Synthesis, characterization, and biological activity of cationic ruthenium-arene complexes with sulfur ligands.

Five cationic ruthenium-arene complexes with the generic formula [Ru(SAc)(S2C·NHC)(p-cymene)](PF6) (5a-e) were prepared in almost quantitative yields using a straightforward one-pot, two-step experimental procedure starting from [RuCl2(p-cymene)]2, an imidazol(in)ium-2-dithiocarboxylate (NHC·CS2) zwitterion, KSAc, and KPF6. These half-sandwich compounds were fully characterized by various analytical techniques and the molecular structures of two of them were solved by X-ray diffraction analysis, which revealed the existence of an intramolecular chalcogen bond between the oxygen atom of the thioacetate ligand and a proximal sulfur atom of the dithiocarboxylate unit. DFT calculations showed that the C=S…O charge transfer amounted to 2.4 kcal mol-1. The dissolution of [Ru(SAc)(S2C·IMes)(p-cymene)](PF6) (5a) in moist DMSO-d6 at room temperature did not cause the dissociation of its sulfur ligands. Instead, p-cymene was slowly released to afford the 12-electron [Ru(SAc)(S2C·IMes)]+ cation that could be detected by mass spectrometry. Monitoring the solvolysis process by 1H NMR spectroscopy showed that more than 22 days were needed to fully decompose the starting ruthenium-arene complex. Compounds 5a-e exhibited a high antiproliferative activity against human glioma Hs683 and human lung carcinoma A549 cancer cells. In particular, the IMes derivative (5a) was the most potent compound of the series, achieving toxicities similar to those displayed by marketed platinum drugs.

The Facile Hydrolysis of Imidazolinium Chlorides (N-Heterocyclic Carbene Precursors) Under Basic Aqueous Conditions.

The hydrolysis of imidazolinium chlorides takes place readily in a basic water/dichloromethane biphasic mixture at room temperature. Experimental parameters were optimized to afford full conversions and high yields of γ-aminoformamides starting from twelve symmetrical substrates with alkyl or aryl substituents on their nitrogen atoms, and five unsymmetrical 1-alkyl-3-arylimidazolinium chlorides. NMR and XRD analyses showed that the cleavage of unsymmetrical salts led to γ-alkylamino-N-arylformamides with a high regioselectivity and that bulky alkyl or aryl groups on the formamide moiety led to the isolation of the (E)-isomer in high stereoisomeric purity (>95 %), whereas smaller and more flexible alkyl substituents afforded mixtures of (E)- and (Z)-rotamers. Control experiments showed that the hydrolysis of 1,3-dimesitylimidazolinium chloride (SIMes ⋅ HCl) did not occur readily in pure or acidic water and that the presence of bulky aromatic substituents on the nitrogen atoms of 1,3-bis(2,6-diisopropylphenyl)imidazolinium chloride (SIDip ⋅ HCl) efficiently slowed down its hydrolysis under basic aqueous conditions. Most strikingly, this work highlighted the critical influence of the counteranion on the reactivity of imidazolinium cations. Indeed, the chloride salts underwent a facile hydrolysis in the presence of water and Na2 CO3 , whereas various other NHC ⋅ HX derivatives reacted much slower or remained essentially inert under these conditions.

Aldiminium and 1,2,3-triazolium dithiocarboxylate zwitterions derived from cyclic (alkyl)(amino) and mesoionic carbenes.

The synthesis of zwitterionic dithiocarboxylate adducts was achieved by deprotonating various aldiminium or 1,2,3-triazolium salts with a strong base, followed by the nucleophilic addition of the in situ-generated cyclic (alkyl)(amino) or mesoionic carbenes (CAACs or MICs) onto carbon disulfide. Nine novel compounds were isolated and fully characterized by 1H and 13C NMR, FTIR, and HRMS techniques. Moreover, the molecular structures of two CAAC·CS2 and two MIC·CS2 betaines were determined by X-ray diffraction analysis. The analytical data recorded for all these adducts were compared with those reported previously for related NHC·CS2 betaines derived from imidazolinium or (benz)imidazolium salts. Due to the absence of electronic communication between the CS2 unit and the orthogonal heterocycle, all the CAAC·CS2, MIC·CS2, and NHC·CS2 zwitterions displayed similar electronic properties and featured the same bite angle. Yet, their steric properties are liable to ample modifications by varying the exact nature of their cationic heterocycle and its substituents.

Synthesis, Characterization, and Biological Activity of Water-Soluble, Dual Anionic and Cationic Ruthenium-Arene Complexes Bearing Imidazol(in)ium-2-dithiocarboxylate Ligands.

An efficient synthetic protocol was devised for the preparation of five cationic ruthenium-arene complexes bearing imidazol(in)ium-2-dithiocarboxylate ligands from the [RuCl2(p-cymene)]2 dimer and 2 equiv of an NHC·CS2 zwitterion. The reactions proceeded cleanly and swiftly in dichloromethane at room temperature to afford the expected [RuCl(p-cymene)(S2C·NHC)]Cl products in quantitative yields. When the [RuCl2(p-cymene)]2 dimer was reacted with only 1 equiv of a dithiolate betaine under the same experimental conditions, a set of five bimetallic compounds with the generic formula [RuCl(p-cymene)(S2C·NHC)][RuCl3(p-cymene)] was obtained in quantitative yields. These novel, dual anionic and cationic ruthenium-arene complexes were fully characterized by various analytical techniques. NMR titrations showed that the chelation of the dithiocarboxylate ligands to afford [RuCl(p-cymene)(S2C·NHC)]+ cations was quantitative and irreversible. Conversely, the formation of the [RuCl3(p-cymene)]- anion was limited by an equilibrium, and this species readily dissociated into Cl- anions and the [RuCl2(p-cymene)]2 dimer. The position of the equilibrium was strongly influenced by the nature of the solvent and was rather insensitive to the temperature. Two monometallic and two bimetallic complexes cocrystallized with water, and their molecular structures were solved by X-ray diffraction analysis. Crystallography revealed the existence of strong interactions between the azolium ring protons of the cationic complexes and neighboring donor groups from the anions or the solvent. The various compounds under investigation were highly soluble in water. They were all strongly cytotoxic against K562 cancer cells. Furthermore, with a selectivity index of 32.1, the [RuCl(p-cymene)(S2C·SIDip)]Cl complex remarkably targeted the erythroleukemic cells vs mouse splenocytes.

Combining enyne metathesis with long-established organic transformations: a powerful strategy for the sustainable synthesis of bioactive molecules.

This account surveys the current progress on the application of intra- and intermolecular enyne metathesis as main key steps in the synthesis of challenging structural motifs and stereochemistries found in bioactive compounds. Special emphasis is placed on ruthenium catalysts as promoters of enyne metathesis to build the desired 1,3-dienic units. The advantageous association of this approach with name reactions like Grignard, Wittig, Diels-Alder, Suzuki-Miyaura, Heck cross-coupling, etc. is illustrated. Examples unveil the generality of such tandem reactions in providing not only the intricate structures of known, in vivo effective substances but also for designing chemically modified analogs as valid alternatives for further therapeutic agents.

Continuous-Flow N-Heterocyclic Carbene Generation and Organocatalysis.

Two methods were assessed for the generation of common N-heterocyclic carbenes (NHCs) from stable imidazol(in)ium precursors using convenient and straightforward continuous-flow setups with either a heterogeneous inorganic base (Cs2CO3 or K3PO4) or a homogeneous organic base (KN(SiMe3)2). In-line quenching with carbon disulfide revealed that the homogeneous strategy was most efficient for the preparation of a small library of NHCs. The generation of free nucleophilic carbenes was next telescoped with two benchmark NHC-catalyzed reactions; namely, the transesterification of vinyl acetate with benzyl alcohol and the amidation of N-Boc-glycine methyl ester with ethanolamine. Both organocatalytic transformations proceeded with total conversion and excellent yields were achieved after extraction, showcasing the first examples of continuous-flow organocatalysis with NHCs.

Probing the Diastereoselectivity of Staudinger Reactions Catalyzed by N-Heterocyclic Carbenes.

The reaction of ethylphenylketene with 1,3-dimesitylimidazol-2-ylidene (IMes) or 1,3-dimesitylimidazolin-2-ylidene (SIMes) afforded the corresponding azolium enolates in high yields. The two zwitterions were fully characterized by various analytical techniques. Their thermal stabilities were monitored by thermogravimetric analysis and the molecular structure of SIMes⋅EtPhCCO was determined by means of X-ray crystallography. A mechanism was proposed to account for the trans-diastereoselectivity observed in the [2+2] cycloaddition of ketenes and N-protected imines catalyzed by N-heterocyclic carbenes and an extensive catalytic screening was performed to test its validity. The steric bulk of the NHC catalyst markedly affected the cis/trans ratio of the model ß-lactam product. The nature of the solvent used to carry out the Staudinger reaction also significantly influenced its diastereoselectivity. Conversely, the nature of the substituent on the N-sulfonated imine reagent and the reaction temperature were less critical parameters.

Efficient synthetic protocols for the preparation of common N-heterocyclic carbene precursors.

The one-pot condensation of glyoxal, two equivalents of cyclohexylamine, and paraformaldehyde in the presence of aqueous HBF4 provided a straightforward access to 1,3-dicyclohexylimidazolium tetrafluoroborate (ICy·HBF4). 1,3-Dibenzylimidazolium tetrafluoroborate (IBn·HBF4) was obtained along the same lines. To synthesize 1,3-diarylmidazolium salts, it was necessary to isolate the intermediate N,N'-diarylethylenediimines prior to their cyclization. Although this additional step required more time and reagents, it led to a much more efficient overall process. It also proved very convenient to carry out the synthesis of imidazolinium salts in parallel to their imidazolium counterparts via the reduction of the diimines into diammonium salts. The critical assembly of the C(2) precarbenic unit was best achieved with paraformaldehyde and chlorotrimethylsilane in the case of imidazolium derivatives, whereas the use of triethyl orthoformate under microwave irradiation was most appropriate for the fast and efficient synthesis of imidazolinium salts. This strategy was applied to the synthesis of six common N-heterocyclic carbene precursors, namely, 1,3-dimesitylimidazolium chloride (IMes·HCl), 1,3-dimesitylimidazolium tetrafluoroborate (IMes·HBF4), 1,3-dimesitylimidazolinium chloride (SIMes·HCl), 1,3-bis(2,6-diisopropylphenyl)imidazolium chloride (IDip·HCl or IPr·HCl), 1,3-bis(2,6-diisopropylphenyl)imidazolinium chloride (SIDip·HCl or SIPr·HCl), and 1,3-bis(2,6-bis(diphenylmethyl)-4-methylphenyl)imidazolium chloride (IDip*·HCl or IPr*·HCl).

N-heterocyclic carbene catalyzed carba-, sulfa-, and phospha-Michael additions with NHC·CO2 adducts as precatalysts.

N-heterocyclic carbene catalyzed Michael additions have been revisited with 1,3-dialkyl- or 1,3-diarylimidazol(in)ium-2-carboxylates, that is, NHC·CO2 adducts, as the source of the free NHC catalysts in solution. Using these precatalysts, a number of efficient carba-, sulfa-, and phospha-Michael additions were achieved very conveniently, without the need for an external strong base to generate the NHC by deprotonation of an azolium salt. To further expand the scope of the procedure, some NHC-catalyzed sulfa-Michael/aldol organocascades were also investigated.

Homoleptic ruthenium(II) complexes bearing imidazol(in)ium-2-dithiocarboxylate ligands: synthesis, characterization, and redox properties.

Five cationic ruthenium(II) chelates with the generic formula [Ru(S2C·NHC)3](PF6)2 were readily obtained upon cleavage of the [RuCl2(p-cymene)]2 dimer with representative imidazol(in)ium-2-dithiocarboxylate zwitterions (NHC·CS2) in the presence of KPF6. The homoleptic complexes were fully characterized by various analytical techniques and the molecular structure of one of them was determined by single-crystal X-ray diffraction analysis. As expected, it featured an octahedral RuS6 core surrounded by three imidazol(in)ium rings and their nitrogen substituents. The robustness of the Ru-S bonds combined with the chelate effect of the κ2-S,S'-dithiocarboxylate units and the steric protection imparted by bulky 1,3-diarylimidazol(in)ium groups most likely accounted for the outstanding stability of these species in solution. Cyclic voltammetry showed that the five homoleptic complexes featured characteristic waves for a monoelectronic redox process corresponding to the RuIII/RuII couple with E1/2 values ranging between 0.97 and 1.27 V vs. Ag/AgCl. This half-wave potential was clearly dependent on the nature of their ancillary ligands as the evolution of the Ep,ox values roughly paralleled the basicity sequence of the NHCs used to prepare them, in line with the trends observed when monitoring the chemical shifts of the CS2- unit on 13C NMR spectroscopy and the CS2- asymmetric stretching vibration wavenumbers on IR spectroscopy.

Mechanistic insight into the Staudinger reaction catalyzed by N-heterocyclic carbenes.

Four zwitterions were prepared by treating 1,3-dimesitylimidazolin-2-ylidene (SIMes) or 1,3-dimesitylimidazol-2-ylidene (IMes) with either N-tosyl benzaldimine or diphenylketene. They were isolated in high yields and characterized by IR and NMR spectroscopy. The molecular structures of three of them were determined by using X-ray crystallography and their thermal stability was monitored by using thermogravimetric analysis. The imidazol(in)ium-2-amides were rather labile white solids that did not show any tendency to tautomerize into the corresponding 1,2,2-triaminoethene derivatives. They displayed a mediocre catalytic activity in the Staudinger reaction of N-tosyl benzaldimine with diphenylketene. In contrast, the imidazol(in)ium-2-enolates were orange-red crystalline materials that remained stable over extended periods of time. Despite their greater stability, these zwitterions turned out to be efficient promoters for the model cycloaddition under scrutiny. As a matter of fact, their catalytic activity matched those recorded with the free carbenes. Altogether, these results provide strong experimental insight into the mechanism of the Staudinger reaction catalyzed by N-heterocyclic carbenes. They also highlight the superior catalytic activity of the imidazole-based carbene IMes compared with its saturated analogue SIMes in the reaction under consideration.

The facile alkylation and iodination of imidazol(in)ium salts in the presence of cesium carbonate.

The alkylation or iodination of imidazol(in)ium salts takes place readily in the presence of Cs2CO3. The procedure is very easy to implement and provides facile and straightforward access to a wealth of C2-substituted azolium salts. Furthermore, a C2α alkylation is also feasible, which extends the chemistry of NHCs and weak bases to their NHO analogues.

Rhodium catalysts with superbulky NHC ligands for the selective α-hydrothiolation of alkynes.

Eight rhodium complexes-including four new compounds-with the generic formula [RhCl(cod)(NHC)] (cod is 1,3-cyclooctadiene) differing by the size of their N-heterocyclic carbene (NHC) ligand were prepared, characterized, and found to be catalytically active in the hydrothiolation of terminal alkynes with aliphatic or aromatic thiols. The steric bulk of the carbene was found to markedly influence the reaction rate and selectivity. In particular, superbulky NHCs led to the almost quantitative formation of the sole α-vinyl sulfide products. The experimental conditions were optimized to allow the straightforward synthesis of a broad range of mono- and disubstituted α-adducts starting from terminal alkynes (18 examples) and thiols (5 examples). Altogether, the procedure devised in this study provides an easy access to α-vinyl sulfides with full atom economy and a low catalyst loading.

Metathesis access to monocyclic iminocyclitol-based therapeutic agents.

By focusing on recent developments on natural and non-natural azasugars (iminocyclitols), this review bolsters the case for the role of olefin metathesis reactions (RCM, CM) as key transformations in the multistep syntheses of pyrrolidine-, piperidine- and azepane-based iminocyclitols, as important therapeutic agents against a range of common diseases and as tools for studying metabolic disorders. Considerable improvements brought about by introduction of one or more metathesis steps are outlined, with emphasis on the exquisite steric control and atom-economical outcome of the overall process. The comparative performance of several established metathesis catalysts is also highlighted.

The use of imidazolium-2-dithiocarboxylates in the formation of gold(I) complexes and gold nanoparticles.

The imidazolium-2-dithiocarboxylate ligands IPr.CS(2), IMes.CS(2), and IDip.CS(2) react with [AuCl(PPh(3))] to yield [(Ph(3)P)Au(S(2)C.IPr)](+), [(Ph(3)P)Au(S(2)C.IMes)](+), and [(Ph(3)P)Au(S(2)C.IDip)](+), respectively. The compounds [(L)Au(S(2)C.IMes)](+) are prepared from the reaction of IMes.CS(2) with [AuCl(L)] (L = PMe(3), PCy(3), CN(t)Bu). The carbene-containing precursor [(IDip)AuCl] reacts with IPr.CS(2) and IMes.CS(2) to afford the complexes [(IDip)Au(S(2)C.IPr)](+) and [(IDip)Au(S(2)C.IMes)](+) with two carbene units, one bound to the metal center and the other to the dithiocarboxylate unit. Treatment of the diphosphine-gold complex [(dppm)(AuCl)(2)] with 1 equiv of IMes.CS(2) yields [(dppm)Au(2)(S(2)C.IMes)](2+), while the reaction of [L(2)(AuCl)(2)] (L(2) = dppb, dppf) with 2 equiv of IMes.CS(2) results in [(L(2)){Au(S(2)C.IMes)}(2)](2+). The homoleptic complexes [Au(S(2)C.IPr)(2)](2+), [Au(S(2)C.IMes)(2)](2+), and [Au(S(2)C.IDip)(2)](2+) are obtained from the reaction of [AuCl(tht)] with 2 equiv of the appropriate imidazolium-2-dithiocarboxylate ligand. The compounds [(Ph(3)P)Au(S(2)C.NHC)](+) (NHC = IMes, IDip) and [(IDip)Au(S(2)C.NHC)](+) (NHC = IPr, IMes) are characterized crystallographically. The IMes.CS(2) ligand is also used to prepare functionalized gold nanoparticles with diameters of 11.5 (+/-1.2) and 2.6 (+/-0.3) nm.

Tandem catalysis of ring-closing metathesis/atom transfer radical reactions with homobimetallic ruthenium-arene complexes.

The tandem catalysis of ring-closing metathesis/atom transfer radical reactions was investigated with the homobimetallic ruthenium-indenylidene complex [(p-cymene)Ru(µ-Cl)3RuCl(3-phenyl-1-indenylidene)(PCy3)] (1) to generate active species in situ. The two catalytic processes were first carried out independently in a case study before the whole sequence was optimized and applied to the synthesis of several polyhalogenated bicyclic γ-lactams and lactones from α,ω-diene substrates bearing trihaloacetamide or trichloroacetate functionalities. The individual steps were carefully monitored by ¹H and ³¹P NMR spectroscopies in order to understand the intimate details of the catalytic cycles. Polyhalogenated substrates and the ethylene released upon metathesis induced the clean transformation of catalyst precursor 1 into the Ru(II)-Ru(III) mixed-valence compound [(p-cymene)Ru(µ-Cl)3RuCl(2)(PCy3)], which was found to be an efficient promoter for atom transfer radical reactions under the adopted experimental conditions.

Facile microwave-assisted synthesis of cyclic amidinium salts.

The cyclization of N,N'-dialkyl or diaryl ethane-1,2-diamines or propane-1,3-diamines with inorganic ammonium salts and orthoesters proceeds briskly under microwave irradiation to afford the corresponding imidazolinium or tetrahydropyrimidinium salts. The transformation is highly versatile and tolerates a wide range of substituents and counterions. It could be scaled from 1 to 50 mmol without any difficulty. Because the workup is equally rapid and straightforward, this experimental procedure provides fast and convenient access to an important class of heterocyclic compounds that have found numerous applications as N-heterocyclic carbene precursors, organocatalysts, and ionic liquids.

N-Heterocyclic carbene-based ruthenium-hydride catalysts for the synthesis of unsymmetrically functionalized double-decker silsesquioxanes.

Ruthenium-N-heterocyclic carbene complexes with the generic formula [RuHCl(CO)(NHC)(PCy3)] exhibit a high catalytic activity toward the (E)-selective silylative coupling of divinyl-substituted double-decker silsesquioxanes with two distinctly substituted styrenes. This process leads to a novel class of unsymmetrically functionalized silsesquioxane derivatives.

Synthesis, characterization, and catalytic evaluation of ruthenium-diphosphine complexes bearing xanthate ligands.

The reaction of [RuCl2(p-cymene)]2 with potassium O-ethylxanthate and a set of nine representative Ph2P-X-PPh2 bidentate phosphines (dppm, dppe, dppp, dppb, dpppe, dppen, dppbz, dppf, and DPEphos) afforded monometallic [Ru(S2COEt)2(diphos)] chelates 1-9 in 62-96% yield. All the products were fully characterized by using various analytical techniques and their molecular structures were determined by X-ray crystallography. They featured a highly distorted octahedral geometry with a S-Ru-S bite angle close to 72° and P-Ru-P angles ranging between 73° and 103°. Bond lengths and IR stretching frequencies recorded for the anionic xanthate ligands strongly suggested a significant contribution of the EtO+[double bond, length as m-dash]CS22- resonance form. 1H NMR and XRD analyses showed that the methylene protons of the ethyl groups were diastereotopic due to a strong locking of their conformation by a neighboring phenyl ring. On cyclic voltammetry, quasi-reversible waves were observed for the Ru2+/Ru3+ redox couples with E1/2 values ranging between 0.65 and 0.80 V vs. Ag/AgCl. The activity of chelates 1-9 was probed in three catalytic processes, viz., the synthesis of vinyl esters from benzoic acid and 1-hexyne, the cyclopropanation of styrene with ethyl diazoacetate, and the atom transfer radical addition of carbon tetrachloride and methyl methacrylate. In the first case, 31P NMR analysis of the reaction mixtures showed that the starting complexes remained mostly unaltered despite the harsh thermal treatment that was applied to them. In the second case, monitoring the rate of nitrogen evolution revealed that all the catalysts under investigation behaved similarly and were rather slow initiators. In the third case, [Ru(S2COEt)2(dppm)] was singled out as a very active and selective catalyst already at 140 °C, whereas most of the other complexes resisted degradation up to 160 °C and were only moderately active. Altogether, these results were in line with the high stability displayed by [Ru(S2COEt)2(diphos)] chelates 1-9.

Synthesis and complexation of superbulky imidazolium-2-dithiocarboxylate ligands.

The superbulky N-heterocyclic carbenes (NHCs) 2,6-bis(diphenylmethyl)-4-methylimidazol-2-ylidene (IDip*Me) and its 4-methoxy analogue (IDip*OMe) reacted instantaneously with carbon disulfide to afford the corresponding imidazolium-2-dithiocarboxylate zwitterions in high yields. These new dithiolate ligands were fully characterized and their coordination chemistry toward common Re(i) and Ru(ii) metal sources was thoroughly investigated. Neutral [ReBr(CO)3(S2C·NHC)] chelates featured three facially-arranged carbonyl groups on a distorted octahedron, whereas cationic [RuCl(p-cymene)(S2C·NHC)]PF6 complexes displayed a piano-stool geometry. The molecular structures of the six new compounds revealed that the NHC·CS2 inner salts were highly flexible. Indeed, the torsion angle between their anionic and cationic moieties varied between ca. 63° in the free ligands and 3° in the ruthenium complexes. Concomitantly, the S-C-S bite angle underwent a contraction from 131° to 110-113° upon chelation. Computation of the %VBur parameter showed that the dithiocarboxylate unit of the NHC·CS2 betaines chiefly determined the steric requirements of the imidazolium moieties, irrespective of the metal center involved in the complexation. The replacement of the p-methyl substituents of IDip*Me with p-methoxy groups in IDip*OMe did not significantly affect the ligand bulkiness. The more electron-donating methoxy group led, however, to small changes in various IR wavenumbers used to probe the electron donor properties of the carbene moiety.