WO2012120070A1

WO2012120070A1 - Method for preparation of 3-(2,3-dimethylphenyl)-2-butenal

Info

Publication number: WO2012120070A1
Application number: PCT/EP2012/053974
Authority: WO
Inventors: Florencio Zaragoza Doerwald; Stephan Elzner; Jeroen Dekker; Govert VERSPUI; Ron DIRKS
Original assignee: Lonza Ltd
Priority date: 2011-03-10
Filing date: 2012-03-08
Publication date: 2012-09-13
Also published as: TW201238603A

Abstract

The invention discloses the aldehyde 3-(2,3-dimethylphenyl)-2-butenal, a method for its preparation from 1-bromo-2,3-dimethylbenzene and crotonaldehyde, and its use in perfumes.

Description

Method for preparation of 3-(2,3-Dimethylphenyl)-2-butenal

The invention discloses the aldehyde 3-(2,3-dimethylphenyl)-2-butenal, a method for its preparation from l-bromo-2,3-dimethylbenzene and crotonaldehyde, and its use in perfumes.

Aromatic aldehydes are widely used as flavors and fragrances in cosmetics, perfumes, and numerous household products. Alpha, beta-unsaturated aromatic aldehydes, such as substituted cinnamic aldehydes, are known to have distinct fragrance and are therefore used in the perfume industry

WO 98/45237 A discloses certain aromatic aldehydes, a method for producing them starting from acetophenone acetals, their use as perfumes and their use as intermediates for the preparation of 3-arylpropanals. They have a musky fragrance. Littke et al. in J. Am. Chem. Soc. 2001, 123, 6989-7000 disclose inter alia the reaction of aryl bromides with alpha,beta-unsaturated esters in the presence of Pd/P(t-Bu)3/Cy₂ Me.

Aldehydes as substrates are not mentioned in the disclosure.

WO 03/048107 A discloses the reaction of halogen aromates with olefins in the presence of a palladium catalyst, a sterically demanding nitrogen base and a dipolar aprotic solvent. The only exemplified olefin is acrylamide.

Stadler et al. in Synlett 2008, 4, 597-599 disclose the reaction of aryl bromide with crotonaldehyde in MP as solvent in the presence of one mol equivalent of

tetrabutylammonium chloride, 2 mol% of Pd(OAc)₂ and a molar excess of NaOAc. 2- bromotoluene as aryl bromide provides 46% yield; 2,2'-Me₂C₆H₃ as substrate provides no yield.

The perfume and household product industry has a constant need for new perfumes with interesting, new and not yet available fragrances in order to increase the available choice of fragrances and to adapt the fragrances to the ever changing demand of fashion. Furthermore the respective substances need to be synthesized economically and with consistent quality. High purity and strong fragrances are desired. The present invention provides the alpha, beta- unsaturated aromatic aldehyde 3-(2,3-dimethylphenyl)-2-butenal, which has strong and interesting, aldehydic fragrance, intensely spicy and sweet, and an improved process for the production thereof.

Further there was a need for a process for preparation of 3-(2,3-dimethylphenyl)-2-butenal which provides high yields, reduces purification efforts and makes an efficient preparation possible.

In the following text,

halogen means F, CI, Br or I, preferably CI, Br or I;

"alkyl" means linear, branched or cyclic alkyl; if not otherwise stated. Examples of "alkyl" include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, adamantyl, and the like;

"cyclo alkyl" is intended to include a cyclo aliphatic, bicyclo aliphatic and tricycle aliphatic residue;

Ac means acetyl; DIPEA means N-ethyl-N,N-diisopropylamine; DABCO means 1,4- diazabicyclo[2.2.2]octane; tBu means tertiary butyl; DMF means N,N-dimethylformamide; MP means N-methyl-2-pyrrolidone, l-methyl-2-pyrrolidone or N-methyl-2-pyrrolidinone; DMA means Ν,Ν-dimethylacetamide; TUF means tetrahydrofuran; and dba means 1,5- diphenylpenta-l,4-dien-3-one: hexanes means mixture of isomeric hexanes; if not otherwise stated.

The terms "palladium source" and "Pd source" are used synonymously.

Subject of the invention is a method (A) for the preparation of a compound of formula (I),

wherein in formula (I) the double bond marked with (a) has either (Z) or (E) configuration; method (a) comprises a reaction (A) of a compound of formula (II) with crotonaldehyde in the presence of a palladium source (Aa) and a base (Ab);

Rl is selected from the group consisting of CI, Br, I, O-SO₂-CF₃, O-SO₂-C₆H₄-CH₃ and 0-S0₂-Ph; wherein

palladium source (Aa) is selected from the group consisting of Pd(0) on a support, Pd(0) complex and Pd(II) complex; base (Ab) is selected from the group consisting of N(R2)(R3)R4, 1,4-diazabicyclo [2.2.2] octane, a carboxylate, carbonate, hydrogen carbonate, phosphate,

monohydrogenphosphate or dihydrogenphosphate salt of Na or of K, and mixtures thereof;

R2, R3 and R4 are identical of different and independently from each other selected from the group consisting of H, C_1-15 alkyl, C5-6 cycloalkyl and phenyl.

Preferably Rl is selected from the group consisting of CI, Br and I, more preferably Rl is CI or Br, even more preferably Rl is Br. If Pd(0) on a support is used as a palladium source (Aa), the support is preferably BaS0₄ or charcoal.

Preferably the palladium source (Aa) is selected from the group consisting of PdCl₂,

Pd(OAc)₂, Pd(dba)₂, Pd₂(dba)₃, PdCl₂(PhCN)₂, PdCl₂(MeCN)₂, PdCl₂(PPh₃)₂, Pd(P(tBu)₃)₂, Pd₂(P(tBu)₃)₃, Pd(P(l-adamantyl)₃)₂, Pd₂(P(l-adamantyl)₃)₃, Pd(PPh₃)₄ and Pd on charcoal;

more preferably from the group consisting of PdCl₂, Pd(OAc)₂, Pd(dba)₂, Pd₂(dba)₃,

PdCl₂(PhCN)₂, PdCl₂(MeCN)₂, PdCl₂(PPh₃)₂, Pd(P(tBu)₃)₂, Pd(P(l-adamantyl)₃)₂ and Pd(PPh₃)₄;

even more preferably from the group consisting of Pd(OAc)₂, Pd(dba)₂, Pd₂(dba)₃,

Pd(P(tBu)₃)₂, Pd(P(l-adamantyl)₃)₂ and PdCl₂(MeCN)₂;

especially the palladium source (Aa) is Pd(OAc)₂, Pd₂(dba)₃ and Pd(P(tBu)₃)₂. Preferably, the base (Ab) is selected from the group consisting of N(R2)(R3)R4, 1,4- diazabicyclo [2.2.2] octane, a C_1-10 carboxylate, carbonate, hydrogen carbonate, phosphate, monohydrogenphosphate or dihydrogenphosphate salt of Na or of K, and mixtures thereof;

more preferably, the base (Ab) is selected from the group consisting of N-ethyl-N,N- diisopropylamine, Et₃, diazabicyclo [2.2.2] octane, N,N-dimethylaniline, dicyclohexylmethylamine, dicyclohexylamine, diisopropylamine, NaOAc, Na₂C0₃, NaHC0₃, KOAc, K₂C0₃ and K₃P0₄;

even more preferably from the group consisting of N-ethyl-N,N-diisopropylamine, Et₃,

Ν,Ν-dimethylaniline, dicyclohexylmethylamine, NaOAc, Na₂C0₃, NaHC0₃, KOAc, K₂C0₃ and K₃P0₄;

especially from the group consisting of NaOAc, N-ethyl-N,N-diisopropylamine and NEt₃; in particular the base (Ab) is NaOAc or N-ethyl-N,N-diisopropylamine.

In one embodiment, reaction (A) is done or carried out without the addition of a ligand (Ac) or an ammonium salt (Ae).

In another embodiment, reaction (A) is done or carried out in the presence of a ligand (Ac).

Ligand (Ac) is added to the reaction mixture, so that the reaction mixture comprises the palladium source (Aa), the base (Ab) and the ligand (Ac). Ligand (Ac), palladium source (Aa) and base (Ab) can be added in any sequence.

The ligand (Ac) is P(R5)(R6)R7;

R5, R6 and R7 are identical or different and independently from each other selected from the group consisting of

Ci-15 alkyl;

phenyl, biphenyl and naphthyl, the phenyl, biphenyl and naphthyl being unsubstituted or substituted by 1, 2, 3 or 4 identical or different substituents independently from each other selected from the group consisting of halogen, CMO alkyl, Ci_-4 alkoxy, cyano and nitro;

ferrocenyl;

di(tert-butyl)phosphino substituted ferrocenyl;

heteroaryl, the heteroaryl being a 5 or 6-membered aromatic carbon ring with one or two endocyclic heteroatoms selected from the group consisting of O, S and N, the ring being unsubstituted or substituted with 1, 2 or 3 identical or different substituents independently from each selected from the group consisting of halogen, C_1-10 alkyl, C_1-4 alkoxy, cyano and nitro;

Ci-15 alkoxy;

O-phenyl, O-biphenyl, O-naphthyl, the O-phenyl, O-biphenyl and O-naphthyl being unsubstituted or substituted by 1, 2, 3 or 4 identical or different substituents independently from each other selected from the group consisting of halogen, Ci-io alkyl, C_{1 -4} alkoxy, cyano and nitro; and

O-heteroaiyl, the heteroaryl being a 5 or 6-membered aromatic carbon ring with one or two endocyclic heteroatoms selected from the group consisting of O, S and N, the ring being unsubstituted or substituted with 1, 2 or 3 identical or different substituents independently from each selected from the group consisting of halogen, C_1-10 alkyl, C_1-4 alkoxy, cyano and nitro. Preferably the ligand (Ac) is selected from the group consisting of PBu₃, P(o-tolyl)₃, PPh₃, P(l-adamantyl)₃, P(Bu)(l-adamantyl)₂, tris(2,4-di-(tert-butyl)phenyl)phosphite, P(tBu)₂(2-biphenylyl), P(tBu)₃, tri(cyclohexyl)phosphine, triphenylphosphite, tri(l- naphthyl)phosphine and 1, l'-bis(di(tert-butyl)phosphino)ferrocene;

more preferably from the group consisting of P(o-tolyl)₃, P(l-adamantyl)₃, P(Bu)(l- adamantyl)₂, P(tBu)₂(2-biphenylyl), P(tBu)₃, tri(cyclohexyl)phosphine and tri(l- naphthyl)phosphine;

even more preferably from the group consisting of P(o-tolyl)₃, P(l-adamantyl)₃, P(Bu)(l- adamantyl)₂, P(tBu)₃ and P(tBu)₂(2-biphenylyl);

especially the ligand (Ac) is P(tBu)₃.

In another embodiment, reaction (A) is done or carried out in the presence of an ammonium salt (Ae). Ammonium salt (Ae) is added to the reaction mixture, so that the reaction mixture comprises the palladium source (Aa), the base (Ab) and the ammonium salt (Ae). Ammonium salt (Ae), palladium source (Aa) and base (Ab) can be added in any sequence.

The ammonium salt (Ae) is N(R10)(R1 1)(R12)R13)⁺X

R10, Rl 1, R12 and R13 are identical or different and independently from each other selected from the group consisting of

Ci-15 alkyl; phenyl, biphenyl and naphthyl, the phenyl, biphenyl and naphthyl being unsubstituted or substituted by 1, 2, 3 or 4 identical or different substituents independently from each other selected from the group consisting of halogen, C_1-10 alkyl, C_1-4 alkoxy, cyano and nitro;

Ci-io alkylene aryl, the aryl of the C_1-10 alkylene aryl being phenyl, biphenyl or

naphthyl, the phenyl, biphenyl and naphthyl being unsubstituted or substituted by 1, 2, 3 or 4 identical or different substituents independently from each other selected from the group consisting of halogen, C_1-10 alkyl, C_1-4 alkoxy, cyano and nitro;

X is selected from the group consisting of F, CI, Br, phosphate, hydrogenphosphate,

dihydrogenphosphate, C_1-10 carboxylate, sulfate and hydrogen sulfate; preferably, X is selected from the group consisting of CI, Br, hydrogenphosphate, acetate and hydrogen sulfate.

Preferably,

Ci-12 alkyl;

phenyl, the phenyl being unsubstituted or substituted by 1 or 2 identical or different substituents independently from each other selected from the group consisting of F, CI, Br, Ci.4 alkyl, Ci_-4 alkoxy;

benzyl;

More preferably, the ammonium salt (Ae) is selected from the group consisting of Bu₄N⁺X ^~, MeN(Bu)₃ ⁺X , dodecyl-N(Me)₃ ⁺X benzylN(Bu)₃ ⁺X benzylN(Me)3⁺X^~ and Me4N⁺X ^~; and with X being selected from the group consisting of CI, Br,

hydrogenphosphate, acetate and hydrogen sulfate;

even more preferably from the group consisting of Bu₄N⁺X ^~, MeN(Bu)₃ ⁺X , dodecyl-

N(Me)₃ ⁺X benzylN(Bu)₃ ⁺X^~ and benzylN(Me)3⁺X and with X being CI;

in particular the ammonium salt (Ae) Bu₄N⁺Cr. Both a ligand (Ac) and an ammonium salt (Ae) can be present in reaction (A).

In one embodiment, reaction (A) is done or carried out without a solvent (Ad).

In another embodiment, reaction (A) is done or carried out in a solvent (Ad).

The solvent (Ad) is selected from the group consisting of DMF, MP, DMA,

N-methylacetamide, acetonitrile, propionitrile, ethyl acetate, butyl acetate, THF, methyl-THF, dioxane, toluene, xylene and mixtures thereof. Preferably the solvent (Ad) is selected from the group consisting of DMF, NMP, DMA, N- methylacetamide, acetonitrile and propionitrile;

more preferably from the group consisting of DMF, NMP and DMA;

especially the solvent (Ad) is DMF or NMP. In one particular embodiment (PE1),

the palladium source (Aa) is Pd₂(dba)₃, the base (Ab) is N-ethyl-N,N-diisopropylamine and the ligand (Ac) is P(tBu)₃.

In another particular embodiment (PE2), the palladium source (Aa) is Pd(P(t-Bu)₃)₂ and the base (Ab) is N-ethyl-N,N-diisopropylamine; preferably in this embodiment, no ligand (Ac) is used.

In another particular embodiment (PE3), the palladium source (Aa) is Pd(OAc)₂, the base (Ab) is NaOAc and the ammonium salt (Ae) is Bu₄N⁺Cr.

Preferably, the solvent (Ad) in embodiments (PE1), (PE2) and (PE3) is DMF or NMP.

More preferably, the solvent (Ad) in embodiments (PE1) and (PE2) is DMF; and the solvent (Ad) in embodiment (PE3) is NMP.

Usually reaction (A) provides a mixture of (E) and (Z) stereoisomers of compound of formula (I). These two stereoisomers can be separated by conventional procedures known in organic chemistry.

Preferably, the reaction temperature of reaction (A) is from 0 to 200 °C, more preferably from 10 to 150 °C, even more preferably from 20 to 130 °C. Preferably, the reaction (A) is done at a pressure of from atmospheric pressure to 10 bar, more preferably of from atmospheric pressure to 5 bar, even more preferably of from atmospheric pressure to 4 bar. Preferably, the progress of the reaction is monitored by standard techniques, such as nuclear magnetic resonance spectroscopy ( MR), infrared spectroscopy (IR), high performance liquid chromatography (HPLC), liquid chromatography mass spectrometry (LCMS), or thin layer chromatography (TLC), and work-up of the reaction mixture can start, when the conversion of the starting material exceeds 95%, or when no more starting material can be detected. The time required for this to occur will depend on the precise reaction temperature and the precise concentrations of all reagents and catalysts, and will vary from batch to batch.

Preferably, the reaction time of reaction (A) is from 30 min to 48 h, more preferably from 1 h to 36 h, even more preferably from 2 h to 24 h.

Preferably, the molar amount of crotonaldehyde is from 0.5 to 10 fold, more preferably from 1 to 5 fold, and even more preferably from 1 to 3 fold, of the molar amount of compound of formula (II). Preferably, the amount of palladium source (Aa) is from 0.01 mol% to 10 mol%, more preferably from 0.1 mol% to 5 mol%, even more preferably from 0.3 mol% to 3 mol%, especially from 0.3 mol% to 1.2 mol%, the mol% based on the molar amount of compound of formula (II). Preferably, the molar amount of base (Ab) is from 0.5 to 5 fold, more preferably from 1 to 3 fold, even more preferably from 1 to 2 fold, of the molar amount of compound of formula (II).

Preferably, if ligand (Ac) is present in the reaction (A), the molar amount of ligand (Ac) is from 0.1 to 7 fold, more preferably from 0.5 to 5 fold, even more preferably from 1 to 4 fold, especially even more preferably from 1 to 2.1 fold, of the molar amount of palladium source (Aa). Preferably, if ammonium salt (Ae) is present in the reaction (A), the molar amount of ammonium salt (Ae) is from 0.01 to 5 fold, more preferably from 0.05 to 2 fold, even more preferably from 0.1 to 1.1 fold, of the molar amount of compound of formula (II). Preferably, the amount of solvent (Ad) is from 0.5 to 50 fold, more preferably from 2 to 40 fold, even more preferably from 5 to 35 fold, of the weight of compound of formula (II).

In another particular embodiment (PE10),

the molar amount of crotonaldehyde is from 1 to 3 fold, of the molar amount of compound of formula (II); and

the amount of palladium source (Aa) is from 0.3 mol% to 3 mol%, preferably from 0.3 mol% to 1.2 mol%, the mol% based on the molar amount of compound of formula (II); and the molar amount of base (Ab) is from 1 to 2 fold, of the molar amount of compound of formula (II); and

the molar amount of ligand (Ac) is from 1 to 4 fold, preferably from 1 to 2.1 fold, of the molar amount of palladium source (Aa).

In another particular embodiment (PE20),

the amount of palladium source (Aa) is from 0.3 mol% to 3 mol%, preferably from 0.3 mol% to 1.2 mol%, the mol% based on the molar amount of compound of formula (II); and the molar amount of base (Ab) is from 1 to 2 fold, of the molar amount of compound of formula (II).

In another particular embodiment (PE30),

the molar amount of ammonium salt (Ae) is from 0.05 to 2 fold, preferably from 0.1 to 1.1 fold, of the molar amount of compound of formula (II). Preferably, the amount of solvent (Ad) is in the embodiments (PE10), (PE20) and (PE30) from 5 to 35 fold of the weight of compound of formula (II). In one more particular embodiment (PEl-10),

embodiment (PE1) is combined with embodiment (PE10).

In another more particular embodiment (PE2-20),

embodiment (PE2) is combined with embodiment (PE20).

In another more particular embodiment (PE3-30),

embodiment (PE3) is combined with embodiment (PE30).

Even more particular, the solvent (Ad) in embodiments (PEl-10), (PE2-20) and (PE3-30) is DMF or MP.

Especially particular, the solvent (Ad) in embodiments (PEl-10) and (PE2-20) is DMF; and solvent (Ad) in embodiment (PE3-30) is NMP.

In a further embodiment, the crotonaldehyde is dosed during the reaction at a rate similar to its consumption, preferably at such a rate, that stationary amount of crotonaldehyde during the reaction is at least 5 mol% but does not exceed 50 mol%, of the initial molar amount of compound of formula (II).

The stationary amount of crotonaldehyde in the reaction mixture is monitored during the reaction by standard techniques, preferably it is monitored online or by taking samples by infrared spectroscopy (IR), gas chromatography (GC) or nuclear magnetic resonance spectroscopy (NMR).

In a further embodiment, when a ligand (Ac) is used, the palladium source (Aa) and the ligand (Ac) are premixed in a small amount of solvent (Ad), preferably in 0.001 weight-% to 20 weight-%, more preferably in 0.01 weight-% to 5 weight-%, of solvent (Ad), the weight-%) are based on the total weight of solvent (Ad) to be used. Preferably, this premixture is stirred for 1 to 60 min at a temperature of from 0 °C to 100 °C, preferably of from 20 °C to 100 °C, and then the premixture is added to a mixture comprising the compound of formula (II) and solvent (Ad).

Preferably, the reaction (A) is done under inert atmosphere. After the reaction (A), the compound of formula (I) is can be isolated from the reaction mixture resulting from reaction (A) by standard methods known to the skilled person such as evaporation of volatile components from the reaction mixture, dilution of the reaction mixture with water, acidification, extraction, washing, drying, concentration, crystallization, distillation and any combination thereof.

Preferably, acidification is done by the addition of an acid (A-acidify), preferably of an aqueous solution of the acid (A-acidify).

Preferably, acid (A-acidify) is selected from the group consisting hydrochloric acid and sulfuric acid.

Acid (A-acidify) is an acid commonly used in the isolation of organic reaction products from a reaction mixture,

Preferably, the acid (A-acidify) is added in such an amount, that the pH of the resulting mixture is from 0 to 7, more preferably from 1 to 4, even more preferably from 2 to 4.

The palladium source (Aa) can optionally be recovered by adding to the reaction mixture after reaction (A) an insoluble substance, which binds palladium, such as charcoal or BaS0₄, or a commercial scavenger for noble metals, which are known to the skilled person, and filtering said insoluble substance, loaded with the palladium source (Aa), off.

Preferably, the volatile components of the reaction mixture are removed by evaporation under reduced pressure. Any extraction of an aqueous is preferably done with a solvent (A-extr), solvent (A-extr) is selected from the group consisting of toluene, benzene, dichloromethane, chloroform, acetic acid Ci-8 alkyl ester and mixtures thereof.

Preferable, the acetic acid C_1-8 alkyl ester is an acetic acid C_1-4 alkyl ester, more preferably ethyl acetate, isopropyl acetate or butyl acetate.

Preferably, solvent (A-extract) is toluene, ethyl acetate or isopropyl acetate.

The compound of formula (I) can be isolated by dilution of the reaction mixture with water, acidification, followed by extraction with a solvent (A-extr) and followed by concentration and optional distillation of the extract. Preferably, the optional washing of any organic phase after the reaction during isolation is done with water or with brine.

Even more preferably, the reaction mixture is first concentrated under reduced pressure, then diluted and acidified with an aqueous acid, and extracted with toluene.

Optionally, any organic phase can be dried, preferably with magnesium sulfate or sodium sulfate.

Any concentration is preferably done by distillation, preferably under reduced pressure.

The compound of formula (I) can be purified, preferably by crystallization or distillation under reduced pressure.

In some cases, an aldehyde is isolated in its hydrated form. It can be, that under some of the mentioned isolation parameters after addition of water, it is possible that the hydrate of the compound of formula (I) is formed and isolated.

Using the process described herein, usually a mixture of E- and Z-isomers is obtained. Both isomers and their mixture are useful as fragrance.

Further subject of the invention is a compound of formula (I), with the compound of formula (I) being as defined above, also with all its preferred embodiments, and a mixture of the E- and Z-isomers of compound of formula (I).

Further subject of the invention is the use of compound of formula (I) as a fragrance, preferably in perfumes or house hold products.

Further subject of the invention is the use of compound of formula (II) for the preparation of compound of formula (I) by reaction of compound of formula (II) with crotonaldehyde.

The process of the present invention makes it possible to build the whole carbon framework of compound of formula (I) in a single and highly convergent step, using two fragments of similar molecular weight. This improves the overall yield of the process, if compared to a more linear, stepwise process, such as the one disclosed in WO 98/45237 A. Moreover, because two fragments of similar molecular weight are used in the late stage of the synthesis, which can be readily separated from the much higher-boiling compound of formula (I), the final product of this process is more easily purified and more easily obtained in a form of high odorous of fragrance purity or high fragrance purity, than if an intermediate of similar molecular weight as the final product would be used in a C-C-bond forming step. This is particularly important for products destined for use as fragrance.

The product is distinguished by a very special fragrance much sought after in the fragrance industry.

Examples

Methods:

GC apparatus: Thermo Focus;

column: RXi-5MS 15 m, ID 320 μιη, df 0.25 μιη;

flow: 2.5 ml/min;

carrier gas: He;

split ratio: 32;

injector temperature: 230 °C;

injection volume: 1 μΐ;

detection: flame ionization;

detector temperature: 250 °C

GC-method:

Initial temperature: 60 °C; initial time 2.0 min, ramp: 40 K/min; final temperature: 250 °C; final time 1.0 min;

For GC-analysis and yield determination, 100 μΐ of a reaction mixture were diluted with MeCN (l .O ml).

The yield of compound of formula (I) (as a mixture of Z/E isomers) was determined by GC using as internal standard tetradecane, or by NMR using as reference compound 4-nitro- benzaldehyde. For this purpose GC detector response factors were determined graphically and the yield was determined comparison of the peak areas for all starting materials and products.

The compound of formula (I), which was used as reference for yield determination, was prepared according to example lc and further isolated as follows: the reaction mixture was filtered and concentrated under reduced pressure. The residue was redissolved in

dichloromethane and washed with water and brine. The dichloromethane phase was concentrated, and the residue purified by column chromatography (silica gel, heptane/ AcOEt 9 to 1), followed by bulb-to-bulb distillation (140 to 180 °C, 0.12 mbar). 1.0 g (5.40 mmol) 1- bromo-2,3-dimethylbenzene yielded 0.51 g (59% yield) of compound of formula (I) as almost colorless oil, 95% pure by GC.

The 1H NMR spectrum indicated this oil to be a mixture of the two stereoisomers.

1H NMR (400 MHz, CDC1₃) δ 2.16, 2.18, 2.22, 2.31, 2.45 (5 x s, 9H), 5.94 and 6.14 (2 x d, J

= 8 Hz, 1H), 6.93 (m, 1H), 7.12 (m, 2H), 9.22 and 10.16 (2 x d, J = 8 Hz, 1H). Examples la to lh

To a mixture of l-bromo-2,3-dimethylbenzene (100 mg, 0.54 mmol), crotonaldehyde (76 mg, 1.08 mmol), tetradecane (13.4 mg, internal standard) and solvent (3.0 ml), the base (0.81 mmol) and a solution of ligand (0.2 M, 0.054 mmol) and Pd₂(dba)₃ (0.014 mmol) in toluene were added. The mixture was stirred at 100 °C for 18 h. Details and results are given in the table 1.

Examples 2a to 2f

To a mixture of l-bromo-2,3-dimethylbenzene (100 mg, 0.54 mmol), crotonaldehyde (76 mg, 1.08 mmol), tetradecane (13.4 mg, internal standard) and solvent (3.0 ml), the base (0.81 mmol) and a solution of ligand (0.2 M, 0.011 mmol) and Pd₂(dba)₃ (0.0028 mmol) in toluene were added. The mixture was stirred at 100 °C for 18 h. Details and results are given in the table 2. Table 2

Example ligand base solvent yield of compound of formula (I)

2a di(tert-butyl)(2-biphenylyl)-phosphine NaOAc DMF 12%

2b P(2-tolyl)₃ NaOAc DMF 18%

2c P(t-Bu)₃ DIPEA DMF 78%

2d tricyclohexylphosphine NaOAc DMF 5%

2e tri( 1 -naphthyl)phosphine NaOAc DMF 12%

2f tris(2,4-di(t-butyl)phenyl)phosphite NaOAc DMF 4%

Example 3a to 3e

To a mixture of compound of formula (II) (0.64 mmol), crotonaldehyde (76 mg, 1.08 mmol), tetradecane (13.4 mg, internal standard) and DMF (3.0 ml), DIPEA (0.81 mmol) and a solution of ligand (0.2 M, 0.011 mmol) and Pd source (0.0054 mmol) in toluene were added. The mixture was stirred at 100 °C for 21 h. Details and results are given in table 3.

Example 4a to 4f

To a mixture of l-bromo-2,3-dimethylbenzene (100 mg, 0.54 mmol), crotonaldehyde (76 mg, 1.08 mmol), tetradecane (13.4 mg, internal standard) and DMF (3.0 ml), DIPEA (0.81 mmol), Pd source (0.0054 mmol), and a solution of ligand in toluene in a concentration of 0.2 mmol ligand per milliliter toluene were added. The mixture was stirred at 100 °C for 18 h. Details and results are given in table 4. Table 4

Example Ligand molar ratio Pd source yield of compound

ligand Pd source of formula (I)

4a P(t-Bu)₃ 2: 1 Pd₂(dba)₃ 73%

4b P(t-Bu)₃ 1 :2 Pd/C 12%

4c P(t-Bu)₃ 1 : 1 Pd/C 25%

4d P(t-Bu)₃ 1 :2 Pd/C 44%

4e — 0: 1 Pd(P(t-Bu)₃)₂ 82%

4f — 0: 1 Pd₂Br₂(P(t-Bu)₃)₄ 30%

Example 5

A mixture of Pd(OAc)₂ (5.3 mg, 0.023 mmol), N-methyl-2-pyrrolidinone (11.5 ml), 1-bromo- 2,3-dimethylbenzene (0.405 g, 2.18 mmol), Bu₄NCl (0.382 g, 1.38 mmol), powdered NaOAc (0.22 g, 2.68 mmol), and crotonic aldehyde (0.31 g, 4.43 mmol) was stirred at 110 °C for 2 h. Aqueous saturated NaHC0₃-solution (40 ml) was added, and the mixture was extracted with toluene (3 x 20 ml). The combined extracts were washed once with brine, dried (MgS0₄), and concentrated under reduced pressure, to yield 0.79 g of an oil. The yield of compound of formula (I) was 18 % of the theoretical yield expected from the amount of l-bromo-2,3- dimethylbenzene which was used, as determined by 1H NMR with the internal standard.

Claims

1. A method (A) for the preparation of a compound of formula (I),

R2, R3 andR4 are identical of different and independently from each other selected from the group consisting of H, C_1-15 alkyl, C5-6 cycloalkyl and phenyl.

2. Method (A) according to claim 1, wherein

Rl is selected from the group consisting of CI, Br and I.

3. Method (A) according to claim 1 or 2, wherein

Rl is Br.

4. Method (A) according to one or more of claim 1 to 3, wherein

the support is BaS0₄ or charcoal.

5. Method (A) according to one or more of claim 1 to 4, wherein

the palladium source (Aa) is selected from the group consisting of PdCl₂, Pd(OAc)₂, Pd(dba)₂, Pd₂(dba)₃, PdCl₂(PhCN)₂, PdCl₂(MeCN)₂, PdCl₂(PPh₃)₂, Pd(P(tBu)₃)₂, Pd₂(P(tBu)₃)₃, Pd(P(l-adamantyl)₃)₂, Pd₂(P(l-adamantyl)₃)₃, Pd(PPh₃)₄ and Pd on charcoal;

6. Method (A) according to one or more of claim 1 to 5, wherein

the base (Ab) is selected from the group consisting of N-ethyl-N,N-diisopropylamine, NE¾, diazabicyclo [2.2.2] octane, Ν,Ν-dimethylaniline, dicyclohexylmethylamine, dicyclohexylamine, diisopropylamine, NaOAc, Na₂C0₃, NaHC0₃, KOAc, K₂C0₃ and K₃P0₄.

7. Method (A) according to one or more of claim 1 to 6, wherein

the palladium source (Aa) is Pd(P(t-Bu)₃)₂ and the base (Ab) is N-ethyl-N,N- diisopropylamine.

8. Method (A) according to one or more of claim 1 to 7, wherein

reaction (A) is done in the presence of a ligand (Ac);

ligand (Ac) is P(R5)(R6)R7;

Ci-15 alkyl;

ferrocenyl;

di(tert-butyl)phosphino substituted ferrocenyl; heteroaryl, the heteroaryl being a 5 or 6-membered aromatic carbon ring with one or two endocyclic heteroatoms selected from the group consisting of O, S and N, the ring being unsubstituted or substituted with 1, 2 or 3 identical or different substituents independently from each selected from the group consisting of halogen, C_1-10 alkyl, C_1-4 alkoxy, cyano and nitro;

Ci-15 alkoxy;

O-heteroaiyl, the heteroaryl being a 5 or 6-membered aromatic carbon ring with one or two endocyclic heteroatoms selected from the group consisting of O, S and N, the ring being unsubstituted or substituted with 1, 2 or 3 identical or different substituents independently from each selected from the group consisting of halogen, C_1-10 alkyl, C_1-4 alkoxy, cyano and nitro.

9. Method (A) according to claim 8, wherein

the ligand (Ac) is selected from the group consisting of PBu₃, P(o-tolyl)₃, PPh₃, P(l- adamantyl)₃, P(Bu)(l-adamantyl)₂, tris(2,4-di-(tert-butyl)phenyl)phosphite, P(tBu)₂(2- biphenylyl), P(tBu)₃, tri(cyclohexyl)phosphine, triphenylphosphite, tri(l- naphthyl)phosphine and 1, l'-bis(di(tert-butyl)phosphino)ferrocene.

10. Method (A) according to claim 8, wherein

the ligand (Ac) is P(tBu)₃.

1 1. Method (A) according to claim 8, wherein

12. Method (A) according to one or more of claim 1 to 7, wherein

reaction (A) is done in the presence of an ammonium salt (Ae);

ammonium salt (Ae) is N(R10)(R1 1)(R12)R13)⁺X^~;

R10, Rl 1, R12 and R13 are identical or different and independently from each other selected from the group consisting of Ci-15 alkyl;

phenyl, biphenyl and naphthyl, the phenyl, biphenyl and naphthyl being unsubstituted or substituted by 1, 2, 3 or 4 identical or different substituents independently from each other selected from the group consisting of halogen, C_1-10 alkyl, C_1-4 alkoxy, cyano and nitro;

dihydrogenphosphate, C_1-10 carboxylate, sulfate and hydrogen sulfate.

13. Method (A) according to claim 12, wherein

Ci-12 alkyl;

phenyl, the phenyl being unsubstituted or substituted by 1 or 2 identical or different substituents independently from each other selected from the group consisting of F, CI, Br, Ci_-4 alkyl, Ci_-4 alkoxy;

benzyl;

dihydrogenphosphate, C_1-10 carboxylate, sulfate and hydrogen sulfate.

14. Method (A) according to claim 12, wherein

the ammonium salt (Ae) is selected from the group consisting of Bu₄N⁺X ^~, MeN(Bu)₃ ⁺X , dodecyl-N(Me)₃ ⁺X benzylN(Bu)₃ ⁺X benzylN(Me)3⁺X^~ and Me4N⁺X and with X being selected from the group consisting of CI, Br, hydrogenphosphate, acetate and hydrogen sulfate.

15. Method (A) according to claim 12, wherein

the ammonium salt (Ae) Bu₄N⁺C .

16. Method (A) according to claim 12, wherein the palladium source (Aa) is Pd(OAc)₂, the base (Ab) is NaOAc and the ammonium salt (Ae)

17. Method (A) according to one or more of claim 1 to 16, wherein reaction (A) is carried out in a solvent (Ad);

solvent (Ad) is selected from the group consisting of DMF, NMP, DMA, N-methylacetamide, acetonitrile, propionitrile, ethyl acetate, butyl acetate, THF, methyl-THF, dioxane, toluene, xylene and mixtures thereof.

18. Method (A) according to claim 17, wherein

the solvent (Ad) is selected from the group consisting of DMF, NMP, DMA, N- methylacetamide, acetonitrile and propionitrile.

19. Method (A) according to claim 17, wherein

the solvent (Ad) is DMF or NMP.