EP2109597A1

EP2109597A1 - Process for preparing dienones

Info

Publication number: EP2109597A1
Application number: EP08707406A
Authority: EP
Inventors: Werner Bonrath
Original assignee: DSM IP Assets BV
Current assignee: DSM IP Assets BV
Priority date: 2007-01-30
Filing date: 2008-01-30
Publication date: 2009-10-21
Also published as: WO2008092655A1

Abstract

The present invention relates to processes for preparing dienones and intermediates in this process.

Description

Process for preparing dienones

The present invention relates to a process for preparing dienones and intermediates useful in preparing dienones.

Dienones, in particular 6-methyl-octa-3,5-dien-2-one, 6-methyl-octa-4,5-dien-2-one, 7- methyl-nona-5,6-dien-3-one, 3,6-dimethyl-octa-4,5-dien-2-one, 7-methyl-nona-4,6-dien-3- one and 3,6-dimethyl-octa-3,5-dien-2-one are interesting compounds for the flavour and fragrances industry.

Processes for the synthesis of dienones are known, which are based on pyrolysis of tertiary-acetylenic carbinyl acetoacetates.

US 741 ,047 discloses a process for the production of a doubly unsaturated ketone which comprises pyrolysing a tertiary acetylenic carbinyl acetonate in the presence of an acidic catalyst. The acetoacetates are prepared by the reaction of the corresponding carbinols with diketene.

DE 1 078 112 discloses a process for the preparation of dienones, wherein esters from the general formula of tertiary acetylenic carbinyl acetoacetates are pyrolized, wherein the pyrolysis is conducted in the presence of lower aluminium trialcoholates and a lower fatty acid.

However, the known processes for the preparation of dienones have the disadvantages of low yields, complicated chemistry such as handling of the aluminium compounds, and the waste formation, such as decarboxylation during pyrolysis.

Therefore, there is still a need for further methods of synthesizing dienones, in particular 6-methyl-octa-3,5-dien-2-one, 6-methyl-octa-4,5-dien-2-one, 7-methyl-nona-5,6-dien-3-on, 3,6-dimethyl-octa-4,5-dien-2-on, 7-methyl-nona-4,6-dien-3-one and 3,6-dimethyl-octa-3,5- dien-2-one, which avoid these prior art problems. In particular there is a need for a process for the preparation of dienones, which provides dienones in high yield and high purity.

It has now been found that the desired dienones can be advantageously synthesized according to the following reaction schemes 1a and 1b:

6-methyl-octa-4,5-dien-2- one (2)

0 -3⁰C OH-ZMeOH (24 %)

2-butanαne

Scheme 1a

(B)

3-Methyl-1-pentin-3-ol (EBIt 2-Mettιoxy-but-2-ene (BMEl

3.6-Dimethyl-octa-4.5-dien-2-one (A)

Scheme 1b

The advantage of this reaction is that the dienones (2), (A) and (B) can be synthesized in excellent yield (based on (2) alone or the sum of (A) + (B)) and purity, in particular as the high temperatures as needed for pyrolysis have not to be applied. Further it has been found that dienones (C) and (D) can be advantageously synthesized from dienones (A) and (B) according to the following scheme 2:

7-Methyl-nona-S.6-dien-3-one (B) 7-Methyl-πona-4.6-dien-3-one (D)

OH-

3.6-Dimethyl-octa-4.5-dien-2-one (A) 3.6-Dimethyl-octa-3.5-dien-2-one (C)

Scheme 2

Therefore, the present invention relates to a process for the preparation of a compound of the formulas Ma or Mb

or a mixture of compounds of formulas Na and Mb, wherein R¹, R², R³ and R⁴ are independently from each other H or a C, - C₂₅ hydrocarbon moiety, which process comprises the step of reacting a compound of the formula III

wherein R³ and R⁴ are defined as above and R⁵ is H, with a compound of the formula IV

wherein R¹ and R² are defined as above and R⁶ is a hydroxy protecting group.

Within this application the wavy line depicted by " " indicates a single bond and the stereochemistry relating to the double bond bound therewith is E or Z or a mixture thereof.

It is noted that in cases where R¹ and R² are selected equally, then the compounds of formulas Ha and Mb are equal.

As C₁-C₂S hydrocarbon moiety of residues R¹, R², R³ and R⁴ each branched or nonbranched alkyl, branched or nonbranched cyclo-alkyl, branched or nonbranched alkenyl, branched or nonbranched cyclo-alkenyl, or aryl group, which can optionally be substituted, can be present. Preferably, the hydrocarbon moiety is a straight, branched or cyclic C_rC₁₆ alkyl or a straight, branched or cyclic C₂-C₁₆ alkenyl or a C₆-C₁₆ aryl, such as phenyl or naphthyl, which aryl may optionally be substituted by an C₁-C₆ alkyl group. More preferably, R¹, R², R³ and R⁴ are independently a hydrogen, a C₁-C₆ alkyl, or a C₂-C₆ alkenyl, in particular methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tertbutyl, n-pentyl and n-hexyl. Most preferred, but independent from each other R¹ is hydrogen, methyl or ethyl, in particular hydrogen or methyl, R² is hydrogen, methyl or ethyl, in particular hydrogen or methyl, R³ is hydrogen or methyl, in particular methyl, and R⁴ is methyl, ethyl or n-propyl, in particular ethyl.

In one preferred embodiment of the process of the present application, residues R² is H or C₁-C₆ alkyl, in particular C₂-C₆ alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tertbutyl, n-pentyl and n-hexyl, and R¹ is H or methyl.

In one preferred embodiment of the processes of the present application, residues R³ and R⁴ are different hydrocarbon moieties and the double bond including the carbon atom R³ and R⁴ are attached to is preferably in E-configuration. Most preferably, R³ is methyl and R⁴ is ethyl. The present application also comprises embodiments wherein residues R¹ and R² are equal. In this case the compounds of formulas Na and Hb are equal. Therefore the mixture of the compounds of formulas Ma and Hb only comprises more than one compound if residues R¹ and R² are different.

In yet another embodiment R¹ is hydrogen and R² is methyl.

R⁵ is hydrogen and R⁶ is a hydroxy protecting group. As protecting groups for the protected hydroxy group usual protecting groups known to the person skilled in the art may be used. Suitable protecting groups are exemplified in WO 03/044011 , the content of which is incorporated by references herein. A preferred protecting group for R⁶ is a methyl group.

In a preferred embodiment R¹ is hydrogen, R² is a methyl group and R⁶ is a Ci-C₄ alkyl group (e.g. methyl, ethyl, propyl or butyl).

The reaction of the compound of the formula III with the compound of the formula IV of the process of the present invention can be carried out in any usual solvent, which preferably provides sufficient solubility to the starting materials used, e.g. C₃ to C₁₂ hydrocarbons. However, the reaction of the compound of the formula III with the compound of the formula IV of the process of the present invention is preferably carried out without additional solvents. The reaction can be carried out under acid catalysis. As suitable acid any preferably strong acid, preferably a Brønsted acid, pKgi-4,5 can be used, preferably a strong inorganic acid, e.g. phosphoric acid or sulphur-VI containing acid, e.g. p-toluene sulfonic acid, methyl sulfonic acid or sulfuric acid, the latter being particularly preferred. The reaction is preferably carried out in a temperature range of 90⁰C to 200⁰C, more preferably 100⁰C to 150°C, in particular at about 105⁰C, depending on the specific starting materials used. The reaction can be carried out under inert atmosphere (e.g. argon atmosphere) and is preferably carried out under increased atmospheric pressure, e.g. in a pressure range of 1 - 20 bar absolute, in particular 1 ,5 to 5 bar absolute.

The compounds of formulas Ha and lib, or a mixture thereof, which are preferably obtained by the process of the present invention, can advantageously be used to obtain a compound of the below formulas Ia, Ib or a mixture thereof by isomerisation. Therefore, the process of the present invention preferably further comprises the step of isomerising a compound of formulas Ma or Hb

or a mixture of compounds of formulas Ma and lib, wherein R¹, R², R³ and R⁴ are defined as above to obtain a compound of formula Ia

or a mixture of compounds of formulas Ia and Ib, wherein R¹, R², R³ and R⁴ are defined as above.

The isomerisation reactions for the preparation of a compound of formulas Ia or Ib or a mixture thereof can be carried out in any suitable solvent, e.g. water, alcohol, such as methanol or ethanol, or esters such as ethylacetate. The preferred solvent is methanol. Preferably the isomerisation reactions are catalyzed by an alkaline compound. As suitable alkaline compound hydroxide containing compounds such as NaOH, KOH or similar can be used, preferably NaOH is used. In a specific embodiment, the isomerisation is carried out in the absence of alcohol as solvent. For example, the isomerisation can be carried out with alkaline compound in water. The isomerisation reactions are preferably carried out in a temperature range of -15°C to +15°C, e.g. at about O⁰C. The isomerisation reactions can be carried out under inert atmosphere, such as argon atmosphere. The products, i.e. the compounds of the formulas Ia₁ Ib or a mixture thereof, can be purified according to methods known in the art, preferably the compounds of the formulas Ia, Ib or a mixture thereof are extracted from the raw reaction product with an organic solvent, e.g. methyltertbutylether (MTBE). The product can be further purified, e.g. by distillation.

In one embodiment of the processes of the present invention the compounds of formulas Ha, lib or mixtures thereof are obtained as described above and isomerised to obtain compounds of formulas Ia, Ib or mixtures thereof. The compounds of formulas Ma, lib or mixtures thereof can be purified before the isomerisation reactions to obtain the compounds of formulas Ia, Ib or mixtures thereof are conducted. However, more preferred the compounds of formula Ha and Hb or mixtures thereof are isomerised to obtain compounds of formulas Ia, Ib or mixtures thereof without prior purification, i.e. the raw product from the process of the present invention to prepare the compounds of formulas Ha, Nb or mixtures thereof is subjected to an isomerisation reaction as described above to obtain the corresponding compounds of formulas Ia, Ib or mixtures thereof.

In one embodiment of the processes of the present invention the isomerisation reaction for the preparation of a compound of formula Ia or Ib is carried out such that the compounds of formulas Ha, Hb or mixtures thereof are prepared as described above and the compound of formula Ha or the compound of formula lib are separated and/or purified, before isomerisation to the corresponding compound of formula Ia or Ib₁ respectively. Useful separation and purification methods are known to the person skilled in the art, such as chromatographic separation and purification methods. Preferably, however, mixtures of compounds of formulas Ha and lib, which are preferably obtained as described above, are isomerised to obtain a mixture of compounds of formulas Ia and Ib.

In the most preferred embodiment of the process of the present invention R¹ is hydrogen, R² is hydrogen or methyl, R³ is methyl and R⁴ is ethyl, such that the compound of the formula Ma is 6-methyl-octa-4,5-dien-2-one (2) or 3,6-dimethyl-octa-4,5-dien-2-one (A), the compound of formula Hb is 7-methyl-nona-5,6-dien-3-one (B), the compound of the formula Ia is 6-methyl-octa-3,5-dien-2-one (1) or 3,6-methyl-octa-3,5-dien-2-one (C) and the compound of the formula Ib is 7-methyl-nona-4,6-dien-3-one (D).

According to the processes of the present invention dienones, in particular 6-methyl-octa- 4,5-dien-2-one (2), 3,6-dimethyl-octa-4,5-dien-2-one (A), 7-methyl-nona-5,6-dien-3-one (B), 6-methyl-octa-3,5-dien-2-one (1), 3,6-dimethyl-octa-3,5-dien-2-one (C) and 7-methyl-nona- 4,6-dien-3-one (D), can be advantageously obtained in excellent yields and in excellent purity. The yield may be at least 90%, preferably it is at least 92%, more preferably at least 95%, e.g. 95%-99%, most preferably more than 95%. The present invention further relates to the compound of formula V

wherein R¹, R², R³ and R⁴ are defined as above.

The compounds of formula V are useful in the preparation of dienones, in particular compounds of the formulas Ha, lib, and mixtures thereof, and compounds of the formulas Ia, Ib, and mixtures thereof.

The compound of formula V wherein R¹ is hydrogen, R² is hydrogen or methyl, R³ is methyl and R⁴ is ethyl is useful in the preparation of 6-methyl-octa-4,5-dien-2-one (2), 3,6-dimethyl- octa-4,5-dien-2-one (A), 7-methyl-nona-5,6-dien-3-one (B), 6-methyl-octa-3,5-dien-2-one (1), 3,6-dimethyl-octa-3,5-dien-2-one (C) and 7-methyl-nona-4,6-dien-3-one (D).

The present invention further relates to the compound of formula Ia

wherein R¹, R², R³ and R⁴ are defined as above, with the proviso that R¹ and R² are not both hydrogen. The compounds of formula Ia can be prepared according to the process as described above. Preferably the compounds of formula Ia are compounds C and D or E/Z isomers thereof.

Within this application all formulas also comprise the compounds which are enantiomers and E/Z isomers of the compounds depicted by the formulas. Within this application, all educts, intermediates and products to be used in the process of the present invention can be used as racemates or enantiomerically enriched mixtures, e.g. mixtures which are enriched in one enantiomer or comprise only one substantially purified enantiomer.

Each process of the present invention can further comprise one or more steps of separation or enrichment of enantiomers, e.g. steps of racemic separation. Methods of separation or enrichment of enantiomers are known in the art.

Preferably, the stereoconfiguration of reducts, intermediates and products is chosen such that when used in processes for the present invention, the intermediates and products resulting from said processes show the stereoconfiguration suitable for the preparation of 6- methyl-octa-4,5-dien-2-one, 6-methyl-octa-3,5-dien-2-one, 3,6-dimethyl-octa-4,5-dien-2- one, 7-methyl-nona-5,6-dien-3-one, 3,6-dimethyl-octa-3,5-dien-2-one and 7-methyl-nona- 4,6-dien-3-one.

The present invention will now be further illustrated by the following examples which are not intended to be limiting.

Example 1 : 6-methyl-octa-4,5-dien-2-one (2) (compound of formula Ma)

Ketonization, with sulfuric acid as catalyst on a small scale in a 33 ml autoclave

3.63 g 3-Methyl-1-pentin-3-ol (EBI) (99.5 area%), 36.8 mmol, and 51.7 mg H₂SO₄ (6.97 w% in methanol), = 0.1 mol%, are weighed in to a 33 ml Hastelloy C4 autoclave. 8.24 g 2-

Methoxy-propene (IPM) (96.5 area%), 110.3 mmol = 3 eq, are weighed to this mixture and then the reactor was immediately closed and placed in the aluminum heating block of the lab-shaker LSR/L-V (Adolf Kϋhner AG, Birsfelden). The same procedure was done for three other autoclaves.

The shaker frequency was set to 250 min^"1, the reaction temperature was 105 ⁰C, the reaction time was 120 minutes (incl. 15 minutes heating-up)

After reaction all the autoclaves were cooled down to room temperature in an ice-bath, opened and neutralized with sodium-acetate. The 4 reaction mixtures were united, solved in

200 ml methyl-tert-butyl-ether (MTBE) and 3 times extracted with 30 ml water deionized (total 120 ml) to wash out the DMP. All water phases were rewashed with 30 ml MTBE. The united organic phases were dried with Na₂SO₄, filtered and concentrated under vacuum at

40⁰C and 10 mbar. The crude product was distilled bulb-to-bulb under vacuum. The product fraction was taken at Tj (Temperature Jacket) 105 ⁰C and 8 mbar. Yield was 19.5 g of a yellowish oil, analyzed by GC area%, GC MS, IR, MA and NMR (NMR-data is shown below).

GC area: 93% (area%)

GC MS M⁺ = 138

IR peaks: 2967.44, 2934.18, 2904.98, 2877.57, 2853.32, 1964.94, 1714.51 , 1622.79,

1572.04, 1454.78, 1421.74, 1397.39, 1355.56, 1329.85, 1308.55, 1269.86, 1231.31 ,

1218.02, 1155.48, 1065.23, 1051.75, 1004.47, 966.99, 924.6, 870.42, 821.96, 787.47,

752.95.

MA

Calcul. C: 78.21 H: 10.21

Found C: 77.41/77.08 H: 10.16/9.87

Example 2: 6-methyl-octa-4,5-dien-2-one (2) (compound of formula Ma)

Ketonization, at ambient pressure on a larger scale in a 5 liter double-walled reactor

1 100 g EBI (99.5 area%), 11.152 mol, and 15.69 g H₂SO₄ (6.97 w% in methanol), = 0.1 mol%, were mixed in a 5I double-walled reactor connected to a julabo thermostat F32 (filled with syltherm oil XLT) and equipped with a PT 100, 2 stainless steel intermig stirrers (Ekato) and two condensers each 30 cm long. The reactor system was overlaid with argon. At room temperature and stirring (250rpm) 2500 g IPM (96.5 area%), 33.457 mol = 3 eq were added to this mixture. The internal temperature was rising during this process up to 40 ⁰C. The jacket temperature (Tj) was first set to 60 ⁰C and then within 30 minutes slowly increased (intense reflux) up to 70 ⁰C. Within 8 hours the internal temperature increased from 50 ⁰C up to 70 ⁰C. During the 12 hour after reaction time the color of the reaction mixture turned from light yellow to amber. The reaction mixture was actively cooled down to room temperature. For the work-up 2 liters of MTBE were added to the reaction mixture and then extracted 3 times with 500 ml water deionized (total 1.5 liters). The MTBE is necessary to separate the phases, because the water is soluble in 2,2-dimethoxypropane (DMP). The water phase was not re-extracted with MTBE (results in a one phase system). The organic phase was dried with Na₂SO₄, filtered and concentrated under vacuum at 40°C and 10 mbar. The crude product was distilled in a 2 liter two-necked round-bottomed flask with an oil bath, magnetic stirrer, PT 100, 30 cm Vigreux-column, Liebig-condenser, two-way fraction-separator, cold trap, membrane vacuum-pump. The first product fraction was taken at TJ 74 - 75⁰C₁ internal temperature (T,) 64 - 66°C, distillate temperature (head) (T_H) 59 - 60⁰C and 8 mbar.

Example 3: 6-methyl-octa-4,5-dien-2-one (2) (compound of formula Ua)

Ketonization on a larger scale in a 1 liter autoclave

In experiments a) - d) a stainless steel batch reactor from Medimex - High Pressure, number 910470 MED. 243 (build 1995), with a nominal volume of 1.0 liter, a operative temperature up to 220 ⁰C and a maximum pressure of 20 bar was used. The heating system of the reactor is provided by electrical heating spirals located in the jacket. Cooling is obtained by water flowing through the reactor jacket. The temperature control comprises three thermocouples for the measurement of the inner reactor, jacket and cooling temperatures, with precision of ± 0.05 ⁰C. A sensor measures the pressure with a precision of ± 0.05 bar. The stirrer is a stainless steel four-propeller with a speed range from 0 to 1200 rpm, from Flender ATB-Loher, number EAFY63/2B-7/N12 (0.25 kW). The sampling was done via a stainless steel capillary and a thin spiraled stainless steel tube connected to the sampling flask. The reactor is also connected to a safety and a data control system.

1.7 g of the catalyst H₂SO₄ (6.97 w% in methanol), =0.1 mol% were solved in 120.9 g EBI (99.5 area%), 1.23 mol and poured in to the reactor. 274.7 g IPM (96.5 area%), 3.68 mol = 3 eq were added. Total volume in all experiments was 500 ml. The reactor was immediately closed and the stirrer was started (Set on 500 rpm). The reaction mixture was heated up to set temperature (Ti) and then, the experiment was carried out at isothermal conditions. The sampling was done by using the stainless steel capillary connected to an ice cooled, thin- spiralled, stainless steel tube. The collected sample was directly neutralized with sodium acetate. The sample was analyzed by gas chromatography (area%). After the reaction time, the reaction mixture was cooled to 25 ⁰C. A sample of the reaction mixture was collected through the sample valve and capillary by introducing low-pressure nitrogen in to the reactor.

The conversion time, conversion rate and the obtained yields of examples a) to d) are summarized in the following table.

Conversion and yield based on area%.

Example 4: 6-methyl-octa-3,5-dien-2-one (1) (compound of formula Ia)

lsomerisation of (2) with NaOH (aq.) in methanol on a small scale

A 25 ml two-necked round-bottomed flask equipped with magnetic stirrer, PT 100, dropping funnel, condenser with argon overlay and dry-ice/alcohol bath was used. Between 0 and 4 ⁰C and over 45 minutes 8 g 6-methyl-octa-3,4-dien-2-on (2) (92.97 area% = 53 mmol) were drop wise added to a mixture of 86.5 mg NaOH (aq.) 24w% in water deionized = 0.52 mmol and 2.9 g methanol. The reaction was very exothermic and had to be controlled with the dry-ice/alcohol bath. There is a change in color from light yellow to amber. The solution was neutralized with 29 mg acetic acid (= 0.48 mmol) which caused a discoloration. For the work-up the low-boilers were evaporated at Tj 40 ° and down to 10 mbar. The residue was solved in 50 ml MTBE and extracted once with 2.9 g water deionized. After separation the water phase was re-extracted with 10 ml MTBE. The united organic phases were dried with Na₂SO₄, filtered and concentrated under vacuum at 40⁰C and down to 10 mbar. The crude product was distilled bulb-to-bulb under vacuum. The product fraction was taken at Tj up to 105 ⁰C and 9 mbar.

Yield :7.13 g of a yellowish oil, analyzed by GC area%, GC MS, IR, MA and NMR. (NMR- data is shown below).

GC 95.4% E/Z + E/E 6-methyl-octa-3,5-dien-2-on (1) (obtained E/Z to E/E ratio ~ 58:42) GC MS: M⁺ = 138 IR peaks: 3042.89, 2968.65, 2936.45, 2877.12, 1683.97, 1667.13, 1627.47, 1586.08,

1445.58, 1428.33, 1377.39, 1359.20, 1309.04, 1272.26, 1252.62, 1207.9, 1165.83,

1142.38, 1062.58, 1015.36, 1000.53, 971.08, 884.87, 829.91 , 790.42, 768.32, 622.47.

MA:

Calcul. C: 78.21 H: 10.21

Found C: 76.99/76.90 H: 10.11/10.16

Analytics of examples 1 and 4

1. NMR data

NMR spectra were recorded in CDCIg on a Bruker Avance 300 spectrometer equipped with

5 mm BBO BB-1H probe head. NMR data are given relative to TMS: δ_c 0.0 ppm, δ_H 0.00 ppm, (Tables 1 and 2). Assignments were based on extensive 1 D and 2D NMR experiments, including NOESY, HSQC and HMBC.

Compound 1: 6-Methyl-octa-4,5-dien-2-one (example 1)

Characteristic ⁵J coupling constants in the order of 3 Hz between H-4 and both CH₂-7 and CH3-6 indicating an allene moiety were observed.

Compound 2: (3E,5£)-6-Methyl-octa-3,5-dien-2-one (example 4)

The large value of J_H3-_H4 (15.3 Hz) indicated the configuration at this double bond to be trans. This assignment was confirmed by a NOESY experiment showing a positive NOE between H-4 and CH₃-I . The configuration at Δ⁵⁶ was shown by the same experiment to be also trans. A positive NOE between H-4 and CH₃-6, and between H-5 and CH₂-8 was observed.

Compound 3: (3£,5Z)-6-Methyl-octa-3,5-dien-2-one (example 4)

The large value of J_H3-_H4 (15.3 Hz) indicated the configuration at this double bond to be trans. This assignment was confirmed by a NOESY experiment showing a positive NOE between H-4 and CH₃-I . The configuration at Δ⁵⁶was shown by the same experiment to be cis. A positive NOE between H-5 and CH₃-Q, and between H-4 and CH₂-7 was observed. Table 1 : ¹H NMR data of compounds 1, 2 and 3 (δ in ppm, J in Hz)^a.

Position 1 2 3

1 2.11 (3H₁S) 2.21 (3H₁ s) 2.20 (3H, s)

9

3 2.99 (2H, d, J = 7.3) 6.01 (1H, d, J = 6.00 (1H, d, J = 15.3) 15.3) 4 5.10 (1H, ttq, J = 7.37 (1H, dd, J = 7.35 (1H, dd, J = 7.3, 3.2, 2.6) 15.3, 11.4) 15.3, 11.6)

5 5.93 (1H, brd, J = 5.89 (1H, d, J = 11.4) 11.6)

D

7 1.88 (2H, dq, J = 2.08 (2H, q J = 7.5) 2.26 (2H, q, J = = 7.6) 7.4, 3.2)

8 0.92 (3H₁1, J =7.4) 1.00 (3H,t, J = 7.5) 1.00 (3H,t, J = 7.6)

CH₃-6 1.63 (3H, d, J = 2.6) 1.84 (3H₁ d J = 0.8) 1.82(3H,s)

^as: singlet, d doublet, t triplet, q quartet, br broad

Table 2: C NMR data of compounds 1, 2 and 3 (δ in m.

2. Gaschromatography (GC area%)

System Instrument: HP 6890 gas chromatograph with split injector and FID

HP 6890 auto sampler

Data acquisition and reporting, HP ChemStation

Inlet Split ratio 75 : 1

Injector temperature 250⁰C

Injection volume 1 μl

Column Stationary phase Optima-1

Length x diameter 30m x 530μm; Film 3μm

Column material Fused silica

Producer Macherey Nagel

Initial flow 3.6 ml/min

Mode Constant flow

Column 50°C (10 min) 6°C/min → 12O⁰C (0 min) 10°C/min → 300°C (0 min). temperature Total 40 min Front Detector Detector temperature: 300°C

Makeup Gas type Helium 45 ml/min

Hydrogen flow 40 ml/min Air flow 450 ml/min

Example 5: mixture of 3,6-dimethyl-octa^4,5-dien-2-one (A) and 7-methyl-nona-5,6- dien-3-one (B)

Procedure for the acid catalyzed C4-elongation of 3-methyl-1-penten-3-ol (EBI) with 2- methoxy-but-2-ene (BME) to a mixture of 3,6-dimethyl-octa-4,5-dien-2-one (A) and the isomer 7-methyl-nona-5,6-dien-3-one (B) (C10-allenketone).

108 25 g EBI (99.5 area%, 1.0975 mol), 1.544 g H₂SO₄ in methanol (6.97w%, 1.097 mmol, 0.1 mol% based on EBI) and 295.8 g BME (95.9 area%, 3.292 mol, 3eq) were mixed in a 1- liter stainless steel autoclave. Under stirring at 500 rpm the internal temperature was brought within 30 minutes to 105 ⁰C and hold there for another 90 minutes (max. pressure 2.3 bar absolute). The reaction mixture was cooled to room temperature (50 minutes), neutralized with 1.5 g sodium acetate, stirred for another 30 minutes and filtered. The low- boilers were distilled off at 40 ⁰C under vacuum (80 mbar). The crude product was purified by distillation. The crude product was transferred into a 500 ml three-necked round bottom flask equipped with magnetic stirrer, PT 100 temperature measurement, and a 15 cm Vigreux column combined with a Liebig condenser, and distilled at head temperature 63 - 74°C, 10 mbar (internal temperature 66°C). Yield A+B 164.3 g (95%) based on starting material, ratio A : B = 3.

The structure of A and B was characterized by GC MS, IR, elementary analyses, and ¹H-, and ¹³C-NMR spectroscopy.

NMR data

NMR spectra were recorded on a Bruker Avance 300 spectrometer equipped with 5 mm BBO BB-1 H probe head operating at 300 MHz for ¹H and 75.5 MHz for ¹³C. Spectra were recorded in CDCI₃ and referenced to solvent signals: δ_H 7.26 / δ_c 77.0 (corresponds to δ_H 7.20 / δ_c 76.0 relative to TMS). Multiplicity for ¹³C is given as implied by DEPT: C = s, CH = d, CH₂ = t, CH₃ = q. Assignments were based on 1 D and 2D NMR spectral data, including COSY and HMBC.

Comments: Compounds A and B are present as a mixture in a ratio of roughly 3:1 (mol-%). NMR spectral data further suggests compound A to be present as a mixture of diastereomers. In the ¹³C NMR spectrum two signals usually differing in their chemical shift by less than 0.1 ppm can be assigned to almost every carbon atom of compound A. In the ¹H NMR spectrum two signals differing by 0.004 ppm can be assigned to H-3.

Compound A: 3,6-dimethyl-octa-4,5-dien-2-one

¹H NMR δ 5.12 (1 H, m, H-4), 3.08 (1 H, dq, J = 7.0, 6.9 Hz, H-3), 2.163 and 2.159 (3H, s, H₃- 1), 1.98 (2H, qd, J = 7.4, 3.2 Hz, H₂-7), 1.71 (3H, br d, J = 2.8 Hz, CH₃-6), 1.15 (3H, 6, J = 6.9 Hz, CH₃-3), 0.99 (3H, t, J = 7.4 Hz, H₃-8).

¹³C NMR δ 209.90 and 209.88 (s, C-2), 201.39 and 201.28 (s, C-5), 103.93 and 103.87 (s, C-6), 91.06 and 91.02 (d, C-4), 47.96 and 47.83 (d, C-3), 27.51 (q, C-1), 26.91 and/or 26.87 (t, C-7), 18.90 and/or 18.86 and/or 18.84 (q, CH₃-6), 15.69 and 15.60 (q, CH₃-3), 12.22 and/or 12.19 (q, C-8).

Compound B: 7-methyl-nona-5,6-dien-3-one

¹H NMR δ 5.14 (1 H, m, H-5), 3.04 (2H, d, J = 7.2 Hz, H₂-4), 2.48 (2H, q, J = 7.4 Hz, H₂-2), 1.93 (2H, qd, J = 7.4, 3.2 Hz, H₂-8), 1.68 (3H₁ br d, J = 2.8 Hz, CH₃-7), 1.05 (1 H, t, J = 7.4 Hz, H₃-I), 0.98 (3H, t, J = 7.4 Hz, H₃-9). ¹³C NMR δ 209.7 (s, C-3), 202.4 (s, C-6), 102.3 (s, C-7), 83.9 (d, C-5), 43.5 (t, C-4), 35.1 (t, C-2), 26.9 (t, C-8), 18.9 (q, CH₃-7), 12.2 (q, C-9), 7.8 (q, C-1).

Example 6: Mixture of 3,6-dimethyl-octa-3,5-dien-2-one (C) and 7-methyl-nona-4,6- dien-3-one (D)

Procedure for the base catalyzed rearrangement of a mixture of 3,6-dimethyl-octa-4,5-dien- 2-one (A) and the isomer 7-methyl-nona-5,6-dien-3-one (B) (C10-allenketones) to a mixture of the E/Z mixture of 3,6-dimethyl-octa-3,5-dien-2-one (C) and the E/Z mixture of 7-methyl- nona-4,6-dien-3-one (D) (C10-ketones).

In a 1.5 liter 4-necked round bottomed flask equipped with a propeller stirrer, a PT 100 temperature measurement and an argon overlay 304 g C10-allenketones (A+B) (97.3 area%, 1.942 mol) were drop wise added over 30 minutes between 0 - 5°C internal temperature to a mixture of 18.3 ml of sodium hydroxide (28% in water) and 622 ml methanol. The temperature was controlled with a dry ice/alcohol bath. The reaction mixture was stirred for 30 minutes at 0 - 3⁰C. The reaction mixture was neutralized with 23.2 ml of acetic acid, the solvent was evaporated at 40° (20 mbar). The residue was solved in 1 liter tert-butyl methyl ether (TBME), extracted 3 times with 100 ml of deionized. water, the water layers were extracted with 200 ml tert-butyl methyl ether and the combined organic layers were dried with Na₂SO₄, filtered, and the solvent was evaporated at 40°C (20 mbar). The crude product was purified by distillation. Head temperature 77 - 93°C, pressure 10 mbar (internal temperature 87 - 93°C).

Yield C+D 292 g (99%) based on starting material, ratio C : D = 1.2.

The structures of C and D were characterized by GC MS, IR, elementary analyses, and ¹H-,

¹³C-NMR spectroscopy.

Claims

1. Process for the preparation of a compound of formulas Na or lib

or a mixture of compounds of formulas Ma and lib, wherein R¹, R², R³ and R⁴ are independently from each other H or a C₁-C_2S hydrocarbon moiety,

which process comprises the step of reacting a compound of the formula III

wherein R³ and R⁴ are defined as above and R⁵ is H,

with a compound of the formula IV

2. Process according to claim 1 , wherein the reaction is conducted in the presence of an acid.

3. Process according to claim 2, wherein the acid is phosphoric acid or sulfuric acid.

4. Process according to any of the preceding claims, wherein R¹ is H or C₁-C₆ alkyl and R² is H or methyl.

5. Process according to any of the preceding claims, wherein R³ is CH₃ and R⁴ is C₂- C₆ alkyl.

6. Process according to any of the preceding claims, which further comprises the step of isomerising a compound of the formulas Ha or Hb

or a mixture of compounds of formulas Ha and lib, wherein R¹, R², R³ and R⁴ are independent from each other H or a C₁-C_2S hydrocarbon moiety to obtain a compound of formulas Ia or Ib

7. Process according to claim 6, wherein the compound of formulas Ha or lib or the mixture thereof is purified before isomerisation.

8. Process according to claim 6, wherein the compound according to formulas Ha or Hb or the mixture thereof is isomerised without prior purification.

9. Process according to any of claims 6-8, wherein the isomerisation is conducted under alkaline conditions.

10. Process according to any of claims 6 - 9, wherein R¹ is H or Ci-C₆ alkyl and R² is H or methyl.

11. Process according to any of the claims 6 - 10, wherein R³ is CH₃ and R⁴ is C₂-C₆ alkyl.

12. Process according to any of the preceding claims, wherein the compound of the formulas Ha or lib is 6-methyl-octa-4,5-dien-2-one, 3,6-dimethyl-octa-4,5-dien-2-one, or 7- methyl-nona-5,6-dien-3-one.

13. Process according to any of the claims 6-12, wherein the compound of the formulas Ia or Ib is 6-methyl-octa-3,5-dien-2-one, 3,6-dimethyl-octa-3,5-dien-2-one, or 7-methyl-nona-4,6-dien-3-one.

14. Compound of formula V

wherein R¹, R², R³ and R⁴ are defined as in claim 1.

15. Use of the compound of claim 14 for the preparation of dienones.

16. Use of the compound of claim 14, wherein R¹ is hydrogen, R² is hydrogen or methyl, R³ is methyl and R⁴ is ethyl for the preparation of 6-methyl-octa-3,5-dien-2-one, 3,6- dimethyl-octa-3,5-dien-2-one, 7-methyl-nona-4,6-dien-3-one or a mixture thereof.

17. Compound of formula Ia

wherein R¹, R², R³ and R⁴ are defined as in claim 6, with the proviso that R¹ and R² are not both hydrogen.

18. The process of any one of claims 1-13, wherein R¹ is hydrogen and R² is a methyl group.

19. The process of claim 18, wherein R⁶ is a C₁-C₄ alkyl group.

20. The process of any one of claims 1-13, 18 and 19, wherein the yield in compound Ha and/or lib is at least 90%.