WO2026003142A1

WO2026003142A1 - Process

Info

Publication number: WO2026003142A1
Application number: PCT/EP2025/068016
Authority: WO
Inventors: Nathalie JOSET; Martin Alan LOVCHIK; Fridtjof Schroeder
Original assignee: Givaudan SA
Current assignee: Givaudan SA
Priority date: 2024-06-27
Filing date: 2025-06-26
Publication date: 2026-01-02
Anticipated expiration: 2026-12-27
Also published as: GB202409304D0

Abstract

There is provided a method for the selective epoxidation of farnesene using a catalyst comprising a metal M complexed with a salen ligand of formula (I).

Description

PROCESS

TECHNICAL FIELD

The present invention relates to improved catalysts for selective epoxidation and to improved methods for making intermediates in the production of fragrances such as Amberketal and Amberketal homologues by epoxidation starting from [3-farnesene.

BACKGROUND

Amberketal provides a powerful and tenacious ambery and woody odour that is useful in fragrance compositions alone or in combination with other woody or ambery ingredients. Amberketal is traditionally prepared from Manool via a number of chemical transformations. However, the supply of natural Manool is limited. It is therefore desirable to provide a new efficient and cost effective synthetic route to obtain Amberketal and Amberketal homologues.

A synthetic route to Amberketal homologues (Formula A) comprising contacting a compound of Formula B (wherein R1 is H, methyl or ethyl) with a squalene-hopene cyclase (SHC) enzyme or enzyme variant has been disclosed in WO2021/209482 (PCT/EP2021/059618).

Formula B Formula A

An access to the compound of formula B is described in WO2022/268840 and in WO2024/023154. Both synthetic routes begin with a selective epoxidation of [3-farnesene, leading to a mixture of two epoxides, one of which is further converted to the compound of formula B.

It is therefore desirable to provide a new efficient access to the desired epoxide of [3-farnesene to improve the access to compounds of Formula B, which can then be used in the production of Amberketal and Amberketal homologues.

SUMMARY In accordance with a first aspect of the present invention there is provided a catalyst comprising a metal M complexed with a salen ligand of formula (I) wherein each R¹ is independently hydrogen, an alkyl group, an aryl group, or both R¹ together with the carbon atoms to which R¹ are attached form a cycloalkylene group, an arylene group, two or more cycloalkylene groups connected by a single bond or an alkyl group or two or more arylene groups connected by a single bond or an alkyl group, or a cycloalkylene and an arylene group connected by a single bond or an alkyl group; each R² is independently hydrogen or an alkyl group, or both R² together with the carbon atoms to which R² are attached form a cycloalkylene group or an arylene group;

R³ is selected from hydrogen, an optionally substituted alkyl group, an optionally substituted aryl group, a hydroxyl, an amino group; m is selected from 0 to 4.

In accordance with a second aspect of the present invention there is provided a catalyst of formula (X) comprising a metal M complexed with a salen ligand wherein each R¹ is independently hydrogen, an alkyl group, an aryl group, or both R¹ together with the carbon atoms to which R¹ are attached form a cycloalkylene group, an arylene group, two or more cycloalkylene groups connected by a single bond or an alkyl group or two or more arylene groups connected by a single bond or an alkyl group, or a cycloalkylene and an arylene group connected by a single bond or an alkyl group; each R² is independently hydrogen or an alkyl group, or both R² together with the carbon atoms to which R² are attached form a cycloalkylene group or an arylene group;

R³ is selected from hydrogen, an optionally substituted alkyl group, an optionally substituted aryl group, a hydroxyl, an amino group;

R⁴ is selected from tert-butyl and tert-pentyl; m is selected from 0 to 4; the metal M is selected from the group consisting of Mn and V; and

Y is selected from the group consisting of acetate, tetrafluoroborate, triflate, nitrate, bromide, hexafluorophosphate, perchlorate and alkoxide.

In accordance with a third aspect of the present invention there is provided a method for making a catalyst comprising a metal M complexed with a salen ligand of formula (I)

In accordance with a fourth aspect of the present invention there is provided a method for making a catalyst of formula (X) comprising a metal M complexed with a salen ligand

Formula (X). In accordance with a fifth aspect of the present invention there is provided a method for making a compound of Formula (II), a compound of Formula (III) or a mixture thereof,

Formula (II) Formula (III) wherein the method comprises contacting a compound of Formula (IV) with a catalyst comprising a metal M complexed with a salen ligand of formula (I) wherein each R¹ is independently hydrogen, an alkyl group, an aryl group, or both R¹ together with the carbon atoms to which R¹ are attached form a cycloalkylene group, an arylene group, two or more cycloalkylene groups connected by a single bond or an alkyl group or two or more arylene groups connected by a single bond or an alkyl group, or a cycloalkylene and an arylene group connected by a single bond or an alkyl group; each R² is independently hydrogen or an alkyl group, or both R² together with the carbon atoms to which R² are attached form a cycloalkylene group or an arylene group;

R³ is selected from hydrogen, an optionally substituted alkyl group, an optionally substituted aryl group, a hydroxyl, an amino group; m is selected from 0 to 4;

In accordance with a sixth aspect of the present invention there is provided a method for making a compound of Formula (II), a compound of Formula (III) or a mixture thereof,

Formula (II) Formula (III) wherein the method comprises contacting a compound of Formula (IV) with a catalyst of formula (X) comprising a metal M complexed with a salen ligand wherein each R¹ is independently hydrogen, an alkyl group, an aryl group, or both R¹ together with the carbon atoms to which R¹ are attached form a cycloalkylene group, an arylene group, two or more cycloalkylene groups connected by a single bond or an alkyl group or two or more arylene groups connected by a single bond or an alkyl group, or a cycloalkylene and an arylene group connected by a single bond or an alkyl group; each R² is independently hydrogen or an alkyl group, or both R² together with the carbon atoms to which R² are attached form a cycloalkylene group or an arylene group;

Y is selected from the group consisting of acetate, tetrafluoroborate, triflate, nitrate, bromide, hexafluorophosphate, perchlorate and alkoxide. In accordance with a seventh aspect of the present invention there is provided, there is provided a method of making compounds of Formula B and/or Amberketal, the method comprising the step of making a compound of Formula (II), a compound of Formula (III) or a mixture thereof, Formula (II) Formula (III) by contacting a compound of Formula (IV) with a catalyst comprising a metal M complexed with a salen ligand of formula (I) or with a catalyst of formula (X) comprising a metal M complexed with a salen ligand

Certain embodiments of any aspect of the present invention may provide one or more of the following advantages:

Efficient and selective epoxidation;

Easier handling of the catalyst; • Lower catalyst loading required; and

• Simple catalyst design.

The details, examples and preferences provided in relation to any particular one or more of the stated aspects of the present invention will be further described herein and apply equally to all aspects of the present invention. Any combination of the embodiments, examples and preferences described herein in all possible variations thereof is encompassed by the present invention unless otherwise indicated herein, or otherwise clearly contradicted by context.

DETAILED DESCRIPTION

The present invention is based on the surprising finding that a catalyst comprising a metal M complexed with a salen ligand selectively oxidizes a compound of Formula (IV) at the 1 ,3-diene unit, producing a compound of Formula (II), a compound of Formula (III), or a mixture thereof.

There is therefore provided herein a catalyst comprising a metal M complexed with a salen ligand of formula (I) wherein each R¹ is independently hydrogen, an alkyl group, an aryl group, or both R¹ together with the carbon atoms to which R¹ are attached form a cycloalkylene group, an arylene group, two or more cycloalkylene groups connected by a single bond or an alkyl group or two or more arylene groups connected by a single bond or an alkyl group, or a cycloalkylene and an arylene group connected by a single bond or an alkyl group; each R² is independently hydrogen or an alkyl group, or both R² together with the carbon atoms to which R² are attached form a cycloalkylene group or an arylene group;

R³ is selected from hydrogen, an optionally substituted alkyl group, an optionally substituted aryl group, a hydroxyl, an amino group; m is selected from 0 to 4. In some examples, each R¹ is independently hydrogen, a C1 to C10 alkyl group, or a C5 to C10 aryl group or both R¹ together with the carbon atoms to which R¹ are attached form a C5 to C10 cycloalkylene group, a C5 to C10 arylene group, two or more C5 to C10 cycloalkylene groups connected by a single bond or a C1 to C5 alkyl group (for example, a methyl group), two or more C5 to C10 arylene groups connected by a single bond or a C1 to C5 alkyl group (for example, a methyl group) or a C5 to C10 cycloalkylene group and a C5 to C10 arylene group connected by a single bond or a C1 to C5 alkyl group (for example, a methyl group). In some examples, each R¹ is the same or different, or both R¹ together with the carbon atoms to which R¹ are attached form a cycloalkylene group. In some examples, each R¹ is the same. In some examples, both R¹ together with the carbon atoms to which R¹ are attached form a cycloalkylene group, wherein m is optionally 0.

In some examples, each R¹ is independently hydrogen, a C1 to C10 alkyl group, or a C5 to C10 aryl group or both R¹ together with the carbon atoms to which R¹ are attached form a C5 to C10 cycloalkylene group. In some examples, both R¹ together with the carbon atoms to which R¹ are attached form a C5 to C10 cycloalkylene group and wherein m is 0. In some examples, each R¹ is independently a C1 to C6 alkyl group, or a C5 or C6 aryl group or both R¹ together with the carbon atoms to which R¹ are attached are a C5 to C7 cycloalkylene group and m is optionally 0. In some examples, both R¹ together with the carbon atoms to which R¹ are attached form a cyclohexylene group and m is 0.

In some examples, each R² is independently hydrogen or a C1 to C10 alkyl group. In some examples, each R² is the same or different. In some examples, each R² is the same. In some examples, each R² is hydrogen. In some examples, each or both R² form together with the carbon atoms to which R² are attached a cycloalkylene group, for example a C5 to C7 cycloalkylene group, or an arylene group.

In some examples, R³ is selected from hydrogen, an optionally substituted C1 to C10 alkyl group, an optionally substituted C6 to C14 aryl group, hydroxyl or an amino group.

Due to the nature of residues R¹, R² and/ or R³, the salen ligand of formula (I) may contain chiral centers, and therefore might be present as an optically active mixture or a racemic mixture.

In some examples, m is selected from 0 to 1. In some examples, m is 0. For example, there is provided herein a catalyst comprising a metal M complexed with a salen ligand of formula (I) as described above, wherein the metal M is selected from the group consisting of Mn and V. Such metals allow for a good efficiency of the epoxidation reaction, and they are available at an affordable price.

In some examples, the metal M is Mn. Catalysts with Mn as metal M show good performance in terms of turnover and selectivity.

For example, the metal M can be provided as a salt, for example selected from the group consisting of Mn(acac)₂, Mn(OAc)₂, MnCI₂, MnF₂, MnPO₄, MnSO₄, MnO₂, Mnl₂, MnO, Mn(NO₃)₂, MnCO₃, VOSO₄, VO(acac)₂ or the corresponding hydrate. Alternatively, the metal M can be selected from the group consisting of Mn(acac)₃, Mn(OAc)₃ or the corresponding hydrate. For example, the metal M salt is Mn(acac)₂, Mn(OAc)₂, MnCI₂.

Without being bound by theory, applicant believes that the metal can be provided in different forms, which are then converted, if necessary, to Mn=O complexed by the ligand, thereby forming the effecting catalyst.

For example, there is provided herein a catalyst comprising a metal M complexed with a salen ligand of formula (I) as described above, wherein the metal M is further complexed with a further ligand Y selected from the group consisting of acetate, tetrafluoroborate, triflate, nitrate, bromide, hexafluorophosphate, perchlorate and alkoxide (for example methoxide or ethoxide). In some examples, the further ligand Y is acetate.

The further ligand Y is capable of coordination, for example axial coordination, with the metal of the catalyst or can be present as counter ion. The further ligand Y enables easier purification of the catalyst by crystallization, while the catalyst remains efficient and selective during the epoxidation reaction. Said purification is beneficial for the simplicity of the process and handling of the catalyst.

For example, the further ligand Y can be provided as a salt, for example as sodium, lithium, silver, or quaternary amine salt. For example, the further ligand Y can be provided along with the metal M in the form of its salt. Alternatively, the further ligand Y can be provided by the addition of an alkoxyde: potassium, lithium, sodium methoxide, ethoxide, tert-butoxide, tertamylate. Such complexes comprising the further ligand Y can provide good yields and selectivity for the epoxidation reaction.

In some examples, there is provided a catalyst comprising a metal M complexed with a salen ligand of formula (I) as described above, wherein R¹, R² and R³ is hydrogen.

In some examples, there is a provided a catalyst comprising a metal M complexed with a salen ligand of formula (I) as described above, wherein m is 0.

In some examples, there is provided a catalyst comprising a metal M complexed with a salen ligand of formula (I) as described above, wherein R¹, R² and R³ is hydrogen and m is 0.

For the desired epoxidation of [3-farnesene the diamine bridging unit of the salen ligand can be designed simple, as it does not affect the regioselectivity. Therefore, by reducing the complexity of the salen ligand, the cost of the catalysts can be reduced.

However, also more complex salen ligands, for example with chiral diamine bridging units, can be used to obtain efficient and selective epoxidation of the compound of Formula (IV). Typically, such salen ligands would influence the enantioselectivity of a reaction, which, however, does not apply in the present case.

In some examples, there is provided a catalyst comprising a metal M complexed with a salen ligand of formula (I) as described above, wherein R¹, R² and R³ is hydrogen, m is 0, the metal is Mn, and wherein the metal M is further complexed with a further ligand Y selected from the group consisting of acetate, tetrafluoroborate, triflate, nitrate, bromide, hexafluorophosphate, perchlorate and alkoxide. In some examples, the further ligand Y is acetate.

In a further aspect of the present invention, there is provided a catalyst of formula (X) comprising a metal M complexed with a salen ligand

Formula (X) wherein each R¹ is independently hydrogen, an alkyl group, an aryl group, or both R¹ together with the carbon atoms to which R¹ are attached form a cycloalkylene group, an arylene group, two or more cycloalkylene groups connected by a single bond or an alkyl group or two or more arylene groups connected by a single bond or an alkyl group, or a cycloalkylene and an arylene group connected by a single bond or an alkyl group; each R² is independently hydrogen or an alkyl group, or both R² together with the carbon atoms to which R² are attached form a cycloalkylene group or an arylene group;

In some examples of the catalyst of formula (X), each R¹ is independently hydrogen, a C1 to C10 alkyl group, or a C5 to C10 aryl group or both R¹ together with the carbon atoms to which R¹ are attached form a C5 to C10 cycloalkylene group, a C5 to C10 arylene group, two or more C5 to C10 cycloalkylene groups connected by a single bond or a C1 to C5 alkyl group (for example, a methyl group), two or more C5 to C10 arylene groups connected by a single bond or a C1 to C5 alkyl group (for example, a methyl group) or a C5 to C10 cycloalkylene group and a C5 to C10 arylene group connected by a single bond or a C1 to C5 alkyl group (for example, a methyl group). In some examples, each R¹ is the same or different, or both R¹ together with the carbon atoms to which R¹ are attached form a cycloalkylene group. In some examples, each R¹ is the same. In some examples, both R¹ together with the carbon atoms to which R¹ are attached form a cycloalkylene group, wherein m is optionally 0.

In some examples of the catalyst of formula (X), each R¹ is independently hydrogen, a C1 to C10 alkyl group, or a C5 to C10 aryl group or both R¹ together with the carbon atoms to which R¹ are attached form a C5 to C10 cycloalkylene group. In some examples, both R¹ together with the carbon atoms to which R¹ are attached form a C5 to C10 cycloalkylene group and wherein m is 0. In some examples, each R¹ is independently a C1 to C6 alkyl group, or a C5 or C6 aryl group or both R¹ together with the carbon atoms to which R¹ are attached are a C5 to C7 cycloalkylene group and m is optionally 0. In some examples, both R¹ together with the carbon atoms to which R¹ are attached form a cyclohexylene group and m is 0.

In some examples of the catalyst of formula (X), each R² is independently hydrogen or a C1 to C10 alkyl group. In some examples, each R² is the same or different. In some examples, each R² is the same. In some examples, each R² is hydrogen. In some examples, each or both R² form together with the carbon atoms to which R² are attached a cycloalkylene group, for example a C5 to C7 cycloalkylene group, or an arylene group.

In some examples of the catalyst of formula (X), R³ is selected from hydrogen, an optionally substituted C1 to C10 alkyl group, an optionally substituted C6 to C14 aryl group, hydroxyl or an amino group.

In some examples of the catalyst of formula (X), R⁴ is selected from tert-butyl (f-Bu) and tertpentyl (f-Pe). In some examples, each R⁴ is the same or different. In some examples, each R⁴ is the same.

Due to the nature of residues R¹, R² and/ or R³, the catalyst of formula (X) may contain chiral centers, and therefore might be present as an optically active mixture or a racemic mixture.

In some examples of the catalyst of formula (X), m is selected from 0 to 4, preferably from 0 to 1. In some examples, m is 0.

In some examples of the catalyst of formula (X), the metal M is selected from the group consisting of Mn and V, preferably Mn.

In some examples of the catalyst of formula (X), Y is selected from the group consisting of acetate, tetrafluoroborate, triflate, nitrate, bromide, hexafluorophosphate, perchlorate and alkoxide (for example methoxide or ethoxide).

In some examples of the catalyst of formula (X), R¹, R² and R³ is hydrogen.

In some examples of the catalyst of formula (X), m is 0.

In some examples of the catalyst of formula (X), R¹, R² and R³ is hydrogen and m is 0.

In some examples of the catalyst of formula (X), R¹, R² and R³ is hydrogen, m is 0, the metal is

Mn, ligand Y is selected from the group consisting of acetate, tetrafluoroborate, triflate, nitrate, bromide, hexafluorophosphate, perchlorate and alkoxide (for example methoxide or ethoxide). In some examples, the ligand Y is acetate.

The catalyst comprising a metal M complexed with a salen ligand of formula (I) and/or the catalyst of formula (X) is useful for the efficient and selective epoxidation of [3-farnesene, the compound of Formula (IV). In particular, the catalyst can be used for the selective epoxidation of the diene unit of the compound of Formula (IV), leading to the compound of Formula (II), the compound of Formula (III) or a mixture thereof. It is particularly surprising that neither of the other double bonds in the compound of Formula (IV) are oxidized, resulting in only two of the possible regioisomeric products.

Furthermore, the selection of further ligand Y allows for an easier purification of the catalyst by crystallization, while the catalyst remains efficient and selective during the epoxidation reaction. Such a purification is beneficial for the simplicity of the process and handling of the catalyst.

In a further aspect of the present invention, there is provided a method for making a catalyst comprising a metal M complexed with a salen ligand of formula (I)

The method comprises the steps of: a) mixing the salen ligand of formula (I) with a metal salt in a solvent, b) treating said mixture with an oxidant (preferable H₂O₂, oxygen, air, NaOCI, t-BuOOH), and c) optionally adding a salt to introduce the further ligand Y.

For example, the solvent of step a) can be any solvent. For example, the solvent is methanol, ethanol, or dichloromethane, or a mixture comprising one or more of those solvents.

For example, the oxidant of step b) is selected from the group consisting of H₂O₂, oxygen, air, NaOCI, ‘-BuOOH. For example, the optional addition of a salt to introduce the further ligand Y is required, when it is not provided already with the metal salt.

In a further aspect of the present invention, there is provided a method for making a catalyst of formula (X) comprising a metal M complexed with a salen ligand

The method comprises the steps of: a) mixing the salen ligand with a metal salt in a solvent, b) treating said mixture with an oxidant (preferable H₂O₂, oxygen, air, NaOCI, t-BuOOH), and optionally adding a salt to introduce the further ligand Y.

For example, the oxidant of step b) is selected from the group consisting of H₂O₂, oxygen, air, NaOCI, ‘-BuOOH.

For example, the optional addition of a salt to introduce the further ligand Y is required, when it is not provided already with the metal salt.

In a further aspect of the present invention, there is provided herein a method for making a compound of Formula (II), a compound of Formula (III) or a mixture thereof, Formula (II) Formula (III) wherein the method comprises contacting a compound of Formula (IV) Formula (IV) with a catalyst comprising a metal M complexed with a salen ligand of formula (I)

Formula (I) wherein each R¹ is independently hydrogen, an alkyl group, an aryl group, or both R¹ together with the carbon atoms to which R¹ are attached form a cycloalkylene group, an arylene group, two or more cycloalkylene groups connected by a single bond or an alkyl group or two or more arylene groups connected by a single bond or an alkyl group, or a cycloalkylene and an arylene group connected by a single bond or an alkyl group; each R² is independently hydrogen or an alkyl group, or both R² together with the carbon atoms to which R² are attached form a cycloalkylene group or an arylene group;

In some examples, each R¹ is independently hydrogen, a C1 to C10 alkyl group, or a C5 to C10 aryl group or both R¹ together with the carbon atoms to which R¹ are attached form a C5 to C10 cycloalkylene group, a C5 to C10 arylene group, two or more C5 to C10 cycloalkylene groups connected by a single bond or a C1 to C5 alkyl group (for example, a methyl group), two or more C5 to C10 arylene groups connected by a single bond or a C1 to C5 alkyl group

(for example, a methyl group) or a C5 to C10 cycloalkylene group and a C5 to C10 arylene group connected by a single bond or a C1 to C5 alkyl group (for example, a methyl group). In some examples, each R¹ is the same or different, or both R¹ together with the carbon atoms to which R¹ are attached form a cycloalkylene group. In some examples, each R¹ is the same. In some examples, both R¹ together with the carbon atoms to which R¹ are attached form a cycloalkylene group, wherein m is optionally 0.

In some examples, m is selected from 0 to 1. In some examples, m is 0.

For example, there is provided herein a catalyst comprising a metal M complexed with a salen ligand of formula (I) as described above, wherein the metal M is selected from the group consisting of Mn and V. In some examples, the metal M is Mn.

In some examples, there is a provided a catalyst comprising a metal M complexed with a salen ligand of formula (I) as described above, wherein R¹, R² and R³ is hydrogen.

In some examples, there is a provided a catalyst comprising a metal M complexed with a salen ligand of formula (I) as described above, wherein m is 0. In some examples, there is provided a catalyst comprising a metal M complexed with a salen ligand of formula (I) as described above, wherein R¹, R² and R³ is hydrogen and m is 0.

The catalyst with a salen ligand of formula (I), having tert-pentyl (f-Pe) residues in a specific substitution pattern on the phenyl rings, is useful for the efficient and selective epoxidation of P-farnesene, the compound of Formula (IV). In particular, the catalyst can be used for the selective epoxidation of the diene unit of the compound of Formula (IV), leading to the compound of Formula (II), the compound of Formula (III) or a mixture thereof. It is particularly surprising that neither of the other double bonds in the compound of Formula (IV) are oxidized, resulting in only two of the possible regioisomeric products. The specific substitution pattern has a strong impact on the turnover, allowing the use of this catalyst with much lower quantities.

Furthermore, the selectivity of the epoxidation reaction towards the formation of the compound of Formula (III) (the exo-isomer) is slightly impacted by the number, position and selection of the alkyl residues at the benzene rings of the salen ligand.

The compound of Formula (IV) is [3-farnesene, an isomer of farnesene, which may be referred to as 7,11 -dimethyl-3-methylene- 1 ,6,10-dodecatriene. The compound of Formula (IV) may be (6E)-[3-farnesene, which may be referred to as 7,11-dimethyl-3-methylene-1 ,6E,10- dodecatriene. The compound of Formula (IV) may be the compound with CAS number [18794- 84-8] or the compound with CAS number [77129-48-7], The stereochemistry of the double bond (i.e., the double bond between C6 and C7 of the compound of Formula (IV)) remains unchanged during the method for making a compound of Formula (II), a compound of Formula (III) or a mixture thereof.

The compound of formula (IV) may be replaced by a mixture comprising optionally further isomers of farnesene, e.g. (6Z)-[3-farnesene (CAS 28973-97-9) and a-farnesene (3,7,11- trimethyldodeca-1 ,3,6,10-tetraene) which includes (E,E)-a-farnesene (CAS 502-61-4), (Z,E)-a- farnesene (CAS 26560-14-5), (E,Z)-a-farnesene (CAS 28973-98-0) and (Z,Z)-a-farnesene (CAS 28973-99-1), cyclic isomers might be also present.

For example, there is provided the method for making a compound of Formula (II), a compound of Formula (III) or a mixture thereof, wherein the catalyst comprises a metal M complexed with a salen ligand of formula (I) as described above, wherein R¹, R² and R³ is hydrogen, m is 0, the metal is Mn, and wherein the metal M is further complexed with a further ligand Y selected from the group consisting of acetate, tetrafluoroborate, triflate, nitrate, bromide, hexafluorophosphate, perchlorate and alkoxide. In some examples, the further ligand Y is acetate.

There is further provided a method for making a compound of Formula (II), a compound of Formula (III) or a mixture thereof,

Formula (II) Formula (III) wherein the method comprises contacting a compound of Formula (IV) Formula (IV) with a catalyst of formula (X) comprising a metal M complexed with a salen ligand

Formula (X) wherein each R¹ is independently hydrogen, an alkyl group, an aryl group, or both R¹ together with the carbon atoms to which R¹ are attached form a cycloalkylene group, an arylene group, two or more cycloalkylene groups connected by a single bond or an alkyl group or two or more arylene groups connected by a single bond or an alkyl group, or a cycloalkylene and an arylene group connected by a single bond or an alkyl group; each R² is independently hydrogen or an alkyl group, or both R² together with the carbon atoms to which R² are attached form a cycloalkylene group or an arylene group; R³ is selected from hydrogen, an optionally substituted alkyl group, an optionally substituted aryl group, a hydroxyl, an amino group;

The method for making a compound of Formula (II), a compound of Formula (III) or a mixture thereof may be a method for making a mixture of a compound of Formula (II) and a compound of Formula (III). In some examples, the mixture of a compound of Formula (II) and a compound of Formula (III) may be about a 99:1 to about 1 :99 mixture, for example, about a 90:1 to about a 1 :90 mixture, about a 80:20 to 20:80 mixture, about a 60:40 to about a 40:60 mixture, for example, about a 59:41 to about a 41 :59 mixture, for example, about a 57:43 to about a 43:57 mixture or about a 50:50 mixture. In some examples, the mixture may be about a 1 :1 mixture of compounds of Formula (II) and Formula (III). In some examples, the mixture of a compound of Formula (II) and a compound of Formula (III) may be about a 43:57, or about 44:56, or about 45:55.

For example, the catalyst is employed in about 0.01 - 0.6 mol% catalyst loading, preferably about 0.05 - 0.5 mol%, preferably about 0.1 - 0.4 mol%, for example 0.3 mol% catalyst loading.

For example, the catalyst comprising a metal M complexed with a salen ligand of formula (I) as described above is employed in about 0.01 - 0.6 mol% catalyst loading, preferably about 0.05 - 0.5 mol%, preferably about 0.1 - 0.4 mol%, for example 0.3 mol% catalyst loading.

For example, the catalyst of formula (X) as described above is employed in about 0.01 - 0.6 mol% catalyst loading, preferably about 0.05 - 0.5 mol%, preferably about 0.1 - 0.4 mol%, for example 0.3 mol% catalyst loading.

Such a catalyst loading for the epoxidation of the compound of Formula (IV) provides the desired product with a high yield and conversion. In comparison to catalysts known from prior art, a relative low catalyst loading is providing an improved yield and conversion. The step of contacting the compound of Formula (IV) with a catalyst comprising a metal M complexed with a salen ligand of formula (I) or with a catalyst of formula (X) comprising a metal M complexed with a salen ligand is carried out in the presence of an oxidant.

In some examples, the oxidant may be selected from a hypochlorite, a peroxide, a periodate, a percarbonate and molecular oxygen. In some examples, the hypochlorite may be sodium hypochlorite (NaOCI), sodium hypobromite (NaOBr) or Calcium hypochlorite (Ca(OCI)₂). In some examples, the peroxide may be hydrogen peroxide, anhydrous urea-hydrogen peroxide, dimethyldioxirane, or tert-butylhydroperoxide (tBuOOH). In some examples, the periodate may be IO₄ ^_ or IO₆ ^5-. In some examples, the percarbonate may be sodium percarbonate (Na₂CO₃- 1.5 H₂O₂). In some examples, the oxidant may be sodium hypochlorite or hydrogen peroxide.

For example, about 1 eq. of the oxidant is needed to obtain the epoxidation reaction in good yields and in reasonable time. However, also lower or higher amounts of the oxidant can be used.

The compound of Formula (II), the compound of Formula (III) or a mixture thereof, obtained by the methods described above can be further converted by methods as described in WO2022/268840A1 and WO2024/023154 into compounds of Formula B, which are useful intermediates in the production of Amberketal and Amberketal homologues.

So in a further aspect of the present invention, there is provided a method of making compounds of Formula B and/or Amberketal,

Formula B Formula A the method comprising the step of making a compound of Formula (II), a compound of Formula

(III) or a mixture thereof,

Formula (II) Formula (III) wherein the method comprises contacting a compound of Formula (IV) with a catalyst comprising a metal M complexed with a salen ligand of formula (I) or with a catalyst of formula (X) comprising a metal M complexed with a salen ligand

Formula (X), with the catalyst as described above.

The invention is now further described with reference to the following non-limiting examples. These examples are for the purpose of illustration only, and it is understood that variations and modifications can be made by one skilled in the art. EXAMPLES

Example 1 : Synthesis of 2-hydroxy-3,5-di-tert-pentylbenzaldehyde

2-hydroxy-3,5-di-tert-pentylbenzaldehyde can be synthesized, starting from 2,4-di-terf- pentylphenol and following different procedures described in the literature, for example in Journal of Organic Chemistry, 67, 2702-2704, 2002, or in Organic Letters, 24(38), 6968-6972, 2022.

Example 2: Synthesis of 6,6'-((1E,TE)-(ethane-1 ,2-diylbis-(azaneylylidene))- bis(methaneylylidene))-bis(2,4-di-tert-pentylphenol)

6,6'-((1E,1'E)-(ethane-1 ,2-diylbis(azaneylylidene))-bis(methaneylylidene))-bis(2,4-di-ferf- pentyl-phenol) can be synthesized according to the procedure described in the following publication: Inorganica Chimica Acta, 359, 197-203, 2006.

Example 3: Synthesis of TCH-Mn-f-Pe-salen

6,6'-((1E,1'E)-(ethane-1 ,2-diylbis(azaneylylidene))-bis(methaneylylidene))-bis(2,4-di-ferf- pentylphenol) (10 g) was dissolved in ethanol (70 mL) under nitrogen. Manganese acetate tetrahydrate (5.4 g) and hydrogen peroxide (2.07 g, 30% wt) were added slowly over 5 min at room temperature. Sodium chloride (1.28 g) was then added and the dark brown reaction mixture was stirred at reflux for 2h. Ethanol was evaporated in vacuo and the residue was dissolved in dichloromethane/water (50%). The phases were separated and the aqueous layer was extracted once with dichloromethane (150 mL). The organic phases were combined and washed once with water (150 mL). The organic phase was dried over MgSO₄, filtered and the solvent was removed in vacuo to give 11.7 g of [CI]-Mn-f-Pe-salen as a brown solid.

Anal. Calcd for Cseh^CIMnl^ (M 637.23): C, 67.86%; H, 8.54; N, 4.40. Found: C, 68.04%; H, 8.73; N, 4.44. LCMS (+) ESI (relative abundance): 601.4 (100%, [M - Cl]⁺).

Example 4: Synthesis of |AcO1-Mn-f-Pe-salen catalyst:

6,6'-((1E,1'E)-(ethane-1 ,2-diylbis(azaneylylidene))-bis(methaneylylidene))-bis(2,4-di-tert- pentylphenol) (125.0 g) was suspended in ethanol (1.11 L). Mn(OAc)2(H2O)₄ (66.96 g) was added, followed by hydrogen peroxide (38.73 g, 30% wt). The mixture was heated to reflux and stirred for 1 h. Ethanol was removed in vacuo, methyl tert-butyl ether (MtBE) (1.1 L) was added to the residue which was then washed with water (850 mL). The organic solvent was removed under vacuo, heptane (660 mL) was added and the mixture was cooled to -20°C. The suspension was filtered and washed with cold heptane (150 mL). The brown solid was dried in vacuo to give [AcO]-Mn-f-Pe-salen (93.3 g) as a brown solid.

Anal. Calcd for C₃₈H₅7MnN₂O₄ + C₂H₄O₂ (M + AcOH 720.87): C, 66.65%; H, 8.53; N, 3.89. Found: C, 66.88%; H, 8.72; N, 4.06. LCMS (-) ESI (relative abundance): 719.5 (50%, [M + OAc] ) 660.8 (100%, [M] ), 646.9 (48%).

Example 5: Synthesis of TXI-Mn-f-Pe-salen catalyst:

(X: BF₄‘, CF₃SO₃“ and NO₃ ): AgX (X“ = BF₄“, CF₃SO₃“, NO₃“ ) (9.4 mmol) was respectively added to the [CI]-Mn-f-Pe-salen (3.1 mmol) in dichloromethane (78 ml) at room temperature and the mixture was stirred for 3 h. The mixture was then cooled to -10° and AgCI was filtered off. The filtrate was concentrated in vacuo to give crude [X]-Mn-f-Pe-salen.

[BF₄]-f-Pe-Mn-salen: Crude [BF₄]-f-Pe-Mn-salen (2.04 g) was suspended in heptane (14 mL) and heated to reflux for 30 minutes before being filtered hot. The suspension was filtered, washed with heptane and dried in vacuo to give 1.48 g of a brown solid.

LCMS (-) ESI (relative abundance): 775.4 (100%, [M+BF₄] ), 688.5 (30%, [M] ), 646.5 (48%).

[TfO]- f-Pe-Mn-salen: Crude [TfO]- f-Pe-Mn-salen (2.26 g) was suspended in dichloromethane (7 mL) and heated to reflux for 30 minutes before being cooled down to 0°C. Cold pentane (12 mL) was added to the solution which was then aged at -20°C for 24h. The suspension was filtered and washed with cold pentane (-20°C) and dried in vacuo to give 1.7 g of a brown solid.

LCMS (-) ESI (relative abundance): 899.4 (22%, [M+TfO] ), 750.5 (6%, [M] ), 149.2 (100%, [OTf] ).

[NO₃]- f-Pe-Mn-salen: Crude [NO₃]- f-Pe-Mn-salen (2.07g) was suspended in heptane (14 mL) and heated to reflux for 1 h45 before being filtered hot. The cake was then washed with hot heptane, collected and dried in vacuo to give 1 .25 g of a brown solid.

LCMS (-) ESI (relative abundance): 1326.2 (10%, [2M] ), 725.4 (22%, [M+NO₃] ), 663.2 (100%, [M] ).

Example 6: Epoxidation reactions using various catalysts: The epoxidation of (E)-[3-farnesene was performed as described in WO2022268840 producing a crude mixture containing (E)-[3--farnesene and (E)-[3-farnesene epoxides (Comp. II and III) which was then filtered through a pad of silica and Kugelrohr-distilled (120°C, 0.033 mbar). * qNMR purities of distilled mixture

The tested catalysts provide good results. It can be seen that the catalyst with terf-pentyl (f-Pe) residues on the phenyl rings allows for lower catalyst loading, while the yield and the selectivity towards the compound of formula (III) is improved. The further ligand Y improves the handling of the catalyst.

Claims

1. A method for making a compound of Formula (II), a compound of Formula (III) or a mixture thereof,

Formula (II) Formula (III) wherein the method comprises contacting a compound of Formula (IV) Formula (IV) with a catalyst comprising a metal M complexed with a salen ligand of formula (I) wherein each R¹ is independently hydrogen, an alkyl group, an aryl group, or both R¹ together with the carbon atoms to which R¹ are attached form a cycloalkylene group, an arylene group, two or more cycloalkylene groups connected by a single bond or an alkyl group or two or more arylene groups connected by a single bond or an alkyl group, or a cycloalkylene and an arylene group connected by a single bond or an alkyl group; each R² is independently hydrogen or an alkyl group, or both R² together with the carbon atoms to which R² are attached form a cycloalkylene group or an arylene group; R³ is selected from hydrogen, an optionally substituted alkyl group, an optionally substituted aryl group, a hydroxyl, an amino group; m is selected from 0 to 4.

2. The method according to claim 1 , wherein the metal M is selected from the group consisting of Mn and V.

3. The method according to claim 2, wherein the metal M is further complexed with a ligand Y selected from the group consisting of acetate, tetrafluoroborate, triflate, nitrate, bromide, hexafluorophosphate, perchlorate and alkoxide.

4. The method according to any one of the previous claims, wherein R¹, R² and R³ is hydrogen.

5. The method according to any one of the previous claims, wherein m is 0.

6. The method according to claim 1 , wherein R¹, R² and R³ is hydrogen; m is 0; M is Mn; and wherein the metal M is further complexed with a ligand Y selected from the group consisting of acetate, tetrafluoroborate, triflate, nitrate, bromide, hexafluorophosphate, perchlorate and alkoxide, preferably acetate.

7. The method according to any one of the previous claims, comprising the making of the catalyst comprising a metal M complexed with a salen ligand of formula (I) wherein the making of the catalyst comprising a metal M complexed with a salen ligand of formula (I) comprises the steps of: a) mixing the salen ligand of formula (I) with a metal salt in a solvent, b) treating said mixture with an oxidant (preferable H2O2, oxygen, air, NaOCI, t- BuOOH), and c) optionally adding a salt to introduce the further ligand Y.

8. A method for making a compound of Formula (II), a compound of Formula (III) or a mixture thereof,

9. The method according to claim 8 comprising the making of a catalyst of formula (X) comprising a metal M complexed with a salen ligand

Formula (X), wherein the making of the catalyst of formula (X) comprises a metal M complexed with a salen ligand comprises the steps of: a) mixing the salen ligand with a metal salt in a solvent, b) treating said mixture with an oxidant (preferable H2O2, oxygen, air, NaOCI, t- BuOOH), and c) optionally adding a salt to introduce the further ligand Y.

10. The method according to any one of the previous claims, wherein the catalyst is employed in about 0.01 - 0.6 mol% catalyst loading, preferably about 0.05 - 0.5 mol%, preferably about 0.1 - 0.4 mol%, for example 0.3 mol% catalyst loading.

11. A method of making compounds of Formula B and/or Amberketal, the method comprising the step of for making a compound of Formula (II), a compound of Formula (III) or a mixture thereof,

Formula (II) Formula (III) according to any one of the previous claims.

12. A catalyst comprising a metal M complexed with a salen ligand of formula (I) wherein each R¹ is independently hydrogen, an alkyl group, an aryl group, or both R¹ together with the carbon atoms to which R¹ are attached form a cycloalkylene group, an arylene group, two or more cycloalkylene groups connected by a single bond or an alkyl group or two or more arylene groups connected by a single bond or an alkyl group, or a cycloalkylene and an arylene group connected by a single bond or an alkyl group; each R² is independently hydrogen or an alkyl group, or both R² together with the carbon atoms to which R² are attached form a cycloalkylene group or an arylene group;

13. A method for making a catalyst comprising a metal M complexed with a salen ligand of formula (I) comprising the steps of: a) mixing the salen ligand of formula (I) with a metal salt in a solvent, b) treating said mixture with an oxidant (preferable H2O2, oxygen, air, NaOCI, t- BuOOH), and c) optionally adding a salt to introduce the further ligand Y.

14. A catalyst of formula (X) comprising a metal M complexed with a salen ligand

15. A method for making a catalyst of formula (X) comprising a metal M complexed with a salen ligand

Formula (X), comprising the steps of: a) mixing the salen ligand with a metal salt in a solvent, b) treating said mixture with an oxidant (preferable H2O2, oxygen, air, NaOCI, t- BuOOH), and c) optionally adding a salt to introduce the further ligand Y.