Process for preparing alpha delta di-carbonyl derivatives

Abstract

The present invention relates to the field of organic synthesis and more specifically it concerns a process for preparing a compound of formula (I), preparing a compound of formula (V) and a compound of formula (VI).

Description

[0001] PROCESS FOR PREPARING ALPHA DELTA DI-CARBONYL DERIVATIVES

[0002] Technical Field

[0003] The present invention relates to the field of organic synthesis and more specifically it concerns a process for preparing a compound of formula (I), preparing a compound of formula (V) and a compound of formula (VI).

[0004] Background of the Invention

[0005] Alpha, delta-dicarbonyl compounds are a class of organic compounds characterized by the presence of carbonyl groups (C=O) positioned at the alpha and delta positions relative to each other on a carbon chain. These compounds are of substantial interest in the fragrance and flavor industry due to their versatility and role as intermediates in the synthesis of complex perfuming ingredients.

[0006] The utility of alpha, delta-dicarbonyl derivatives stems from their ability to undergo further chemical transformations, leading to the formation of a diverse array of aromatic and nonaromatic compounds used in the manufacture of perfumes, flavorings, and other fragrance-related products. The quality and properties of these final products are often dependent on the structure and substitution pattern of the alpha, delta-dicarbonyl intermediates used in their synthesis.

[0007] Historically, the preparation of highly substituted alpha, delta-dicarbonyl derivatives has presented significant challenges. Traditional methods often involve complex reaction conditions, require expensive reagents, or yield products with limited selectivity and purity. Furthermore, existing processes may be inefficient or unsuitable for large-scale industrial production due to issues related to yield, cost, or environmental impact.

[0008] There is, therefore, a continuous need for improved methods that provide efficient, scalable, and cost-effective synthesis of highly substituted alpha, delta-dicarbonyl derivatives. Such methods would enhance the production capabilities of the fragrance industry, enabling the development of new and innovative perfuming ingredients while addressing the limitations of prior art processes. The present invention addresses these needs by providing a novel process for preparing highly substituted alpha, delta-dicarbonyl derivatives with improved yield, selectivity, and costefficiency. The inventive process is designed to overcome the limitations of conventional methods, offering enhanced industrial applicability and contributing to advancements in the synthesis of perfuming ingredients of significant interest.

[0009] Summary of the Invention

[0010] The invention relates to a novel process for the preparation of a compound of formula (I), with a high yield and high selectivity starting from a compound of formula (II). The invention’s process represents a new efficient route towards compounds of formula (I).

[0011] A first object of the present invention is a process for the preparation of a compound of formula O RT O

[0012] R2 R3 R5

[0013]

[0014] (I)

[0015] in the form of any of its stereoisomers or mixtures thereof,

[0016] comprising a hydroformylation step starting from a compound of formula

[0017] O RT

[0018] R5

[0019]

[0020] R2 R3

[0021] CD

[0022] in the form of any of its stereoisomers or mixtures thereof,

[0023] wherein

[0024] R1 represents a C1-22 hydrocarbyl group and

[0025] R2, R3, R4, R5, each independently, represent a hydrogen or a C1-22 hydrocarbyl group.

[0026] A second object of the invention is process for preparing a compound of formula (V) and / or of formula (VI)

[0027] (VI)

[0028]

[0029] comprising the steps of:

[0030] a) Preparing a compound of formula (I) according to the process according to the first object of the invention and

[0031] b) Preparing a compound of formula (V) and / or a compound of formula (VI) from the compound obtained in step a) in the presence of an acid or a base,

[0032] wherein RI_5have the same meaning as defined above.

[0033] A third object of the invention is a compound of formula (I), in the form of any of its stereoisomers or mixtures thereof, wherein Ri is a C1-3 alkyl group and wherein R2, R3, R4, R5, each independently, represent a hydrogen or C1-3 alkyl group, with the proviso that the compound of formula (I) is not 3,7-dimethyl-5-oxooctanal, 3,4-dimethyl-5-oxohexanal, 4-ethyl-3-methyl-5-oxohexanal, or 3,4,4-trimethyl-5-oxohexanal.

[0034] Description of the Invention

[0035] It has now been surprisingly found that valuable compounds of formula (I) can be obtained from new chemical intermediates as defined herein below in formula (II), (III) and (IV). The invention’s process represents a new route towards compounds of formula (V) and (VI) comprising the formation of a compound of formula (I) with overall high yield, compared to the methods known from the prior art.

[0036] A first object of the invention is therefore a process for the preparation of a compound of formula (I)

[0037] O RT O

[0038] 2 K3 R5

[0039]

[0040] (I)

[0041] in the form of any of its stereoisomers or mixtures thereof,

[0042] comprising a hydroformylation step starting from a compound of formula (II)

[0043]

[0044] (II)

[0045] in the form of any of its stereoisomers or mixtures thereof,

[0046] wherein

[0047] Ri represents a C1-22 hydrocarbyl group and

[0048] R2, R3, R4, R5, each independently, represent a hydrogen or a C1-22 hydrocarbyl group.

[0049] For the sake of clarity, by the expression “any one of its stereoisomers or mixtures thereof’, or the similar it is meant the normal meaning understood by a person skilled in the art, i.e. that the compound of formula (I) and (II) can be pure enantiomer or a mixture of enantiomers. In other words, the compound of formula (I) and (II) may possess at least one stereocenter, which can have two different stereoconformations (e.g. R or S). The compounds of formula (I) and (I I) may even be in the form of a pure diastereomer or in the form of a mixture of diastereomers when compounds of formula (I) and (II) possess more than one stereocenter. The compounds of formula (I) and (II) can be in racemic form or scalemic form. Therefore, the compounds of formula (I) and (II) can be one stereoisomer or in the form of a composition of matter comprising, or consisting of, various stereoisomers.

[0050] For the sake of clarity, the double bond present in formula (II) may be a cis configuration corresponding to the Z isomer, a trans configuration corresponding to the E isomer or a mixture thereof.

[0051] The term “hydrocarbyl group” refers to a chemical group consisting of carbon and hydrogen atoms. The term also encompasses groups wherein one or more carbon and / or hydrogen can be optionally replaced by one or more heteroatoms, selected from oxygen, nitrogen, or sulfur.

[0052] According to an embodiment, R2, R3, R4 R5 each independently represent a hydrogen or a Ci-22 hydrocarbyl group, wherein the hydrocarbyl group is selected from the group consisting of each alkyl, alkenyl, aryl, cycloalkyl, hetero alkyl, hetero alkenyl, heteroaryl and mixtures thereof.

[0053] According to an embodiment, R2, R3, R4 R5 each independently represent a hydrogen or a Ci- 22 hydrocarbyl group, wherein the hydrocarbyl group is selected from the group consisting of each alkyl, aryl, cycloalkyl, hetero alkyl, heteroaryl and mixtures thereof. The term “alkyl” and “alkenyl” are understood as comprising branched and linear alkyl and alkenyl groups. The term “alkyl group” refers to a saturated hydrocarbyl chain, which may be linear or branched, comprising carbon and hydrogen atoms and having the general formula CnH2n+i, where n is an integer. The term “alkenyl group” refers to an unsaturated hydrocarbyl chain comprising 1, 2 or 3 olefinic bonds, preferably 1 or 2 olefinic bonds.

[0054] The term “hetero alkyl group” refers to a linear or branched alkyl group wherein one or more carbon atoms are replaced by one or more heteroatoms. Heteroatoms in this definition are elements other than carbon and hydrogen, such as oxygen, nitrogen, sulfur, or phosphorus. The heteroalkyl group retains the general structure and reactivity characteristics of a conventional alkyl group, but with the inclusion of these heteroatoms.

[0055] The term “hetero alkenyl group” refers to a chemical group that features a carbon-carbon double bond where one or more carbon atoms in this structure are replaced by heteroatoms. Heteroatoms are elements other than carbon and hydrogen, such as oxygen, nitrogen, sulfur, or phosphorus.

[0056] The term “aryl group” designates the normal meaning in the art, i.e., an aromatic hydrocarbyl group such as phenyl, pyridine, biphenyl, anthryl or naphthyl group optionally substituted. Nonlimiting examples of the optional substituent of the aryl group may include a Ci_4alkyl or alkoxy group, a hydroxy group or a halogen atom.

[0057] Preferably, an aryl group is selected from the group consisting of phenyl tolyl, xylyl, naphthyl, biphenyl and mixtures thereof.

[0058] The term “cycloalkyl group” is understood as comprising a monocyclic or fused, spiro snf / or bridged bicyclic or tricyclic cycloalkyl group, preferably, monocyclic cycloalkyl group.

[0059] The term “heteroaryl group” refers to a chemical group that features an aryl motif where one or more carbon atoms in this structure are replaced by heteroatoms. Heteroatoms are elements other than carbon and hydrogen, such as oxygen, nitrogen, sulfur, or phosphorus.

[0060] According to an embodiment, Ri represents a C1-3 alkyl, C1-3 alkenyl, C1-3 heteroalkyl or C1-3 heteroalkenyl group.

[0061] According to an embodiment, R1 represents a C1-3 alkyl or C1-3 heteroalkyl group. According to an embodiment, Ri is a C1-3 alkyl group.

[0062] According to a preferred embodiment, R1 is a methyl group.

[0063] According to an embodiment, R2, R3, R4, R5, each independently represent a hydrogen, C1-3 alkyl, C1-3 alkenyl, C1-3 hetero alkyl or C1-3 hetero alkenyl group.

[0064] According to an embodiment, R2, R3, R4, R5, each independently represent a hydrogen, C1-3 alkyl or C1-3 hetero alkyl group.

[0065] According to a preferred embodiment, R2, R3, R4, R5, each independently represents a hydrogen or C1-3 alkyl group.

[0066] According to a preferred embodiment, R2, R3, and R4each independently represents a C1-3 alkyl group.

[0067] According to a preferred embodiment, R2, R3, and R4each independently represents a methyl group.

[0068] According to a preferred embodiment, R5 represents a hydrogen.

[0069] According to a preferred embodiment, R2, R3, and R4each independently represents a methyl group and R5represents a hydrogen.

[0070] According to a preferred embodiment, R1 is a C1-3 alkyl group and R2, R3, R4, R5, each independently represent a hydrogen or a C1-22 hydrocarbyl group, wherein the hydrocarbyl group is selected from the group consisting of each alkyl, aryl, cycloalkyl, hetero alkyl, heteroaryl and mixtures thereof.

[0071] According to a preferred embodiment, R1 is a C1-3 alkyl group and R2, R3, R4, R5, each independently, represent a hydrogen, C1-3 alkyl or C1-3 hetero alkyl group.

[0072] According to a preferred embodiment, R1 is a C1-3 alkyl group and R2, R3, R4, R5, each independently, represent a hydrogen or C1-3 alkyl group. According to a preferred embodiment, Ri, R2, R3, and R4each independently represent a C1-3 alkyl group.

[0073] According to a preferred embodiment, R1, R2, R3, and R4each independently represent a methyl group.

[0074] According to a preferred embodiment, R1, R2, R3, and R4each independently represent a methyl group and R5represents a hydrogen.

[0075] According to a preferred embodiment, the compound of formula (I) is 3,4,4-trimethyl-5-oxoheptanal.

[0076] According to a preferred embodiment, the compound of formula (II) is 4,4,5-trimethylhex-5-en-3-one.

[0077] According to a preferred embodiment, the compound of formula (I) is 3,4,4-trimethyl-5-oxoheptanal and the compound of formula (II) is 4,4,5-trimethylhex-5-en-3-one.

[0078] For the sake of clarity it is to be understood that the term “hydroformylation” or the similar, by a person skilled in the art, i.e. the reaction is performed in the presence of a metal catalyst, preferably a transition metal catalyst, even more preferably a catalyst comprising a transition metal from the group selected of rhodium, cobalt or platinum, and even more preferably wherein the metal catalyst is a rhodium catalyst.

[0079] In a preferred embodiment, the reaction further comprises carbon monoxide, hydrogen gas and optionally a phosphorous ligand.

[0080] The carbon monoxide and hydrogen gas may be generated in situ from the decomposition of any of methyl formate, formic acid, oxalic acid, formaldehyde and mixtures thereof.

[0081] According to an embodiment, the hydroformylation is performed in the presence of a rhodium complex. The rhodium complexes that can be used in the present invention include but are not limited to Rh(acac)(CO)2, [Rh(OCOC8Hi5)2]2, RhCh, Rh2AcO4, [Rh(OAc)(COD)]2, Rh4(CO)i2, Rh6(CO)i6, RhCI(CO)(PPh3)2, Rh(C2H4)2(acac), [Rh(CI)(COD)]2, [Rh(CI)(COE)2]2, [Rh(OAc)(CO)2]2, Rh(acac)(COD), HRh(CO)(PPh3)3, RhCI(PPh3)3, [Rh(NBD)2]BF4, [Rh(OMe)(COD)]2and [Rh(OH)(COD)]2wherein acac represents an acetyl acetonate group, Ac an acetyl group, COD a 1 ,5-cyclooctadiene group, COE a cyclooctene group, Ph a phenyl group. Particularly, the rhodium complex may be selected from the group consisting of Rh(acac)(CO)2, [Rh(OCOC8Hi5)2]2, [Rh(OAc)(COD)]2, RhCI(CO)(PPh3)2, Rh(C2H4)2(acac), [Rh(CI)(COD)]2, [Rh(CI)(COE)2]2, [Rh(OAc)(CO)2]2, Rh(acac)(COD), HRh(CO)(PPh3)3, RhCI(PPh3)3, [Rh(NBD)2]BF4, [Rh(OMe)(COD)]2, and [Rh(OH)(COD)]2. Even more particularly, the rhodium complex may be selected from the group consisting of Rh(acac)(CO)2, [Rh(OCOC8Hi5)2]2, Rh(acac)(COD), HRh(CO)(PPh3)3, [Rh(OMe)(COD)]2and [Rh(OH)(COD)]2. Said complex can be added into the reaction medium of the invention’s process in a large range of concentrations.

[0082] According to an embodiment, the metal catalyst, preferably the rhodium complex is present in an amount of at least 0.0001 mol%, preferably of at least 0.001 mol%, even more preferably of at least 0.0025 mol% relative to the amount of compound of formula (II).

[0083] According to an embodiment, the metal catalyst, preferably the rhodium complex is present in an amount of less than or equal to 5 mol%, preferably of less than or equal to 2 mol%, relative to the amount of compound of formula (II).

[0084] According to an embodiment, the metal catalyst, preferably the rhodium complex is present in a range from 0.0001 mol% to 5 mol%, preferably from 0.001 mol% to 5 mol%, more preferably from 0.0025 mol% to 2 mol%, relative to the amount of a compound of formula (II).

[0085] It goes without saying that the optimum concentration of the complex will depend, as the person skilled in the art knows, on the nature of the latter, on the nature of the substrate, on the nature of the ligand, on the reaction temperature as well as on the desired time of reaction.

[0086] According to an embodiment, the hydroformylation is performed in the presence of a mono- or bidentate phosphorous ligand, preferably a mono- or bidentate phosphite or phosphine ligand, even more preferably a mono- or bidentate phosphite ligand. Particularly, the phosphorous ligand may be a monodentate phosphorous ligand, preferably a monodentate phosphite or phosphine ligand, even more preferably a monodentate phosphite ligand.

[0087] According to an embodiment, the hydroformylation may be performed in the presence of a monodentate phosphite ligand of formula P(OR6)3, wherein R6is a Ci-C22group, such as linear or branched alkyl, cycloalkyl, alkoxy or aryloxy group optionally substituted, substituted or unsubstituted phenyl, diphenyl, 2-furanyl, naphthyl or di-naphthyl group, or two R6groups are taken together and form a phosphatrioxa-adamantane and the other R6group has the same meaning as above. More particularly R6may represent a substituted or unsubstituted phenyl, diphenyl, naphthyl or di-naphthyl group. Preferably, the monodentate phosphorous ligand is a phosphite.

[0088] Illustrative monodentate phosphites include, for example, trialkyl phosphites, dialkyl aryl phosphites, alkyl diaryl phosphites, triaryl phosphites, and the like, such as, for example, trimethyl phosphite, triethyl phosphite, butyldiethyl phosphite, tri-n-propyl phosphite, tri-n-butyl phosphite, tri-2-ethylhexyl phosphite, tri-n-5 octyl phosphite, tri-n-dodecyl phosphite, dimethylphenyl phosphite, diethylphenyl phosphite, methyldiphenyl phosphite, ethyldiphenyl phosphite, triphenyl phosphite, trinaphthyl phosphite, bis(3,6,8-tri-t-butyl-2-naphthyl)methylphosphite, bis(3,6,8-tri-t-butyl-2-naphthyl)cyclohexylphosphite, tris(3,6-di-t-butyl-2-naphthyl)phosphite, bis(3,6,8-trl-tbutyl-2-naphthyl)(4-biphenyl)phosphite, bis(3,6,8-tri-t-butyl-2-naphthyl)phenylphosphite, bis(3,6,8-tri-t-butyl-2-naphthyl)(4-benzoylphenyl)phos-phite, bis(3,6,8-tri-t-butyl-2-naphthyl) (4-sulfonylphenyl)phosphite, tris(2,6-dimethoxyphenyl) phosphite, tris(4-methoxyphenyl) phosphite, tris(2,4,6-trimethylphenyl) phosphite, tris(2,4-di-tert-butyl phenyl) phosphite, tris(2,4,6-trimethylphenyl) phosphite, and the like.

[0089] Even more preferably, the monodentate phosphite ligand is selected from the group consisting of triphenyl phosphite, tris(2,4-di-tert-butylphenyl) phosphite, tris(2,6-dimethoxyphenyl) phosphite, tris(4-methoxyphenyl) phosphite, tris(2,4,6-trimethylphenyl) phosphite, tri-n-butyl phosphite, tri-2-ethylhexyl phosphite and mixtures thereof.

[0090] According to any one of the above embodiments, the hydroformylation is performed in presence of a bidentate phosphite or phosphonite ligand of formula

[0091] (R7O)2P -X- P(OR7)2 (A)

[0092] wherein R7, each independently, represents an alkyl, preferably containing 1 to 20 carbon atoms, or an aryl, preferably containing 6 to 20 carbon atoms, and X represents a bridging group such as phenylene, biphenylene ora linear or branched alkylene chain containing 1 to 10 carbon atoms, or a heterocyclic group such as pyridine or furan.

[0093] For the sake of clarity, the term “heterocyclic” refers to a ring structure composed of at least one atom other than carbon (a heteroatom) within the ring. Common heteroatoms include nitrogen, oxygen, sulfur, and phosphorus. Heterocyclic compounds can vary in ring size and may include both aromatic and non-aromatic rings. Non-limiting examples of suitable bidentate phosphorous ligands include 1 ,2-bis(diphenylphosphite)ethane, 1 ,3-bis(diphenylphosphite)propane, 1 ,4-bis(diphenyl-phosphite)butane, bis(diphenylphosphite)methane, 1 ,2-bis(diphenylphosphite)benzene, 1 ,1'-bis(diphenylphosphite)ferrocene, bis(diphenylphosphite)pyridine, 1 ,2-bis(dimethylphosphite)-ethane, 1 ,2-bis(diethylphosphite)ethane, and 1 ,3-bis(dimethylphosphite)propane.

[0094] According to an embodiment, the hydroformylation may be performed in the presence of a monodentate phosphine ligand of formula P(R8)3wherein R8is a C1-C20 group, such as linear or branched alkyl, cycloalkyl, alkoxy or aryloxy group optionally substituted, substituted or unsubstituted phenyl, diphenyl, 2-furanyl, naphtyl, or di-naphtyl group, or two R8groups are taken together and form a phosphatrioxa-adamantane and the other R8group has the same meaning as defined above. More particularly R8may represent a substituted or unsubstituted phenyl, diphenyl, naphtyl or di-naphtyl group. Possible substituents can be those cited below for the group R9.

[0095] According to an embodiment, the hydroformylation may be performed in the presence of a bidentate phosphine ligand of formula

[0096] (R9)2P - Q - P(R9)2(B)

[0097] wherein each R9, independently from each other, represents a C -5 heteroaryl group, a C6-20 aromatic group optionally substituted or a cyclohexyl group optionally substituted, or the two R9are bonded to the same P atom, taken together, represent a 1 ,1’-biphenyl-2,2’-dioxy, a 1 ,1’-biphenyl-2,2’-dimethyl or a 1 ,1’-biphenyl-2,2’-diyl, each optionally substituted; and Q represents a group of formula

[0098] - a)

[0099]

[0100] wherein q is 0 or 1 , each T, each independently, represents an oxygen atom or a CH2group, each R10, each independently, represents a hydrogen atom or a Ci-8alkyl group, and Z represents an oxygen or sulfur atom or a C(Rn)2, Si(Ri2)2 or NRn group in which R11 is a hydrogen atom or a R12, R12 representing a C 1.4 linear or branched alkyl group, preferably methyl group; or

[0101] - b)

[0102]

[0103] in the form of any of its enantiomers, and wherein q is 0 or 1 , r is 0 or 1 , each T, each independently, represent an oxygen atom or a CH2 group, R13, each independently, represent a hydrogen atom, a methoxy group or a C1-4 alkyl group optionally substituted by one to three halogen atoms or alkoxy groups; or two adjacent R13 may be taken together and represent a (CH2)4group; or

[0104] - c)

[0105]

[0106] in the form of any of its enantiomers, and wherein T, q and R13 have the same meaning as defined above;

[0107] and the wavy lines indicate the position of the bond between said Q group and the rest of the compound (B).

[0108] According to any one of the above embodiments, Q may be a group of formula (i) or (ii). According to any one of the above embodiments, each R9may be a furan-2-yl group, a 1 H-pyrrol-1-yl group, a C6-2o aromatic group optionally substituted or a cyclohexyl group optionally substituted.

[0109] According to any one of the above embodiments, by “aromatic group or ring” it is meant a phenyl or naphthyl group, and in particular a phenyl group.

[0110] According to anyone of the above embodiments, each R9may be a phenyl group, a cyclohexyl group, a 3,5-dimethyl-phenyl, a 3,5-di(CF3)-phenyl, a 3,5-dimethyl-4-methoxy-phenyl group.

[0111] According to any one of the above embodiments, the R10 may be a hydrogen atom.

[0112] According to any one of the above embodiments, Z may be a CMe2, SiMe2, NH or NMe group. Particularly, Z may be a CMe2group. According to any one of the above embodiments, non-limiting examples of possible substituents of R9are one, two, three or four groups selected amongst the halogen atoms, or C1-20 alkoxy, alkyl, alkenyl, pyridyl or perhalo-hydrocarbyl group. Two substituents may be taken together to form a C4-10 cycloalkyl group. The expression “perhalo-hydrocarbyl” has here the usual meaning in the art, e.g. a group such as CF3for instance. In particular said substituents are one or two halogen atoms, such as F or Cl, or C1-4 alkoxy or alkyl groups, or CF3groups.

[0113] According to any one of the above embodiments, said R9may be non-substituted.

[0114] According to any one of the above embodiments, the ligand of formula (B) can be in a racemic or optically active form.

[0115] The phosphorous ligand can be added into the reaction medium of the invention’s process in a large range of concentrations.

[0116] As non-limiting examples, one can cite as phosphorous ligand concentration values those ranging from about 0.0001 mol% to about 50 mol%, relative to the amount of the compound of formula (II), preferably from 0.001 mol% to about 50 mol%, relative to the amount of the compound of formula (II), preferably from about 0.001 mol% to about 15 mol%, relative to the amount of the compound of formula (II).

[0117] The optimum concentration of the phosphorous ligand will depend, as the person skilled in the art knows, on the nature of the latter, on the nature of the substrate, on the nature of the metal complex, on the reaction temperature as well as on the desired time of reaction.

[0118] Preferably, either a Rh complex having at least bound one phosphorous ligand, preferably a phosphite based ligand, bound to the Rh atom or a Rh complex having no phosphorous ligand bound to the Rh atom in combination with a phosphorous ligand, preferably a phosphite based ligand, is used. In the later case, a complex having a phosphorous ligand, preferably a phosphite based ligand, bound to the Rh atom can be formed in situ.

[0119] According to any one of the above embodiments, carbon monoxide and hydrogen gas may be generated in situ by known methods by the person skilled in the art, e.g. from methyl formate, formic acid, or formaldehyde. The CO / H2gas volume ratio is comprised between 2 / 1 to 1 / 5, preferably between 1 / 1 to 1 / 5 or preferably between 2 / 1 to 1 / 2, preferably between 1.5 / 1 to 1 / 1.5 and more preferably the ratio is 1 / 1.

[0120] The reaction can be carried out in the presence or absence of a solvent. When a solvent is required or used for practical reasons, then any solvent current in such reaction type can be used for the purposes of the invention. Non-limiting examples include C6-12 aromatic solvents such as toluene, 1,3-diisopropylbenzene, cumene or pseudocumene, or mixtures thereof, alcoholic solvents such as methanol, ethanol, 2-methylbutan-2-ol or mixtures thereof, hydrocarbyl solvents such as cyclohexane, heptane or mixtures thereof, esteric solvent such as n-butyl acetate, / so-propyl acetate, ethyl acetate or ethereal solvents such as methyl tetrahydrofuran, tetrahydrofuran or mixtures thereof. The choice of the solvent is function of the nature of the substrate and / or catalyst and the person skilled in the art is well able to select the solvent most suitable in each case to optimize the reaction. The hydroformylation reaction can be carried out at a temperature in the range comprised between 50 °C and 150 °C, more preferably in the range comprised between 80 °C and 130 °C, or even between 90 °C and 110 °C. Of course, a person skilled in the art is also able to select the preferred temperature according to the melting and boiling point of the starting and final products as well as the desired time of reaction or conversion.

[0121] According to an embodiment, the process is carried out in the absence of a solvent or in the presence of a solvent, preferably in the absence of a solvent.

[0122] According to an embodiment, the solvent is an alcoholic solvent.

[0123] The hydroformylation can be carried out at a CO / H2 pressure comprised between 1 bar and 50 bar, preferably in the range of between 10 bar and 50 bar, more preferably in the range of between 10 bar and 25 bar. Of course, a person skilled in the art is well able to adjust the pressure as a function of the catalyst load and of the dilution of the substrate in the solvent.

[0124] According to an embodiment, the compound of formula (II) is formed by the the reaction of compound (III) and compound (IV),

[0125] Ri R ■2

[0126]

[0127] ■5 ■3

[0128] (HI) (IV)

[0129] wherein R1, R2, R3, R4, R5 have the same meaning as defined above, in the presence of a Lewis acid. All definitions and embodiments related to Ri, R2, R3, R4 and R5 for compounds of formula (I) and (II) apply mutatis mutandis for the compound of formula (III) and (IV).

[0130] The term “Lewis acid” refers to a chemical species that is capable of accepting an electron pair from a Lewis base to form a coordinate covalent bond. A Lewis acid is characterized by having an electron-deficient center, typically a metal ion or a molecule with an incomplete octet, that can readily interact with a donor molecule. This electron-pair accepting property enables Lewis acids to catalyze various chemical reactions, including those involving nucleophilic attack or complex formation. Examples of Lewis acids include metal cations such as Al3+, transition metal complexes, and certain organic compounds like boron trifluoride (BF3).

[0131] According to an embodiment, the process may further comprise the step of forming a compound of formula (V) and / or formula (VI)

[0132] o o

[0133] R3 IL R ^3 11 D

[0134] K2I TK2I II

[0135] Rf y ^OH Ri J

[0136]

[0137] R5 R5

[0138] (V) (VI)

[0139] in the presence of an acid or base, wherein R1, R2, R3, R4and R5have the same meaning as defined above.

[0140] All definitions and embodiments related to R1, R2, R3, R4 and R5 for compounds of formula (I) and (II) apply mutatis mutandis for the compound of formula (V) and (VI).

[0141] The term “acid” encompasses any substance that can either donate a proton (H+) or accept an electron pair, thus participating in acid-base reactions. Specifically, this definition includes Bransted acids, which are substances capable of donating a proton to a Bransted- base, resulting in an increase in the concentration of hydrogen ions in solution, such as hydrochloric acid (HCI) and sulfuric acid (H2SO4). It also includes Lewis acids according to the definition above.

[0142] The term “base” encompasses any substance that can either accept a proton (H+) or donate an electron pair, thereby participating in acid-base reactions. Specifically, a base includes Bransted bases, which are substances that accept a proton from a Bransted- acid, leading to the formation of a conjugate acid and increasing the concentration of hydroxide ions in solution, such as ammonia (NH3) and sodium hydroxide (NaOH). It also includes Lewis bases, which are substances that donate an electron pair to a Lewis acid to form a coordinate covalent bond, characterized by having a lone pair of electrons available for donation, such as water (H2O) and ethylamine (C2H5NH2).

[0143] According to an embodiment, a compound of formula (I), (V) or (VI) is used to form

[0144] (R)-1-((1S,3R,6R)-2,2,3,6-tetramethylcyclohexyl)hexan-3-ol,(S)-1-((1S,3R,6R)-2,2,3,6-tetra-methylcyclohexyl)hexan-3-ol or a mixture thereof.

[0145] According to an embodiment, a compound of formula (I), (V) or (VI) is used to form (E)-4-((1 R,3S,6R)-2,2,3,6-tetramethylcyclohexyl)but-3-en-2-one, (E)-4-((1 R,3R,6R)-2,2,3,6-tetra-methylcyclohexyl)but-3-en-2-one or a mixture thereof.

[0146] A second object of the invention is process for preparing a compound of formula (V) and or of formula (VI)

[0147]

[0148] (V) (VI)

[0149] comprising the steps of:

[0150] a) Preparing a compound of formula (I) according to the process of the first aspect of the invention and

[0151] b) Preparing a compound of formula (V) and / or a compound of formula (VI) from the compound obtained in step a) in the presence of an acid or a base,

[0152] wherein R1.5 have the same meaning as defined above.

[0153] All definitions and embodiments related to the first object of the invention apply mutatis mutandis for the second object of the invention.

[0154] A third object of the invention is a compound of formula (I), in the form of any of its stereoisomers or mixtures thereof, wherein R1 is a C1-3 alkyl group and wherein R2, R3, R4, R5, each independently, represent a hydrogen or C1-3 alkyl group, with the proviso that the compound of formula (I) is not 3,7-dimethyl-5-oxooctanal, 3,4-dimethyl-5-oxohexanal, 4-ethyl-3-methyl-5-oxohexanal, or 3,4,4-trimethyl-5-oxohexanal.

[0155] According to an embodiment there is provided a compound of formula (I) in the form of any of its stereoisomers or mixtures thereof, wherein Ri is a C1-3 alkyl group, R4is a C1-3 alkyl group, and R2, R3, and R5are each independently a hydrogen or C1-3 alkyl group, with the proviso that at least one of R2and R3represent a C1-3 alkyl group.

[0156] According to an embodiment the compound of formula (I) is not 2,2,3-trimethyl-5-oxohexanal, 3-ethyl-2,2-dimethyl-5-oxohexanal, 2,2,3-trimethyl-5-oxoheptanal, or 3-ethyl-2,2-dimethyl-5-oxoheptanal.

[0157] According to an embodiment the compound of formula (I) is 3,4,4-trimethyl-5-oxoheptanal.

[0158] According to an embodiment the compound of formula (I) is present in a reaction mixture obtained from the process of the first aspect of the invention.

[0159] According to an embodiment, the compound of formula (I) is in isolated form.

[0160] The term “isolated” refers to the compound being separated from other components present in the reaction mixture in which it was synthesized.

[0161] According to an embodiment, the compound of formula (I) is not present in a reaction mixture.

[0162] The following Examples illustrate the invention without limiting its scope. Examples

[0163] The invention will now be described in further detail by way of the following examples, wherein the abbreviations have the usual meaning in the art, the temperatures are indicated in degrees centigrade (°C). NMR spectra were recorded at 20 °C on Bruker AV 300, AV 400, or AV 500 MHz spectrometers. Chemical shifts are reported in ppm relative to solvent signals (chloroform, 5H = 7.26 ppm, <5C = 77.0 ppm). Gas chromatography was performed on an Agilent 7890 A Series equipped with a DB1 column (10 m x 0.10 mm x 0.10 pm).

[0164] Example 1

[0165] Preparation of 3,4,4-trimethyl-5-oxohexanal from 3,3,4-trimethylpent-4-en-2-one

[0166] O I o

[0167]

[0168] A 75 mL high pressure equipment was charged under air with 3,3,4-trimethylpent-4-en-2-one (5.03 g, 38.86 mmol, 97.5% purity), tris(2,4-di-tert-butylphenyl) phosphite (76.5 mg, 0.1159 mmol, 98% purity) and Rh(acac)(CO)2 (5.1 mg, 0.0198 mmol). The reactor was closed, purged with H2 / CO (1 / 1, 4 x5 bar), pressurized to 10 bar and heated to 90 °C under vigorous stirring for 24 h. Aftercooling and depressurization, gas chromatography (GC) of the reaction mixture showed <1% 3,3,4-trimethylpent-4-en-2-one, and 3,4,4-trimethyl-5-oxohexanal (95.7%). Purification via column chromatography (Et2O I pentane, 1 / 1).

[0169] 1H NMR (500 MHz, CDCI3) 59.70 (dd, J = 2.6, 1.1 Hz, 1H), 2.55 -2.41 (m, 1H), 2.34 (dd, J = 17.1, 3.1 Hz, 1H), 2.19-2.10 (m, 1H), 2.09 (s, 3H), 1.01 (d, J = 2.9 Hz, 6H), 0.83 (d, J = 6.8 Hz, 3H).

[0170] 13C NMR (126 MHz, CDCh) 5213.5, 201.9, 50.5, 46.8, 33.1, 25.4, 21.1, 20.8, 15.4.

[0171] Example 2

[0172] Preparation of 3,4,4-trimethyl-5-oxoheptanal from 4,4,5-trimethylhex-5-en-3-one

[0173] O I o

[0174]

[0175] A 75 mL high pressure equipment was charged under air with 4,4,5-trimethylhex-5-en-3-one (5.03 g, 33.79 mmol, 94.2% purity), tris(2,4-di-tert-butylphenyl) phosphite (67.0 mg, 0.1015 mmol, 98% purity) and Rh(acac)(CO)2(4.4 mg, 0.0171 mmol). The reactor was closed, purged with H2 / CO (1 / 1, 4 x5 bar), pressurized to 10 bar and heated to 90 °C under vigorous stirring for 48 h. Aftercooling and depressurization, GC of the reaction mixture showed <1% 4,4,5-trimethylhex-5-en-3-one, and 3,4,4-trimethyl-5-oxoheptanal (94.1%). Purification via column chromatography (Et201 pentane, 1 / 1).

[0176] 1H NMR (500 MHz, CDCI3) 09.71 (dd, J = 2.8, 1.0 Hz, 1 H), 2.56 - 2.49 (m, 1 H), 2.47 (q, J = 7.2 Hz, 2H), 2.34 (dd, J = 16.7, 3.0 Hz, 1H), 2.14 (ddd, J = 16.7, 10.1, 2.7 Hz, 1H), 1.04 (s, 3H), 1.03 (s, 3H), 1.00 (t, J = 7.2 Hz, 3H), 0.83 (d, J = 6.9 Hz, 3H).

[0177] 13C NMR (126 MHz, CDCI3) 0216.0, 202.0, 50.3, 46.9, 33.3, 30.5, 21.4, 20.9, 15.5, 8.2.

[0178] Example 3

[0179] Preparation of 3,4,4-trimethyl-5-oxooctanal from 2,3,3-trimethylhept-1-en-4-one

[0180] O I o

[0181]

[0182] A 75 mL high pressure equipment was charged under air with 2,3,3-trimethylhept-1-en-4-one (5.01 g, 30.76 mmol, 94.7% purity), tris(2,4-di-tert-butylphenyl) phosphite (62.4 mg , 0.0945 mmol, 98% purity) and Rh(acac)(CO)2(4.4 mg, 0.0171 mmol). The reactorwas closed, purged with H2 / CO (1 / 1, 4 x 5 bar), pressurized to 10 bar and heated to 90 °C under vigorous stirring for 24 h. After cooling and depressurization, GC of the reaction mixture showed <1% 2,3,3-trimethylhept-1-en-4-one, and 3,4,4-trimethyl-5-oxooctanal (92.6%). Purification via column chromatography (Et2O I pentane, 1 / 1).

[0183] 1H NMR (500 MHz, CDCI3) 59.69 (dd, J = 2.8, 1.0 Hz, 1 H), 2.50 (dtt, J = 9.9, 6.9, 3.5 Hz, 1H), 2.40 (td, J= 7.1, 1.4 Hz, 2H), 2.32 (dd, J= 16.7, 3.0 Hz, 1H), 2.12 (ddd, J= 16.7, 10.1, 2.7 Hz, 1 H), 1.53 (h, J = 7.4 Hz, 2H), 1.01 (s, 3H), 1.01 (s, 3H), 0.85 (t, J = 7.4 Hz, 3H), 0.82 (d, J = 6.8 Hz, 3H).

[0184] 13C NMR (126 MHz, CDCI3) 5215.3, 202.0, 50.2, 46.9, 39.1 , 33.1 , 21.2, 20.8, 17.3, 15.4, 13.8.

[0185] Example 4

[0186] Preparation of 3,4,4-trimethyl-5-oxononanal from 2,3,3-trimethyloct-1-en-4-one

[0187] O I o

[0188]

[0189] A 75 mL high pressure equipment was charged under air with 2,3,3-trimethyloct-1-en-4-one (5.00 g, 28.35 mmol, 95.4 % purity), tris(2,4-di-tert-butylphenyl) phosphite (63.1 mg, 0.0956 mmol, 98% purity) and Rh(acac)(CO)2(4.5 mg, 0.0174 mmol). The reactorwas closed, purged with H2 / CO (1 / 1, 4 x 5 bar), pressurized to 10 bar and heated to 90 °C under vigorous stirring for 24 h. After cooling and depressurization, GC of the reaction mixture showed <1% of 2,3,3-trimethyloct-1-en-4-one, and 3,4,4-trimethyl-5-oxononanal (92.9%). Purification via column chromatography (Et2O / pentane, 1 / 1).1H NMR (500 MHz, CDCI3) 09.71 (dd, J = 2.8, 1.0 Hz, 1 H), 2.55 - 2.47 (m, 1 H), 2.43 (td, J = 7.1, 1.7 Hz, 2H), 2.33 (dd, J= 16.8, 3.0 Hz, 1H), 2.13 (ddd, J= 16.7, 10.2, 2.8 Hz, 1H), 1.54 - 1.45 (m, 2H), 1.30 - 1.21 (m, 2H), 1.02 (s, 3H), 1.02 (s, 3H), 0.87 (t, J = 7.4 Hz, 3H), 0.83 (d, J = 6.9 Hz, 3H).

[0190] 13C NMR (126 MHz, CDCI3) 0215.4, 202.0, 50.3, 46.9, 37.0, 33.1 , 26.1 , 22.5, 21.2, 20.8, 15.4, 14.0.

[0191] Example 5

[0192] Preparation of 3,4,4-trimethyl-5-oxo-decanal from 2,3,3-trimethylnon-1-en-4-one

[0193] O I o

[0194]

[0195] A 75 mL high pressure equipment was charged under air with 2,3,3-trimethylnon-1-en-4-one (5.08 g, 25.36 mmol, 91 % purity), tris(2,4-di-tert-butylphenyl) phosphite (57.1 mg, 0.0865 mmol, 98% purity), and Rh(acac)(CO)2(4.0 mg, 0.155 mmol).

[0196] The reactor was closed, purged with H2 / CO (1 / 1, 4 x 5 bar), pressurized to 10 bar and heated to 90 °C under vigorous stirring for 24 h. After cooling and depressurization, GC of the reaction mixture showed <1% of 2,3,3-trimethylnon-1-en-4-one, and 3,4,4-trimethyl-5-oxo-decanal (92.1 %). Purification via column chromatography (Et2O I pentane, 1 / 1).

[0197] 1H NMR (500 MHz, CDCI3) 59.70 (dd, J = 2.8, 1.1 Hz, 1H), 2.55 -2.46 (m, 1H), 2.41 (td, J = 7.2, 1.9 Hz, 2H), 2.32 (dd, J= 16.6, 3.0 Hz, 1H), 2.13 (ddd, J= 16.8, 10.2, 2.8 Hz, 1H), 1.50 (p, J = 7.4 Hz, 2H), 1.31 - 1.16 (m, 4H), 1.02 (s, 3H), 1.01 (d, J = 3.0 Hz, 3H), 0.84 (d, J = 7.1 Hz, 3H), 0.81 (d, J= 7.2 Hz, 3H).

[0198] 13C NMR (126 MHz, CDCI3) 5215.5, 201.9, 50.2, 46.9, 37.2, 33.1, 31.5, 23.6, 22.6, 21.2, 20.7, 15.4, 13.9.

[0199] Example 6

[0200] Preparation of 3,4,4, 6-tetramethyl-5-oxo-heptanal from 2,4,4,5-tetramethylhex-5-en-3-one O I o

[0201]

[0202] X - A 75 mL high pressure equipment was charged under air with 2,4,4,5-tetramethylhex-5-en-3-one

[0203] (5.0 g, 31.12 mmol, 96 % purity), tris(2,4-di-tert-butylphenyl) phosphite (62.1 mg, 0.0941 mmol, 98% purity) and Rh(acac)(CO)2(4.3 mg, 0.0167 mmol).

[0204] The reactor was closed, purged with H2 / CO (1 / 1, 4 x 5 bar), pressurized to 10 bar and heated to 90 °C under vigorous stirring for 24 h. After cooling and depressurization, GC of the reaction mixture showed <1% of 2,4,4,5-tetramethylhex-5-en-3-one, and 3,4,4,6-tetramethyl-5-oxo-heptanal (94.1 %). Purification via column chromatography (Et20 I pentane, 1 / 1).

[0205] 1H NMR (500 MHz, CDCI3) 09.74 (dd, J= 2.9, 1.0 Hz, 1H), 3.12 (hept, J = 6.7 Hz, 1H), 2.56 (dtt, J= 9.7, 6.8, 3.5 Hz, 1H), 2.34 (dd, J= 16.7, 2.8 Hz, 1H), 2.16 (ddd, J= 16.7, 10.3, 2.8 Hz, 1H), 1.08 (s, 3H), 1.06 (s, 3H), 1.04 (d, J= 6.6 Hz, 3H), 1.02 (d, J= 6.6 Hz, 3H), 0.87 (d, J = 6.8 Hz, 3H).

[0206] 13C NMR (126 MHz, CDCI3) 0219.4, 201.9, 50.9, 47.1, 34.3, 32.2, 21.1, 20.3, 20.3, 20.1, 15.4.

[0207] Example 7

[0208] Preparation of 3,4,4, 6-tetramethyl-5-oxo-octanal from 2,3,3,5-tetramethylhept-1-en-4-one

[0209]

[0210] A 75 mL high pressure equipment was charged under air with 2,3,3,5-tetramethylhept-1-en-4-one (5.01 g, 28.16 mmol, 94.6 % purity), tris(2,4-di-tert-butylphenyl) phosphite (58.9 mg, 0.0892 mmol, 98% purity) and Rh(acac)(CO)2(3.7 mg, 0.0143 mmol).

[0211] The reactor was closed, purged with H2 / CO (1 / 1, 4 x 5 bar), pressurized to 10 bar and heated to 90 °C under vigorous stirring for 24 h. After cooling and depressurization, GC of the reaction mixture showed <1% of 2,3,3,5-tetramethylhept-1-en-4-one, and 3,4,4,6-tetramethyl-5-oxo-octanal (92.9 %). Purification via column chromatography (Et2O I pentane, 1 / 1).

[0212] 1H NMR (500 MHz, CDCI3) 59.73 (dt, J = 2.9, 1.3 Hz, 1 H), 2.93 - 2.82 (m, 1 H), 2.61 - 2.50 (m, 1H), 2.34 (ddd, J= 16.6, 10.8, 2.7 Hz, 1H), 2.20 -2.08 (m, 1H), 1.63 - 1.50 (m, 1H), 1.37 - 1.28 (m, 1H), 1.08 (d, J= 10.5 Hz, 3H), 1.04 (d, J= 11.8 Hz, 3H), 1.00 (dd, J= 11.5, 6.7 Hz, 3H), 0.88- 0.81 (m, 6H).

[0213] 13C NMR (126 MHz, CDCI3) 5219.0 (d), 202.1 (d), 50.7 (d), 47.2, 41.5 (d), 32.1 (d), 27.2 (d), 21.4 (d), 20.0 (d), 17.4 (d), 15.3 (d), 12.0 (d).

Claims

CLAIMS1. A process for the preparation of a compound of formula (I)O RT OR2 R3 R5(I)in the form of any of its stereoisomers or mixtures thereof,comprising a hydroformylation step starting from a compound of formula (II)O RTR5R2 R3CDin the form of any of its stereoisomers or mixtures thereof,whereinR1 represents a C1-22 hydrocarbyl group, andR2, R3, R4, R5, each independently, represent a hydrogen or a C1-22 hydrocarbyl group.

2. The process according to claim 1 , wherein R1 is a C1-3 alkyl group.

3. The process according to any of the previous claims, wherein R2, R3, R4 R5 each independently represent a hydrogen or a C1-22 hydrocarbyl group, wherein the hydrocarbyl group is selected from the group consisting of each alkyl, aryl, cycloalkyl, hetero alkyl, heteroaryl and mixtures thereof.

4. The process according to any of the previous claims, wherein R2, R3, R , R5, each independently, represent a hydrogen, C1-3 alkyl or C1-3 hetero alkyl group.

5. The process according to any of the previous claims, wherein R2, R3, R , R5, each independently represent a hydrogen or C1-3 alkyl group.

6. The process according to any of the previous claims, wherein the compound of formula (I) is 3,4,4-trimethyl-5-oxoheptanal and the compound of formula (II) is 4,4,5- trimethylhex-5-en-3-one.

7. The process according to any of the previous claims, wherein hydroformylation step is performed in the presence of a rhodium complex, preferably wherein the rhodium complex is selected from the group consisting of Rh(acac)(CO)2, [Rh(OCOC8Hi5)2]2, Rh(acac)(COD), HRh(CO)(PPh3)3, [Rh(OMe)(COD)]2and [Rh(OH)(COD)]2.

8. The process according to any of the previous claims, wherein the hydroformylation is performed in the presence of a mono- or bidentate phosphorous ligand, preferably a mono- or bidentate phosphite ligand.

9. The process according to any of the previous claims, wherein the rhodium complex is present in a range from 0.0001 mol% to 5 mol%, preferably from 0.001 mol% to 5 mol%, relative to the amount of the compound of formula (II).

10. The process according to any of the previous claims, wherein the process is carried out in the absence of a solvent or in the presence of a solvent, preferably in the absence of a solvent.

11. The process according to any of the previous claims, wherein the compound of formula (II) is formed by the reaction of compound (III) and compound (IV),Ri R ■2O O■5 ■3(HI)wherein Ri, R2, R3, R4, R5 have the same meaning as defined in claims 1 to 6, in the presence of a Lewis acid.

12. A process for preparing a compound of formula (V) and / or of formula (VI)Ri Y OHRs(V) (VI)comprising the steps of:a) Preparing a compound of formula (I) according to the process of any of claims 1 to 11 andb) Preparing a compound of formula (V) and / or a compound of formula (VI) from the compound obtained in step a) in the presence of an acid or a base,wherein Ri, R2, R3, R4, R5 have the same meaning as defined in claims 1 to 6.

13. A compound of formula (I)O RT Owherein Ri is a C1-3 alkyl group and wherein R2, R3, R4, R5, each independently, represent a hydrogen or C1-3 alkyl group, with the proviso that the compound of formula (I) is not 3,7-dimethyl-5-oxooctanal, 3,4-dimethyl-5-oxohexanal, 4-ethyl-3-methyl-5- oxohexanal, or 3,4,4-trimethyl-5-oxohexanal.

14. A compound according to claim 13, wherein the compound of formula (I) is in isolated form.

15. A compound according to claim 13 or 14, wherein the compound of formula (I) is not present in a reaction mixture.

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