Production of adipic acid and derivatives thereof

This application claims the benefit of the European Patent Applications EP17382245.3 and EP18382041.4 filed on May 3rd, 2017 and January 25th, 2018, respectively.

The present invention relates to a method for the preparation of adipic acid and derivatives thereof. The method of the invention comprises contacting a 1 ,3-butadiene derivative with carbon dioxide in the presence of a nickel catalyst and allows the preparation of adipic acid derivatives under mild reaction conditions, with appropriate yield and high selectivity.

BACKGROUND ART Adipic acid represents a key commodity chemical in the industry, being one of the building blocks of polymers such as nylon 6,6 and being also used in coatings, plasticizers and detergents. About 2.5 million tons of adipic acid are prepared each year globally. Typically, the preparation of adipic acid goes through the hydrogenation of benzene to produce cyclohexane that is further oxidized in air with cobalt catalysts to produce a mixture of cyclohexanol and cyclohexanone (also called "KA oil"). This mixture is further treated with nitric acid to produce adipic acid. Although highly efficient, this process requires a large number of steps from crude oil (benzene production by catalytic reforming followed by hydrogenation to cyclohexane and oxidation to KA oil) and is poorly sustainable, as it releases highly polluting nitrous oxides.

Alternative processes have been reported for the preparation of adipic acid, starting from 1 ,3-butadiene compounds and using hydroformylation reactions in the presence of water or methanol, producing adipic acid in its free form or methyl esters respectively. Such processes usually require the intervention of highly expensive precious metal catalysts in the homogeneous phase and/or the implementation of harsh reaction conditions -such as high pressures of carbon monoxide and elevated temperatures- to achieve satisfactory yields of adipic acid. In the patent US 4,316,047, the BASF company reports a hydroformylation reaction of 1 ,3-butadiene catalysed with readily available cobalt carbonyl catalysts but operated at a pressure range of 300 to 1 ,000 bar and a temperature higher than 100 °C. In these conditions, the process requires a high energetic input.

The direct carboxylation of 1 ,3 butadiene derivatives by catalytic insertion of carbon dioxide into the double bonds has also been studied. Matthessen and co-workers have reported in that sense an electrochemical method using Nickel as cathode, Magnesium as anode, acetonitrile as solvent and tetrabutylammonium bromide as supporting electrolyte for the direct electrolytic carboxylation of dienes, especially for the carboxylation of hexa- 2,4-diene which provides the corresponding dicarboxylated product in 74% yield when a pressure of 5 bar of CO2 is used. Current density of 5 mA per cm ² was found necessary to achieve this yield, which represents a significant energetic cost.

In a similar approach, Li and co-workers report an electrocatalytic system for the dicarboxylation of dienes using nickel as cathode, aluminium as anode, Λ/,/V-dimethylformamide (DMF) as solvent and tetrabutylammonium bromide as supporting electrolyte. The reported method employs high pressures of carbon dioxide (3 MPa) and high current densities (10 mA per cm ² ). Reported current efficiency is in both cases lower than 50%, which indicates significant energetic loss over the course of the process. In a more recent work,

Steinmann and co-workers report the electrochemical dicarboxylation of 2,3- dimethylbutadiene using nickel as cathode, aluminium as anode, N,N- dimethylformamide (DMF) as solvent and tetrabutylammonium bromide as supporting electrolyte, a pressure of carbon dioxide of 30 bar and a current density of 5 or 8 mA per square centimeter. Dicarboxylation of the studied substrate occurred with a 65% yield and a low Faraday yield, accounting for the poor efficiency of the process.

In a different approach, Derien and co-workers report the dicarboxylation of 1 ,4-diphenylbutadiene using a catalytic system obtainable by contacting a nickel(ll) bromide salt with a tridentate nitrogenated and non-aromatic ligand (pentaethyldiethylenetriamine), in the presence of an electrochemical cell and thereby producing an active nickel (0) species. The reaction takes place in atmospheric pressure of carbon dioxide. A yield of 60% is reported for the dicarboxylated product. The authors however point that cycloocta-1 ,3-diene and 2, 5-dimethylhexa-1 ,3-diene are poorly reactive in the same conditions, which indicates that this methodology is not applicable to a broad range of substrates.

Takimoto and co-workers have also described a two-step synthetic sequence involving a nickel (0) catalyst and organometallic reagents for the

dicarboxylation of butadiene derivatives, especially those bearing an aromatic group. The used nickel (0) complex is formed in situ by treating nickel (0) cyclooctadiene with two equivalents of 1 ,8-diazabicyclo-[5.4.0]undec-7-ene (DBU), designed as a ligand of choice for the carboxylation of butadiene derivatives. The 1 ,3 diene is described to form an allyl nickel complex as a result of the first carboxylation reaction. According to the authors, organozinc reagents are necessary to allow the second carboxylation process to take place from the allyl nickel complex formed in situ. The treatment with an organometallic reagent is then carried out in a second synthetic step to yield the dicarboxylated product as a diester.

Hoberg and co-workers reported in 1984 a nickel(O) mediated dicarboxylation reaction of 1 ,3-butadiene, using a nickel(O) complex with a bidentate tetramethylenediamine ligand. The nickel (0) complex is formed in situ from Ni(cyclooctadiene)2 and two equivalents of ligand. When treated with excess 1 ,3 butadiene and carbon dioxide at low temperatures (from -78 °C to -15 °C), the nickel complex reacts to form a monocarboxylated product. The resulting monocarboxylated product can then be treated with pyridine under a CO2 atmosphere for 5 days. The resulting dicarboxylate nickel complex was subsequently converted to a diester with methanol in acidic conditions to yield the corresponding diester in 3.4% overall yield (with respect to engaged 1 ,3- butadiene) over the three synthetic steps. In a similar approach, Behr and coworkers reported in 1986 a nickel(O) mediated dicarboxylation reaction of 1 ,3,7-octatriene using a nickel(O) complex ligated to a bidentate 2,2'-bipyridine ligand. In these conditions, a mixture of mono- and dicarboxylated products has been reported. In this case, nickel is also used in stoichiometric amounts.

From what is known in the state of the art, it derives that there is still the need for providing a process for the catalytic, one-step dicarboxylation of butadiene derivatives operating in mild conditions, and providing good yields and high selectivity. SUMMARY OF THE INVENTION

The inventors have developed a catalytic process for the dicarboxylation of 1 ,3-butadiene derivatives. The developed process involves the use of a nickel(O) catalyst formed in situ via the reduction of a nickel(ll) complex formed from a nickel (II) salt and a ligand .

Thus, in a first aspect, the invention relates to a process for the production of a compound of formula (I) or a salt thereof, or a stereoisomer or mixture thereof either of the compound of formula (I) or of any of its salts:

wherein:

n is 0 or 1 ;

the dashed line represents a carbon-carbon double bond or a carbon-carbon single bound; provided that

when n is 0, the dashed line represents a carbon-carbon double bond; and

when n is 1 , the dashed line represents a carbon-carbon single bond; each one of Ri, R2, R3, R4, R5 and R6 are radicals independently selected from the group consisting of hydrogen; (Ci-Ci2)alkyl; and a known ring system comprising from 1 to 4 saturated, partially unsaturated or aromatic rings, the rings being isolated, partially fused or totally fused, having from 3 to 8 members selected from the group consisting of C, CH, CH ₂ , N, NH, O and S, and being optionally substituted with one or more radicals selected from the group consisting of halogen, (Ci-C6)alkyl, (Ci-C6)haloalkyl, (Ci- C6)alkylcarbonyl, (Ci-C6)alkyloxy, (Ci-C6)alkyloxycarbonyl, (Ci- C6)alkylcarbonyloxy, formyl, cyano, and nitro;

each one of X and Y are radicals independently selected from the group consisting of hydrogen, halogen, and hydroxyl; or, alternatively, X and Y, together with the carbon atoms to which they are attached form a saturated or unsaturated ring comprising from 3 to 6 members selected from -C-, -CH-, and -CH ₂ -, the ring being optionally substituted with one or more radicals selected from the group consisting of halogen, (Ci-C6)alkyl, (Ci-C6)haloalkyl, (Ci-C6)alkylcarbonyl, (Ci-C6)alkyloxy, (Ci-C6)alkyloxycarbonyl, (Ci- C6)alkylcarbonyloxy, formyl, cyano and nitro; the process comprising, when the compound of formula (I) is one of formula (Γ) or a salt thereof

where Ri to R6 are as defined above, and the wavy line represents that the compound is in the (Z) or (E) configuration, or a mixture thereof, the step of (i) contacting a compound of formula (II)

being Ri to R6 and the wavy line as defined above, with carbon dioxide in a polar aprotic solvent, in the presence of:

(a) a catalytically effective amount of a nickel(ll) salt ;

(b) reducing means selected from a metal, an electrochemical reducing means and a photochemical reducing means, and

(c) a ligand of formula (L)

(L)

wherein:

each one of R ₇ , R7', R9 and Rg' are radicals independently selected from the group consisting of hydrogen, (CrCi ₂ )alkyl, and (Ci- Ci2)haloalkyl;

each one of F¾ and Rs' are radicals independently selected from the group consisting of hydrogen; halogen; (Ci-Ci2)alkyl; (Ci-Ci2)haloalkyl; (Ci-Ci2)alkyloxy; and a known ring system comprising from 1 to 4 saturated, partially unsaturated or aromatic rings, the rings being isolated, partially fused or totally fused, having from 5 to 6 members selected from the group consisting of C, CH, CH ₂ , N, NH, O and S, and being optionally substituted with one or more radicals selected from the group consisting of (Ci-C6)alkyl, (Ci-C6)alkoxy, (Ci-C6)haloalkyl and halogen; and

each one of Rio and Rio' are radicals independently selected from the group consisting of hydrogen, a (Ci-Ci2)alkyl, a (Ci-Ci2)haloalkyl, and a (Ci-Ci2)alkyloxy; or, alternatively, Rio and Rio' together with the carbon atoms to which they are attached form a phenyl ring; and when the com ound of formula (I) is one of formula (!"):

the process further comprises the step of: (ii) transforming the compound of formula (Ι') in (I").

Table 1 below shows that the nature of ligand "L" allows the performance of the catalytic reaction with an appropriate yield and a remarkable selectivity of (Z):(E) isomers under different reaction conditions of temperature, time and Ni salts.

In addition to the above, Table 2 provided below also shows that the one-pot dicarboxylation only worked in the case that Ni catalyst is provided in the reaction medium in the form of a nickel (II) salt. In fact, when the prior art nickel (0) complex Ni(cyclooctadiene)2 was used instead of the a nickel (II) salt, no dicarboxylation occurred. It was also found by the present inventors that the nature of the reducing means was critical for achieving the dicarboxylation of the compound of formula (I): under same reaction conditions of Ni salt and L ligand, it was found that the dicarboxilation did not occur when other reducing meanss already reported in the prior art, such as Mn/Cr alloy or tetrakis- (dimethylamino)ethylene, were used.

The particular nature of the catalyst, solvent, ligand, and reducing means, as specified in the first aspect of the invention, confers to the process the further advantages of (a) being performed in a single step and (b) taking place under mild conditions, using atmospheric pressure of carbon dioxide and low reaction temperatures, being an eco-friendly process.

The process of the invention provides a derivative of hex-3-enedioic acid which can then subsequently treated following conventional olefin chemistry to produce a derivative of adipic acid.

Altogether, these data allow concluding that the process of the invention means a great advance in the field of the synthesis of apidic acid and its derivatives.

DETAILED DESCRIPTION OF THE INVENTION

All terms as used herein in this application, unless otherwise stated, shall be understood in their ordinary meaning as known in the art. Other more specific definitions for certain terms as used in the present application are as set forth below and are intended to apply uniformly through-out the specification and claims unless an otherwise expressly set out definition provides a broader definition.

For the purposes of the invention, any ranges given include both the lower and the upper end-points of the range. Ranges given, such as temperatures, times, and the like, should be considered approximate, unless specifically stated.

Unless specified otherwise, all amount indications are provided on a molar basis, with absolute indications being provided in the unit of moles and relative indications being provided as mol%. The term "mol%" is to be understood as the number of moles of a particular component with respect to the total number of moles of the compound of formula (II) engaged in the step (i) of the process of the invention.

Unless specified otherwise, all indications of point values are intended to allow variation of ±10%, preferably of ±5% and most preferably ±0% of the specified value around the point value. Unless specified otherwise, the term "comprising" is intended to permit the additional presence of unspecified further components or measures. It is however a preferred embodiment that no further components or measures are present, i.e. the term "comprising" encompasses also the meaning "consisting of as a preferred embodiment.

Unless specified otherwise, the term "nickel (II) salt" refers to a single inorganic or organic salt or to a mixture of inorganic or organic salts of nickel (II). In one embodiment, the nickel (II) salt is a salt with an halide anion or an oxoanion. In one embodiment, the nickel (II) salt is selected from the group consisting of nickel (II) halide, nickel (II) sulphate, nickel (II) perchlorate, nickel (II) trifluoromethanesulfonate, nickel (II) hexafluoroacetylacetonate, nickel (II) sulfamate, nickel (II) carbonate, nickel (II) oxalate, a tetrabromonickelate salt, a compound of formula Ni(OOCRis)2 wherein Ri ₈ is (Ci-Ci2)alkyl, and solvates thereof.

Unless specified otherwise, the term "polar aprotic solvent" is intended to refer to a solvent which does not release any protons when the process of the first aspect of the invention is performed. The solvent has a dielectric constant (the ratio of the electrical capacity of a capacitor filled with the solvent to the electrical capacity of the evacuated capacitor (at 20°C unless otherwise indicated)) above 25.0 and/or a dipole moment above 2.5 D. Typical examples are N-methylpyrrolidone (NMP), Ν,Ν-dimethylformamide (DMF), N,N- dimethylacetamide (DMA), acetonitrile, dimethylsulfoxide (DMSO), HMPT, hexamethylphosphoramide (HMPA), nitrobenzene, formamide, nitromethane, and propylene carbonate. In one embodiment, the polar aprotic solvent is selected from DMA, DMF, DMSO, HMPA, formamide, nitrobenzene, nitromethane, particularly is selected from DMA, DMF, DMSO, HMPA, formamide, and more particularly from DMF and DMSO.

Unless specified otherwise, the term "catalytically effective amount" refers to the amount of Ni salt which gives rise to an increase in yield or reaction rate of at least 10% in comparison with the corresponding reaction when carried out in the absence of the Ni salt.

In the course of step (i) of the process of the invention, salts of the compound of formula (Γ) may be formed, for instance when the reducing means is a metal (such as Al, Mn or Zn). As a consequence, a salt of the compound of formula (Γ) may be obtained in step (i). In these cases, wherein the resulting compound from step (i) or (ii) is a salt of the compound of formula (Γ) or (I"), respectively, the process further comprises an acidic treatment of said salt. The skilled person in the art using the general knowledge is able to select the reagents and particular conditions to achieve the hydrolysis of the

carboxylates of formula (Γ) and (I") to achieve the compound of formula (I). By "acidic treatment" is understood that the compound of formula (Γ) or (I") is mixed with one or more acids. The acids useful for performing the acidification have a pKa lower than 4.

Alternatively, it is possible the preparation of a salt of the compound of formula (I). The term "salt" embraces salts commonly used to form alkali metal salts, alkali-earth metal salts, transition metal salts and addition salts of free acids. In addition, the term "salt" embraces a compound of formula (I) wherein one or both carboxylic groups are in the form of -COOM, M representing a counter- ion. Illustrative non-limitative examples of inorganic counter-ions are ammonium ions of formula NJ ⁴⁺ wherein each J being independently hydrogen or a (Ci-C ₄ )alkyl radical, alkali ions such as Li ⁺ , Na ⁺ , Cs ⁺ and K ⁺ as well as an alkaline earth ions such as Mg ²⁺ and Ca ²⁺ or metals such as Al ³⁺ , Mn ²⁺ or Zn ²⁺ .

The preparation of salts from the parent compound of formula (I) can be performed by conventional chemical methods, such as a treatment with a base, or by ion exchange techniques (e.g. resins). Generally, such salts are, for example, prepared by reacting the free acid forms of these compounds with a stoichiometric amount of the base in water or in an organic solvent or in a mixture of them. The molar ratio between the product of formula (I) and the base will depend on the charge of the counter-ion: if the counter-ion carries "n" positive charges, the molar ratio counter-ions: carboxylic acid groups is 1/n: 1 (if only one of the two carboxylic groups is transformed in the salt) or 2/n:1 (when both carboxylic groups are transformed in salts). The compound of formula (I) and its salts may differ in some physical properties but they are equivalent for the purposes of the present invention.

In the context of the invention, "molar ratio" means the ratio of the number of moles of one specimen with respect to the number of moles of another specimen.

The compounds of formula (I), (Γ), (I"), and (II) may be in crystalline form either as free solvation compounds or as solvates (e.g. hydrates) and it is intended that both forms are within the scope of the present invention.

Methods of solvation are generally known within the art.

These compounds also have chiral centres that can give rise to various stereoisomers. As used herein, the term "stereoisomer" refers to all isomers of individual compounds that differ only in the orientation of their atoms in space. The term stereoisomer includes mirror image isomers (enantiomers), mixtures of mirror image isomers (racemates, racemic mixtures), geometric (cis/trans or syn/anti or E/Z) isomers, and isomers of compounds with more than one chiral center that are not mirror images of one another (diastereoisomers). The present invention relates to each of these stereoisomers and also mixtures thereof.

Diastereoisomers and enantiomers can be separated by conventional techniques such as chromatography or fractional crystallization. Optical isomers can be resolved by conventional techniques of optical resolution to give optically pure isomers. This resolution can be carried out on any chiral synthetic intermediates or on compounds of the invention. Optically pure isomers can also be individually obtained using enantiospecific synthesis methods known in the art.

Unless expressly specified otherwise, all references to carbon-carbon double bonds are intended to characterize both cis (Z) and trans (E) geometries. This applies even to cases where a structural formula is shown that may suggest a particular cis (Z) or trans (E) geometry when applying standard conventions for drawing chemical formulae. The terms "E-Z" configuration refers to the absolute stereochemistry of double bonds having two, three or four substituents following the lUPAC convention. In particular, the term "Z-isomer" refers to a double bond wherein the two groups of higher priority are on the same side of the double bond; and the term "E-isomer" refers to a double bond wherein the two groups of higher priority are on opposite sides of the double bond.

In the context of the invention, the terms "halo" and "halogen" are used interchangeably and refer to a halogen group selected from chloro, fluoro, bromo and iodo.

In the context of the invention, the term "alkyl" refers to a saturated linear or branched hydrocarbon chain containing the number of carbon atoms indicated in the claims and in the description. Examples of alkyl groups include, but are not limited to: methyl, ethyl, propyl, iso-propyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonanyl and decanyl.

In the context of the invention, the term "(Ci-C6)haloalkyl" refers to a saturated linear or branched hydrocarbon chain containing from 1 to 6 carbon atom members, wherein at least one hydrogen is replaced by a halogen.

The term "(Ci-C ₆ )alkyloxy" means "-O-(Ci-C ₆ )alkyl", in which the term "alkyl" has the previously given definition. Examples of alkyloxy group include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy.

The term "(Ci-C6)alkylcarbonyl" means "-C(O)-(Ci-C6)alkyl , in which the term "alkyl" has the previously given definition. Examples of such radicals include, but are not limited to, methylcarbonyl and ethylcarbonyl. The term "(Ci-C6)alkylcarbonyloxy" means -C(O)-O-(Ci-C6)alkyl. Examples of alkylcarbonyloxy group include, but are not limited to, acetate, propionate and t-butylcarbonyloxy. The term "(Ci-C6)alkyloxycarbonyl" means -O-C(O)-(Ci-C6)alkyl. Examples of such radicals include, but are not limited to, substituted or unsubstituted methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl and hexyloxycarbonyl.

According to the present invention, the term "known ring system" refers to a ring system which is known in the art and so intends to exclude those ring systems that are not chemically possible.

According to the present invention a ring system formed by "isolated" rings means that the ring system is formed by two, three or four rings and said rings are bound via a bond from the atom of one ring to the atom of the other ring. The term "isolated" also embraces the embodiment in which the ring system has only one ring. Illustrative non-limitative examples of ring systems consisting of one ring are those derived from: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopropenyl, cyclobutenyl,

cyclopentenyl, phenyl, biphenylyl, and cycloheptenyl. According to the present invention when the ring system has "totally fused" rings, it means that the ring system is formed by two, three or four rings in which two or more atoms are common to two adjoining rings. Illustrative non- limitative examples are 1 ,2,3,4-tetrahydronaphthyl, 1 -naphthyl, 2-naphthyl, anthryl, or phenanthryl.

According to the present invention when the ring system is "partially fused", it means that the ring system is formed by three or four rings, being at least two of said rings totally fused (i.e. two or more atoms being common to the two adjoining rings) and the remaining ring(s) being bound via a bond from the atom of one ring to the atom of one of the fused rings.

In one embodiment of the first aspect of the invention, the ring system is selected from a (C ₃ -C8)cycloalkyl, (C6-C2o)aryl, and (C ₅ -C2o)heteroaryl. In the context of the invention, the term "(C ₃ -C8)cycloalkyl" refers to a saturated hydrocarbon carbocyclic ring system radical group containing from 3 to 8 the number of carbon atoms members, the system comprising from 1 to 3 rings indicated in the claims and in the description. Examples of cycloalkyl groups radicals include, but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. The term "(C6-C2o)aryl" means, unless otherwise stated, a C-radical of a ring system from 6 to 20 carbon atoms, the system comprising from 1 to 3 rings, the ring bearing the C-radical being aromatic, and where each one of the rings forming the ring system: is saturated, partially unsaturated, or aromatic; and is isolated, partially fused or totally fused. The aryl can be optionally substituted with one or more radicals selected from halogen, (Ci-C6)alkyl, (Ci-

C6)haloalkyl, (Ci-C6)alkylcarbonyl, (Ci-C6)alkyloxy, (Ci-C6)alkyloxycarbonyl, (Ci-C6)alkylcarbonyloxy, formyl, cyano and nitro and the like. Non-limiting examples of unsubstituted aryl groups include phenyl, naphthyl,

phenanthrenyl, anthracenyl, and biphenyl. Examples of substituted aryl groups include, but are not limited to phenyl, chlorophenyl, trifluoromethylphenyl, chlorofluorophenyl, and aminophenyl.

The term "(C ₅ -C2o)heteroaryl" represents a C- radical of a ring system from 5 to 20 members, the system comprising from 1 to 3 rings, wherein at least one of the rings is aromatic and contains from one to four heteroatoms

independently selected from O, S and N, and wherein each one of the rings forming the ring system: is saturated, partially unsaturated or aromatic; and is isolated, partially fused or totally fused, alone or in combination,. The heteroaryl can be optionally substituted with one or more radicals selected from halogen, (Ci-C ₆ )alkyl, (Ci-C ₆ )haloalkyl, (Ci-C ₆ )alkylcarbonyl, (d-

C6)alkyloxy, (Ci-C6)alkyloxycarbonyl, (Ci-C6)alkylcarbonyloxy, formyl, cyano and nitro. Examples of heteroaryls include, but are not limited to pyridinyl, pyrazinyl, pyrrolyl, furanyl, thiophenyl, or benzothiophenyl,. The term "formyl" refers to a -CHO (aldehyde) group.

In the context of the invention, a "solvate" of a nickel(ll) salt refers to a crystalline nickel(ll) salt that contains at least one solvent molecule in the unit cell of the crystal structure. More preferably, said solvent molecule is aprotic. As mentioned above, methods of solvation are generally known within the art.

In the context of the invention, "a metal" refers to non-charged, non- complexed metal atoms or clusters belonging to groups 3 to 12 of the periodic table, although it can be solvated. In one embodiment of the invention, optionally in combination with any of the embodiments provided above or below, the metal is a transition metal, such as Zn or Mn. In another

embodiment of the invention, the reducing means is Al. In another

embodiment of the invention, the reducing means is Zn or Mn.

In the context of the invention, a "photochemical reducing means" refers to a photochemical system comprising at least a light source, a photosensitizer and an electron donor compound, said photochemical system being able to reduce nickel (II) to nickel (0). Suitable photochemical reduction means may consist of the combination of a photosensitizer with an electron donor compound. Suitable photosensitizers are known in the art and may be selected from the group consisting of ruthenium (II) or iridium (I) coordination complexes with at least one bidentate nitrogenated ligand with Ru(ll) or lr(l), such as [Ru(bpy)3] ²⁺ and the like or [lr(ppy) ₂ (bpy)] ⁺ and the like, being bpy 2,2'-bipyridine and ppy 2-phenylpyridine. Suitable electron donors in photochemical reduction means are known in the art and may be selected from tertiary amines, such as trimethylamine or trimethylamine and alcohols. When the reducing agent is a photochemical reduction means, the method of the invention is further carried out under light irradiation, preferably using visible light or ultra-violet irradiation.

In the context of the invention, an "electrochemical reducing means" refers to a cell, or device able to reduce nickel (II) to nickel (0). Illustrative non-limitative examples of electrochemical reducing means are a cathode, an

electrochemical half-cell or a source of electrons.

As described above, the invention relates to a process for the production of a compound of formula (I) from a compound of formula (II).

In a particular embodiment of the first aspect of the invention, optionally in combination with one or more of the embodiments described above or below, the nickel (II) salt used in step (i) is an halide or oxoanion nickel (II) salt. In a particular embodiment of the first aspect of the invention, optionally in combination with one or more of the embodiments described above or below, the nickel (II) salt used in step (i) is selected from the group consisting of nickel (II) halide, nickel (II) sulphate, tetrabutylammoniunn nickel (II)

tetrabromonickelate, nickel (II) perchlorate, and nickel (II)

trifluoromethanesulfonate, nickel (II) hexafluoroacetylacetonate, nickel (II) sulfamate, nickel (II) carbonate, nickel (II) oxalate, and a compound of formula Ni(OOCRis)2 wherein Ri ₈ is (Ci-Ci2)alkyl. In a particular embodiment of the first aspect of the invention, optionally in combination with one or more of the embodiments described above or below, the nickel (II) salt used in step (i) is selected from the group consisting of nickel (II) chloride, nickel (II) bromide, nickel (II) iodide, nickel (II) acetate and solvates thereof. More particularly, the nickel (II) salt used in step (i) is selected from the group consisting of nickel (II) chloride, nickel (II) bromide and solvates thereof. Even more particularly, the nickel (II) salt used in step (i) is selected from the group consisting of nickel (II) chloride, nickel (II) bromide and solvates thereof with 1 ,2-dimethoxyethane (dme). Even more particularly, the nickel (II) salt used in step (i) is nickel (II) chloride or a solvate thereof. Even more particularly, the nickel (II) salt used in step (i) is a solvate of nickel (II) chloride with 1 ,2-dimethoxyethane. In other particular embodiments, optionally in combination with one or more of the embodiments described above or below, the nickel (II) salt used in step (i) is further selected from tetrabromonickelate salts. More particularly, the nickel (II) salt used in step (i) is tetrabutylammonium tetrabromonickelate. Such tetrabromonickelate compounds are known in the art and their preparation has been reported by Menges and co-workers in Angew. Chemie - Int. Ed. 2016, 55 (4), 1282-1285. In a particular embodiment of the first aspect of the invention, optionally in combination with one or more of the embodiments described above or below, the nickel (II) salt is used in a catalytically effective amount in the range from 1 to 20 mol%. More particularly, the nickel (II) salt is used in a catalytically effective amount in the range from 1 to 10 mol%. Even more particularly, the nickel (II) salt is used in a catalytically effective amount in the range from 5 to 10 mol%.ln more particular embodiments, the nickel (II) salt is used in a catalytically effective amount of 5 mol%.

In a particular embodiment of the first aspect of the invention, optionally in combination with one or more of the embodiments described above or below, the reducing means used in step (i) is selected from a metal and an

electrochemical reducing means. In another particular embodiment of the first aspect of the invention, optionally in combination with one or more of the embodiments described above or below, the reducing means used in step (i) is selected from a metal and a photochemical reducing means. In a more particular embodiment of the first aspect of the invention, optionally in combination with one or more of the embodiments described above or below, the reducing means used in step (i) is a metal.

In a particular embodiment of the first aspect of the invention, optionally in combination with one or more of the embodiments described above or below, the reducing means used in step (i) is manganese or zinc. More particularly, optionally in combination with one or more of the embodiments described above or below, the reducing means used in step (i) is manganese (Mn).

In one embodiment of the first aspect of the invention, optionally in

combination with one or more of the embodiments described above or below, the reducing means used in step (i) is manganese or zinc, and the molar ratio between the nickel (II) salt and the reducing means is in the range from 1 :1 to 1 :2. In one embodiment of the first aspect of the invention, optionally in combination with one or more of the embodiments described above or below, the reducing means used in step (i) is manganese or zinc, and the molar ratio between the nickel (II) salt and the reducing means is in the range from 1 :1 to 1 :1 .5. In another embodiment, optionally in combination with one or more of the embodiments described above or below, when the reducing means used in step (i) is a metal, the molar ratio between the nickel (II) salt and the reducing means is in the range comprised from 1 : 1 to 1 :2.

In another particular embodiment of the first aspect of the invention, optionally in combination with one or more of the embodiments described above or below, the reducing means used in step (i) is a photochemical reducing means comprising a photosensitizer, a light source and an electron donor. Suitable photosensitizers are known in the art and may be selected from the group consisting of organic dyes, such as those described in Chem.

Rev., 2016, 1 16, 10075, and light-harvesting coordination complexes.

Preferably, the suitable photosensitizer comprised in the photocatalytic reduction means is selected from the light-harvesting coordination complexes of copper (I), iron (II), ruthenium (II) or iridium (III) with at least one bidentate nitrogenated ligand. More preferably, the suitable photosensitizer comprised in the photocatalytic reduction means is selected from the group consisting of the complexes of formulae [Ru(bpy)3] ²⁺ , [lr(ppy) ₃ ] and [lr(ppy) ₂ (bpy)] ⁺ , wherein bpy represents 2,2'-bipyridine wherein each pyridine ring is optionally substituted with one ore more radicals selected from the group consisting of halo, a linear or branched (C^C _g ) alkyl group and (C^C _g Jhaloalkyl group; and wherein ppy represents 2-phenylpyridine wherein each of the pyridine and phenyl rings are optionally substituted with one or more radicals selected from the group consisting of halo, a linear or branched (C^C _g Jalkyl group and (C^ C ₆ )haloalkyl group. Suitable electron donors in photochemical reduction means are known in the art and may be selected from tertiary amines. Preferably, the suitable electron donor comprised in the photochemical reduction means is a compound of formula N(RR'R") wherein each of R, R' and R" is a linear or branched (C^ C ₆ )alkyl group, being R, R' and R" the same or different and wherein the alkyl group may further be substituted with one or more hydroxyl groups. More preferably, the suitable electron donor comprised in the photochemical reduction means is selected from the group consisting of trimethylamine, trimethylamine, triethanolamine and diisopropylethylamine. When the reducing agent is a photochemical reduction means, the method of the invention is further carried out under light irradiation, preferably using visible light or ultraviolet irradiation.

When the reducing agent is a photochemical reduction means, the amount of photosensitizer compound comprised in the photochemical reduction means ranges from 0.001 to 0.1 mole per each mole of compound of formula (III). Typically, the amount of photosensitizer compound comprised in the

photochemical reduction means is of 0.01 mole per each mole of compound of formula (III). When the reducing agent is a photochemical reduction means, the amount of electron donor compound comprised in the photochemical reduction means ranges from 1 to 10 moles per each mole of compound of formula (III).

Typically, the amount of electron donor compound comprised in the

photochemical reduction means is of 3 moles per each mole of compound of formula (III).

In a particular embodiment of the first aspect of the invention, optionally in combination with one or more of the embodiments described above or below, the compound of formula (L) is used in an amount comprised in the range from 1 to 20 mol%. More particularly, the compound of formula (L) is used in an amount of about 10 mol%. Even more particularly, the compound of formula (L) is used in an amount of about 5 mol%.

In another particular embodiment of the first aspect of the invention, optionally in combination with one or more of the embodiments described above or below, the molar ratio between the nickel (II) salt used in step (i) and the compound of formula (L) is 1 :1 .

In another particular embodiment of the first aspect of the invention, optionally in combination with one or more of the embodiments described above or below, the reducing means used in step (i) is manganese or zinc, being the molar ratio between nickel (II) salt and the reducing means in the range from 1 : 1 to 1 :2, and the molar ratio between the nickel (II) salt used in step (i) and the compound of formula (L) is 1 :1 . In one embodiment of the first aspect of the invention, optionally in combination with one or more of the embodiments described above or below, the reducing means used in step (i) is manganese or zinc, the molar ratio between the nickel (II) salt and the reducing means is in the range from 1 :1 to 1 : 1 .5, and the molar ratio between the nickel (II) salt used in step (i) and the compound of formula (L) is 1 :1 .

In a particular embodiment of the first aspect of the invention, optionally in combination with one or more of the embodiments described above or below, the compound of formula (L) used in step (i) is one wherein at least one of R ₇ , R ₇ ', Rs and Rs' is not hydrogen. More particularly, the compound of formula (L) used in step (i) is one wherein at least two of R ₇ , R ₇ ', Rs and Rs' are not hydrogen. Even more particularly, the compound of formula (L) used in step (i) is one wherein at least three of R ₇ , R ₇ ', Rs and Rs' are not hydrogen.

In a particular embodiment of the first aspect of the invention, optionally in combination with one or more of the embodiments described above or below, the compound of formula (L) used in step (i) is one wherein R ₈ and Rs' are the same. In another embodiment, optionally in combination with one or more of the embodiments described above or below, R ₈ and Rs' represent a (Ce- C2o)aryl. More particularly, optionally in combination with one or more of the embodiments described above or below, the compound of formula (L) used in step (i) is one wherein R ₈ and Rs' are the same or different and are selected from the group consisting of hydrogen, phenyl, methyl, tert-butyl, methyloxy and phenyl substituted with one or more methoxy groups. More particularly, optionally in combination with one or more of the embodiments described above or below, the compound of formula (L) used in step (i) is one wherein Rs and Rs'are both phenyl.

In a particular embodiment of the first aspect of the invention, optionally in combination with one or more of the embodiments described above or below, the compound of formula (L) used in step (i) is one wherein R ₉ and Rg' are the same. More particularly, optionally in combination with one or more of the embodiments described above or below, the compound of formula (L) used in step (i) is one wherein R ₉ and Rg' are selected from the group consisting of hydrogen and (Ci-Ci ₂ )alkyl. More particularly, optionally in combination with one or more of the embodiments described above or below, the compound of formula (L) used in step (i) is one wherein Rg and Rg'are selected from the group consisting of hydrogen and methyl. More particularly, optionally in combination with one or more of the embodiments described above or below, the compound of formula (L) used in step (i) is one wherein Rg and Rg'are both hydrogen.

In a particular embodiment of the first aspect of the invention, optionally in combination with one or more of the embodiments described above or below, the compound of formula (L) used in step (i) is one wherein Rio and Rio' are both hydrogen; or, alternatively, Rio and Rio', together with the carbon atoms to which they are attached form a phenyl ring. More particularly, optionally in combination with one or more of the embodiments described above or below, the compound of formula (L) used in step (i) is one wherein Rio and Rio', together with the carbon atoms to which they are attached form a phenyl ring.

In a particular embodiment of the first aspect of the invention, optionally in combination with one or more of the embodiments described above or below, the compound of formula (L) used in step (i) is one wherein R ₇ and R ₇ ' are each independently selected from the group consisting of: hydrogen, (Ci- Ci ₂ )alkyl, and (Ci-Ci ₂ )haloalkyl. In a particular embodiment of the first aspect of the invention, optionally in combination with one or more of the

embodiments described above or below, the compound of formula (L) used in step (i) is one wherein R ₇ and R ₇ ' are each independently selected from the group consisting of: hydrogen, methyl, n-butyl and trifluoromethyl. More particularly, optionally in combination with one or more of the embodiments described above or below, the compound of formula (L) used in step (i) is one wherein R ₇ and R ₇ ' are the same. Even more particularly, optionally in combination with one or more of the embodiments described above or below, the compound of formula (L) used in step (i) is one wherein R ₇ and R ₇ ' are both hydrogen. In a particular embodiment of the first aspect of the invention, optionally in combination with one or more of the embodiments described above or below, the compound of formula (L) used in step (i) is a ligand of formula l_i

Li

wherein:

R ₇ is selected from hydrogen, (Ci-C6)alkyl and (Ci-C6)haloalkyl;

R' ₇ , Re, and R's are independently selected from hydrogen and (Ci-Ci2)alkyl or, alternatively, a ligand of formula L ₂

L ₂

wherein:

R ₇ , R' ₇ , R9, and R'g are independently selected from hydrogen and (Ci- Ci2)alkyl; and

Rs and R's are selected from hydrogen, (Ci-C6)alkyl, phenyl and phenyl substituted with at least one radical selected from (CrC6)alkyl, (CrC6)alkoxy, (Ci-C6)haloalkyl and halogen.

In another embodiment, optionally in combination with one or more of the embodiments described above or below, the compound of formula (L) used in step (i) is one of formula l_i wherein R ₇ is selected from the group consisting of hydrogen, methyl, n-butyl, and trifluoromethyl; R' ₇ is selected from the group consisting of hydrogen and methyl; and Rs and R's is selected from the group consisting of hydrogen and tert-butyl.

In another embodiment, optionally in combination with one or more of the embodiments described above or below, the compound of formula (L) used in step (i) is one of formula L ₂ , wherein R ₇ and R' ₇ are independently selected from the group consisting of hydrogen, methyl, and n-butyl; R ₉ and R'g are independently selected from hydrogen and methyl; and Rs and R's are independently selected from the group consisting of hydrogen, methyl, phenyl and phenyl substituted with two methoxy radicals.

In another embodiment, optionally in combination with one or more of the embodiments described above or below, the compound of formula (L) used in step (i) is selected from the group consisting of:

In another embodiment, optionally in combination with one or more of the embodiments described above or below, the compound of formula (L) used in step (i) is one wherein Rio and R ₁ 0', together with the carbon atoms to which they are attached form a phenyl ring, R ₇ and R ₇ ' are independently selected from hydrogen and methyl, and Rs and Rs' are both phenyl.

In another embodiment, optionally in combination with one or more of the embodiments described above or below, the compound of formula (L) used in step (i) is one wherein Rio and Rio', together with the carbon atoms to which they are attached form a phenyl ring, R ₇ and R ₇ ' are both hydrogen and Rs and Rs' are both phenyl (i.e., "L ₂ g").

In another embodiment, optionally in combination with one or more of the embodiments described above or below, the compound of formula (L) used in step (i) is one wherein Rio and Rio', together with the carbon atoms to which they are attached form a phenyl ring, R ₇ is methyl, R ₇ ' is hydrogen and Rs and Rs' are both phenyl (i.e., "L _2d "):

L _2d In a particular embodiment of the first aspect of the invention, optionally in combination with one or more of the embodiments described above or below, step (i) of the process is further carried out in the presence of a halide salt which is soluble in the polar aprotic solvent. It is advantageous as it allows for decreasing reaction times and obtaining higher yields in the formation of the compound of formula (Γ) (see Table 6 below). In another embodiment, optionally in combination with one or more of the embodiments described above or below, the soluble halide salt is a soluble bromide salt. In another embodiment, optionally in combination with one or more of the embodiments described above or below, the soluble halide salt is an ammonium bromide salt or a tetra(Ci-C6)alkylammonium bromide salt . In another embodiment, optionally in combination with one or more of the embodiments described above or below, the soluble halide salt is tetrabutylammonium bromide (TBAB). When the process of the invention is carried out in the presence of a soluble halide salt, said salt is particularly used in an amount in the range from 1 to 100 mol%, preferably from 5 to 50 mol%, and more preferably from 5 to 20 mol%.

In a particular embodiment of the first aspect of the invention, optionally in combination with one or more of the embodiments described above or below, step (i) of the process is carried out at a pressure of carbon dioxide in the range from 0.8 to 5 atmospheres. In another embodiment, optionally in combination with one or more of the embodiments described above or below, step (i) of the process is carried out at a pressure of carbon dioxide in the range from 0.8 to 1 .2 atmospheres. In another embodiment, optionally in combination with one or more of the embodiments described above or below, step (i) of the process is carried out at a pressure of carbon dioxide of 1 atmosphere. In a particular embodiment of the first aspect of the invention, optionally in combination with one or more of the embodiments described above or below, step (i) of the process is carried out in the presence of a polar aprotic solvent selected from the group consisting of Ν,Ν-dimethylformamide (DMF), N,N- dimethylacetamide (DMA), N-methylpyrrolidinone (NMP) and

dimethylsulfoxide (DMSO). In another embodiment, optionally in combination with one or more of the embodiments described above or below, step (i) of the process is carried out in a polar aprotic solvent selected from the group consisting of Ν,Ν-dimethylformamide (DMF), Ν,Ν-dimethylacetamide (DMA) and N-methylpyrrolidinone (NMP). In a preferred embodiment, optionally in combination with one or more of the embodiments described above or below, step (i) of the process is carried out in Ν,Ν-dimethylacetamide (DMA). Step (i) may be carried out at concentration of the compound of formula (II) in the range from 0.1 to 2 moles per liter. More particularly, step (i) may be carried out at concentration of the compound of formula (II) in the range from 0.4 to 1 .2 moles per liter. More particularly, step (i) may be carried out at

concentration of the compound of formula (II) of 0.5 mole per liter. In another embodiment, optionally in combination with any of the

embodiments provided above or below, step (i) is performed at a temperature in the range from 5 to 70 °C, more particularly in the range from 40 to 70 °C and even more particularly at a temperature of 50 °C. As defined above, the compound of formula (Γ) can further be subjected to appropriate reaction conditions to transform it into a compound of formula (I"). In the context of the invention, the term "appropriate reaction conditions" refers to conditions of reaction allowing for the formation of the compound of formula (I") in a yield higher than 10%. As will be obvious to the skilled in the art, standard olefin chemical reactivity principles can be applied to the compound of formula (Γ). Sufficient reaction conditions for the conversion of a compound of formula (Γ) into a compound of formula (I") are known in the art and will become apparent to the skilled in the art. Such reaction conditions are also well described in chemistry textbooks such as Chapter 20 of Clayden, Jonathan; Greeves, Nick; Warren, Stuart; Wothers, Peter (2001 ); Organic Chemistry (1 st ed.), Oxford University Press, ISBN 978-0-19-850346-0. For instance, when in the compound of formula (I) n is 1 and the dashed bond is a carbon-carbon single bond, and both X and Y are hydrogen, step (ii) comprises submitting the compound of formula (Γ) obtained in step (i) to a catalytic hydrogenation reaction, preferably by contacting the compound obtained in step (i) with hydrogen in the presence of a palladium catalyst.

Also, for instance, when in the compound of formula (I) both X and Y are halogen, step (ii) can comprise contacting the compound obtained in step (i) with molecular halogen. Similarly, when in the compound of formula (I) X is hydrogen and Y is a radical selected from halogen, hydroxyl and (Ci-

C6)alkyloxy, step (ii) comprises contacting the compound of formula (Γ) with a compound of formula H-Y, wherein Y is as defined in the first aspect of the invention. Also, when in the compound of formula (I) X and Y, together with the carbon atoms to which they are attached form a saturated or unsaturated

hydrocarbon ring comprising from 3 to 6 members, as defined in the first aspect of the invention, step (ii) of the process of the invention comprises submitting the compound obtained in step (i) to a cycloaddition reaction.

In a particular embodiment, optionally in combination with one or more of the embodiments described above or below, the compound of formula (II) is one wherein each of Ri , R2, R3, R ₄ , R5 and R6 is independently selected from the group consisting of hydrogen, (Ci-Ci2)alkyl and a known ring system comprising from 1 to 4 6-membered aromatic carbocyclic rings, the rings being isolated, partially or totally fused and being optionally substituted with one or more radicals selected from the group consisting of halogen, (Ci- C ₆ )alkyl, (Ci-C ₆ )haloalkyl, (Ci-C ₆ )alkylcarbonyl, (Ci-C ₆ )alkyloxy, (d- C6)alkyloxycarbonyl, (Ci-C6)alkylcarbonyloxy, formyl, cyano and nitro.

More particularly, optionally in combination with one or more of the

embodiments described above or below, the compound of formula (II) is one wherein each of Ri , R2, R3, R ₄ , R5 and R6 is independently selected from the group consisting of hydrogen, (Ci-Ce)alkyl, phenyl and phenyl substituted with one or more radicals selected from the group consisting of halogen, (Ci- C ₆ )alkyl, (Ci-C ₆ )haloalkyl, (Ci-C ₆ )alkylcarbonyl, (Ci-C ₆ )alkyloxy, (d- C6)alkyloxycarbonyl, (Ci-C6)alkylcarbonyloxy, formyl, cyano and nitro. Even more particularly, the compound of formula (II) is one wherein each of Ri , R2, R3, R4, R5 and R6 is independently selected from the group consisting of hydrogen, (Ci-C6)alkyl, phenyl and phenyl substituted with one radical selected from the group consisting of (Ci-C6)alkyl, and (Ci-C6)alkyloxy.

In another particular embodiment, optionally in combination with one or more of the embodiments described above or below, the compound of formula (II) is one wherein at least two of Ri , R2, R3, R ₄ , R5 and R6 are hydrogen. In another particular embodiment, optionally in combination with one or more of the embodiments described above or below, the compound of formula (II) is one wherein at least three of Ri , R2, R3, R ₄ , R5 and R6 are hydrogen.

In another particular embodiment, optionally in combination with one or more of the embodiments described above or below, the compound of formula (II) is one wherein at least four of Ri , R2, R3, R ₄ , R5 and R6 are hydrogen. More particularly, at least five of Ri , R2, R3, R4, R5 and R6 are hydrogen. Even more particularly, Ri , R ₂ , R3, R4, R5 and R6 are hydrogen.

In a particular embodiment, optionally in combination with one or more of the embodiments described above or below, the compound of formula (II) is one wherein each of X and Y is independently selected from the group consisting of hydrogen, halogen, and hydroxyl. More particularly, optionally in

combination with one or more of the embodiments described above or below, the compound of formula (II) is one wherein X and Y are both hydrogen.

EXAMPLES Preparative Examples

Preparative example 1: 4,7-bis(2,4-dimethoxyphenyl)-2,9-dimethyl-1 ,10- phenanthroline (L¾)

4,7-dichloro-2,9-dimethyl-1 ,10-phenanthroline (350mg, 1 .26 mmol), (2,4- dimethoxyphenyl)boronic acid (504 mg, 2.77 mmol) and potassium phosphate (805mg, 3.78 mmol) were dissolved in 15 mL of a 1 ,4-dioxane:water (2:1 ) mixture and heated to 100 °C for 24 hours. Solvent was evaporated and it was purified in a chromatography column with silica gel to give the desired compound as a brown solid (172 mg, 29% yield).

¹ H NMR (500 MHz, Chloroform-c/) δ = 8.22 (s, 1 H), 7.99 (d, J = 9.3 Hz, 1 H), 7.64 - 7.58 (m, 3H), 7.55 (s, 1 H), 7.40 (s, 1 H), 7.23 - 7.17 (m, 1 H), 6.66 -

6.60 (m, 2H), 3.89 (s, 3H), 3.68 (s, 3H), 2.94 (s, 3H), 2.91 (s, 3H), 2.91 (s, 6H) ppm.

Preparative example 2: 2-methyl-4,7-diphenyl-1 ,10-phenanthroline (L _2c i)

Bathophenanthroline (400mg, 1 .2 mmol) was dissolved in toluene and cooled down to 0°C. A few drops of MeLi were added until the reaction turned red. From this point 1 equiv of MeLi (0.75 mL, 1 .6 M in Et ₂ O) was added and it was stirred for 30 minutes. The reaction was quenched with water and it was extracted with dichloromethane. The organic phases were collected, washed with brine and dried over magnesium sulfate. The solution was filtered, 3 equivalents of MnO ₂ were added and it was stirred for one hour at room temperature. Silica gel was added to the reaction flask, the solvent was evaporated under reduced pressure and it was purified in a chromatography column with silica gel (DCM:MeOH 100:0 to 95:5) to give the desired compound as a light orange-brown solid (260 mg, 63% yield).

¹ H NMR (500 MHz, CDCI ₃ ) δ 9.25 (d, J = 4.5 Hz, 1 H), 7.81 (d, J = 9.4 Hz, 1 H), 7.78 (d, J = 9.4 Hz, 1 H), 7.55 (d, J = 4.5 Hz, 1 H), 7.54 - 7.44 (m, 1 1 H), 3.01 (s, 3H) ppm Preparative example 3: 4,4'-di-terf-butyl-6-butyl-2,2'-bipyridine (Li _d )

Following an analogue procedure to the synthesis of L _2c i, but using 4,4'-di-terf- butyl-2,2'-bipyridine as starting material and n-butyllithium in place of methyllithium, Li _d was obtained as a brown solid.

¹ H NMR (400 MHz, Chloroform-c/) δ = 8.60 (dd, J = 5.2, 0.8 Hz, 1 H), 8.46 (dd, J = 2.0, 0.8 Hz, 1 H), 8.19 (d, J = 1 .8 Hz, 1 H), 7.32 - 7.27 (m, 1 H), 7.16 (d, J = 1 .8 Hz, 1 H), 2.97 - 2.77 (m, 2H), 1 .89 - 1 .77 (m, 2H), 1 .53 - 1 .45 (m, 2H), 1 .41 (s, 9H), 1 .39 (s, 9H), 1 .01 (t, J = 7.4 Hz, 3H).

Preparative example 4: 4,4'-di-terf-butyl-6-methyl-2,2'-bipyridine (l_i _e )

Following an analogue procedure to the synthesis of L _2c i, but using 4,4'-di-terf- butyl-2,2'-bipyridine as starting material, l_i _e was obtained as a was employed to obtain the desired ligand as an off-white solid.

¹ H NMR (400 MHz, Benzene-c/ ₆ ) δ = 9.01 (dd, J = 2.0, 0.8 Hz, 1 H), 8.92 (dd, J = 1 .8, 0.6 Hz, 1 H), 8.64 (dd, J = 5.1 , 0.8 Hz, 1 H), 7.01 -6.98 (m, 1 H), 6.93 (dd, J = 5.2, 2.0 Hz, 1 H), 2.58 (d, J = 0.6 Hz, 3H), 1 .19 (s, 9H), 1 .14 (s, 9H) ppm.

Example 1 : Carboxylation of buta-1 ,3-dien-1 -ylbenzene

10 mol% Ni(ll) salt

10 mol% ligand L

Mn (2 equivalents)

DMF (concentration)

temperature, time

C0 ₂ (1 atm)

(Ila) (Z)-(l'a) (E)-(l'a) General Procedure A: An oven-dried Schlenk tube containing a stirring bar was charged with manganese (0.4 mmol, 22mg), the ligand indicated in Table 1 (0.02mmol), and the nickel (II) salt indicated in Table 1 (0.02 mmol). The tube was connected to a vacuum line where it was evacuated and back-filled 5 under a CO2 flow at least three times. The 1 ,3-diene (0.2 mmol) and the

solvent were added into the tube under CO2 flow (concentration as indicated in Table 1 ). Once added, the Schlenk tube was closed under CO2 (1 atm) and stirred for the time indicated in Table 1 at the temperature indicated in Table 1 . The mixture was then quenched with 2 M HCI to hydrolyze the resulting

0 carboxylate and extracted 3 times with ethyl acetate. The combined organic

phases were washed with brine and dried over MgSO ₄ and concentrated under reduce pressure. Fluorene was added as a standard and an aliquot was taken, the solvent was removed and residue was dissolved in CDCI3. The yield and selectivity of the reactions were measured by ¹ H NMR spectroscopy5 on Bruker Advance 300, 400 and 500 Ultrashield spectrometers operating at 300, 400 and 500 MHz respectively. ¹³ C-NMR spectra were recorded at room temperature using Bruker Advance 400 Ultrashield spectrometer operating at 100 MHz. All NMR samples were recorded in CDCI3 at room temperature. 0 Z : ¹ H NMR (500 MHz, Chloroform-c/) δ 7.38 - 7.24 (m, 5H), 6.12 (ddt, J =

1 1 .1 , 9.5, 1 .7 Hz, 1 H), 5.83 (dtd, J = 10.8, 7.3, 1 .2 Hz, 1 H), 4.54 (dd, J = 9.6, 1 .2 Hz, 1 H), 3.26 - 3.08 (m, 2H).

E: ¹ H NMR (500 MHz, Chloroform-c/) δ 7.43 - 7.14 (m, 5H), 6.00 (ddt, J =

5 15.4, 8.3, 1 .4 Hz, 1 H), 5.72 (dtd, J = 15.3, 7.0, 1 .1 Hz, 1 H), 4.33 (d, J = 8.3

Hz, 1 H), 3.26 - 3.08 (m, 2H).

Table 1

T Nickel [ ] t Yield Selectivity:

Entry Ligand

(°C) (II) salt (M) (h) I 'a (%) (Z)-(l'a) :(E)-(l'a )

1 6-methyl-2,2'-bipyridine 25 NiCI ₂ 0.5 40 48 2.7:1

6-butyl-4,4'-di-terf-butyl-

2 25 NiCI ₂ 0.5 40 29 3.1 :1

2,2'-bipyridine

6-methyl-4,4'-di-terf-butyl-

3 25 NiCI ₂ 0.5 40 23 3.6:1

2,2'-bipyridine

NiBr ₂

4 1 ,10-phenanthroline 50 0.5 64 14 6:1

■dme

5 2-methyl-1 ,10- 40 NiCI ₂ 0.25 48 46 3.6:1 T Nickel [ ] t Yield Selectivity:

Entry Ligand

(°C) (II) salt (M) (h) I 'a (%) (Z)-(l'a) :(E)-(l'a ) phenanthroline

2-butyl-1 ,10-

6 40 NiCI ₂ 0.25 48 42 7.4:1

phenanthroline

4,7-diphenyl-1 ,10-

7 phenanthroline 25 NiCI ₂ 0.5 40 61 4.5:1

(bathophenanthroline)

4,7-dimethyl-1 ,10- NiBr ₂

8 50 0.5 64 16 2.2:1

phenanthroline ^■ dme

2-methyl-4,7-diphenyl-

9 25 NiCI ₂ 0.5 40 49 6.0:1

1 ,10-phenanthroline

2-methyl-4,7-diphenyl-

10 40 NiCI ₂ 0.25 48 46 8.2:1

1 ,10-phenanthroline

2-methyl-4,7-dinnethoxy-

1 1 40 NiCI ₂ 0.25 48 33 5.6:1

1 ,10-phenanthroline

2,3,4,7,8-pentamethyl-

12 40 NiCI ₂ 0.25 48 45 4.0:1

1 ,10-phenanthroline

2,9-dimethyl-4,7-

13 dimethoxy-1 ,10- 40 NiCI ₂ 0.25 48 15 7.0:1

phenanthroline

Entries 1 to 13 indicate that the compound of formula L used in the process of the invention is useful for the dicarboxylation of a compound of formula (I).

Nickel (II) salt scope

(E)-(l'a)

0

Following General Procedure A, but using bathophenanthroline as a ligand, manganese as a reducing means, dimethylacetamide as a solvent (0.5 M concentration), dicarboxylation of (lla) was carried out at 50 °C for a reaction time of 16 h, using the nickel (II) salt indicated in Table 2, yielding the

5 compound (I'a) as indicated in Table 2. Table 2

¹ entry 4 is to be considered a comparative example.

Reducing means and solvent scope

Following General Procedure A, but replacing manganese by the reducing means indicated in Table 3, and using bathophenanthroline as a ligand, nickel (II) chloride as a nickel (II) salt, and the solvent indicated in Table 3 (0.5 M concentration), dicarboxylation of (lla) was carried out at 25 °C for a reaction time of 48 h, yielding the compound (I'a) as indicated in Table 3.

Table 3

¹ entries 3,4 and 6 are to be considered comparative examples (reported reducing means or solvent is out of the scope of the process of the invention) Scope of reaction conditions

Following General Procedure A, but using bathophenanthroline as a ligand, nickel (II) chloride as a nickel (II) salt in the amount indicated in Table 4, DMF as a solvent (concentration indicated in Table 4), manganese as a reducing means and further adding 10 mol% (0.1 eq) of tetrabutylammonium bromide (TBABr), dicarboxylation of (I la) was carried out at the temperature and for the reaction time indicated in Table 4, yielding the compound (I'a) as indicated in Table 4.

Table 4

Example 2: Dicarboxylation of 1 -(buta-1 ,3-dien-1 -yl)-4-isobutylbenzene

Following General Procedure A (see Example 1 ), but using 1 -(buta-1 ,3-dien-1 - yl)-4-isobutylbenzene as starting material, bathophenanthroline as a ligand, the nickel (II) salt indicated in Table 5, manganese as a reducing means, DMF as a solvent (0.5 M) and further adding tetrabutylammoniunn bromide (TBAB) in the amount indicated in Table 5, dicarboxylation of (Mb) was carried out at the temperature and for the reaction time indicated in Table 5, yielding the compound (I'b) as indicated in Table 5.

Table 5

TBABr means amount of tetrabutylammonium bormide

Z: ¹ H NMR (500 MHz, Chloroform-c/) δ 7.26 (d, J = 8.1 Hz, 2H), 7.13 (d, J = 8.2 Hz, 2H), 6.14 (ddt, J = 1 1 .1 , 9.5, 1 .8 Hz, 1 H), 5.84 (dtd, J = 10.8, 7.2, 1 .2 Hz, 1 H), 4.53 (dd, J = 9.6, 1 .1 Hz, 1 H), 3.30 - 3.10 (m, 2H), 2.47 (d, J = 7.2 Hz, 2H), 1 .86 (hept, J = 6.8 Hz, 1 H), 0.92 (d, J = 6.6 Hz, 6H).

E: ¹ H NMR (500 MHz, Chloroform-c/) δ 7.23 (d, J = 8.3 Hz, 2H), 7.13 (d, J = 8.2 Hz, 2H), 6.02 (ddt, J = 15.5, 8.4, 1 .4 Hz, 1 H), 5.73 (dtd, J = 15.3, 7.0, 1 .0 Hz, 1 H), 4.33 (d, J = 8.6 Hz, 1 H), 3.15 (ddd, J = 17.6, 7.1 , 1 .8 Hz, 2H), 2.47 (d, J = 7.2 Hz, 2H), 1 .86 (hept, J = 6.8 Hz, 1 H), 0.92 (d, J = 6.6 Hz, 6H).

Example 3: Dicarboxylation of 1 -(buta-1 ,3-dien-1 -yl)-4-methoxybenzene

30 °C, 40 h

(lie)

C0 ₂ (1 atm) (I'c)

Following General Procedure A (see Example 1 ), but using 1 -(buta-1 ,3-dien-1 - yl)-4-methoxybenzene as starting material, bathophenanthroline as a ligand, nickel chloride as nickel salt (10 mol%), DMF as a solvent (0.5 M),

manganese as a reducing means and further adding an additive in the amount indicated in Table 6, dicarboxylation of (lie) was carried out at 30 °C and for 40 h, yielding the compound (I'c) as indicated in Table 6.

Table 6

1 entries 2, 3, 5, 6, 7, 8 and 9 are to be considered comparative examples

Z: ¹ H NMR (500 MHz, Chloroform-c/) δ 7.25 (d, J = 8.7 Hz, 2H), 6.86 (d, J = 8.7 Hz, 2H), 6.09 (ddt, J = 1 1 .0, 9.4, 1 .7 Hz, 1 H), 5.81 (dtd, J = 10.8, 7.3, 1 .2 Hz, 1 H), 4.48 (d, J = 9.4 Hz, 1 H), 3.78 (s, 3H), 3.25 - 3.07 (m, 2H).

E: ¹ H NMR (500 MHz, Chloroform-c/) δ 7.22 (d, J = 8.7 Hz, 2H), 6.87 (d, J = 8.7 Hz, 2H), 5.97 (ddt, J = 15.4, 8.1 , 1 .4 Hz, 1 H), 5.69 (ddd, J = 15.9, 7.3, 6.2 Hz, 1 H), 4.28 (d, J = 8.2 Hz, 1 H), 3.78 (s, 3H), 3.26 - 3.06 (m, 2H). Example 4: Preparation of 2-phenylhexanedioic acid

An oven-dried Schlenck tube containing a stirring bar was charged with manganese (0.3 mmol), bathophenanthroline (0.02mmol, 6.6mg), NiCI ₂ -dme (0.02 mmol, 4.4 mg) and TBAB (0.02mmol, 6.4 mg). The tube was connected to a vacuum line where it was evacuated and back-filled under a CO ₂ flow at least three times. The 1 ,3-diene (0.2 mmol) and the solvent (0.4 ml_) were added into the tube under CO ₂ flow. Once added, the Schlenk tube was closed under CO ₂ (1 atm) and stirred for 16 hours at the desired temperature. The mixture was quenched with 2 M HCI to hydrolyze the resulting

carboxylate and extracted 3 times with ethyl acetate. The combined organic phases were washed with brine and dried over MgSO ₄ and concentrated under reduce pressure. The residue was purified by flash chromatography on silica gel (hexane/EtOAc/HCOOH mixtures, tipically 50/50/0.5) to deliver the corresponding products. The isolated biscarboxylic acid was dissolved in methanol, and the solution was added to a flask containing 5% of Pd/C. A ballon hydrogen was connected to the flask, purged for 2 minutes and stirred at room temperature for 2 hours. The solution was filtered through celite and the solvent was removed under reduced pressure to give the substituted adipic acid in 74% isolated yield.

Example 5: Preparation of 2-hexylhex-3-enedioic acid

50 °C, 16 h

An oven-dried Schlenck tube containing a stirring bar was charged with manganese (0.3 mmol), 2-methyl-4,7-diphenyl-1 ,10-phenanthroline

(0.02mmol, 6.9 mg), NiBr ₂ dme (0.02 mmol, 6.2 mg) and TBAB (0.02mmol, 6.4 mg). The tube was connected to a vacuum line where it was evacuated and back-filled under a CO2 flow at least three times. The 1 ,3-diene (0.2 mmol, 27.7 mg) and the solvent (0.4 ml_) were added into the tube under CO2 flow. Once added, the Schlenk tube was closed under CO2 (1 atm) and stirred for 16 hours at 50°C. The mixture was quenched with 2 M HCI to hydrolyze the resulting carboxylate and extracted 3 times with ethyl acetate. The combined organic phases were washed with brine and dried over MgSO ₄ and concentrated under reduce pressure. The residue was purified by flash chromatography on silica gel (hexane/EtOAc/HCOOH mixtures, typically 50/50/0.5) to deliver 31 .3 mg (69% yield, 1 .5:1 Z:E ratio) of the corresponding product.

E: ¹ H N MR (400 MHz, Chloroform-c/) δ 5.79 (dt, J = 10.8, 7.3 Hz, 1 H), 5.61 (dd, J = 10.9, 9.4 Hz, 1 H), 3.34 - 3.1 1 (m, 3H), 1 .92 - 1 .74 (m, 1 H), 1 .64 - 1 .51 (m, 1 H), 1 .37- 1 .23 (m, 8H), 0.90 (t, J = 6.7 Hz, 3H). Z: ¹ H NMR (400 MHz, Chloroform-c/) δ 5.74 - 5.67 (m, 1 H), 5.65 - 5.59 (m, 1 H), 3.32 - 3.1 1 (m, 3H), 1 .90 - 1 .74 (m, 2H), 1 1 .64 - 1 .51 (m, 1 H), 1 .40 - 1 .23 (m, 8H), 0.90 (t, J = 6.9 Hz, 3H). Example 6: Preparation of hex-3-enedioic acid

10% NiCI ₂ -dme

10% Bathophenanthroline

1.5 eq. Mn H0 ₂ C C0 ₂ H

DMA (0.5 M), C0 ₂ (1 atm)

10% TBAB 25% yield

50 °C, 16 h

An oven-dried Schlenck tube containing a stirring bar was charged with manganese (0.3 mmol), bathophenanthroline (0.02mmol, 6.6mg), NiC^-dme (0.02 mmol, 4.4 mg) and TBAB (0.02mmol, 6.4 mg). The tube was connected to a vacuum line where it was evacuated and back-filled under a CO ₂ flow at least three times.1 ,3-Butadiene (15% wt. in hexanes, 0.2 mmol, 1 10 μΙ_) and the DMA (0.4 mL) were added into the tube under CO ₂ flow. Once added, the Schlenk tube was closed under CO ₂ (1 atm) and stirred for 16 hours at 50°C. The mixture was quenched with 2 M HCI to hydrolyze the resulting

carboxylate and extracted 3 times with ethyl acetate. The combined organic phases were washed with brine and dried over MgSO ₄ and concentrated under reduce pressure. The residue was purified by flash chromatography on silica gel (hexane/EtOAc/HCOOH mixtures, typically 50/50/0.5) to deliver 7.2 mg (25% yield, 10:1 Z:E ratio) of the corresponding product.

Example 7: Alternative procedure for the carboxylation of buta-1 ,3-dien-1 - ylbenzene

(I la) (Z)-(l'a) (E)-(l'a)

General Procedure B: An oven-dried schlenk tuve containing a stirring bar was charged with the corresponding reducing agent, ligand and nickel source. The schlenk tube was then evacuated and back-filled under a CO ₂ flow (this sequence was repeated three times). Under atmospheric pressure of CO2, buta-1 ,3-dien-1 -ylbenzene (0.20 mmol) and solvent were subsequently added by syringe and the solution was warmed up to 50 °C. The mixture was then carefully quenched with 2 M HCI, and 1 equivalent of fluorene was added. The crude was extracted with EtOAc, and a sample of such solution was analyzed by ¹ H NMR. When required, the obtained carboxylation product was purified by conventional flash chromatography in silica gel using hexanes/EtOAc/HCO ₂ H 70/30/0.5. Table 7 shows the obtained results for the dicarboxylation of buta-1 ,3-dien-1 - ylbenzene in different conditions

Table 7

Yield

Entry Deviation from General Procedure B Ratio (Z)-(l'a):(E)-(l'a)

(%)

1 None 79 2.4

2 Using NiBr ₂ dme as nickel (II) salt 38 3.2

3 Using Ni(COD) ₂ as nickel (II) salt 0 -

4 Using NiBr ₂ dme + 10 mol% TBABr 70 2.2

5 Using Ni(COD) ₂ + 10 mol% TBABr 60 1 .4

Using 10 mol% NiBr ₄ (TBA) ₂ and 10

6 70 5

mol% L _2d at 25 °C

7 DMF as a solvent 30 2.3

8 NMP as a solvent 44 2.1

9 Zn as reducing means 41 2.4

10 2,2'-bipyridine instead of L _2d 8 -

6-methyl-2,2'-bipyridine instead of

1 1 46 2.5

L _2d

6,6'-dimethyl-2,2'-bipyridine instead

12 30 2.0

of L _2d

13 Phenanthroline instead of L _2d 4 -

4,7-diphenyl-1 ,10-phenanthroline

14 56 2.0

instead of L _2d

2,9-dimethyl-4,7-diphenyl-1 ,10-

15 33 3.0

phenanthroline instead of L _2d

16 PPh ₃ or PCy3 instead of L _2d 0 - 17 No Ni (II) salt, L _2d or Mn 0 -

2-methyl-phenanthroline instead of

18 50 2.1

L _2d

2-trifluoromethyl-4,7-diphenyl-1 ,10-

19 4 - phenanthroline instead of L _2d

Table 7 shows that general procedure B represents optimal conditions to carry out step (i) of the process of the invention. It also shows that, when nickel(ll) salts other than tetrabromonickelate are used, higher yields are obtained when the step (i) is further carried out in the presence of a halide source, such as tetrabutylammonium bromide (TBABr).

Example 8: Carboxylation of various butadiene compounds

50 °C, CO ₂ (1 bar)

then, TMSCHN ₂ &

B ₂ (OH) ₄ -H ₂ O

General Procedure C: Step (i) An oven-dried Schlenk tube equipped with a magnetic stirring bar was charged with Mn dust (16.5 mg, 0.3 mmol, 1 .5 equiv), L _2d (3.5 mg, 0.01 mmol, 0.05 equiv) and NiBr ₄ (TBA) ₂ (8.7 mg, 0.01 mmol, 0.05 equiv). The schlenk tube was filled with CO ₂ by applying three vacuum/CO ₂ cycles. Subsequently, the 1 ,3-diene (0.20 mmol, 1 equiv) was added by syringe followed by DMA (0.40 ml_) with a constant flow of CO ₂ . The Schlenk flask was tightly sealed and stirred at 50°C for 60 hours (unless stated otherwise) after which it was quenched by careful addition of HCI 2M. The reaction mixture was diluted with water and extracted 3 times with EtOAc. The combined organic phases were washed with brine, dried over MgSO ₄ and filtered. The solvent was then removed under vacuum. Step (ii) The residue of step (i) was dissolved in a 1 :1 MeOH:Et ₂ O mixture and cooled down to 0°C. TMSCHN ₂ (0.4 ml_ of a 2 M solution in Et ₂ O, 4 equiv) was added dropwise and after 30 minutes silica gel was added and solvent was removed under vacuum. The compound was purified by column chromatography

(hexane/EtOAc mixtures), and the product was directly reduced by mixing it with 10% Pd/C (10.6 mg, 5 mol%), B ₂ (OH) ₄ (35.8 mg, 0.4 mmol, 2 equiv) and H ₂ O (18 μΙ_, 1 mmol, 5 equiv) in dichloromethane (2 mL) and stirred at room temperature for 24 h. The solution was filtered through celite and the solvent was removed under reduced pressure to obtain the corresponding product.

Table 8 shows the results of the dicarboxylation of various butadiene compounds in the conditions described above:

Table 8

Example 9: Alternative procedure for the carboxylation of butadienes

R,

RP

50 °C, CO ₂ (1 bar)

then, H ₂ Pd/C General procedure C: step (i) An oven-dried Schlenk tube equipped with a magnetic stirring bar was charged with Mn dust (1 1 .0 mg, 0.2 mmol, 1 .0 equiv), the ligand indicated in Table 9 (0.02 mmol, 0.10 equiv) and

NiBr ₄ (TBA) ₂ (17.4 mg, 0.02 mmol, 0.10 equiv). The schlenk tube was filled with carbon dioxide by applying three cycles of vacuum/CO2. Subsequently, the 1 ,3-diene (0.40 mmol, 2 equiv) was added by syringe followed by DMA (0.40 mL) with a constant flow of CO2. The Schlenk flask was tightly sealed and stirred at 50 °C for 60 hours (unless stated otherwise) after which it was quenched by careful addition of HCI 2M. The reaction mixture was diluted with water and extracted 3 times with EtOAc.The combined organic phases were washed with brine, dried over MgSO ₄ and filtered. The solvent was then removed under vacuum and it was purified by column chromatography (hexane/EtOAc/HCOOH 75/25/0 to 50/50/0.5). Step (ii) The product was reduced by mixing it with 10% Pd/C (10.6 mg, 5 mol%) in MeOH (2 mL) under H ₂ atmosphere at room temperatura for 24 h. The solution was filtered through celite and the solvent was removed under reduced pressure to obtain the targeted product.

Table 9 shows the results of the dicarboxylation of various butadiene compounds in the conditions described above:

Table 9

PRIOR ART DISCLOSED IN THE APPLICATION

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