3-(2,3-Dimethylphenyl)-2-butenal and its use as perfume

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

Aromatic aldehydes are widely used as flavours 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.

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 a new alpha, beta-unsaturated aromatic aldehyde, which has strong and interesting, aldehydic fragrance, intensely spicy and sweet, and an improved process for the production thereof.

In the following text, halogen means F, CI, Br or I, preferably CI, Br or I; alkyl means linear, branched and cyclic alkyl; BuLi means n-butyl lithium; if not otherwise specified.

Subject of the invention is a compound of formula (I),

wherein the double bond marked with (a) has either (Z) or (E) configuration, and a mixture of the E- and Z-isomers. Using the process described herein, usually a mixture of E- and Z-isomers are obtained. Both isomers are useful as fragrance.

Further subject of the invention is a method (A) for the preparation of a compound of formula (I), with the compound of formula (I) being as defined above, also with all its preferred embodiments, method (A) comprises a reaction (A) of a compound of formula (II) with an acid (A) in the presence of water;

Rl R2 wherein

Rl and R2 are identical or different and independently from each other C1-4 alkyl, or Rl and R2 are connected with each other and represent together a -(CH ₂ )2- or a -(CH ₂ ) ₃ - group, forming thereby with the two oxygens, to which Rl and R2 are attached, and the C atom, which connects the two oxygen atoms, a five or six membered ring; acid (A) is selected from the group consisting of C1-4 monocarboxylic acids, C _2- 6 dicarboxylic acids, perchlorinated C _2-4 monocarboxylic acids, perfluorinated C _2-4 monocarboxylic acids, hydrochloric acid, p-toluenesulfonic acid, methanesulfonic acid, sulfuric acid, acidic ion exchange resin commonly used in organic synthesis, and mixtures thereof.

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

Preferably, Rl and R2 are identical or different and are independently from each other methyl or ethyl;

more preferably, Rl and R2 are identical and are methyl or ethyl; even more preferably, Rl and R2 are methyl.

Preferably, the acidic ion exchange resin is selected from the group consisting of copolymers of styrene and divinylbenzene and of perfluorinated branched or linear poly ethylenes, these polymers being functionalized with SO ₃ H groups.

More preferably, the acidic ion exchange resin is selected from the group consisting of

copolymers of styrene and divinylbenzene containing more than 5% of

divinylbenzene, preferably being macroreticular, and of perfluorinated polyethylenes, these polymers being functionalized with SO ₃ H groups.

Preferably, acid (A) is selected from the group consisting of formic acid, acetic acid,

propionic acid, butyric acid, trichloroacetic acid, trifluoroacetic acid, hydrochloric acid, p-toluenesulfonic acid, methanesulfonic acid, sulfuric acid, and an acidic ion exchange resin and mixtures thereof.

More preferably, acid (A) is acetic acid.

Optionally, reaction (A) is done in a solvent (A), the solvent (A) is selected from the group consisting of tetrahydrofuran (THF), acetonitrile, propionitrile, C _1-4 alcohols, and mixtures thereof.

Preferably, solvent (A) is THF.

Reaction (A) can be done in the presence of a salt (A); salt (A) is, independently from acid (A), an alkali metal salt derived from an acid as defined above for acid (A), also with all its preferred embodiments.

More preferably, salt (A) is an alkali metal salt derived from an acid selected from the group formic acid, acetic acid, propionic acid, butyric acid, trichloroacetic acid,

trifluoroacetic acid, hydrochloric acid, p-toluenesulfonic acid, methanesulfonic acid, sulfuric acid, and an acidic ion exchange resin and mixtures thereof.

Preferably, salt (A) is an alkali metal salt derived from sodium or potassium.

Even more preferably, salt (A) is selected from the group consisting of sodium acetate,

potassium acetate, sodium formiate and potassium formiate.

Especially, the salt (A) is sodium acetate.

Preferably, salt (A) is derived from the acid (A) which is used. In particular, acid (A) is acetic acid and salt (A) is sodium acetate.

Preferably, the reaction temperature of reaction (A) is from 0 to 200 °C, more preferably from 10 to 100 °C, even more preferably from 85 to 95 °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 2 bar.

Preferably, the progress of the reaction is monitored by standard techniques, such as nuclear magnetic resonance spectroscopy ( MR), infrared spectrospcopy (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 may 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 24 h, even more preferably from 3 h to 12 h.

Preferably, the molar amount of water is from 1 to 100 fold, more preferably from 1 to 50 fold, even more preferably from 1 to 10 fold, of the molar amount of compound of formula (II).

Preferably, from 0.01 to 100 mol equivalents, more preferably from 0.1 to 50 mol equivalents, even more preferably from 1 to 10 mol equivalents of acid (A) are used, the mol equivalents being based on the mol of compound of formula (II).

Preferably, the amount of solvent (A) is from 0.5 to 20 fold, more preferably from 1 to 10 fold, even more preferably of from 2 to 5 fold, of the weight of compound of formula (II).

Preferably, the molar amount of salt (A) is from 0.01 to 10 fold, more preferably from 0.05 to 5 fold, even more preferably from 0.1 to 2 fold, of the molar amount of acid (A). Preferably, the combined amount of acid (A) and water, and of an optional solvent (A) and of an optional salt (A), is from 2 to 20 fold, more preferably from 3 to 10 fold, even more preferably from 5 to 7 fold, of the weight of compound of formula (II).

Preferably, the reaction (A) is done under inert atmosphere.

After the reaction (A), the compound of formula (I) is optionally isolated by standard methods such as evaporation of volatile components, extraction, washing, drying, concentration, crystallization and/or distillation.

Preferably, the volatile components of the reaction mixture are removed by evaporation under reduced pressure.

Preferably, the non-volatile residue is basified by the addition of an aqueous solution of a base (A-basify), preferably the base (A-basify) is sodium bicarbonate.

Preferably, the base (A-basify) is added in such an amount, that the pH of the resulting mixture is from 7 to 12, more preferably from 8 to 10, even more preferably from 8 to 9.

Alternatively, the compound of formula (I) can be isolated by dilution of the reaction mixture with water, followed by extraction with a solvent selected from toluene, benzene, or a acetic acid Ci-8 alkyl ester, preferably an acetic acid C _1-4 alkyl ester, more preferably ethyl acetate, isopropyl acetate, or butyl acetate, 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, with an aqueous solution of a base (A-wash) or with brine.

Preferably, the base (A-wash) is sodium bicarbonate.

Preferably, any aqueous phase can be extracted, preferably the extraction is done with a solvent (A-extract).

Preferably, solvent (A-extract) is toluene, ethyl acetate, or isopropyl acetate. Even more preferably, the reaction mixture is first concentrated under reduced pressure, then diluted with water, and extracted with toluene.

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

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.

Further subject of the invention is a compound of formula (II), with the compound of formula (II) being as defined above, also with all its preferred embodiments.

Compound of formula (II) is a chiral compound and the formula (II) comprises any enantiomer and any mixture of enantiomers of compound of formula (II).

Further subject of the invention is a method (B) for the preparation of a compound of formula (II), with the compound of formula (II) being as defined above, also with all its preferred embodiments, method (B) comprises a reaction (B) in a solvent (B), the reaction (B) comprises three consecutive steps (a), (b) and (c), which are carried out in the solvent (B); step (a) is a reaction (al) of compound of formula (III) with a reagent (Bal);

wherein

R3 is halogen;

reagent (Bal) is selected from the group consisting of C _1-4 alkyl magnesium halogenide, C _1-4 alkyl lithium, lithium, sodium, magnesium, aluminum, zinc, or calcium; step (b) is mixing a compound of formula (IV) with the reaction mixture resulting from step

(a);

Rl R2

wherein Rl and R2 have the same definition as above, also with all their preferred

embodiments; step (c) is mixing a reagent (Be) with the reaction mixture resulting from step (b);

reagent (Be) being water, C _1-4 alcohol or a mixture thereof; solvent (B) is selected from the group consisting of benzene, toluene, xylene, hexane, cyclohexane, C _1-4 alkyl cyclohexane, heptane, THF, di-Ci-4 alkyl ether, methyl-THF, 1,2- dimethoxy ethane, 1,4-dioxane, C _1-4 trialkyl amine and mixtures thereof; step (b) is carried out directly after reaction (al), or a reaction (a2) is done after reaction (al) and before step (b) by the addition of a reagent (Ba2) to the reaction mixture resulting from the reaction (al);

reagent (Ba2) is selected from the group consisting of halogenides of, C _1-4 alcoholates of and mixed halogenides C _1-4 alcoholates of Zn, Al, Ca, Zr and/or Ti, and mixtures thereof.

Compounds of formula (III) and of formula (IV) are known compounds and can be prepared according to known methods.

Reaction (al) is optionally done in the presence of a catalyst (B), catalyst (B) being selected from the group consisting of LiCl, TiCl ₄ , B1CI ₃ and PbCl ₂ .

Preferably, R3 is Br. Preferably, reagent (Bal) is sodium, magnesium, aluminum, isopropyl magnesium chloride, n-butyl lithium, sec-butyl lithium or tert-butyl lithium;

more preferably, reagent (Bal) is sodium, magnesium, aluminum, n-butyl lithium, sec-butyl lithium or tert-butyl lithium;

even more preferably reagent (Bal) is n-butyl lithium.

If a reaction (a2) is done, then reagent (Bal) is preferably selected from the group consisting of Ci-4 alkyl magnesium halogenide, C _1-4 alkyl lithium, lithium, sodium and magnesium;

more preferably of C _1-4 alkyl magnesium halogenide, n-butyl lithium, sec-butyl lithium, tert- butyl lithium, lithium, sodium and magnesium,

even more preferably of n-butyl lithium, lithium, sodium and magnesium.

Preferably, reagent (Be) is water.

Preferably, solvent (B) is selected from the group consisting of benzene, toluene, xylene, hexane, cyclohexane, methyl cyclohexane, heptane, THF, diethylether, dibutylether, methyl-THF, 1,2-dimethoxy ethane, 1,4-dioxane, triethylamine and mixtures thereof; more preferably, solvent (B) is THF.

Preferably, reagent (Ba2) is selected from the group consisting of zinc chloride, aluminium trichloride, aluminum triisopropoxide and titanium triisopropoxy chloride.

Preferably, the reaction temperature of reaction (B) is from -100 to 100 °C, more preferably from -80 to 40 °C, even more preferably from -60 to 20 °C.

Preferably, the reaction (B) is done at atmospheric pressure.

Preferably, the reaction time of reaction (B) is from 30 min to 48 h, more preferably from 1 to 24 h, even more preferably from 2 to 12 h.

Preferably, the amount of solvent (B) is from 2 to 40 fold, more preferably from 3 to 10 fold, even more preferably from 5 to 7 fold, of the weight of compound of formula (III). Preferably, from 0.9 to 10 mol equivalents, more preferably from 1.0 to 5.0 mol equivalents, even more preferably from 1.0 to 2.0 mol equivalents of compound of formula (IV) are used, the mol equivalents being based the mol of compound of formula (III).

Preferably, from 0.9 to 10 mol equivalents, more preferably from 1.0 to 5.0 mol equivalents, even more preferably from 1.0 to 2.0 mol equivalents of reagent (Bal) are used, the mol equivalents being based on the mol of compound of formula (III).

Preferably, from 1.0 to 50 mol equivalents, more preferably from 1.0 to 30 mol equivalents, even more preferably from 1.0 to 10 mol equivalents of reagent (Be) are used, the mol equivalents being based the mol of compound of formula (III).

Preferably, from 0.9 to 10 mol equivalents, more preferably from 1.0 to 5.0 mol equivalents, even more preferably from 1.0 to 2.0 mol equivalents of reagent (Ba2) are used, the mol equivalents being based on the mol of compound of formula (III).

Preferably, the reaction (B) is done under inert atmosphere. Suitable inert gases are argon, other noble gases, lower boiling alkanes, preferably C _1-3 alkanes (methane, ethane and propane), and nitrogen.

After the reaction (B), the compound of formula (II) is isolated by standard methods such as evaporation of volatile components, extraction, optional washing and drying, concentration and crystallization or distillation.

Preferably, any aqueous phase can be extracted, preferably the extraction is done with a solvent (B-extract).

Preferably, solvent (B-extract) is toluene, ethyl acetate, or isopropyl acetate. Optionally, any organic phase can be dried, preferably with magnesium sulphate. Concentration is preferably done by distillation, preferably under reduced pressure. The compound of formula (II) can be purified, preferably by crystallization or distillation under reduced pressure.

Preferably, compound of formula (I) is made by a compound of formula (II) which has been made by method (B).

Preferably method (B) and method (A) are done consecutively without isolating the compound of formula (II), preferably solvent (B) and the optional solvent (A) are identical.

More preferably method (B) and method (A) are done in one pot, and solvent (B) and the optional solvent (A) are identical.

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).

Further subject of the invention is the use of compound of formula (III) for the preparation of compound of formula (II).

Compared to prior art, the process of the present invention offers several advantages.

Importantly, the whole carbon framework of compound of formula (I) is built in a single, 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

List of Abbreviations and Raw materials

hexanes mixture of isomeric hexanes

THF tetrahydrofuran

quant. quantitative, i.e. 100% yield

Example 1

To a solution of a compound of formula (III-l) (5.75 g, 31

in THF (60 mL) at -50 °C, BuLi (15 mL, 1.6 M in hexanes, 24 mmol) was added. The mixture was stirred at -50 °C for 0.5 h, and compound of formula (IV-I) (4.7 ml, 3.8 g, 29 mmol)

was added dropwise within 10 min. Stirring at -50 °C was continued for 0.5 h, and the temperature was then allowed to rise to 0 °C within 0.5 h. Water (60 ml) was added, the THF was evaporated under reduced pressure, the residue was extracted with AcOEt (4 x 50 mL), the combined extracts were washed twice with brine, dried with MgS0 ₄ , and concentrated under reduced pressure to yield 5.01 g of compound of formula (II- 1).

1H NMR (400 MHz, CDC1 ₃ ) δ 1.61 (s, 3H), 2.17 (dd, J = 8 Hz, 15 Hz, 1H), 2.29 (s, 3H), 2.36 (s, 3H), 2.50 (dd, J = 3 Hz, 15 Hz, 1H), 3.19 (s, 3H), 3.30 (s, 3H), 4.14 (s, br, 1H), 4.18 (dd, J = 3 Hz, 8 Hz, 1H), 7.08 (m, 2H), 7.50 (m, 1H).

Example 2

A mixture of compound of formula (II- 1), prepared according to example 1, (0.51 g, 2.14 mmol), acetic acid (2.7 ml), water (0.2 mL), and sodium acetate (0.51 g) was stirred at 100 °C for 3 h. The mixture was diluted with water, basified to a pH > 7 by addition of solid

NaHC0 ₃ , and then extracted with AcOEt. The combined extracts were washed with brine, dried (MgS0 ₄ ), and concentrated under reduced pressure, to yield 0.4 g of compound of formula (I), as an oil. The 1H NMR spectrum indicated this oil to be a 3 : 1 mixture of two stereoisomers.

1H NMR (400 MHz, CDC1 ₃ ) 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).

Example 3

LiCl (0.62 g, 15 mmol) and l/5th of the compound of formula (ΠΙ-1) (100 % amount of compound of formula (III- 1 ) are 1.0 g, 5.4 mmol) were added to a suspension of magnesium (0.19 g, 7.8 mmol) in THF (2.5 ml). The mixture was stirred for 1 h at 40 °C, and the rest of the compound of formula (ΠΙ-l) and THF (12 ml) were added. When most of the magnesium had dissolved, the mixture was cooled to -35 °C, and a solution of compound of formula (IV- I) (1.0 ml, 6.2 mmol) in THF (1 ml) was added. The mixture was stirred at -40 °C for 1 h, allowed to warm to -10 °C, and a saturated aqueous solution of potassium carbonate (10 ml) was added. THF was evaporated under reduced pressure, and the residue was extracted with toluene (3 x 30 ml). The combined extracts were washed with brine, dried (MgS0 ₄ ), and concentrated under reduced pressure. 1H NMR of the residue revealed a product mixture containing 5 to 10 weight-% of compound of formula (II- 1).

Example 4

A mixture of compound of formula (II- 1 ) (0.51 g, 2.14 mmol), prepared according to example 1, THF (7 ml), and aqueous hydrochloric acid (32%, 12 ml) was stirred at 60 °C for 2 h and at room temperature for 3 days. The mixture was diluted with toluene (20 ml) and concentrated under reduced pressure, to yield 0.4 g of compound of formula (I) as an oil.

The 1H NMR spectrum indicated this oil to be a 3 : 1 mixture of two stereoisomers.