CIS-2-ACETYL-I ,2,3,4,5,6,7, 8-OCTAHYDRO-l ,2,8, 8-TETRAMETHYLNAPHTHALENE

This invention relates to a process of cyclisation promoted by Lewis acids, especially organoaluminium halides.

The compound c/^-acetyl-l^^^jS _j όJjδ-octahydro-l^^^-tetramethylnaphthalene (Formula I)

I (hereinafter β-GW), is the olfactorily most potent isomer of the commercialized fragrance mixture known as Georgywood (see Frater, Mϋller and Schroder, "Tetrahedron" Asymmetry, 15 (2004), 3967-3972). ("Georgywood" is a trade mark of Givaudan SA.).

The skilled person will realise that there are two enantiomers of β-GW. The one hereinabove shown as Formula I is the preferred enantiomer (it has the stronger fragrance), but the mixture of both enantiomers also has valuable properties. For the avoidance of doubt, all molecules depicted by structural formulae are, for the purposes of this invention, considered to cover both-the depicted enantiomer as well as the mixture of both enantiomers.

It is known that β-GW can be prepared by cyclisation of cώ-l-[l ,2~dimethyl-4(4-methyl- pent-3-enyl)-cyclohex-3-enyl]-ethanone (Formula II)

(hereinafter Ψ-GW) using a Bronsted acid, such as H ₃ PO ₄ . Such a method is disclosed in United States patent 5,707,961. The problem with this method is that the product is a mixture of β-GW and the undesirable iso-Georgywood (hereinafter IGW ~ see Formula III), which cannot be converted to β-GW.

III

It is therefore desirable to increase the proportion of β-GW by avoiding the formation of IGW.

It has now been found that it is possible to carry out such a cyclisation reation with the result being an enhanced proportion of β-GW in the final mixture. The invention therefore provides a process of preparation of β-GW from Ψ-GW, comprising the reaction of Ψ-GW with more than one molar equivalent of a Lewis acid in the absence of solvent or in the presence of a non-complexing solvent.

The product of this reaction is a mixture of β-GW, Georgywood-enolether (GWEE) (Formula IV) and γ-Georgywood (γ-GW - Formula V).

IV V

IGW may be present in a proportion of about 1-5% by weight, but it is generally completely absent.

This product mixture is very useful, as it can be converted to β-GW, as is hereinunder described.

The Lewis acids for use in this reaction may be selected from the group of MX _n -type Lewis acids with M = metal, X = halide and n = 3-5. Preferred Lewis acids include (but are not limited to) BBr ₃ , BCl ₃ , BF ₃ , AlBr ₃ , AlCl ₃ , ZrCl ₄ , ZrBr ₄ , TiCl ₄ and TiBr ₄ . A combination of such acids may be used; in this case the sum of the molar equivalents of each Lewis acid must be greater than 1.

Examples of non-complexing solvents include (but are not limited to) hydrocarbons, chlorinated hydrocarbons, nitroalkanes, toluene, chlorobenzene and cyclohexane. Naturally

a mixture of two or more such solvents may be used.

The skilled person will be able to perform this reaction using the normal skill of the art known for the handling of Lewis acids. This includes water-free conditions under an atmosphere of argon or nitrogen, mixing of the reagents and substrates under cooling and conducting the reaction at a temperature typical for each Lewis acid, in case of the abovementioned Lewis acids at temperatures between -50°C and O ⁰ C.

The GWEE / γ-GW / β-GW mixture thus obtained can be converted in a second acid- promoted cyclization step to pure β-GW. This is an advantage compared to the β-GW / IGW mixture of US 5,707,961, where such a conversion is not possible. The overall yield of β-GW from Ψ-GW, however, does not exceed 45% (after distillation).

In a preferred embodiment of the invention, it has been found that the use of a particular class of Lewis acids brings substantial improvements in yield and selectivity. The invention therefore provides a process for the preparation of β-GW from Ψ-GW, comprising the reaction of Ψ-GW with more than two molar equivalents of an organoaluminium dihalide RAlX _{2 1} where R is Cj-C ₃ linear alkyl and X is Cl or Br, in the absence of solvent or in the presence of a non-complexing solvent.

The organoaluminium dihalide is preferably selected from the group consisting of methylaluminium dichloride (MADC), ethylaluminium dichloride (EADC) and methylaluminium sesquichloride (MASC). MADC is the preferred Lewis acid and may be prepared by any convenient method. However, specifically excluded from the class of MADCs useful in this invention is the crude reaction product prepared by the following method:

(i) reacting by heating a material of the formula R ₃ Al ₂ X ₃ , where R is C1-C4 alkyl and X is selected from bromine and iodine, with an aluminium- containing material selected from metallic aluminium and a mixture of metallic aluminium and aluminium trichloride in an atmosphere of methyl chloride, with the proviso that, when R is methyl and X is iodine, the aluminium-containing material is a mixture of aluminium and aluminium

trichloride; and

(ii) when the aluminium-containing material is metallic aluminium, adding

aluminium trichloride to this reaction mixture and heating, to give a crude reaction product.

This method has already been disclosed in published International Application WO 2005/0016938 (PCT/CH2004/000505).

It has also been discovered that the organoaluminium dihalides hereinabove described can catalyse the cyclisation reaction, provided more than 1 molar equivalent of another Lewis acid is added to block the carbonyl group. The invention therefore additionally provides a process for the preparation of β-GW from Ψ-GW, comprising the reaction of Ψ-GW with a combination of aluminium chloride and a catalytic amount of organoaluminium dihalide, there being present one molar equivalent maximum of aluminium trichloride, the total of aluminium chloride and organoaluminium halide being greater than one molar equivalent.

It should be noted that, in this particular embodiment of the invention, the use of a crude MADC product, as described in WO 2005/0016938, is not excluded.

In a further embodiment of the invention, the organoaluminium dihalides may be also prepared in situ from trialkylaluminium compounds AlR ₃ or dialkylaluminium halides R ₂ AlX in the presence of AlX ₃ (with R = Ci-C ₃ ) and X = Br, Cl).

By "catalytic amount" is meant from 0.05-0.95 molar equivalents of the organoaluminium dihalide. Preferably 0.9-0.95 molar equivalents OfAlCl ₃ is employed in combination with 0.15-0.25 molar equivalents MADC. The reaction is carried out at elevated temperatures, preferably at 50 ⁰ C, in non-complexing solvents (as described above), preferably toluene or chlorobenzene.

Conducting the reaction with aluminium chloride and catalytic amounts of MADC has the advantage that much less of the relatively expensive and hazardous MADC is needed, compared to the stoichiometric reaction with MADC alone, which needs at least 2 molar

equivalents of this reagent. In addition, less of the greenhouse gas methane is produced during work-up and less aluminium wastes are generated.

This invention makes it possible to prepare mixtures of Georgywood that are much richer in the desirable β-GW than those previously obtained. The invention therefore also provides a Georgywood mixture that contains at least 70%, preferably from 85-95% β-GW, obtainable by a process as hereinabove described. .

The invention is further described with reference to the following non-limiting examples, which describe preferred embodiments.

Example 1 Cyclization of ψ-GW with AlCl ₃ followed by isomerization of the resulting β-, γ-, enolether- mixture to β-GW: c/-f-2-acetyl-l,2,3,4,5,6,7,8-octahydro-l,2,8,8- tetramethylnaphtha-lene:

2 g (8.5 mmol) ψ-GW in 1Og toluene are cooled under nitrogen and stirring to -50 ⁰ C, where BBr ₃ (3.2 g, 13 mmol) are added dropwise via syringe. After 7 h at -5O ⁰ C, 2 M HCl is added at this temperature. Back at 25°C the mixture is extracted with /-butyl methyl ether. The organic phase is washed with NaHCO ₃ and water until pH =7, dried over MgSO ₄ and concentrated under reduced pressure. Bulb-to bulb distillation at 90°-120° / 0.05 Torr gives 1.1 g of a β-, γ-, enolether-mixture, which is dissolved in toluene and treated withp- toluenesulfonic acid (40 mg, 0.2 mmol). After 4 h at 100 ⁰ C the organic phase is washed with Na ₂ CO ₃ and water until pH = 7, dried and concentrated under reduced pressure giving 1.2 g of a brown oil, which is bulb-to-bulb distilled at 12O ⁰ C / 0.05 Torr giving 0.8 g (40%) β-GW with ~ 90% purity according to GC and NMR. IR (film): 2930 m, 17005 (C=O), 1560 m, 1377 m, 1357 m, 1240 w, 1220 w, 1090 m. GC/MS: 234 (25%, [M] ⁺ ), 219 (15%, [M - CH ₃ ] ⁺ ), 191 (100%, [M - Ac] ⁺ , 161 (20%), 135 (65%), 121 (40%), 105 (40%), 91 (30%), 69 (30%), 43 (55%). ¹ H-NMR (CDCl ₃ , 400 MHz): 0.85 (d, 3H, J = 6.9 Hz, Cl-Me), 0.99 (s, 3H), 1.02 (s, 3H), 1.06 (s, 3H), 1.4-2.2 (10 H, 5 CH ₂ ), 2.15 (s, 3 H, Ac-Me), 2.36 (q, 1 H, J = 6.9 Hz, Cl-H) ppm. ¹³ C-NMR (CDCl ₃ , 400 MHz): 19.1 (CH ₂ ), 19.7 (CH ₃ ), 21.0 (CH ₃ ), 22.5

(CH ₂ ), 24.9 (CH ₃ ), 27.7 (CH ₂ ), 28.9 (CH ₃ ), 29.4 (CH ₃ ), 30.8 (CH ₂ ), 34.0 (C), 35.4 (CH), 40.1 (CH ₂ ), 50.7 (C), 125.9 (C=), 136.9 (C=), 214.5 (C=O) ppm.

Example 2 Cyclization of ψ- to β-GW with commercial MADC:

20 g (85 mmol) ψ-GW dissolved in lOOg toluene is added under ice cooling to 157 g (0.21 mol) MADC (1 M in hexane). The mixture is heated to 70°C for 2-3 h, then quenched under ice-cooling with 40 g ethanol, then with 2M HCl. The organic phase is separated and the aqueous phase extracted with t-butyl methyl ether. The combined organic layers are washed with cone. NaCl, then with water until pH = 7. The organic phase is dried over MgSO ₄ , filtered and concentrated under reduced pressure. The residue is distilled over a short Vigreux column (124°C / 0.1 Torr) to give 16g (80%) of β-GW as a colorless liquid and a purity of- 90% according to GC and NMR. The analytical data of the product are consistent with the ones described in example 1.

Example 3 Cyclization of ψ- to β-GW with AlCl ₃ and catalytic amounts of MADC:

15 g (64 mmol) ψ-GW dissolved in toluene (50 g) is added to a suspension of 8.1 g anhydrous AlCl ₃ (61 mmol) in toluene (15 ml) under ice-cooling, nitrogen and stirring. After addition of MADC (16 ml, 16 mmol) in hexane (1 M) the brown-red solution is heated to 55 ⁰ C for 4 h. Work-up as described in example 2 and bulb-to-bulb distillation gives 10.5 g (70%) of β-GW as a colorless oil and a purity of 88% according to GC and NMR. The analytical data of the product are consistent with the ones described in example 1.