US20040097745A9 - Cross-metathesis reaction of functionalized and substituted olefins using group 8 transition metal carbene complexes as metathesis catalysts - Google Patents

Cross-metathesis reaction of functionalized and substituted olefins using group 8 transition metal carbene complexes as metathesis catalysts Download PDF

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US20040097745A9
US20040097745A9 US10/114,418 US11441802A US2004097745A9 US 20040097745 A9 US20040097745 A9 US 20040097745A9 US 11441802 A US11441802 A US 11441802A US 2004097745 A9 US2004097745 A9 US 2004097745A9
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substituted
group
hydrocarbyl
heteroatom
hydrogen
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US20030100776A1 (en
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Robert Grubbs
Arnab Chatterjee
Tae-Lim Choi
Steven Goldberg
Jennifer Love
John Morgan
Daniel Sanders
Matthias Scholl
F. Toste
Tina Trnka
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California Institute of Technology CalTech
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Definitions

  • This invention relates generally to a method for carrying out an olefin metathesis reaction using a Group 8 transition metal complex as a catalyst, and more particularly relates to a method for carrying out cross-metathesis reactions using the aforementioned catalyst wherein at least one of the olefinic reactants is a functionalized olefin, a geminal disubstituted olefin, a trisubstituted olefin, and/or a quaternary allylic olefin.
  • Methods are also provided for the catalysis of stereoselective olefin metathesis reactions, and for the creation of chemical diversity by carrying out a plurality of olefin metathesis reactions using a single olefinic substrate and different metathesis partners, to generate a plurality of structurally distinct products.
  • M is a Group 8 transition metal such as ruthenium or osmium
  • X and X′ are anionic ligands
  • L and L′ are neutral electron donors
  • metathesis catalysts have been prepared with phosphine ligands, e.g., triphenylphosphine or dimethylphenylphospine, exemplified by the well-defined, metathesis-active ruthenium alkylidene complexes (II) and (III)
  • N-heterocyclic carbene ligands offer many advantages, including readily tunable steric bulk, vastly increased electron donor character, and compatibility with a variety of metal species.
  • replacement of one of the phosphine ligands in these complexes significantly improves thermal stability.
  • the vast majority of research on these carbene ligands has focused on their generation and isolation, a feat finally accomplished by Arduengo and coworkers within the last ten years (see, e.g., Arduengo et al. (1999) Acc. Chem. Res. 32:913-921).
  • Representative of these second generation catalysts are the four ruthenium complexes (IVA), (IVB), (VA) and (VB):
  • IesH 2 represents 1,3-dimesityl-4,5-dihydroimidazol-2-ylidene
  • transition metal carbene complexes particularly those containing a ligand having the 4,5-dihydroimidazol-2-ylidene structure, such as in IMesH 2 , have been found to address a number of previously unsolved problems in olefin metathesis reactions, particularly cross-metathesis reactions. These problems span a variety of reactions and starting materials. The following discussion focuses on representative problems in the art that have now been addressed by way of the present invention.
  • Olefinic Phosphonates and Other Functionalized Olefins as Cross-Metathesis Reactants Olefins that contain phosphonate functionality are used extensively in synthetic organic chemistry. For example, allylic phosphonates are employed in the preparation of dienes and polyenes by Horner-Emmons olefination, providing products with improved stereoselectivity as compared to the corresponding phosphonium salts; see Crombie et al. (1969) J. Chem. Soc., Chem. Commun. at 1024; and Whang et al. (1992) J. Org. Chem. 56 :7177.
  • Vinylphosphonates are important synthetic intermediates and have been investigated as biologically active compounds. Vinylphosphonates have been used as intermediates in stereoselective synthesis of trisubstituted olefins and in heterocycle synthesis; see Shen et al. (2000) Synthesis, p. 99; Tago et al. (2000) Org. Lett. 2:1975; Kouno et al. (1998) J. Org. Chem. 63:6239; and Kouno et al. (2000) J. Org. Chem. 65:4326. The synthesis of vinylphosphonates has also been widely examined and a variety of non-catalytic approaches have been described in the literature.
  • Recent metal-catalyzed methods include palladium catalyzed cross-coupling (see, e.g., Holt et al. (1989), Tetrahedron Lett. 30:5393; Han et al. (1996), J. Am. Chem. Soc. 118:1571; Kazankova et al. (1999), Tetrahedron Lett. 40:569; Okauchi et al. (1999), Tetrahedron Lett. 40:5337; Zhong et al. (2000), Synth. Commun. 30:273; and Han et al. (2000), J. Am. Chem. Soc.
  • the invention in one embodiment, is directed to this pressing need in the art, and provides a method that not only accomplishes the aforementioned goals, but is also useful in a more generalized process for creating functional group diversity in a population of olefinic products prepared using cross-metathesis.
  • Trisubstituted and quaternary allylic olefinic substituents are, of course, present in a diverse array of organic molecules, including pharmaceuticals, natural products, and functionalized polymers, and the difficulty in generating such compounds has been a substantial limitation.
  • the methodology of the present invention overcomes this limitation and now provides an efficient and versatile way to synthesize 1,1,2-trisubstituted olefins as well as 1,2-disubstituted olefins containing one quaternary allylic carbon atom.
  • the present invention is addressed to the aforementioned needs in the art, and provides a novel process for using certain Group 8 transition metal complexes to catalyze a variety of olefin metathesis reactions, primarily cross-metathesis reactions.
  • the complexes used are metal carbenes comprised of a Group 8 transition metal, particularly ruthenium or osmium, which preferably, although not necessarily, contain an N-heterocyclic carbene ligand.
  • Such complexes are highly active catalysts of olefin metathesis reactions, including the cross-metathesis reactions described in detail herein.
  • the present complexes allow an olefinic reactant to be substituted with a functional group without compromising the efficiency or selectivity of a metathesis reaction involving that olefin.
  • the present invention also allows the second reactant, i.e., the olefin metathesis partner, to be substituted with a functional group.
  • the functional group may or may not be a ligand for the metal complex; the present method is not limited in this regard.
  • the olefinic reactant may also be di-substituted at one of the olefinic carbon atoms, as is the case with 2-methyl-2-butene, for example, or may be a quaternary allylic olefin, i.e., an olefin directly substituted at one or both of the olefinic carbon atoms with the moiety -CH 2 -CR 3 where R is other than hydrogen.
  • M is a Group 8 transition metal, particularly Ru or Os;
  • X 1 and X 2 may be the same or different, and are anionic ligands or polymers
  • R 1 is selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl, substituted heteroatom-containing hydrocarbyl, and carboxyl;
  • R 2 is selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl, and substituted heteroatom-containing hydrocarbyl;
  • L is a neutral electron donor ligand
  • L 1 is a neutral electron donor ligand having the structure of formula (VII)
  • X and Y are heteroatoms selected from N, O, S, and P;
  • p is zero when X is O or S, and is 1 when X is N or P;
  • q is zero when Y is O or S, and is 1 when Y is N or P;
  • Q 1 , Q 2 , Q 3 , and Q 4 are linkers, e.g., hydrocarbylene (including substituted hydrocarbylene, heteroatom-containing hydrocarbylene, and substituted heteroatom-containing hydrocarbylene, such as substituted and/or heteroatom-containing alkylene) or —(CO)—;
  • linkers e.g., hydrocarbylene (including substituted hydrocarbylene, heteroatom-containing hydrocarbylene, and substituted heteroatom-containing hydrocarbylene, such as substituted and/or heteroatom-containing alkylene) or —(CO)—;
  • w, x, y and z are independently zero or 1;
  • R 3 , R 3A , R 4 , and R 4A are independently selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl, and substituted heteroatom-containing hydrocarbyl,
  • any two or more of X 1 , X 2 , L, R 1 , R 2 , R 3 , R 3A , R 4 , and R 4A can be taken together to form a chelating multidentate ligand.
  • L is an N-heterocyclic carbene having the structure of formula (VIIA)
  • R 3 and R 4 are defined above, with preferably at least one of R 3 and R 4 , and more preferably both R 3 and R 4 , being alicyclic or aromatic of one to about five rings, and optionally containing one or more heteroatoms and/or substituents.
  • Q is a linker, typically a hydrocarbylene linker, including substituted hydrocarbylene, heteroatom-containing hydrocarbylene, and substituted heteroatom-containing hydrocarbylene linkers, wherein two or more substituents on adjacent atoms within Q may also be linked to form an additional cyclic structure, which may be similarly substituted to provide a fused polycyclic structure of two to about five cyclic groups.
  • Q is often, although again not necessarily, a two-atom linkage or a three-atom linkage. Accordingly, the metal carbene complex of formula (VIA) may also be represented as follows:
  • a method for synthesizing olefins substituted with a functional group by cross-metathesis using a Group 8 transition metal catalyst having the structure of formula (VI).
  • At least one of the two olefinic reactants is substituted with one or more functional groups, which may or may not be in protected form (e.g., a hydroxyl group may be protected as an acyloxy or benzyloxy group). More specifically, at least one of the two olefinic reactants has the structure of formula (VIII)
  • Fn is a functional group such as phosphonato, phosphoryl, phosphanyl, phosphino, sulfonato, C 1 -C 20 alkylsulfanyl, C 5 -C 20 arylsulfanyl, C 1 -C 20 alkylsulfonyl, C 5 -C 20 arylsulfonyl, C 1 -C 20 alkylsulfinyl, C 5 -C 20 arylsulfinyl, sulfonamido, amino, amido, imino, nitro, nitroso, hydroxyl, C 1 -C 20 alkoxy, C 5 -C 20 aryloxy, C 2 -C 20 alkoxycarbonyl, C 5 -C 20 aryloxycarbonyl, carboxyl, carboxylato, mercapto, formyl, C 1 -C 20 thioester, cyano, cyanato,
  • n is zero or 1;
  • Z is a hydrocarbylene or a substituted and/or heteroatom-containing hydrocarbylene linking group such as an alkylene, substituted alkylene, heteroalkylene, substituted heteroalkene, arylene, substituted arylene, heteroarylene, or substituted heteroarylene linkage; and
  • R 5 , R 6 , and R 7 are independently selected from the group consisting of hydrogen, -(Z) n -Fn, hydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl, and substituted heteroatom-containing hydrocarbyl, and, if substituted hydrocarbyl or substituted heteroatom-containing hydrocarbyl, wherein one or more of the substituents may be -(Z) n -Fn.
  • Fn is a phosphonate and Z is CH 2 , such that the reactant is an allylphosphonate (when n is 1) and a vinylphosphonate (when n is zero).
  • the product of the cross-metathesis reaction is also an olefin substituted with a -(Z) n -Fn group.
  • a method for synthesizing directly halogenated olefins by cross-metathesis using a catalyst having the structure of formula (VI).
  • a catalyst having the structure of formula (VI) having the structure of formula (VI).
  • at least one of the olefinic reactants has the structure of formula (IX)
  • X 3 is halo
  • R 8 , R 9 , and R 10 are independently selected from the group consisting of hydrogen, halo, hydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl, substituted heteroatom-containing hydrocarbyl, and -(Z) n -Fn where n, Z and Fn are as defined above.
  • a method for synthesizing substituted olefins, particularly trisubstituted and quaternary allylic olefins, wherein the method comprises using the complex of formula (VI) to catalyze a cross-metathesis reaction between a geminal disubstituted olefin or a quaternary allylic olefin, and a second olefin. If it is a geminal disubstituted olefin, the first olefin has the structure (X)
  • R 11 , R 12 , R 13 , and R 14 are selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl, substituted heteroatom-containing hydrocarbyl, and -(Z) n -Fn where n, Z and Fn are as defined above, with the proviso that R 11 and R 12 , or R 13 and R 14 , are other than hydrogen. If it is a quaternary allylic olefin, the first olefin has the structure (XI)
  • R 11 and R 12 are as defined previously, and R 15 , R 16 , and R 17 are any nonhydrogen substituents, e.g., alkyl, aryl, heteroalkyl, heteroaryl, -(Z) n -Fn (where n, Z, and Fn are as defined above with respect to formula (VIII)), or the like.
  • the second olefin has a molecular structure given by R 18 R 19 C ⁇ CR 20 R 21 wherein R 18 , R 19 , R 20 , and R 21 may be hydrogen, hydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl, substituted heteroatom-containing hydrocarbyl, -(Z) n -Fn, etc.
  • R 18 , R 19 , R 20 , and R 21 may be hydrogen, hydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl, substituted heteroatom-containing hydrocarbyl, -(Z) n -Fn, etc.
  • the second olefin may have a molecular structure encompassed by any one of the above generic formulae (VIII), (IX), (X), and (XI), or may be a simple structure such as ethylene per se.
  • the invention is additionally useful in providing a method for controlling the stereoselectivity of an olefin cross-metathesis reaction, and in providing a cross-metathesis product in which the thermodynamically less favored cis configuration predominates.
  • the reaction is carried out using selected olefinic reactants, with one olefinic reactant substituted in a 1,2-cis configuration.
  • the catalyst used has the structure of formula (VI), with R 3 and R 4 representing bulky ligands, e.g., bicyclic or polycyclic ligands that may or may not be aromatic.
  • complexes of formula (VI) are used to catalyze a plurality of cross-metathesis reactions from a common olefinic reactant to generate chemical diversity, i.e., to provide a plurality of products having related structures but retaining a distinguishing feature, such that each synthesized compound is different from each other synthesized compound.
  • Each olefinic reactant can be substituted with functional groups, yielding cross-metathesis products containing those groups, and thus providing the option of further derivatization.
  • alkyl refers to a linear, branched or cyclic saturated hydrocarbon group typically although not necessarily containing 1 to about 20 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, octyl, decyl, and the like, as well as cycloalkyl groups such as cyclopentyl, cyclohexyl and the like. Generally, although again not necessarily, alkyl groups herein contain 1 to about 12 carbon atoms.
  • lower alkyl intends an alkyl group of 1 to 6 carbon atoms
  • cycloalkyl intends a cyclic alkyl group, typically having 4 to 8, preferably 5 to 7, carbon atoms.
  • substituted alkyl refers to alkyl substituted with one or more substituent groups
  • heteroatom-containing alkyl and “heteroalkyl” refer to alkyl in which at least one carbon atom is replaced with a heteroatom. If not otherwise indicated, the terms “alkyl” and “lower alkyl” include linear, branched, cyclic, unsubstituted, substituted, and/or heteroatom-containing alkyl and lower alkyl, respectively.
  • alkylene refers to a difunctional linear, branched or cyclic alkyl group, where “alkyl” is as defined above.
  • alkenyl refers to a linear, branched or cyclic hydrocarbon group of 2 to 20 carbon atoms containing at least one double bond, such as ethenyl, n-propenyl, isopropenyl, n-butenyl, isobutenyl, octenyl, decenyl, tetradecenyl, hexadecenyl, eicosenyl, tetracosenyl, and the like.
  • Preferred alkenyl groups herein contain 2 to 12 carbon atoms.
  • lower alkenyl intends an alkenyl group of 2 to 6 carbon atoms
  • specific term “cycloalkenyl” intends a cyclic alkenyl group, preferably having 5 to 8 carbon atoms.
  • substituted alkenyl refers to alkenyl substituted with one or more substituent groups
  • heteroatom-containing alkenyl and “heteroalkenyl” refer to alkenyl in which at least one carbon atom is replaced with a heteroatom. If not otherwise indicated, the terms “alkenyl” and “lower alkenyl” include linear, branched, cyclic, unsubstituted, substituted, and/or heteroatom-containing alkenyl and lower alkenyl, respectively.
  • alkenylene refers to a difunctional linear, branched or cyclic alkenyl group, where “alkenyl” is as defined above.
  • alkynyl refers to a linear or branched hydrocarbon group of 2 to 20 carbon atoms containing at least one triple bond, such as ethynyl, n-propynyl, and the like. Preferred alkynyl groups herein contain 2 to 12 carbon atoms. The term “lower alkynyl” intends an alkynyl group of 2 to 6 carbon atoms.
  • substituted alkynyl refers to alkynyl substituted with one or more substituent groups
  • heteroatom-containing alkynyl and “heteroalkynyl” refer to alkynyl in which at least one carbon atom is replaced with a heteroatom. If not otherwise indicated, the terms “alkynyl” and “lower alkynyl” include linear, branched, unsubstituted, substituted, and/or heteroatom-containing alkynyl and lower alkynyl, respectively.
  • alkoxy intends an alkyl group bound through a single, terminal ether linkage; that is, an “alkoxy” group may be represented as —O-alkyl where alkyl is as defmed above.
  • a “lower alkoxy” group intends an alkoxy group containing 1 to 6 carbon atoms.
  • alkenyloxy and lower alkenyloxy respectively refer to an alkenyl and lower alkenyl group bound through a single, terminal ether linkage
  • alkynyloxy and “lower alkynyloxy” respectively refer to an alkynyl and lower alkynyl group bound through a single, terminal ether linkage.
  • aryl refers to an aromatic substituent containing a single aromatic ring or multiple aromatic rings that are fused together, directly linked, or indirectly linked (such that the different aromatic rings are bound to a common group such as a methylene or ethylene moiety).
  • Preferred aryl groups contain one aromatic ring or 2 to 4 fused or linked aromatic rings, e.g., phenyl, naphthyl, biphenyl, and the like.
  • Substituted aryl refers to an aryl moiety substituted with one or more substituent groups
  • heteroatom-containing aryl and “heteroaryl” refer to aryl in which at least one carbon atom is replaced with a heteroatom.
  • aromatic and “arylene” include heteroaromatic, substituted aromatic, and substituted heteroaromatic species.
  • aryloxy refers to an aryl group bound through a single, terminal ether linkage.
  • An “aryloxy” group may be represented as —O-aryl where aryl is as defined above.
  • aralkyl refers to an alkyl group with an aryl substituent
  • aralkylene refers to an alkylene group with an aryl substituent
  • alkaryl refers to an aryl group that has an alkyl substituent
  • alkarylene refers to an arylene group with an alkyl substituent
  • alicyclic refers to an aliphatic cyclic moiety, which may or may not be bicyclic or polycyclic.
  • halo and “halogen” are used in the conventional sense to refer to a chloro, bromo, fluoro or iodo substituent.
  • haloalkyl refers to an alkyl, alkenyl or alkynyl group, respectively, in which at least one of the hydrogen atoms in the group has been replaced with a halogen atom.
  • Hydrocarbyl refers to univalent hydrocarbyl radicals containing 1 to about 30 carbon atoms, preferably 1 to about 20 carbon atoms, most preferably 1 to about 12 carbon atoms, including linear, branched, cyclic, saturated and unsaturated species, such as alkyl groups, alkenyl groups, aryl groups, and the like.
  • lower hydrocarbyl intends a hydrocarbyl group of 1 to 6 carbon atoms
  • hydrocarbylene intends a divalent hydrocarbyl moiety containing 1 to about 30 carbon atoms, preferably 1 to about 20 carbon atoms, most preferably 1 to about 12 carbon atoms, including linear, branched, cyclic, saturated and unsaturated species.
  • lower hydrocarbylene intends a hydrocarbylene group of 1 to 6 carbon atoms.
  • Substituted hydrocarbyl refers to hydrocarbyl substituted with one or more substituent groups
  • heteroatom-containing hydrocarbyl and heterohydrocarbyl refer to hydrocarbyl in which at least one carbon atom is replaced with a heteroatom
  • substituted hydrocarbylene refers to hydrocarbylene substituted with one or more substituent groups
  • hydrocarbyl and hydrocarbylene are to be interpreted as including substituted and/or heteroatom-containing hydrocarbyl and hydrocarbylene moieties, respectively.
  • heteroatom-containing hydrocarbyl group refers to a hydrocarbon molecule or a hydrocarbyl molecular fragment in which one or more carbon atoms is replaced with an atom other than carbon, e.g., nitrogen, oxygen, sulfur, phosphorus or silicon, typically nitrogen, oxygen or sulfur.
  • heteroalkyl refers to an alkyl substituent that is heteroatom-containing
  • heterocyclic refers to a cyclic substituent that is heteroatom-containing
  • heteroaryl and heteroaromatic respectively refer to “aryl” and “aromatic” substituents that are heteroatom-containing, and the like.
  • a “heterocyclic” group or compound may or may not be aromatic, and further that “heterocycles” may be monocyclic, bicyclic, or polycyclic as described above with respect to the term “aryl.”
  • substituted as in “substituted hydrocarbyl,” “substituted alkyl,” “substituted aryl,” and the like, as alluded to in some of the aforementioned definitions, is meant that in the hydrocarbyl, alkyl, aryl, or other moiety at least one hydrogen atom bound to a carbon (or other) atom is replaced with one or more non-hydrogen substituents.
  • substituents include, without limitation: functional groups such as halogen, phosphonato, phosphoryl, phosphanyl, phosphino, sulfonato, C 1 -C 20 alkylsulfanyl, C 5 -C 20 arylsulfanyl, C 1 -C 20 alkylsulfonyl, C 5 -C 20 arylsulfonyl, C 1 -C 20 alkylsulfinyl, C 5 -C 20 arylsulfinyl, sulfonamido, amino, amido, imino, nitro, nitroso, hydroxyl, C 1 -C 20 alkoxy, C 5 -C 20 aryloxy, C 2 -C 20 alkoxycarbonyl, C 5 -C 20 aryloxycarbonyl, carboxyl, carboxylato, mercapto, formyl, C 1 -C 20 thioester, cyano
  • the aforementioned functional groups may, if a particular group permits, be further substituted with one or more additional functional groups or with one or more hydrocarbyl moieties such as those specifically enumerated above.
  • the above-mentioned hydrocarbyl moieties may be further substituted with one or more functional groups or additional hydrocarbyl moieties such as those specifically enumerated.
  • substituted appears prior to a list of possible substituted groups, it is intended that the term apply to every member of that group. That is, the phrase “substituted alkyl, alkenyl and alkynyl” is to be interpreted as “substituted alkyl, substituted alkenyl and substituted alkynyl.” Similarly, “optionally substituted alkyl, alkenyl and alkynyl” is to be interpreted as “optionally substituted alkyl, optionally substituted alkenyl and optionally substituted alkynyl.”
  • amino is used herein to refer to the group —NZ 1 Z 2 , where each of Z 1 and Z 2 is independently selected from the group consisting of hydrogen and optionally substituted alkyl, alkenyl, alkynyl, aryl, aralkyl, alkaryl and heterocyclic.
  • stereoselective refers to a chemical reaction that preferentially results in one stereoisomer relative to a second stereoisomer, i.e., gives rise to a product of which the ratio of a desired stereoisomer to a less desired stereoisomer is greater than 1:1.
  • “Optional” or “optionally” means that the subsequently described circumstance may or may not occur, so that the description includes instances where the circumstance occurs and instances where it does not.
  • the phrase “optionally substituted” means that a non-hydrogen substituent may or may not be present on a given atom, and, thus, the description includes structures wherein a non-hydrogen substituent is present and structures wherein a non-hydrogen substituent is not present.
  • the cross-metathesis reactions of the invention are carried out catalytically, using a Group 8 transition metal complex that preferably contains two different ligands.
  • These transition metal carbene complexes include a metal center in a +2 oxidation state, have an electron count of 16, and are penta-coordinated.
  • the preferred catalysts herein have the structure of formula (VIA)
  • M which serves as the transition metal center in the +2 oxidation state, is a Group 8 transition metal, particularly ruthenium or osmium. In a preferred embodiment, M is ruthenium.
  • X 1 and X 2 are anionic ligands or polymers, and may be the same or different, or are linked together to form a cyclic group, typically although not necessarily a five- to eight-membered ring.
  • X 1 and X 2 are each independently hydrogen, halide, or one of the following groups: C 1 -C 20 alkyl, C 5 -C 20 aryl, C 1 -C 20 alkoxy, C 5 -C 20 aryloxy, C 3 -C 20 alkyldiketonate, C 5 -C 20 aryldiketonate, C 2 -C 20 alkoxycarbonyl, C 5 -C 20 aryloxycarbonyl, C 2 -C 20 acyl, C 1 -C 20 alkylsulfonato, C 5 -C 20 arylsulfonato, C 1 -C 20 alkylsulfanyl, C 1 -C 20 arylsulf
  • X 1 and X 2 may be substituted with one or more moieties selected from the group consisting of C 1 -C 10 alkyl, C 1 -C 10 alkoxy, aryl, and halide, which may, in turn, with the exception of halide, be further substituted with one or more groups selected from halide, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, and phenyl.
  • X 1 and X 2 are halide, benzoate, C 2 -C 6 acyl, C 2 -C 6 alkoxycarbonyl, C 1 -C 6 alkyl, phenoxy, C 1 -C 6 alkoxy, C 1 -C 6 alkylsulfanyl, aryl, or C 1 -C 6 alkylsulfonyl.
  • X 1 and X 2 are each halide, CF 3 CO 2 , CH 3 CO 2 , CFH 2 CO 2 , (CH 3 ) 3 CO, (CF 3 ) 2 (CH 3 )CO, (CF 3 )(CH 3 ) 2 CO, PhO, MeO, EtO, tosylate, mesylate, or trifluoromethanesulfonate.
  • X 1 and X 2 are each chloride.
  • the complex may also be attached to a solid support, such as to a polymeric substrate, and this attachment may be effected by means of X 1 and/or X 2 , in which case X 1 and/or x 2 is a polymer.
  • R 1 is selected from the group consisting of hydrogen, hydrocarbyl (e.g., alkyl, alkenyl, alkynyl, aryl, aralkyl, alkaryl, etc.), substituted hydrocarbyl (e.g., substituted alkyl, alkenyl, alkynyl, aryl, aralkyl, alkaryl, etc.), heteroatom-containing hydrocarbyl (e.g., heteroatom-containing alkyl, alkenyl, alkynyl, aryl, aralkyl, alkaryl, etc.), and substituted heteroatom-containing hydrocarbyl (e.g., substituted heteroatom-containing alkyl, alkenyl, alkynyl, aryl, aralkyl, alkaryl, etc.), and carboxyl
  • R 2 is selected from the group consisting of hydrogen, hydrocarbyl (e.g., alkyl, alkenyl, alkynyl, aryl, a
  • R 1 and R 2 may also be linked to form a cyclic group, which may be aliphatic or aromatic, and may contain substituents and/or heteroatoms. Generally, such a cyclic group will contain 4 to 12, preferably 5 to 8, ring atoms.
  • the R 1 substituent is hydrogen and the R 2 substituent is selected from the group consisting of C 1 -C 20 alkyl, C 2 -C 20 alkenyl, and aryl. More preferably, R 2 is phenyl, vinyl, methyl, isopropyl, or t-butyl, optionally substituted with one or more moieties selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 alkoxy, phenyl, and a functional group Fn.
  • R 2 is phenyl or vinyl substituted with one or more moieties selected from the group consisting of methyl, ethyl, chloro, bromo, iodo fluoro, nitro, dimethylamino, methyl, methoxy, and phenyl.
  • L is a neutral electron donor ligand, and may or may not be linked to R 2 .
  • suitable L moieties include, without limitation, phosphine, sulfonated phosphine, phosphite, phosphinite, phosphonite, arsine, stibine, ether (including cyclic ethers), amine, amide, imine, sulfoxide, carboxyl, nitrosyl, pyridine, substituted pyridine (e.g., halogenated pyridine), imidazole, substituted imidazole (e.g., halogenated imidazole), pyrazine (e.g., substituted pyrazine), and thioether.
  • L is a phosphine of the formula PR 5 R 6 R 7 , where R 5 , R 6 , and R 7 are each independently aryl or C 1 -C 10 alkyl, particularly primary alkyl, secondary alkyl or cycloalkyl.
  • L is selected from the group consisting of —P(cyclohexyl) 3 , —P(cyclopentyl) 3 , —P(isopropyl) 3 , —P(phenyl) 3 , —P(phenyl) 2 (R 7 ) and —P(phenyl)(R 7 ) 2 , in which R 7 is alkyl, typically lower alkyl.
  • weaker ligands such as the nitrogen-containing heterocycles, which enhance catalytic activity presumably because of the requirement that the L ligand dissociate for initiation to occur.
  • X and Y are heteroatoms typically selected from N, O, S, and P. Since O and S are divalent, p is necessarily zero when X is O or S, and q is necessarily zero when Y is o or S. However, when X is N or P, then p is 1, and when Y is N or P, then q is 1. In a preferred embodiment, both X and Y are N.
  • Q 1 , Q 2 , Q 3 , and Q 4 are linkers, e.g., hydrocarbylene (including substituted hydrocarbylene, heteroatom-containing hydrocarbylene, and substituted heteroatom-containing hydrocarbylene, such as substituted and/or heteroatom-containing alkylene) or —(CO)—, and w, x, y and z are independently zero or 1, meaning that each linker is optional. Preferably, w, x, y and z are all zero.
  • R 3 , R 3A , R 4 , and R 4A are independently selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl, and substituted heteroatom-containing hydrocarbyl, wherein R 3A and R 4A may be linked to form a cyclic group.
  • any two or more (typically two, three or four) of X 1 , X 2 , L, R 1 , R 2 , R 3 , R 3A , R 4 , and R 4A can be taken together to form a chelating multidentate ligand, as disclosed, for example, in U.S. Pat. No. 5,312,940 to Grubbs et al.
  • bidentate ligands include, but are not limited to, bisphosphines, dialkoxides, alkyldiketonates, and aryldiketonates.
  • Specific examples include —P(Ph) 2 CH 2 CH 2 P(Ph) 2 —, —As(Ph) 2 CH 2 CH 2 As(Ph 2 )—, —P(Ph) 2 CH 2 CH 2 C(CF 3 ) 2 O—, binaphtholate dianions, pinacol dianions, —P(CH 3 ) 2 (CH 2 ) 2 P(CH 3 ) 2 — and —OC(CH 3 ) 2 (CH 3 ) 2 CO—.
  • Preferred bidentate ligands are —P(Ph) 2 CH 2 CH 2 P(Ph) 2 — and —P(CH 3 ) 2 (CH 2 ) 2 P(CH 3 ) 2 —.
  • Tridentate ligands include, but are not limited to, (CH 3 ) 2 NCH 2 CH 2 P(Ph)CH 2 CH 2 N(CH 3 ) 2 .
  • Other preferred tridentate ligands are those in which any three of X 1 , X 2 , L, R 1 , R 2 , R 3 , R 3A , R 4 , and R 4A (e.g., X, L, and any one of R 3 , R 3A , R 4 , and R 4A ) are taken together to be cyclopentadienyl, indenyl or fluorenyl, each optionally substituted with C 2 -C 20 alkenyl, C 2 -C 20 alkynyl, C 1 -C 20 alkyl, C 5 -C 20 aryl, C 1 -C 20 alkoxy C 2 -C 20 alkenyloxy, C 2 -C 20 alkynyloxy, C 5 -C 20 aryloxy, C
  • X, L, and any one of R 3 , R 3A , R 4 , and R 4A are taken together to be cyclopentadienyl or indenyl, each optionally substituted with vinyl, C 1 -C 10 alkyl, C 5 -C 20 aryl, C 1 -C 10 carboxylate, C 2 -C 10 alkoxycarbonyl, C 1 -C 10 alkoxy, C 5 -C 20 aryloxy, each optionally substituted with C 1 -C 6 alkyl, halogen, C 1 -C 6 alkoxy or with a phenyl group optionally substituted with halogen, C 1 -C 6 alkyl or C 1 -C 6 alkoxy.
  • X, L, and any one of R 3 , R 3A , R 4 , and R 4A may be taken together to be cyclopentadienyl, optionally substituted with vinyl, hydrogen, Me or Ph.
  • Tetradentate ligands include, but are not limited to O 2 C(CH 2 ) 2 P(Ph)(CH 2 ) 2 P(Ph)(CH 2 ) 2 CO 2 , phthalocyanines, and porphyrins.
  • the catalyst has the structure of formula (VIB)
  • R 3 and R 4 are defined above, with preferably at least one of R 3 and R 4 , and more preferably both R 3 and R 4 , being alicyclic or aromatic of one to about five rings, and optionally containing one or more heteroatoms and/or substituents.
  • Q is a linker, typically a hydrocarbylene linker, including substituted hydrocarbylene, heteroatom-containing hydrocarbylene, and substituted heteroatom-containing hydrocarbylene linkers, wherein two or more substituents on adjacent atoms within Q may also be linked to form an additional cyclic structure, which may be similarly substituted to provide a fused polycyclic structure of two to five cyclic groups.
  • Q is a two-atom linkage having the structure —CR 22 R 22A —CR 23 R 23A — or —CR 22 ⁇ CR 23 —, more preferably —CR 22 R 22A —CR 23 R 23A— , in which case the complex has the structure of formula (VIC)
  • R 22 , R 22 A, R 23 , and R 23A are independently selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl, substituted heteroatom-containing hydrocarbyl, and functional groups (i.e., Fn, as defined previously), e.g., C 1 -C 20 alkyl, C 2 -C 20 alkenyl, C 2 -C 20 alkynyl, aryl, C 1 -C 20 carboxylate, C 1 -C 20 alkoxy, C 2 -C 20 alkenyloxy, C 2 -C 20 alkynyloxy, aryloxy, C 2 -C 20 alkoxycarbonyl, C 1 -C 20 alkylthio, arylthio, C 1 -C 20 alkylsulfonyl, and C 1 -C 20 alkylsulfinyl, optionally substituted with one or more moieties selected from the group consisting
  • R 22 , R 22A , R 23 , and R 23A may be linked to form a substituted or unsubstituted, saturated or unsaturated ring structure, e.g., a C 4 -C 12 alicyclic group or a C 5 or C 6 aryl group, which may itself be substituted, e.g., with linked or fused alicyclic or aromatic groups, or with other substituents.
  • a substituted or unsubstituted, saturated or unsaturated ring structure e.g., a C 4 -C 12 alicyclic group or a C 5 or C 6 aryl group, which may itself be substituted, e.g., with linked or fused alicyclic or aromatic groups, or with other substituents.
  • N-heterocyclic carbene ligands incorporated into complex thus include, but are not limited to, the following:
  • R 3 and R 4 are preferably aromatic, substituted aromatic, heteroaromatic, substituted heteroaromatic, alicyclic, or substituted alicyclic, composed of from one to about five cyclic groups.
  • R 3 and R 4 are aromatic, they are typically although not necessarily composed of one or two aromatic rings, which may or may not be substituted, e.g., R 3 and R 4 may be phenyl, substituted phenyl, biphenyl, substituted biphenyl, or the like.
  • R 3 and R 4 are the same and have the structure (XII)
  • R 24 , R 25 , and R 26 are each independently hydrogen, C 1 -C 20 alkyl, substituted C 1 -C 20 alkyl, C 1 -C 20 heteroalkyl, substituted C 1 -C 20 heteroalkyl, C 5 -C 20 aryl, substituted C 5 -C 20 aryl, C 5 -C 20 heteroaryl, C 5 -C 30 aralkyl, C 5 -C 30 alkaryl, or halogen.
  • R 24 , R 25 , and R 26 are each independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, hydroxyl, halogen, phenyl, and lower alkyl-substituted phenyl (e.g., dimethylphenyl).
  • R 24 , R 25 , and R 26 are the same and are each methyl.
  • R 3 and R 4 are alicyclic, they are generally composed of a C 7 -C 20 , preferably a C 7 -C 12 , alicyclic structure, e.g., diisopinocamphenyl. Complexes formed with such ligands are exemplified by the complex containing the diisopinocamphenyl-substituted ligand shown in structural formula (XIV).
  • R 24 , R 25 , and R 26 are the same and are each methyl.
  • R 3 and R 4 are each biphenylyl or substituted biphenylyl.
  • Catalysts formed with such ligands are exemplified by the complex containing the 2,4,2′,6′-tetramethylbiphenylyl-(i.e., 2,6-dimethyl-3-(2′,6′-dimethylphenyl)phenyl) substituted ligand shown below as structural formula (XIII), preparation of which is described in detail in as illustrated in Example 8.
  • R 3 and R 4 are alicyclic, they are generally composed of a C 7 -C 20 , preferably a C 7 -C 12 , alicyclic structure, e.g., diisopinocamphenyl.
  • alicyclic structure e.g., diisopinocamphenyl.
  • Ligands containing bulky, electron-.donating groups such as those illustrated in the complexes of formulae (XIII) and (XIV) provide for very highly active olefin metathesis catalysts. Such catalysts are thus suitable to catalyze reactions for which other, less active catalysts are ineffective, and are also useful in enhancing the stereoselectivity of a catalyzed cross-metathesis reaction.
  • Mes represents mesityl (2,4,6-trimethylphenyl)
  • iPr is isopropyl
  • Ph is phenyl
  • Cy is cyclohexyl
  • the present invention provides a method for using olefin cross-metathesis to synthesize olefins substituted with functional groups.
  • the reaction is carried out with a functional group-substituted olefinic reactant, and may in fact be carried out with two such functionalized olefins as cross-metathesis reactants.
  • the reaction is catalyzed using a transition metal carbene complex as described in part (II) of this section, and involves reaction between a first olefinic reactant substituted with one or more functional groups, and a second olefinic reactant that may or may not be substituted.
  • the functional groups may or may not be in protected form (e.g., a hydroxyl group may be protected as an acyloxy or benzyloxy group). More specifically, the first olefinic reactant has the structure of formula (VIII)
  • Fn is a functional group such as phosphonato, phosphoryl, phosphanyl, phosphino, sulfonato, C 1 -C 20 alkylsulfanyl, C 5 -C 20 arylsulfanyl, C 1 -C 20 alkylsulfonyl, C 5 -C 20 arylsulfonyl, C 1 -C 20 alkylsulfinyl, C 5 -C 20 arylsulfinyl, sulfonamido, amino, amido, imino, nitro, nitroso, hydroxyl, C 1 -C 20 alkoxy, C 5 -C 20 aryloxy, C 2 -C 20 alkoxycarbonyl, C 5 -C 20 aryloxycarbonyl, carboxyl, carboxylato, mercapto, formyl, C 1 -C 20 thioester, cyano, cyanato,
  • n is zero or 1;
  • R 5 , R 6 , and R 7 are independently selected from the group consisting of hydrogen, -(Z) n -Fn, hydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl, and substituted heteroatom-containing hydrocarbyl, and, if substituted hydrocarbyl or substituted heteroatom-containing hydrocarbyl, one or more substituents may be -(Z) n -Fn.
  • the functional group will generally not be directly bound to the olefinic carbon through a heteroatom containing one or more lone pairs of electrons, e.g., an oxygen, sulfur, nitrogen or phosphorus atom, or through an electron-rich metal or metalloid such as Ge, Sn, As, Sb, Se, Te, etc. With such functional groups, there will normally be an intervening linkage Z, i.e., n is 1.
  • R 5 and at least one of R 6 and R 7 is hydrogen, Fn is a phosphonate, and Z is lower alkylene, and in a most preferred embodiment, R 5 , R 6 and R 7 are hydrogen, and Z is methylene, such that the first olefinic reactant is a vinylphosphonate having the structure of formula (XII)
  • R 27 and R 28 are hydrocarbyl, preferably lower hydrocarbyl, and most preferably are lower alkyl such as methyl or ethyl.
  • IMesH 2 is as defined previously, Cy is cyclohexyl, and Ph is phenyl.
  • Terminal olefins were reacted with commercially available diethyl vinylphosphonate as described in Example 4.
  • Table 1 cross-metathesis with an olefinic ester resulted in a 95% yield of product, almost exclusively as the (E) isomer (Table 1, Entry 1).
  • No dimerization of the vinylphosphonate was detected by 1 H-NMR, allowing for selective cross-metathesis.
  • Alkyl halide (Entry 2) and unprotected aldehyde functionalities (Entry 3) were well tolerated with the ruthenium catalyst (V). Allyl benzene also gave the desired metathesis product, without olefin isomerization (Entry 4).
  • the functional group Fn is not necessarily phosphonate.
  • a significant advantage of the present methodology is that the olefinic reactants can be substituted with one or more of a host of functional groups, even if those functional groups are potential ligands for the catalyst.
  • catalyst (V) has been used to effect cross-metathesis reactions using allylboronates as starting materials. Such reactions are quite useful in the stereoselective synthesis of homoallylic alcohols.
  • the accessibility of functionalized allyl boron reagents was quite limited, and such complexes are traditionally prepared by allylmetal addition to haloboranes or hydroboration of 1,3-dienes, methods that can be incompatible with complex substrates and/or many desired functional groups.
  • the present invention enables a one pot cross-metathesis/allylboration reaction that affords densely functionalized homoallylic alcohols, as illustrated using pinacol allyl boronate according to the following scheme:
  • catalyst (V) has been used to prepare secondary allylic alcohols from other protected or unprotected secondary allylic reactants. Examples of such reactions are summarized in Table 5. TABLE 5 Isolated Allylic Substit. Olefin Cross Partner Equiv. Product Yield(%) E/Z ratio 2.0 eq. 92 13:1 2.0 eq. 88 >20:1 2.0 eq. 38 18:1 2.0 eq. 82 11:1 0.5 eq. 53 6.7:1 0.5 eq. 61 >20:1 1.5 eq. 60 6:1
  • catalyst (V) has been used to dimerize the allylic sulfide 3-methylsulfanyl-propene according to the following scheme:
  • complex (V) has been used to catalyze cross-metathesis reactions with other functionalized olefins, as described in Example 6 and as indicated in Table 6: TABLE 6 Entry 1 2 3 4 5 6
  • the present method is applicable not only to dimerization of functionalized allylic olefins, but extends to catalytic reaction of such compounds as substrates for cross-metathesis, regardless of the oxidation state of a particular atom in the functional group (e.g., phosphorus-containing functional groups in the form of phosphines, protected phosphines, and phosphonates) or the nature of the functional group (e.g., the reaction proceeds with an allyl amine as well).
  • a particular atom in the functional group e.g., phosphorus-containing functional groups in the form of phosphines, protected phosphines, and phosphonates
  • the reaction proceeds with an allyl amine as well.
  • the versatility of the present methodology is applied to create functional diversity, i.e., to create a plurality of different olefinic products from a single olefinic reactant. This is carried out by conducting a plurality of olefin metathesis reactions each employing a common first olefinic reactant but a different second olefinic reactant. In this way, a plurality of analogs is provided sharing some structural commonality but having a distinguishing feature. As each olefinic reactant may be substituted with functional groups, cross-metathesis products result that contain those groups, thus providing the option of further derivatization. This can be illustrated by reference to the following schemes:
  • n and Z are as defined previously, and Fn 1 , Fn 2 , Fn 3 , and Fn 4 are as defined for Fn or may include other functional groups, e.g., carboxylate, alkoxy, etc.
  • the olefinic reactants may be further substituted on the olefinic carbon atoms with additional -(Z) n -Fn groups, or with other moieties such as R 5 , R 6 , and R 7 , defined above with respect to the olefins of formula (VIII).
  • the method may be generally characterized as a process for generating a plurality of structurally diverse functionalized olefins from a common olefinic reactant via a cross-metathesis reaction, the method involving the following steps:
  • step (c) optionally repeating step (b) with a plurality of olefinic reactants each having a different molecular structure.
  • the present invention provides a straightforward method for carrying out an olefin cross-metathesis reaction using an a-halogenated olefin in order to provide a directly halogenated olefinic product.
  • the catalyst used may be the complex of formula (VIB), or it may be an alternative complex of formula (VI) wherein L 1 is a neutral electron donor other than an N-heterocyclic carbene.
  • the catalyst may be a bis(phosphine), in which case both L and L 1 of formula (VI) are phosphine ligands such as triphenylphosphine.
  • At least one of the olefinic reactants has the structure of formula (IX)
  • X 3 is halo
  • R 8 , R 9 , and R 10 are independently selected from the group consisting of hydrogen, halo, hydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl, substituted heteroatom-containing hydrocarbyl, and -(Z) n -Fn where n, Z and Fn are as defined previously with respect to formula (VIII).
  • the second olefinic reactant has the same structure, or the structure R 18 R 19 C ⁇ CR 20 R 21 wherein R 18 , R 19 , R 20 , and R 21 are as defied previously.
  • an olefin metathesis catalyst (L)(L 1 )X 1 X 2 Ru ⁇ CR 1 R 2 such as (H 2 IMes)(PCy 3 )Cl 2 Ru ⁇ CHPh reacts with 1,1-difluoroethylene to yield the corresponding methylidene (H 2 IMes)(PCy 3 )Cl 2 Ru ⁇ CH 2 and difluorocarbene (H 2 IMes)(PCy 3 )Cl 2 Ru ⁇ CF 2 complexes.
  • H 2 IMes methylidene
  • PCy 3 difluorocarbene
  • greater than 98% of the difluorocarbene complex forms, and it can be isolated in pure form by column chromatography.
  • the activity of (H 2 IMes)(PCy 3 )Cl 2 Ru ⁇ CF 2 can be enhanced by the addition of HCl or CuCl, which aid in the dissociation of PCy 3 from the metal center.
  • the bis(pyridine) derivative of the catalyst, (H 2 IMes)(py) 2 Cl 2 Ru ⁇ CF 2 is somewhat more active for subsequent metathesis reactions than the PCy 3 complex, presumably because the pyridine ligands are less basic and thus more labile.
  • the bis(phosphine) olefin metathesis catalyst (PCy 3 ) 2 Cl 2 Ru ⁇ CHPh reacts with 1,1-difluoroethylene to yield the corresponding methylidene (PCy 3 ) 2 Cl 2 Ru ⁇ CH 2 and difluorocarbene (PCy 3 ) 2 Cl 2 Ru ⁇ CF 2 complexes.
  • a method for synthesizing substituted olefins, particularly geminal disubstituted olefins, 1,1,2-trisubstituted olefins and quaternary allylic olefins, wherein the method comprises using the complex of formula (VI) to catalyze a cross-metathesis reaction between a geminal disubstituted olefin, a 1,1,2-trisubstituted olefin, or a quaternary allylic olefin, and a second olefin. If it is a geminal disubstituted olefin or a 1,1,2-trisubstituted olefin, the first olefin has the structure (X)
  • R 11 , R 12 , R 13 , and R 14 are selected from the group consisting of hydrogen, halo, hydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl, substituted heteroatom-containing hydrocarbyl, and -(Z) n -Fn where n, Z and Fn are as defined above, with the provisos that R 11 and R 12 , or R 13 and R 14 are other than hydrogen for a geminal disubstituted olefin, and that R 11 , R 12 , and R 13 are other than hydrogen for a 1,1,2-trisubstituted olefin. If it is a quaternary allylic olefin, the first olefin has the structure (XI)
  • R 11 and R 12 are as defined previously, and R 15 , R 16 , and R 17 are nonhydrogen substituents.
  • the second olefin has a molecular structure given by R 18 R 19 C ⁇ CR 20 R 21 wherein R 18 , R 19 , R 20 , and R 21 may be hydrogen, hydrocarbyl substituted hydrocarbyl, heteroatom-containing hydrocarbyl, or substituted heteroatom-containing hydrocarbyl.
  • the reaction is carried out with the two olefinic reactants in a mole ratio in the range of about 1:3 to 3:1, at a temperature in the range of about 20° C. to about 40° C., for a time period in the range of about 4 to 16 hours. Typically, about 0.01 to 7.5 mole % catalyst is used.
  • the reaction is also viable if there is a large excess of one reactant, such as is the case when one reactant serves as a solvent for the reaction mixture.
  • a stereoselective method for carrying out an olefin cross-metathesis reaction wherein the stereochemistry of the olefinic product may be either cis or trans, as desired.
  • the catalyst used has the structure of formula (VIB), wherein the nitrogen atoms of the N-heterocyclic carbene ligand are substituted with bulky substituents, i.e., R 3 and R 4 are aromatic, substituted aromatic, heteroaromatic, substituted aromatic, alicyclic, or substituted alicyclic.
  • R 3 and R 4 substituent are preferred, e.g., bicyclic or polycyclic ligands that may or may not be aromatic. If R 3 and R 4 are aromatic, they are generally composed of two to five aromatic rings that may be fused or linked (e.g., biphenyl or substituted biphenyl), and if R 3 and R 4 are alicyclic, they are generally composed of a C 7 -C 20 , preferably a C 7 -C 12 , alicyclic structure that may or may not be substituted.
  • R 3 and R 4 groups thus include the alicyclic groups norbornyl, adamantyl, camphenyl, isobornyl, any of which may be substituted, e.g., with a lower alkyl group (as in diisopinocamphenyl, as shown in the structure of formula (XIV)), and the bicyclic groups biphenylyl and 2′,6′-dimethyl-3′-(2′′,6′′-dimethylphenyl (as shown in the structure of formula (XIII)).
  • IMesH 2 Cl was prepared according to a modified version of the procedure described in Scholl et al. (1999) Org. Lett. 1:953-956 and Jafarpour et al. (2000) Organometallics 19:2055-2057. Unless otherwise specified, all other reagents were purchased from commercial suppliers and used without further purification. All other solvents were purified by passage through a solvent column (containing activated A-2 alumina; see Pangborn et al. (1996) Organometallics 15:1518-1520.). Analytical thin-layer chromatography (TLC) was performed using silica gel 60 F254 precoated plates (0.25 mm thickness) with a fluorescent indicator.
  • TLC thin-layer chromatography
  • the product (9.4 g, 93%) was obtained as a white solid and dried in vacuo.
  • the reaction mixture was then heated at 120° C. for 5 hr under Ar. Then, the reaction mixture was cooled to an ambient temperature and hexane (200 mL) was added.
  • Analogous ruthenium alkylidene complexes can be prepared using the aforementioned protocol and differently substituted phosphines, alkynes, etc., as indicated in the following two examples.
  • Example 2 The procedure of Example 2 was employed using [Ru(COD)Cl 2 ] n (300 mg, 1 mmol), IMesH 2 Cl (0.74 g, 2 mmol), triphenylphosphine (280 mg, 1 mmol), and KN(SiMe 3 ) 2 (380 mg, 1.9 mmol), giving 550 mg (68%) of complex (3).
  • 1 H NMR (CD 2 Cl 2 ): ⁇ 18.49 (d, J 11.1 Hz, 1H).
  • RuCl 2 ( ⁇ CHPh)(PCy 3 ).(phenylmethylene-bis(tricyclohexylphosphine) ruthenium dichloride, “catalyst (I)”) (6.00 g, 7.29 mmol, 1.0 eq.), IMesH 2 HCl salt prepared above (2 eq.), and potassium t-butoxide (2 eq.) were placed in a Schlenk flask. 60 mL of anhydrous degassed hexanes (Aldrich SureSeal boffle) were added. A vacuum was applied to further degas the reaction mixture, which was then heated to 60° C. for 24 hours. The suspension changed color from purple to orange-brown over the reaction time.
  • the product mixture contains approximately 40% methylidene and 60% difluorocarbene, as well as styrene (H 2 C ⁇ CHPh) and ⁇ , ⁇ -difluorostyrene (F 2 C ⁇ CHPh).
  • the amount of difluorocarbene complex formed increased to greater than 98% when the reaction was carried out at 60° C. instead.
  • the bis(phosphine) olefin metathesis catalyst [(PCy 3 ) 2 Cl 2 Ru ⁇ CHPh] reacts with 1,1 -difluoroethylene to yield the corresponding methylidene [(PCy 3 ) 2 Cl 2 Ru ⁇ CH 2 ] and difluorocarbene [(PCy 3 ) 2 Cl 2 Ru ⁇ CF 2 ] complexes.
  • reaction mixture was then reduced in volume to 0.5 mL and purified directly on a silica gel column (2 ⁇ 10 cm), eluting with 1:1 hexane:ethyl acetate to provide the cross product (62 mg, 90% yield) as viscous oil/semi solid as confirmed by 1 H and 13 C-NMR.
  • the bottle was backfilled to ⁇ 2 psi with nitrogen, sealed, and allowed to slowly warm to room temperature, at which time it was transferred to an oil bath at 40° C. After stirring for 12-18 hours, the bottle was removed from the oil bath and allowed to cool to room temperature. The isobutylene was slowly vented off at room temperature until the pressure apparatus could be safely disassembled. The remaining mixture was taken up in organic solvent for subsequent silica gel chromatography and/or spectrographic characterization.
  • reaction mixture was allowed to stir at room temperature for 12 hours, and was then reduced in volume to 0.5 mL and purified directly on a silica gel column (2 ⁇ 10 cm), eluting with 20:1 hexane:ethyl acetate to provide the cross-metathesis product (316 mg, 1.337 mmol, 91% yield) as a viscous oils.
  • reaction mixture was then reduced in volume to 0.5 mL and purified directly on a silica gel column (2 ⁇ 10 cm), eluting with 50:1 hexane:ethyl acetate to provide the cross-metathesis product (92 mg, 0.5891 mmol, 93% yield) as a viscous oils.
  • reaction mixture was then reduced in volume to 0.5 mL and purified directly on a silica gel column (2 ⁇ 10 cm), eluting with 20:1 hexane:ethyl acetate to provide the cross product (54 mg, 0.27 mmol, 88% yield) as a viscous oils.
  • the reaction was concentrated to a third of its original volume under vacuum and transferred to a silica gel column (1.5 ⁇ 16′′).
  • the product was quickly eluted with 5:1 heptane:ether.
  • the second, brown band was collected and stripped of solvent.
  • the oily residue that remained was redissolved in a minimum amount of benzene and lyophylized to yield 0.080 g of the desired product as a brown powder (19%).
  • a representative cross-metathesis reaction can be conducted with 5 mol % of the catalyst in a reaction with a 2:1 ratio of cis-2-butene-1,4-diacetate and an ⁇ -terminal olefin at 40° C. in methylene chloride for 6 hours to generate the cross-metathesis allylic acetate product as a 2.2:1 mixture of trans and cis isomers in 60% overall yield.

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US20070155975A1 (en) 2007-07-05
US9403854B2 (en) 2016-08-02
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WO2002079126A1 (fr) 2002-10-10
US20030100776A1 (en) 2003-05-29
EP1373170A1 (fr) 2004-01-02
EP1373170A4 (fr) 2007-03-21
CA2442368A1 (fr) 2002-10-10

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