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.

Special Issue on Ruthenium Complexes.

The organic chemistry of ruthenium has been one of the most vigorously growing research areas over the past decades. Considerable effort has been extended towards the design and application of a broad series of ruthenium complexes, which culminated with the development by Ryoji Noyori (2001 Nobel Prize for Chemistry) of chiral ruthenium catalysts for stereoselective hydrogenation reactions [1], and the discovery by Robert H. Grubbs (2005 Nobel Prize for Chemistry) of well-defined ruthenium- benzylidene catalysts for olefin metathesis [2] [...].

ROMP Synthesis of Iron-Containing Organometallic Polymers.

The paper overviews iron-containing polymers prepared by controlled "living" ring-opening metathesis polymerization (ROMP). Developments in the design and synthesis of this class of organometallic polymers are highlighted, pinpointing methodologies and newest trends in advanced applications of hybrid materials based on polymers functionalized with iron motifs.

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.

Editorial of Special Issue Ruthenium Complex: The Expanding Chemistry of the Ruthenium Complexes.

Recent trends in Ru complex chemistry are surveyed with emphasis on the development of anticancer drugs and applications in catalysis, polymers, materials science and nanotechnology.

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).

Recent advances in metathesis-derived polymers containing transition metals in the side chain.

This account critically surveys the field of side-chain transition metal-containing polymers as prepared by controlled living ring-opening metathesis polymerization (ROMP) of the respective metal-incorporating monomers. Ferrocene- and other metallocene-modified polymers, macromolecules including metal-carbonyl complexes, polymers tethering early or late transition metal complexes, etc. are herein discussed. Recent advances in the design and syntheses reported mainly during the last three years are highlighted, with special emphasis on new trends for superior applications of these hybrid materials.

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.

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.

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.

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.

Microwave-assisted Olefin Metathesis as Pivotal Step in the Synthesis of Bioactive Compounds.

Over the last two decades, olefin metathesis has emerged as a new avenue in the design of new routes for the synthesis of natural products and active pharmaceutical ingredients. In many cases, syntheses based on olefin metathesis strategies provide significant routes in terms of increasing the overall yields, improving the synthesis scope, and decreasing the number of steps. On the other hand, over the last decade, microwave-assisted chemistry has experienced an incredible development, which rapidly opened new areas in organic synthesis and in homogeneous catalysis. In this review article, we highlight applications of microwaveheated olefin metathesis reactions as pivotal steps in the total synthesis of biologically active compounds. By drawing selected examples from the recent literature, we aim to illustrate the great synthetic power and variety of metathesis reactions, as well as the beneficial effects of microwave irradiation over conventional heating sources. The majority of the selected applications of microwave-assisted olefin metathesis cover the synthesis of medium-ring cycles, macrocycles, and peptidomimetics by means of ring-closing metathesis (RCM) and crossmetathesis (CM) routes.

The half-sandwich 18- and 16-electron arene ruthenium iminophosphonamide complexes.

Novel half-sandwich 18e and 16e arene ruthenium iminophosphonamide complexes [(η6-C6Me6)RuCl{(R'N)2PR2}] (3a-c) and [(η6-C6Me6)Ru{(R'N)2PR2}]+(X-) (4a-c) (a, R = Ph, R' = p-Tol; b, R = Et, R' = p-Tol; c, R = Ph, R' = Me. X = BF4, PF6 or BArF4) were synthesized. The elongated Ru-Cl bond in the 18e complexes is shown to dissociate even in apolar solvents to form the corresponding 16e cations, which can be readily isolated as salts with non-coordinating anions. The coordinatively unsaturated 16e complexes are stable species due to efficient π-electron donation from the nitrogen atoms of the zwitterionic NPN-ligand. The ruthenium iminophosphonamides are moderately active in the ROMP polymerization of norbornene; the 16e complexes 4a,b yield high molecular weight polymers (Mn∼ 300 × 103) with a narrow distribution Mw/Mn∼ 1.6, while the 18e complexes 3a,b give polymers of lower molecular weight (Mn < 50 × 103) with a wider polydispersity index Mw/Mn∼ 2.5.

Ruthenium catalysts bearing a benzimidazolylidene ligand for the metathetical ring-closure of tetrasubstituted cycloolefins.

Deprotonation of 1,3-di(2-tolyl)benzimidazolium tetrafluoroborate with a strong base afforded 1,3-di(2-tolyl)benzimidazol-2-ylidene (BTol), which dimerized progressively into the corresponding dibenzotetraazafulvalene. The complexes [RhCl(COD)(BTol)] (COD is 1,5-cyclooctadiene) and cis-[RhCl(CO)2(BTol)] were synthesized to probe the steric and electronic parameters of BTol. Comparison of the percentage of buried volume (%VBur) and of the Tolman electronic parameter (TEP) of BTol with those determined previously for 1,3-dimesitylbenzimidazol-2-ylidene (BMes) revealed that the two N-heterocyclic carbenes displayed similar electron donicities, yet the 2-tolyl substituents took a slightly greater share of the rhodium coordination sphere than the mesityl groups, due to a more pronounced tilt. The anti,anti conformation adopted by BTol in the molecular structure of [RhCl(COD)(BTol)] ensured nonetheless a remarkably unhindered access to the metal center, as evidenced by steric maps. Second-generation ruthenium-benzylidene and isopropoxybenzylidene complexes featuring the BTol ligand were obtained via phosphine exchange from the first generation Grubbs and Hoveyda-Grubbs catalysts, respectively. The atropisomerism of the 2-tolyl substituents within [RuCl2(=CHPh)(PCy3)(BTol)] was investigated by using variable temperature NMR spectroscopy, and the molecular structures of all four possible rotamers of [RuCl2(=CH-o-O(i)PrC6H4)(BTol)] were determined by X-ray crystallography. Both complexes were highly active at promoting the ring-closing metathesis (RCM) of model α,ω-dienes. The replacement of BMes with BTol was particularly beneficial to achieve the ring-closure of tetrasubstituted cycloalkenes. More specifically, the stable isopropoxybenzylidene chelate enabled an almost quantitative RCM of two challenging substrates, viz., diethyl 2,2-bis(2-methylallyl)malonate and N,N-bis(2-methylallyl)tosylamide, within a few hours at 60 °C.

Highly Efficient Ruthenium-Based Catalytic Systems for the Controlled Free-Radical Polymerization of Vinyl Monomers.

A new set of ruthenium complexes such as 1 and 2 (the Grubbs ruthenium-carbene complex) has been shown to mediate the controlled atom-transfer radical polymerization (ATRP) of vinyl monomers with exceptional efficiency. Furthermore, there is a striking parallelism between the catalytic activity of these compounds in olefin metathesis and in ATRP.

Assessing the ligand properties of 1,3-dimesitylbenzimidazol-2-ylidene in ruthenium-catalyzed olefin metathesis.

The deprotonation of 1,3-dimesitylbenzimidazolium tetrafluoroborate with a strong base afforded 1,3-dimesitylbenzimidazol-2-ylidene (BMes), which was further reacted in situ with rhodium or ruthenium complexes to afford three new organometallic products. The compounds [RhCl(COD)(BMes)] (COD is 1,5-cyclooctadiene) and cis-[RhCl(CO)2(BMes)] were used to probe the steric and electronic parameters of BMes. Comparison of the percentage of buried volume (%V(Bur)) and of the Tolman electronic parameter (TEP) of BMes with those determined previously for 1,3-dimesitylimidazol-2-ylidene (IMes) and 1,3-dimesitylimidazolin-2-ylidene (SIMes) revealed that the three N-heterocyclic carbenes (NHCs) had very similar profiles. Nonetheless, changes in the hydrocarbon backbone subtly affected the stereoelectronic properties of these ligands. Accordingly, the corresponding [RuCl2(PCy3)(NHC)(=CHPh)] complexes displayed different catalytic behaviors in the ring-closing metathesis (RCM) of α,ω-dienes. In the benchmark cyclization of diethyl 2,2-diallylmalonate, the new [RuCl2(PCy3)(BMes)(=CHPh)] compound (1d) performed slightly better than the Grubbs second-generation catalyst (1a), which was in turn significantly more active than the related [RuCl2(PCy3)(IMes)(=CHPh)] initiator (1b). For the formation of a model trisubstituted cycloolefin, complex 1d ranked in-between catalyst precursors 1a and 1b, whereas in the RCM of tetrasubstituted cycloalkenes it lost its catalytic efficiency much more rapidly.

Retracing the evolution of monometallic ruthenium-arene catalysts for C-C bond formation.

Preformed or in situ generated monometallic ruthenium-arene complexes with the generic formula RuX(2)(arene)(L) (L = phosphine or N-heterocyclic carbene) are versatile and efficient catalyst precursors for olefin metathesis and atom transfer radical reactions. Their synthesis is usually accomplished using simple and straightforward experimental procedures starting from the [RuCl(2)(p-cymene)](2) dimer. This article retraces their evolution over the past 20 years and highlights similarities and differences with the parallel development of well-defined RuX(2)(=CHR)(L(1))(L(2)) ruthenium-alkylidene catalysts.

Ruthenium alkylidenes: modulation of a new class of catalysts for controlled radical polymerization of vinyl monomers.

Air-stable and readily available ruthenium benzylidene complexes of the general type [RuCl2(=CHPh)(L)(L')] (L, L' = PCy3 and/or N-heterocyclic carbene) constitute a new class of catalyst precursors for atom-transfer radical polymerization (ATRP) of methyl methacrylate and styrene, and provide an unprecedented example for the involvement of ruthenium alkylidenes in radical reactions. They promote the polymerization of various monomers with good to excellent yields, and in a controlled way with methyl methacrylate and styrene. Variations of their basic structural motif provide insights into the essential parameters responsible for catalytic activity. The ligands L (PCy3 and/or N-heterocyclic carbene) turned out to play a particularly important role in determining the rate of the polymerizations. A similarly pronounced influence is exerted by the substituents on the N-heterocyclic carbene. Our results indicate that the catalysts decompose quickly under ATRP conditions, and polymerizations are mediated by both [RuCl2(=CHPh)(L)(L')] complexes and ruthenium species bereft of the benzylidene moiety, through a pathway in which both tricyclohexylphosphane and/or N-heterocyclic carbene ligands remain bound to the metal center. Polymerization of n-butyl acrylate and vinyl acetate is not controlled and most probably takes place through a redox-initiated free-radical process.

The modulating possibilities of dicarbollide clusters: optimizing the Kharasch catalysts.

exo-Cluster dicarbollides substitution has allowed tuning of the E degrees (Ru(II)/Ru(III)) potential to obtain the best-performing Kharasch catalyst. We postulate that this is possible through the to-and-fro electron movement between the boron cluster and the sulfonium moieties.