The present invention relates to a method for the pre¬ paration of a secondary allylic ester of alcohol from the 5. corresponding isomeric tertiary allylic alcohol by 1,3-trans position of the oxygen in this. The invention more particu¬ larly relates to such a method which involves an acid cataly zed allylic rearrangement in the presence of a carboxylic acid for formation of the ester of the secondary alcohol. Th 10. formed ester can then by hydrolysed, transesterified or redu ced to give the free secondary allylic alcohol.

The method of the invention can be applied generally in the preparation of a secondary allylic ester or alcohol but is of particular importance for the preparation of phero 15. mone components and fragance substances. A particularly pre¬ ferred embodiment of the invention thus relates to the pre¬ paration of a pheromone compound, namely 2-methyl-6-methyl- ene-2,7-octadien-4-ol which is called ipsdienol and is an active attracant for bark beetles. 20. Ipsdienol has been prepared via several routes includ¬ ing syntheses involving allylic rearrangements. 2-Methyl-6- -methylene-3,7-octadien-2-ol, called amitinol, which is' the isomeric tertiary allylic alcohol of ipsdienol has for examp le been transformed into ipsdienol via a five-step procedure 25. involving chlorination and allylic rearrangement (Mori, K. Agr. Biol. Chem. 38 (1974) 20.5). An attempt has also been ^' made to prepare ipsdienol by direct acid catalyzed rearrange¬ ment of amitinol. However, this attempt was not succesful (Karlsen, S. et al, Acta Chem. Scand. B30 (1976) &6r ) . 30. The method of the present invention is carried out in the presence of a carboxylic acid and can be classified as an iso erisation under solvolysis, i.e. a nucleophilic sub¬ stitution reaction wherein the nucleophilic reagent, the carboxylic acid, forms part of the solvent. The method gives 35. an efficient transformation of the tertiary allylic aclohol into the isomeric secondary ester, or alcohol after further reaction, with good yields and low amounts of hydrocarbons. As has been mentioned above, the method is of particular in¬ terest for the preparation of pheromones and fragrance sub-

stances. As will be described in more detail below, the in¬ vention offers a possibility of producing the important phe- ro one component ipsdienol in a manner which is advantageous both from an economical and a technical point of view. 5. The present invention thus relates to a method for the preparation of a secondary allylic ester or alcohol from the corresponding isomeric tertiary allylic alcohol by rearrange¬ ment of the oxygen in 1-position in the tertiary alcohol for formation of the secondary ester with the oxygen in 3-posi-

10. tion. The method is chracteristic in that the tertiary alco¬ hol is subj'ected to an acid catalyzed allylic rearrangement in the presence of a carboxylic acid. This rearrangement leads to an ester and the free secondary alcohol can be ob¬ tained from this by hydrolysis, reduction or transesterifi-

15- cation.

Generalized, the method thus involves the transforma¬ tion of a molecule fragment f into 0

The method can be applied to any molecule containing an ali- 25. phatic or cycloaliphatic fragment as above. The mild condi¬ tions of the process allows the reaction to be carried out - also for substances which further comprise comparatively acid-labile groups, such as e.g. furans as shown in the examples. The rearrangement is carried out in the presence 30. of a carboxylic acid. Carboxylic acids having 1 to 5 carbon atoms are preferably used and acetic acid is particularly preferred. The rearrangement is carried out in the presence of the carboxylic acid and this is hereby used as part of the solvent for the reaction and the carboxylic acid is pre- 35- ferably the sole solvent, although inert solvents can be present if desired.

The reaction is carried out in the presence of cata¬ lytic amounts of an acid. Suitable acid catalysts are strong Brδnsted- and Lewis acids. As some examples can be mentioned

sulphuric acid, trifluoromethanesulphonic acid, aluminium chloride, boron trifluoride etherate etc. Perchloric acid is particularly preferred as catalyst. The reaction is re¬ markably rapid at room temperature. The temperature is not 5. critical, and cooling or heating can be used depending on the properties of the carboxylic acid. When it is desired to prepare the secondary alcohol this can be formed from the ester by conventional alkaline hydrolysis, transesteri¬ fication or reduction with a hydride reagent, such as lith-

10. ium aluminum hydride. Alkaline hydrolysis is the preferred manner of producing the free secondary alcohol.

Preparation of ipsdienol is a preferred embodiment of the present invention. Bark beetles of the Ips genus are major pestes in conifer forests and the bark beetle Ips ty-

15. pographus is responsible for serious mass attacks on spruce. Ipsdienol is a known pheromone component of Ips typographus, i.e. ipsdienol is a signal substance secreted from the insect and giving rise to a certain response from other individuals of the same species. In recent years pheromones have been

20. more widely used in insect pest control and racemic ipsdie¬ nol is used in lures which have been successfully used for trapping Ips typographus on a large scale. As mentioned ear¬ lier, several routes are known for the preparation of ips¬ dienol. However, there is still a need for simple and in-

25 _' expensive procedures leading to this compound. The present invention offers such a procedure.

Prom the tertiary allylic alcohol 2-meth-yl-6-methylene- -3,7-octadien-2-ol, amitinol, of formula

ipsdienol can be prepared by solvolytic isomerisation accord¬ ing to the present invention followed by hydrolysis, reduc- 35. tion or transesterification. Ipsdienol is obtained as the racemic mixture with*

OMPI

Amitinol can readily be prepared from inexpensive myr- cene, (2-methyl-6-methylene-2,7-octadien) , and most simply by sensitized photooxidation (Baeckstrδm, -P. et al Acta Chem. Scand B36 (1982) 3D. In this reaction two isomeric alco- 5*- hols are formed in equal amounts as the major products, amitinol as above and the secondary allylic alcohol 2-methyl-

The secondary alcohol will not react at the solvolytic iso- merisation according to the invention. Preliminary fields tests have shown that this secondary alcohol does not have

15. a negative influence on the biological effect of ipsdienol. It is thus possible to subject a mixture of alcohols obtain¬ ed from photooxidation of myrcene to the rearrangement accord¬ ing to the present invention and the obtained product con¬ taining racemic ipsdienol and unreacted 2-methy1-6-methylene-

20. -l,7-octadien-3-ol can, without separation, be used as a pheromone or a component in a pheromone agent. Since the secondary alcohol remains intact it can readily be separa¬ ted, if desired.

The above described synthetic route for preparation

25- of ipsdienol from myrcene is both simple and inexpensive. The solvolytic isomerisation is preferably carried out in acetic acid and preferably using perchloric acid as cata¬ lyst. Ipsdienol acetate is readily formed from the tertia¬ ry alcohol in high yields, around 85 per cent, and only mi-

30. nor amounts of hydrocarbons are formed, less than 5 per cent. Alkaline hydrolysis, reduction or transesterification of the acetate give a quantitative yield of ipsdienol.

Another preferred embodiment of the invention concerns the preparation of the compound l,5-dimethyl-l,5-cycloocta-

35- dien-3-ol and esters of this. The alcohol

has a great potential in the preparation of fragrance sub¬ stances and pheromone components. The esters, and particu-

STE

OMPI

synt

ent process is equivalent to a regiospecific allylic oxidation of l,5-dimethyl-l,5-cyclooctadien. Such a regiospecific oxi¬ dation cannot be carried out with any known reagent.- This de 10. pends primarily on the methyl substituents which react con¬ siderably faster than the allylic positions on the ring at reaction with oxidation reagents giving allylic oxidation. Photooxidation of l,5-dimethyl-l,5-cyclooctadien results in a mixture of products but since the selected conditions for

15. the rearrangement of tertiary alcohol to secondary ester according to the invention do not influence secondary alco¬ hols in the mixture the formed ester of l,5-dimethyl-l,5- -cyclooctadien-3-ol can readily be separated from the react¬ ion mixture by liquid chromatography. The compounds which

20. have the same retention volume as the ester can then readily be separated from l,5-dimethyl-l,5-cyclooctadien-3-ol ob¬ tained after further treatment, by repeated liquid chromato¬ graphy. In this manner a unique method for preparation of pure l,5-dimethyl-l,5-cyclooctadien-3-ol is obtained.

25. The invention is further illustrated in the following examples which, however, are not intended to limit the same.

The NMR-spectra in the examples were recorded on a Varian EM 360 (60 MHz) or a Bruker WP200 ^; (200 MHz) spectro¬ meter using deuteriochloroform containing tetramethylsilane

30. as solvent. Silica gel chromatography was performed with

Merck Kieselgel 60, 230-400 mesh. Gas-liquid chromatography (GLC) was performed with a capillary column, 25 m, coated with carbowax 20M, 70-l8θ°C. Thin-layer chromatography (TLC) was performed with silica gel, 15 per cent ethyl acetate in

35. hexane, developed with vanillin-sulfuric acid.

Example 1

Preparation of 2-methyl-6-methylene-2,7-octadien-4-ol, ra- .- cemic ipsdienol

Perchloric acid (90 % _t one drop) was added to glacial 5. acetic acid (10 ml) and this solution was added (30 sec) to a stirred solution of (E)-2-methyl-6-methylene-3 _s 7-octadien- -2-ol (1.28 g, 8.42 mol) in glacial acetid acid (10 ml). No discoloration occurred. After additional 120 sec the re¬ action mixture was poured into brine (50 ml). Extraction

10. with three portions of pentane followed by washing of the combined extracts once with NaHCO, solution, drying (MgSO^) and solvent removal gave ipsdienyl acetate (1.42 g, 7-32 mmol, 87 % ) containing < 5 . hydrocarbon (GLC). The product was treated with KOH solution (10 % in MeOH, 15 ml) at room

15. temperature for 3 h, poured into brine (50 ml) and extract¬ ed with three portions of pentane. Drying (MgSO*.) and sol¬ vent removal gave essentially pure (GLC, TLC) ipsdienol (1.06 g, 6.96 mmol, 95 % ) in 83 % overall yield. Column chromato¬ graphy on silica gel led to partial decomposition of the

20. acetate. Hydrolysis of the collected acetate gave a quanti¬ tative yield of ipsdienol but the overall yield was lowered to 60-75 % . Example 2 Preparation of l,5-dimethyl-l,5-cyclooctadien-3-ol

25. a) Preparation of the starting material, the tertiary allyl¬ ic alcohol l,5-dimethyl-2,5-cyclooctadien-l-ol, which, like the final product, is a new compound. l,5-Dimethyl-l,5-cyclooctadiene (10 g) was dissolved in chloroform (350 ml) containing tetrabutylammonium (TBA)-

30. -solubilized rose bengal (•^-'1.5 g/1) and TBA-borohydride

(14 g) . The solution was irradiated with a constant flow of oxygen bubbling from the bottom of the immersion well react¬ or fitted with an 400 W high pressure sodium light source. After 30 min a second portion of TBA-borohydride (7 g) was

35- added and after 45 min irradiation was stopped and the chlo¬ roform was removed under reduced pressure. Potassium iodide (20 g) in water (25 ml) and ether (250 ml) were added and the mixture was stirred for 1 h. The formed precipitate was filtered off and washed once with brine and dried (MgSOu).

OMPI

graphed on silica. Treatment of the combined alcohol con¬ taining fractions (5.6 g) with pyridine (20 ml) and acetic anhydride 20 ml) and work up by pouring into brine (100 ml) 5- and extraction with pet-ether (3 x 20 ml) gave secondary acetates and non-acetylated tertiary alcohol. Chromatography on neutral alumina gave l,5-dimethyl-2,5-cyclooctadiene-l- -ol (4.91 g, 44 % ) . Spectro data:

10. MS: M 152, base peak 43

NMR 200 MHz (CDCl,) ; cT 5.81-5•69 (1H), 5.75-5-53 (2 H) , 2.97-2.73 (2 H), 2.35-2-29 (2 H), 1.86-1.76 (5 H) , 1.33 (3 H), ΓS 1.6 (1 H,-0H). b) l,5-Dimethyl-3-acetoxy-l,5-cyclooctadiene was prepared

15- from l,5-dimethyl-2,5-cyclooctadien-l-ol and was further converted to l,5-dimethyl-l,5-cyclooctadien-3-ol. The iso- merisation was carried out in acetic acid and with perchlor¬ ic acid as the catalyst and the procedure was carried out as described in Example 1. With chromatographic separation af-

20. ter each step the final yield was 61 % . Spectro data: MS: 166, base peak 85

NMR 200 MHz (CDCl,); ^ -3 -5.29 (2 H) , 5-01 (1 H) , 2.69-2.57, (2 H), 2.43-2.00 (4 R ) , s 1.5 (l H,-0H).

2 • Example 3

Preparation of 2-methyl-5-(3-furyl)-2 -pentene-4-ol

The tertiary alcohol 2-methyl-5-(3-f ryl)-3-pentene-2- -ol was prepared according to Baeckstrδm, P. et ^r al, Ac a Chem. Scand. B36 (1982) 31.

30. The tertiary alcohol was converted to 2-methyl-5-

-(3-furyl)-4-acetoxy-2-pentene which was further converted

and using acetic acid in the isomerisation and perchloric acid as cata lyst. With chromatographic separation after each step the final yield was of the same order as in Example 2.

Spectro data for this new compound were as follows: MS: T 166, base peak 85

NMR 200 MHz (CDCl,); ^* 7-37 (1 H) , 7-30 (I H) , 6.33 (1 H), 5.25-5.20 (1 H), 4.52-4.48 (1 H) , 2.64-2.60 (2 H) , 1.73 (3 H), 5. 1.66 (3 H), 1.5 (1 H,-0H).