PROCESS FOR THE PREPARATION OF SUBSTITUTED ARYL KETONES

FIELD OF THE INVENTION

The present invention relates to a process for providing substituted aryl ketones. Furthermore, the invention relates to intermediates of said process and the use of substituted aryl ketones obtained by the inventive process for the preparation of triazole compound of formula (I).

BACKGROUND OF THE INVENTION

The aryl ketones provided by the process according to the present invention are valuable intermediate compounds for the synthesis of triazole compounds having pesticidal, in particular fungicidal activity. Triazole compounds that are accessible via aryl ketone intermediate are, for example, described in WO 2013/007767 (PCT/EP2012/063626) and WO 2014/108286 (PCT/EP2013/077083) that are directed to fungicidal substituted 2-[2-halogenoalkyl-4-phenoxy- phenyl]-1 -[1 ,2,4]triazole-yl-ethanol compounds.

WO 2015/091045 (PCT/EP2014/076839) describes a process for providing substituted phenoxy phenyl ketones from respective aryl bromides using a Grignard reagent in the presence of a copper catalyst.

The known art describes the use of stoichiometric amounts of organometallic reagents, that too frequently, in the presence of transition metal catalyst. For example, the use of a stoichiometric amount of magnesium leads to a high waste stream which requires extensive solvent recovery, waste throughput and waste treatment. Another disadvantage associated with the prior art is the use of a semi-batch process, which requires maintenance of variable temperature range at dif- ferent reaction stages and, thus, the constant monitoring of the reaction becomes necessary. Further, the processes known in the literature to prepare a compound analogous to the compound of formula V and/or Va are either disadvantageous in terms of the reaction conditions, the yields, and/or the work-up requirements or suffer from several limitations rendering them hardly suitable for industrial scale production. Substituted aryl ketones compounds, particularly compounds of formula V and/or Va can be used as versatile intermediates in the preparation of several heterocyclic derivatives. Consequently, the methods known in the art are sometimes not suitable for the efficient synthesis of substituted aryl ketones compounds, particularly compounds of formula V and/or Va. An object of the present invention was to provide an improved process for the synthesis of substituted aryl ketones that are valuable intermediates for the preparation of fungicidal active triazole compounds. The invention also relates to intermediates of said process. Furthermore, the object underlying the present invention was to optimize the synthesis of triazole compounds using said aryl ketones. The present invention includes several advantages, for example, more efficient process having minimal waste throughput and waste treatment. The presently claimed process is shown to avoid the need for carefully controlled reaction conditions, tedious multiple purification techniques, and the use of stoichiometric amounts of organometallic reagents. Description

This object is achieved by the processes described in detail hereafter.

A first aspect of the present invention relates to a process for the preparation of a compound of the general formula (I) or its salts

(I)

wherein

R ² is hydrogen, Ci-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, Cs-Cs-cycloalkyl, Cs-Cs-cycloalkyl- Ci-C6-alkyl, phenyl, phenyl-Ci-C4-alkyl, phenyl-C2-C4-alkenyl or phenyl-C2-C4-alkynyl; whereby the aliphatic moieties of R ² are unsubstituted or further substituted by 1 , 2 or 3 identical or different groups R ^12a which are independently selected from the group consist- ing of halogen, OH, CN, nitro, Ci-C4-alkoxy, Cs-Cs-cycloalkyl, Cs-Cs-halocycloalkyl, C1-C4- halogenalkoxy and phenyl moieties or R ² are unsubstituted or further substituted by 1 , 2, 3, 4 or 5 identical or different groups R ^12b which are independently selected from halogen, OH, CN, nitro, Ci-C4-alkoxy, Cs-Cs-cycloalkyl, Cs-Cs-halocycloalkyl and C1-C4- halogenalkoxy; and

R ⁴ is F or CI;

comprising at least the steps of:

(A) reacting a compound of formula (II)

(I I)

wherein

R ³ is F and X is Br, CI, I or Ci-C4-alkoxy; or

3 is CI I , SO3-CF3, SO3-C4H6-CH3, S0 ₃ -CH ₃ or Ci-C ₄ -alkoxy; or wherein R ⁴ is F or CI, and X is Br, I , SO3-CF3, SO3-C4H6-CH3, SO3-CH3 or Ci-C ₄ -alkoxy; with a compound of general formula (I II)

^° \

(Hi)

wherein

R ¹ is OR ⁵ or NR ⁶ R ⁷ , wherein R ⁵ is d-Ce-alkyl or Cs-Cs-cycloalkyl, and R ⁶ and R ⁷ identical or different, are hydrogen, Ci-C6-alkyl, Cs-Cs-cycloalkyl, or C(=0)-Ci-C6-alkyl in the presence of at least one metal, at least one base and at least one phosphine compound, to obtain a compound of general

(IV)

wherein R ⁴ is F or CI;

R ¹ is OR ⁵ or NR ⁶ R ⁷ , wherein R ⁵ is d-Ce-alkyl or C ₃ -C ₈ -cycloalkyl, and R ⁶ and R ⁷ , identical or different, are hydrogen, Ci-C6-alkyl, Cs-Cs-cycloalkyl; (B) converting a compound of general formula (IV) in the presence of at least one acid or at least one base or at least one buffer int of general formula (V) or (Va),

(V) or (Va),

wherein

in a compound of formula (V) R ³ is F or CI and

in a compound of formula (Va) R ³ is

wherein R ⁴ is F or CI.

The process of preparing compound of formula (I) further comprising the step of

(C) converting the compound of general formula (V) in the presence of at least one base into a compound of general formula (Va)

(Va)

wherein

R ⁴ is F or CI.

The process of preparing compound of formula (I) further comprising the steps of (D) converting the compound of formula (Va) in the presence of trimethylsulf(ox)onium halide ((CH3)3S ⁺ (O)Hah) (VII), wherein Hal is halogen, or in the presence of trimethylsulfonium methyl- sulfate of the formula (VIII) (CH3)3 a compound of general formula (VI),

(VI),

wherein

R ⁴ is F or CI,

(E) reacting the compound of formula (VI) with 1 H-1 ,2,4-triazole in the presence of at least one base to obtain compounds of formula (I), wherein R ² is hydrogen, and

(F) optionally reacting a compound of formula (I), wherein R ² is hydrogen, in the presence of at least one base with at least one compound of formula R ² -LG; wherein LG is a leaving group and R ² is Ci-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, Cs-Cs-cycloalkyl, C3-Cs-cycloalkyl-Ci-C6- alkyl, phenyl, phenyl-Ci-C4-alkyl, phenyl-C2-C4-alkenyl or phenyl-C2-C4-alkynyl; whereby the aliphatic moieties of R ² are unsubstituted or further substituted by 1 , 2 or 3 identical or different groups R ^12a which are independently selected from the group consisting of halogen, OH, CN, nitro, Ci-C4-alkoxy, Cs-Cs-cycloalkyl, Cs-Cs-halocycloalkyl and Ci-C4-halogenalkoxy and the cycloalkyi and phenyl moieties or R ² are unsubstituted or further substituted by 1 , 2, 3, 4 or 5 identical or different groups R ^12b which are independently selected from halogen, OH, CN, nitro, Ci-C4-alkoxy, Cs-Cs-cycloalkyl, Cs-Cs-halocycloalkyl and Ci-C4-halogenalkoxy;

to obtain a compound of general formula (I),

wherein R ² is Ci-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, Cs-Cs-cycloalkyl, C3-Cs-cycloalkyl-Ci-C6- alkyl, phenyl, phenyl-Ci-C4-alkyl, phenyl-C2-C4-alkenyl or phenyl-C2-C4-alkynyl; whereby the aliphatic moieties of R ² are unsubstituted or further substituted by 1 , 2 or 3 identical or different groups R ^12a which are independently selected from the group consisting of halogen, OH, CN, nitro, Ci-C4-alkoxy, Cs-Cs-cycloalkyl, Cs-Cs-halocycloalkyl and Ci-C4-halogenalkoxy and the cycloalkyi and phenyl moieties or R ² are unsubstituted or further substituted by 1 , 2, 3, 4 or 5 identical or different groups R ^12b which are independently selected from halogen, OH, CN, nitro, Ci-C4-alkoxy, Cs-Cs-cycloalkyl, Cs-Cs-halocycloalkyl and Ci-C4-halogenalkoxy.

Further aspect of the present invention relates to a process for the preparation of a compound of the general formula (I) or its salts according to following reaction sequence:

The R ¹ , R ² , R ³ and R ⁴ are as defined above.

Starting materials used in the process are commercially available or can be prepared by methods known in the literature.

The "present invention", "invention" or "process of the present invention" refers to one or more of the steps (A), (B), (C), (D), (E) and (F).

Salts of the compounds according to the invention can be formed in a customary manner, for example, by reacting the compound with an acid of the anion in question if the compounds according to the invention have a basic functionality or by reacting acidic compounds according to the invention with a suitable base. Salts of the compounds prepared according to the invention are preferably agriculturally and/or veterinary acceptable salts, preferably agriculturally acceptable salts.

The organic moieties or groups mentioned in the above definitions of the variables are - like the term halogen - collective terms for individual listings of the individual group members. The term "Cv-Cw" indicates the number of carbon atom possible in each case.

The term "halogen" refers to fluoro, chloro, bromo and iodo.

The term "Ci-C6-alkyl" refers to a straight-chained or branched saturated hydrocarbon group having 1 to 6 carbon atoms, for example, methyl, ethyl, propyl, 1 -methylethyl, butyl, 1 - methylpropyl, 2-methylpropyl, 1 ,1 -dimethylethyl, pentyl, 1 -methylbutyl, 2-methylbutyl, 3- methylbutyl, 2,2-dimethylpropyl, 1 -ethylpropyl, 1 ,1 -dimethylpropyl, 1 ,2-dimethylpropyl, hexyl, 1 - methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1 ,1 -dimethylbutyl, 1 ,2- dimethylbutyl, 1 ,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1 - ethylbutyl, 2-ethylbutyl, 1 ,1 ,2-trimethylpropyl, 1 ,2,2-trimethylpropyl, 1 -ethyl-1 -methylpropyl and 1 -ethyl-2-methylpropyl. Likewise, the term "Ci-Ci2-alkyl" refers to a straight-chained or branched alkyl group having 1 to 12 carbon atoms, such as ethyl, n-propyl, 1 -methylethyl, octyl, 1 - methylpropyl, 2-methylheptyl and 1 ,1 -dimethylethyl.

The term "Ci-C6-haloalkyl" refers to an alkyl group having 1 or 6 carbon atoms as defined above, wherein some or all of the hydrogen atoms in these groups may be replaced by halogen atoms as mentioned above. Examples are "Ci-C2-haloalkyl" groups such as chloromethyl, bro- momethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chloro- fluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 1 -chloroethyl, 1 -bromoethyl, 1 - fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2-fluoroethyl, 2-chloro- 2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl or pentafluoroethyl. The term "C2-C6-alkenyl" refers to a straight-chain or branched unsaturated hydrocarbon radical having 2 to 6 carbon atoms and a double bond in any position. Examples are "C2-C4-alkenyl" groups, such as ethenyl, 1 -propenyl, 2-propenyl, 1 -methylethenyl, 1 -butenyl, 2-butenyl, 3- butenyl, 1 -methyl-1 -propenyl, 2-methyl-1 -propenyl, 1 -methyl-2-propenyl, 2-methyl-2-propenyl. The term "C2-C6-alkynyl" refers to a straight-chain or branched unsaturated hydrocarbon radical having 2 to 6 carbon atoms and containing at least one triple bond. Examples are "C2-C4 al- kynyl" groups, such as ethynyl, prop-1 -ynyl, prop-2-ynyl, but-1 -ynyl, but-2-ynyl, but-3-ynyl, 1 - methyl-prop-2-ynyl .

The term "Cs-Cs-cycloalkyl" refers to monocyclic saturated hydrocarbon radicals having 3 to 8 carbon ring members, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.

The term "C3-C8-cycloalkyl-Ci-C4-alkyl" refers to alkyl having 1 to 4 carbon atoms (as defined above), wherein one hydrogen atom of the alkyl radical is replaced by a cycloalkyl radical having 3 to 8 carbon atoms (as defined above).

The term "Cs-Cs-halocycloalkyl" refers to monocyclic saturated hydrocarbon radicals having 3 to 8 carbon ring members (as defined above), wherein one hydrogen atom is replaced by halogen, such as such as halocyclopropyl, in particular 1 -fluorocyclopropyl or 1 -chlorocyclopropyl.

The term "Ci-C4-alkoxy" refers to a straight-chain or branched alkyl group having 1 to 4 carbon atoms which is bonded via an oxygen, at any position in the alkyl group. Examples are "C1-C4- alkoxy" groups, such as methoxy, ethoxy, n-propoxy, 1 -methylethoxy, butoxy, 1 -methylpropoxy, 2-methylpropoxy or 1 ,1 -dimethylethoxy.

The term "Ci-C4-haloalkoxy" refers to a Ci-C4-alkoxy radical as defined above, wherein some or all of the hydrogen atoms in these groups may be replaced by halogen atoms as mentioned above. Examples are "Ci-C4-haloalkoxy" groups, such as OCH2F, OCHF2, OCF3, OCH2CI, OCHCI2, OCCI3, chlorofluoromethoxy, dichlorofluoromethoxy, chlorodifluoromethoxy, 2- fluoroethoxy, 2-chloroethoxy, 2-bromoethoxy, 2-iodoethoxy, 2,2-difluoroethoxy, 2,2,2- trifluoroethoxy, 2-chloro-2-fluoroethoxy, 2-chloro-2,2-difluoroethoxy, 2,2-dichloro-2-fluoroethoxy, 2,2,2-trichloroethoxy, OC2F5, 2-fluoropropoxy, 3-fluoropropoxy, 2,2-difluoropropoxy, 2- chloropropoxy, 3-chloropropoxy, 2,3-dichloropropoxy, 2-bromo ^« propoxy, 3-bromopropoxy, 3,3,3- trifluoropropoxy, 3,3,3-trichloropropoxy, OCH2-C2F5, OCF2-C2F5, 1 -fluoromethyl-2-fluoroethoxy, 1 -chloromethyl-2-chloroethoxy, 1 -bromomethyl-2-bromoethoxy, 4-fluorobutoxy, 4-chlorobutoxy, 4-bromobutoxy or nonafluorobutoxy.

The term "phenyl-Ci-C4-alkyl" refers to alkyl having 1 to 6 carbon atoms (as defined above), wherein one hydrogen atom of the alkyl radical is replaced by a phenyl radical. Likewise, the terms "phenyl-C2-C4-alkenyl" and "phenyl-C2-C4-alkynyl" refer to alkenyl and alkynyl, respectively, wherein one hydrogen atom of the aforementioned radicals is replaced by a phenyl radical. The term "C ₅ -Ci4-aryl" refers to represents Cs-C-u-aryl radicals, for example phenyl or naphthyl. The term "C ₅ -Ci2-heteroaryl" means an aryl group where at least one carbon atom on the hydrocarbon chain normally carrying 5 to 12 carbon atoms is substituted by another atom selected from N, O, or S, for example, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazinyl, thienyl, furanyl, pyrrolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, triazolyl, thiadiazolyl, oxadiazolyl, and tetrazolyl rings, and the fused bicyclic moieties formed by fusing one of these monocyclic groups with a phenyl ring or with any of the heteroaromatic monocyclic groups to form a Cs-do bicyclic group such as indolyl, benzimidazolyl, indazolyl, benzotriazolyl, isoquino- linyl, quinolinyl, benzothiazolyl, benzofuranyl, benzothienyl, benzisoxazolyl, pyrazolopyridyl, quinazolinyl, quinoxalinyl, cinnolinyl, and the like. Any monocyclic or fused ring bicyclic system which has the characteristics of aromaticity in terms of electron distribution throughout the ring system is included in this definition.

The term "Cs-Cs-cycloalkenyl" refers to monocyclic unsaturated hydrocarbon radical having 3 to 8 carbon ring members and a double bond in any position, for example cyclobutenyl, cyclopen- tenyl, cyclohexenyl or cyclooctenyl.

The term "C ₅ -Ci2-membered heterocycloalkyl" refers to saturated 5 to 12 membered, hydrocarbon cycle having one free valence wherein one or more of the carbon atoms of the saturated cycle is replaced, independently from each other, by a heteroatom selected from N, S, O and P. For examples C3-C6-membered heterocycloalkyl are cyclopropyl, oxiranyl, cyclopentyl, pyrrol- idyl, cyclohexyl, piperidyl and morpholinyl.

The term "C ₅ -Ci4-membered heterocycloalkenyl" refers to monovalent or bivalent nonaromatic 5 to 8 membered monocyclic, 8 to 12 membered bicyclic, or 1 1 to 14 membered tricyclic ring sys- tern having one or more heteroatoms, such as O, N, S, P or Se and one or more double bonds. The term "buffer" refers to that resists change in pH and contains either a weak acid and a soluble ionic salt of the acid or a weak base and a soluble ionic salt of the base.

The term "substituted" if not specified otherwise refers to substituted with 1 , 2 or maximum possible number of substituents. If substituents are more than one, then they are independently from each other are same or different, if not mentioned other-wise.

Meaning of the terms that are not defined herein are generally known to a person skilled in the art or in the literature.

Preferred embodiments of the present invention are described below.

Step (A) of the present invention for the preparation of formula I is particularly as follows.

(A) Reacting a compound of formula (II

(II)

wherein

R ³ is F and X is Br, CI, I or Ci-C4-alkoxy; or

R ³ is CI and X is Br, I , SO3-CF3, SO3-C4H6-CH3, S0 ₃ -CH ₃ or Ci-C ₄ -alkoxy; or wherein R ⁴ is F or CI, and X is Br, I , SO3-CF3,

SO3-C4H6-CH3, SO3-CH3 or Ci-C ₄ -alkoxy;

with a compound of general formula (I II)

(H i)

wherein

R is OR ⁵ or NR ⁶ R ⁷ , wherein R ⁵ is d-Ce-alkyl or C ₃ -C ₈ -cycloalkyl, and R ⁶ and R ⁷ are, identical or different, are hydrogen, Ci-C6-alkyl, Cs-Cs-cycloalkyl, or C(=0)-Ci-C ₆ -alkyl

in the presence of at least one metal, at least one base and at least one phosphine compound, to obtain a compound of general formu

(IV)

wherein

R ³ is F, CI or Y°^ wherein R ⁴ is F or CI;

R ¹ is OR ⁵ or NR ⁶ R ⁷ , wherein R ⁵ is d-Ce-alkyl or C ₃ -C ₈ -cycloalkyl, and R ⁶ and R ⁷ , identical or different, are hydrogen, Ci-C6-alkyl, Cs-Cs-cycloalkyl.

In one embodiment of the invention, R ¹ is OR ⁵ or NR ⁶ R ⁷ , wherein R ⁵ is Ci-C6-alkyl or C3-C8- cycloalkyl, and R ⁶ and R ⁷ are, identical or different, are hydrogen, Ci-C6-alkyl, Cs-Cs-cycloalkyl, or C(=0)-Ci-C ₆ -alkyl.

In another embodiment, R ¹ is OR ⁵ wherein R ⁵ is Ci-C4-alkyl or Cs-Cs-cycloalkyl.

In another embodiment, R ⁵ is ethyl, n-propyl, iso-butyl or n-butyl.

In another embodiment, R ⁵ is n-butyl or iso-butyl.

In another embodiment, R ¹ is NR ⁶ R ⁷ wherein R ⁶ and R ⁷ are, identical or different, are hydrogen, d-Ce-alkyl, Cs-Cs-cycloalkyl, or C(=0)-Ci-C ₆ -alkyl.

In one embodiment of the invention, R ² is hydrogen, Ci-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3-Cs-cycloalkyl, C3-Cs-cycloalkyl-Ci-C6-alkyl, phenyl, phenyl-Ci-C4-alkyl, phenyl-C2-C4-alkenyl or phenyl-C2-C4-alkynyl; whereby the aliphatic moieties of R ² are unsubstituted or further substi- tuted by 1 , 2 or 3 identical or different groups R ^12a which are independently selected from the group consisting of halogen, OH, CN, nitro, Ci-C4-alkoxy, Cs-Cs-cycloalkyl, Cs-Cs-halocycloalkyl, Ci-C4-halogenalkoxy and phenyl moieties or R ² are unsubstituted or further substituted by 1 , 2, 3, 4 or 5 identical or different groups R ^12b which are independently selected from halogen, OH, CN, nitro, Ci-C4-alkoxy, Cs-Cs-cycloalkyl, Cs-Cs-halocycloalkyl and Ci-C4-halogenalkoxy.

In another embodiment, R ² is hydrogen, Ci-C6-alkyl, Cs-Cs-cycloalkyl, allyl, propargyl or benzyl. In another preferred embodiment, R ² is hydrogen, methyl, ethyl, n-propyl, n-butyl or benzyl. In yet another preferred embodim hydrogen.

In one embodiment R ³ is F, CI or

In another preferred embodiment R ³ is F or CI, more preferably R ³ is F.

In one embodiment in step (A), X is Br, CI, I, SO3-CF3, SO3-C4H6-CH3, S0 ₃ -CH ₃ or Ci-C ₄ -alkoxy. In yet another embodiment X is Br, CI, I, SO3-CF3, SOs^He-CHs or SO3-CH3.

In more preferred embodiment R ³ is F or CI and X is Ci-C4-alkoxy.

In another preferred embodiment R ³ is F and X is Br, CI, I, SO3-CF3, SO3-C4H6-CH3, S0 ₃ -CH ₃ or Ci-C ₄ -alkoxy. In another preferred embodiment R ³ is F and X is CI.

In yet another preferred embodiment R ³ is

and X is Br, CI, I, SO3-CF3, SO3-C4H6-CH3, S0 ₃ -CH ₃ or Ci-C ₄ -alkoxy.

In more preferred embodiment R ³ is F and X is Br.

In one embodiment R ⁴ is F or CI.

In preferred embodiment R ⁴ is CI.

The temperatures and the duration times of the reactions may be varied in broad ranges, which the person skilled in the art knows from analogous reactions. The temperatures often depend on the reflux temperature of the solvents or at higher temperature under pressure. Other reactions are preferably performed at room temperature, for example, at about 25°C, or under ice cooling, for example, at about 0°C. The end of the reaction can be monitored by methods known to a person skilled in the art, for example, thin layer chromatography or HPLC or GC. In an embodiment, the volume ratio of reactants to solvent is in the range of 1 :40 to 1 :0.

In another embodiment, the volume ratio of reactants to solvent is in the range of 1 :40 to 1 :5. If not otherwise indicated, the reactants can in principle be contacted with one another in any desired sequence.

The person skilled in the art knows when the reactants or reagents are moisture sensitive, so that the reaction should be carried out under inert gases such as under a nitrogen atmosphere, and dried solvents should be used.

The person skilled in the art also knows the best work-up of the reaction mixture after the end of the reaction.

In the present invention, step (A) takes place in the presence of at least one metal, at least one base and at least one phosphine compound and optionally at least one solvent, wherein the at least one metal is preferably in a form of a free state of formula M or in a form of a metal complex of formula M(L) _n .

In the present invention, step (A) takes preferably place in the presence of at least one metal, at least one base, at least one phosphine compound and at least one solvent, wherein the at least one metal is preferably in a form of a free state of formula M or in a form of a metal complex of formula M(L) _n .

In the following, preferred embodiments regarding step (A) of the invention are provided. It is to be understood that the preferred embodiments mentioned above and those still to be illustrated below of step (A) of the invention are to be understood as preferred alone or in combination with each other.

In one embodiment, the at least one metal (M) is selected from the group consisting of nickel (Ni), cobalt (Co), iron (Fe), ruthenium (Ru), rhodium (Rh), palladium (Pd), iridium (Ir), platinum (Pt), silver (Ag), copper (Cu), zinc (Zn), molybdenum (Mo) and tungsten (W).

In preferred embodiment, at least one metal (M) selected from the group consisting of palladi- urn (Pd), nickel (Ni), copper (Cu) and iron (Fe).

In one embodiment L, identical or different, is CI, Br, I, P(C5-Ci ₄ -aryl) _m , P(C5-Ci2-heteroaryl) _m , P(C5-Ci2-heteroaryl)m(C ₅ -Ci4-aryl)3-m, CN, d-C ₆ -alkyl, Ci-C ₆ -alkyl-0-Ci-C ₆ -alkyl, -0-CO-Ci-C ₆ - alkyl, OH, nitro, -0-Ci-C6-alkyl, Ci-C ₄ -haloalkoxy, Cs-Cs-cycloalkyl, Cs-Cs-halocycloalkyl, C3-C8- cycloalkenyl, Cs-C-u-aryl, C5-Ci4-aryl-(CH2)o-(Q)p-(CH2)o-C5-Ci4-aryl and 1 ,1 '- b/s(diphenyl phos- phino)ferrocene ; whereby Q represents a bridging group selected from the group consisting of - CR ⁸ R ⁹ , -0-, -S-, -NR ¹⁰ R ¹¹ , -SiR ¹² R ¹³ and -CO-, wherein R ⁸ and R ⁹ , identical or different, are hydrogen, C1-C12 alkyl, Cs-C-u-aryl or C5-Ci2-heteroaryl; wherein R ¹⁰ , R ¹¹ , R ¹² and R ¹³ , identical or different, are hydrogen or C1-C4 alkyl or R ¹⁰ together with R ¹¹ forms Cs-Ci2-membered heterocy- cloalkyl, Cs-Ci2-membered heterocycloalkenyl or Cs-Ci2-membered heteroaryl and L is unsubstituted or further substituted by 1 , 2, 3, 4 or 5 identical or different groups selected from the group consisting of CI; F; Br; I; CN; -N0 ₂ ; -NR ¹⁰ R ¹¹ , -P(phenyl) ₂ , -OH, unsubstituted or substituted Ci-Ci2-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, unsubstituted or substituted Cs-C-u-aryl, unsubstituted or substituted C5-Ci2-heteroaryl, Cs-Ci2-membered heterocycloalkyl, C5-C12- membered heterocycloalkenyl, -0-(CH ₂ ) _r -0-, -C(=0)R ¹⁴ -C(=0)-0-R ¹⁵ -C=N-R ¹⁶ , -SO3H, -O-C1- C6-alkyl and -0-Si-Ci-C4-alkyl; wherein

R ¹⁴ is hydrogen or Ci-C4-alkyl;

R ¹⁵ is hydrogen or Ci-C4-alkyl;

R ¹⁶ is hydrogen, Ci-Ci2-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, Cs-C-u-aryl, Cs-Ci2-heteroaryl or C3-Ci2-cycloalkyl;

n is 0,1 ,2,3,4,5 or 6

m is 1 ,2 or 3;

o is 0,1 or 2

p is 0,1 or 2 and

r is 1 ,2,3,4 or 5.

In yet another embodiment, L is, identical or different, CI, Br, I, P(C5-Ci4-aryl) _m , CN, unsubstituted or substituted Ci-Ci2-alkyl, Ci-C4-alkoxy, Cs-Cs-cycloalkenyl, -0-CO-Ci-C6-alkyl, Cs-C-u-aryl, 1 ,1 '- b/s(diphenyl phosphino)ferrocene and C5-Ci4-aryl-(CH2)o-(Q)p-(CH2)o-C5-Ci4-aryl;

wherein

m is 1 ,2 or 3;

o is 0,1 or 2

p is 0,1 or 2

In more preferred embodiment L is CI, -OCOCH3, P(Phenyl)3, P(o-tolyl)3, CN, dibenzylidene acetone, -CH3CN, 1 ,5-cyclooctadiene or 1 ,1 '- b/s(diphenyl phosphino) ferrocene.

In another embodiment Ln is supported on silica gel, dendrimers, polystyrenes or mesoporous siliceous foam, for example as described in Vivek et. al., Tetrahedron, 63, 2007, 6949-6976. In another embodiment R ⁸ is hydrogen, C1-C12 alkyl, Cs-C-u-aryl or C5-Ci2-heteroaryl.

In another embodiment R ⁸ is hydrogen, methyl or ethyl.

In another embodiment R ⁹ is hydrogen, C1-C12 alkyl, Cs-C-u-aryl or C5-Ci2-heteroaryl.

In more preferred embodiment R ⁹ is hydrogen.

In another embodiment R ¹⁰ is hydrogen, methyl, ethyl, propyl or n-butyl.

In another embodiment R ¹¹ is hydrogen, methyl, ethyl, propyl or butyl.

In another embodiment R ¹² is hydrogen, methyl, ethyl, propyl or butyl.

In another embodiment R ¹³ is hydrogen, methyl, ethyl, propyl or butyl.

In another preferred embodiment R ¹³ is hydrogen, methyl or ethyl.

In yet another embodiment R ¹⁰ together with R ¹¹ forms Cs-Ci2-membered heterocycloalkyl, C5-

Ci2-membered heterocycloalkenyl or Cs-Ci2-membered heteroaryl.

In another embodiment R ¹⁴ is hydrogen or Ci-C4-alkyl.

In yet another embodiment R ¹⁴ is hydrogen, methyl, ethyl, propyl or butyl. In another embodiment R ¹⁵ is hydrogen, methyl, ethyl, propyl or butyl.

In another embodiment R ¹⁶ is hydrogen, Ci-Ci2-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, Cs-C-u-aryl, C5-Ci2-heteroaryl or C3-Ci2-cycloalkyl.

In another embodiment n is 0,1 ,2,3,4,5 or 6.

In yet another preferred embodiment n is 0,1 or 2.

In yet another preferred embodiment n is 3,4,5 or 6.

In more preferred embodiment n is 2, 3 or 4.

In another embodiment m is 1 ,2 or 3.

In another embodiment o is 0,1 or 2

In another embodiment p is 0,1 or 2 and

In another embodiment r is 1 ,2,3,4 or 5.

In more preferred embodiment, M, L and n are as follows in Table 1 :

Table 1

The amount of at least one M and/or MLn is in the range of 1 :0.0001 to 1 :0.07 equivalent, in particular less than 0.05 equivalent, more preferably 1 :0.005 to 1 :0.0005 equivalent per 1 equivalent of the compound of formula (II).

In one embodiment the phosphine compound is PX1X2X3 or (PXiX2)2(B) _q , whereby Χι , X2 and X ₃ , identical or different, are F, CI, Br, I, -NR ¹⁷ R ¹⁸ , hydrogen, -O-d-Ce-alkyl, -0-CO-Ci-C ₆ -alkyl, Ci-Ci2-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, Cs-C-u-aryl, Cs-Ci2-heteroaryl, C3-Ci2-cycloalkyl, C3- Ci2-cycloalkenyl, C3-Ci2-heterocycloalkyl, C3-Ci2-heterocycloalkenyl or -Si-(Ci-Ci2-alkyl)3, whereby B is CR ¹⁹ R ²⁰ , -0-, -phenyl-O-phenyl-, -S-, -NR ¹⁷ R ¹⁸ , -SiR ²¹ R ²² or -C(=0)-, wherein R ¹⁹ and R ²⁰ , identical or different, are hydrogen, Ci-Ci2-alkyl, Cs-C-u-aryl or Cs-Ci2-heteroaryl, wherein R ¹⁷ , R ¹⁸ , R ²¹ and R ²² , identical or different, are hydrogen or Ci-C4-alkyl or R ¹⁷ together with R ¹⁸ forms heterocycloalkyl, heterocycloalkenyl or Cs-Ci2-heteroaryl; whereby Xi , X2 and X3 , identical or different, are unsubstituted or substituted by 1 , 2, 3, 4 or 5 identical or different groups selected from the group consisting of CI; F; Br; I; CN; -NO2; -NR ¹⁷ R ¹⁸ , -P(phenyl)2, -OH, unsubstituted or substituted Ci-Ci2-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, unsubstituted or substi- tuted C ₅ -Ci4-aryl, unsubstituted or substituted C ₅ -Ci ₂ -heteroaryl, -0-(CH ₂ ) _r -0-, -C(=0)R ²³ , - C(=0)-0-R ²⁴ , -C=N-R ²⁵ , -SO3H, -O-Ci-Ce-alkyl and -0-Si-Ci-C ₄ -alkyl, C ₅ -Ci ₂ -membered heterocycloalkyl, C5-Ci2-membered heterocycloalkenyl and C5-Ci2-heteroaryl;

wherein q is 1 ,2,3,4,5 or 6;

r is 1 ,2,3,4 or 5; R ²³ is hydrogen or Ci-C4-alkyl;

R ²⁴ is hydrogen or Ci-C4-alkyl; and

R ²⁵ is hydrogen, Ci-Ci2-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, Cs-C-u-aryl, C5-Ci2-heteroaryl or C3- Ci2-cycloalkyl;

or their acceptable salts thereof.

In another embodiment Χι, X2 and X3, identical or different, are Ci-Ci2-alkyl, Cs-C-u-aryl or C5- Ci2-heteroaryl.

In more preferred embodiment Xi, X2 and X3, identical or different, are methyl, ethyl, propyl, 1 - methylethyl, butyl, 1 -methylpropyl, 2-methylpropyl, 1 ,1 -dimethylethyl, pentyl, 1 -methylbutyl, 2- methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1 -ethylpropyl, 1 ,1 -dimethylpropyl, 1 ,2- dimethylpropyl, hexyl, 1 -methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1 ,1 - dimethylbutyl, 1 ,2-dimethylbutyl, 1 ,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3- dimethylbutyl, 1 -ethylbutyl, 2-ethylbutyl, 1 ,1 ,2-trimethylpropyl, 1 ,2,2-trimethylpropyl, 1 -ethyl-1 - methylpropyl and 1 -ethyl-2-methylpropyl, n-octyl, 1 -methylpropyl, 2-methylheptyl or 1 ,1 - dimethylethyl.

In yet another preferred embodiment Xi, X2 and X3, identical or different, are phenyl or naphthyl. in yet another preferred embodiment Xi, X2 and X3, identical or different, are pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazinyl, thienyl, furanyl, pyrrolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, triazolyl, thiadiazolyl, oxadiazolyl, and tetrazolyl rings, and the fused bicy- die moieties formed by fusing one of these monocyclic groups with a phenyl ring or with any of the heteroaromatic monocyclic groups to form a Cs-C-io bicyclic group such as indolyl, benzim- idazolyl, indazolyl, benzotriazolyl, isoquinolinyl, quinolinyl, benzothiazolyl, benzofuranyl, ben- zothienyl, benzisoxazolyl, pyrazolopyridyl, quinazolinyl, quinoxalinyl or cinnolinyl.

In another embodiment R ¹⁷ is hydrogen or C1-C4 alkyl.

In another embodiment R ¹⁷ is hydrogen, methyl, ethyl, propyl or butyl.

In another embodiment R ¹⁸ is hydrogen, methyl, ethyl, propyl or butyl.

In another preferred embodiment R ¹⁸ is hydrogen.

In yet another embodiment R ¹⁷ together with R ¹⁸ forms Cs-Ci2-membered heterocycloalkyl, C5-

Ci4-membered heterocycloalkenyl or C5-Ci2-heteroaryl.

In another embodiment R ¹⁹ is hydrogen, Ci-Ci2-alkyl, Cs-C-u-aryl or C5-Ci2-heteroaryl.

In yet another embodiment R ¹⁹ is hydrogen, methyl ethyl, propyl, phenyl or naphthyl.

In another embodiment R ²⁰ is hydrogen, Ci-Ci2-alkyl, Cs-C-u-aryl or C5-Ci2-heteroaryl.

In yet another embodiment R ²⁰ is hydrogen, methyl ethyl, propyl or butyl.

In another embodiment R ²¹ is hydrogen or C1-C4 alkyl.

In another preferred embodiment R ²¹ is hydrogen.

In another embodiment R ²² is hydrogen, methyl, ethyl, propyl or butyl.

In yet another embodiment R ²² is hydrogen, methyl or ethyl.

In another embodiment R ²³ is hydrogen or Ci-C4-alkyl.

In another preferred embodiment R ²³ is hydrogen, methyl, ethyl, propyl or butyl

In another embodiment R ²⁴ is hydrogen methyl, ethyl, propyl or butyl.

In another embodiment, at least one phosphine compound is allyldiphenylphosphine; 1 ,3- b/s(diphenylphosphino)propane; di-fe/£butyl(phenyl)phosphine tetrafluoroborate; (2- ammonioethyl) di-fe/7-butylphosphonium b/s(tetrafluoroborate); (2-ammonioethyl) diiso- propylphosphonium b/s(tetrafluoroborate); (3-ammoniopropyl) di-fe/7-butylphosphonium b/s(tetrafluoroborate); (3-ammoniopropyl) diisopropylphosphonium b/s(tetrafluoroborate);

b/_^3,5-b/_^trifluoromethyl)phenyl)(2^6'-b^^

benzyldiphenylphosphine; (2-biphenyl)di-1 -adamantylphosphine; 1 -[2-[bis(tert- butyl)phosphino]phenyl]-3,5-diphenyl-1 H-pyrazole; b/s[2-(diadamantylphosphino)ethyl]amine; 2-

butylphosphinomethyl)pyridine; b/s(dicyclohexylphosphinophenyl)ether;

b/s(diethylamino)phenylphosphine; b/s(dimethylamino)chlorophosphine; 2-[b/s(3,5- dimethylphenyl)phosphino]benzaldehyde; b/s[4-(3,3,4,4,5,5,5-heptafluoro-2,2- b/s(trifluoromethyl)pentyl)phenyl]phenylphosphine; b/s(2-methoxyphenyl)phosphine; b/s[4- (1 Η,Ι H,2H,2H-perfluorodecyl)phenyl]phenylphosphine; 1 ,1 '-b/s(phenylphosphinidene)ferrocene; (2-bromophenyl)dicyclohexylphosphine; (2-bromophenyl)diphenylphosphine; tert- butyldicyclohexylphosphine; te/f-butyldicyclohexylphosphonium tetrafluoroborate; tert- butyldiisopropylphosphine; fe/7-butyldiphenylphosphine; 1 -(dicyclohexylphosphino)-2,2- Diphenyl-1 -methylcyclopropane; cyclohexyldiphenylphosphine; di(1 -adamantyl)-2- dimethylaminophenylphosphine; di-1 -adamantylphosphine; di(1 -adamantyl)-(2- triisopropylsiloxyphenyl)phosphine; (5H-dibenzo[a,d]cyclohepten-5-yl)diphenylphosphine; di- fe/7-butylcyclohexylphosphine; di-fe/7-butyl Ν,Ν-diisopropylphosphoramidite; 6\-tert- butylmethylphosphine; di-te/f-butyl(methyl)phosphonium tetrafluoroborate; 6\-tert- butyl(methyl)phosphonium tetrafluoroborate; di-fe/7-butylneopentylphosphine; 6\-tert- butylneopentylphosphonium tetrafluoroborate; di-fe/7-butylphenylphosphine; 6\-tert- butylphosphate potassium salt; 2'-(di-fe/?-butylphosphino)acetophenone ethylene ketal; 2-(di- te/f-butylphosphino)dimethylaminobenzene; 2-(di-fe/7-butylphosphino)ethylamine; 2-{{6\-tert- butylphosphinomethyl)-6-diethylaminomethyl)pyridine; 5-(di-te/f-butylphosphino)-1 -(naphthalen- 1 -yl)-1 H-pyrazole; 5-(di-fe/£butylphosphino)-1 ', 3', 5'-triphenyl-1 'H-[1 ,4']bipyrazole; 3-(di-fe/£ butylphosphonium)propane sulfonate; Ρ,Ρ-dichloroferrocenylphosphine; dicyclohexyl-(2,6- diisopropylphenyl)phosphine; dicyclohexyl(4-(N,N-dimethylamino)phenyl)phosphine; dicyclo- hexyl(ethyl)phosphine; dicyclohexyl(4-isopropylphenyl)phosphine; dicyclohexyl(2- methylphenyl)phosphine; dicyclohexylphenylphosphine; 2'-

(dicyclohexylphosphino)acetophenone ethylene ketal; 2-(dicyclohexylphosphino)benzophenone; 2-(dicyclohexylphosphino)-N,N-diisopropyl-1 H-indole-1 -carboxamide; N -(dicyclohexyl phos- phino)-2-(2'-methoxyphenyl)indole; 2-[(dicyclohexylphosphino)methyl]-1 ,3-b/s(2,6- diisopropylphenyl)-4,5-dimethylimidazolium iodide; 2-(2-dicyclohexylphosphinophenyl)-1 ,3- dioxolane; 2-[2-(dicyclohexylphosphino)phenyl]-N-methylindole; dicyclohexyl(2,4,6- trimethylphenyl)phosphine; diethylphenylphosphine; diethylphosphine; 4-(diethylphosphino)- Ν,Ν-dimethylaniline; 9-[2-(diisopropylphosphino)phenyl]-9H-carbazole; 2-[di(2- methoxyphenyl)phosphino]benzenesulfonic acid; dimethylaminophenylchlorophosphine; 4- (dimethylamino)phenyldiphenylphosphine; 2-(1 ,1 -dimethylpropyl)-6- (diphenylphosphino)pyridine; diphenyl(2-methoxyphenyl)phosphine; 4- diphenylphosphanylbenzoic acid; 2-(diphenylphosphino)benzaldehyde; 2- (diphenylphosphino)benzaldehyde oxime; 3-(diphenylphosphino)benzenesulfonic acid sodium salt; 2-(diphenylphosphino)benzoic acid; 4-(diphenylphosphino)benzoic acid; N-[2- (diphenylphosphino)benzylidene] cyclohexylamine; 2-(diphenylphosphino)-N,N- dimethylbenzylamine; 2-(diphenylphosphino)ethanaminium tetrafluoroborate; 2- (diphenylphosphino)ethylamine; 2-(2-(diphenylphosphino)ethyl)pyridine; 3- (diphenylphosphino)propan-l -aminium tetrafluoroborate; 3-(diphenylphosphino)-1 -propylamine; 4-(diphenylphosphino) styrene; 2-(diphenylphosphino)-N,N,N-trimethylbenzylammonium tri- flate;diphenyl-2-pyridylphosphine; diphenyl(o-tolyl)phosphine; diphenyl(p-tolyl)phosphine; di- phenylvinylphosphine; 2-(di-p-tolylphosphino)benzaldehyde; ethyldiphenylphosphine; [4- (3, 3,4,4,5, 5,6,6,7, 7,8,8,9, 9, 10, 10, 10-heptadecafluorodecyl)phenyl] diphenylphosphine; (4- hydroxyphenyl)diphenylphosphine; isopropyldiphenylphosphine; 1 -methyl-2-(2- dicyclohexylphosphinophenyl)-1 H-benzoimidazole; 1 -methyl-2-(2-diisopropylphosphinophenyl)- 1 H-benzoimidazole; methyldiphenylphosphine; 1 -methyl-2-(2-diphenylphosphinophenyl)-1 H- benzoimidazole; 1 ,2,3,4,5-pentaphenyl-1 '-(di-te/f-butylphosphino)ferrocene; phenylb/s[4- (3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctyl)phenyl]phosphi ne; phenyldi(o-tolyl)phosphine; phe- nylphosphine; 4,4'-(phenylphosphinidene)b/s(benzenesulfonic acid) dipotassium salt hydrate; tetrapropylphosphonium bromide; triallylphosphine; tribenzylphosphine; tributylphosphine; tri-n- butylphosphine; tri-fe/7-butylphosphine; tri-fe/7-butylphosphine; tri-fe/7-butylphosphine; tributylphosphine tetrafluoroborate; tri-fe/7-butylphosphonium tetrafluoroborate; tricyclohex- ylphosphine; tricyclohexylphosphine; tricyclohexylphosphine; tricyclohexylphosphine tetrafluoroborate; tricyclopentylphosphine; tricyclopentylphosphine tetrafluoroborate; tri- ethylphosphine; triethylphosphine; ((4-trifluoromethyl)phenyl)di-te/f-butylphosphine, tri(2- furyl)phosphine; ((2,4,6-tri-isopropyl)phenyl)di-cyclohexylphosphine; triisopropylphosphine; triisopropylphosphonium tetrafluoroborate; trimethylphosphine; trimethylphosphonium tetra- fluoroborate; tri-1 -naphthylphosphine; trioctylphosphine; triphenylphosphine; triphenylphosphine hydrobromide; 4-(triphenylphosphonio)butane-1 -sulfonate; tripropylphosphine; tris[3,5- b/s(trifluoromethyl)phenyl]phosphine; tris(4-chlorophenyl)phosphine;

tris(diethylamino)phosphine; tris(2,6-dimethoxyphenyl)phosphine;

tris(dimethylamino)phosphine; tris(3,5-dimethylphenyl)phosphine; tris(2,4-dimethyl-5- sulfanatophenyl)phosphine trisodium salt; tris[2-(diphenylphosphino)ethyl]phosphine; tris(4- fluorophenyl)phosphine; tris[4-(heptadecafluorooctyl)phenyl]phosphine;

tris(hydroxymethyl)phosphine; tris(4-methoxy-3,5-dimethylphenyl)phosphine; tris(o- methoxyphenyl)phosphine; tris(4-methoxyphenyl)phosphine; tris(4-methyl-1 - piperazinyl)phosphine; tris(pentafluorophenyl)phosphine; tris(1 -pyrrolidinyl)phosphine; tris[4- (tridecafluorohexyl)phenyl]phosphine; tris[4-(3,3,4,4,5,5,6,6,7,7,8,8,8- tridecafluorooctyl)phenyl]phosphine; tris(4-trifluoromethylphenyl)phosphine; tris(2,4,6- trimethoxyphenyl)phosphine; tris(2,4,6-trimethylphenyl)phosphine; tris(trimethylsilyl)phosphine; tri(o-tolyl)phosphine; tri(p-tolyl)phosphine; tri-o-tolylphosphine tetrafluoroborate; and 2- (dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl- 1 ,1 '-biphenyl or acceptable salts thereof.

The amount of at least one phosphine compound is in the range of 1 :0.001 to 1 :0.25 equivalent, in particular in the range of 1 :0.001 to 1 :0.1 equivalent per 1 equivalent of the compound of formula (II).

In an embodiment, reaction temperature of the step (A) is kept within a range of from 40°C to 150°C, preferably in the range of from 50°C to 130°C, more preferably in the range of from 55°C to 120°C. Generally, it is also preferred to have a reaction temperature of at least 70 °C, in particular at least 95°C. In a further embodiment, the temperature is at least 90°C to 140°C.

In present invention, the at least one solvent of step (A) is alcohol, ether, amide or aromatic solvent. In one embodiment, solvent of step (A) is 2-methylbutan-2-ol, benzyl alcohol, 1 ,4-butanediol, 1 ,2,4-butanetriol, 2-butanol, 1 -butanol, 2-methylpropan-1 -ol, 2-methylpropan-2-ol, methanol, 2- (2-methoxyethoxy)ethanol, 2-methyl-1 -butanol, 2-methyl-1 -pentanol, 3-methyl-2-butanol, diethy- lene glycol, ethanol, ethylene glycol, 2-ethylhexanol, furfuryl alcohol, glycerol, propan-2-ol, neo- pentyl alcohol, 1 -pentanol, 2-pentanol, 1 ,3-propanediol, 1 -propanol, propylene glycol, butyl ether, diethyl ether, diethylene glycol diethyl ether, diglyme, diisopropyl ether, dimethoxye- thane, dimethoxymethane, 1 ,4-dioxane, dimethylacetamide, dimethylformamide, formamide, N- methyl-2-pyrrolidone, N-methylformamide, 2-pyrrolidone, N-vinylacetamide, N-vinylpyrrolidone, toluene, xylene or mono-chlorobenzene.

In more preferred embodiment the solvent is 1 -butanol, 2-methylpropan-2-ol, 2-methylpropan-1 - ol, 2-methylbutan-2-ol, 1 -propanol, propan-2-ol or 1 -pentanol, even more preferably 1 -butanol or 2-methylpropan-1 -ol.

In an embodiment, the volume ratio of the compound of formula II to solvent is in the range of 1 :30 to 1 :0.

Step (B) for the preparation of compounds of formula V and/or Va particularly is as follows:

(B) Converting a compound of general formula (IV) in the presence of at least one acid or at least one base or at least one b ound of general formula (V) or (Va),

(V) or (Va),

wherein

in a compound of formula (V) R ³ is F or CI and in a compound of formula (Va) R ³ is

wherein R ⁴ is F or CI.

In the present invention the at least one acid of step (B) is organic acid or inorganic acid.

In one embodiment, the at least one organic acid of step (B) is oxalic acid, formic acid, malonic acid, acetic acid, citric acid, propionic acid or butyric acid.

In another embodiment, the at least one inorganic acid of step (B) is phosphoric acid, sulphuric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid or nitric acid, more preferable hydrochloric acid.

The amount of at least one acid is in the range of 1 :0.01 to 1 :50 equivalent, in particular in the range of 1 :0.1 to 1 :20 equivalent per 1 equivalent of the compound of formula (II).

In the present invention the at least one buffer of step (B) is sodium acetate.

In present invention at least one base of step (A) and/or step (B) is an organic base and/or inorganic base.

In one embodiment an organic base is N(R ²⁶ )3, N-methyl piperidine, N-methyl pyrrolidine, N- methyl morpholine, piperidine, dimethyl amino pyridine, pyridine, lithium hexamethyldisilazide, sodium hexamethyldisilazide and tetra-Ci-C6-alkyl ammonium hydroxide, wherein R ²⁶ is, identical or different, hydrogen, Ci-C6-alkyl, Cs-C-u-aryl, or C3-C6-cycloalkyl.

In another embodiment an inorganic base is alkali metal hydroxide, alkaline earth hydroxide, alkali metal bicarbonate, alkaline earth bicarbonate, alkali metal carbonate, alkaline earth car- bonate, alkali metal phosphate, alkali metal alkoxide or alkaline earth alkoxide.

In more preferred embodiment an inorganic base is lithium hydroxide, sodium hydroxide, potassium hydroxide, rubidium hydroxide, cesium hydroxide magnesium hydroxide, calcium hydroxide, strontium hydroxide, barium hydroxide, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, rubidium bicarbonate, cesium bicarbonate, magnesium bicarbonate, calcium bi- carbonate, strontium bicarbonate, barium bicarbonate, lithium carbonate, sodium carbonate, potassium carbonate, rubidium carbonate, cesium carbonate, magnesium carbonate, calcium carbonate, strontium carbonate, barium carbonate, monosodium phosphate, disodium phosphate, trisodium phosphate, monopotassium phosphate, dipotassium phosphate, tripotassium phosphate, NaOR ²⁷ , KOR ²⁷ , RbOR ²⁷ , CsOR ²⁷ , Mg(OR ²⁷ ) ₂ , Ca(OR ²⁷ ) ₂ and Ba(OR ²⁷ ) ₂ ; whereby R ²⁷ is, identical or different, Ci-C4-alkyl.

In yet another preferred embodiment an inorganic base is sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, monosodium phosphate, disodium phosphate, trisodium phosphate, monopotassium phosphate, dipotassium phosphate, tripotassium phosphate, NaOR ²⁷ and KOR ²⁷ ' whereby R ²⁷ is, identical or different, Ci-C4-alkyl.

The amount of at least one base used in step (A) and/or step (B) is preferably equal to or less than 5 equivalent, in particular less than 4 equivalent, more preferably equal to or more than 0.8 equivalent, even more preferably equal to or more than 1 equivalents per 1 equivalent of the compound of formula (II). Preferably, at least 1 equivalent, more preferably at least 1 .2 equivalent, more specifically at least 1 .4 equivalent base per 1 equivalent of the compound of formula (II) is used.

In an embodiment, reaction temperature of the step (B) is kept within a range of from -30°C to 1 10°C, preferably in the range of from 5°C to 100°C, more preferably in the range of from 20°C to 70°C. Generally, it is also preferred to have a reaction temperature of at least 20 °C, in particular at least room temperature, in particular at least 25°C. In a further embodiment, the tem- perature is at least 30°C. It may be preferred if the temperature is at least 35°C.

Step (C) for the preparation of compound of formula Va particularly is as follows:

In the present invention the compound of general formula (V) is converted into a compound of general formula (Va) in the presence of at least one base.

(Va)

wherein

R ⁴ is F or CI.

Step (D) for the preparation of compound of formula VI particularly is as follows: In the present invention the compound of formula (Va) is converted into a compound of general formula (VI) in the presence of trimethylsulf(ox)onium halide ((CH3)3S ⁺ (O)Hah) (VII) or in the presence of trimethylsulfonium methylsulfate of the formula (VIII) (CH3)3S ⁺ CH3SO4 ^" ,

(VI),

wherein

R ⁴ is F or CI,

Hal is halogen.

In this process step using trimethylsulfonium methylsulfate of the formula VIII, preferably, 1 to 4 equivalents, in particular 1 .2 to 3.5 eq, more specifically 1 .5 to 3.3 eq, of water in relation to one equivalent of compound of formula II are used. It may be favorable, if more than 1 .5 eq of water, in particular more than 1.5 eq of water to 4 eq of water, more specifically more than 1.5 eq to 3.5 eq of water, even more particularly more than 1 .5 eq water to 2.5 eq water per mole of compound of formula II are used. In particular the ratios of 1.6 to 3.8, more specifically 1 .7 to 3.3 eq, more specifically 1.8 to 2.8 eq or 1.9 to 2.5 of water per mole of compound of formula II may be favorable according to the present invention.

In general, the reagent of formula VIII can be prepared from dimethylsulfide and dimethylsulfate. According to one embodiment, reagent VIII is prepared in-situ by adding dimethylsulfate to the reaction mixture containing dimethylsulfide. The dimethylsulfide is usually used in excess.

Steps (E) and (F) for the preparation of compound of formula I particularly is as follows:

(E) In the present invention the compound of formula (VI) is reacted with 1 H-1 ,2,4-triazole in the presence of at least one base to obtain compounds of formula (I) wherein R ² is hydrogen, and

(F) optionally reacting a compound of formula (I), wherein R ² is hydrogen, in the presence of at least one base with at least one compound of formula R ² -LG; wherein LG is a leaving group and R ² is Ci-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, Cs-Cs-cycloalkyl, C3-Cs-cycloalkyl-Ci-C6- alkyl, phenyl, phenyl-Ci-C4-alkyl, phenyl-C2-C4-alkenyl or phenyl-C2-C4-alkynyl; whereby the aliphatic moieties of R ² are unsubstituted or further substituted by 1 , 2 or 3 identical or different groups R ^12a which are independently selected from the group consisting of halogen, OH, CN, nitro, Ci-C4-alkoxy, Cs-Cs-cycloalkyl, Cs-Cs-halocycloalkyl and Ci-C4-halogenalkoxy and the cycloalkyl and phenyl moieties or R ² are unsubstituted or further substituted by 1 , 2, 3, 4 or 5 identical or different groups R ^12b which are independently selected from halogen, OH, CN, nitro, Ci-C4-alkoxy, Cs-Cs-cycloalkyl, Cs-Cs-halocycloalkyl and Ci-C4-halogenalkoxy;

to obtain a compound of general formula (I),

wherein R ² is Ci-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, Cs-Cs-cycloalkyl, C3-Cs-cycloalkyl-Ci-C6- alkyl, phenyl, phenyl-Ci-C4-alkyl, phenyl-C2-C4-alkenyl or phenyl-C2-C4-alkynyl; whereby the aliphatic moieties of R ² are unsubstituted or further substituted by 1 , 2 or 3 identical or different groups R ^12a which are independently selected from the group consisting of halogen, OH, CN, nitro, Ci-C4-alkoxy, Cs-Cs-cycloalkyl, Cs-Cs-halocycloalkyl and Ci-C4-halogenalkoxy and the cycloalkyl and phenyl moieties or R ² are unsubstituted or further substituted by 1 , 2, 3, 4 or 5 identical or different groups R ^12b which are independently selected from halogen, OH, CN, nitro, Ci-C4-alkoxy, Cs-Cs-cycloalkyl, Cs-Cs-halocycloalkyl and Ci-C4-halogenalkoxy.

preferably in aqueous solution in the presence of a base.

Reacting the oxirane of the formula (VI) with 1 H-1 ,2,4-triazole and a base, resulting in com- pounds of formula (I), wherein R ² is hydrogen,

and, for obtaining compounds wherein R ² is different from hydrogen, derivatizing the compound of formula (I) under basic conditions with R ² -LG, wherein LG is a nucleophilically replaceable leaving group as defined above.

In the present invention at least two steps of step (A) to (F) are carried out in a single pot.

In preferred embodiment the steps (A) and (B) are carried out in a single pot.

In one embodiment at least one compound from compounds of formulae (IV), (V), (Va) and (VI) is not isolated.

In preferred embodiment at least one compound from compounds of formulae (IV), (V) and (Va) is not isolated.

A second aspect of the present invention relates to a compound of formula (IVa)

(IVa)

wherein

Z is Ci-C ₆ alkyl.

In one embodiment Z is selected from methyl, ethyl, propyl, 1 -methylethyl, n-butyl, 1 - methylpropyl, 2-methylpropyl, 1 ,1 -dimethylethyl, pentyl, 1 -methylbutyl, 2-methylbutyl, 3- methylbutyl, 2,2-dimethylpropyl, 1 -ethylpropyl, 1 ,1-dimethylpropyl, 1 ,2-dimethylpropyl, hexyl, 1 - methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1 ,1 -dimethylbutyl, 1 ,2- dimethylbutyl, 1 ,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1 - ethylbutyl, 2-ethylbutyl, 1 ,1 ,2-trimethylpropyl, 1 ,2,2-trimethylpropyl, 1 -ethyl-1 -methylpropyl and 1 -ethyl-2-methylpropyl.

In preferred embodiment Z is n-butyl or 2-methylpropyl.

EXAMPLES

The characterization can be done by coupled High Performance Liquid Chromatography / mass spectrometry (HPLC/MS), Gas chromatography (GC), by NMR or by their melting points.

HPLC method 1 : Waters Xbridge C18, 150mmx4.6mm IDx5um

Gradient A= Water, B= Acetonitrile.

Flow= 1 .4 ml/min., column oven temperature= 30 °C

Gradient program= 10% B - 100% B - 5min, hold for 2min, 3min - 10% B.

Run Time = 10 min HPLC method 2: Agilent Eclipse C18, 150mmx4.6mm IDx5um

Gradient A= 0.1 % TFA in Water, B= 0.1 % TFA in Acetonitrile.

Flow= 1 .4 ml/min., column oven temperature= 30 °C

Gradient program= 10% B - 100% B - 5min, hold for 2min, 3min - 10% B.

Run Time = 10 min

LCMS method: Agilent Eclipse C18, 150mmx4.6mm IDx5um

Gradient A= 0.05% ammonia in Water, B= 0.05% ammonia in Methanol

Flow= 1 .2 ml/min., column oven temperature= 30° C

Gradient program= 10 % B to 100 % B in 1.5 min., hold for 1 min 100 % B, 2 min - 10 % B Run time: 4.5 min

GCMS method: RTX-5 MS, 30mx0.25mmx0.25um

Carrier gas= Helium; Ion source temperature= 230 °C; Interface temperature= 280 °C

Gradient program= 50 °C hold for 1 min, 35 °C/min to 300 °C, hold for 3 min at 300 °C

Run time: 1 1.2 min;

1H-NMR: The signals are characterized by chemical shift (ppm) vs. tetramethylsilane, by their multiplicity and by their integral (relative number of hydrogen atoms given). The following abbreviations are used to characterize the multiplicity of the signals: m = multiplet, q = quartet, t = triplet, d = doublet and s = singlet.

Abbreviations used are: h for hour(s), min for minute(s), rt for retention time and ambient tem- perature for 20-25°C.

General Procedure:

With due modification of the starting compounds, the compound of formula V or Va can be prepared by procedures as given in below schemes.

Step (A)

A stirred solution of substituted trifluoromethyl benzene (1 eq.) in a solvent such as n-butanol, iso-butanol, n-propanol, iso-propanol (3 to 15 volume of formula II) was degassed at temperature range of 55°C to 120°C. To the stirred solution was added a base (0.8 to 5 equivalent of formula II), vinyl ether, metal (1 :0.001 to 1 :0.07 equivalent of formula II) and phosphine compound (0 to 0.25 equivalent of formula II). The reaction was again degassed and subsequently heated to 70°C - 100°C. The reaction mixture was stirred for 10-18 hours at 100°C. After the completion of the reaction, the temperature of the reaction mixture was bought to 25°C and the mixture was filtered through celite bed. The celite bed was washed with solvent such as n- butanol and filtrate was concentrated to obtain the desired coupled product. tep (B)

The coupled product and acid such as aqueous hydrochloric acid were stirred together at 25°C for 0.5-2 hours. After the completion of the reaction, the organic phase was separated from aqueous phase, washed with water and distilled under reduced pressure to obtain the desired product.

Example 1 : Preparation of 1 -[4-fluoro-2-(trifluoromethyl)phenyl]ethenone

1 a: Preparation of 1 -(1 -butoxyvinyl)-4-fluoro-2-(trifluoromethyl)benzene

A 500ml_-three-necked flask equipped with a Teflon-blade stirrer, reflux condenser and thermo pocket was charged with 1 -bromo-4-fluoro-2-(trifluoromethyl)benzene (40 g) and n-butanol (120 ml_). The resulting mixture was degassed with nitrogen at 25°C for 30 minutes. To the stirred solution was added potassium carbonate (27.2 g), n-butyl vinyl ether (53.4 ml_), palladium acetate (18.4 mg) and di-tert-butyl(phenyl)phosphine tetrafluoroborate (51 mg). The reaction mix- ture was again degassed with nitrogen for 15 minutes while stirring and heated to 100°C. The reaction mixture was stirred for 12-18 hours at 100°C. After the completion of the reaction, the temperature of the reaction mixture was bought to 25°C and the mixture was filtered through celite bed. The celite bed was washed with n-butanol (100 ml.) and filtrate was concentrated to obtain 1 -(1 -butoxyvinyl)-4-fluoro-2-(trifluoromethyl)benzene [m/z = 263 amu (M+H ⁺ )].

Vo: A 500ml_-three-necked flask equipped with magnetic bar and thermo pocket was charged with 1 -(1 -butoxyvinyl)-4-fluoro-2-(trifluoromethyl)benzene (55 g) and 6 M aq. hydrochloric acid (120 ml.) at 25°C. The reaction mixture was stirred for 1 hour. The two phases were separated and the organic phase was washed with water. The organic phase was separated and product was distilled under reduced pressure using 12 cm long glass column to obtain 1 -[4-fluoro-2- (trifluoromethyl)phenyl]ethenone.

Yield (%): 76 [m/z = 207 amu (M+H ⁺ )]; H NMR (300 MHz, CDCI ₃ ): 2.51 (s, 3H), 7.19-7.26 (m, 1 H), 7.33-7.37 (m, 1 H), 7.43-7.48 (m, 1 H).

Example 2: Preparation of 1 -[4-fluoro-2-(trifluoromethyl)phenyl]ethenone

A 50ml_-three-necked flask equipped with a Teflon-blade stirrer, reflux condenser and thermo pocket was charged with 1 -bromo-4-fluoro-2-(trifluoromethyl)benzene (2 g) and n-butanol (6 ml_), potassium carbonate (1 .36 g) and n-butyl vinyl ether (2.67 ml.) at 25°C. The resulting mixture was degassed with nitrogen at 25°C for 30 minutes followed by palladium acetate (5.5 mg) and 2-(dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-tri-/so-pro pyl-1 ,1 '-biphenyl (26.5 mg). The reaction mixture was again degassed with nitrogen for 15 minutes while stirring and heated to 100°C. The reaction mixture was stirred for 16-18 hours at 100°C. After the completion of the reaction, the temperature of the reaction mixture was bought to 25°C and the mixture was filtered through celite bed. The celite bed was washed with n-butanol (6 ml.) and filtrate was transferred to a 50ml_-three-necked flask equipped with magnetic bar and thermo pocket and 6 M aq. hydrochloric acid (6 ml.) was added at 25°C. The reaction mixture was stirred for 1 hour. The reaction mixture was extracted with methyl-fe/7-butyl ether (6 mL). The two phases were separated and the organic phase was washed with water. The organic phase was separated and product was distilled under reduced pressure to obtain 1 -[4-fluoro-2- (trifluoromethyl)phenyl]ethenone.

Yield (%): 88 [m/z = 207 amu {U+W)\

Examples 3-8: The following examples in Table 2 further illustrate the process for the preparation of compound of formula V (steps A and B) of the present invention and do not restrict the invention in any manner.

Table 2

Example 9: Process for the preparation of 1 -[4-(4-chlorophenoxy)-2- (trifluoromethyl)phenyl]ethenone

9a: The 1 -[4-fluoro-2-(trifluoromethyl)phenyl]ethenone was prepared by following any of the aforementioned examples.

9b: A 50ml-three-necked flask equipped with a Teflon-blade stirrer, reflux condenser, and a thermos-pocket was charged with dimethyl formamide (4 mL), 1 -[4-fluoro-2- (trifluoromethyl)phenyl]ethenone (1 .0 g, 1.0 eq.), 4- chlorophenol (0.62 g, 1.0 eq) and potassium carbonate (1 .0 g, 1.0 eq). The resulting reaction mixture was stirred at 1 10 °C for 2 h and reac- tion was monitored by HPLC. The reaction was quenched with water (2 mL) and extracted with methyl-fe/7-butyl ether (5 mL x 3). The combined organic layer was dried with sodium sulphate and concentrated to afford the title compound.

Yield (%) = 85