Diastereoselective synthesis of diisoeugenol in the presence of a catalyst

Abstract

A method for preparing a compound (X) comprising the following step: formulae (VIII), (IX), (X) wherein R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are independently selected from: a hydrogen; a hydroxyl; an alkoxy, preferably a methoxy; a thioalkyl; an amino; and a linear, branched, cyclic or acyclic aliphatic chain, comprising at least one of the functions selected from an alkyl, an alkenyl, an alkynyl, an aryl and a heteroaryl; said aliphatic chain optionally comprising at least one of the following atoms or groups: a halogen; -O-; -N-; -S-; -CO-; ester -CO-O-; amide -CO-N-; thioester -CO-S-; carbonate -O-CO-O-; carbamate -O-CO-N-; and using a catalyst comprising a compound selected from at least one of the components chosen from a sulfonic acid and a metal complex of formula M(OTf)n, wherein M is a metal atom and n is an integer from 1 to 4, preferably n is an integer from 2 to 4.

Description

[0001] Description

[0002] Title of the invention: Diastereoselective synthesis of diisoeugenol in the presence of a catalyst

[0003] [1]The present invention is in the field of the synthesis of isomers of diisoeugenol, or one of its derivatives, and relates more particularly to cycloaddition reactions using isoeugenol, or one of its derivatives in the presence of a catalyst.

[0004] [2] Bibliographic references in the following text are noted in the description text as follows: [] ; and listed in the reference table.

[0005] State of the art

[0006] [3]Isoeugenol, which serves as the starting material for the synthesis of diisoeugenol, is an isomer of eugenol. Eugenol is a naturally occurring phenol that can be obtained from several plants, including clove buds, cinnamon bark, tulsi leaves, turmeric, pepper, ginger, oregano, and thyme. [1] Isoeugenol, a positional isomer of eugenol, is one of the major volatiles emitted by the petunia, Petunia hybrida, [2]; and isoeugenol can also be isolated from clove oil [3] or lignin [4]. Alternatively, isoeugenol can be synthesized by isomerization of eugenol. [5]

[0007] [4]Thus, in addition to the isolation of isoeugenol from natural resources, the isomerization of eugenol allows access to isoeugenol following several synthetic routes all involving an isomerization reaction of the CC double bond. The synthesis of isoeugenol from eugenol can be carried out in a basic medium and / or in the presence of a metal catalyst with variable ratios between the different positional isomers obtained depending on the synthetic route considered [6-13],

[0008] [5]Isoeugenol is itself a reagent of choice for the preparation of diisoeugenol, and the preparation of diisoeugenol from isoeugenol is known to be carried out by catalysis in the presence of a strong Bronsted acid, such as HCl

[0014] , or by using UV irradiation

[0015] , or even electrochemical processes

[0016] , however these different methods must be carried out under conditions that are too drastic (high acid and / or catalyst load, reflux for several hours, etc.) and / or show yields or even selectivity that are too low.

[0009] [6]Other reactions have also been developed to obtain the targeted product from the same reagent, and the first synthetic route identified as belonging to "green chemistry" for the preparation of diisoeugenol was carried out using a complex catalytic system incorporating BF3'OEt2, or FeCh or SiCh-OSChH; according to this synthetic route, which involves a [3+2] cycloaddition, no more than 80% of the γ-diisoeugenol configuration isomer could be isolated

[0017] ,

[0010] [7]The last synthetic route presented above has the advantage of showing the desired diastereoselectivity, given that diisoeugenol contains three asymmetric carbons and therefore six possible diastereoisomers (or diastereomers) among which the two diastereomers: a-diisoeugenol and y-diisoeugenol, the majority production of y-diisoeugenol constitutes an advance in this regard, although the yields remain too low.

[0011] [8]The following diagram recalls the main molecules discussed in this introduction, with eugenol of formula (I), isoeugenol of formula (II), and diisoeugenol of formula (III) where the three asymmetric carbons are identified by an asterisk: [9]Other synthetic routes involving a [3+2] cycloaddition are described, including a reaction using the Ag(OTf) / AuCl

[0018] catalytic system, to allow the isolation of two diastereoisomers in a 10:1 ratio in favor of the a configuration, corresponding to the compound of formula (IV); the y configuration, corresponding to the compound of formula (V):

[0012]

[0010] Another synthetic route by cyclization [3+2], using 0.75 mol% of Fe(OTf)3 in the presence of a chiral ligand, makes it possible to isolate more than 99% of diisoeugenol in the y configuration (compound of formula (V))

[0019] , It is specified that the starting compound of formula (II) is a cis / trans mixture considering the ethylenic bond.

[0013]

[0011] Although there are solutions developed to achieve the targeted diastereoisomers as described above, the preparation and use of diisoeugenol and its derivatives is however faced with various pitfalls. According to the synthesis routes set out above, the targeted molecules are often difficult to access in sufficiently large quantities to envisage industrial-scale manufacturing, and the preparation of these molecules requires improving yields and / or diastereoselectivity.

[0014]

[0012] This is all the more worrying since diisoeugenol and its derivatives are molecules of choice for their use as antioxidants, for example in the food industry

[0020] . Furthermore, pharmacological properties of diisoeugenol have been reported, such as cytotoxicity for cancer cells

[0021] , anti-inflammatory

[0022] , antioxidant

[0022] , spasmolytic, hypertensive and inhibitory activities of thromboxane formation

[0023] ; for example, water-soluble derivatives of N-alkyl-V-(2-hydroxyalkyl)aminomethyl have thus been used as active substances in the treatment of liver diseases (compound VI, RI: h, alkyl, halogen, phenyl; R2: H, phenyl; R3: H, methyl; R4: alkyl, phenyl).O,O'-disubstituted diisoeugenol showed a spontaneous hypertensive and spasmolytic effect (compound VII, n being an integer taken from 2 to 4; R: one of the groups, optionally substituted, chosen from: dialkylamine, piperidine, morpholine, piperazine), which was even stronger than that of papaverine

[0024] :.

[0015]

[0013] To overcome these drawbacks, one of the objectives of the present invention is to obtain a process for the synthesis of diisoeugenol giving access to the preparation of the compound with a yield and diastereoselectivity better than those of the prior art. Description of the invention

[0016]

[0014] The present invention relates to a process for the preparation of a compound (X) comprising the following step: in which the groups R 1 , R 2 , R 3 , R 4 , R s , R 7 , R s , R 9 and R 10 are independently selected from: hydrogen; hydroxyl; alkoxy, preferably methoxy; thioalkyl; amino; and a linear, branched, cyclic or acyclic aliphatic chain, comprising at least one of the functions chosen from alkyl, alkenyl, alkynyl, aryl and heteroaryl; preferably the group R 5 is hydrogen; and said aliphatic chain optionally comprising at least one of the following atoms or groups: halogen, -O-; -N-; -S-; -CO-; ester -CO-O-; amide -CO-N-; thioester -CO-S-; carbonate -O-CO-O-; carbamate -O-CO-N-;

[0017] ; and implementing a catalyst comprising a compound selected from at least one of the elements chosen between a sulfonic acid and a metal complex of formula M(OTf) n, wherein M is a metal atom and n is an integer from 1 to 4, preferably n is an integer from 2 to

[0018] 4.

[0019]

[0015] The terms "alkoxy" (or "alkyloxy") and "thioalkyl" refer to an alkyl group, as defined above, attached to the parent molecular moiety through an oxygen atom ("alkoxy") or through a sulfur atom ("thioalkyl"). Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, tert-butoxy, neopentoxy, and n-hexoxy. Examples of thioalkyl groups include, but are not limited to, methylthio, ethylthio, propylthio, isopropylthio, n-butylthio, etc.

[0020]

[0016] The term "hydroxyl", as used herein, refers to a group having the structure -OH.

[0021]

[0017] The term "amino" means a group having the structure -N(R)2 in which each occurrence of R is independently hydrogen or an aliphatic, heteroaliphatic, aromatic or heteroaromatic group, where the R groups, taken together, may form a heterocyclic group.

[0022]

[0018] Preferably, and independently for the substituents Ri, R2, R3, R4, Rs, Re, R7, Rs, R9 and Rio the alkyl function comprises from 1 to 12 carbon atoms.

[0023]

[0019] Preferably, and independently for the substituents Ri, R2, R3, R4, Rs, Re, R7, Rs, R9 and Rio the alkenyl function comprises from 2 to 12 carbon atoms.

[0024]

[0020] Preferably, and independently for the substituents Ri, R2, R3, R4, Rs, Re, R7, Rs, R9 and Rio, the alkynyl function comprises from 2 to 12 carbon atoms.

[0025]

[0021] The term "aryl" refers to aromatic groups. In certain embodiments of the present invention, the term "aryl" refers to a mono- or bicyclic carbocyclic ring system having one or two rings satisfying Huckel's rule for aromaticity, including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl and the like. Preferably, and independently for substituents R1, R2, R3, R4, Rs, R5, R7, R8, R9 and R10 the aryl function comprises from 6 to 10 carbon atoms.

[0026]

[0022] The term "heteroaryl" refers to heteroaromatic groups. Preferably, and independently for the substituents R1, R2, R3, R4, Rs, Re, R7, Rs, R9 and R10 the heteroaryl function comprises from 4 to 10 carbon atoms.

[0027]

[0023] Compounds (VIII) and (IX) comprise at least one of the Z and E isomers of the alkenes, which correspond respectively to the following compounds (Villa); (VUIb); (IXa) and (IXb):

[0028]

[0024] The groups of compound (X) according to the invention positioned in the ortho position on the aromatic rings among Ri, R2, R3, R4, Ro, R7, Rs, R9 and Rio can together form a ring preferably comprising from 5 to 7 atoms; more particularly, the groups Ri and R2; R2 and R3; R3 and R4; Ro and R7; R7 and Rs; Rs and R9 and / or R9 and Rio together form such a ring, advantageously said ring is a ring with 5 atoms comprising an acetal function; preferably, the groups R2 and R3, on the one hand, and the groups R7 and Rs, on the other hand, together form such a ring.

[0029]

[0025] Preferably, the process for the preparation of a compound (X) described above within the scope of the invention relates to the preparation of a compound selected from the following compounds (III) and (Xa) to (Xc):

[0030] (III) (Xc)

[0031]

[0026] The four compounds (III) and (Xa) to (Xc) advantageously comprise the compounds which can also be qualified: - for compound (Xa) as asarone dimer;

[0032] - for the compound (Xb) of isosafrole dimer;

[0033] - for the compound (Xc) of metanethole; and

[0034] - for the compound (III) of diisoeugenol.

[0027] Preferably, the compound (X) obtained according to the process of the invention comprises only at least one of the following two isomers:

[0035] (X-1) (X-2)

[0036]

[0028] Preferably, the process according to the invention is suitable for the preparation of a compound chosen from diisoeugenol and a diisoeugenol derivative and / or involves the preparation of compound (XIII) which is obtained from compounds (XI) and (XII) in accordance with the following reaction scheme:

[0037] in which the group R' i is selected from: a hydrogen; a linear, branched, cyclic or acyclic aliphatic chain, comprising at least one of the functions chosen from an alkyl, an alkenyl, an alkynyl, an aryl and a heteroaryl, preferably the group R' i is selected from a hydrogen; a linear, branched, cyclic or acyclic aliphatic chain, comprising at least one of the functions chosen from an alkyl, an alkenyl, and an alkynyl; and preferably R' i is an alkyl; and said aliphatic chain optionally comprising at least one of the following atoms or groups: halogen, -O-; -N-; -S-; -CO-; ester -CO-O-; amide

[0038] -CO-N-; thioester -CO-S-; carbonate -O-CO-O-; carbamate -O-CO-N-; and preferably said aliphatic chain optionally comprises at least one of the following atoms or groups: -O-; -N-; -S-; -CO-; ester -CO-O-; amide -CO-N-; thioester -CO-S-; carbonate -O-CO-O-; carbamate -O-CO-N-; in which the group R' 2 is selected from hydrogen; and a group -CHR11-NR12-CH-R13-CHR14OH; Ru is selected from hydrogen, alkyl, halogen, and phenyl; Ri 2 and Ri 3 are independently selected from hydrogen and alkyl; and Ri 4 is selected from alkyl and phenyl; and implementing the catalyst comprising a compound selected from at least one of the elements chosen between a sulfonic acid and a metal complex of formula M(OTf) n , wherein M is a metal atom and n is an integer from 1 to 4, preferably n is an integer from 2 to 4.

[0039]

[0029] Compounds (X) and / or (XIII) are advantageously chosen from diisoeugenol and diisoeugenol derivatives, the expression “diisoeugenol derivative” used in the context of the invention defines organic molecules comprising the carbon skeleton of diisoeugenol as represented as compound (III) and for which:

[0040] - the phenol functions are protected by an organic group incorporating carbon, hydrogen and possibly oxygen, nitrogen, halogen and / or sulfur atoms; and / or

[0041] - the hydrogens of the aromatic groups are substituted by organic substituents incorporating carbon, hydrogen and possibly oxygen, nitrogen, halogen and / or sulfur atoms.

[0042]

[0030] The term "catalyst" as used previously in the context of the invention must be interpreted with reference to its commonly accepted definition in the field of organic chemistry, and the effect of which can only be kinetic since its presence in the reaction medium cannot modify the thermodynamic quantities that are the variation in enthalpy and the variation in free enthalpy; when a reaction can evolve in several permitted thermodynamic directions, an appropriate catalyst will make it possible to accelerate only one of these evolutions to obtain selectivity among the different permitted reaction paths.The desired qualities of a catalyst correspond in particular to its ability to accelerate the reaction in the selected synthesis route, while being taken in the lowest possible concentration in the reaction medium and with a turnover frequency (TOF) which must be as high as possible; the TOF being defined as the turnover number (TON) per unit of time. The TON corresponds to the number of moles of reactant / substrate that one mole of catalyst can transform before becoming inactivated.

[0043]

[0031] The inventors have unexpectedly demonstrated that it is possible to carry out syntheses of diisoeugenol and its derivatives following a simple catalytic process, which makes it possible to save energy, to avoid long purification steps, from easily accessible chemical species and to obtain better yields compared to usual syntheses.

[0044]

[0032] The catalyst may be a silver catalyst such as AgOTf, with the exception of AgOTf taken in combination with a cocatalyst comprising gold Au, and most particularly with the exception of the combination AgOTf taken together with a 1:1 molar quantity of AuCl or AuBn.

[0045]

[0033] Preferably, the atom M in the context of the process according to the invention is a metal atom with the exception of the Ag atom taken in combination with a cocatalyst comprising the element Au.

[0046]

[0034] Preferably, the atom M in the context of the method according to the invention is a metal atom with the exception of at least one of the elements selected from Ag and Fe, and preferably M being selected from a metal atom of an alkali metal; a metal atom of an alkaline earth metal such as Mg; a metal atom of a metal selected from the metals of the d block such as Ti, Cu and Zn; and a metal atom of a metal selected from the metals of the f block, such as La.

[0047]

[0035] Preferably, the metal complex of formula M(OTf) n described in the context of the method according to the invention is selected from the following complexes: Ti(OTf)4, Zr(OTf)4, and Hf(OTf)4. Preferably, it is Ti(OTf)4.

[0048]

[0036] Preferably, the metal complex of formula M(OTf) ndescribed in the context of the process according to the invention is Cu(OTf)2. The inventors have demonstrated quite fortuitously that the copper catalyst was a candidate of choice for obtaining excellent results in terms of chemoselectivity in favor of the alpha and gamma diastereomers of diisoeugenol which correspond to compounds (IV) and (V), as explained in the preamble to the present description.

[0049]

[0037] Preferably, the sulfonic acid is selected from TfOH (triflic acid) and / or MesOH (methanesulfonic acid), preferably MesOH; which MesOH is more in line with a sustainable development dynamic, given that it is considered a compound classified in the category of green chemistry molecules. Indeed, methanesulfonic acid, the simplest alkanesulfonic acid, is a strong organic acid which is widely known for its exceptional chemical and physical characteristics

[0025] , Often considered a "green acid", MesOH is easily biodegradable and less toxic and corrosive than mineral acids

[0026] .

[0050]

[0038] Preferably, the group R'i is a methyl or an alkyl selected from linear alkyls comprising from 2 to 4 carbon atoms; said C2-C4 alkyl being substituted by a group selected from a dialkylamine, piperidine, morpholine and piperazine, optionally comprising an alkyl or an aromatic group, preferably a phenyl, on at least one of their heteroatoms.

[0051]

[0039] Preferably, the group R'i is a methyl and the group R'2 is a hydrogen.

[0052]

[0040] More preferably, the reaction mixture comprises a mixture of diastereoisomers of diisoeugenol, α-diisoeugenol, i.e. compound (IV) and γ-diisoeugenol, i.e. compound (V):

[0053] (IV) (V)

[0054]

[0041] More advantageously, the molar ratio of the compounds (IV) and (V) obtained is X: Y, such that X > 70; Y < 30.

[0055]

[0042] Preferably, the α-diisoeugenol is obtained in a content greater than or equal to 85% taken relative to all the diastereoisomers of the diisoeugenol obtained in the reaction mixture.

[0056]

[0043] Preferably, the reaction solvent is selected from at least one of the solvents between toluene, anisole, THF, MeTHF and ethyl acetate, preferably the solvent is selected from anisole, MeTHF and ethyl acetate. Advantageously, the solvent is anisole because it allows the process according to the invention to be implemented for industrial use.

[0057]

[0044] Preferably, the catalyst used in the process according to the present invention is used in an amount less than or equal to 1.5% taken as a molar percentage relative to the total number of moles of all the reactants.

[0058]

[0045] The present invention is also described in the detailed description which follows, using the experimental part which details certain embodiments using examples, given solely for illustrative purposes and which should not be considered as limiting, and the figures briefly described in the part which follows.

[0059] Brief description of the figures

[0060]

[0046] [Fig.1] - Figure 1 represents the attributions of the data extracted from the spectra shown in Figure 2 and Figure 3;

[0061]

[0047] [Fig.2] - Figure 2 represents the COSY 'H {'H} NMR spectrum of diisoeugenol (CDCh, 400 MHz); and

[0062]

[0048] [Fig.3] - Figure 3 represents the HSQC NMR spectrum 13 C {'H} of diisoeugenol (CDCh, 100 MHz {400 MHz}).

[0063] Experimental Part

[0064]

[0049] A - SYNTHESIS OF COMPOUNDS

[0065]

[0050] Materials and methodsAll reactions were carried out under an inert atmosphere using argon. All solvents used are of synthetic quality. Isoeugenol (cis / trans, 98+%) is marketed by Thermoscientifïc® and must be stored in a refrigerator; anisole (99%), acetonitrile (99%) and methanesulfonic acid (98+%) are obtained for sale by Alfa Aesar®. Ethyl acetate (99%) and acetone (99%) are marketed by VWR® Chemicals. Copper triflate (98%) is available for sale by TCI®. Triflic acid is marketed by Fluorochem™ and must be stored in a refrigerator.

[0066]

[0051] In the context of the invention, a mass percentage expressed in % m / m, defines the mass percentage of an ingredient used in the preparation and taken in relation to the total mass of the object considered: a mixture, a material (composite, etc.), a membrane, etc.

[0067]

[0052] NMR 3 H and 13 C

[0068]

[0053] The 'H and 13 C were recorded on a Bruker® Advance III 400 MHz spectrometer. Calibration was performed using the chemical shift of the solvent residual resonance.

[0069]

[0054] Syntheses

[0070]

[0055] Part 1: Syntheses implemented

[0071]

[0056] Example 1:

[0072]

[0057] Representative protocol for 1000 equivalents of isoeugenol

[0073]

[0058] The catalyst (8.3.10“ 3mmol) and the solvent (4.129 g, 4.15 mL, 8.3 mmol) are added to a Schlenk tube under argon. Isoeugenol (1.26 mL, 8.3 mmol) is then added to the reaction medium with a syringe. The reaction is stirred in an oil bath at the indicated temperature until complete conversion.

[0074]

[0059]

[0075]

[0076]

[0060] The results are shown in Table 1.

[0077] [Table 1]

[0078]

[0061] Example 2

[0079] Synthesis of diisoeugenol (1-ethyl-5-hydroxy-3-(4-hydroxy-5-methoxyphenyl)-6-methoxy-2-methylindane) from copper triflate. In the glove box, an oven-dried Schlenk tube was loaded with copper triflate (3.6 mg, 0.01 mmol) and 0.35 mL of dry toluene. Outside the glove box, under argon, diisoeugenol (0.15 mL, 160 mg, 1 mmol) was added by syringe to the reaction mixture. The reaction mixture was vigorously stirred for 5 minutes at room temperature. Heat evolution and precipitation were observed during the reaction. At the end of the reaction, dichloromethane was added and a small filtration through a Celite column was performed (95% yield). A yellowish powder was obtained ( = 85:15); mp = 178-180°C. Reactions were carried out on a gram scale.

[0080]

[0062] The NMR spectrograms and peak assignments are shown in Figures 1, 2 and 3.

[0081]

[0063]

[0082]

[0064] Example 3

[0083] The protocol and reaction scheme are identical to those presented in example 1.

[0084]

[0065]

[0085]

[0066] TON (TumOver Number) is the number of moles of reaction product obtained per mole of catalyst used. TOF (TumOver Frequency) is the TON per unit of time. The value of entry 1 was calculated from reference 19, that of entry 2 from reference 18 and those of entries 6 to 8 from reference 17.

[0086]

[0067] Derivatives of iron (entries 1 and 8), boron (entry 7) and silver (entry 2) allow the conversion of isoeugenol but with low catalytic activities (TOF < 10 h 1 in all cases). On the other hand, the use of catalysts, such as Cu(OTf)2 HOTf and MesOH, for the [3+2] cycloaddition of isoeugenol is much more efficient (80 < TOF < 2300 h 1) and allows to obtain excellent catalytic productivity unlike the heterogeneous catalyst SiO2-OSO3H. Reference

[0087]

[0068] The following table lists the references cited previously in the text:

[0088] [Table 2]

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[0123] https: / / doi.org / 10.1103 / PhysRevLett.108.1101 , Google Scholar Crossref , CAS 10. X. Xua, S. Zong, W. Chen, and D. Liu, Chem. Eng. J., 2019, 369, 470–479

Claims

Claims

1. A process for the preparation of a compound (X) comprising in which the groups R 1 , R 2 , R 3 , R 4 , R s , R 7 , R s , R 9 and R 10 are independently selected from: hydrogen; hydroxyl; alkoxy, preferably methoxy; thioalkyl; amino; and a linear, branched, cyclic or acyclic aliphatic chain, comprising at least one of the functions chosen from alkyl, alkenyl, alkynyl, aryl and heteroaryl; preferably the group R 5 is hydrogen; and said aliphatic chain optionally comprising at least one of the following atoms or groups: halogen; -O-; -N-; -S-; -CO-; ester - CO-O-; amide -CO-N-; thioester -CO-S-; carbonate -O-CO-O-; carbamate - O-CO-N-; ; and implementing a catalyst comprising a compound selected from at least one of the elements chosen between a sulfonic acid and a complex metal of formula M(OTf)n , wherein M is a metal atom and n is an integer from 1 to 4, preferably n is an integer from 2 to 4.

2. A process according to claim 1, wherein compound (XIII) is obtained from compounds (XI) and (XII) according to the following reaction scheme: in which the group R' i is selected from: a hydrogen; a linear, branched, cyclic or acyclic aliphatic chain, comprising at least one of the functions chosen from an alkyl, an alkenyl, an alkynyl, an aryl and a heteroaryl, preferably the group R' i is selected from a hydrogen; a linear, branched, cyclic or acyclic aliphatic chain, comprising at least one of the functions chosen from an alkyl, an alkenyl, and an alkynyl; and preferably R' i is an alkyl; and said aliphatic chain optionally comprising at least one of the following atoms or groups: halogen, -O-; -N-; -S-; -CO-; ester -COO amide -CO-N-; thioester -CO-S-; carbonate -O-CO-O-; carbamate -O- CO-N-; and preferably said aliphatic chain optionally comprises at least one of the following atoms or groups: -O-; -N-; -S-; -CO-; ester -CO-O-; amide -CO-N-; thioester -CO-S-; carbonate -O-CO-O-; carbamate -O-CO-N-; in which the group R'2 is selected from hydrogen; and a group -CHR11-NR12-CH-R13-CHR14OH; Ru is selected from hydrogen, alkyl, halogen, and phenyl; R12 and R13 are independently selected from hydrogen and alkyl; and Rn is selected from alkyl and phenyl; and using the catalyst comprising a compound selected from at least one of the elements chosen between a sulfonic acid and a metal complex of formula M(OTf) n , wherein M is a metal atom and n is an integer from 1 to 4, preferably n is an integer from 2 to 4.

3. A method according to claim 1 or 2, wherein M in the context of the method according to the invention is a metal atom except for the Ag atom taken in combination with a cocatalyst comprising the element Au, and preferably M being selected from a metal atom of an alkali metal; a metal atom of an alkaline earth metal such as Mg; a metal atom of a metal selected from d-block metals such as Ti, Cu and Zn; and a metal atom of a metal selected from f-block metals, such as La.

4. Method according to one of claims 1 to 3, in which the metal complex of formula M(OTf) n is Cu(OTf)2.

5. Method according to one of claims 1 to 4, in which the sulfonic acid is selected from at least one of the acids between TfOH and MesOH, preferably MesOH.

6. Method according to one of claims 2 to 5, in which the group R' 1 is a methyl or an alkyl selected from linear alkyls comprising from 2 to 4 carbon atoms; said C2-C4 alkyl being substituted by a group selected from a dialkylamine, piperidine, morpholine and piperazine, optionally comprising an alkyl or an aromatic group, preferably a phenyl, on at least one of their heteroatoms.

7. Method according to one of claims 2 to 5, in which the group R'i is a methyl and the group R'2 is a hydrogen.

8. The method of claim 7, wherein the reaction mixture comprises a mixture of diastereoisomers of diisoeugenol, α-diisoeugenol or compound (IV), and γ-diisoeugenol or compound (V): (IV) (V)

9. Process according to claim 8, wherein the molar ratio of the compounds (IV) and (V) obtained is X: Y, such that X > 70; Y < 30.

10. Process according to one of claims 8 or 9, in which α-diisoeugenol is obtained in a content greater than or equal to 85% taken relative to all the diastereoisomers of the diisoeugenol obtained in the reaction mixture.

11. A method according to one of claims 1 to 10, wherein the reaction solvent is selected from at least one of toluene, anisole, THF, MeTHF and ethyl acetate.

12. Process according to one of claims 1 to 11, in which said catalyst is used in an amount less than or equal to 1.5% taken as a molar percentage relative to the total number of moles of all the reactants.

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