Copper-Catalyzed Coupling between ortho-Haloanilines and Lactams/Amides: Synthesis of Benzimidazoles and Telmisartan.

An efficient copper-catalyzed synthesis of (annelated) benzimidazoles is reported. This transformation is based on a simple and straightforward one-pot sequence involving a copper-catalyzed cross coupling between o-haloanilines and lactams/amides followed by a subsequent cyclization under acidic conditions. A variety of (annelated) benzimidazoles could be easily obtained in high yields from readily available starting materials, and this procedure could be further applied to the synthesis of the antihypertensive blockbuster drug telmisartan.

Ammonium Salts as Convenient Radical Precursors Using Iridium Photoredox Catalysis.

Ammonium salts are usually considered as highly challenging to reduce into the corresponding radicals because of the strength of their carbon-nitrogen bond. Here, we disclose that several ammonium salts can be readily activated using iridium photoredox catalysis to form radicals and illustrate the synthetic utility of this activation of strong C-N bonds with hydrodeamination reactions and radical couplings. Cyclic voltammetry was exploited to rationalize the reactivity observed for the activation of these ammonium salts.

A general synthesis of azetidines by copper-catalysed photoinduced anti-Baldwin radical cyclization of ynamides.

A general anti-Baldwin radical 4-exo-dig cyclization from nitrogen-substituted alkynes is reported. Upon reaction with a heteroleptic copper complex in the presence of an amine and under visible light irradiation, a range of ynamides were shown to smoothly cyclize to the corresponding azetidines, useful building blocks in natural product synthesis and medicinal chemistry, with full control of the regioselectivity of the cyclization resulting from a unique and underrated radical 4-exo-dig pathway.

[(DPEPhos)(bcp)Cu]PF6: A General and Broadly Applicable Copper-Based Photoredox Catalyst.

Our group recently reported the use of [(DPEPhos)(bcp)Cu]PF6 as a general copper-based photoredox catalyst which proved efficient to promote the activation of a broad variety of organic halides, including unactivated ones. These can then participate in various radical transformations such as reduction and cyclization reactions, as well as in the direct arylation of several (hetero)arenes. These transformations provide a straightforward access to a range of small molecules of interest in synthetic chemistry, as well as to biologically active natural products. Altogether, [(DPEPhos)(bcp)Cu]PF6 acts as a convenient photoredox catalyst which appears to be an attractive, cheap and complementary alternative to the state-of-the-art iridium- and ruthenium-based photoredox catalysts. Here, we report a detailed protocol for the synthesis of [(DPEPhos)(bcp)Cu]PF6, as well as NMR and spectroscopic characterizations, and we illustrate its use in synthetic chemistry for the direct arylation of (hetero)arenes and radical cyclization of organic halides. In particular, the direct arylation of N-methylpyrrole with 4-iodobenzonitrile to afford 4-(1-methyl-1H-pyrrol-2-yl)benzonitrile and the radical cyclization of N-benzoyl-N-[(2-iodoquinolin-3-yl)methyl]cyanamide to afford natural product luotonin A are detailed. The scope and limitations of this copper-based photoredox catalyst are also briefly discussed.

Visible-Light-Controlled Ruthenium-Catalyzed Olefin Metathesis.

Olefin metathesis is now one of the most efficient ways to create new carbon-carbon bonds. While most efforts focused on the development of ever-more efficient catalysts, a particular attention has recently been devoted to developing latent metathesis catalysts, inactive species that need an external stimulus to become active. This furnishes an increased control over the reaction which is crucial for applications in materials science. Here, we report our work on the development of a new system to achieve visible-light-controlled metathesis by merging olefin metathesis and photoredox catalysis. The combination of a ruthenium metathesis catalyst bearing two N-heterocyclic carbenes with an oxidizing pyrylium photocatalyst affords excellent temporal and spatial resolution using only visible light as stimulus. Applications of this system in synthesis, as well as in polymer patterning and photolithography with spatially resolved ring-opening metathesis polymerization, are described.

Beyond Friedel and Crafts: Innate Alkylation of C-H Bonds in Arenes.

Alkylated arenes are ubiquitous molecules and building blocks commonly utilized in most areas of science. Despite its apparent simplicity, the regioselective alkylation of arenes is still a challenging transformation in a lot of cases. Classical methods for the introduction of alkyl groups to arenes, such as the venerable Friedel-Crafts reaction, radical additions, metalation or prefunctionalization of the arene followed by further alkylation, as well as alternatives such as the directed alkylation of C-H bonds, still suffer from severe limitations in terms of scope, efficiency, and selectivity. This can be addressed by exploiting the innate reactivity of some (hetero)arenes, in which electronic and steric properties, governed (or not) by the presence of one (or multiple) heteroatom(s), ensure high levels of regioselectivity. These innate alkylations of C-H bonds in (hetero)arenes will be overviewed comprehensively in this Review.

Beyond Friedel and Crafts: Directed Alkylation of C-H Bonds in Arenes.

Alkylation of arenes is one of the most fundamental transformations in chemical synthesis and leads to privileged scaffolds in many areas of science. Classical methods for the introduction of alkyl groups to arenes are mostly based on the Friedel-Crafts reaction, radical additions, metalation, or prefunctionalization of the arene: these methods, however, suffer from limitations in scope, efficiency, and selectivity. Moreover, they are based on the innate reactivity of the starting arene, favoring the alkylation at a certain position and rendering the introduction of alkyl chains at other positions much more challenging. This can be addressed by the use of a directing group that facilitates, in the presence of a metal catalyst, the regioselective alkylation of a C-H bond. These directed alkylations of C-H bonds in arenes will be comprehensively summarized in this Review.

Copper-catalyzed direct alkylation of heteroarenes.

An efficient and broadly applicable process is reported for the direct alkylation of C-H bonds in heteroarenes, privileged scaffolds in many areas of science. This reaction is based on the copper-catalyzed addition of alkyl radicals generated from activated secondary and tertiary alkyl bromides to a wide range of arenes, including furans, thiophenes, pyrroles, and their benzo-fused derivatives, as well as coumarins and quinolinones.

Cationic polycyclization of ynamides: building up molecular complexity.

Polycyclization reactions are among the most efficient synthetic tools for the synthesis of complex, polycyclic molecules in a single operation from simple starting materials. We report in this manuscript a full account on the discovery and development of a novel cationic polycyclization from readily available ynamides. Simple activation of these building blocks under acidic conditions enables the generation of highly reactive activated keteniminium ions, which triggers an unprecedented cationic polycyclization yielding highly substituted polycyclic nitrogen heterocycles possessing up to seven fused cycles and three contiguous stereocenters.

Room-temperature direct alkynylation of arenes with copper acetylides.

C-H bond in azoles and polyhalogenated arenes can be smoothly activated by copper acetylides to give the corresponding alkynylated (hetero)arenes by simple reaction at room temperature in the presence of phenanthroline and lithium tert-butoxide under an oxygen atmosphere. These stable, unreactive, and readily available polymers act as especially efficient and practical reagents for the introduction of an alkyne group to a wide number of arenes under remarkably mild conditions.

Keteniminium ion-initiated cascade cationic polycyclization.

A novel and efficient keteniminium-initiated cationic polycyclization is reported. This reaction, which only requires triflic acid or bistriflimide as promoters, affords a straightforward entry to polycyclic nitrogen heterocycles possessing up to three contiguous stereocenters and seven fused cycles. These complex, polycyclic molecules can be obtained in a single operation from readily available ynamides which were shown to be remarkable building blocks for multiple, consecutive cationic transformations.

Impact of copper-catalyzed cross-coupling reactions in natural product synthesis: the emergence of new retrosynthetic paradigms.

Copper-catalyzed Ullmann-Goldberg-type cross-coupling reactions have undergone nothing short of a renaissance over the last decade and an impressive number of procedures are now available for the formation of C-N, C-O and C-S bonds with remarkable efficiencies and surgical precision. These reactions have been recently integrated into natural product synthesis, which clearly resulted in the emergence of new retrosynthetic paradigms and bond disconnections. The impact of copper-catalyzed cross-coupling reactions in natural product synthesis will be overviewed in this article with an emphasis on the evolution of strategies due to copper catalysis, mostly by comparison with alternative tactics and their relative efficiencies.

Unprecedented synthesis of alkynylphosphine-boranes through room-temperature oxidative alkynylation.

An original and user-friendly synthesis of alkynylphosphine-boranes, useful building blocks in organic synthesis, based on an oxidative P-alkynylation reaction with readily available copper acetylides is reported. The ability of a secondary phosphine protected with a borane to undergo oxidative coupling without oxidation of the P-moiety is demonstrated for the first time. The reaction, which proceeds at room temperature, is applicable to the preparation of enantioenriched and structurally complex alkynylphosphine-boranes.