Stereoconvergent Synthesis of Z-1,3-Disubstituted-1,3-Dienes by Uphill Photocatalysis.

A variety of 1-aryl-1,3-dienes were isomerized from E to Z isomers by photocatalysis using Ru(bpy)3 [PF6 ]2 and blue LED light. Enrichment of the Z-isomer is thought to occur by selective triplet energy transfer from the photocatalyst to the stereoisomeric mixture. The 1,3-diene starting materials are easily made by catalytic ene-yne metathesis (EYM). To access 1,3-diene Z-stereoisomers directly, a one pot procedure was developed. Additional 1,3-dienes were investigated for both isomerization and Z-enrichment. The combination of cross EYM with photocatalysis allows for the stereoconvergent synthesis of Z-1,3-dienes.

Preparation of Dienyl Boronates by Tandem Ene-Yne Metathesis/Dienyl Isomerization: Ready Access to Diene Building Blocks for the Synthesis of Polyenes.

The ene-yne metathesis of alkenyl boronates with terminal alkynes is reported. These challenging metatheses were accomplished using a Grubbs catalyst bearing the cyclic alkyl amino carbene (CAAC) ligand, whereas N-heterocyclic carbene (NHC) derived catalysts gave lower yields. Subsequent dienyl isomerization via a cobalt-catalyzed hydrogen atom transfer (HAT) furnished the more substituted dienyl boronate with high EE/EZ ratios. Finally, the resulting dienyl boronate products were successfully used in Suzuki-Miyaura cross-coupling reactions and in a Diels-Alder cycloaddition.

Ene-Yne Metathesis of Allylphosphonates and Allylphosphates: Synthesis of Phosphorus-Containing 1,3-Dienes.

A variety of ene-yne cross metathesis reactions were performed using unsaturated phosphonate and phosphate reagents, affording the corresponding phosphorylated 1,3-diene products in good to excellent yields. These difficult ene-yne metatheses employed a Grubbs catalyst bearing a cyclic amino alkyl carbene ligand. A variety of terminal alkynes of varying substitution underwent the reaction, and different phosphorus-containing alkenes were found to give the conjugated diene products in high yields. The resulting dienes were further transformed by Horner-type Wittig reactions and a Diels-Alder cycloaddition.

A Macrocyclic Ruthenium Carbene for Size-Selective Alkene Metathesis.

The synthesis of a macrocyclic Ru carbene catalyst for selective cross alkene metathesis is reported. The new catalyst showed different reactivity for various type 1 alkenes in homodimerization which correlated with the aggregrate size of the allylic substituent. The altered reactivity profile allowed for selective product formation in competition cross alkene metathesis between two different type 1 alkenes and tert-butyl acrylate. Selectivity in these reactions is attributed to the ability of the macrocyclic catalyst to differentiate alkenes based on their size. Two preparative examples of cross metathesis with the macrocyclic catalyst are also provided.

Mild Isomerization of Conjugated Dienes Using Co-Mediated Hydrogen Atom Transfer.

A mild and high yielding rearrangement of 1,3-disubstituted-1,3-dienes to 1,1,4-trisubstituted-1,3-dienes using a cobaloxime catalyst and a silane cocatalyst is reported. Chiral centers near the conjugated diene were not racemized. Deuterium labeling studies are consistent with a hydrogen atom transfer mechanism, and radical intermediates were found to be accessible due to the observed ring opening of a cyclopropane ring.

Highly Selective Ring Expansion of Bicyclo[3.1.0]hexenes.

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.

From Resting State to the Steady State: Mechanistic Studies of Ene-Yne Metathesis Promoted by the Hoveyda Complex.

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.

Two Ene-Yne Metathesis Approaches to the Total Synthesis of Amphidinolide P.

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.

Gold(I)-promoted heterocyclization of internal alkynes: a comparative study of direct metallate 5-endo-dig cyclization versus a stepwise cyclization.

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.

Inhibitory effect of ethylene in ene-yne metathesis: the case for ruthenacyclobutane resting states.

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 L(n)Ru═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.

Removal of ruthenium using a silica gel supported reagent.

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.

Ruthenium hydride-promoted dienyl isomerization: access to highly substituted 1,3-dienes.

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.

Geminal alkene-alkyne cross metathesis using a relay strategy.

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.

Alkene metathesis approach to ß-unsubstituted anti-allylic alcohols and their use in ene-yne metathesis.

The synthesis of ß-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 ß-alkenyl group, which facilitated the aldol step. The ß-substituted enals serve as acrolein surrogates. The products were employed in ene-yne cross metathesis.

Atom economy in the metathesis cross-coupling of alkenes and alkynes.

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.

Ligand-promoted carbene insertion into the aryl substituent of an N-heterocyclic carbene ligand in ruthenium-based metathesis catalysts.

Addition of L = carbon monoxide or aryl isocyanides to the Grubbs second-generation carbene complexes Ru(H(2)IMes)(CHR)(PCy(3))Cl(2) (H(2)IMes = 1,3-dimesityl-4,5-dihydroimidazol-2-ylidene; R = Ph, Me, H, CH=CMe(2)) 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}L(2)(PCy(3))Cl(2). Insertions are also promoted for other PR(3) substituted complexes by carbon monoxide and aryl isocyanides, and for the phosphine-free Hoveyda-Blechert complex Ru(H(2)IMes)(CH(i-PrOC(6)H(4)))Cl(2) 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 (PPh(3)) and carbene (CH(OC(6)H(4)-p-NO(2)) ligands are both present. Insertion depends on the added ligand, the carbene substituent, and to a lesser degree on the PR(3) ligand trans to the N-heterocyclic carbene.

Enyne metathesis/Brønsted acid-promoted heterocyclization.

The "one-pot" synthesis of nitrogen heterocycles and an oxygen heterocycle by enyne metathesis and in situ cyclization is reported.

Enyne cross-metathesis with strained, geminally-substituted alkenes: direct access to highly substituted 1,3-dienes.

Angle strain in methylene cyclobutane was used to drive a cross-enyne metathesis with 1-alkynes, giving 1,1,3-trisubstituted 1,3-dienes in good isolated yields. An extensive survey of Grubbs' second-generation catalysts led to an optimized reaction conducted at 0 degrees C.

Alkenol-alkyne cross metathesis.

Allyl alcohols and their homologues were used in the enyne cross metathesis to prepare hydroxy-functionalized dienes. An isomerization was found to occur under prolonged heating, and a method for conversion to ( E)-diene product is also reported.