Process for preparing cyclic aldehydes

Abstract

The present invention relates to the field of organic synthesis and more specifically it concerns a process for preparing compound of formula (I), (I) starting from compound of formula (II), (II) in the presence of a Lewis acid or a mixture of a Lewis acid and at least one Bronsted acid or a mixture of at least two Bronsted acids.

Description

[0001] PROCESS FOR PREPARING CYCLIC ALDEHYDES

[0002] Technical field

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

[0004] Background

[0005] Carbonyls are one of the most common and significant functional groups in organic chemistry. Indeed, the function offers a range of possibilities of interesting reactions and versatile strategies. Many methods have been developed for the synthesis of these functional groups. The interconversion of hindered ketones into their corresponding aldehydes is an important reaction in organic synthesis.

[0006] In particular, the conversion from tetramethylcyclohexanone to its corresponding aldehyde is an important process step in the production of polysubstituted cyclohexanes. Such polysubstituted cyclohexanes are molecules of great interest with an enormous potential in perfume elaboration.

[0007] However, the synthesis of poly substituted cyclohexanes includes major drawbacks, such as a large number of step and resulting high production costs. These molecules are consequently extremely expensive, and their use is therefore restrained.

[0008] So, there is still a need to develop a more straightforward approach toward the interconversion of hindered ketones to their corresponding aldehyde while improving the yield and keeping the stereoselectivity.

[0009] The present invention allows obtaining compounds of formula (I) from reacting hydroxy ethers of formula (II) in the presence of a Lewis acid or a mixture of a Lewis acid and at least one Bronsted acid or a mixture of at least two Bronsted acids.

[0010] Summary of the Invention

[0011] The invention relates to a novel process allowing the preparation of compound of formula (I) by bringing a compound of formula (II) in contact with a Lewis acid or a mixture of a Lewis acid and at least one Bronsted acid or a mixture of at least two Bronsted acids.

[0012] In a first aspect, the object of the present invention is a process for the preparation of a compound of formula (I) wherein R1 represents a C1-C12 alkyl, C2-C12 alkenyl, C3-C12 cycloalkyl, C3-C12 cycloalkenyl, Ce-C aryl group, each optionally substituted with one or more C1-C12 alkyl, C2-C12 alkenyl, C1-C12 alkoxy group(s), R2 represents a C1-C12 alkyl, C2-C12 alkenyl, C3- C12 cycloalkyl, C3-C12 cycloalkenyl, Ce-Cu aryl group, each optionally substituted with one or more C1-C12 alkyl, C2-C12 alkenyl, C1-C12 alkoxy group(s) and R1 and R2, when taken together, form a C5-C7 cycloalkyl or cycloalkenyl moiety, optionally substituted with one or more, C1-C12 alkyl, C2-C12 alkenyl, C1-C12 alkoxy group(s), by bringing a compound of formula (II) wherein R1 and R2 have the same meaning as defined in formula (I) and R3 represents C1-C10 alkyl, C2-C12 alkenyl, each optionally substituted with one or more oxygen atoms, or an alkyl end capped diol-based polyether having 3-12 units of one or more monomers, wherein the monomers are each independently selected from C i-Ce alkane diols, and wherein the alkyl end cap is Ci-Ce alkyl, in contact with a Lewis acid or a mixture of a Lewis acid and at least one Bronsted acid or a mixture of at least two Bronsted acids.

[0013] In a second aspect, the present invention provides a compound of formula (V): wherein the solid-dashed line represents a single or double bond; wherein the number of double bonds is 0 or 1 ; wherein R3 is as defined in formula (II); and wherein each of R4, R5, R6 and R7 is independently from each other H or a C1-C4 alkyl group. The compound of formula (V) is suitable as substrate for the process of the present invention. Description of the invention

[0014] Surprisingly, it has now been discovered that the compound of formula (I) can be produced in an advantageous manner by means of a one-step reaction of compound of formula (II) in the presence of a Lewis acid or a mixture of a Lewis acid and at least one Bronsted acid or a mixture of at least two Bronsted acids. The invention’s process allows a fast and simple interconversion of hindered ketones into their corresponding aldehydes in high yields by avoiding toxic reagents and multiple reaction steps. Particularly in the presence of a Lewis acid or a mixture of at least two Bronsted acids the conversion of compounds of formula (II) to compounds of formula (I) show a high selectivity towards the aldehyde of formula (I). In other words, with the addition of a Lewis acid or a mixture of a Lewis acid and at least one Bronsted acid or a mixture of at least two Bronsted acids the formation of unwanted side products is significantly decreased or even completely avoided.

[0015] Therefore, a first object of the present invention is a process for the preparation of wherein R1 represents a C1-C12 alkyl, C2-C12 alkenyl, C3-C12 cycloalkyl, C3-C12 cycloalkenyl, Ce-Cu aryl group, each optionally substituted with one or more C1-C12 alkyl, C2-C12 alkenyl, C1-C12 alkoxy group(s), R2 represents a C1-C12 alkyl, C2-C12 alkenyl, C3- C12 cycloalkyl, C3-C12 cycloalkenyl, Ce-Cu aryl group, each optionally substituted with one or more C1-C12 alkyl, C2-C12 alkenyl, C1-C12 alkoxy group(s) and R1 and R2, when taken together, form a C5-C12 cycloalkyl or cycloalkenyl moiety, optionally substituted with one or more, each independently, C1-C12 alkyl, C2-C12 alkenyl, C1-C12 alkoxy group(s), by bringing a compound of formula (II)

[0016] ,OR3

[0017] LOH

[0018] R1 R2

[0019] (II) wherein R1 and R2 have the same meaning as defined in formula (I) and R3 represents C1-C10 alkyl, C2-C12 alkenyl, each optionally comprised with one or more oxygen atoms, or an alkyl end capped diol-based polyether having 3-12 units of one or more monomers, wherein the monomers are each independently selected from Ci-Ce alkane diols, and wherein the alkyl end cap is Ci-Ce alkyl, in contact with a Lewis acid or a mixture of a Lewis acid and at least one Bronsted acid or a mixture of at least two Bronsted acids.

[0020] Preferably, the monomers are each independently selected from C1-C4 alkane diols, more preferably the monomers are ethane- 1,2-diol, propane-1, 3-diol, butane-l,4-diol. Preferably, the alkyl end cap is methyl, ethyl, propyl , butyl or methoxy ethyl. The monomers may be identical or different. Preferably, the monomers are identical.

[0021] By “Lewis acid”, it is understood a molecular entity that is an electron-pair acceptor and therefore able to react with a Lewis base to form a Lewis adduct, by sharing the electron pair furnished by the Lewis base as defined by IUPAC ('Lewis acid' in IUPAC Compendium of Chemical Terminology, 3rd ed. International Union of Pure and Applied Chemistry; 2006. Online version 3.0.1, 2019).

[0022] By “Bronsted acid”, it is understood a molecular entity capable of donating a proton to a base or the corresponding chemical species as defined by IUPAC ('Bronsted acid' in IUPAC Compendium of Chemical Terminology, 3rd ed. International Union of Pure and Applied Chemistry; 2006. Online version 3.0.1, 2019).

[0023] By “alkyl end capped diol-based polyether” it is meant the commonly known and accepted definition, i.e. an alkyl end capped diol-based polyether is the ether derivable from a polyether polyol in which the remaining hydroxyl groups have been reacted with an alkylating agent to form the corresponding ether.

[0024] The terms “alkyl” and “alkenyl” are understood as comprising branched and linear alkyl and alkenyl groups. The terms “alkenyl” and “cycloalkenyl” is understood as comprising 1, 2 or 3 olefinic double bonds, preferably 1 or 2 olefinic double bonds. The terms “cycloalkyl” and “cycloalkenyl” are understood as comprising a monocyclic or fused, spiro and / or bridged bicyclic or tricyclic cycloalkyl and cycloalkenyl, groups, preferably monocyclic cycloalkyl and cycloalkenyl groups.

[0025] By “comprising an oxygen atom” or “comprising at least one oxygen atom” it is understood that the compound or moiety comprises one or more of any functional group that is derivable from an oxygen atom. In particular, any =0 or -OH or -O- group. In other words, a compound moiety comprising at least one oxygen atom is any carbonyl group, such as carboxylic acids, ketones, aldehydes, amides; and / or any hydroxy group such as alcohols, phenols and enols; and / or any ether. According to any embodiments of the invention, R1 represents a C1-C10 alkyl, C2- C10 alkenyl, C3-C10 cycloalkyl, C3-C10 cycloalkenyl, C6-C12 aryl group, each optionally substituted with one or more Ci-Ce alkyl, C2-C6 alkenyl, C1-C12 alkoxy group(s), R2 represents a Ci-Ce alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, Ce-Cio aryl group, each optionally substituted with one or more Ci-Ce alkyl, C2-C6 alkenyl, Ci-Ce alkoxy group(s)

[0026] According to any embodiments of the invention, R1 represents a Ci-Cs alkyl, C2-C8 alkenyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, Ce-Cio aryl group, each optionally substituted with one or more Ci-Ce alkyl, C2-C6 alkenyl, C1-C12 alkoxy group(s), R2 represents a Ci-Ce alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, Ce-Cio aryl group, each optionally substituted with one or more Ci-Ce alkyl, C2-C6 alkenyl, Ci-Ce alkoxy group(s)

[0027] According to any embodiments of the invention, R1 represents a Ci-Ce alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, Ce-Cio aryl group, each optionally substituted with one or more Ci-Ce alkyl, C2-C6 alkenyl, C1-C12 alkoxy group(s), R2 represents a Ci-Ce alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, Ce-Cio aryl group, each optionally substituted with one or more Ci-Ce alkyl, C2-C6 alkenyl, Ci-Ce alkoxy group(s).

[0028] According to any embodiments of the invention, R1 represents a Ci-Ce alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, Ce aryl group, each optionally substituted with one or more C1-C4 alkyl, C2-C4 alkenyl, C1-C4 alkoxy group(s), R2 represents a Ci-Ce alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, Ce aryl group, each optionally substituted with one or more C1-C4 alkyl, C2-C4 alkenyl, C1-C4 alkoxy group(s).

[0029] According to any embodiments of the invention, R1 represents a C1-C4 alkyl, C2-C3 alkenyl, Cs-Ce cycloalkyl, Cs-Ce cycloalkenyl, Ce aryl group, each optionally substituted with one or more C1-C4 alkyl, C2-C3 alkenyl, C1-C4 alkoxy group(s), R2 represents a C1-C4 alkyl, C2-C3 alkenyl, Cs-Ce cycloalkyl, Cs-Ce cycloalkenyl, Ce aryl group, each optionally substituted with one or more C1-C4 alkyl, C2-C3 alkenyl, C1-C4 alkoxy group(s) and Rl.

[0030] According to any embodiment of the invention, Rl and R2 together form a C5-C7 cycloalkyl or cycloalkenyl moiety, each optionally substituted with one or more, each independently, Ci-Ce alkyl, C2-C6 alkenyl, Ci-Ce alkoxy group(s).

[0031] In another embodiment, Rl and R2 together form a Cs-Ce cycloalkyl or cycloalkenyl moiety, optionally substituted with one or more, each independently, C1-C4 alkyl and / or C2-C6 alkenyl and / or Ci-Ce alkoxy group(s). Preferably, R1 and R2 together form a Cs-Ce cycloalkyl or cycloalkenyl moiety, optionally substituted with one or more, each independently, C1-C3 alkyl and / or C2-C4 alkenyl and / or C1-C4 alkoxy group(s). Preferably, R1 and R2 together form a Cs-Ce cycloalkyl or cycloalkenyl moiety, optionally substituted with one or more, each independently, C1-C3 alkyl and / or C2-C3 alkenyl and / or C1-C3 alkoxy group(s). Preferably, R1 and R2 together form a Cs-Ce cycloalkyl or cycloalkenyl moiety, optionally substituted with one or more, each independently, C1-C2 alkyl and / or C2-C3 alkenyl and / or C1-C2 alkoxy group(s). Even more preferably, R1 and R2 together form a Cs-Ce cycloalkyl or cycloalkenyl moiety, optionally substituted with one to four methyl group.

[0032] According to any embodiment of the invention, R3 represents C1-C10 alkyl, C2-C12 alkenyl, each optionally comprising one or more oxygen atoms, or an alkyl end capped diol-based polyether having 3-12 units of one or more monomers, wherein the monomers are each independently selected from Ci-Ce alkane diols and wherein the alkyl end cap is Ci-Ce alkyl. Preferably, the monomers are each independently selected from C1-C4 alkane diols, more preferably the monomers are ethane- 1,2-diol, propane-1.3-diol, butane-1,4- diol. Preferably, the alkyl end cap is methyl, ethyl propyl or butyl. The monomers may be identical or different. Preferably, the monomers are identical.

[0033] In a further embodiment, R3 represents Ci-Cs alkyl, C2-C8 alkenyl, each optionally substituted with one or more oxygen atoms, optionally substituted with one or more oxygen atoms or an alkyl end capped diol-based polyether having 3-12 units of one or more monomers, wherein the monomers are each independently selected from Ci-Ce alkane diols, and wherein the alkyl end cap is Ci-Ce alkyl. Preferably, the monomers are each independently selected from C1-C4 alkane diols, more preferably the monomers are selected from ethane-l,2-diol, propane-1.3-diol and butane- 1,4-diol. Preferably, the alkyl end cap is methyl, ethyl, propyl or butyl. If two or more monomers are present, the monomers are different or identical.

[0034] In a further embodiment, R3 represents Ci-Cs alkyl, C2-C8 alkenyl, each optionally substituted with one or more oxygen atoms, or an alkyl end capped diol-based polyether having 3-10 units of one or more monomers, wherein the monomers are each independently selected from C1-C4 alkane diols and wherein the alkyl end cap is Ci-Ce alkyl. Preferably, the alkyl end cap is methyl, ethyl, propyl or butyl. If two or more monomers are present, the monomers are different or identical. In yet a further embodiment, R3 represents Ci-Ce alkyl, C2-C6 alkenyl, each optionally substituted with one or more oxygen atoms, or an alkyl end capped diol-based poly ether having 3-10 units of one or more monomers, wherein the monomers are selected from ethane- 1,2-diol, propane-1.3-diol and butane-l,4-diol, and wherein the alkyl end cap is Ci-Ce alkyl. Preferably, the alkyl end cap is methyl, ethyl, propyl or butyl. If two or more monomers are present, the monomers are different or identical.

[0035] In one more embodiment, R3 represents C1-C4 alkyl, C2-C4 alkenyl, each optionally substituted with one or more oxygen atoms, or an alkyl end capped diol-based polyether having 3-10 units of one or more monomers, wherein the monomers are selected from ethane- 1,2-diol, propane-1.3-diol and butane-l,4-diol, and the alkyl end cap is methyl, ethyl propyl or butyl. If two or more monomers are present, the monomers are different or identical.

[0036] In another embodiment, R3 represents methyl, ethyl, propyl or butyl. In a further embodiment, R3 represents methyl or ethyl. In a certain embodiment, R3 is 2- methoxyethoxymethyl. In another certain embodiment, R3 is methoxy ethyl.

[0037] It is to be understood, that each of the definitions of Rl, R2 and R3 as disclosed in the above embodiments can also be independently combined with each other.

[0038] According to any embodiments of the invention, a compound of formula (II) is prepared by bringing a compound of formula (III) in contact with a reactive metalorganic species of (halomethoxy)alkyl or with a reactive metalorganic species of a thioether, wherein Rl and R2 in formula (III) have the same meaning as defined in formula (I) and wherein Rl, R2 and R3 in formula (II) have the same meaning as defined above.

[0039] By “(halomethoxy)alkyl” it is understood a compound according to the formula X- CH2-O-R3, wherein X is a halogen atom and R3 is as defined above for Formula (II). In one embodiment, R3 is Ci-Cs alkyl, C2-C8 alkenyl, each optionally comprising one or more oxygen atoms, or an alkyl end capped diol-based polyether having 3-10 units of one or more monomers, wherein the monomers are each independently selected from Ci-Ce alkane diols, and wherein the alkyl end cap is Ci-Ce alkyl. Preferably, the monomers are each independently selected from C1-C4 alkane diols, more preferably the monomers are selected from ethane-l,2-diol, propane- 1.3 -diol and butane- 1,4-diol. Preferably, the alkyl end cap is methyl, ethyl, propyl or butyl. If two or more monomers are present, the monomers can be different or identical. In one embodiment the monomers are ethane-l,2-diol or propane- 1,3-diol.

[0040] According to any embodiment, X is Cl, Br or I and R3 is Ci-Ce alkyl, C2-C6 alkenyl, each optionally substituted with one or more oxygen atoms, or an alkyl end capped diol- based polyether having 3-10 units, wherein the monomers are selected from ethane-1,2- diol, propane- 1.3 -diol and butane-l,4-diol and the alkyl end cap is methyl or ethyl. According to a further embodiment, X is Cl, Br or I and R3 is methyl, ethyl, propyl, butyl, or 2-methoxyethyl. In one embodiment, X is Cl or Br and R3 is methyl or ethyl. In a certain embodiment, the (halomethoxy)alkyl is 2-methoxyethoxymethyl chloride. In another certain embodiment, the (halomethoxy)alkyl is chloromethoxy methane. In a further certain embodiment, the (halomethoxy)alkyl is chloromethoxy ethane. In a further certain embodiment, the (halomethoxy)alkyl is chloromethoxy propane. In a further certain embodiment, the (halomethoxy)alkyl is 1 -(chi oromethoxy)-2 -methoxy ethane. In yet a further certain embodiment, the (halomethoxy)alkyl is chloromethoxy butane.

[0041] According to any embodiment, the (halomethoxy)alkyl is added in 100 mol% to 500 mol% relative to the amount of compound of formula (III). In one embodiment, the (halomethoxy)alkyl is added in 150 mol% to 400 mol% relative to the amount of compound of formula (III). In one more embodiment, the (halomethoxy)alkyl is added in 150 mol% to 300 mol% relative to the amount of compound of formula (III). In a further embodiment, the (halomethoxy)alkyl is added in 100 mol% to 250 mol% relative to the amount of compound of formula (III).

[0042] By a “reactive metalorganic species of (halomethoxy)alkyl” and a “reactive metalorganic species of a thioether” it is understood a compound derived by reacting the (halomethoxy)alkyl or the thioether with metal, metal reagent and / or metal salt in a way suitable to form a metalorganic species which is able to react with a carbonyl group. Such reactive metalorganic species are derivable for example frommetal-halogen corresponding (methoxy)alkyl. According to any embodiment, the reactive organometallic product is obtainable from metal-halogen exchange, metal insertion or by thioether reduction. In other words, the reactive metalorganic species of (halomethoxy)alkyl or the thioether is a compound according to the formula M-(CH2-O-R3)n, or MX-(CH2-O-R3) wherein M is a metal, X is a halogen atom and n is 1, 2, 3, 4 ,5 or 6, optionally including ligands and / or counter ions and wherein R3 is as defined above for formula (II).

[0043] According to an embodiment, the reactive metalorganic species is derived from a (halomethoxy)alkyl or the thioether by a metal exchange reaction giving a compound of the formula M-(CH2-O-R3)n, or MX-(CH2-O-R3) wherein M is a metal, X is a halogen atom and n is 1, 2, 3, 4 ,5 or 6, optionally including ligands and / or counter ions and wherein R3 is as defined above for formula (II).

[0044] According to any embodiment, M is selected from the group consisting of alkali metals, alkaline earth metals and transition metals. In one embodiment M is lithium, magnesium or zinc. Preferably, M is lithium. It is to be understood that magnesium may react with the (halomethoxy)alkyl by metal insertion to form a Grignard Reagent. Such Grignard reagent may be of the formula XM-CH2-O-R3, wherein M is magnesium, X is as defined above for (halomethoxy)alkyl and R3 is as defined above for formula (II). It is further to be understood that zinc may react with the (halomethoxy)alkyl by metal-halogen exchange to form an organozinc compound. Such organozinc compound may be of the formula Zn(CH2-O-R3)2, wherein R3 is as defined above for formula (II). It is further to be understood that lithium may react with the (halomethoxy)alkyl by metal-halogen exchange to form an organolithium compound. Such organolithium compound may be of the formula Li(CH2-O-R3), wherein R3 is as defined above for formula (II).

[0045] According to any embodiment, the reactive organometallic product is obtained by bringing the (halomethoxy)alkyl or the thioether in contact with metal, or metal reagent, wherein the metal is as defined above for M. In one embodiment, the metal or metal reagent is added in 100 mol% to 600 mol% relative to the amount of compound of formula (III). In a further embodiment, the metal is added in 150 mol% to 500 mol% relative to the amount of compound of formula (III). In one more embodiment, the metal or metal reagent is added in 150 mol% to 300 mol% relative to the amount of compound of formula (III). In another embodiment, the metal or metal reagent is added in 200 mol% to 400 mol% relative to the amount of compound of formula (III). In a further embodiment, the (halomethoxy)alkyl is added in 100 mol% to 200 mol% relative to the amount of compound of formula (III).

[0046] According to any embodiment, the reactive metalorganic species of (halomethoxy)alkyl or the thioether comprises a lithium, magnesium or zinc species of (halomethoxy)alkyl or the thioether, preferably a lithium species of (halomethoxy)alkyl or the thioether.

[0047] According to any embodiment, the reactive metalorganic species of (halomethoxy)alkyl is derived from a lithium, magnesium or zinc species and chloromethoxy methyl, chloromethoxy ethyl, chloromethoxy propyl or chloromethoxy butyl. In a certain embodiment, the (methoxy)alkyl is 2-methoxyethoxymethyl. In another certain embodiment, the (methoxy)alkyl is methoxy methyl. In a further certain embodiment, the (methoxy )alkyl is methoxy ethyl. In a further certain embodiment, the (methoxy)alkyl is methoxy propyl. In yet another certain embodiment, the (methoxy)alkyl is methoxy butyl.

[0048] According to any embodiment, the reactive metalorganic species of (halomethoxy)alkyl or the thioether is formed in situ, preferably during the preparation of compounds of formula (II) from compounds of formula (III).

[0049] According to any embodiment, the thioether is a compound according to the formula Rb-S-CH2-OR3, wherein R3 is as defined in formula (II).

[0050] In one embodiment, Rbis Ci-Cs alkyl, C2-C8 alkenyl, C5-C14 aryl, each optionally substituted with one or more C1-C12 alkyl, C2-C12 alkenyl, C1-C12 alkoxy group(s). In a further embodiment, Rbis Ci-Ce alkyl, C2-C6 alkenyl, Ce-Cio aryl, each optionally substituted with one or more C1-C12 alkyl, C2-C12 alkenyl, C1-C12 alkoxy group(s). In a certain embodiment, Rbis phenyl, optionally substituted with one or more C1-C12 alkyl, C2- C12 alkenyl, C1-C12 alkoxy group(s).

[0051] According to any embodiment, the thioether is added in 100 mol% to 500 mol% relative to the amount of compound of formula (III). In one embodiment, the thioether is added in 150 mol% to 400 mol% relative to the amount of compound of formula (III). In one more embodiment, the thioether is added in 150 mol% to 300 mol% relative to the amount of compound of formula (III). In a further embodiment, the thioether is added in 100 mol% to 250 mol% relative to the amount of compound of formula (III).

[0052] According to any embodiment, the reactive organometallic product is obtainable by bringing the thioether in contact with a metal or metal reagent. In one embodiment, the metal or metal reagent is added in 100 mol% to 600 mol% relative to the amount of compound of formula (III). In a further embodiment, the metal or metal reagent is added in 100 mol% to 500 mol% relative to the amount of compound of formula (III). In one more embodiment, the metal or metal reagent is added in 100 mol% to 300 mol% relative to the amount of compound of formula (III). In another embodiment, the metal or metal reagent is added in 150 mol% to 250 mol% relative to the amount of compound of formula (III). In a further embodiment, the metal or metal reagent is added in 100 mol% to 150 mol% relative to the amount of compound of formula (III).

[0053] According to any embodiment, the compound of formula (I) is a compound of wherein the solid-dashed line represents a single or double bond, and wherein the number of double bonds is 0 or 1; and wherein each of R4, R5, R6 and R7 is independently from each other H or a C1-C4 alkyl group; and the compound of formula (II) is a compound of formula (V). wherein the solid-dashed line represents a single or double bond; wherein the number of double bonds is 0 or 1 ; wherein R3 is as defined in formula (II); and wherein each of R4, R5, R6 and R7 is as defined in formula (IV).

[0054] According to any embodiment, each of R4, R5, R6 and R7 is independently from each other H or a C1-C3 alkyl group. In one embodiment, each of R4, R5, R6 and R7 is independently from each other H or methyl or ethyl. In a further embodiment, each of R4, R5, R6 and R7 is independently from each other H or methyl.

[0055] According to any embodiment, the compound of formula (I) is a compound of formula (VII) wherein the solid-dashed line represents a single or double bond and the compound of formula (II) is a compound of formula (VIII)

[0056] (VIII). wherein R3 is as defined in formula (II).

[0057] According to any embodiment, the compound of formula (III) is a compound of formula (VI) wherein the solid-dashed line represents a single or double bond; and wherein the number of double bonds is 0 or 1; and wherein each of R4, R5, R6 and R7 is as defined in formula (IV).

[0058] According to any embodiment, the compound of formula (III) is a compound of formula (IX) wherein the solid-dashed line represents a single or double bond.

[0059] According to any embodiment, the compound of formula (I) is (lS,3R,6R)-2,2,3,6- tetramethylcyclohexane-l-carbaldehyde.

[0060] According to any embodiment, the compound of formula (II) or (V) is 1-

[0061] (methoxymethyl)-2,2,3,6-tetramethylcyclohexan-l-ol, 1 -(ethoxymethyl)-2, 2,3,6- tetramethylcyclohexan-l-ol, l-(propoxymethyl)-2,2,3,6-tetramethyl-cyclohexan-l-ol, 1- (butoxymethyl)-2,2,3,6-tetramethylcyclohexan-l-ol, l-(((2- methoxyethoxy)methoxy)methyl)-2,2,3,6-tetramethylcyclohexan-l -ol or 1 - (ethoxymethyl)-2,5,6,6-tetramethylcyclohex-2-en-l-ol.

[0062] According to any embodiment, the compound of formula (II) or (V) is selected from any racemic mixture of l-(methoxymethyl)-2,2,3,6-tetramethylcyclohexan-l-ol, 1- (ethoxymethyl)-2,2,3,6-tetramethylcyclohexan-l-ol, 1 -(propoxymethy l)-2, 2,3,6- tetramethyl-cyclohexan-l-ol, 1 -(butoxymethyl)-2,2,3,6-tetramethylcyclohexan-l -ol, 1 - (((2-methoxyethoxy)methoxy)methyl)-2,2,3,6-tetramethylcyclohexan-l -ol or 1- (ethoxymethyl)-2, 5, 6, 6-tetramethylcyclohex-2-en-l-ol. According to any embodiment, the compound of formula (II) or (V) is (1R, 3R,6R)-l-(methoxymethyl)-2, 2,3,6- tetramethylcyclohexan-l-ol or (lR,3R,6R)-l-(ethoxymethyl)-2,2,3,6- tetramethylcyclohexan-l-ol or (lR,3R,6R)-l-(propoxymethyl)-2,2,3,6 tetramethylcyclohexan-l-ol or (lR,3R,6R)-l-(butoxymethyl)-2,2,3,6 tetramethylcyclohexan-l-ol or (1R,3R,6R)-1 -(ethoxymethyl)-2, 5,6,6- tetramethylcyclohex-2-en-l -ol or (lR,3R,6R)-l-(((2-methoxyethoxy)methoxy)methyl)-

[0063] 2.2.3.6-tetramethylcyclohexan-l-ol.

[0064] According to any embodiment, the compound of formula (II) or (V) is (1S,3R,6R)- l-(methoxymethyl)-2,2,3,6-tetramethylcyclohexan-l-ol or (lS,3R,6R)-l-(ethoxymethyl)-

[0065] 2.2.3.6-tetramethylcyclohexan-l-ol or (lS,3R,6R)-l-(propoxymethyl)-2,2,3,6- tetramethylcyclohexan-1 -ol or (lS,3R,6R)-l-(butoxymethyl)-2,2,3,6- tetramethylcyclohexan-1 -ol or (1 S,3R,6R)-1 -(ethoxymethyl)-2,5,6,6-tetramethylcyclohex-

[0066] 2-en-l -ol or (1 S,3R,6R)-1 -(((2-methoxy ethoxy )methoxy)methyl)-2, 2,3,6- tetramethylcyclohexan-1 -ol.

[0067] According to any embodiment, the compound of formula (II) or (V) is (1R,3S,6R)-

[0068] 1-(methoxymethyl)-2,2,3,6-tetramethylcyclohexan-l-ol or (lR,3S,6R)-l-(ethoxymethyl)-

[0069] 2,2,3,6-tetramethylcyclohexan-l-ol or (lR,3S,6R)-l-(propoxymethyl)-2,2,3,6- tetramethylcyclohexan-l-ol or (lR,3S,6R)-l-(butoxymethyl)-2,2,3,6- tetramethylcyclohexan-1 -ol or (1R,3S,6R)-1 -(ethoxymethyl)-2,5,6,6-tetramethylcyclohex-

[0070] 2-en-l -ol or (lR,3S,6R)-l-(((2-methoxyethoxy)methoxy)methyl)-2,2,3,6- tetramethylcyclohexan-l-ol

[0071] According to any embodiment, the compound of formula (II) or (V) is (1R,3R,6S)- l-(methoxymethyl)-2,2,3,6-tetramethylcyclohexan-l-ol or (lR,3R,6S)-l-(ethoxymethyl)-

[0072] 2,2,3,6-tetramethylcyclohexan-l-ol or (1R, 3R,6S)-l-(propoxymethyl)-2, 2,3,6- tetramethylcyclohexan-l-ol or (lR,3R,6S)-l-(butoxymethyl)-2,2,3,6- tetramethylcyclohexan-1 -ol or (1R,3R,6S)-1 -(ethoxymethyl)-2.5.6.6-tetramethylcyclohex- 2-en-l-ol or (1R,3R,6S)-1 -(((2-methoxy ethoxy )methoxy)methyl)-2, 2, 3, 6- tetramethylcyclohexan-l-ol

[0073] According to any embodiment, the compound of formula (II) or (V) is (1S,3S,6R)-

[0074] 1-(methoxymethyl)-2,2,3,6-tetramethylcyclohexan-l-ol or (lS,3S,6R)-l-(ethoxymethyl)-

[0075] 2,2,3,6-tetramethylcyclohexan-l-ol or (lS,3S,6R)-l-(propoxymethyl)-2,2,3,6- tetramethylcyclohexan-1 -ol or (1 S,3S,6R)-1 -(butoxymethyl)-2,2,3,6- tetramethylcyclohexan-l-ol or (lS,3S,6R)-l-(ethoxymethyl)-2,5,6,6-tetramethylcyclohex-

[0076] 2-en-l -ol or (1 S,3S,6R)-1 -(((2-methoxy ethoxy )methoxy)methyl)-2, 2,3,6- tetramethylcyclohexan-1 -ol.

[0077] According to any embodiment, the compound of formula (II) or (V) is (1S,3R,6S)-

[0078] 1-(methoxymethyl)-2,2,3,6-tetramethylcyclohexan-l-ol or (lS,3R,6S)-l-(ethoxymethyl)-

[0079] 2,2,3,6-tetramethylcyclohexan-l-ol or (lS,3R,6S)-l-(propoxymethyl)-2,2,3,6- tetramethylcyclohexan-l-ol or (lS,3R,6S)-l-(butoxymethyl)-2,2,3,6- tetramethylcyclohexan-1 -ol or (1 S,3R,6S)-1 -(ethoxymethyl)-2,5,6,6-tetramethylcyclohex-

[0080] 2-en-l-ol or (1 S,3R,6S)-1 -(((2-methoxy ethoxy )methoxy)methyl)-2, 2,3,6- tetramethylcyclohexan-1 -ol.

[0081] According to any embodiment, the compound of formula (II) or (V) is (1R,3S,6S)-

[0082] 1-(methoxymethyl)-2,2,3,6-tetramethylcyclohexan-l-ol or (lR,3S,6S)-l-(ethoxymethyl)-

[0083] 2,2,3,6-tetramethylcyclohexan-l-ol or (lR,3S,6S)-l-(propoxymethyl)-2,2,3,6- tetramethylcyclohexan-l-ol or (lR,3S,6S)-l-(butoxymethyl)-2,2,3,6- tetramethylcyclohexan-l-ol or (lR,3S,6S)-l-(ethoxymethyl)-2,5,6,6-tetramethylcyclohex-

[0084] 2-en-l-ol or (1R,3S,6S)-1 -(((2-methoxy ethoxy )methoxy)methyl)-2, 2, 3, 6- tetramethylcyclohexan-l-ol

[0085] According to any embodiment, the compound of formula (II) or (V) is (1S,3S,6S)-

[0086] 1-(methoxymethyl)-2,2,3,6-tetramethylcyclohexan-l-ol or (lS,3S,6S)-l-(ethoxymethyl)-

[0087] 2,2,3,6-tetramethylcyclohexan-l-ol or (lS,3S,6S)-l-(propoxymethyl)-2,2,3,6- tetramethylcyclohexan-l-ol or (1 S,3R,6S)-1 -(butoxymethyl)-2, 2,3,6- tetramethylcyclohexan-1 -ol or (1 S,3S,6S)-1 -(ethoxymethyl)-2,5,6,6-tetramethylcyclohex-

[0088] 2-en-l-ol or (1 S,3S,6S)-1 -(((2-methoxy ethoxy )methoxy)methyl)-2, 2,3,6- tetramethylcyclohexan-1 -ol. According to any embodiment, the compound of formula (III) is 2, 2, 3, 6- tetramethy Icy clohexan- 1 -one.

[0089] According to any embodiment, the compound of formula (III) is (3R,6R)-2,2,3,6- tetramethy Icy clohexan- 1 -one.

[0090] According to any embodiment, the Lewis acid is selected from the group consisting of boron, tin, bismuth, iron, copper, zinc, indium or aluminum-based Lewis acids or mixtures therefrom.

[0091] In one embodiment, the Lewis acid is selected from the group consisting of boron, tin, bismuth, iron-based Lewis acids or mixtures therefrom.

[0092] According to any embodiment, the Lewis acid is selected from the group consisting of BF3 Et2O, SnCL, Bi(OTf)3 and FeCL or mixtures therefrom. In a certain embodiment the Lewis acid is SnCL. In another certain embodiment the Lewis acid is BF3 EfoO. In a further certain embodiment the Lewis acid is Bi(OTf)3. In yet another certain embodiment the Lewis acid is FeCL.

[0093] In one embodiment, one or more Lewis acids are used. In a further embodiment, a mixture of at least two Lewis acids is used. In another embodiment, the at least two Lewis acids are selected from the group consisting of boron, tin, bismuth, iron, copper, zinc, indium or aluminum-based Lewis acids. In yet another embodiment, the at least two Lewis acids are selected from the group consisting of boron, tin, bismuth, iron-based Lewis acids. In one more embodiment, the at least two Lewis acids are selected from the group consisting of BF3 E^O, SnCL, Bi(OTf)3 and FeCL.

[0094] In a certain embodiment, the Lewis acid is a mixture of SnCL and BF3 Et2O. In another certain embodiment the Lewis acid is a mixture of FeCL and BF3 Et2O. In a further certain embodiment, the Lewis acid is a mixture of Bi(OTf)3 and BF3 Et2O. In yet another certain embodiment, the Lewis acid is a mixture of SnCL and FeCL. In a certain embodiment, the Lewis acid is a mixture of SnCL and Bi(OTfh. In another certain embodiment, the Lewis acid is a mixture of Bi(OTfh and FeCL. According to any embodiment, the Lewis acid is added in a total amount of 0.01 mol% to 100 mol% or 0.5 mol% to 80 mol% or of 5 mol% to 50 mol% or of 10 mol% to 50 mol% or of 10 mol% to 30 mol% of the molar weight of the substrate employed, wherein the substrate is any of the compounds as disclosed above falling under the scope of formula (II). In one embodiment, the Lewis acid is added in an amount of 0.1 to 15 mol% of the molar weight of the substrate employed, wherein the substrate is any of the compounds as disclosed above falling under the scope of formula (II).

[0095] According to any embodiment, a mixture of at least two Bronsted acids is added. In other words, the compound of formula (I) as defined above is prepared by bringing a compound of formula (II) as defined above in contact with a mixture of at least two Bronsted acids.

[0096] In one embodiment, the at least two Bronsted acids comprise a first and a second acid.

[0097] In one embodiment, the mixture of at least two Bronsted acids is selected from the group consisting of oxalic acid, sulfuric acid, acetic acid, formic acid, triflic acid, methanesulfonic acid, phosphoric acid and combinations therefrom.

[0098] In another embodiment, the mixture of at least two Bronsted acids consists of 2, 3, 4 or 5 acids, preferably, the mixture of at least two Bronsted acids consists of 2 or 3 acids. In a certain embodiment, the mixture of at least two Bronsted acids consists of 2 acids

[0099] In a further embodiment, one acid of the at least two Bronsted acids is oxalic acid.

[0100] In one embodiment, the first Bronsted acid is selected from the group consisting of oxalic acid, sulfuric acid, acetic acid, formic acid, triflic acid, methanesulfonic acid, phosphoric acid and combinations therefrom. In a certain embodiment, the first acid is oxalic acid.

[0101] In one embodiment, the second Bronsted acid is selected from the group consisting of oxalic acid, sulfuric acid, acetic acid, formic acid, triflic acid, methanesulfonic acid, phosphoric acid and combinations therefrom. In a certain embodiment, the second acid is sulfuric acid.

[0102] In a further embodiment, the first acid is added in an amount of at least 0.01 mol% of the molar weight of the substrate employed, wherein the substrate is any of the compounds as disclosed above falling under the scope of formula (II). In a further embodiment, the first acid is added in an amount of at least 0.03 mol% of the molar weight of the substrate employed, wherein the substrate is any of the compounds as disclosed above falling under the scope of formula (II). In a further embodiment, the first acid is added in an amount of at least 0.08 mol% of the molar weight of the substrate employed, wherein the substrate is any of the compounds as disclosed above falling under the scope of formula (II). In a certain embodiment, the first acid is added in an amount of at least 0. 1 mol% of the molar weight of the substrate employed, wherein the substrate is any of the compounds as disclosed above falling under the scope of formula (II). In a certain embodiment, the first acid is added in an amount of at least 0.2 mol% of the molar weight of the substrate employed, wherein the substrate is any of the compounds as disclosed above falling under the scope of formula (II). In a certain embodiment, the first acid is added in an amount of at least 0.5 mol% of the molar weight of the substrate employed, wherein the substrate is any of the compounds as disclosed above falling under the scope of formula (II). In a certain embodiment, the first acid is added in an amount of at least 0.8 mol% of the molar weight of the substrate employed, wherein the substrate is any of the compounds as disclosed above falling under the scope of formula (II). In a certain embodiment, the first acid is added in an amount of at least 1 mol% of the molar weight of the substrate employed, wherein the substrate is any of the compounds as disclosed above falling under the scope of formula (II). In a certain embodiment, the first acid is added in an amount of at least 2 mol% of the molar weight of the substrate employed, wherein the substrate is any of the compounds as disclosed above falling under the scope of formula (II). In a certain embodiment, the first acid is added in an amount of at least 5 mol% of the molar weight of the substrate employed, wherein the substrate is any of the compounds as disclosed above falling under the scope of formula (II). In a certain embodiment, the first acid is added in an amount of at least 10 mol% of the molar weight of the substrate employed, wherein the substrate is any of the compounds as disclosed above falling under the scope of formula (II). In a certain embodiment, the first acid is added in an amount of at least 20 mol% of the molar weight of the substrate employed, wherein the substrate is any of the compounds as disclosed above falling under the scope of formula (II). In a certain embodiment, the first acid is added in an amount of at least 50 mol% of the molar weight of the substrate employed, wherein the substrate is any of the compounds as disclosed above falling under the scope of formula (II). In a certain embodiment, the first acid is added in an amount of at least 100 mol% of the molar weight of the substrate employed, wherein the substrate is any of the compounds as disclosed above falling under the scope of formula (II). In a certain embodiment, the first acid is added in an amount of at least 130 mol% of the molar weight of the substrate employed, wherein the substrate is any of the compounds as disclosed above falling under the scope of formula (II). In a certain embodiment, the first acid is added in an amount of at least 150 mol% of the molar weight of the substrate employed, wherein the substrate is any of the compounds as disclosed above falling under the scope of formula (II). In a certain embodiment, the first acid is added in an amount of at least 200 mol% of the molar weight of the substrate employed, wherein the substrate is any of the compounds as disclosed above falling under the scope of formula (II). In a certain embodiment, the first acid is added in an amount of at least 300 mol% of the molar weight of the substrate employed, wherein the substrate is any of the compounds as disclosed above falling under the scope of formula (II). In a certain embodiment, the first acid is added in an amount of at least 500 mol% of the molar weight of the substrate employed, wherein the substrate is any of the compounds as disclosed above falling under the scope of formula (II). In a certain embodiment, the first acid is added in an amount of at least 1000 mol% of the molar weight of the substrate employed, wherein the substrate is any of the compounds as disclosed above falling under the scope of formula (II). In a certain embodiment, the first acid is added in an amount of at least 1300 mol% of the molar weight of the substrate employed, wherein the substrate is any of the compounds as disclosed above falling under the scope of formula (II). In a certain embodiment, the first acid is added in an amount of at least 1500 mol% of the molar weight of the substrate employed, wherein the substrate is any of the compounds as disclosed above falling under the scope of formula (II). In a certain embodiment, the first acid is added in an amount of at least 2000 mol% of the molar weight of the substrate employed, wherein the substrate is any of the compounds as disclosed above falling under the scope of formula (II). the first acid is added in an amount of at least 3000 mol% of the molar weight of the substrate employed, wherein the substrate is any of the compounds as disclosed above falling under the scope of formula (II). In a certain embodiment, the first acid is added in an amount of at least 4000 mol% of the molar weight of the substrate employed, wherein the substrate is any of the compounds as disclosed above falling under the scope of formula (II).

[0103] In a further embodiment, the second acid is added in an amount of at least 0.01 mol% of the molar weight of the substrate employed, wherein the substrate is any of the compounds as disclosed above falling under the scope of formula (II). In a further embodiment, the second acid is added in an amount of at least 0.03 mol% of the molar weight of the substrate employed, wherein the substrate is any of the compounds as disclosed above falling under the scope of formula (II). In a further embodiment, the second acid is added in an amount of at least 0.08 mol% of the molar weight of the substrate employed, wherein the substrate is any of the compounds as disclosed above falling under the scope of formula (II). In a certain embodiment, the second acid is added in an amount of at least 0.1 mol% of the molar weight of the substrate employed, wherein the substrate is any of the compounds as disclosed above falling under the scope of formula (II). In a certain embodiment, the second acid is added in an amount of at least 0.2 mol% of the molar weight of the substrate employed, wherein the substrate is any of the compounds as disclosed above falling under the scope of formula (II). In a certain embodiment, the second acid is added in an amount of at least 0.5 mol% of the molar weight of the substrate employed, wherein the substrate is any of the compounds as disclosed above falling under the scope of formula (II). In a certain embodiment, the second acid is added in an amount of at least 0.8 mol% of the molar weight of the substrate employed, wherein the substrate is any of the compounds as disclosed above falling under the scope of formula (II). In a certain embodiment, the second acid is added in an amount of at least 1 mol% of the molar weight of the substrate employed, wherein the substrate is any of the compounds as disclosed above falling under the scope of formula (II). In a certain embodiment, the second acid is added in an amount of at least 2 mol% of the molar weight of the substrate employed, wherein the substrate is any of the compounds as disclosed above falling under the scope of formula (II). the second acid is added in an amount of at least 5 mol% of the molar weight of the substrate employed, wherein the substrate is any of the compounds as disclosed above falling under the scope of formula (II). In a certain embodiment, the second acid is added in an amount of at least 10 mol% of the molar weight of the substrate employed, wherein the substrate is any of the compounds as disclosed above falling under the scope of formula (II). the second acid is added in an amount of at least 20 mol% of the molar weight of the substrate employed, wherein the substrate is any of the compounds as disclosed above falling under the scope of formula (II). In a certain embodiment, the second acid is added in an amount of at least 50 mol% of the molar weight of the substrate employed, wherein the substrate is any of the compounds as disclosed above falling under the scope of formula (II). In a certain embodiment, the second acid is added in an amount of at least 100 mol% of the molar weight of the substrate employed, wherein the substrate is any of the compounds as disclosed above falling under the scope of formula (II). In a certain embodiment, the second acid is added in an amount of at least 130 mol% of the molar weight of the substrate employed, wherein the substrate is any of the compounds as disclosed above falling under the scope of formula (II). In a certain embodiment, the second acid is added in an amount of at least 150 mol% of the molar weight of the substrate employed, wherein the substrate is any of the compounds as disclosed above falling under the scope of formula (II). the second acid is added in an amount of at least 200 mol% of the molar weight of the substrate employed, wherein the substrate is any of the compounds as disclosed above falling under the scope of formula (II). In a certain embodiment, the second acid is added in an amount of at least 300 mol% of the molar weight of the substrate employed, wherein the substrate is any of the compounds as disclosed above falling under the scope of formula (II). In a certain embodiment, the second acid is added in an amount of at least 500 mol% of the molar weight of the substrate employed, wherein the substrate is any of the compounds as disclosed above falling under the scope of formula (II). In a certain embodiment, the second acid is added in an amount of at least 1000 mol% of the molar weight of the substrate employed, wherein the substrate is any of the compounds as disclosed above falling under the scope of formula (II). In a certain embodiment, the second acid is added in an amount of at least 1300 mol% of the molar weight of the substrate employed, wherein the substrate is any of the compounds as disclosed above falling under the scope of formula (II). the second acid is added in an amount of at least 1500 mol% of the molar weight of the substrate employed, wherein the substrate is any of the compounds as disclosed above falling under the scope of formula (II). In a certain embodiment, the second acid is added in an amount of at least 2000 mol% of the molar weight of the substrate employed, wherein the substrate is any of the compounds as disclosed above falling under the scope of formula (II). In a certain embodiment, the second acid is added in an amount of at least 3000 mol% of the molar weight of the substrate employed, wherein the substrate is any of the compounds as disclosed above falling under the scope of formula (II). In a certain embodiment, the second acid is added in an amount of at least 4000 mol% of the molar weight of the substrate employed, wherein the substrate is any of the compounds as disclosed above falling under the scope of formula (II).

[0104] In another embodiment, the ratio between the first and the second acid is 1 to 20 by weight of the total weight of both, the first and the second acid. In a further certain embodiment, the ratio between the first and the second acid is 1 to 15 by weight of the total weight of both, the first and the second acid. In yet a further embodiment, the ratio between the first and the second acid is 1 to 13 by weight of the total weight of both, the first and the second acid. In a certain embodiment, the ratio between the first and the second acid is 1 to 10 by weight of the total weight of both, the first and the second acid. In a further certain embodiment, the ratio between the first and the second acid is 1 to 8 by weight of the total weight of both, the first and the second acid. In another certain embodiment, the ratio between the first and the second acid is 1 to 6 by weight of the total weight of both, the first and the second acid. In a further certain embodiment, the ratio between the first and the second acid is 1 to 4 by weight of the total weight of both, the first and the second acid. In yet a further embodiment, the ratio between the first and the second acid is 1 to 2 by weight of the total weight of both, the first and the second acid. In yet another certain embodiment, the ratio between the first and the second acid is 1 to 1 by weight of the total weight of both, the first and the second acid.

[0105] In one embodiment, the mixture of at least two Bronsted acids comprises a third acid.

[0106] In a further embodiment, the third acid is added in an amount of at least 0.01 mol% of the molar weight of the substrate employed, wherein the substrate is any of the compounds as disclosed above falling under the scope of formula (II). In a further embodiment, the third acid is added in an amount of at least 0.03 mol% of the molar weight of the substrate employed, wherein the substrate is any of the compounds as disclosed above falling under the scope of formula (II). In a further embodiment, the third acid is added in an amount of at least 0.08 mol% of the molar weight of the substrate employed, wherein the substrate is any of the compounds as disclosed above falling under the scope of formula (II). In a certain embodiment, the third acid is added in an amount of at least 0. 1 mol% of the molar weight of the substrate employed, wherein the substrate is any of the compounds as disclosed above falling under the scope of formula (II). In a certain embodiment, the third acid is added in an amount of at least 0.2 mol% of the molar weight of the substrate employed, wherein the substrate is any of the compounds as disclosed above falling under the scope of formula (II). In a certain embodiment, the third acid is added in an amount of at least 0.5 mol% of the molar weight of the substrate employed, wherein the substrate is any of the compounds as disclosed above falling under the scope of formula (II). In a certain embodiment, the third acid is added in an amount of at least 0.8 mol% of the molar weight of the substrate employed, wherein the substrate is any of the compounds as disclosed above falling under the scope of formula (II). In a certain embodiment, the third acid is added in an amount of at least 1 mol% of the molar weight of the substrate employed, wherein the substrate is any of the compounds as disclosed above falling under the scope of formula (II). In a certain embodiment, the third acid is added in an amount of at least 2 mol% of the molar weight of the substrate employed, wherein the substrate is any of the compounds as disclosed above falling under the scope of formula (II). In a certain embodiment, the third acid is added in an amount of at least 5 mol% of the molar weight of the substrate employed, wherein the substrate is any of the compounds as disclosed above falling under the scope of formula (II). In a certain embodiment, the third acid is added in an amount of at least 10 mol% of the molar weight of the substrate employed, wherein the substrate is any of the compounds as disclosed above falling under the scope of formula (II). In a certain embodiment, the third acid is added in an amount of at least 20 mol% of the molar weight of the substrate employed, wherein the substrate is any of the compounds as disclosed above falling under the scope of formula (II). In a certain embodiment, the third acid is added in an amount of at least 50 mol% of the molar weight of the substrate employed, wherein the substrate is any of the compounds as disclosed above falling under the scope of formula (II). In a certain embodiment, the third acid is added in an amount of at least 100 mol% of the molar weight of the substrate employed, wherein the substrate is any of the compounds as disclosed above falling under the scope of formula (II). In a certain embodiment, the third acid is added in an amount of at least 130 mol% of the molar weight of the substrate employed, wherein the substrate is any of the compounds as disclosed above falling under the scope of formula (II). In a certain embodiment, the third acid is added in an amount of at least 150 mol% of the molar weight of the substrate employed, wherein the substrate is any of the compounds as disclosed above falling under the scope of formula (II). In a certain embodiment, the third acid is added in an amount of at least 200 mol% of the molar weight of the substrate employed, wherein the substrate is any of the compounds as disclosed above falling under the scope of formula (II). In a certain embodiment, the third acid is added in an amount of at least 300 mol% of the molar weight of the substrate employed, wherein the substrate is any of the compounds as disclosed above falling under the scope of formula (II). In a certain embodiment, the third acid is added in an amount of at least 500 mol% of the molar weight of the substrate employed, wherein the substrate is any of the compounds as disclosed above falling under the scope of formula (II). In a certain embodiment, the third acid is added in an amount of at least 1000 mol% of the molar weight of the substrate employed, wherein the substrate is any of the compounds as disclosed above falling under the scope of formula (II). In a certain embodiment, the third acid is added in an amount of at least 1300 mol% of the molar weight of the substrate employed, wherein the substrate is any of the compounds as disclosed above falling under the scope of formula (II). In a certain embodiment, the third acid is added in an amount of at least 1500 mol% of the molar weight of the substrate employed, wherein the substrate is any of the compounds as disclosed above falling under the scope of formula (II). the third acid is added in an amount of at least 2000 mol% of the molar weight of the substrate employed, wherein the substrate is any of the compounds as disclosed above falling under the scope of formula (II). In a certain embodiment, the third acid is added in an amount of at least 3000 mol% of the molar weight of the substrate employed, wherein the substrate is any of the compounds as disclosed above falling under the scope of formula (II). In a certain embodiment, the third acid is added in an amount of at least 4000 mol% of the molar weight of the substrate employed, wherein the substrate is any of the compounds as disclosed above falling under the scope of formula (II).

[0107] In another embodiment, the ratio between the first, the second and the third acid is between 0.001 to 100 to 1000 and 100 to 10 to 1 by weight of the total weight of the three acids. In a certain embodiment, the ratio between the first, the second and the third acid is between 0.005 to 5 to 50 and 5 to 0.5 to 0.05 by weight of the total weight of the three acids. In a certain embodiment, the ratio between the first, the second and the third acid is between 1 to 10 to 100 and 50 to 5 to 0.5 by weight of the total weight of the three acids. In a certain embodiment, the ratio between the first, the second and the third acid is 0.01 to 0.1 to 13 by weight of the total weight of the three acids.

[0108] The Lewis acid may be added in combination with at least one Bronsted acid. In other words, the compound of formula (I) as defined above is prepared by bringing a compound of formula (II) as defined above in contact with a Lewis acid and at least one Bronsted acid. The reaction of compound of formula (II) to form a compound of formula (I) is further accelerated. Additionally, the further utilization of a Bronsted acid demonstrates notable selectivity and an elevated overall conversion rate.

[0109] According to any embodiment, the at least one Bronsted acid is an acid having a pKa value below 5. In one embodiment, the Bronsted acid is an acid has a pKa value below 4. In another embodiment, the Bronsted acid is an acid has a pKa value below 3. In a certain embodiment, the Bronsted acid is an acid having a pKa value between 0 and below 5. In another certain embodiment, the Bronsted acid is an acid having a pKa value between 0 and 4. In a further certain embodiment, the Bronsted acid is an acid having a pKa value between 1 and 4.

[0110] According to any embodiment, the at least one Bronsted acid is selected from the group consisting of sulfuric acid, acetic acid, formic acid, triflic acid, methanesulfonic acid, phosphoric acid, oxalic acid or combinations therefrom. According to any embodiment, the at least one Bronsted acid is a combination from at least two acids selected from the group consisting of sulfuric acid, acetic acid, formic acid, triflic acid, methanesulfonic acid, phosphoric acid and oxalic acid.

[0111] According to any embodiment, the at least one Bronsted acid is a combination from two acids selected from the group consisting of sulfuric acid, acetic acid, formic acid, triflic acid, methanesulfonic acid, phosphoric acid and oxalic acid. According to another embodiment, the Bronsted acid is a combination from three acids selected from the group consisting of sulfuric acid, acetic acid, formic acid, triflic acid, methanesulfonic acid, phosphoric acid and oxalic acid.

[0112] According to one embodiment, the at least one Bronsted acid is formic acid. According to another embodiment, the at least one Bronsted acid is sulfuric acid. According to a further embodiment, the at least one Bronsted acid is triflic acid. According to yet another embodiment, the at least one Bronsted acid is methanesulfonic acid. According to another embodiment, the at least one Bronsted is acetic acid. According to another embodiment, the at least one Bronsted is formic acid.

[0113] According to one embodiment, the at least one Bronsted acid is a combination of formic acid and sulfuric acid. According to another embodiment, the Bronsted acid is a combination of acetic acid and sulfuric acid. According to a further embodiment, the Bronsted acid is a combination of oxalic acid, sulfuric acid and acetic acid.

[0114] According to any embodiment, the at least one Bronsted acid is added in an amount of 0.5 mol% to 340 mol% of the molar weight of the substrate employed, wherein the substrate is any of the compounds as disclosed above falling under the scope of formula (II).

[0115] According to any embodiment, the at least one Bronsted acid is added in an amount of 2 mol% to 250 mol% of the molar weight of the substrate employed, wherein the substrate is any of the compounds as disclosed above falling under the scope of formula (II).

[0116] According to any embodiment, the at least one Bronsted acid is added in an amount of 0.5 to mol% to 20 mol% or 10 to mol% to 17 mol% of the molar weight of the substrate employed, wherein the substrate is any of the compounds as disclosed above falling under the scope of formula (II). According to another embodiment, any Bronsted acid is added in an amount of 10 mol% to 340 mol% or 10 mol% to 130 mol% of the molar weight of the substrate employed, wherein the substrate is any of the compounds as disclosed above falling under the scope of formula (II).

[0117] According to any embodiment, the combination of Lewis acid with a Bronsted acid is BF3-Et2O and formic acid, FeCh and formic acid, or BF3 Et2O and sulfuric acid. According to another embodiment, the combination of Lewis acid with a Bronsted acid is BF3 -Et2O and formic acid. According to another embodiment, the combination of Lewis acid with a Bronsted acid is FeCL and formic acid. According to another embodiment, the combination of Lewis acid with a Bronsted acid is BF3 Et2O and sulfuric acid. In a certain embodiment, the combination of Lewis acid with a Bronsted acid is BF3 Et2O and acetic acid and sulfuric acid. The amounts of Lewis acid and Bronsted acid are as defined above.

[0118] According to any embodiment, the reaction of compound of formula (II) to obtain compound of formula (I) is performed in the presence of a solvent. In one embodiment the solvent is an aprotic solvent. In another embodiment the solvent has a boiling point above 100°C. In a further embodiment the solvent is selected from the group consisting of chorobenzene, toluene, n-butyl acetate, hexane, pentane, iso-butyl acetate, xylene, isoamyl acetate or mixtures thereof. In a certain embodiment, the solvent is toluene. In another certain embodiment, the solvent is n-butyl acetate.

[0119] According to any embodiment, the reaction of compound of formula (III) to obtain compound of formula (II) is performed in the presence of a solvent. In one embodiment the solvent is an aprotic solvent. In another embodiment the solvent is selected from the group consisting of tetrahydrofuran, methyl tetrahydrofuran, 1,4-di oxane, methyl tert-butyl ether, diethyl ether and mixtures thereof.

[0120] According to any embodiment, the compound of formula (II) is reacted at 50°C to 150°C or at 60°C to 120°C or at 70°C to 110°C to obtain the compound of formula (I).

[0121] According to any embodiment, the compound of formula (III) is reacted at -50°C to 50°C or at -30°C to 300°C or at -10°C to 10°C or at 0°C to obtain the compound of formula (II).

[0122] According to any embodiment, the reaction of compound of formula (III) to obtain the compound of formula (II) is conducted without an anionic radical promotor such as naphthalene, benzophenone, anthracene, crown ethers, cryptands, azobisisobutyronitrile, tetramethy Ipiperi dine- 1 -oxy 1, bis(trimethylsilyl)acetamide, potassium tert-butoxide. According to an embodiment, the term “anionic radical promoter” refers to a compound capable of facilitating the generation, stabilization, or transfer of radical anions in a chemical reaction. Such promoters may function by electron transfer, radical initiation, or by coordinating with reactive species to enhance their reactivity. This term encompasses aromatic electron carriers such as naphthalene, benzophenone, and anthracene, macrocyclic ligands such as crown ethers and cryptands, radical initiators such as azobisisobutyronitrile (AIBN) and tetramethy Ipiperi dine- 1 -oxy 1 (TEMPO), as well as strong bases and silylating agents such as bis(trimethylsilyl)acetamide (BSA) and potassium tert -butoxide (KOt-Bu), which can facilitate radical anion formation under appropriate conditions.

[0123] According to an embodiment, the compound of formula (IV) is further processed to a compound of formula (X)

[0124] (X), wherein each of R4, R5, R6 and R7 is independently from each other H or a C1-C4 alkyl group.

[0125] All definition and embodiments related to R4 to R7 disclosed herein-above apply mutatis mutandis to this embodiment.

[0126] According to an embodiment, wherein the compound of formula (IV) is further processed to a compound of formula (XI) wherein each of R4, R5, R6 and R7 is independently from each other H or a C1-C4 alkyl group.

[0127] All definition and embodiments related to R4 to R7 disclosed herein-above apply mutatis mutandis to this embodiment. In a particular embodiment, the compound of formula (IV) is further processed to a compound of formula (XI) by standard methods such as aldol addition condensation or Wittig (like) reaction.

[0128] In a second aspect, the present invention provides a compound of formula (V). wherein the solid-dashed line represents a single or double bond; wherein the number of double bonds is 0 or 1 ; wherein R3 is as defined in formula (II); and wherein each of R4, R5, R6 and R7 is independently from each other H or a C1-C4 alkyl group.

[0129] According to any embodiment, each of R4, R5, R6 and R7 is independently from each other H or a C1-C3 alkyl group. In one embodiment, each of R4, R5, R6 and R7 is independently from each other H or methyl or ethyl. In a further embodiment, each of R4, R5, R6 and R7 is independently from each other H or methyl.

[0130] According to any embodiment, the compound of formula (V) is as defined above.

[0131] According to any embodiment, the compound of formula (II) is as defined above.

[0132] Accordingly, all embodiments and advantages disclosed for the first aspect apply equally to the second, third and the fourth aspects and vice versa.

[0133] According to an embodiment, R3 represents a linear C1-C10 alkyl, C2-C12 alkenyl, each optionally comprising one or more oxygen atoms, or an alkyl end capped diol -based polyether having 3-12 units of one or more monomers, wherein the monomers are each independently selected from Ci-Ce alkane diols, and wherein the alkyl end cap is Ci-Ce alkyl.

[0134] According to an embodiment, either R6 or R7 does not represent H and R3 represents a linear C1-C10 alkyl, C2-C12 alkenyl, each optionally comprising one or more oxygen atoms, or an alkyl end capped diol-based polyether having 3-12 units of one or more monomers, wherein the monomers are each independently selected from Ci-Ce alkane diols, and wherein the alkyl end cap is Ci-Ce alkyl.

[0135] According to an embodiment, R4 and R5 and either R6 or R7 do not represent hydrogen.

[0136] According to an embodiment neither of R4, R5, R6, and R7 represents hydrogen.

[0137] According to an embodiment, either R6 or R7 represents a methyl group or an ethyl group, preferably a methyl group, and R3 represents a linear C1-C10 alkyl, C2-C12 alkenyl, each optionally comprising one or more oxygen atoms, or an alkyl end capped diol-based polyether having 3-12 units of one or more monomers, wherein the monomers are each independently selected from Ci-Ce alkane diols, and wherein the alkyl end cap is Ci-Ce alkyl.

[0138] According to an embodiment, R4 and R5 and either R6 or R7 each independently represent a methyl group or an ethyl group, preferably a methyl group.

[0139] According to an embodiment, R4, R5, R6, and R7 ach independently represent a methyl group or an ethyl group, preferably a methyl group.

[0140] According to an embodiment, l-(Ethoxymethyl)-2,2,6-trimethylcyclohexanol, 2,5- Dimethyl-1-[(1 -methylethoxy )methyl]cyclohexanol, and l-(methoxymethyl)-2,2- dimethylcyclohexanol are excluded from the compound of formula (V).

[0141] In a third aspect, the present invention relates to the use of compounds of formula (II) according to the first aspect of the invention as as an intermediate in the preparation of compounds of formula (I) as defined in the first aspect of the invention.

[0142] All definition and embodiments related to the compounds of formulas (I) and (II) according to the first aspect of the invention apply mutatis mutandis for this aspect of the invention. According to an embodiment, the compound of formula (II) is a compound of formula (V) as defined in the second aspect of the invention.

[0143] All definition and embodiments related to compounds of formula (V) of the second aspect of the invention apply mutatis mutandis for this aspect of the invention.

[0144] In a fourth aspect, the present invention relates to the use of compounds of formula (II) according to the first aspect of the invention as an intermediate in the preparation of polysubstituted cyclohexanes.

[0145] All definition and embodiments related to the compounds of formulas (I) and (II) according to the first aspect of the invention apply mutatis mutandis for this aspect of the invention.

[0146] According to an embodiment, the compound of formula (II) is a compound of formula (V) as defined in the second aspect of the invention.

[0147] All definition and embodiments related to compounds of formula (V) of the second aspect of the invention apply mutatis mutandis for this aspect of the invention.

[0148] Examples

[0149] The invention will now be described in further details by way of the following examples, wherein the abbreviations have the usual meaning in the art, the temperatures are indicated in degrees centigrade (°C); the NMR spectral data were recorded in CDCI3 (if not stated otherwise) with a 500 MHz machine for 'H and13C, the chemical shifts 8 are indicated in ppm with respect to TMS as standard, the coupling constants J are expressed in Hz.

[0150] General procedures

[0151] In the following, general processes for the preparation of the intermediates and reactants are provided. General protocol for chloroether reagent preparation

[0152] Zinc bromide (0.003 % weight) was dissolved in the acetal (formaldehyde dimethyl, diethyl, dipropyl, dibutyl acetal, 1.0 equiv.). The mixture was heated up to 70°C and Benzoyl chloride (1.0 equiv.) was introduced in 15 min. The reaction progression was followed by GC-FID, and the reaction mixture was stirred until total disappearance of the acetal signal. Then, the temperature was increased up to the boiling point of the resulting a-chloroether, and the product was distillated from the ester benzoate by-product.

[0153] General protocol for thioether reagent preparation

[0154] A stirred solution of thiophenol (1.0 equiv.) dissolved in the acetal (formaldehyde dimethyl, diethyl, dipropyl, di butyl acetal, 6.0 equiv.) was cooled down to -78°C. Boron trifluoride etherate (1.0 equiv.) was introduced dropwise, and the reaction mixture was warmed up to 0°C. After Ih, the reaction mixture was poured on an ice-NaOH 10% mix and stirred for 10 min. The reaction mixture was extracted with Et2O, the organic phase was washed with water and brine, dried over MgSCti, filtered and concentrated. Purification afforded the related thioether.

[0155] General protocol 1 for the formation of hydroxy ethers from the corresponding ketone

[0156] To lithium (2.2 equiv.) under inert atmosphere was introduced MeTHF (1.5 M). The reaction mixture was cooled down to 0°C. The ketone of formula (III) (1.0 equiv.) and the a-chloroether reagent (1.3 equiv.) were mixed under inert atmosphere, and the mixture was introduced dropwise in the lithium suspension in Ih. An additional hour after the end of the addition, the reaction mixture was poured on ice and let stirring for a few minutes. Then, the organic layer was recovered, washed with brine, dried over MgSCL. filtered, concentrated, and purified by fractionated distillation.

[0157] General protocol 2 for the formation of hydroxy ethers from the corresponding ketone

[0158] Under argon was charged with Lithium, high sodium (0,5%) granule (3.0 equiv.), MeTHF (1.5 M). The mixture was stirred at RT for 5min. The mixture turned yellow. It was then cooled at 0°C. The ketone of formula (III) (1.0 equiv.), ethoxy methylsulfanylbenzene (1.4 equiv.) and MeTHF (1.5 M) were mixed and added dropwise over the lithium in suspension. The addition took lh30. An additional hour after the end of the addition, the reaction mixture was poured on ice and let stirring for a few minutes. Then, the organic layer was recovered, washed with brine, dried over MgSC filtered, concentrated, and purified by fractionated distillation.

[0159] General protocol for the formation of the cyclic aldehydes from the corresponding hydroxy ethers

[0160] To the hydroxy ether of formula (II) (1.0 equiv.) in Toluene (3M) was added the chosen reagent (Lewis acid, two Bronsted acids or Lewis acid and Brosted acid). The reaction was heated to 90°C, until total conversion of the hydroxy ether. Then, the reaction mixture was cooled down to room temperature and quenched with water. The organic layer was recovered, extracted with NaOH 10% and washed with brine and dried over MgSCL. Purification by fractionated distillation afforded the related aldehyde.

[0161] Example 1

[0162] Preparation of compound of formula (II) starting from compound of formula (III)

[0163] 1 -(methoxymethyl)-2,2.3.6-tetramethylcyclohexan-l -ol

[0164] Following the general protocol 1 or 2 for the formation of hydroxy ethers from the corresponding ketone_using 2,2,3,6-tetramethylcyclohexanone (1.0 equiv.) and chloromethyl methyl ether (1.3 equiv.). Purification by fractionated distillation (5 mbar, Tvap = 78°C) afforded l-(methoxymethyl)-2,2,3,6-tetramethylcyclohexan-l-ol as a colorless oil (77% yield, 42% (lR,3R,6R)-l-(methoxymethyl)-2,2,3,6- tetramethylcyclohexan-l-ol, 30% (lS,3R,6R)-l-(methoxymethyl)-2,2,3,6- tetramethylcyclohexan-l-ol and 18% (lS,3R,6S)-l-(methoxymethyl)-2,2,3,6- tetramethylcyclohexan-l-ol (NMR estimations)).

[0165] ( 1R, 3R, 6R)-l-(methoxymethyl)-2, 2, 3, 6-tetramethylcyclohexan-l-ol:

[0166] *H NMR (CDCh, 500 MHz): 6 (ppm) = 4.96 (s, 1H), 3.35 (dd, J= 9.5Hz, 2H), 3.35 (s, 1H), 1.76 (ddt, J= 2.6, 5.4, 7 Hz, 1H), 1.49 (m, 2H), 1.44 (m, 1H), 1.32 (dtd, J= 2.5, 13.6 Hz, 2H), 0.97 (s, 1H), 0.92 (s, 3H), 0.82 (d, J= 6.66 Hz, 3H), 0.81 (d, J= 6.6 Hz, 3H).

[0167] 13C NMR (CDCh, 100 MHz): 6 (ppm) = 77.0, 75.4, 75.0, 40.6, 38.0, 35.8, 30.7, 30.5, 22.6 (2C), 22.0 (2C), 16.3, 15.3. (IS, 3R, 6R)-l-(methoxymethyl)-2,2, 3, 6-tetramethylcyclohexan-l-ol:

[0168] *H NMR (CDCh, 500 MHz): 6 (ppm) = 4.96 (s, 1H), 3.42 (dd, J = 9.5Hz, 2H), 3.35 (s, 1H), 1.93 (ddt, J= 2.6, 5.4, 7 Hz, 1H), 1.51 (m, 2H), 1.44 (m, 1H), 1.32 (dtd, J= 2.5, 13.6 Hz, 2H), 0.97 (s, 1H), 0.92 (s, 3H), 0.90 (d, J= 6.6 Hz, 3H), 0.82 (d, J= 6.66 Hz, 3H).

[0169] 13C NMR (CDCh, 100 MHz): 6 (ppm) = 77.0, 75.4, 75.7, 41.8, 40.9, 35.8, 30.7, 30.5, 22.6 (2C), 22.0 (2C), 16.3, 15.3.

[0170] (lS,3R,6S)-l-(methoxymethyl)-2, 2, 3, 6-tetramethylcyclohexan-l-ol:

[0171] *H NMR (CDCh, 500 MHz): 6 (ppm) = 4.96 (s, 1H), 3.37 (dd, J = 9.5Hz, 2H), 3.34 (s, 1H), 1.86 (ddt, J= 2.6, 5.4, 7 Hz, 1H), 1.59 (m, 2H), 1.44 (m, 1H), 1.32 (dtd, J= 2.5, 13.6 Hz, 2H), 1.05 (d, J= 7.3 Hz, 3H), 1.00 (s, 1H), 0.93 (s, 3H), 0.91 (d, J= 6.6 Hz, 3H).

[0172] 13C NMR (CDCh, 100 MHz): 6 (ppm) = 77.0, 75.4, 74.0, 43.0, 39.7, 35.8, 30.9, 30.5, 22.6 (2C), 22.0 (2C), 16.2, 15.1

[0173] 1 -(ethoxymethyl)-2,2.3.6-tetramethylcyclohexan-l -ol

[0174] Following the general protocol 1 or 2 for the formation of hydroxy ethers from the corresponding ketone using 2,2,3,6-tetramethylcyclohexanone (1.0 equiv.) and Chloromethyl ethyl ether (1.3 equiv.). Purification by fractionated distillation (5 mbar, Tvap= 95°C) afforded 1 -(ethoxy methyl)-2, 2, 3, 6-tetramethylcyclohexan-l-ol as a colorless oil (87% yield, 42% (lR,3R,6R)-l-(ethoxymethyl)-2, 2, 3, 6-tetramethylcyclohexan-l-ol, 34% (lS,3R,6R)-l-(ethoxymethyl)-2, 2, 3, 6-tetramethylcyclohexan-l-ol and 24% (1S,3R,6S)-1- (ethoxymethyl)-2,2,3,6-tetramethylcyclohexan-l -ol (NMR estimations)).

[0175] ( 1R, 3R, 6R)-l-(ethoxymethyl)-2, 2, 3, 6-tetramethylcyclohexan-l-ol:

[0176] *H NMR (CDCh, 500 MHz): 6 (ppm) = 4.84 (s, 1H), 3.50 (q, J= 7.3 Hz 3H), 3.36 (dd, J = 9.5 Hz, 2H), 1.75 (ddt, J= 3.4, 6.3, 8.9 Hz, 1H), 1.50 (m, 2H), 1.44 (m, 1H), 1.42 (m, 1H), 1.32 (m, 2H), 1.19 (t, J = 7.6 Hz, 3H), 1.07 (dtd, J= 13.7, 11.6, 4.9 Hz, 2H), 0.97 (s, 3H), 0.92 (s, 3H), 0.90 (d, J= 6.77 Hz, 3H), 0.85 (d, J= 7.1 Hz, 2H).

[0177] 13C NMR (CDCh, 100 MHz): 6 (ppm) = 75.0, 72.6, 66.6, 41.8, 38.0, 35.8, 30.9, 30.5, 26.8, 22.7 (2C), 22.1 (2C), 16.3, 16.1, 15.2.

[0178] (IS, 3R, 6R)-l-(ethoxymethyl)-2,2, 3, 6-tetramethylcyclohexan-l-ol: *H NMR (CDCI3, 500 MHz): 6 (ppm) = 4.84 (s, 1H), 3.50 (q, J= 7.3 Hz 3H), 3.35 (dd, J = 9.5 Hz, 2H), 1.93 (ddt, J = 3.8, 6.2, 6.8 Hz, 1H), 1.50 (m, 2H, 1.44 (m, 1H), 1.42 (m, 1H), 1.32 (m, 2H), 1.19 (t, J= 7.6 Hz, 3H), 1.07 (dtd, J= 13.7, 11.6, 4.9 Hz, 2H), 0.97 (s, 3H), 0.92 (s, 3H), 0.82 (d, J= 6.77 Hz, 3H), 0.80 (d, J= 6.9 Hz, 2H).

[0179] 13 , , , , ,

[0180] 13C NMR (CDCI3, 100 MHz): 6 (ppm) = 75.4, 73.8, 67.8, 41.8, 38.0, 35.7, 30.8, 30.4, 22.9, 22.8 (2C), 22.0 (2C), 16.4, 15.3, 10.7. (IS, 3R, 6R)-l-(propoxymethyl)-2,2, 3, 6-tetramethyl-cyclohexan-l-ol:

[0181] *H NMR (CDCI3, 500 MHz): 6 (ppm) = 4.68 (s, 1H), 3.40 (dd, J= 9.2 Hz, 2H), 3.38 (t, J = 6.8 Hz, 2H), 1.93 (ddt, J= 4.1, 6.4, 13.0 Hz, 1H), 1.59 (sext, J= 6.9 Hz, 2H), 1.51 (m, 2H), 1.43 (m, 1H), 1.35 (m, 2H), 1.00 (s, 3H), 0.97 (s, 3H), 0.92 (t, J = 7.4 Hz, 3H), 0.90 , , , , , , , , , , , 6.7 Hz, 3H).

[0182] 13C NMR (CDCI3, 100 MHz): 6 (ppm) = 75.4, 71.0, 67.8, 41.7, 38.0, 35.7, 31.8, 31.6, 30.8, 30.4, 22.8 (2C), 22.0 (2C), 16.4, 16.3, 13.9 (IS, 3R, 6R)-1 -(butoxymethyl) -2, 2, 3, 6-tetramethylcyclohexan-l-ol:

[0183] *H NMR (CDCL, 500 MHz): 6 (ppm) = 4.69 (s, 1H), 3.42 (t, J= 6.4 Hz, 2H), 3.38 (dd, J = 9.5 Hz, 2H), 1.93 (ddt, J= 4.2, 6.8, 10.8 Hz, 1H), 1.75 (m, 1H), 1.54 (m, 1H), 1.36 (m, 2H), 1.33 (quintet, J= 6.2 Hz, 2H), 1.36 (m, 2H), 1.07 (dtd, J= 13.7, 13.3, 4.9 Hz, 2H), 1.00 (s, 3H), 0.97 (s, 3H), 0.92 (t, J = 4.4 Hz, 3H), 0.90 (d, J= 11.5 Hz, 3H), 0.84 (d, J = 6.7 Hz, 3H).

[0184] 13C NMR (CDCI3, 100 MHz): 6 (ppm) = 75.2, 73.6, 71.0, 41.7, 38.0, 35.7, 31.8, 31.6, 30.6,

[0185] 30.4, 22.8 (2C), 22.0 (2C), 16.4, 16.3, 13.9.

[0186] (IS, 3R, 6S)-l-(butoxymethyl)-2, 2, 3, 6-tetramethylcyclohexan-l-ol:

[0187] *H NMR (CDCI3, 500 MHz): 6 (ppm) = 4.69 (s, 1H), 3.42 (t, J= 6.4 Hz, 2H), 3.35 (dd, J = 9.3 Hz, 2H), 1.93 (ddt, J= 4.0, 6.8, 10.4 Hz, 1H), 1.70 (m, 1H), 1.54 (m, 1H), 1.36 (m, 2H), 1.33 (quintet, J= 6.2 Hz, 2H), 1.36 (m, 2H), 1.07 (dtd, J= 13.7, 13.3, 4.9 Hz, 2H), 1.00 (s, 3H), 0.97 (s, 3H), 0.92 (t, J= 4.4 Hz, 3H), ), 0.90 (d, J= 11.5 Hz, 3H), 0.82 (d, J = 6.7 Hz, 3H).

[0188] 13C NMR (CDCh, 100 MHz): 6 (ppm) = 75.9, 73.6, 72.9, 41.7, 38.0, 35.8, 31.8, 31.6, 31.0,

[0189] 30.5, 22.8 (2C), 22.0 (2C), 16.1, 16.2, 13.9.

[0190] Example 2

[0191] Preparation of compound of formula (I) starting from compound of formula (II) in contact with a Lewis acid

[0192] The reaction was performed according to the general protocol for the formation of the cyclic aldehyde from the corresponding hydroxy ether. The Lewis acid BF3 Et20 (0.1 equiv.) was employed. Conversion and selectivity value was calculated from GC-FID data. The use of a Lewis acid gave a total conversion of 100% and a selectivity of 86.3% towards the desired aldehyde of formula (I).

[0193] Example 3 Preparation of compound of formula (I) starting from compound of formula (II) in contact with the combination of two Bronsted acids

[0194] The reaction was performed according to the general protocol for the formation of the cyclic aldehyde from the corresponding hydroxy ether. A combination of sulfuric acid 98% (0.025 equiv.) and acetic acid (6.5 equiv.) was employed. Conversion and selectivity value was calculated from GC-FID data. The combined use of two Bronsted acids gave a total conversion of 100% and a selectivity of 87.3% towards the desired aldehyde of formula (I).

[0195] Example 4

[0196] Preparation of compound of formula (I) starting from compound of formula (II) in contact with a combination of Lewis acid and Bronsted acid.

[0197] The reaction was performed according to the general protocol for the formation of the cyclic aldehyde from the corresponding hydroxy ether. The combination of Lewis acid FeCL (0.1 equiv.) and formic acid (5 equiv.) as the Bronsted acid was employed. Conversion and selectivity value was calculated from GC-FID data. The combined use of Lewis acid and Bronsted acid gave a total conversion of 100% and a selectivity of 85.1% towards the desired aldehyde of formula (I).

[0198] Example 5

[0199] Preparation of compound of formula (I) starting from compound of formula (II) in contact with a combination of Lewis acid and Bronsted acid.

[0200] The reaction was performed according to the general protocol for the formation of the cyclic aldehyde from the corresponding hydroxy ether. The combination of Lewis acid BF3 Et20 (0.1 equiv.) and sulfuric acid 98% (0.1 equiv.) as the Bronsted acid was employed. Conversion and selectivity value was calculated from GC-FID data. The combined use of Lewis acid and Bronsted acid gave a total conversion of 100% and a selectivity of 95.0% towards the desired aldehyde of formula (I). Example 6 (Comparative Example)

[0201] Preparation of compound of formula (I) starting from compound of formula (II) in contact with one Bronsted acid.

[0202] The reaction was performed according to the general protocol for the formation of the cyclic aldehyde from the corresponding hydroxy ether. As the Bronsted acid, sulfuric acid 98% (0.15 equiv.) was employed. Conversion and selectivity value was calculated from GC-FID data. The use of one Bronsted acid gave a total conversion of 100% and a selectivity of 82.3% towards the desired aldehyde of formula (I).

[0203] Conclusion

[0204] As can be seen from the above Examples 2 to 5, and in particular Examples 2, 3 and 5, the combination of sulfuric acid with acetic acid, the combination of sulfuric acid with a Lewis acid or even the use of a Lewis acid gives a significant higher conversion rate than employing sulfuric acid alone.

[0205] Example 7 (Comparative Example)

[0206] Preparation of compound of formula (I) starting from compound of formula (II) in contact with one Bronsted acid.

[0207] The reaction was performed according to the general protocol for the formation of the cyclic aldehyde from the corresponding hydroxy ether. As the Bronsted acid, formic acid (5 equiv.) was employed. Conversion and selectivity value was calculated from GC-FID data. The combined use of two Bronsted acids gave a total conversion of 76.5% and a selectivity of 70.3% towards the desired aldehyde of formula(I).

[0208] Conclusion

[0209] As can be seen from the above Examples 2 to 5, and in particular Example 4, the combination of two Bronsted acids, the combination of formic acid with a Lewis acid or even the use of a Lewis acid gives a significant higher conversion rate than employing formic acid alone. Example 8 l -(Ethoxymethyl)-2.5.6.6-tetramethylcyclohex-2-en-l-ol

[0210] The MeTHF (3M) was introduced on 2.4g (0.35 mol) lithium (2.3 eq.) under argon atmosphere. The mixture was stirred and cooled at 0°C. 23g (0.15 mol) of 2, 5, 6, 6- tetramethylcyclohex-2-en-l-one and 19.3 g (0.2 mol) of (chloromethoxy)ethane were mixed under argon atmosphere and added dropwise in the reaction mixture for 3h. An additional hour after the addition the reaction ended. Then the reaction mixture was putted in ice to quench the lithium. The mixture is washed two times with water and one time with brine, dried under NazSC , filtered and concentrated. The reaction led to a yield of 79.6% and of 76.5% of purity. The crude was purified under a 330g silica column with cyclohexane and ethyl acetate (98:2).

[0211] *H NMR (600 MHz, CDC13) 8 5.62 (t, J = 1.7 Hz, 1H,), 3.51 (q, J = 7.0 Hz, 2H), 3.47 - 3.38 (m, 2H), 2.01 (dd, 1H), 1.75 (s, 3H), 1.67 (ddq, J= 17.6, 11.0, 2.5 Hz, 1H, 1.54 (tdd, J= 12.7, 11.0, 6.2 Hz, 2H, 6-H), 1.18 (t, J= 7.0 Hz, 3H), 0.98 (s, 3H), 0.94 (s, 3H)

[0212] 13C NMR (151 MHz, CDCI3) 8 136.11, 127.52, 77.25, 66.69, 40.60, 34.86, 30.03, 26.92, 19.77, 18.58, 14.93, 11.55.

Claims

Claims1. A process for the preparation of a compound of formula (I)whereinR1 represents a C1-C12 alkyl, C2-C12 alkenyl, C3-C12 cycloalkyl, C3-C12 cycloalkenyl, Ce-C aryl group, each optionally substituted with one or more Ci- C12 alkyl, C2-C12 alkenyl, C1-C12 alkoxy group(s),R2 represents a C1-C12 alkyl, C2-C12 alkenyl, C3-C12 cycloalkyl, C3-C12 cycloalkenyl, Ce-Cu aryl group, each optionally substituted with one or more Ci- C12 alkyl, C2-C12 alkenyl, C1-C12 alkoxy group(s); orR1 and R2, when taken together, form a C5-C7 cycloalkyl or cycloalkenyl moiety, each optionally substituted with one or more C1-C12 alkyl, C2-C12 alkenyl, C1-C12 alkoxy group(s), by bringing a compound of formula (II)..OR3 OHwhereinR1 and R2 have the same meaning as defined in formula (I) andR3 represents C1-C10 alkyl, C2-C12 alkenyl, each optionally comprising one or more oxygen atoms, or an alkyl end capped diol-based polyether having 3-12 units of one or more monomers, wherein the monomers are each independently selected from Ci-Ce alkane diols, and wherein the alkyl end cap is Ci-Ce alkyl, in contact with a Lewis acid, ora mixture of a Lewis acid and at least one Bronsted acid or a mixture of at least two Bronsted acids.

2. The process according to claim 1, whereinR1 represents a C1-C4 alkyl, C2-C3 alkenyl, Cs-Ce cycloalkyl, Cs-Ce cycloalkenyl, Ce aryl group, each optionally substituted with one or more C1-C4 alkyl, C2-C3 alkenyl, C1-C4 alkoxy group(s),R2 represents a C1-C4 alkyl, C2-C3 alkenyl, Cs-Ce cycloalkyl, Cs-Ce cycloalkenyl, Ce aryl group, each optionally substituted with one or more C1-C4 alkyl, C2-C3 alkenyl, C1-C4 alkoxy group(s); orR1 and R2, when taken together, form a Cs-Ce cycloalkyl or cycloalkenyl moiety, each optionally substituted with one or more, each independently, C1-C3 alkyl, C2- C3 alkenyl, C1-C3 alkoxy group(s).

3. The process according to any of the preceding claims, wherein a compound of formula (II),OR3LOHR1 R2(II) is prepared by bringing a compound of formula (III)wherein R1 and R2 have the same meaning as defined in formula (I) in contact with a reactive metalorganic species of (halomethoxy)alkyl or with a reactive metalorganic species of a thioether.

4. The process according to the preceding claims, wherein the compound of formula (I) is a compound of formula (IV)wherein the solid-dashed line represents a single or double bond, and wherein the number of double bonds is 0 or 1; and wherein each of R4, R5, R6 and R7 is independently from each other H or a C1-C4 alkyl group; and the compound of formula (II) is a compound of formula (V)wherein the solid-dashed line represents a single or double bond; wherein the number of double bonds is 0 or 1; wherein R3 is as defined in formula (II); and wherein each of R4, R5, R6 and R7 is as defined in formula (IV).

5. The process according to claim 3, wherein the compound of formula (III) is a compound of formula (VI)wherein the solid-dashed line represents a single or double bond; and wherein the number of double bonds is 0 or 1; and wherein each of R4, R5, R6 and R7 is as defined in formula (IV).

6. The process according to the preceding claims, wherein the Lewis acid is selected from the group consisting of boron, tin, bismuth, iron, copper, zinc, indium or aluminium based Lewis acid or mixtures therefrom, preferably the Lewis acid isselected from the group consisting of BF3 Et2O, SnCU, Bi(OTf)3 and FeCh or mixtures therefrom.

7. The process according to the preceding claims, wherein the at least two Bronsted acids are selected from the group consisting of sulfuric acid, acetic acid, formic acid, triflic acid, methanesulfonic acid, phosphoric acid, oxalic acid or combinations therefrom.

8. The process according to the preceding claims, wherein the at least one Bronsted acid is selected from the group consisting of sulfuric acid, acetic acid, formic acid, triflic acid, methanesulfonic acid, phosphoric acid, oxalic acid or combinations therefrom.

9. The process according to any one of claims 3 and 5, wherein the reactive metalorganic species of (halomethoxy)alkyl or reactive metalorganic species of the thioether comprises a lithium, magnesium or zinc species of (halomethoxy)alkyl or the thioether, preferably a lithium species of (halomethoxy)alkyl or the thioether.

10. The process according to any one of claims 3, 5 and 9, wherein the reactive metalorganic species of (halomethoxy)alkyl is derived from a lithium, magnesium or zinc species and chloromethoxy methyl, chloromethoxy ethyl or chloromethoxy butyl.

11. The process according to any one of claims 3, 5, 9 and 10, wherein the reaction is conducted without an anionic radical promotor.

12. The process according to claim 4, wherein the compound of formula (IV) is further processed to a compound of formula (X)wherein each of R4, R5, R6 and R7 is independently from each other H or a C1-C4 alkyl group.

13. The process according to claim 4, wherein the compound of formula (IV) is further processed to a compound of formula (XI)wherein each of R4, R5, R6 and R7 is independently from each other H or a C1-C4 alkyl group.

14. A compound of formula (V):wherein the solid-dashed line represents a single or double bond; wherein the number of double bonds is 0 or 1; wherein R3 is as defined in formula (II); and wherein each of R4, R5, R6 and R7 is independently from each other H or a C1-C4 alkyl group.

15. The compound according to claim 14, wherein the compound of formula (V) is selected from l-(methoxymethyl)-2,2,3,6-tetramethylcyclohexan-l-ol, 1- (ethoxymethyl)-2,2,3,6-tetramethylcyclohexan-l -ol, 1 -(propoxymethyl)-2,2,3,6- tetramethyl-cyclohexan-l-ol, l-(butoxymethyl)-2,2,3,6-tetramethylcyclohexan-l- ol and l-(ethoxymethyl)-2,5,6,6-tetramethylcyclohex-2-en-l-ol.

16. Use of the compounds of formula (II) as defined in any one of claims 1-4 and 14- 15 as an intermediate in the preparation of compounds of formula (I) as defined in any one of claims 1, 2 and 4.

17. Use of the compounds of formula (II) as defined in any one of claims 1-4 and 14- 15 as an intermediate in the preparation of polysubstituted cyclohexanes

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