In situ IR spectroscopy was used to study the kinetics of addition of L = alkyl and aryl isocyanides to the Grubbs second-generation carbene complex Ru(H2IMes)(CHPh)(PCy3)Cl2 (H2IMes = 1,3-dimesityl-4,5-dihydroimidazol-2-ylidene), which triggers carbene insertion into an aromatic ring of the N-heterocyclic carbene supporting ligand, forming Ru{1-mesityl-3-(7′-Ph-2′,4′,6′-trimethylcycloheptatrienyl)-4,5-dihydroimidazol-2-ylidene}L2(PCy3)Cl2. The rate law was determined to be first order in isocyanide concentration and first order in carbene complex concentration. For various isocyanides CNR the rate increases as R = tert-butyl ≪ cyclohexyl < n-octyl < CH2Ph ≈ CH2CO2Me ≈ CH2SO2C6H4-4-Me < C6H4-4-OMe < C6H4-4-Cl. The proposed mechanism involves reversible addition of isocyanide followed by rate-determining, irreversible carbene insertion and subsequent, rapid addition of the second isocyanide. The carbene insertion is accelerated by the electrophilicity of the carbene, which is enhanced due to ligand binding by isocyanides with lower σ-donor/π-acceptor ratios.

The kinetics of intermolecular ene–yne metathesis (EYM) with the Hoveyda precatalyst (Ru1) has been studied. For 1-hexene metathesis with 2-benzoyloxy-3-butyne, the experimental rate law was determined to be first-order in 1-hexene (0.3–4 M), first-order in initial catalyst concentration, and zero-order for the terminal alkyne. At low catalyst concentrations (0.1 mM), the rate of precatalyst initiation was observed by UV–vis and the alkyne disappearance was observed by in situ FT-IR. Comparison of the rate of precatalyst initiation and the rate of EYM shows that a low, steady-state concentration of active catalyst is rapidly produced. Application of steady-state conditions to the carbene intermediates provided a rate treatment that fit the experimental rate law. Starting from a ruthenium alkylidene complex, competition between 2-isopropoxystyrene and 1-hexene gave a mixture of 2-isopropoxyarylidene and pentylidene species, which were trappable by the Buchner reaction. By varying the relative concentration of these alkenes, 2-isopropoxystyrene was found to be 80 times more effective than 1-hexene in production of their respective Ru complexes. Buchner-trapping of the initiation of Ru1 with excess 1-hexene after 50% loss of Ru1 gave 99% of the Buchner-trapping product derived from precatalyst Ru1. For the initiation process, this shows that there is an alkene-dependent loss of precatalyst Ru1, but this does not directly produce the active catalyst. A faster initiating precatalyst for alkene metathesis gave similar rates of EYM. Buchner-trapping of ene–yne metathesis failed to deliver any products derived from Buchner insertion, consistent with rapid decomposition of carbene intermediates under ene–yne conditions. An internal alkyne, 1,4-diacetoxy-2-butyne, was found to obey a different rate law. Finally, the second-order rate constant for ene–yne metathesis was compared to that previously determined by the Grubbs second-generation carbene complex: Ru1 was found to promote ene–yne metathesis 62 times faster at the same initial precatalyst concentration.

A Ru-carbene-promoted ring expansion of bicyclo[3.1.0]hexenes with terminal alkynes is reported. The reaction delivers seven-membered carbocycles starting from readily available starting materials and was found to be highly regioselective. The resulting seven-membered ring products contain both conjugated diene and cyclopropane substructures that could be selectively reacted in subsequent transformations.

The total synthesis of amphidinolide P was achieved through two different ene–yne metathesis approaches. In each approach, the metathesis step was performed at late stages in the synthesis with all other functionality present. By forging two successful pathways to the synthesis of 1, some of the strengths and weaknesses of metathesis-intensive synthetic strategies were identified.

Ene–yne cross metathesis was assessed for use as a key fragment coupling in a planned total synthesis of amphidinolide P. A terminal alkyne containing a β,γ-epoxide was synthesized and employed as the alkyne partner in an intermolecular ene–yne metathesis. In the alkene substrate, optimal functionality and reaction conditions were determined. An unprotected allyl alcohol was found to be critical for both high yield and high E-selectivity. Fewer equivalents of the alkene resulted in incomplete reaction and side reactions consumed the terminal alkyne. The best ruthenium carbene precatalysts were found to be the Hoveyda–Grubbs carbene complexes.

With cationic gold catalysts, internal alkynes bearing both propargylic acyloxy groups and tosylamide pronucleophiles were found to cyclize to give either five- or six-membered ring nitrogen heterocycles. A wide variety of gold catalysts, counterions, and solvents were examined to elucidate their effect on product distribution. In most cases, the direct 5-endo-dig cyclization was found to be the major pathway leading to good yields of dehydropyrrolidine products. Alkyne substrates bearing additional normal alkyl substituents at the propargylic position gave dehydropiperidines as the major product. This pathway is thought to proceed by way of a 1,2- Rautenstrauch rearrangement to produce a vinyl gold(I) carbene, which undergoes conjugate addition by the nitrogen pronucleophile. Structural and electronic factors were studied in the nitrogen pronucleophile and in the migrating acyloxy group. Each was found to have a minor effect on the product ratio.

Ruthenium hydrides were found to promote the positional isomerization of 1,3-dienes into more highly substituted 1,3-dienes in a stereoconvergent manner. The reaction can be conducted in one pot starting with terminal alkynes and alkenes by triggering decomposition of the Grubbs catalyst into a ruthenium hydride, which promotes the dienyl isomerization. The presence of an alcohol additive plays a helpful role in the reaction, significantly increasing the chemical yields. Mechanistic studies are consistent with hydrometalation of the geminally substituted alkene of the 1,3-diene and transit of the ruthenium atom across the diene framework via a π-allylruthenium intermediate.

Reaction kinetics and mechanistic studies for ethylene–internal alkyne metathesis promoted by the phosphine-free initiator Ru1 (Piers’s catalyst) is described. The kinetic order of reactants and catalyst was determined. The effect of ethylene was studied at different solution concentrations using ethylene gas mixtures applied at constant pressure. Unlike earlier studies with the second-generation Grubbs complex, ethylene was found to show an inverse first-order rate dependence. Under catalytic conditions, a ruthenacyclobutane intermediate was observed by proton NMR spectroscopy at low temperature. Combined with the kinetic study, these data suggest a catalytic cycle involving a reactive LnRu═CH2 species in equilibrium with ethylene to form a ruthenacyclobutane, a catalyst resting state. Rates were determined for a variety of internal alkynes of varying substitution. Also, at low ethylene pressures, preparative syntheses of several 2,3-disubstituted 1,3-butadienes were achieved. Using the kinetic method, several phosphine-free inhibitors were examined for their ability to promote ethylene–alkyne metathesis and to guide selection of the optimal catalyst.

A solid-supported isocyanide ligand was developed to destroy active metathesis catalysts and to remove ruthenium byproducts from metathesis reactions. This method was able to significantly reduce the concentration of residual ruthenium from the organic products of several alkene and ene–yne metathesis reactions, under a variety of different conditions.

A relay strategy was employed to achieve an intermolecular ene–yne metathesis between 1,1-disubstituted alkenes and alkynes. The relay serves to activate an unreactive alkene which will not participate in ene-yne metathesis. The new relay cross ene–yne metathesis gives rise to 1,1,3-trisubstituted-1,3-dienes previously inaccessible by direct ene–yne metathesis methods.

The synthesis of β-unsubstituted, anti-allylic alcohols using a catalytic Evans aldol reaction conjoined with a relay-type ring-closing alkene metathesis is reported. The metathesis step serves to remove a β-alkenyl group, which facilitated the aldol step. The β-substituted enals serve as acrolein surrogates. The products were employed in ene–yne cross metathesis.

A cross ene-yne metathesis has been achieved at a nearly 1:1 stoichiometry of the unsaturated reactants. This allowed the use of more complex alkene reactants without sacrificing excess alkene reactant. In the alkene, different allylic oxygen protecting groups were explored. Interestingly, alkenes containing the allylic hydroxyl group proved to be the most reactive.

The kinetics of intermolecular alkene−alkyne (ene-yne) metathesis promoted by the first generation Grubbs catalyst (Cy3P)2Cl2Ru═CHPh (1) were investigated. The dissociated tricyclohexylphosphine plays an important kinetic role during the initial exchange with the terminal alkyne, resulting in a half-order rate dependence on 1 and first-order dependence on the alkyne.

Addition of L = carbon monoxide or aryl isocyanides to the Grubbs second-generation carbene complexes Ru(H2IMes)(CHR)(PCy3)Cl2 (H2IMes = 1,3-dimesityl-4,5-dihydroimidazol-2-ylidene; R = Ph, Me, H, CH=CMe2) triggers carbene insertion into an aromatic ring of the N-heterocyclic carbene supporting ligand, forming Ru{1-mesityl-3-(-7′-R-2′,4′,6′-trimethylcycloheptatrienyl)-4,5-dihydroimidazol-2-ylidene}L2(PCy3)Cl2. Insertions are also promoted for other PR3 substituted complexes by carbon monoxide and aryl isocyanides, and for the phosphine-free Hoveyda−Blechert complex Ru(H2IMes)(CH(i-PrOC6H4))Cl2 by aryl isocyanides and small phosphites but only after initial displacement of the coordinated ether. Heteroatom substituted carbenes do not undergo CO-promoted insertion unless poorer electron donor phosphine (PPh3) and carbene (CH(OC6H4-p-NO2) ligands are both present. Insertion depends on the added ligand, the carbene substituent, and to a lesser degree on the PR3 ligand trans to the N-heterocyclic carbene.

Carbon monoxide or an aryl isocyanide promotes a benzylidene carbene transfer from ruthenium to tricyclohexylphosphine in the first-generation Grubbs carbene complex. The resulting ruthenium(II) complexes have been isolated and structurally characterized by X-ray crystal structure analysis; a probable mechanism for the ligand-promoted transformation is also discussed.