Asymmetric Synthesis of Densely Functionalized Medium‐Ring Carbocycles and Lactones through Modular Assembly and Ring‐Closing Metathesis of Sulfoximine‐Substituted Trienes and Dienynes

An asymmetric synthesis of densely functionalized 7–11‐membered carbocycles and 9–11‐membered lactones has been developed. Its key steps are a modular assembly of sulfoximine‐substituted C‐ and O‐tethered trienes and C‐tethered dienynes and their Ru‐catalyzed ring‐closing diene and enyne metathesis (RCDEM and RCEYM). The synthesis of the C‐tethered trienes and dienynes includes the following steps: 1) hydroxyalkylation of enantiomerically pure titanated allylic sulfoximines with unsaturated aldehydes, 2) α‐lithiation of alkenylsulfoximines, 3) alkylation, hydroxy‐alkylation, formylation, and acylation of α‐lithioalkenylsulfoximines, and 4) addition of Grignard reagents to α‐formyl(acyl)alkenylsulfoximines. The sulfoximine group provided for high asymmetric induction in steps 1) and 4). RCDEM of the sulfoximine‐substituted trienes with the second‐generation Ru catalyst stereoselectively afforded the corresponding functionalized 7–11‐membered carbocyles. RCDEM of diastereomeric silyloxy‐substituted 1,6,12‐trienes revealed an interesting difference in reactivity. While the (R)‐diastereomer gave the 11‐membered carbocyle, the (S)‐diastereomer delivered in a cascade of cross metathesis and RCDEM 22‐membered macrocycles. RCDEM of cyclic trienes furnished bicyclic carbocycles with a bicyclo[7.4.0]tridecane and bicyclo[9.4.0]pentadecane skeleton. Selective transformations of the sulfoximine‐ and bissilyloxy‐substituted carbocycles were performed including deprotection, cross‐coupling reaction and reduction of the sulfoximine moiety. Esterification of a sulfoximine‐substituted homoallylic alcohol with unsaturated carboxylic acids gave the O‐tethered trienes, RCDEM of which yielded the sulfoximine‐substituted 9–11‐membered lactones. RCEYM of a sulfoximine‐substituted 1,7‐dien‐10‐yne showed an unprecedented dichotomy in ring formation depending on the Ru catalyst. While the second‐generation Ru catalyst gave the 9‐membered exo 1,3‐dienyl carbocycle, the first‐generation Ru catalyst furnished a truncated 9‐membered 1,3‐dieny carbocycle having one CH₂ unit less than the dienyne.     

Ethylene-promoted versus ethylene-free enyne metathesis

The role of ethylene in promoting metathesis of acetylenic enynes is probed within the context of ring-closing enyne metathesis, using first- and second-generation Grubbs catalysts. Under inert atmosphere, rapid catalyst deactivation is observed by calibrated GC-FID analysis for substrates with minimal propargylic bulk. MALDI-TOF mass spectra reveal a Ru(enyne)(2) derivative that exhibits very low reactivity toward both enyne and ethylene. Under ethylene, formation of this species is suppressed. Enynes with bulky propargylic groups are not susceptible to this catalyst deactivation pathway, even under N(2) atmosphere.     

Mechanism of enyne metathesis catalyzed by Grubbs ruthenium-carbene complexes: a DFT study

The complete catalytic cycle of the reaction of alkenes and alkynes to dienes by Grubbs ruthenium carbene complexes has been modeled at the B3LYP/LACV3P**+//B3LYP/LACVP level of theory. The core structures of the substrates and the catalyst were used as models, namely, ethene, ethyne, hept-1-en-6-yne, (Me(3)P)(2)Cl(2)Ru=CH(2), and [C(2)H(4)(NMe)(2)C](Me(3)P)Cl(2)Ru=CH(2). Insight into the electronically most preferred mechanistic pathways was gained for both intermolecular as well as for intramolecular enyne metathesis. Alkene metathesis is predicted to proceed fast and reversible, while the insertion of the alkyne substrate is slower, irreversible, and kinetically regioselectivity determining. Ruthenacyclobut-2-ene structures do not exist as local minima in the catalytic cycle. Instead, vinylcarbene complexes are formed directly. The alkyne insertion step and the cycloreversion of 2-vinyl ruthenacyclobutanes feature comparable predicted overall barriers in intermolecular enyne metathesis. For intramolecular enyne metathesis, a noncyclic alkene fragment of the enyne substrate is first incorporated into the Grubbs catalyst by an alkene metathesis reaction. The subsequent insertion of the alkyne fragment then proceeds intramolecularly. Alkene association, cycloaddition, and cycloreversion to the diene product complex close the catalytic cycle. Rate enhancement by an ethene atmosphere (Mori's conditions) originates from a constantly higher overall alkene concentration that is necessary for the rate-limiting [2 + 2] cycloreversion step to the diene product complex.     

A Fast‐Initiating Ionically Tagged Ruthenium Complex: A Robust Supported Pre‐catalyst for Batch‐Process and Continuous‐Flow Olefin Metathesis

In this study, a new pyridinium‐tagged Ru complex was designed and anchored onto sulfonated silica, thereby forming a robust and highly active supported olefin‐metathesis pre‐catalyst for applications under batch and continuous‐flow conditions. The involvement of an oxazine–benzylidene ligand allowed the reactivity of the formed Ru pre‐catalyst to be efficiently controlled through both steric and electronic activation. The oxazine scaffold facilitated the introduction of the pyridinium tag, thereby affording the corresponding cationic pre‐catalyst in good yield. Excellent activities in ring‐closing (RCM), cross (CM), and enyne metathesis were observed with only 0.5 mol % loading of the pre‐catalyst. When this powerful pre‐catalyst was immobilized onto a silica‐based cationic‐exchange resin, a versatile catalytically active material for batch reactions was generated that also served as fixed‐bed material for flow reactors. This system could be reused at 1 mol % loading to afford metathesis products in high purity with very low ruthenium contamination under batch conditions (below 5 ppm). Scavenging procedures for both batch and flow processes were conducted, which led to a lowering of the ruthenium content to as little as one tenth of the original values.     

Application of a Grubbs–Hoveyda Metathesis Catalyst Noncovalently Immobilized by Fluorous–Fluorous Interactions

A Grubbs–Hoveyda metathesis catalyst bearing a tris(perfluoroalkyl)silyl tag for efficient noncovalent attachment to fluorous silica gel (FSG) was synthesized and employed in ring‐closing metathesis (RCM) reactions in CH₂Cl₂. After the reaction, a solvent switch to a polar system allowed for recovery of the catalyst by filtration and its reuse. The approach was demonstrated for a number of different substrates. Furthermore, it was shown that the application of this catalytic system yielded products with low ruthenium content.     

Immobilization of the Grubbs second-generation ruthenium-carbene complex on poly(ethylene glycol): a highly reactive and recyclable catalyst for ring-closing and cross-metathesis

A poly(ethylene glycol)-bound Hoveyda-Grubbs Ru catalyst derived from the Grubbs second-generation Ru carbene complex was synthesized and shown to be highly reactive in the ring-closing metathesis of a wide variety of diene substrates, yielding di-, tri-, and tetra-substituted carbocyclic and heterocyclic olefins. The immobilized catalyst also proved to be highly reactive and recyclable in cross-metathesis and ring-opening/cross-metathesis. In all cases tested, the catalyst exhibited a high level of recyclability and reusability.     

Zirconium-mediated metathesis of imines: a study of the scope, longevity, and mechanism of a complicated catalytic system

By kinetically stabilizing imidozirconocene complexes through the use of a sterically demanding ligand, or by generating a more thermodynamically stable resting state with addition of diphenylacetylene, we have developed transition metal-catalyzed imine metathesis reactions that are mechanistically analogous to olefin metathesis reactions catalyzed by metal carbene complexes. When 5 mol % of Cp*Cp(THF)Zr=N(t)Bu is used as the catalyst precursor in the metathesis reaction between PhCH=NPh and p-TolCH=N-p-Tol, a 1:1:1:1 equilibrium mixture with the two mixed imines p-TolCH=NPh and PhCH=N-p-Tol is generated in C(6)D(6) at 105 degrees C. The catalyst was still active after 20 days with an estimated 847 turnovers (t(1/2) 170 m; TON = 1.77 h(-1)). When the azametallacyclobutene Cp(2)Zr(N(Tol)C(Ph)=C(Ph)) is used as the catalyst precursor under similar reaction conditions, a total of 410 turnovers are obtained after 4 days (t(1/2) 170 m; TON = 4.3 h(-1)). An extensive kinetic and equilibrium analysis of the metallacyclobutene-catalyzed metathesis of PhCH=N-p-Tol and p-F-C(6)H(4)CH=N-p-F-C(6)H(4) was carried out by monitoring the concentrations of imines and observable metal-containing intermediates over time. Numerical integration methods were used to fit these data to a detailed mechanism involving coordinatively unsaturated (16-electron) imido complexes as critical intermediates. Examination of the scope of reaction between different organic imines revealed characteristic selectivity that appears to be unique to the zirconium-mediated system. Several zirconocene complexes that could generate the catalytically active "CpCp'Zr=NAr" (Cp' = Cp or Cp*) species in situ were found to be effective agents in the metathetical exchange between different N-aryl imines. N-Alkyl aldimines were found to be completely unreactive toward metathesis with N-aryl aldimines, and metathesis reactions involving the two N-alkyl imines TolCH=NPr and PhCH=NMe gave slow or erratic results, depending on the catalyst used. Metathesis was observed between N-aryl ketimines and N-aryl aldimines, but for N-aryl ketimine substrates, the catalyst resting state consists of zirconocene enamido complexes, generated by the formal C-H activation of the alpha position of the ketimine substrates.     

The influence of electronic modifications on rotational barriers of bis‐NHC‐complexes as observed by dynamic NMR spectroscopy

There has been much debate about the σ‐donor and π‐acceptor properties of N‐heterocyclic carbenes (NHCs). While a lot of synthetic modifications have been performed with the goal of optimizing properties of the catalyst to tune reactivity in various transformations (e.g. metathesis), direct methods to characterize σ‐donor and π‐acceptor properties are still few. We believe that dynamic NMR spectroscopy can improve understanding of this aspect. Thus, we investigated the intramolecular dynamics of metathesis precatalysts bearing two NHCs. We chose four systems with one identical NHC ligand (N,N′‐Bis(2,4,6‐trimethylphenyl)‐imidazolinylidene (SIMes) in all four cases) and NHC_ewg ligands bearing four different electron‐withdrawing groups (ewg). Both rotational barriers of the respective Ru‐NHC‐bonds change significantly when the electron density of one of the NHCs (NHC_ewg) is modified. Although it is certainly not possible to fully dissect σ‐donor and π‐acceptor portions of the bonding situations in the respective Ru‐NHC‐bond via dynamic NMR spectroscopy, our studies nevertheless show that the analysis of the rotation around the Ru‐SIMes‐bond can be used as a spectroscopic parameter complementary to cyclic voltammetry. Surprisingly, we observed that the rotation around the Ru‐NHC_ewg‐bond shows the same trend as the initiation rate of a ring‐closing metathesis of the four investigated bis‐NHC‐complexes. Copyright © 2013 John Wiley & Sons, Ltd.     

Direct observation of a 14-electron ruthenacyclobutane relevant to olefin metathesis

The 14-electron ruthenium phosphonium alkylidene complex [(IH2Mes)Cl2Ru=CH(PCy3)][B(C6F5)4], 1b, a highly active olefin metathesis catalyst, reacts with stoichiometric quantities of ethylene at -50 degrees C in CD2Cl2 to generate the ruthenacyclobutane complex [(IH2Mes)Cl2RuCH2CH2CH2], 2, and [CH2=CH(PCy3)][B(C6F5)4] in quantitative yield by NMR spectroscopy. 1H and 13C NMR spectroscopies on 2 and 2-13C3 are consistent with a symmetrical C2v structure, providing the first experimental information concerning this crucial intermediate in ruthenium-mediated olefin metathesis. At -50 degrees C, exchange with free ethylene takes place on the chemical time scale. Complex 2 decomposes in solution upon warming to room temperature, generating propene and unknown ruthenium product(s).     

Aminocarbonyl group containing Hoveyda-Grubbs-type complexes: synthesis and activity in olefin metathesis transformations

Three novel "boomerang" precatalysts bearing different aminocarbonyl functions are reported. Comparative kinetic studies show that this functional group allows for a control of the catalytic activity in metathesis transformations. The scope of the more active catalyst is investigated and shows a good tolerance to various substrates in ring-closing metathesis, enyne metathesis, and cross metathesis. ICP-MS analyses illustrate the good affinity of this catalyst for silica gel, as levels of Ru contamination lower than 6 ppm are detected in the final products.     

Synthesis and reactivity of homogeneous and heterogeneous ruthenium-based metathesis catalysts containing electron-withdrawing ligands

The synthesis and heterogenization of new Grubbs-Hoveyda type metathesis catalysts by chlorine exchange is described. Substitution of one or two chlorine ligands with trifluoroacetate and trifluoromethanesulfonate was accomplished by reaction of [RuCl(2)([double bond]CH-o-iPr-O-C(6)H(4))(IMesH(2))] (IMesH(2) = 1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene) with the silver salts CF(3)COOAg and CF(3)SO(3)Ag, respectively. The resulting compounds, [Ru(CF(3)SO(3))(2)([double bond]CH-o-iPr-O-C(6)H(4))(IMesH(2))] (1), [RuCl(CF(3)SO(3))([double bond]CH-o-iPr-O-C(6)H(4))(IMesH(2))] (2), and [Ru(CF(3)CO(2))(2)([double bond]CH-o-iPr-O-C(6)H(4))(IMesH(2))] (3) were found to be highly active catalysts for ring-closing metathesis (RCM) at elevated temperature (45 degrees C), exceeding known ruthenium-based catalysts in catalytic activity. Turn-over numbers (TONs) up to 1800 were achieved in RCM. Excellent yields were also achieved in enyne metathesis and ring-opening cross metathesis using norborn-5-ene and 7-oxanorborn-5-ene-derivatives. Even more important, 3 was found to be highly active in RCM at room temperature (20 degrees C), allowing TONs up to 1400. Heterogeneous catalysts were synthesized by immobilizing [RuCl(2)([double bond]CH-o-iPr-O-C(6)H(4))(IMesH(2))] on a perfluoroglutaric acid derivatized polystyrene-divinylbenzene (PS-DVB) support (silver form). The resulting supported catalyst [RuCl(polymer-CH(2)-O- CO-CF(2)-CF(2)-CF(2)-COO)([double bond]CH-o-iPr-O-C(6)H(4))(IMesH(2))] (5) showed significantly reduced activities in RCM (TONs = 380) compared with the heterogeneous analogue of 3. The immobilized catalyst, [Ru(polymer-CH(2)-O-CO-CF(2)-CF(2)-CF(2)-COO)(CF(3)CO(2))([double bond]CH-o-iPr-O-C(6)H(4))(IMesH(2))] (4) was obtained by substitution of both Cl ligands of the parent Grubbs-Hoveyda catalyst by addition of CF(3)COOAg to 5. Compound 4 can be prepared in high loadings (160 mg catalyst g(-1) PS-DVB) and possesses excellent activity in RCM with TONs up to 1100 in stirred-batch RCM experiments. Leaching of ruthenium into the reaction mixture was unprecedentedly low, resulting in a ruthenium content <70 ppb (ng g(-1)) in the final RCM-derived products.     

Selective synthesis of chiral dioxabicyclo[4.4.0]decane and dioxabicyclo[5.3.0]decane from 3,4-bisallyloxy-but-1-yne derivatives via ruthenium-catalyzed en-yn-ene metathesis

We prepared a series of chiral 3,4-bisallyloxy-but-1-ynes having syn and anti configurations. Treatment of these substrates with Grubbs catalyst Cl2(PCy3)2Ru=CHPh (3 mol %) preferably gave chiral dioxabicyclo[4.4.0]decane (yields > 55%) in addition to dioxabicyclo[5.3.0]decane in minor proportions. On substitution of the 4-allyloxy group of these substrates with a 4-but-2-enyloxy group, the metathesis reactions produced only dioxabicyclo[5.3.0]decane in the presence of Grubbs ruthenium-imidazolidene carbene catalyst.     

A new concept for the noncovalent binding of a ruthenium-based olefin metathesis catalyst to polymeric phases: preparation of a catalyst on Raschig rings

A new concept for noncovalent immobilization of a ruthenium olefin metathesis catalyst is presented. The 2-isopropoxybenzylidene ligand of a Hoveyda-Grubbs carbene is further modified by an additional amino group (7) and immobilization is achieved by treatment with sulfonated polystyrene forming the corresponding ammonium salt. In this novel strategy for the immobilization of ruthenium-based metathesis catalysts, the amino group plays a two-fold role, being first an active anchor for immobilization and second, after protonation, activating the catalysts (electron donating to electron withdrawing activity switch). The polymeric support was prepared by precipitation polymerization which led to small bead sizes (0.2-2 microm) and large surface areas. Compared to commercial resins this tailor-made phase showed superior properties in immobilization of complex 7. This concept of immobilization was applied to glass-polymer composite megaporous Raschig rings. Ru catalyst 7 on Raschig rings was used under batch conditions in various metathesis reactions, including ring-closing (RCM), cross- (CM) and enyne metathesis, to give products of high chemical purity with very low ruthenium contamination levels (21-102 ppm). The same ring can be used for up to 6 cycles of metathesis.     

1,3-二(2,6-二甲基苯基)-2-四氢咪唑基-苯亚甲基-二吡啶基-二氯合钌 化合物的合成

设计了由1,3-二(2,6-二甲基苯基)-2-四氢咪唑基-苯亚甲基-三苯基膦-二氯合钌(7)和吡啶反应生成无膦型金属钌卡宾化合物1,3-二(2,6-二甲苯基)-2-四氢咪唑基-苯亚甲基-2-吡啶基-二氯合钌(8), 8作为高效催化剂用于丙烯腈和烯丙基苯的交叉交互置换反应. 新化合物7, 8经核磁共振氢谱、碳谱和高分辨率质谱予以证实.     

Highly active trialkoxymolybdenum(VI) alkylidyne catalysts synthesized by a reductive recycle strategy

A systematic study of alkyne metathesis catalyzed by trialkoxymolybdenum(VI) alkylidyne complexes is reported, in which substrate functional groups, alkynyl substituents, and catalyst ligands are varied. Sterically hindered trisamidomolybdenum(VI) propylidyne complex 5 was prepared conveniently through a previously communicated reductive recycle strategy. Alcoholysis of 5 with various phenols/alcohols provides a set of active catalysts for alkyne metathesis at room temperature, among which the catalyst with p-nitrophenol as ligand shows the highest catalytic activity and is compatible with a variety of functional groups and solvents. A key finding that enabled the use of highly active molybdenum(VI) catalysts is replacement of the commonly used propynyl substituents on the starting alkyne substrates with butynyl groups. Under reduced pressure using 1,2,4-trichlorobenzene as an involatile solvent, the alkyne metathesis of butynyl substituted compounds proceeds well at 30 degrees C providing high yields (83%-97%) of dimers. Rationalization of the special role played by butynyl substrates is discussed.     

Olefin metathesis featuring ruthenium indenylidene complexes with a sterically demanding NHC ligand

The synthesis and characterization of two new ruthenium indenylidene complexes [RuCl(2)(SIPr)(Py)(Ind)] 6 and [RuCl(2)(SIPr)(3-BrPy)(Ind)] 7 featuring the sterically demanding N-heterocyclic carbene 1,3-bis(2,6-di isopropylphenyl)-4,5-dihydroimidazol-2-ylidene (SIPr) are reported. Remarkable activity was observed with these complexes in ring closing, enyne, and cross metathesis of olefins at low catalyst loadings. The performance of SIPr-bearing complexes 6 and 7 as well as [RuCl(2)(SIPr)(PCy(3))(Ind)] 5 in ring opening metathesis polymerization is also disclosed. This work highlights the enormous influence of the neutral "spectator" ligands on catalyst activity and stability.     

1,3-二(2,6-二甲基苯基)-2-四氢咪唑基-苯亚甲基-二吡啶基-二氯合钌化合物的合成

设计了由1,3-二(2,6-二甲基苯基)-2-四氢咪唑基-苯亚甲基-三苯基膦-二氯合钌(7)和吡啶反应生成无膦型金属钌卡宾化合物1,3-二(2,6-二甲苯基)-2-四氢咪唑基-苯亚甲基-2-吡啶基-二氯合钌(8),8作为高效催化剂用于丙烯腈和烯丙基苯的交叉交互置换反应.新化合物7,8经核磁共振氢谱、碳谱和高分辨率质谱予以证实.     

A simple and practical phase-separation approach to the recycling of a homogeneous metathesis catalyst

The air stable asarone-derived Ru carbene 16, a robust olefin metathesis catalyst, can be easily separated after reaction by deposition on silica gel and reused up to nine times. This procedure provides products of excellent purity with low Ru content.     

Mechanism and activity of ruthenium olefin metathesis catalysts: the role of ligands and substrates from a theoretical perspective

The reaction mechanism of olefin metathesis by ruthenium carbene catalysts is studied by gradient-corrected density functional calculations (BP86). Alternative reaction mechanisms for the reaction of the "first-generation" Grubbs-type catalyst (PCy(3))(2)Cl(2)Ru=CH(2) (1) for the reaction with ethylene are studied. The most likely dissociative mechanism with trans olefin coordination is investigated for the metathesis reaction between the "first-" and the "second-generation" Grubbs-type catalysts 1 and (H(2)IMes)(PCy(3))Cl(2)Ru=CH(2) (2) with different substrates, ethylene, ethyl vinyl ether, and norbornene, and a profound influence of the substrate is found. In contrast to the degenerate reaction with ethylene, the reactions with ethyl vinyl ether and norbornene are strongly exergonic by 8-15 kcal/mol, and this excess energy is released after passing through the metallacyclobutane structure. While the metallacyclobutane is in a deep potential minimum for degenerate metathesis reactions, the energy barrier for the [2+2] cycloreversion vanishes for the most exergonic reactions. On the free energy surface under typical experimental conditions, the rate-limiting steps for the overall reactions are then either metallacyclobutane formation for 1 or phosphane ligand dissociation for 2.     

A pyridine-containing ruthenium–indenylidene complex: Synthesis and activity in ring-closing metathesis

The reaction of Cl₂Ru(PCy₃)₂(3-phenylindenylidene) with excess pyridine leads to the new pyridine-containing ruthenium-based complex: Cl₂Ru(PCy₃)(Py)₂(3-phenylindenylidene) in good yield. This catalyst has been fully characterized and tested in ring-closing metathesis. Its moderate activity has been examined by kinetic studies using several substrates and different reaction conditions.