Copper-Catalyzed Sulfimidation in Aqueous Media: a Fast, Chemoselective and Biomolecule-Compatible Reaction.

Performing transition metal-catalyzed reactions in cells and living systems has equipped scientists with a toolbox to study biological processes and release drugs on demand. Thus far, an impressive scope of reactions has been performed in these settings, but many are yet to be introduced. Nitrene transfer presents a rather unexplored new-to-nature reaction. The reaction products are frequently encountered motifs in pharmaceuticals, presenting opportunities for the controlled, intracellular synthesis of drugs. Hence, we explored the transition metal-catalyzed sulfimidation reaction in water for future in vivo application. Two Cu(I) complexes containing trispyrazolylborate ligands (Tpx ) were selected, and the catalytic system was evaluated with the aid of three fitness factors. The excellent nitrene transfer reactivity and high chemoselectivity of the catalysts, coupled with good biomolecule compatibility, successfully enabled the sulfimidation of thioethers in aqueous media. We envision that this copper-catalyzed sulfimidation reaction could be an interesting starting point to unlock the potential of nitrene transfer catalysis in vivo.

Molecular Dynamic Simulations of Aqueous Micellar Organometallic Catalysis: Methane Functionalization as a Case Study.

Molecular Dynamics (MD) simulations constitute a powerful tool that provides a 3D perspective of the dynamical behavior of chemical systems. Herein the first MD study of the dynamics of a catalytic organometallic system, in micellar media, is presented. The challenging methane catalytic functionalization into ethyl propionate through a silver-catalyzed process has been targeted as the case study. The intimate nature of the micelles formed with the surfactants sodium dodecylsulfate (SDS) and potassium perfluorooctane sulfonate (PFOS) has been ascertained, as well as the relative distribution of the main actors in this transformation, namely methane, the diazo reagent and the silver catalyst, the latter in two different forms: the initial compound and a silver-carbene intermediate. Catalyst deactivation occurs with halide containing surfactants dodecyltrimethylammonium chloride (DTAC) and Triton X-100. Computed simulations allow explaining the experimental results, indicating that micelles behave differently regarding the degree of accumulation and the local distribution of the reactants and their effect in the molecular collisions leading to net reaction.

Intramolecular Interception of the Remote Position of Vinylcarbene Silver Complex Intermediates by C(sp3 )-H Bond Insertion.

The trapping of the elusive vinylogous position of a vinyl carbene with an aliphatic C(sp3 )-H bond has been achieved for the first time during a silver-catalyzed carbene/alkyne metathesis (CAM) process. A Tpx -containing silver complex first promotes the generation of a donor-acceptor silver carbene which triggers CAM, generating a subsequent donor-donor vinyl silver carbene species, which then undergoes a selective vinylogous C(sp3 )-H bond insertion, leading to the synthesis of a new family of benzoazepines. Density functional theory (DFT) calculations unveil the reaction mechanism, which allows proposing that the C-H bond insertion reaction takes place in a stepwise manner, with the hydrogen shift being the rate determining step.

Carbene-Controlled Regioselective Functionalization of Linear Alkanes under Silver Catalysis.

Control of the regioselectivity in the functionalization of C-H bonds of linear alkanes C2H2n+2 via carbene transfer from diazo compounds is restricted to the use of rhodium-based catalysts, which govern the reaction outcome employing donor-acceptor diazo reagents. At variance with that catalyst-controlled strategy, we present an alternative approach in which employing the appropriate silver complexes containing trispyrazolylborate ligands as catalysts with large differences in their steric and electronic properties, the regioselection is mainly governed by the diazo reagent, which leads to the functionalization of primary or secondary sites of linear alkanes (lacking any activating or directing groups). Donor-acceptor aryl diazoacetates exclusively provide the functionalization of the secondary sites of hexane or pentane, whereas acceptor ethyl diazoacetate leads to an unprecedented level of primary functionalization.

Introducing the Catalytic Amination of Silanes via Nitrene Insertion.

The direct functionalization of Si-H bonds by the nitrene insertion methodology is described. A copper(I) complex bearing a trispyrazolylborate ligand catalyzes the transfer of a nitrene group from PhI═NTs to the Si-H bond of silanes, disilanes, and siloxanes, leading to the exclusive formation of Si-NH moieties in the first example of this transformation. The process tolerates other functionalities in the substrate such as several C-H bonds and alkyne and alkene moieties directly bonded to the silicon center. Density functional theory (DFT) calculations provide a mechanistic interpretation consisting of a Si-H homolytic cleavage and subsequent rebound to the Si-centered radical.

Two Copper-Carbenes from One Diazo Compound.

Many transition-metal complexes MLn decompose diazo compounds N2═CR1R2 generating metal-carbenes LnM═CR1R2 which transfer the carbene group to other substrates, constituting an important tool in organic synthesis. All previous reports have shown that the CR1R2 fragment at the metal-carbene remains intact from the parent diazo compound. Herein we report the detection and isolation of a monosubstituted copper carbene where the CR1R2 ligand has undergone a modification from the initial diazo reagent. When TpMsCu(THF) (TpMs = hydrotris(3-mesityl)pyrazolylborate ligand) was reacted with N,N-diethyl diazoacetamide [N2═C(H)(CONEt2)], the stable copper carbene TpMsCu═C(H)(NEt2) was isolated, resulting from a decarbonylation process, with carbon monoxide being trapped as TpMsCu(CO). The simultaneous observation of products derived from the intramolecular carbene insertion reaction into C-H bonds demonstrates that the expected TpMsCu═C(H)(CONEt2) complex is also formed. Experimental data, DFT calculations, and microkinetic models allow us to propose that the latter undergoes CO loss en route to the former.

Copper-Catalyzed Dehydrogenative Amidation of Light Alkanes.

The functionalization of C-H bonds in light alkanes, particularly to form C-N bonds, remains a challenge. We report the dehydrogenative coupling of amides with C1-C4 hydrocarbons to form N-alkyl amide products with tBuOOtBu as oxidant, and a copper complex of a phenanthroline-type ligand as catalyst. The reactions occurred in good yields in benzene or supercritical carbon dioxide as solvents. This strategy allowed for the determination of the relative reactivity of these alkane C-H bonds toward this amination process and showed, in contrast to prior work with larger alkanes, that the reactivity correlated with bond dissociation energies.

Intermolecular Allene Functionalization by Silver-Nitrene Catalysis.

Under silver catalysis conditions, using [Tp*,BrAg]2 as the catalyst precursor, allenes react with PhI═NTs in the first example of efficient metal-mediated intermolecular nitrene transfer to such substrates. The nature of the substituent at the allene seems crucial for the reaction outcome since arylallenes are converted into azetidine derivatives, whereas methylene aziridines are the products resulting from alkylallenes. Mechanistic studies allow proposing that azetidines are formed through unstable cyclopropylimine intermediates, which further incorporate a second nitrene group, both processes being silver-mediated. Methylene aziridines from alkylallenes derive from catalytic nitrene addition to the allene double bonds. Both routes have resulted to be productive for further synthetic transformations affording aminocyclopropanes.

Alkoxydiaminophosphine Ligands as Surrogates of NHCs in Copper Catalysis.

A family of phosphine ligands containing a five-membered ring similar to the popular N-heterocyclic carbene ligands and an alkoxy third substituent has been developed. These alkoxydiaminophosphine ligands (ADAP) can be generated in one pot and reacted with a copper(I) source leading to the high yield isolation of complexes [(ADAP)CuX]2 (X=Cl, Br). The dinuclear nature of these compounds has been established by means of X-ray studies and DOSY experiments. A screening of the catalytic properties of these complexes toward carbene-transfer reactions from diazocompounds to C-H bonds (alkane, arene), olefins or N-H bonds, as well as in CuAAC or nitrene transfer reactions have shown a performance at least similar, if not better, than their (NHC)CuCl analogues, opening a new window in copper catalysis with these readily tunable ADAP ligands.

Copper-catalysed radical reactions of alkenes, alkynes and cyclopropanes with N-F reagents.

The mild generation of nitrogen-centred radicals from N-F reagents has become a convenient synthetic tool. This methodology provides access to the aminative difunctionalisation of alkenes and alkynes and the radical ring-opening of cyclopropanes, among other similar transformations. This review article aims to provide an overview of recent developments of such processes involving radical reactions and N-F reagents using copper-based catalysts.

A Quantitative Model for Alkane Nucleophilicity Based on C-H Bond Structural/Topological Descriptors.

A first quantitative model for calculating the nucleophilicity of alkanes is described. A statistical treatment was applied to the analysis of the reactivity of 29 different alkane C-H bonds towards in situ generated metal carbene electrophiles. The correlation of the recently reported experimental reactivity with two different sets of descriptors comprising a total of 86 parameters was studied, resulting in the quantitative descriptor-based alkane nucleophilicity (QDEAN) model. This model consists of an equation with only six structural/topological descriptors, and reproduces the relative reactivity of the alkane C-H bonds. This reactivity can be calculated from parameters emerging from the schematic drawing of the alkane and a simple set of sums.

Improving Catalyst Activity in Hydrocarbon Functionalization by Remote Pyrene-Graphene Stacking.

A copper complex bearing an N-heterocyclic carbene ligand with a pyrene "tail" attached to the backbone has been prepared and supported on reduced graphene oxide (rGO). The free and supported copper materials have been employed as homogeneous and heterogeneous catalysts in the functionalization of hydrocarbons such as n-hexane, cyclohexane, and benzene through incorporation of the CHCO2 Et unit from ethyl diazoacetate. The graphene-anchored complex displays higher reaction rates and induces higher yields than its soluble counterpart, features that can be rationalized in terms of a decrease in electron density at the metal center due to a remote net electronic flux from the supported copper complex to the graphene surface.

Trispyrazolylborate Ligands Supported on Vinyl Addition Polynorbornenes and Their Copper Derivatives as Recyclable Catalysts.

Polynorbornenes prepared by vinyl addition polymerization and bearing pendant alkenyl groups serve as skeletons to support trispyrazolylborate ligands (Tpx ) built at those alkenyl sites. Reaction with CuI in acetonitrile led to VA-PNB-Tpx Cu(NCMe) (VA-PBN=vinyl addition polynorbornene) with a 0.8-1.4 mmol incorporation of Cu per gram of polymer. The presence of tetracoordinated copper(I) ions was been assessed by FTIR studies on the corresponding VA-PNB-Tpx Cu(CO) adducts, in agreement with those on discrete Tpx Cu(CO). The new materials were employed as heterogeneous catalysts in several carbene- and nitrene-transfer reactions, showing a behavior similar to that of the homogeneous counterparts but also being recycled several times maintaining a high degree of activity and selectivity. This is the first example of supported Tpx ligands onto polymeric supports with catalytic applications.

Ruthenium-Catalyzed Heck-Type Alkenylation of Alkyl Bromides.

The complex [Cp*RuCl(PPh3)2] displays a high catalytic activity for the Heck-type alkenylation of alkyl bromides in the first example using this metal under thermal conditions. The coupling reaction proceeds efficiently with a variety of functionalized tertiary, secondary, and primary alkyl bromides. The presence of Hünig's base has been revealed to be crucial for this transformation. Preliminary mechanistic studies support the participation of alkyl radicals in the reaction.

Copper-Catalyzed N-F Bond Activation for Uniform Intramolecular C-H Amination Yielding Pyrrolidines and Piperidines.

The dual function of the N-F bond as an effective oxidant and subsequent nitrogen source in intramolecular aliphatic C-H functionalization reactions is explored. Copper catalysis is demonstrated to exercise full regio- and chemoselectivity control, which opens new synthetic avenues to nitrogenated heterocycles with predictable ring sizes. For the first time, a uniform catalysis manifold has been identified for the construction of both pyrrolidine and piperidine cores. The individual steps of this new copper oxidation catalysis were elucidated by control experiments and computational studies, clarifying the singularity of the N-F function and characterizing the catalytic cycle to be based on a copper(I/II) manifold.

Gold-catalyzed ethylene cyclopropanation.

Ethylene can be directly converted into ethyl 1-cyclopropylcarboxylate upon reaction with ethyl diazoacetate (N2CHCO2Et, EDA) in the presence of catalytic amounts of IPrAuCl/NaBArF 4 (IPr = 1,3-bis(2,6-diisopropylphenyl)imidazole-2-ylidene; BArF 4 = tetrakis(3,5-bis(trifluoromethyl)phenyl)borate).

Catalytic Functionalization of C-H Bonds of Azulene by Carbene/Nitrene Incorporation.

The selective catalytic functionalization of the C-H bond of azulene upon incorporation of carbene or nitrene units with metal-based catalysts is described. Ethyl diazoacetate or ArI═NTs are employed as carbene or nitrene precursors, respectively. The azulene derivatives are subsequently employed as building blocks toward more complex structures with potential use as biodegradable materials.

Enantio- and Diastereoselective Cyclopropanation of 1-Alkenylboronates: Synthesis of 1-Boryl-2,3-Disubstituted Cyclopropanes.

A novel, highly enantio- and diastereoselective synthesis of 1-boryl-2,3-disubstituted cyclopropanes has been developed by means of the cyclopropanation of alkenylboronates with ethyl diazoacetate in the presence of catalytic amounts of a chiral copper(I) complex. The products can also be directly accessed from alkynes through an operationally simple, sequential hydroboration-cyclopropanation protocol. The resulting enantioenriched 1-boryl-2,3-disubstituted cyclopropanes are versatile synthetic intermediates that undergo further transformations at the carbon-boron bond.

Measuring the Relative Reactivity of the Carbon-Hydrogen Bonds of Alkanes as Nucleophiles.

We report quantitative measurements of the relative reactivities of a series of C-H bonds of gaseous or liquid Cn H2n+2 alkanes (n=1-8, 29 different C-H bonds) towards in situ generated electrophiles (copper, silver, and rhodium carbenes), with methane as the reference. This strategy surpasses the drawback of previous model reactions of alkanes with strong electrophiles suffering from C-C cleavage processes, which precluded direct comparison of the relative reactivities of alkane C-H bonds.

Functional-Group-Tolerant, Silver-Catalyzed N-N Bond Formation by Nitrene Transfer to Amines.

Silver(I) promotes the highly chemoselective N-amidation of tertiary amines under catalytic conditions to form aminimides by nitrene transfer from PhI═NTs. Remarkably, this transformation proceeds in a selective manner in the presence of olefins and other functional groups without formation of the commonly observed aziridines or C-H insertion products. The methodology can be applied not only to rather simple tertiary amines but also to complex natural molecules such as brucine or quinine, where the products derived from N-N bond formation were exclusively formed. Theoretical mechanistic studies have shown that this selective N-amidation reaction proceeds through triplet silver nitrenes.