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A nickel-catalyzed three-component reaction involving terminal alkynes, boronic acids, and alkyl halides is presented herein. Trisubstituted alkenes can be obtained in a highly regio- and stereocontrolled manner by the simultaneous addition of both aryl and alkyl groups across the triple bond in a radical-mediated process. The reaction, devoid of air- and moisture-sensitive organometallic reagents and catalysts, is operationally simple and offers a broad scope and functional-group tolerance.

Methods to incorporate atmospheric CO2 into organic molecules are on demand. Here we present two Pd-catalyzed multicomponent reactions that provide functionalized oxazolidinones from propargylamines, aryl halides and CO2 as starting materials. These transformations, devoid of high CO2 pressures, represent a streamlined stereocontrolled synthesis of previously inaccessible versions of these useful heterocycles in an atom-economic manner, as up to four new single bonds are formed in a single synthetic operation.

Synergistic gold–palladium catalytic processes have been intensively sought during the past decade, because the combination of the carbophilic Lewis acidity of Au with the redox properties of Pd within a catalytic cycle is particularly appealing for the synthesis of novel functionalized compounds. We demonstrate here the feasibility of a Au–Pd bimetallic catalytic system based on the generation of competent Au and Pd species by anionic ligand exchange. This strategy enabled the preparation of a variety of substituted butenolides in a simple and efficient way.

Several selective and potent EphB4 inhibitors have been discovered, optimized and biophysically characterized by our groups over the past years. On the outset of these discoveries high throughput docking techniques were applied. Herein, we review the optimization campaigns started from three of these hits (Xan-A1, Pyr-A1 and Qui-A1) with emphasis on their in depth in vitro and in vivo characterization, together with previously unpublished angiogenesis and fluorescence based assays.

A Pd-catalyzed three component reaction involving terminal alkynes, boronic acids, and perfluoroalkyl iodides is presented here. Trisubstituted perfluoroalkenes can be obtained in a highly regio- and stereocontrolled manner by the simultaneous addition of both aryl and CnFm groups across the triple bond in a radical-mediated process. The reaction is operationally simple offering a broad scope and functional group tolerance.

Two highly stereoselective radical-mediated syntheses of densely functionalized indanes and dibenzocycloheptadienes from ortho-vinyl- and ortho-vinylaryl-substituted N-(arylsulfonyl)-acrylamides, respectively, are presented.

The addition of a variety of radicals to the double bond of N-(arylsulfonyl)acrylamides can trigger cyclization/aryl migration/desulfonylation cascades via amidyl radical intermediates 2. Herein, we demonstrate the synthetic utility of these intermediates in subsequent C–C and C–X bond-forming events to rapidly build up molecular complexity. First, we describe a regioselective one-pot synthesis of CF3-, SCF3-, Ph2(O)P-, and N3-containing indolo[2,1-a]isoquinolin-6(5H)-ones from N-[(2-ethynyl)arylsulfonyl]acrylamides through a multi-step radical reaction cascade. The process involves the one-pot formation of four new bonds (one C–X, two C–C, and one C–N), a formal 1,4-aryl migration, and desulfonylation of the starting material. Second, we present a one-pot synthesis of 3,3-disubstituted-2-dihydropyridinones from N-(arylsulfonyl)acrylamides and 1,3-dicarbonyl compounds. In this case, a silver-catalyzed radical cascade process involving the sequential formation of two new C–C bonds and one C–N bond, a forma...

The aminofluorination of alkenes has become an attractive platform for the synthesis of β-amino-fluorinated compounds, valuable building blocks in medicinal and agricultural chemistry. The novel methodologies disclosed in recent years have unraveled a broad array of reaction mechanisms, so that the interest in these transformations transcends the mere synthetic aspects. This review aims to summarize the most relevant findings in this area attending at the nature of the fluorine source, and thus the specific mechanism operating in each of these transformations, namely electrophilic, nucleophilic, radical, and late transition metal-catalyzed reactions.

Review: recent methodologies for the simultaneous formation of C—CF3 and C—C or C-heteroatom bonds by formal addition reactions to alkenes; 70 refs.

Two radical-mediated processes of activated alkenes, namely arylphosphonylation and arylazidation, are described. The difunctionalization of alkenes by a tandem process that involves radical addition, 1,4-aryl migration, and desulfonylation generates α-aryl-β-heterofunctionalized amides bearing a quaternary stereocenter when the substituent on the nitrogen atom is an aryl group. Alternatively, heterooxindoles or spirobicycles can be obtained with excellent regioselectivity in the presence of an alkyl substituent on the nitrogen atom.

Bu4NI is able to activate Togni reagent (II) to generate a highly reactive iodine (III) species, which smoothly reacts with alkenes to form a new C—CF3 bond.

The reaction affords α-aryl-βtrifluoromethylamides with a quaternary stereocenter or trifluoromethylated oxindoles from the N-aryl or N-alkyl substrates of the types (I) or (X), respectively.

The intramolecular metal-free aminofluorination of unactivated alkenes works with aryl iodonium difluorides as the reagent.

Some of the most synthetically useful methods to construct molecular complexity include Diels–Alder, [1,3]-dipolar- and [m+n]-cycloadditions. In this context, the efficient generation of 1,n-dipole...

The development of new methodologies catalyzed by late transition metals involving cycloisomerizations of strained rings can open new venues for the synthesis of structurally complex molecules with interesting biological activities. Herein we summarize, from both a synthetic as well as a mechanistic point of view, the most recent developments in gold-catalyzed ring expansions.

The gold-catalyzed alkene aminooxygenation and aminoamidation reactions are highly regioselective in several cases, thus complementing 5-exo palladium-catalyzed processes.

An efficient method for the synthesis of α-fluoroenones (II) is elaborated using a gold-catalyzed rearrangement of propargyl acetates (I) in the presence of a fluorination agent.

Alkynes are selectively transformed into α-fluoro acetals (III) and α-fluoro ketones (IV) in the presence of alcohols and Selectfluor as a stoichiometric source of fluorine, and catalytic amounts of gold.

The field of homogeneous gold catalysis has developed exponentially over the past ten years. Even if the array of gold-mediated transformations is extremely broad, a common feature stems from the ability of gold to activate unsaturated moieties due to the strong relativistic effects governing its coordination behavior. Starting with a short historical perspective, this review compiles the recent advances in two fundamental areas: first, the rearrangement of propargylic carboxylates and second, ring-expansion processes, both topics of interest in our research group at the Organic Chemistry Institute of the University of Zurich.

A novel gold-catalyzed ethynylation of aromatic rings with electron-deficient alkynes via gold catalyzed C-H activation of both C(sp)-H and C(sp(2))-H bonds has been developed. This transformation provides aromatic propiolates difficult to prepare by other methods, highlighting the synthetic potential of gold chemistry.

The different methods for the hydroarylation of alkynes (also known simply as arylation of alkynes or alkenylation of arenes) catalyzed by transition metals are presented as a function of the proposed mechanisms. Related iodonium-promoted and protic acid-catalyzed cyclizations of alkynyl arenes are also reviewed. 1 Introduction 2 Reactions via Metal Vinylidenes 2.1 Inter- and Intramolecular Reactions of Metal Vinylidenes with Arenes 2.2 Electrocyclizations of Dienynes via Metal Vinylidenes 3 Hydroarylation of Alkynes via π-Alkyne-Metal Complexes 3.1 Intermolecular Hydroarylation of Alkynes Catalyzed by Metal Triflates 3.2 Hydroarylation of Alkynes Catalyzed by Group 8-1 Metal Complexes 3.2.1 Intermolecular Hydroarylation Catalyzed by Pd(II) and Pt(II) 3.2.2 Intermolecular Hydroarylation Catalyzed by Au(III) and Au(I) 3.2.3 Intramolecular Hydroarylation Catalyzed by Pd(0) or Pd(II) 3.2.4 Intramolecular Hydroarylation of Alkynes with Ag(I) 3.2.5 Intramolecular Hydroarylation Catalyzed by Pt(II), Pt(IV), Ru(II), and Other Metal Complexes 3.3 Related Reactions Mediated by Protic Acids or Iodonium Cation 4 Synthesis of Phenols by Metal-Catalyzed Reaction of Furans with Alkynes 5 Summary and Outlook

In this tutorial review we summarize the two major pathways followed in the reaction of alkenes with alkynes catalysed by electrophilic transition metals. If the metal coordinates simultaneously to the alkyne and the alkene, an oxidative cyclometallation can ensue to give a metallacyclopentene, which usually evolves by [small beta]-hydrogen elimination to give Alder-ene cycloisomerisation derivatives. On the other hand, coordination of the metal to the alkyne promotes the attack of the alkene to give metal cyclopropyl carbenes.

Alkynophilic cationic gold(I) complexes are very active catalysts for reactions of enynes that proceed exclusively through cyclopropyl carbene complexes as intermediates (see scheme). With such catalysts, the first examples of endocyclic skeletal rearrangements under mild conditions have been observed.