Metathesis Products Research Articles

Unravelling the olefin cross metathesis on solid support. Factors affecting the reaction outcome

Olefin cross metathesis on solid support under a variety of conditions is described. A comprehensive analysis considering diverse factors governing the reaction outcome gives a series of patterns for the application of this useful methodology in organic synthesis. If the intrasite reaction is not possible, homodimerization of the soluble olefin is crucial. When the homodimer is less reactive than its monomer, reaction outcome depends on the homodimerization rate, which, in turn, depends on the precatalyst used and the reaction conditions. If the site-site interaction is a feasible process, the cross metathesis product is obtained exclusively when the newly-formed double bond is resilient to further metathetic events. Taking into account these considerations, we have demonstrated that excellent results in terms of cross metathesis coupling can be obtained under the optimized conditions, and that microwave irradiation is also an interesting alternative for the development of a practical and energy-efficient cross metathesis on solid support.

Novel epothilone lactones by an unusual diversion of the Grubbs' metathesis reaction

An unusual reaction with Grubbs' catalyst during the synthesis of bridged epothilones yielded five-membered internal lactones instead of the expected metathesis products. Three of the lactones have activities comparable to epothilone D.

Sigma bond metathesis with pentamethylcyclopentadienyl ligands in sterically crowded (C5Me5)3M complexes

To further explore the reactivity of the (C(5)Me(5))(-) ligand in the sterically crowded (C(5)Me(5))(3)M complexes, reactions with PhEEPh (E = S, Se, Te) have been examined. With M = La, Pr, Nd, Sm, and Y, PhSSPh reacts to form the expected reduction products, [(C(5)Me(5))(2)M(SPh)](2), but the major organic byproduct is not the sterically induced reduction product, (C(5)Me(5))(2). Instead, the sigma bond metathesis product, C(5)Me(5)SPh, is the major byproduct. In contrast, reactions with (C(5)Me(5))(3)Ce and (C(5)Me(5))(3)U gave a mixture of C(5)Me(5)SPh and (C(5)Me(5))(2) as byproducts. PhSSPh reactions with the lanthanide nitrile adducts, (C(5)Me(5))(3)Ln(NCCMe(3))(2) (Ln = La, Ce) and (C(5)Me(5))(3)Nd(NCCMe(3)), formed [(C(5)Me(5))(2)Ln(SPh)(NCCMe(3))](2) and only C(5)Me(5)SPh as the byproduct. PhSeSePh reactions paralleled the PhSSPh results, but reactions of PhTeTePh with (C(5)Me(5))(3)La, (C(5)Me(5))(3)Sm, and (C(5)Me(5))(3)La(NCCMe(3))(2) gave only (C(5)Me(5))(2) as a byproduct.

Chemoselective olefin metathesis transformations mediated by ruthenium complexes

Over the past decade, ruthenium-mediated metathesis transformations, including polymerization reactions, cross-metathesis, ring-closing metathesis, enyne metathesis, ring-rearrangement metathesis, and also tandem processes, represent one of the most studied families of organic reactions. This has translated into the development of a large number of structurally diverse catalysts. Whereas most of these investigations are focused on determining catalytic performance, only rare examples of studies dealing with chemoselectivity have been reported to date. Usually, variations are observed in product conversions but rarely in product distributions. In this critical review, we provide an overview of the stereochemistry of newly formed C=C bonds either in ring-closing or cross-metathesis as a function of the catalyst structure. A discussion of disparities encountered in macrocyclisation reactions leading (or not) to the formation of dimeric products is also presented. Since distinctive metathesis products could be isolated as a function of the ligand borne by the ruthenium centre--phosphine or N-heterocyclic carbene in the dissymetrization of trienes, enyne metathesis and ring rearrangements, these topics are also discussed (72 references).

A simple oxidative procedure for the removal of ruthenium residues from metathesis reaction products

Ruthenium residues can be easily and rapidly removed from Grubbs metathesis products by washing with 15% aqueous hydrogen peroxide, which converts any ruthenium complexes into highly insoluble ruthenium dioxide, which then catalyzes the conversion of excess peroxide into water and oxygen. Ruthenium levels lower than 2 ppm can be routinely obtained; an additional advantage is that any phosphines are also rapidly oxidized to the corresponding, more polar phosphine oxides thereby facilitating their removal as well in many cases.

Regioselective Domino Metathesis of Unsymmetrical 7-Oxanorbornenes with Electron-Rich Vinyl Acetate toward Biologically Active Glutamate Analogues.

In this article a regioselective domino metathesis reaction of unsymmetrical 7-oxanorbornenes, readily available by a tandem Ugi/Diels-Alder reaction as a key step, promoted by the Hoveyda-Grubbs second-generation catalyst in the presence of electron-rich vinyl acetate as a cross metathesis (CM) substrate is reported. The mechanism for the unusually high regioselectivity observed in the CM reaction was investigated, and a reaction course where a Fischer-type carbene ["Ru"= CH(OAc)] generates a steric interaction is proposed. The metathesis products were further converted to four artificial glutamate analogues whose structures were inspired by naturally derived excitatory glutamate analogues, dysiherbaine and neodysiherbaine. Interestingly, one of the synthetic analogues (28a) induced a cataleptic state in mice. Further electrophysiological studies suggest that 28a might inhibit excitatory synaptic transmission by a yet unknown indirect pathway.

Concerning the Reaction Pathway of the Metathesis Reaction involving WW and CN Triple Bonds: A Theoretical Study

The original "chop-chop" reaction reported by Schrock [J. Am. Chem. Soc. 1982, 104, 4291] involving W(2)(O(t)Bu)(6) and organic nitriles, RC[triple bond]N to give the metal alkylidyne and nitride products ((t)BuO)(3)WC[triple bond]R and ((t)BuO)(3)WC[triple bond]N, has been examined by a density functional theory based calculation where the bulky (t)BuO ligands have been substituted by MeO. The reaction between W(2)(OMe)(6) and MeCN proceeds via a ditungstaazacyclobutadiene intermediate having a planar W(2)CN core, I, with a structure related to that seen for Mo(2)(OCH(2)(t)Bu)(6)(mu-NCNMe(2)). Another possible intermediate having a pseudo tetrahedral W(2)CN core, II, a ditungstaazatetrahedrane was examined and shown to have a higher energy. The interconversion of I and II was found to be energetically unfavorable with respect to their formation of metathesis products. The highest energy transition state involving the conversion of I to products was comparable to that for the conversion of II to products but the initial formation of I from the reaction between W(2)(OMe)(6) and MeCN was favored over the formation of II. The related reaction between Mo(2)(OMe)(6) and MeCN was shown to be thermodynamically unfavorable with respect to either adduct formation or metathesis products. However the reaction between Mo(2)(OMe)(6) and Me(2)NCN did yield a thermodynamically favored 1:1 adduct with a structure related to I.

A short approach to the synthesis of the ritonavir and lopinavir core and its C-3 epimer via cross metathesis

A short synthesis of hydroxyethylene dipeptide isostere, a core unit of the HIV-protease inhibitors ritonavir and lopinavir, its C-3 epimer and C 2 symmetric diamino diol is described. The crucial aspects of the synthesis are self-cross metathesis and exploitation of C 2-symmetric of the metathesis product 8 to obtain the required skeleton.

Preparation of Photoreactive Oligomers by ADMET Polymerization of [(C5H4(CH2)8CH═CH2)Mo(CO)3]2

Polymerization of the [(η5-C5H4(CH2)8CH═CH2)Mo(CO)3]2 complex by acyclic diene metathesis polymerization (ADMET) is reported. The polymerization reactions were performed using Schrock’s catalyst, which resulted in formation of a polydisperse oligomer (Mn = 2300 and Mw/Mn = 4.3) with Mo−Mo bonds in the oligomer chain. Under dilute solvent conditions, the reaction was shown to favor the formation of the ring-closing metathesis (RCM) product. The ADMET oligomer was photochemically degradable, and irradiation with λ > 520 nm light in CCl4 resulted in cleavage of the oligomer backbone and formation of the metal chloride complex [μ-C5H4(CH2)8CH═CH(CH2)8C5H4{Mo(CO)3Cl}2]. The RCM product was also irradiated and the photochemical product is identical to that formed by irradiation of the oligomer. Copolymerization of [(η5-C5H4(CH2)8CH═CH2)Mo(CO)3]2 with 1,9-decadiene using Grubbs’ second-generation catalyst resulted in a higher molecular weight oligomer (Mn = 3400, Mw/Mn = 3.9).

Ring-closing metathesis for the synthesis of heteroaromatics: evaluating routes to pyridines and pyridazines

Ring-closing olefin metathesis (RCM) has been applied to the efficient synthesis of densely and diversely substituted pyridine and pyridazine frameworks. Routes to suitable metathesis precursors have been investigated and the scope of the metathesis step has been probed. The metathesis products function as precursors to the target heteroaromatic structures via elimination of a suitable leaving group, which also facilitates earlier steps by serving as a protecting group at nitrogen. Further functionalisation of the metathesis products is possible both prior to and after aromatisation. The net result is a powerful strategy for the de novo synthesis of highly substituted heteroaromatic scaffolds.

Reactivity of Cationic Terminal Borylene Complexes: Novel Mechanisms for Insertion and Metathesis Chemistry Involving Strongly Lewis Acidic Ligand Systems

The reactions of terminal borylene complexes of the type [CpFe(CO)(2)(BNR2)](+) (R = `Pr, Cy) with heteroallenes have been investigated by quantum-chemical methods, in an attempt to explain the experimentally observed product distributions. Reaction with dicyclohexylcarbodiimide (CyNCNCy) gives a bis-insertion product, in which 1 equiv of carbodiimide is assimilated into each of the Fe=B and B=N double bonds to form a spirocyclic boronium system. In contrast, isocyanates (R'NCO, R' = Ph, 2,6-wXy1, CY; XYl = C6H3Me2) react to give isonitrile complexes of the type [CpFe(CO)(2)(CNR')]+, via a net oxygen abstraction (or formal metathesis) process. Both carbodiimide and socyanate substrates are shown to prefer initial attack at the Fe=B bond rather than the B=N bond of the borylene complex. Further mechanistic studies reveal that the carbodiimide reaction ultimately leads to the bis-insertion compounds [CpFe(CO)(2)C(NCy)(2)B(NCY)(2)CNR2](+), rather than to the isonitrile system [CpFe(CO)(2)(CNCy)](+), on the basis of both thermodynamic (product stability) and kinetic considerations (barrier heights). The mechanism of the initial carbodiimide insertion process is unusual in that it involves coordination of the substrate at the (borylene) ligand followed by migration of the metal fragment, rather than a more conventional process: i.e., coordination of the unsaturated substrate at the metal followed by ligand migration. In the case of isocyanate substrates, metathesis products are competitive with those from the insertion pathway. Direct, single-step metathesis reactivity to give products containing a coordinated isonitrile ligand (i.e. [CpFe(CO)(2)(CNR')](+)) is facile if initial coordination of the isocyanate at boron occurs via the oxygen donor (which is kinetically favored); insertion chemistry is feasible when the isocyanate attacks initially via the nitrogen atom. However, even in the latter case, further reaction of the monoinsertion product so formed with excess isocyanate offers a number of facile (low energetic barrier) routes which also generate ['CpFe(CO)(2)(CNR')](+), rather than the bis-insertion product [CpFe(CO)(2)C(NR')(O)B(NR')(O)CNR2](+) (i.e., the direct analogue of the observed products in the carbodiimide reaction).

Design and Synthesis of Piperidine-Containing Sphingoid Base Analogues

We report an approach that allows the efficient synthesis of the designed sphingoid base analogues in which the conformational restriction is introduced by incorporation of a cyclic moiety between the 2-amino group and the C-4 carbon atom of the sphingoid base. Our synthesis features a tandem enyne/diene-ene metathesis reaction that provides access to the designed framework. The diene moiety of the metathesis product is stereoselectively elaborated for the synthesis of the designed analogues. The preliminary biological evaluation indicates that the designed constrained analogues are much more effective than prototype natural sphingoid bases at inhibiting cancer cell growth.

Metathesis in Pure Water Mediated by Supramolecular Additives

Abstractmagnified imageSupramolecular, water‐soluble additives based on calix[n]arenes exhibit a beneficial influence on the ring‐closing and cross metathesis of non‐polar substrates in pure aqueous medium using standard Grubbs‐II and Hoveyda‐II catalysts. The catalytic activity observed in water is virtually the same as that in pure methanol. Quantitative yields of metathesis product can be achieved under mild aerobic conditions in/on water by (micro)solubilization of both the catalyst and starting materials by the macrocycles.

A fluorous-tagged "safety catch" linker for preparing heterocycles by ring-closing metathesis.

A fluorous-tagged “safety catch” linker is described for the synthesis of heterocycles with use of ring-closing metathesis. The linker facilitiates the purification of metathesis substrates, the removal of the catalyst, the functionalization of the products, and the release of only metathesis products. The synthesis of a range of heterocycles is described.

Reactions of Diazo Compounds with Alkenes Catalysed by [RuCl(cod)(Cp)]: Effect of the Substituents in the Formation of Cyclopropanation or Metathesis Products

The reaction of diazo compounds with alkenes catalysed by complex [RuCl(cod)(Cp)] (cod = 1,5-cyclooctadiene, Cp = cyclopentadienyl) has been studied. The catalytic cycle involves in the first step the decomposition of the diazo derivative to afford the reactive [RuCl(Cp){=C(R(1))R(2)}] intermediate and a mechanism is proposed for this step based on a kinetic study of the simple coupling reaction of ethyl diazoacetate. The evolution of the Ru-carbene intermediate in the presence of alkenes depends on the nature of the substituents at both the diazo N(2)=C(R(1))R(2) (R(1), R(2) = Ph, H; Ph, CO(2)Me; Ph, Ph; C(R(1))R(2) = fluorene) and the olefin substrates R(3)(H)C=C(H)R(4) (R(3), R(4) = CO(2)Et, CO(2)Et; Ph, Ph; Ph, Me; Ph, H; Me, Br; Me, CN; Ph, CN; H, CN; CN, CN). A remarkable reactivity of the complex was recorded, especially towards unstable aryldiazo compounds and electron-poor olefins. The results obtained indicate that either cyclopropanation or metathesis products can be formed: the first products are favoured by the presence of a cyano substituent at the double bond and the second ones by a phenyl.

Synthesis of Natural-Product-Like Molecules with Over Eighty Distinct Scaffolds

Synthesis of Natural-Product-Like Molecules with Over Eighty Distinct Scaffolds

Synthesis and Structural Characterization of Constrained-Geometry Organolanthanide Chlorides and Alkyls Incorporating the Ligand [η5:σ-(C9H6)C2B10H10]2−

Interaction of 1-indenyl-1,2-carborane (1) with 2 equiv of KH in refluxing THF gave the dipotassium salt [K2][(C9H6)C2B10H10]. Treatment of [K2][(C9H6)C2B10H10] with 1 equiv of LnCl3 in THF generated the ionic complex [K(THF)6][{η5:σ-(C9H6)C2B10H10}2La(THF)] (2) for early lanthanide or organolanthanide chloride complexes [{η5:σ-(C9H6)C2B10H10}Ln(THF)2(μ-Cl)2K(THF)2]2 (Ln = Y (3a), Gd (3b), Er (3c), Yb (3d)) for late lanthanides. Reaction of 3 with nucleophile NaCp or KCH2C6H4-o-NMe2 afforded the corresponding salt metathesis products [η5:σ-(C9H6)C2B10H10]Ln(η5-C5H5)(THF)2 (Ln = Y (4a), Gd (4b)) or [η5:σ-(C9H6)C2B10H10]Ln(CH2C6H4-o-NMe2)(DME) (Ln = Y (5a), Er (5c)), respectively. Complexes 5 were also synthesized via the alkane elimination reaction of 1-indenyl-1,2-carborane with Ln(CH2C6H4-o-NMe2)3. They represent the first examples of organolanthanide alkyl complexes incorporating a carboranyl ligand. These complexes were fully characterized by various spectroscopic techniques and elemental analyses. Som...

Gas-phase metathesis of 1-hexene over a WO3/SiO2 catalyst: Search for optimal reaction conditions

Abstract The performance of an 8 wt% WO3/SiO2 catalyst has been investigated for the metathesis of 1-hexene in a gas-phase fixed-bed reactor. The operating conditions (reaction temperature, feed composition and space time) were optimized for the yield of decene, the primary metathesis product, using a full factorial experimental design and a probabilistic two-factor search. A combined sequence of oxidative and reductive catalyst pre-treatments, followed by a nitrogen purge, led to the best yields of decene. It was found that at 380 °C, with 55 mol% 1-hexene in the feed and at 2874 g min mol−1, a decene yield of 12.8% can be obtained, with a 1-hexene conversion of 94%. Pre-treatment of the catalyst with only hydrogen and nitrogen resulted in a lower conversion of 1-hexene, selectivity and yield of primary products, possibly due to over-reduction of the active tungsten surface phase. Under the experimental conditions employed, the reaction was neither limited by extra- nor intraparticle mass transfer resistance effects.

Stereoselective synthesis of 1,6-dioxaspiro[4.5]decane chiral spiroketal skeleton via C2-symmetric approach using crossmetathesis

A common asymmetric approach for the synthesis of a 1,6-dioxaspiro[4.5]decane chiral spiroketal system, which is a subunit of various natural products, is described and the key aspects of the synthesis are self-crossmetathesis and exploitation of C 2-symmetric of the metathesis product 5 to obtain the required chiral spiroketal.

8‐Amidoquinoline, 8‐(Trialkylsilylamido)quinoline, 2‐Pyridylmethylamide, and (2‐Pyridylmethyl)(trialkylsilyl)amide Complexes of Gallium

AbstractLithium 8‐amidoquinoline (1) and lithium 8‐(trialkylsilylamido)quinoline [SiMe2tBu (2), SiiPr3 (3)] react with dimethylgallium chloride to the metathesis products dimethylgallium 8‐amidoquinoline (4) as well as dimethylgallium 8‐(trialkylsilylamido)quinoline [SiMe2tBu (5), SiiPr3 (6)]. The gallium atoms are in distorted tetrahedral environments. During the synthesis of 5, orange dimethylgallium 2‐butyl‐8‐(tert‐butyldimethylsilylamido)quinoline (7) was found as by‐product. The metathesis reactions of Me2GaCl with LiN(R)CH2Py (Py = 2‐pyridyl) yield the corresponding 2‐pyridylmethylamides Me2Ga‐N(H)CH2Py (8), Me2Ga‐N(SiMe2tBu)CH2Py (9) and Me2Ga‐N(SiiPr3)CH2Py (10). In these complexes the gallium atoms show a distorted tetrahedral coordination sphere. However, derivative 8 crystallizes dimeric with bridging amido units whereas in 9 and 10 the 2‐pyridylmethylamido moieties act as bidentate ligands leading to monomeric molecules.