Ruthenium-catalyzed isomerization of cyclohexenyl aldehydes, esters, or ketones

Abstract

The present disclosure relates to a process for the isomerization of 2- alkyl-cyclohex-3-enyl aldehydes, esters, or ketones into mixtures comprising the corresponding 2-alkyl-cyclohex-2-enyl aldehydes, esters, or ketones using a suitable organometallic ruthenium complex as pre-catalyst. Mixtures comprising the corresponding 2-alkylene- cyclohexyl aldehydes, esters, or ketones may also be obtained.

Description

[0001] RUTHENI UM-CATALYZED ISOMERIZATION OF CYCLOHEXENYL ALDEHYDES, ESTERS, OR KETONES

[0002] Field of the Disclosure

[0003] The present disclosure relates to the field of organic synthesis. More particularly, it provides a process for the isomerization of 2-alkyl-cyclohex-3-enyl aldehydes, esters, or ketones into mixtures comprising the corresponding 2-alkyl-cyclohex-2- enyl aldehydes, esters, or ketones using a suitable organometallic ruthenium complex as pre-catalyst. Mixtures comprising the corresponding 2-alkylene- cyclohexyl aldehydes, esters, or ketones may also be obtained.

[0004] Background of the Disclosure

[0005] 2-Alkyl-cyclohex-2-enyl aldehydes, esters, or ketones are useful materials in the perfumery industry. Such compounds can be used as perfuming ingredients or as starting material for the construction of compounds having more complex structures. Some methods for preparing 2-alkyl-cyclohex-2-enyl aldehydes, esters, or ketones are known.

[0006] For example, WO 2005 / 061426 (Firmenich SA) describes a process for the carboncarbon double bond isomerization of a 2-alkyl-cyclohex-3-enyl alkyl or alkenyl ketone into a mixture comprising the corresponding 2-alkyl-cyclohex-2-enyl ketones and the corresponding 2-alkylene-cyclohexyl ketones, using a ruthenium precursor of the formula [Ru(diene)(allyl)2], [Ru(dienyl)2], [Ru(tetraene)(ene)] or [Ru(diene)(triene)] and an acid.

[0007] CN108101760A (Wanhua Chemical Group Co Ltd) describes the formation of 2,6,6- trimethylcyclohex-2-ene-1-carbaldehyde, also known as a-cyclocitral, from 2,6,6- trimethylcyclohex-3-ene-1-carbaldehyde using a nickel(O) catalyst.

[0008] However, such known methods may be cumbersome to implement at an industrial scale due to one or more disadvantages, such as the need for stoichiometric amounts of costly or unavailable reagents, use of environmentally unfriendly solvents, the need for low reaction temperatures, low selectivity, or poor yields of desired products, to name a few.

[0009] Therefore, there is an ongoing need for improved processes for the isomerization of 2-alkyl-cyclohex-3-enyl aldehydes, esters, or ketones into mixtures comprising the corresponding 2-alkyl-cyclohex-2-enyl aldehydes, esters, or ketones.

[0010] Summary of the Disclosure

[0011] The following aspects of the present disclosure seek to address one or more of the problems described hereinabove.

[0012] In a first aspect, the present disclosure relates to a process for producing a mixture comprising at least a compound of formula (la), wherein each R1represents, independently, a hydrogen atom or a linear or branched C1-C6 alkyl group, typically methyl group, and R2represents a hydrogen atom, linear or branched Ci-Ce alkyl, a C2-C6 alkenyl group, or a Ci-Ce alkoxy group; the process comprising reacting a compound of formula (II), wherein R1and R2have the same meaning as indicated above; with a compound of formula (III)

[0013] {[(L1)mRu(L2)2]n(S)v} (III), wherein n is 1 or 2, v is 0 or 1 , m is 1 or 2,

[0014] S is a coordinated molecule of a polar aprotic solvent or water;

[0015] L1represents a diene, monophosphine, diphosphine, or triphosphine;

[0016] L2represents a p-diketonate or carboxylate OCOR3, wherein R3represents a linear or branched C1-C18 alkyl group, a linear or branched C2-C18 alkenyl group, a C3-C10 cycloalkyl group, an Ar group, or a CHR4Ar group, wherein Ar represents a Ce-C aryl, typically phenyl, optionally substituted by one or more halogen atoms, one or more alkoxy groups, or combination thereof, and wherein R4is a OH or NH2group; in the presence of a protic acid of formula HX, wherein X is CIO4; R5SO3', wherein R5is Cl, F, Ci-Cs fluoroalkyl or fluoroaryl group; PFe’, SbCle', AsCle', SbFe', AsFe', B(R6)4; wherein R6is F or an aryl group; or a Lewis acid; under an inert atmosphere, in the presence of an additive, wherein the additive is a diene or a phosphine.

[0017] In a second aspect, the present disclosure relates to a catalyst formed by reacting a compound of formula (III)

[0018] {[(L1)mRu(L2)2]n(S)v} (III), wherein n is 1 or 2, v is 0 or 1 , m is 1 or 2,

[0019] S is a coordinated molecule of a polar aprotic solvent or water; L1represents a diene, monophosphine, diphosphine, or triphosphine;

[0020] L2represents a p-diketonate or carboxylate OCOR3, wherein R3represents a linear or branched C1-C18 alkyl group, a linear or branched C2-C18 alkenyl group, a C3-C10 cycloalkyl group, an Ar group, or a CHR4Ar group, wherein Ar represents a Ce-C aryl, typically phenyl, optionally substituted by one or more halogen atoms, one or more alkoxy groups, or combination thereof, and wherein R4is a OH or NH2 group; in the presence of a protic acid of formula HX, wherein X is CIO4; R5SO3', wherein R5is Cl, F, Ci-Cs fluoroalkyl or fluoroaryl group; PFe’, SbCle', AsCle', SbFe', AsFe', B(R6)4; wherein R6is F or an aryl group; or a Lewis acid; under an inert atmosphere, in the presence of an additive, wherein the additive is a diene or a phosphine.

[0021] Brief Description of the Figures

[0022] FIG. 1 shows the use of various complexes of Formula (III) for the conversion of rac- 1-((1 R,2S)-2,6,6-trimethylcyclohex-3-en-1-yl)ethan-1-one to the corresponding product (GC %) over time in an exemplary process according to the present disclosure.

[0023] FIG. 2 shows the use of various complexes of Formula (III), temperatures, and corresponding product (GC %) formed over time in an exemplary process according to the present disclosure.

[0024] FIG. 3 shows the use of various complexes of Formula (III), additives, amounts of additive, and corresponding product (GC %) formed over time in an exemplary process according to the present disclosure.

[0025] FIG. 4 shows the use of various complexes of Formula (III), temperatures, and corresponding product (GC %) formed over time in an exemplary process according to the present disclosure. FIG. 5 shows the use of varying amounts of ruthenium complex and corresponding product (GC %) formed over time in an exemplary process according to the present disclosure.

[0026] FIG. 6 shows the effect of temperature and corresponding product (GC %) formed over time in an exemplary process according to the present disclosure.

[0027] FIG. 7 shows the effect of water, temperature, and corresponding product (GC %) formed over time in an exemplary process according to the present disclosure.

[0028] FIG. 8 shows the effect of equivalents of additive relative to Ru, and corresponding product (GC %) formed over time in an exemplary process according to the present disclosure.

[0029] FIG. 9 shows the effect of the quantity of boron trifluoride adduct, and corresponding product (GC %) formed over time in an exemplary process according to the present disclosure.

[0030] FIG. 10 shows the use of various boron trifluoride adducts used, and corresponding product (GC %) formed over time in an exemplary process according to the present disclosure.

[0031] FIG. 11 shows the use of various Lewis acids used, and corresponding product (GC %) formed over time in an exemplary process according to the present disclosure.

[0032] FIG. 12 shows the amount of ruthenium complex used, the additive used, the amount of additive used, and corresponding product (GC %) formed over time in an exemplary process according to the present disclosure.

[0033] FIG. 13 shows the use of various monophosphines, and corresponding product (GC %) formed over time in an exemplary process according to the present disclosure.

[0034] FIG. 14 shows the use of various monophosphines, and corresponding product (GC %) formed over time in an exemplary process according to the present disclosure. FIG. 15 shows the use of Ru complexes having various carboxylate ligands, and corresponding product (GC %) formed over time in an exemplary process according to the present disclosure.

[0035] FIG. 16 shows the use of Ru complexes having various carboxylate ligands, and corresponding product (GC %) formed over time in an exemplary process according to the present disclosure.

[0036] FIG. 17 shows the use of various amounts of (COD)Ru(acac)2, and corresponding product (GC %) formed over time in an exemplary process according to the present disclosure.

[0037] FIG. 18 shows the use of (COD)Ru(acac)2 under various temperatures, and corresponding product (GC %) formed over time in an exemplary process according to the present disclosure.

[0038] FIG. 19 shows the use of (COD)Ru(acac)2 with varying amounts of COD additive, and corresponding product (GC %) formed over time in an exemplary process according to the present disclosure.

[0039] FIG. 20 shows the use of varying amounts of (COD)Ru(acac)2, various additives, various amounts of the additives, and corresponding product (GC %) formed over time in an exemplary process according to the present disclosure.

[0040] FIG. 21 shows the conversion of rac-methyl (1 R,2S)-2,6,6-trimethylcyclohex-3-ene- 1 -carboxylate (trans delta isomer) to methyl 2,6,6-trimethylcyclohex-2-ene-1- carboxylate (“alpha isomer”), reagents, and corresponding product (GC %) formed over time in an exemplary process according to the present disclosure.

[0041] FIG. 22 shows the conversion of rac-(E)-1-((1 R,2S)-2,6,6-trimethylcyclohex-3-en-1- yl)but-2-en-1-one (“trans delta damascene”) to (E)-1-(2,6,6-trimethylcyclohex-2-en- 1-yl)but-2-en-1-one (“alpha damascene”), reagents, and corresponding product (GC %) formed over time in an exemplary process according to the present disclosure. Detailed Description

[0042] As used herein, the terms “a”, “an”, or “the” means “one or more” or “at least one” unless otherwise stated.

[0043] While compositions and methods are described in terms of “comprising,” “containing,” or “including” various components or steps, the compositions and methods can also “consist essentially of’ or “consist of’ the various components, substances and steps. As used herein the term “consisting essentially of’ shall be construed to mean including the listed components, substances or steps and such additional components, substances or steps which do not materially affect the basic and novel properties of the composition or method. In some embodiments, a composition in accordance with embodiments of the present disclosure that “consists essentially of’ the recited components or substances does not include any additional components or substances that alter the basic and novel properties of the composition.

[0044] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this specification pertains.

[0045] It should be understood that any numerical range recited herein is intended to include all sub-ranges subsumed therein. For example, a range of “1 to 10” is intended to include all sub-ranges between and including the recited minimum value of 1 and the recited maximum value of 10; that is, having a minimum value equal to or greater than 1 and a maximum value of equal to or less than 10. Because the disclosed numerical ranges are continuous, they include every value between the minimum and maximum values. Unless expressly indicated otherwise, the various numerical ranges specified in this application are approximations.

[0046] As used herein, and unless otherwise indicated, the term “about” or “approximately’ means an acceptable error for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined. In certain embodiments, the term “about” or “approximately” means within 1 , 2, 3, or 4 standard deviations. In certain embodiments, the term “about” or “approximately” means within 50%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range.

[0047] Throughout the present disclosure, various chemical names and structures may be recited. Unless otherwise stated, any stereoisomers, such as enantiomers, diastereomers, anomers, epimers, and the like; and geometric isomers, such as cis / trans or E / Z isomers, of the recited chemical name or structure are contemplated. As would be understood by those of ordinary skill in the art, stereoisomers may possess one stereocenter, giving rise to enantiomers, or more than one stereocenter, giving rise to diastereomers, each stereocenter having one of two different stereochemistries (i.e. , R or S). Enantiomers may be characterized by their ability to rotate oncoming plane-polarized light to the right, designated as dextrorotatory, “(+)” or“D”, or to the left, designated as levorotatory, or“L”. Enantiomers may exist as racemic mixtures or scalemic mixtures. Geometric isomers refer to isomers in which the spatial relationship of atoms around a double bond are different, typically designated E or Z according to conventional understanding in the chemical art. Geometric isomers may also exist as mixtures of E and Z isomers. All of the aforementioned isomeric variations of the chemical names or structures recited herein are included.

[0048] As used herein, the terminology "(Cx-Cy)", “Cx-Cy”, or“Cx-y” in reference to an organic group, wherein x and y are each integers, means that the group may contain from x carbon atoms to y carbon atoms per group.

[0049] As used herein, the term "alkyl" means a monovalent straight or branched saturated hydrocarbon radical, more typically, a monovalent straight or branched saturated (C1-C22) hydrocarbon radical, such as, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, hexyl, octyl, hexadecyl, octadecyl, eicosyl, behenyl, tricontyl, and tetracontyl.

[0050] As used herein, the term "cycloalkyl" means a monovalent saturated cyclic hydrocarbon radical, more typically a saturated cyclic (C3-C22) hydrocarbon radical, such as, for example, cyclopropyl, cyclobutyl, cyclopentyl, cycloheptyl, cyclooctyl, and the like.

[0051] As used herein, the term "alkoxy" or “alkoxyl” refers to an O-alkyl radical, in which alkyl is as defined herein. Exemplary alkoxy groups, typically Ci-Ce alkoxy, include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertbutoxy, pentoxy, and the like.

[0052] As used herein, the term "alkenyl" means an unsaturated straight or branched hydrocarbon radical, more typically an unsaturated straight, branched, (C2-C22) hydrocarbon radical, that contains one or more carbon-carbon double bonds, including, for example, ethenyl (vinyl), n-propenyl, and iso-propenyl, and allyl.

[0053] As used herein, the term "aryl" means a monovalent unsaturated hydrocarbon radical containing one or more six-membered carbon rings in which the unsaturation may be represented by three conjugated double bonds. Aryl radicals include monocyclic aryl and polycyclic aryl. “Polycyclic aryl” refers to a monovalent unsaturated hydrocarbon radical containing more than one six-membered carbon ring in which the unsaturation may be represented by three conjugated double bonds wherein adjacent rings may be linked to each other by one or more bonds or divalent bridging groups or may be fused together. Aryl radicals may be substituted at one or more carbons of the ring or rings. Examples of aryl radicals include, but are not limited to, phenyl, methylphenyl, isopropylphenyl, tert-butylphenyl, methoxyphenyl, dimethylphenyl, trimethylphenyl, chlorophenyl, trichloromethylphenyl, triisobutyl phenyl, anthracenyl, naphthyl, phenanthrenyl, fluorenyl, and pyrenyl.

[0054] Any substituent or radical described herein may optionally be substituted at one or more carbon atoms with one or more, same or different, substituents described herein. For instance, an alkyl group may be further substituted with an aryl group or another alkyl group. Any substituent or radical described herein may also optionally be substituted at one or more carbon atoms with one or more substituents selected from the group consisting of halogen, such as, for example, F, Cl, Br, and I; nitro (NO2), cyano (CN), amino (NH2), and hydroxy (OH). As used herein, the term "haloalkyl" means an alkyl radical, more typically a (C1-C22) alkyl radical, that is substituted with one or more halogen atoms, such as fluorine, chlorine, bromine, and iodine. Examples of haloalkyl groups include, but are not limited to, fluoroalkyl and chloroalkyl groups. Examples of fluoroalkyl groups include, for example, difluoromethyl, trifluoromethyl, perfluoroalkyl, 1 H,1 H,2H,2H- perfluorooctyl, perfluoroethyl, and -CH2CF3.

[0055] As used herein, the term "haloaryl" means an aryl radical that is substituted with one or more halogen atoms, such as fluorine, chlorine, bromine, and iodine. Examples of haloaryl groups include, but are not limited to, fluoroaryl and chloroaryl groups. Exemplary fluoroaryl groups include, but are not limited to, fluorophenyl, difluorophenyl, perfluorophenyl, and the like.

[0056] Throughout the present disclosure, various publications may be incorporated by reference. Should the meaning of any language in such publications incorporated by reference conflict with the meaning of the language of the present disclosure, the meaning of the language of the present disclosure shall take precedence, unless otherwise indicated.

[0057] In the first aspect, the present disclosure relates to a process for producing a mixture comprising at least a compound of formula (la), wherein each R1represents, independently, a hydrogen atom or a linear or branched Ci-Ce alkyl group, typically methyl group, and R2represents a hydrogen atom, linear or branched Ci-Ce alkyl, a C2-C6 alkenyl group, or a Ci-Ce alkoxy group. The mixture produced by the process described herein may further comprise isomerized products that are also desirable. In an embodiment, the mixture further comprises one or more compounds selected from the group consisting of compounds of formula (lb), and compounds of formula (Id), wherein each R1represents, independently, a hydrogen atom or a linear or branched C1-C6 alkyl group, typically methyl group, and R2represents a hydrogen atom, linear or branched Ci-Ce alkyl, a C2-C6 alkenyl group, or a Ci-Ce alkoxy group.

[0058] In another embodiment, in compounds according to formula (la), (lb), (Ic), or (Id), each R1represents, independently, a hydrogen atom or a methyl group, and R2represents a hydrogen atom, linear or branched C1-C4 alkyl, typically methyl group; a C2-C5 alkenyl group, typically 1 -alkenyl group, more typically 1 -propenyl group; or a C1-C5 alkoxy group, typically methoxy group.

[0059] In an embodiment, in compounds according to formula (la), (lb), (Ic), or (Id), each R1represents, independently, a hydrogen atom or a methyl group, and R2represents a hydrogen atom, a methyl group, a 1 -propenyl group, or a methoxy group.

[0060] In an embodiment, the compound of formula (la) is a compound of formula (la’) wherein R1and R2are as defined.

[0061] In an embodiment, the mixture further comprises one or more compounds selected from the group consisting of compounds of formula (lb’), compounds of formula (Ic’), and compounds of formula (Id’), wherein each R1and R2are as defined.

[0062] In the process according to the present disclosure, the compound of formula (II), wherein R1and R2have the same meaning as indicated hereinabove, acts as the starting material or substrate.

[0063] In an embodiment, in compounds according to formula (II), each R1represents, independently, a hydrogen atom or a methyl group, and R2represents a hydrogen atom, linear or branched C1-C4 alkyl, typically methyl group; a C2-C5 alkenyl group, typically 1 -alkenyl group, more typically 1 -propenyl group; or a C1-C5 alkoxy group, typically methoxy group.

[0064] In another embodiment, in compounds according to formula (II), each R1represents, independently, a hydrogen atom or a methyl group, and R2represents a hydrogen atom, a methyl group, a 1 -propenyl group, or a methoxy group.

[0065] The compound according to formula (II) may be in optically active form. It is understood that when the compound according to formula (II) is in optically active form, the resulting product(s), i.e., compounds of formula (la), (lb), (Ic), (Id), or, in some embodiments, compounds of formula (la’), (lb’), (lc’), or (Id’), are also in optically active form.

[0066] In an embodiment, the substrate is a compound according to formula (II) selected from the group consisting of 1-((1 R,2S)-2,6,6-trimethylcyclohex-3-en-1-yl)ethan-1- one, 1-((1S,2R)-2,6,6-trimethylcyclohex-3-en-1-yl)ethan-1-one, methyl (1 R,2S)-2,6,6- trimethylcyclohex-3-ene-1 -carboxylate, methyl (1 S,2R)-2,6,6-trimethylcyclohex-3- ene-1 -carboxylate, (E)-1-((1 R,2S)-2,6,6-trimethylcyclohex-3-en-1-yl)but-2-en-1-one, (E)-1-((1 S,2R)-2,6,6-trimethylcyclohex-3-en-1-yl)but-2-en-1-one, and any mixture thereof.

[0067] The compound of formula (III) is a ruthenium-based precursor catalyst, and is represented by:

[0068] {[(L1)mRu(L2)2]n(S)v} (III), wherein n is 1 or 2, v is 0 or 1 , m is 1 or 2,

[0069] S is a coordinated molecule of a polar aprotic solvent or water;

[0070] L1represents a diene, monophosphine, diphosphine, or triphosphine;

[0071] L2represents a p-diketonate or carboxylate OCOR3, wherein R3represents a linear or branched C1-C18 alkyl group, a linear or branched C2-C18 alkenyl group, a C3-C10 cycloalkyl group, an Ar group, or a CHR4Ar group, wherein Ar represents a Ce-C aryl, typically phenyl, optionally substituted by one or more halogen atoms, one or more alkoxy groups, or combination thereof, and wherein R4is a OH or NH2group.

[0072] According to the present disclosure, S is a coordinated molecule of a polar aprotic solvent or water. As used herein, "polar aprotic solvent" refers to a solvent that has a pKa above 18 and a dielectric constant £ above 20, said constant being measured at standard conditions. Said constant can be retrieved in chemical Handbooks such as "Handbook of Chemistry and Physics", 87th edition, 2006- 2007, page 15-13 to 15-23, ISBN 978-0-8493-0487-3, or such as March's "Advanced Organic Chemistry" 5th edition, ISBN 0-471-58589-0, or any other similar reference. In some instances, "polar aprotic solvent" includes solvents that are dipolar and non-protogenic. Exemplary coordinated molecules S include, but are not limited to, C2-12 amides, typically C3-8 N-alkyl or N, N-dialkyl amides, such as acetamide, N,N- dimethylacetamide, N,N-dimethyl-formamide, N-acetyl piperidine or N-acetylpyrrolidine; C2-6 sulfoxides, such as DMSO, Ce-9 N-alkyl lactams, such as N-methyl pyrrolidone; C4-8 carbamates or urea, such as tetramethylurea; C4-8 amines, such a tert-butylamine, and any mixture thereof.

[0073] In an embodiment, S is a coordinated molecule of water, n is 1 or 2, and v is 1.

[0074] L1represents a diene, monophosphine, diphosphine, or triphosphine. In an embodiment, L1represents a diene or monophosphine.

[0075] Suitable dienes are linear or branched C4-C15 hydrocarbons comprising two carboncarbon double bonds or cyclic C7-C20 hydrocarbons comprising two carbon-carbon double bonds. In some embodiments, the diene is a C7-C12, typically C7-C10, hydrocarbon compound comprising two carbon-carbon double bonds, and may be optionally substituted. Exemplary dienes include, but are not limited to, 1 ,5- cyclooctadiene, 1 ,3-cyclooctadiene, norbornadiene (NBD), 1 ,4-heptadiene, 2,3, 4- trimethylpenta-1 ,3-diene, 2,4-dimethylpenta-2,4-diene, and mixtures thereof.

[0076] Monophosphines, diphosphines, and triphosphines belong to the class of compounds known as phosphines.

[0077] Monophosphines are generally of the formula PR3, wherein each occurrence of R is a C1-C12 group, such as linear, branched or cyclic alkyl, alkoxy or aryloxy group which may be optionally substituted; substituted or unsubstituted phenyl, diphenyl, 2- furanyl, naphthyl, or di-naphthyl group. In some embodiments, each occurrence of R represents a substituted or unsubstituted phenyl, diphenyl or naphthyl or di-naphthyl group. Two R groups may be taken together and form a phosphatrioxa-adamantane group and the other R group has the same meaning as above. Exemplary monophosphines include, but are not limited to, trimethylphosphine, tributylphosphine, triphenylphosphine, trioctylphosphine, triisobutylphosphine, triethylphosphine, 2-dicyclohexylphosphino-2’,4’,6’-triisopropylbiphenyl, diphenylphosphine, tricyclohexylphosphine, 2-dicyclohexylphosphino-2’,6’- dimethoxybiphenyl, tri-tert-butylphosphine, tri(o-tolyl)phosphine, 2- (dicyclohexylphosphino)-3,6-dimethoxy-2’, 4’, 6’ -triisopropyl-1 ,1 ’-biphenyl, 2-di-tert- butylphosphino-2’,4’,6’-triisopropylbiphenyl, di( 1 -adamantyl)-n-butylphosphine, (2- biphenyl)di-tert-butylphosphine, 2-dicyclohexylphosphino-2’-(N,N- dimethylamino)biphenyl, 2-(di-tert-butylphosphino)-2’,4’,6’- triisopropyl-3,6- dimethoxy-1 ,1 ’-biphenyl, (2-biphenyl)dicyclohexylphosphine, (4-(N,N- dimethylamino)phenyl)di-tert-butyl phosphine, and the like. Diphosphines are generally C5-C50 bidentate ligands in which the coordinating groups are two phosphorous atoms. In some embodiments, the two phosphorus atoms of diphosphine ligands are separated by at least 2 carbon atoms and by at most 4 carbon atoms. Exemplary diphosphines include, but are not limited to, 1 ,1- bis(diphenylphosphino)methane, 1 ,2-bis(dimethylphosphino)ethane, 1 ,2- bis(diisopropylphosphino)ethane, 1 ,2-bis(diphenylphosphino)benzene, 1 ,2- bis(diphenylphosphino)ethane, a derivative of phenylanisylmethylphosphine, bis(dicyclohexylphosphino)ethane, 1 ,3-bis(diphenylphosphino)propane, 1 ,4- bis(diphenylphosphino)butane, (s,s)-diop (o-isopropylidene-2,3-dihydroxy-1 ,4- bis(diphenylphosphino)butane), 2,3-bis(diphenylphosphino)butane, 2,2'- bis(diphenylphosphino)-1 , 1 '-binaphthyl, 4,5-bis(diphenylphosphino)-9,9- dimethylxanthene, bis[(2-diphenylphosphino)phenyl] ether, 4,4,4',4',6,6'-hexamethyl- 2,2'-spirobichromane-8,8'-diylbis(diphenylphosphane), 4,4'-bi-1 ,3-benzodioxole-5,5'- diylbis(diphenylphosphane), 1 ,1 '-bis(diphenylphosphino)ferrocene, 1 ,2-bis(2,5- dimethylphospholano)benzene, (diphenylphosphino)ferrocenyl- ethyldicyclohexylphosphinel ,5-diaza-3,7-diphosphacyclooctanes, 1 ,5-diaza-3,7- diphosphacyclooctanes, and the like. Triphosphines contain three phosphorus atoms capable of coordinating with a metallic center. Exemplary triphosphines include, but are not limited to, 1 ,1 ,1-tris(diphenylphosphinomethyl)ethane, bis(diphenylphosphinoethyl)phenylphosphine, and the like.

[0078] In an embodiment, m is 1 and L1is a diene, typically selected from the group consisting of 1 ,5-cyclooctadiene (COD), norbornadiene (NBD), and 1 ,4-heptadiene. In another embodiment, m is 1 and L1is a diphosphine, typically selected from the group consisting of 2, 2'-bis(diphenylphosphino)-1 ,1 '-binaphthyl, 1 ,4- bis(diphenylphosphino)butane, 1 ,2-bis(diphenylphosphino)ethane, and 1 ,1- bis(diphenylphosphino)methane. In yet another embodiment, m is 2 and L1is a monophosphine, typically triphenylphosphine.

[0079] L2represents a p-diketonate or carboxylate OCOR3, wherein R3represents a linear or branched C1-C18 alkyl group, a linear or branched C2-C18 alkenyl group, a C3-C10 cycloalkyl group, an Ar group, or a CHR4Ar group, wherein Ar represents a Ce-C aryl, typically phenyl, optionally substituted by one or more halogen atoms, one or more alkoxy groups, or combination thereof, and wherein R4is a OH or NH2 group.

[0080] As would be understood by a person of ordinary skill in the art, a p-diketonate is a ligand comprising a C(=O)-CH=C(O') group. The p-diketonate is represented by the formula R’-C(=O)-CH=C(O-)-R” wherein R’ and R”, independently from each other, are a C1-6 alkyl group, typically a C1-4 alkyl group, such as a methyl, propyl, isopropyl or a tertbutyl group. Non-limiting examples of suitable p-diketonates, include, but are not limited to, 4-oxopent-2-en-2-olate (also known as “acetoacetonate” or "acetylacetonate"); 2,2-dimethyl-5-oxohex-3-en-3-olate; 2,6-dimethyl-5-oxohept-3- en-3-olate; 2,2,6,6-tetramethyl-5-oxohept-3-en-3-olate, and the like. In an embodiment, L2represents a p-diketonate, typically 4-oxopent-2-en-2-olate.

[0081] Carboxylates are ligands that comprise a C(=O)O' group and are typically represented by the formula OCOR3, in which R3is defined herein. In an embodiment, L2represents a carboxylate OCOR3, wherein R3represents a p- methoxyphenyl, o-methoxyphenyl, styryl, CH2CH(CHs)2, CH2C(CHs)3, CH(CHs)2, C(CHS)3, C(CH3)2(CH2CH3), CF3, cyclopropyl, cyclohexyl, adamantyl, pentafluorophenyl, p-chlorophenyl, phenyl, or CH(Ph)2, typically CH2CH(CHs)2, CH2C(CH3)3, CH(CH3)2, C(CH3)3, C(CH3)2(CH2CH3), CF3, cyclopropyl, cyclohexyl, adamantyl, pentafluorophenyl, p-chlorophenyl, phenyl, or CH(Ph)2. Unless otherwise stated, “Ph” represents a phenyl group. In an embodiment, L2represents a carboxylate OCOR3, wherein R3represents C(CHs)3. Exemplary compounds of formula (III) include, but are not limited to, compounds in which L1is diene or diphosphine, L2is carboxylate, which are described in WO 2011 / 145032 (Firmenich SA).

[0082] The compounds of formula (III) may be obtained from commercial sources or synthesized according to methods known to those of ordinary skill in the art. For example, a suitable method is described in WO 2011 / 145032 (Firmenich SA), which is incorporated herein by reference. Generally, compounds of formula (III) in which L1is a diene ligand, i.e. , {[(diene)Ru(L2)2]n(S)v}, can be synthesized by reaction of polymeric [(diene)RuCl2]n with the ligand L2in DMF in the presence of MOH, wherein M is an alkali metal cation, typically KOH. Compounds of formula (III) in which L1is a monophosphine, diphosphine, or triphosphine can be made by reacting {[(diene)Ru(L2)2]n(S)v} with suitable amounts of the desired monophosphine, diphosphine, or triphosphine. The desired complexes are generally recovered by filtration, either directly precipitating from the reaction mixture or being further precipitated upon reaction completion using precipitation methods known to those of ordinary skill in the art.

[0083] The amount of the compound of formula (III) is not particularly limited. However, good results may be obtained using less than stoichiometric amounts. In an embodiment, the compound of formula (III) is present in a catalytic amount. In another embodiment, the compound of formula (III) is present in an amount of from 0.0010 mol% to 0.40 mol%, typically 0.0025 mol% to 0.20 mol%, more typically 0.005 mol% to 0.15 mol%, relative to the molar amount of compound of formula (II).

[0084] The process of the present disclosure employs the use of an acid, which may be a protic acid or a Lewis acid. Suitable protic acids are of formula HX, wherein X is CIOT, R5SC>3', wherein R5is Cl, F, Ci-Cs fluoroalkyl or fluoroaryl group; PFe’, SbCle', AsCle', SbFe', AsFe', B(R6)4', wherein R6is F or an aryl group.

[0085] As would be understood by those of ordinary skill in the art, Lewis acids are defined as chemical species that are capable of accepting an electron pair from an electron donor (Lewis base). Suitable Lewis acids are of the formula MX’Pwherein M is a metal, X’ is a weakly or non-coordinating ligand and p is 1 , 2 or 3 and depend on the oxidation state of the metal and the nature of the anion (dianion or monanion). When the metal is a monovalent metal cation, then p is 1 , when the metal is a divalent metal cation, then p is 2 when X’ is a monoanion or p is 1 when X’ is a dianion, and when the metal is a trivalent metal cation, then p is 3 when X’ is a monoanion or p is 2 when X’ is a dianion and another X’ is a monoanion. Nonlimiting examples of suitable weakly or non-coordinating ligands include, but are not limited to, BF4 , CIO4; PFe’, HSO4; SO42; TfO’, NTf2’, TsO’, CISOs’, and the like. It is understood that whereas p is 2 or 3, then each of X’ group may be identical or different. As used herein, “Tf’ represents trifluoromethanesulfonyl group and “Ts” represents p-toluenesulfonyl group.

[0086] In some embodiments, p may be 2 and 3. In such an embodiment, the Lewis acid is of formula MX’2 or MX’3, wherein M is a metal selected from the group consisting of B, Bi and Fe and X is a F’ or Cl’ or a triflate, sulfate or hydrogenosulfate group or a mixture thereof. In some embodiments, the metal may be selected from the group of Bi and Fe and X’ may be selected from the group of Cl- or a triflate, sulfate or hydrogenosulfate group and a mixture thereof.

[0087] Other suitable Lewis acids are of the formula B(R7)s, or an adduct thereof, wherein R7represents a halogen, typically Br or F; alkoxyl, aryl, or fluoroaryl group.

[0088] Still other suitable Lewis acids are of the formula FeXs, FeX2, AgX, AIY3, BiYs, FeYs, FeY2, SnY2, SnY4, AgY, AgY2, SbYs, AsYs, PY5, or an adduct thereof, wherein X is a group as defined above and Y is Cl, F, SO3R8, wherein R8is Ci-Cs fluoroalkyl or fluoroaryl group; OOCR9, wherein R9is a Ci-Cs linear or branched alkyl group; or OR10, wherein R10is a Ci-Cs linear or branched alkyl group.

[0089] The amount of acid used is not particularly limited. However, in an embodiment, the protic acid or the Lewis acid is present in an amount of from 1 to 3 molar equivalents, typically 2 to 3 molar equivalents, relative to the molar amount of compound of formula (III).

[0090] In an embodiment, the Lewis acid is a Lewis acid of formula BF3 or a BF3 adduct selected from the group consisting of BF3.NH2EL BF3.(H2O)2, BF3.(CH3COOH)2, BF3.Et2O, and BF3.B112O, more typically in the form of an adduct selected from the group consisting of BF3.(H2O)2, BF3.(CH3COOH)2, BF3.Et2O, and BF3.BU2O.

[0091] The process of the present disclosure employs the use of an additive, wherein the additive is a diene, such as the dienes described herein, or a phosphine, such as the monophosphine, diphosphine, or triphosphine described herein. The additive may be the same as or different from the diene or phosphine ligand used as L1. In an embodiment, the additive is 1 ,5-cyclooctadiene or triphenylphosphine.

[0092] The amount of additive is not particularly limited. In an embodiment, the additive is present in an amount of from 0 to 25 molar equivalents, typically 1 to 23 molar equivalents, more typically 2 to 15 molar equivalents, relative to the molar amount of compound of formula (III). In an embodiment, the additive is present in an amount of from 0.01 to 25 molar equivalents, typically 0.1 to 25 molar equivalents, more typically 0.5 to 25 molar equivalents, relative to the molar amount of compound of formula (III). In an embodiment, the additive is present in an amount of from 3 to 25 molar equivalents, typically 7 to 25 molar equivalents, relative to the molar amount of compound of formula (III).

[0093] Optionally, the process of the present disclosure may be conducted using a nonaromatic weakly- or non-coordinating solvent. As used herein, a non-coordinating or weakly coordinating solvent is a solvent which does not significantly deactivate the catalyst and allows the substrate to interact with the catalyst, which is a concept well- known to those ordinary skill in the art of catalysis. In other words, a weakly- or noncoordinating solvent is a solvent which does not coordinate at all the Ru center of the catalyst, or which has a coordination stability constant inferior to that of the substrate to be isomerized. In general, any solvent that is inert under the experimental conditions and can solubilize the substrate and catalyst is particularly suitable. In an embodiment, the process is carried out in the presence of a non-aromatic weakly- or non-coordinating solvent selected from the group consisting of a chlorinated hydrocarbon, a saturated or unsaturated hydrocarbon, an ether, an ester, a weakly coordinating ketone (sterically hindered ketone), and mixtures thereof. In an embodiment, the non-aromatic weakly- or non-coordinating solvent is selected from the group consisting of CH2CI2, heptane, octane, dibutyl ether, diethyl ether, butyl acetate, methyl tert-butyl ether, diisopropylketone, and mixtures thereof.

[0094] The process of the present disclosure as mentioned is carried out under an inert, or an essentially oxygen free atmosphere. A person of ordinary skill in the art knows what is meant by an inert atmosphere, and as non-limiting examples of such atmosphere, one may cite a nitrogen or argon atmosphere.

[0095] The process may be conducted over a broad range of temperatures. A person of ordinary skill in the art would be able to select the suitable temperature as a function of the melting and boiling point as well as of the specific properties of any solvents used as well as the desired time of reaction or conversion. However, in an embodiment, the process is conducted at a temperature of from 45 to 150 °C, typically from 90 to 135 °C, more typically 100 to 135 °C. In another embodiment, the process is conducted at a temperature of from 115 to 125 °C.

[0096] Upon reaction completion, the desired products may be isolated using methods known to those of ordinary skill in the art. For example, water may be added to the reaction mixture to quench the catalyst and the lower aqueous phase removed. The organic phase may then be washed several times with water, dried, typically with a drying agent, such as anhydrous sodium sulfate, filtered, and then concentrated. Optionally, after solvent concentration, flash distillation under vacuum may be performed.

[0097] In the second aspect, the present disclosure relates to a catalyst formed by reacting a compound of formula (III)

[0098] {[(L1)mRu(L2)2]n(S)v} (III), wherein n is 1 or 2, v is 0 or 1 , m is 1 or 2

[0099] S is a coordinated molecule of a polar aprotic solvent or water; L1represents a diene, monophosphine, diphosphine, or triphosphine;

[0100] L2represents a p-diketonate or carboxylate OCOR3, wherein R3represents a linear or branched C1-C18 alkyl group, a linear or branched C2-C18 alkenyl group, a C3-C10 cycloalkyl group, an Ar group, or a CHR4Ar group, wherein Ar represents a Ce-C aryl, typically phenyl, optionally substituted by one or more halogen atoms, one or more alkoxy groups, or combination thereof, and wherein R4is a OH or NH2 group; in the presence of a protic acid of formula HX, wherein X is CIO4; R5SO3', wherein R5is Cl, F, Ci-Cs fluoroalkyl or fluoroaryl group; PFe’, SbCle', AsCle', SbFe', AsFe', B(R6)4; wherein R6is F or an aryl group; or a Lewis acid; under an inert atmosphere, in the presence of an additive, wherein the additive is a diene or a phosphine.

[0101] In an embodiment, S is a coordinated molecule of a polar aprotic solvent or water. In a particular embodiment, S is a coordinated molecule of water, n is 1 or 2, and v is 1.

[0102] In an embodiment, L1represents a diene or monophosphine. In an embodiment, L1represents a diene selected from the group consisting of 1 ,5-cyclooctadiene, 1 ,3- cyclooctadiene, norbornadiene (NBD), 1 ,4-heptadiene, 2,3,4-trimethylpenta-1 ,3- diene, 2,4-dimethylpenta-2,4-diene, and any mixture thereof. In an embodiment, L1represents a monophosphine selected from the groups consisting of trimethylphosphine, tributylphosphine, triphenylphosphine, trioctylphosphine, triisobutylphosphine, triethylphosphine, 2-dicyclohexylphosphino-2’,4’,6’- triisopropylbiphenyl, diphenylphosphine, tricyclohexylphosphine, 2- dicyclohexylphosphino-2’,6’-dimethoxybiphenyl, tri-tert-butylphosphine, tri(o- tolyl)phosphine, 2-(dicyclohexylphosphino)-3,6-dimethoxy-2’,4’,6’-triisopropyl-1 ,1’- biphenyl, 2-d i-tert-butyl phosph ino-2’ ,4’ ,6’-triisopropyl biphenyl , di( 1 -adamantyl)-n- butylphosphine, (2-biphenyl)di-tert-butylphosphine, 2-dicyclohexylphosphino-2’-(N,N- dimethylamino)biphenyl, 2-(di-tert-butylphosphino)-2’,4’,6’- triisopropyl-3,6- dimethoxy-1 ,1 ’-biphenyl, (2-biphenyl)dicyclohexylphosphine, (4-(N,N- dimethylamino)phenyl)di-tert-butyl phosphine, and any mixture thereof. In an embodiment, m is 1 and L1is a diene, typically selected from the group consisting of 1 ,5-cyclooctadiene (COD), norbornadiene (NBD), and 1 ,4-heptadiene. In another embodiment, m is 2 and L1is a monophosphine, typically triphenylphosphine. In certain embodiments, L1is not 6,6'-dimethoxybiphenyl-2,2'- diyl)bis(bis(3,5-di-tert-butylphenyl)phosphine or any stereoisomer thereof.

[0103] In an embodiment, L2represents a p-diketonate selected from the group consisting of 4-oxopent-2-en-2-olate (also known as “acetoacetonate” or "acetylacetonate"); 2,2-dimethyl-5-oxohex-3-en-3-olate; 2,6-dimethyl-5-oxohept-3-en-3-olate; 2, 2,6,6- tetramethyl-5-oxohept-3-en-3-olate, and any mixture thereof. In an embodiment, L2represents 4-oxopent-2-en-2-olate. In an embodiment, L2represents a carboxylate OCOR3, wherein R3represents a p-methoxyphenyl, o-methoxyphenyl, styryl, CH2CH(CH3)2, CH2C(CH3)3, CH(CH3)2, C(CH3)3, C(CH3)2(CH2CH3), CF3, cyclopropyl, cyclohexyl, adamantyl, pentafluorophenyl, p-chlorophenyl, phenyl, or CH(Ph)2, typically CH2CH(CH3)2, CH2C(CH3)3, CH(CH3)2, C(CH3)3, C(CH3)2(CH2CH3), CF3, cyclopropyl, cyclohexyl, adamantyl, pentafluorophenyl, p-chlorophenyl, phenyl, or CH(Ph)2. In an embodiment, L2represents a carboxylate OCOR3, wherein R3represents C(CH3)3.

[0104] In certain embodiments, the catalyst formed by reacting a compound of formula (III) with the protic acid or Lewis acid, and the additive is not [Ru(n5-C8Hn){(R)-6,6'- dimethoxybiphenyl-2,2'-diyl)bis(bis(3,5-di-tert-butylphenyl)phosphine}][BF4].

[0105] In the process described herein, the compound of formula (III), the protic acid or Lewis acid, and the additive together form a catalyst that has been found to facilitate the desired isomerization of substrates according to formula (II) into the corresponding isomerized products complying with formula (la) and, in some embodiments, formula (lb), formula (Ic), or formula (Id).

[0106] Mention is made of the use of a catalyst described herein for producing a mixture comprising at least a compound of formula (la) from a compound of formula (II).

[0107] The processes and catalysts according to the present disclosure are further illustrated by the following non-limiting examples. Examples

[0108] Unless otherwise indicated, the following general procedure was used for the isomerization reaction. Solid ruthenium complex of Formula (III), obtained according to known methods, was placed in a Schlenk tube. It was degassed by performing vacuum / nitrogen cycles (3 times). Previously inerted substrate was then loaded under nitrogen atmosphere in the same Schlenk tube and the reaction mixture was degassed by performing vacuum / nitrogen cycles under stirring (three times).

[0109] Previously inerted additive and boron trifluoride adduct were then added sequentially under nitrogen to the stirred reaction mixture that was then degassed again performing vacuum / nitrogen cycles under stirring (three times). It was then heated to the desired temperature while being maintained under nitrogen atmosphere during the whole reaction which progress was followed by GC analysis upon sampling under nitrogen atmosphere. Upon reaction completion, the Schlenk tube was cooled down to 20°C.

[0110] Example 1

[0111] Various ruthenium complexes of formula {[(L)mRu(OCOtBu)2]n(H2O)v}, were used to conduct the isomerization reaction to convert rac-1-((1 R,2S)-2,6,6-trimethylcyclohex- 3-en-1-yl)ethan-1-one (“trans delta methyl ketone” or“TDMK”) to 1 -(2,6,6- trimethylcyclohex-2-en-1-yl)ethan-1-one (“AMK”) according to the general procedure described herein. Complexes were used in which the ligand L were varied and in which the values m, n, or v were varied. The complex was used in an amount resulting in 0.1 mol% Ru, relative to the substrate TDMK. The additive was 1 ,5- cyclooctadiene (COD) (15 eq. I Ru) and the boron trifluoride adduct was BF3.BU2O (2 eq. I Ru). The reaction was carried out neat at a temperature of 120 °C. FIG. 1 shows the different ligands and values of m, n, and v, and corresponding AMK (GC %) formed over time. Yields of up to 76% (by GC) AMK were obtained. Example 2.

[0112] The isomerization reaction of Example 1 was carried out, except that the temperature used was 90 °C or 120 °C. FIG. 2 shows the ligands, values of m, n, and v, temperature, and corresponding AMK (GC %) formed over time. Yields of up to 76% (by GC) AMK were obtained.

[0113] Example 3.

[0114] The isomerization reaction of Example 1 was carried out, except that the additive and the amount of additive were varied. FIG. 3 shows the ligands, values of m, n, and v, additive, amount of additive, and corresponding AMK (GC %) formed over time. Yields of up to 87% (by GC) AMK were obtained.

[0115] Example 4.

[0116] The isomerization reaction of Example 1 was carried out, except that ruthenium complexes of formula {[(L1)mRu(OCOtBu)2]n(H2O)v} were used. The temperature of the reaction was 90 °C or 120 °C. FIG. 4 shows the ligands, values of m, n, and v, temperature, and corresponding AMK (GC %) formed over time. Yields of up to 76% (by GC) AMK were obtained.

[0117] Example 5.

[0118] The isomerization reaction of Example 1 was carried out, except that the ruthenium complex of formula {[(COD)Ru(OCOtBu)2]2(H2O)} was used and the amount of ruthenium complex was varied. FIG. 5 shows the amount of ruthenium complex used and corresponding AMK (GC %) formed over time. Yields of up to 85% (by GC) AMK were obtained.

[0119] Example 6.

[0120] The isomerization reaction of Example 1 was carried out, except that the ruthenium complex of formula {[(COD)Ru(OCOtBu)2]2(H2O)} was used at an amount of 0.1 mol% Ru and the temperature was varied from 90 °C to 135 °C. FIG. 6 shows the temperature and corresponding AMK (GC %) formed over time. Yields of up to 77% (by GC) AMK were obtained.

[0121] Example 7.

[0122] The isomerization reaction of Example 1 was carried out, except that ruthenium complexes of formula {[(COD)Ru(OCOtBu)2]n(H2O)v} were used. The temperature of the reaction was 90 °C or 120 °C. FIG. 7 shows the values of n and v, temperature, and corresponding AMK (GC %) formed over time. Yields of up to 76% (by GC) AMK were obtained.

[0123] Example 8.

[0124] The isomerization reaction of Example 1 was carried out, except that the ruthenium complex of formula {[(COD)Ru(OCOtBu)2]2(H2O)} was used at an amount of 0.1 mol% Ru and the amount of additive COD was varied from 0 to 22.5 eq. I Ru. FIG. 8 shows the equivalents of COD relative to Ru, and corresponding AMK (GC %) formed over time. Yields of up to 76% (by GC) AMK were obtained.

[0125] Example 9.

[0126] The isomerization reaction of Example 1 was carried out, except that the ruthenium complex of formula {[(COD)Ru(OCOtBu)2]2(H2O)} was used at an amount of 0.1 mol% Ru and the amount of boron trifluoride adduct BF3.BU2O was varied from 0 to 3 eq. I Ru. FIG. 9 shows the equivalents of boron trifluoride adduct relative to Ru, and corresponding AMK (GC %) formed over time. Yields of up to 76% (by GC) AMK were obtained.

[0127] Example 10.

[0128] The isomerization reaction of Example 1 was carried out, except that the ruthenium complex of formula {[(COD)Ru(OCOtBu)2]2(H2O)} was used at an amount of 0.1 mol% Ru and various boron trifluoride adducts were used. The amount of the boron trifluoride adduct was fixed at 2 eq. I Ru. FIG. 10 shows the boron trifluoride adducts used, and corresponding AMK (GC %) formed over time. Yields of up to 76% (by GO) AMK were obtained.

[0129] Example 11.

[0130] The isomerization reaction of Example 1 was carried out, except that the ruthenium complex of formula {[(COD)Ru(OCOtBu)2]2(H2O)} was used at an amount of 0.1 mol% Ru and the boron trifluoride adduct was replaced by various Lewis acids. The amount of the Lewis acid was fixed at 2 eq. I Ru. FIG. 11 shows the Lewis acids used, and corresponding AMK (GC %) formed over time. Yields of up to 76% (by GC) AMK were obtained.

[0131] Example 12.

[0132] The isomerization reaction of Example 1 was carried out, except that the ruthenium complex of formula {[(COD)Ru(OCOtBu)2]2(H2O)} was used at an amount of from 0.005 to 0.1 mol% Ru, the additive was varied, and the amount of additive was varied from 7 to 20 eq. I Ru. FIG. 12 shows the amount of ruthenium complex used, the additive used, the amount of additive used, and corresponding AMK (GC %) formed over time. Yields of up to 87% (by GC) AMK were obtained.

[0133] Example 13.

[0134] The isomerization reaction of Example 1 was carried out, except that the ruthenium complex of formula {[(COD)Ru(OCOtBu)2]2(H2O)} was used at an amount of 0.05 mol% Ru and the additive used was a monophosphine in an amount of 7 eq. I Ru. FIG. 13 shows the monophosphines used, and corresponding AMK (GC %) formed over time. Yields of up to 87% (by GC) AMK were obtained.

[0135] Example 14.

[0136] The isomerization reaction of Example 1 was carried out, except that the ruthenium complex of formula {[(COD)Ru(OCOtBu)2]2(H2O)} was used at an amount of 0.05 mol% Ru and the additive used was a monophosphine different from those used in Example 13 in an amount of 7 eq. I Ru. FIG. 14 shows the monophosphines used, and corresponding AMK (GC %) formed over time. Yields of up to 87% (by GO) AM K were obtained.

[0137] Example 15.

[0138] The isomerization reaction of Example 1 was carried out, except that the ruthenium complex of formula {[(COD)Ru(OCOR)2]n(H2O)v} was used at an amount of 0.1 mol% Ru. The R group in the carboxylate ligand was varied. FIG. 15 shows the various carboxylate ligands in which R was varied, and corresponding AMK (GC %) formed over time. Yields of up to 81% (by GC) AMK were obtained.

[0139] Example 16.

[0140] The isomerization reaction of Example 1 was carried out, except that the ruthenium complex of formula {[(COD)Ru(OCOR)2]n(H2O)v} was used at an amount of 0.1 mol% Ru. The R group in the carboxylate ligand was varied with groups different from those in Example 15. FIG. 16 shows the various carboxylate ligands in which R was varied, and corresponding AMK (GC %) formed over time. Yields of up to 78% (by GC) AMK were obtained.

[0141] Example 17.

[0142] The isomerization reaction of Example 1 was carried out, except that the ruthenium complex of formula (COD)Ru(acac)2 was used in various amounts (from 0.05 mol% 0.15 mol% Ru). FIG. 17 shows the various amounts of (COD)Ru(acac)2, and corresponding AMK (GC %) formed over time. Yields of up to 84% (by GC) AMK were obtained.

[0143] Example 18.

[0144] The isomerization reaction of Example 1 was carried out, except that the ruthenium complex of formula (COD)Ru(acac)2 was used in an amount of 0.1 mol% Ru and the temperature was varied from 105 to 135 °C. FIG. 18 shows the various temperatures, and corresponding AMK (GC %) formed over time. Yields of up to 78% (by GC) AMK were obtained.

[0145] Example 19.

[0146] The isomerization reaction of Example 1 was carried out, except that the ruthenium complex of formula (COD)Ru(acac)2 was used in an amount of 0.1 mol% Ru and the amount of COD additive was varied from 0 to 22.5 eq. COD I Ru. FIG. 19 shows the varying amounts of COD additive used, and corresponding AMK (GC %) formed over time. Yields of up to 76% (by GC) AMK were obtained.

[0147] Example 20.

[0148] The isomerization reaction of Example 1 was carried out, except that the ruthenium complex of formula (COD)Ru(acac)2 was used in various amounts (from 0.01 mol% 0.1 mol% Ru), the additive was varied, and the amount of additive was varied from 7 to 15 eq. / Ru. FIG. 20 shows the varying amounts of Ru complex used, the various additives, various amounts of the additives used, and corresponding AMK (GC %) formed over time. Yields of up to 83% (by GC) AMK were obtained.

[0149] Example 21.

[0150] (PPh3)2Ru(OCOtBu)2 or {[(COD)Ru(OCOtBu)2]2(H2O)} (0.1 mol % Ru) were used to conduct the isomerization reaction to convert rac-methyl (1 R,2S)-2,6,6- trimethylcyclohex-3-ene-1 -carboxylate (“trans delta isomer”) to methyl 2,6,6- trimethylcyclohex-2-ene-1 -carboxylate (“alpha isomer”) according to the general procedure described herein. The additive was either 1 ,5-cyclooctadiene (COD) (15 eq. I Ru) or PPhs (5 eq. I Ru). The boron trifluoride adduct was BF3.BU2O (2 eq. I Ru). The reaction was carried out neat at a temperature of 120 °C. FIG. 21 shows the reagents, and corresponding alpha isomer (GC %) formed over time. Yields of up to 50% (by GC) alpha isomer were obtained. Example 22.

[0151] (PPhs)2Ru(OCOtBu)2 or {[(COD)Ru(OCOtBu)2]2(H2O)} (0.05 mol % Ru) were used to conduct the isomerization reaction to convert rac-(E)-1-((1 R,2S)-2,6,6- trimethylcyclohex-3-en-1-yl)but-2-en-1-one (“trans delta damascene”) to (E)-1- (2,6,6-trimethylcyclohex-2-en-1-yl)but-2-en-1-one (“alpha damascene”) according to the general procedure described herein. The additive was either 1 ,5-cyclooctadiene (COD) (15 eq. I Ru) or PPhs (5 eq. I Ru). The boron trifluoride adduct was BF3.BU2O (2 eq. I Ru). The reaction was carried out neat at a temperature of 120 °C. FIG. 22 shows the reagents, and corresponding alpha damascene (GC %) formed over time. Yields of up to 74% (by GC) alpha isomer were obtained.

[0152] The disclosed subject matter has been described with reference to specific details of particular embodiments thereof. It is not intended that such details be regarded as limitations upon the scope of the disclosed subject matter except insofar as and to the extent that they are included in the accompanying claims.

[0153] Therefore, the exemplary embodiments described herein are well adapted to attain the ends and advantages mentioned as well as those that are inherent therein. The particular embodiments disclosed above are illustrative only, as the exemplary embodiments described herein may be modified and practiced in different but equivalent manners apparent to those of ordinary skill in the art having the benefit of the teachings herein. Furthermore, no limitations are intended to the details of construction or design herein shown, other than as described in the claims below. It is therefore evident that the particular illustrative embodiments disclosed above may be altered, combined, or modified and all such variations are considered within the scope and spirit of the exemplary embodiments described herein. The exemplary embodiments described herein illustratively disclosed herein suitably may be practiced in the absence of any element that is not specifically disclosed herein and / or any optional element disclosed herein.

Claims

WHAT IS CLAIMED IS:1 . A process for producing a mixture comprising at least a compound of formula (la),wherein each R1represents, independently, a hydrogen atom or a linear or branched C1-C6 alkyl group, typically methyl group, and R2represents a hydrogen atom, linear or branched Ci-Ce alkyl, a C2-C6 alkenyl group, or a Ci-Ce alkoxy group; the process comprising reacting a compound of formula (II),wherein R1and R2have the same meaning as indicated above; with a compound of formula (III){[(L1)mRu(L2)2]n(S)v} (III), wherein n is 1 or 2, v is 0 or 1 , m is 1 or 2,S is a coordinated molecule of a polar aprotic solvent or water;L1represents a diene, monophosphine, diphosphine, or triphosphine;L2represents a p-diketonate or carboxylate OCOR3, wherein R3represents a linear or branched C1-C18 alkyl group, a linear or branched C2-C18 alkenyl group, a C3-C10 cycloalkyl group, an Ar group, or a CHR4Ar group, wherein Ar represents a Ce-C aryl, typically phenyl, optionally substituted by one or more halogen atoms, one or more alkoxy groups, or combination thereof, and wherein R4is a OH or NH2 group; in the presence of a protic acid of formula HX, wherein X is CIOT, R5SO3', wherein R5is Cl, F, Ci-Cs fluoroalkyl or fluoroaryl group; PFe’, SbCle', AsCle', SbFe', AsFe', B(R6)4; wherein R6is F or an aryl group; or a Lewis acid; under an inert atmosphere, in the presence of an additive, wherein the additive is a diene or a phosphine.

2. The process according to claim 1 , wherein the mixture further comprises one or more compounds selected from the group consisting of compounds of formula (lb),compounds of formula (Ic),and compounds of formula (Id),wherein each R1represents, independently, a hydrogen atom or a linear or branched Ci-Ce alkyl group, typically methyl group, and R2represents a hydrogen atom, linear or branched Ci-Ce alkyl, a C2-C6 alkenyl group, or a Ci-Ce alkoxy group.

3. The process according to claim 1 or 2, wherein the compound of formula (III) is present in a catalytic amount.

4. The process according to any one of claims 1 to 3, wherein S is a coordinated molecule of water, n is 1 or 2, and v is 1 .

5. The process according to any one of claims 1 to 4, wherein the additive is 1 ,5- cyclooctadiene or triphenylphosphine.

6. The process according to any one of claims 1 to 5, wherein the process is conducted in the presence of a Lewis acid of formula B(R7)s, or an adduct thereof, wherein R7represents a halogen, typically Br or F; alkoxyl, aryl, or fluoroaryl group, or a Lewis acid of formula FeXs, FeX2, AgX, AIY3, BiYs, FeYs, FeY2, SnY2, SnY4, AgY, AgY2, SbYs, AsYs, PY5, or an adduct thereof, wherein X is a group as defined above and Y is Cl, F, SO3R8, wherein R8is Ci-Cs fluoroalkyl or fluoroaryl group; OOCR9, wherein R9is a Ci-Cs linear or branched alkyl group; or OR10, wherein R10is a Ci-Cs linear or branched alkyl group.

7. The process according to claim 6, wherein the process is conducted in the presence of a Lewis acid of formula B(R7)s, or an adduct thereof, wherein R7represents a halogen, typically Br or F; alkoxyl, aryl, or fluoroaryl group.

8. The process according to claim 6 or 7, wherein the process is conducted in the presence of a Lewis acid of formula BF3 or a BF3 adduct selected from the groupconsisting of BF3.NH2Et, BF3.(H2O)2, BF3.(CH3COOH)2, BF3.Et2O, and BF3.Bu2O, more typically in the form of an adduct selected from the group consisting of BF3.(H2O)2, BF3.(CH3COOH)2, BF3.Et2O, and BF3.Bu2O.

9. The process according to any one of claims 1 to 8, wherein m is 1 and L1is a diene, typically selected from the group consisting of 1 ,5-cyclooctadiene (COD), norbornadiene (NBD), and 1 ,4-heptadiene, or m is 2 and L1is a monophosphine, typically triphenylphosphine.

10. The process according to any one of claims 1 to 9, wherein L2represents a carboxylate OCOR3, wherein R3represents a p-methoxyphenyl, o-methoxyphenyl, styryl, CH2CH(CH3)2, CH2C(CH3)3, CH(CH3)2, C(CH3)3, C(CH3)2(CH2CH3), CF3, cyclopropyl, cyclohexyl, adamantyl, pentafluorophenyl, p-chlorophenyl, phenyl, or CH(Ph)2, typically CH2CH(CH3)2, CH2C(CH3)3, CH(CH3)2, C(CH3)3, C(CH3)2(CH2CH3), CF3, cyclopropyl, cyclohexyl, adamantyl, pentafluorophenyl, p- chlorophenyl, phenyl, or CH(Ph)2.11 . The process according to any one of claims 1 to 10, wherein the compound of formula (la) is a compound of formula (la’)wherein R1and R2are as defined.

12. The process according to any one of claims 1 to 1 1 , wherein the mixture further comprises one or more compounds selected from the group consisting of compounds of formula (lb’),and compounds of formula (Id’),wherein each R1and R2are as defined.

13. A catalyst formed by reacting a compound of formula (III){[(L1)mRu(L2)2]n(S)v} (III), wherein n is 1 or 2, v is 0 or 1 , m is 1 or 2S is a coordinated molecule of a polar aprotic solvent or water;L1represents a diene, monophosphine, diphosphine, or triphosphine;L2represents a p-diketonate or carboxylate OCOR3, wherein R3represents a linear or branched C1-C18 alkyl group, a linear or branched C2-C18 alkenyl group, a C3-C10 cycloalkyl group, an Ar group, or a CHR4Ar group, wherein Ar represents a Ce-C aryl, typically phenyl, optionally substituted by one or more halogen atoms, one or more alkoxy groups, or combination thereof, and wherein R4is a OH or NH2 group; in the presence of a protic acid of formula HX, wherein X is CIO4; R5SO3', wherein R5is Cl, F, Ci-Cs fluoroalkyl or fluoroaryl group; PFe’, SbCle', AsCle', SbFe', AsFe', B(R6)4; wherein R6is F or an aryl group; or a Lewis acid; under an inert atmosphere, in the presence of an additive, wherein the additive is a diene or a phosphine.

14. Use of a catalyst according to claim 13 for producing a mixture comprising at least a compound of formula (la),wherein each R1represents, independently, a hydrogen atom or a linear or branched C1-C6 alkyl group, typically methyl group, and R2represents a hydrogen atom, linear or branched Ci-Ce alkyl, a C2-C6 alkenyl group, or a Ci-Ce alkoxy group; from a compound of formula (II),wherein R1and R2have the same meaning as indicated above.