are common precursors for diverse synthetic manipulations. This chapter covers enantioselective hydroformylation from its inception, presents the most common metal precursors and ligands, and includes all examples that produce aldehydes with yields above 20% and enantioselectivity above 60:40 er. The initial discussion focuses on the mechanism and stereochemistry, and on the regio‐ and enantioselectivity‐determining steps in particular, as these are crucial for overall yield. The “Scope and Limitations” section is divided by substrate type and offers examples of exceptional catalytic systems that have been reported for each. The application of enantioselective hydroformylation to synthetic procedures is discussed by highlighting some reported examples, comparing it to other protocols that also afford chiral aldehydes, and exploring the standard experimental conditions. The intention of this review is to demonstrate the power and scope of enantioselective hydroformylation to researchers, and to provide a suitable starting point for those interested in its application to their own synthetic strategies.
