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.

Rhodium-Catalyzed Direct ortho-Arylation of Anilines.

An efficient and broadly applicable rhodium-catalyzed direct ortho-arylation of anilines with aryl iodides relying on readily available aminophosphines as traceless directing groups is reported. Its scope and functional group compatibility were both found to be quite broad as a large variety of both aminophosphines and (hetero)aryl iodides, including complex ones, could be utilized. The ortho-arylated anilines could be obtained in high average yields, without any competing diarylation and with full regioselectivity, which constitutes a major step forward compared to other processes. The reaction is moreover not limited to aryl iodides, as an aryl bromide and a triflate could be successfully used, and could be extended to diarylation. Mechanistic studies revealed the key and unique role of the aminophosphine, acting not only as a substrate but also as a ligand for the rhodium catalyst.

Copper-Catalyzed, Ligand-Controlled N(sp3)- or N(sp)-Selective Arylation of Cyanamides.

Cyanamides possess both nucleophilic and electrophilic centers, and their arylation reactions are known to proceed at N(sp3) and C(sp) sites, leading to N-aryl cyanamides or amidines. N(sp) selectivity has also been reported only in the presence of amines, thus leading to guanidines. Herein, we report a general copper-catalyzed ligand-controlled Chan-Lam-Evans arylation of cyanamides proceeding regioselectively at the N(sp3) or N(sp) atoms and leading to either N-aryl cyanamides or dissymmetric carbodiimides. The nature of the ligand, either a bipyridine or a diamine, controls the product distribution and thus offers a divergent entry to useful building blocks from readily available cyanamides.

Synthesis of Tetrahydrofurans and Pyrrolidines by Copper-Catalyzed Oxy/Aminoarylation of Alkenes.

An efficient copper-catalyzed inter/intramolecular oxy/aminoarylation of γ-hydroxy/aminoalkenes with diaryliodonium triflates is reported. Simple activation of these arylating agents with copper(II) triflate in dichloromethane triggers a smooth activation of the alkene, which is simultaneously trapped by the internal nucleophile, yielding, depending upon its nature, a range of highly substituted tetrahydrofurans and pyrrolidines. The cyclization was moreover found to be stereospecific, with diastereoisomeric alkenes yielding diastereoisomers of the cyclized product, and could be extended to oxyalkynylation.

Structure-Property Relationships in a New Family of Photoactive Diimine-Diphosphine Copper(I) Complexes.

A new family of heteroleptic diimine-diphosphine copper(I) complexes is reported, with six new complexes compared to benchmark [Cu(bcp)(DPEPhos)]PF6 . These new complexes are based on 1,4,5,8-tetraazaphenanthrene (TAP) ligands with representative electronic properties as well as substitution patterns and DPEPhos and XantPhos as diphosphine ligands. Their photophysical and electrochemical properties were investigated and correlated with the number and position of substituents on the TAP ligands. Stern-Volmer studies using Hünig's base as reductive quencher demonstrated the influence of the complex photoreduction potential and of the excited state lifetime on the photoreactivity. This study refines the structure-property relationship profile for heteroleptic copper(I) complexes and confirms that such profiles are of high interest to design new copper complexes as optimized photoredox catalysts.

Photoactive Copper Complexes: Properties and Applications.

Photocatalyzed and photosensitized chemical processes have seen growing interest recently and have become among the most active areas of chemical research, notably due to their applications in fields such as medicine, chemical synthesis, material science or environmental chemistry. Among all homogeneous catalytic systems reported to date, photoactive copper(I) complexes have been shown to be especially attractive, not only as alternative to noble metal complexes, and have been extensively studied and utilized recently. They are at the core of this review article which is divided into two main sections. The first one focuses on an exhaustive and comprehensive overview of the structural, photophysical and electrochemical properties of mononuclear copper(I) complexes, typical examples highlighting the most critical structural parameters and their impact on the properties being presented to enlighten future design of photoactive copper(I) complexes. The second section is devoted to their main areas of application (photoredox catalysis of organic reactions and polymerization, hydrogen production, photoreduction of carbon dioxide and dye-sensitized solar cells), illustrating their progression from early systems to the current state-of-the-art and showcasing how some limitations of photoactive copper(I) complexes can be overcome with their high versatility.

Phosphine-catalyzed regio- and stereo-selective hydroboration of ynamides to (Z)-ß-borylenamides.

We report a tri-n-butyl phosphine catalyzed regio- and stereo-selective hydroboration of ynamides to yield (Z)-ß-borylenamides in good yields. Surprisingly, a formal cis addition to the triple bond was observed as confirmed by NMR and X-ray crystallography. 31P NMR studies suggest that a zwitterionic vinylphosphonium intermediate is key in the mechanism. The resulting products were further transformed to ß-CF3 enamides via stereoretentive trifluoromethylation.

Photoinduced, copper-catalysed direct perfluoroalkylation of heteroarenes.

An efficient and general process is reported for the photoinduced, copper-catalysed direct perfluoroalkylation of C-H bonds in a broad range of heteroarenes with commercially available perfluoroalkyl iodides. This redox neutral process is simply based on the use of [Cu(bcp)DPEPhos]PF6 as the photoredox catalyst in the presence of potassium acetate and smoothly operates at room temperature.

Direct Perfluoroalkylation of C-H Bonds in (Hetero)arenes.

Perfluoroalkylated (hetero)arenes represent an extremely important family of molecules commonly utilized in many areas such as medicinal chemistry, agrochemistry and material sciences. Due to their unique properties, they have attracted significant interest from synthetic chemists and various methods have been developed for their synthesis. Among them, the direct perfluoroalkylation of C(sp2 )-H bonds in (hetero)arenes is one of the most attractive and straightforward ones, provided that it proceeds with high levels of regioselectivity. In this review article, a comprehensive overview of advances in this field is presented, with a special focus on the reaction mechanisms involved in these transformations and their regioselectivity. All methods available have been classified according to the nature of the perfluoroalkyl chain introduced, trifluoromethylation reactions being overviewed in a separate section, and to the nature of the reagents/catalysts required.

Copper-Catalyzed Carbonylative Cross-Coupling of Alkyl Iodides and Amines.

A general copper-catalyzed carbonylative cross-coupling between amines and alkyl iodides is reported. Using a simple combination of catalytic amounts of copper(I) chloride and N,N,N',N",N"-pentamethyldiethylenetriamine in the presence of sodium hydroxide under carbon monoxide pressure, a broad range of alkyl iodides and amines can be efficiently coupled to the corresponding amides that are obtained in good to excellent yields. Notable features of this process - the first one relying on a base metal catalyst - include the availability and low cost of the catalytic system, its successful use with primary, secondary, tertiary alkyl iodides and all classes of amines - with no or limited competing nucleophilic substitution without CO incorporation - as well as its efficiency with complex alkyl iodides and amines. Mechanistic studies demonstrated that a radical pathway is operative and the key role of CO.

Selective Nickel-Catalyzed Hydrodeacetoxylation of Aryl Acetates.

Acetate serves as a renewable and easily installed leaving group for selective deoxygenation of phenolics (ArOH). Ni-catalyzed hydrodeacetoxylation of aryl acetates (Ar-OAc) with HBpin in a green carbonate solvent selectively delivers the corresponding deoxygenated arenes (ArH). The method is also applicable to highly challenging guaiacyl and syringyl acetates, leaving -OMe groups intact without arene reduction. Renewable 4-propylguaiacol obtained from pine can also be transformed without significant loss in yield versus oil derived feedstock. The observed chemoselectivity for Ar-OAc versus ArO-Ac bond cleavage was rationalized based on mechanistic experiments and DFT calculations. ArOH side-product formation is attributed to direct competitive Ni-catalyzed reduction of the C=O bond. Hydrodeacyloxylation of a set of aryl alkanoates featured interesting chemoselectivity with a dramatic influence of the length and structure of the alkyl chain on catalysis.

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.

Copper-Catalyzed Direct Perfluoroalkylation of Heteroarenes.

An efficient and broadly applicable process is reported for the copper-catalyzed direct perfluoroalkylation of C-H bonds in heteroarenes with commercially available perfluoroalkyl iodides. This reaction is based on a simple combination of copper(I) iodide and 1,10-phenanthroline enabling the easy reduction of perfluoroalkyl iodides to the corresponding radical species that add to a wide range of heteroarenes including benzofurans, benzothiophenes, (aza)indoles, furans and pyrroles. High levels of regioselectivity were obtained in all cases and the efficiency and robustness of this process was highlighted by the direct perfluoroalkylation of furan-containing peptides.

Straightforward Synthesis of Indenes by Gold-Catalyzed Intramolecular Hydroalkylation of Ynamides.

An original and straightforward entry to polysubstituted indenes from readily available ynamides is reported. Upon reaction with a N-heterocyclic carbene-gold complex under mild conditions, activated keteniminium ions are generated whose unique electrophilicity triggers a [1,5]-hydride shift and a subsequent cyclization. The presence of an endocyclic enamide in the densely functionalized resulting indenes was shown to be especially useful and versatile, offering a range of opportunities for their further postfunctionalization.

Divergent Synthesis of α-Fluorinated Carbonyl and Carboxyl Derivatives by Double Electrophilic Activation of Amides.

A straightforward and divergent entry to α-fluorinated carbonyl and carboxyl derivatives is reported. Upon activation of amides with triflic anhydride and a 2-halo-pyridine and subsequent trapping of the resulting keteniminium ions with nucleophiles followed by a second electrophilic activation with NFSI and final hydrolysis, a range of amides can be transformed to α-fluorinated ketones, esters, and amides under mild conditions. Moreover, this reaction can be performed to yield enantioenriched products with a traceless chiral auxiliary.

A general, versatile and divergent synthesis of selectively deuterated amines.

Deuterated organic molecules are of utmost importance in many areas of science and have been recently intensively investigated in medicinal chemistry due to their enhanced metabolic stability. The development of efficient and broadly applicable methods for the selective incorporation of deuterium atoms into organic molecules from readily available starting materials and reagents is therefore of extreme importance. Such methods however often lack generality and selectivity, notably in the nitrogen series. With nitrogen-containing molecules being indeed ubiquitous in medicinal chemistry, there is a strong need for efficient methods enabling the selective synthesis of deuterated amines. In this perspective, we report herein a general, versatile, divergent and metal-free synthesis of amines selectively deuterated at their α and/or ß positions. Upon simple treatment of readily available ynamides with a mixture of triflic acid and triethylsilane, either deuterated or not, a range of amines can be smoothly obtained with high levels of deuterium incorporation by a unique sequence involving a domino keteniminium/iminium activation.

Transient Directing Groups in Metal-Organic Cooperative Catalysis.

The direct functionalization of C-H bonds is among the most fundamental chemical transformations in organic synthesis. However, when the innate reactivity of the substrate cannot be utilized for the functionalization of a given single C-H bond, this selective C-H bond functionalization mostly relies on the use of directing groups that allow bringing the catalyst in close proximity to the C-H bond to be activated and these directing groups need to be installed before and cleaved after the transformation, which involves two additional undesired synthetic operations. These additional steps dramatically reduce the overall impact and the attractiveness of C-H bond functionalization techniques since classical approaches based on substrate pre-functionalization are sometimes still more straightforward and appealing. During the past decade, a different approach involving both the in situ installation and removal of the directing group, which can then often be used in a catalytic manner, has emerged: the transient directing group strategy. In addition to its innovative character, this strategy has brought C-H bond functionalization to an unprecedented level of usefulness and has enabled the development of remarkably efficient processes for the direct and selective introduction of functional groups onto both aromatic and aliphatic substrates. The processes unlocked by the development of these transient directing groups will be comprehensively overviewed in this review article.

Expedient Synthesis of Bridged Bicyclic Nitrogen Scaffolds via Orthogonal Tandem Catalysis.

Bridged nitrogen bicyclic skeletons have been accessed via unprecedented site- and diastereoselective orthogonal tandem catalysis from readily accessible reactants in a step economic manner. Directed Pd-catalyzed γ-C(sp3 )-H olefination of aminocyclohexane with gem-dibromoalkenes, followed by a consecutive intramolecular Cu-catalyzed amidation of the 1-bromo-1-alkenylated product delivers the interesting normorphan skeleton. The tandem protocol can be applied on substituted aminocyclohexanes and aminoheterocycles, easily providing access to the corresponding substituted, aza- and oxa-analogues. The Cu catalyst of the Ullmann-Goldberg reaction additionally avoids off-cycle Pd catalyst scavenging by alkenylated reaction product. The picolinamide directing group stabilizes the enamine of the 7-alkylidenenormorphan, allowing further product post functionalizations. Without Cu catalyst, regio- and diastereoselective Pd-catalyzed γ-C(sp3 )-H olefination is achieved.

Efficient and Divergent Synthesis of α-Halogenated Amides and Esters by Double Electrophilic Activation of Ynamides.

An efficient and modular entry to α-halogenated amides and esters is reported. This reaction is based on an underestimated double electrophilic activation of ynamides sequentially involving highly reactive activated keteniminium and iminium ions. Upon simple reaction with HCl and an electrophilic halogenation reagent in the presence of water or an alcohol, a broad range of ynamides can be transformed, in a highly divergent manner, to α-halo amides and esters with high efficiency and under mild conditions.

[(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.