DE2515011A1 - METHOD OF MANUFACTURING SYMMETRIC OLEFINS - Google Patents

Description

Hamburg, April 4th 19 75 173 675 478.13 (LP)

Priority: April 5, 1974, U.S.A., Pat. 458 065

Applicant:

The Regents of the University of California Berkeley, CaI., USA

Process for the production of symmetrical olefins

The invention relates to a process for the production of symmetrical olefins and can be particularly advantageous use to obtain trans-ß-carotene and dimestrol.

Higher molecular weight olefins are currently mostly only available to technology as non-uniform products, because the known ones Manufacturing processes produce mixtures of in many cases

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Isomers and homologues which cannot or only with difficulty in uniform Olefins can be broken down. Accordingly, it already existed the desire to synthesize olefins by addition reactions of aldehydes and / or ketones, whereby compounds are formed should be that instead of the C = O groups that are present in the starting aldehydes or ketones, new C bonds would contain. However, the previously known methods for carrying out such reactions have the disadvantage that they are typically complex. For example, it is known that provitamin A, ß-carotene, through a multi-stage process, as described, for example, in U.S. Patent 3,078,256, issued February 19, 1963 to Wittig et al. to manufacture. A quaternary phosphonium halide is converted into the corresponding phosphonium ylide and this Ylid reacted with a suitable aldehyde to form ß-carotene. Apart from that, these well-known procedures are of a complex nature, many of the reaction components required for this are compounds that in turn are difficult to obtain. For example, the quaternary phosphonium halides used in the process of the above Wittig patents mentioned are required, as are other comparable compounds, such as those used as intermediates in similar Process for the production of β-carotene, for example those in US Pat. Nos. 3,622,633; 3,408,414; and 3,600,473 which for Surmatis issued and on November 23, 19 71 and October 29, 196 8 and August 17, 1971, respectively, are described,

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can be produced by means of processes that are already relatively complex in themselves.

Other known methods for the synthesis of trans-β-carotene land-like carotenoids that are multilevel and complex, are described, for example, in U.S. Patents 2,846,487 and 2,846,475 issued to Isler on August 5, 1958; U.S. Patents 3,000,982 and 3,441,623 issued to Surmatis on September 19, 1961 and April 29, 1969, respectively; U.S. Patent 2,945,069 issued to Stern on July 12, 1960; U.S. Patent 3,007,976 issued to Eiter et al. November 7, 1961; and U.S. Patent 3,408,406 issued to Chechak et al October 29, 196 8.

The invention is based on the object of proposing a method for synthesizing symmetrical olefins, which is simple and readily available reaction components can be used for its implementation in numerous cases.

This object is achieved by means of a process for the production of symmetrical olefins, which is characterized according to the invention in that aldehydes and / or ketones are used Special Ti (II) implements. The process according to the invention can be used particularly advantageously for the synthesis of trans-β-carotene and dimestrol (<*., <A .'-diethyl-4, 4'-dimethoxystilbene or Diethylstilbestrol dimethyl ether).

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The process according to the invention involves a reductive coupling reaction of nuclei or aldehydes with reactive divalent titanium, Ti (II), with the formation of the corresponding symmetrical olefins, according to the following general Reaction scheme:

The reactive special titanium (II) can easily be reduced by reduction obtained from Ti (III) or Ti (IV) with a suitable reducing agent such as lithium aluminum hydride. The desired ketone or aldehyde P recurs or is then combined with the resulting Ti (II) implemented, and for this purpose, the reaction component is preferably added to the Ti (II) solution. So you have a simple one-step method for the synthesis of the corresponding symmetrical olefins for Disposal.

The inventive method has the advantage that it is a simple process for the synthesis of symmetrical Is olefins, can be used in the readily available reaction components, which is particularly advantageous for Synthesis of trans-ß-carotene and dimestrol, which are easy and smoothly from readily available precursor compounds such as for example, vitamin A aldehyde (retinal) or methoxypropiophenone can be obtained.

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In the process according to the invention, the titanium compound used as a reaction component reacts with an aldehyde or Ketone in such a way that a reductive coupling of the aldehyde or ketone molecules takes place, with the C = O groups of the starting substances be replaced by C = C bonds. This reaction can be exemplified using benzophenone as follows:

Ti (II) P> Φ

<2) @>

The reactive divalent titanium is preferably formed by reducing Ti (III) or TI (IV) with a suitable reducing agent, such as, for example, lithium aluminum hydride. Other reducing agents which are equally suitable for this purpose are, for example, zinc, magnesium, calcium hydride and lithium borohydride. In any case, the reactive special Ti (II) compound is prepared in such a way that soluble or partially soluble salts of higher value titanium, for example TiCl ₃ or TiCl., Are inert in a suitable organic solvent such as tetrahydrofuran Conditions, for example in sticks to ff or argon atmosphere, slurried and treated with a reducing agent, as mentioned above, for example. The reaction components are usually refluxed for a while so that the reactive specialty Ti compound, that is Ti (II), is formed.

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The aldehyde or ketone precursor is then mixed with the Ti (II) reaction component implemented and then the resulting solution is acidified. Then you can get the symmetrical olefin win as a reaction product by means of customary procedures and generally in yields of up to 95%.

It is true that the reaction mechanism on which the reactive coupling of aldehydes and ketones which takes place in the process according to the invention is based has not yet been theoretically elucidated in detail. The previous idea is that the reactive divalent titanium donates an electron to a molecule of the ketone or aldehyde, so that an anion radical is formed which, according to the classic pinacol reaction, dimerizes to a dialcohol as an intermediate. The dialcohol then reacts with another Ti (II) to form a cyclic intermediate which then decomposes to _{form the oil fin product and TiO 2.} This probable course of the reaction can be shown schematically as follows:

^Z I I

The probability of reaction used in this reaction scheme is very convincing. When you get the reaction

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performs with an insufficient amount of reducing agent, the pinacol intermediates can be removed from the reaction mixture isolate. Furthermore, if a pinacol is treated with a reactive Ti (II) reaction component, olefins can be obtained. It is also known that Ti (III), in turn, does not attack ketones, and it is also known that it does Ti (II) is a sufficiently strong reducing agent that it can cause a pinacol reaction: Ti (II) ■ Ti (III) + e ~; 0.37 volts.

It must be noted that the reaction mechanism on which the process according to the invention is based is based on the presence of reactive Ti (II). This reactive special Ti (II) is obtained through the reduction process discussed here. The reactive special Ti (II) should not be confused with known compounds of Ti in the divalent oxidation state, such as TiCl ₂ . TiCl ₂ is a completely insoluble polymeric mass and is completely inactive. It is necessary for the process according to the invention to produce a soluble and reactive Ti (II) by active reduction of compounds of the titanium which is in a higher oxidation state, for example TiCl ₃ , TiCl ₄ .

The inventive method is useful for aldehydes and ketones of all kinds, including cyclic aldehydes and Ketones, because under the reaction conditions used there is no risk of a

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Splitting of the ring link takes place. Example I. Beta-carotene, produced by the action of titanium trichloride

and lithium aluminum hydride on retinal

A slurry of titanium trichloride (1.54 g, 10.0 mmol) in 30 ml was made under an inert atmosphere (nitrogen or argon) dry tetrahydrofuran and carefully powdered lithium aluminum hydride (190 mg, 5.0 mmol) given. The resulting solution was stirred for two hours at room temperature to form the Ti (H) reaction component and a solution of retinal (1.42 g, 5.0 mmol) in 5 ml of dry tetrahydrofuran. The solution was stirred for an additional 15 hours at room temperature, and then poured into 50 ml of 2 η aqueous hydrochloric acid. The solution was extracted several times with ether, the ether extracts were combined, washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated by removing the solvent on a rotary evaporator. The residue was purified by chromatography on silica gel. Elution with hexane yielded 1.14 g (85% yield) of beta-carotene, which was determined by thin-layer chromatography against an authentic comparison sample, based on the characteristic ultraviolet spectra

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trums and identified by its melting point, m.p. 180-182 ° became.

Example II

Beta-carotene, produced by the action of titanium tetrachloride and lithium aluminum hydride on retinal

It was made by dissolving titanium tetrachloride (1.10 ml, 10.0 mmol) prepared a solution in 25 ml of dry tetrahydrofuran under an inert atmosphere (nitrogen or argon). To do this, was careful Lithium aluminum hydride (190 mg, 5.0 mmol) was added and the resulting solution was used to form the active Ti (II) reactant Stirred for two hours at room temperature. Then a solution of retinal (1.42 g, 5.0 mmol) in 5 ml dry tetrahydrofuran added, and the reaction mixture was stirred at room temperature overnight. Thereafter, the solution was poured into 50 ml of 2η aqueous hydrochloric acid, and it was extracted several times with ether. The ether extracts were combined, washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and removed by removing the Solvent concentrated in a rotary evaporator. The residue was purified further by chromatography on silica gel. Elution with hexane gave 1.0 g (75% yield) of beta-carotene obtained as opposed to that by thin layer chromatography an authentic comparison sample and by determining the melting point, 180-182 °, was identified.

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Example III

Beta-carotene, produced by the action of titanium trichloride and magnesium on retinal

Under an inert atmosphere (nitrogen or argon) it became a slurry from titanium trichloride (770 mg, 5.0 mmol) in 20 ml dry Tetrahydrofuran was prepared and magnesium turnings (120 mg, 5.0 mmol) were added. The resulting mixture was refluxed overnight to form the Ti (II) reaction component, and a solution of retinal (710 mg, 2.5 mmol) in 5 ml of dry tetrahydrofuran was added. After refluxing for two hours, the solution became Poured into 50 ml of 2 η aqueous hydrochloric acid and extracted several times with ether. The ether extracts were combined with saturated aqueous sodium chloride solution, dried over magnesium sulfate and removed by removing the solvent concentrated in a rotary evaporator. The residue was chromatographed cleaned on silica gel. Elution with hexane gave beta-carotene, 130 mg (20% yield), which was determined by thin layer chromatography compared to an authentic comparative example and identified on the basis of the characteristic Ul travi ο bold spectrum became.

Example IV

Beta-carotene, produced by the action of titanium tetrachloride and magnesium on retinal

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Magnesium turnings (243 mg, 10.0 mmol) were slurried in 20 ml of dry tetrahydrofuran under an inert atmosphere (nitrogen or argon) and a solution of titanium tetrachloride (0.55 ml, 5.0 mmol) in 3 ml of dry benzene was added added quickly. The resulting solution was used to form the active The Ti (II) reaction component was stirred at 50 ° overnight, and a solution of retinal (710 mg, 2.5 mmol) in 5 ml of dry tetrahydrofuran was added. After refluxing for an additional two hours, the solution was allowed to dissolve Cool to room temperature, poured it into 50 ml of 2 η aqueous hydrochloric acid and extracted with ether. The ether extracts were combined, washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and removed by removal of the solvent concentrated in a rotary evaporator. The residue was purified chromatographically on silica gel. Elution with hexane gave 130 mg (20% yield) of a product which, by thin layer chromatography, compared with an authentic comparative example and on the basis of the characteristic ultraviolet spectrum identified as beta-carotene.

Example V Production of beta-carotene through the action of titanium trichloride

and zinc on retinal

Under an inert atmosphere (nitrogen or argon), a slurry of titanium trichloride (770 mg, 5.0 mmol) in 20 ml of dry

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kenem tetrahydrofuran prepared, and to this slurry zinc dust (325 mg, 5.0 mmol) was added. The resulting The mixture was refluxed overnight to form the Ti (II) reactants and a solution of Added retinal (710 mg, 2.5 mmol) in 5 ml of dry tetrahydrofuran. After refluxing for another two hours the solution was dissolved in 50 ml of 2 η aqueous hydrochloric acid poured out, and it was extracted several times with ether. The ether extracts were combined with saturated aqueous Washed sodium chloride solution, dried over magnesium sulfate and by removing the solvent in a rotary evaporator concentrated. The residue was chromatographed on silica gel cleaned; elution with hexane produced 400 mg (60% yield) of beta-carotene, which was identified by means of thin-layer chromatography against an authentic comparison sample and on the basis of the characteristic ultraviolet spectrum.

Example VI

Beta-carotene, produced by the action of titanium tetrachloride and zinc on retinal

In an inert atmosphere (nitrogen or argon) zinc dust became (654 mg, 10.0 mmol) slurried in 20 ml of dry tetrahydrofuran, and a solution of titanium tetrachloride (0.55 ml, 5.0 mmol) in 3 ml of dry benzene was added quickly. The re-

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The resulting solution was used to form the active Ti (II) reactant refluxed overnight and a solution of retinal (710 mg, 2.5 mmol) in 5 ml of dry Tetrahydrofuran added. After further refluxing for two hours, the solution became room temperature cooled, poured into 50 ml of 2 η aqueous hydrochloric acid and extracted with ether. The ether extracts were combined, washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and removed by removing the solvent concentrated in a rotary evaporator. The residue was purified by chromatography on a silica gel column. The elution with hexane gave 43Ο mg (65% yield) of beta-carotene, which crystallized in a flask. Opposed by thin layer chromatography an authentic comparison sample and by comparing the melting point of a recrystallized sample, melting point 180 - 182 °, the beta-carotene was identified.

Example VII

Dimestrol ( th, cL ^l -diethyl-4,4 ^l -dimethoxystilbene; diethylstilbestrol dimethyl ether), produced by the action of titanium trichloride and lithium aluminum hydride on para-methoxypropiophenone

A slurry was made under an inert atmosphere Titanium trichloride (1.54 g, 10.0 mmol) in 30 ml of dry tetrahydrofuran prepared, and it was carefully pulverized

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Lithium aluminum hydride (190 mg, 5.0 mmol) was added. The resulting Solution was stirred for two hours at room temperature and the Ti (II) reactant formed. Then a solution of para-methoxypropiophenone (820 mg, 5 mmol) in 5 ml of dry tetrahydrofuran was added. The reaction mixture was refluxed for four hours, and then poured into 50 ml of 2 η aqueous hydrochloric acid. The solution was extracted several times with ether, the ether extracts were combined, washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and removed by removal of the solvent concentrated in a rotary evaporator. The residue was purified by chromatography on aluminum oxide, and 6 30 mg (85% yield) of Dimes trol were recovered; M.p. 124 °.

Example VIII

Dimestrol ( cL , o (/ - diethyl-4,4'-dimethoxystilbene; diethylstilbestrol dimethyl ether), produced by the action of titanium tetrachloride and zinc on para-methoxypropiophenone

Under an inert atmosphere, zinc dust (654 mg, 10.0 mmol) in Slurried 20 ml of dry tetrahydrofuran, and a solution of titanium tetrahydrofuran (0.55 ml, 5.0 mmol) in 3 ml added dry benzene. The resulting mixture was allowed to form the active Ti (II) reactant overnight

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refluxed, then a solution of para-methoxypropiophenone (500 mg, 3.0 mmol) in 5 ml of dry tetrahydrofuran was added. After refluxing for twelve hours had been treated, the solution was cooled to room temperature, poured into 50 ml of 2 η aqueous hydrochloric acid and with Ether extracted. The ether extracts were combined, washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and removed by removing the solvent concentrated in a rotary evaporator. The residue was purified by chromatography on silica gel, and 410 mg (91%) on Di meat ro 1 obtained by IR absorption, nuclear magnetic resonance and Mass spectrum was identified. M.p. 124 °.

EXAMPLE IX Cycloheptylidenecycloheptane produced by the action of Titanium trichloride and lithium aluminum hydride on cycloheptanone

A slurry of titanium trichloride (1.23 g, 8.0 mmol) in 30 ml of dry tetrahydrofuran was prepared under a sticky atmosphere, and powdered lithium aluminum hydride (152 mg, 4.0 mmol) was carefully added. The resulting solution became a to form the Ti (II) reactant Stirred for 1 hour at room temperature, and a solution of cycloheptanone (450 mg, 4.0 mmol) in 5 ml of tetrahydrofuran was added given. The reaction mixture was refluxed for 4 hours

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treated, then was poured into 50 ml of 2 η aqueous hydrochloric acid. The solution was extracted several times with ether, the ether extracts were combined, washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated by removing the solvent in a rotary evaporator. The resulting product (400 mg, 95% yield) was pure cycloheptylidenecycloheptane. It was identified on the basis of its spectral properties (infrared spectrum, mass spectrum, nuclear magnetic resonance spectrum).

Example X Tetraphenylethylene, produced by the action of titanium tri-

chloride and lithium aluminum hydride on benzophenone

A slurry of titanium trichloride (3.10 g, 20.0 mmol) in 40 ml of dry tetrahydrofuran was made under a sticky atmosphere and powdered lithium aluminum hydride (380 mg, 10.0 mmol) was carefully added. The resulting The solution was stirred at room temperature for one hour to form the Ti (II) reactant, and it became a solution of benzophenone (1.82 g, 10.0 mmol) in 5 ml of dry tetrahydrofuran was added. The reaction mixture was fifteen hours treated under reflux, then poured into 50 ml of 2 η aqueous hydrochloric acid and extracted several times with ether. The ether extracts

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were combined with saturated aqueous sodium chloride solution washed, dried over magnesium sulfate and removed by removal of the solvent concentrated in a rotary evaporator. The crystalline residue consisted of 1.55 g (95% yield) Tetraphenylethylene, based on its spectral properties (Infrared and ultraviolet spectrum) and by its melting point, Mp. 220-221 °, was identified.

Example XI

Cyclododecanylidenecyclododecane produced by the action of Titanium trichloride and lithium aluminum hydride on cyclododecanone

£> o

A slurry of titanium trichloride was turned into a sticky atmosphere (3.10 g, 20.0 mmol) prepared in 40 ml of dry tetrahydrofuran, and powdered lithium aluminum hydride (380 mg, 10.0 mmol) was carefully added. The resulting solution was stirred at room temperature for one hour to form the Ti (II) reactant, and a solution became out Cyclododecanone (1.82 mg, 10.0 mmol) in 10 ml of dry tetrahydrofuran added. The reaction mixture was refluxed for twelve hours, then was added to 50 ml of 2 η aqueous Poured out hydrochloric acid and extracted several times with ether. the

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Ether extracts were combined with saturated aqueous sodium chloride solution washed, dried over magnesium sulfate and by removing the solvent in a rotary evaporator concentrated. The crystalline residue consisted of 1.40 g (85%) of cyclododecanylidenecyclododecane, which on the basis of its spectral properties (Infrared spectrum, nuclear magnetic resonance, mass spectrum) and identified by its melting point became.

Example XII

Adamantylidene adamantane, produced by the action of titanium trichloride and lithium aluminum hydride on adamantanone

It became a slurry of titanium trichloride under a nitrogen atmosphere (3.10 g, 20.0 mmol) in 40 ml of dry tetrahydrofuran and powdered lithium aluminum hydride (380 mg, 10.0 mmol) was added carefully. The resulting solution became educated for one hour at room temperature The Ti (II) reactant was stirred and a solution of adamantanone (1.50 g, 10.0 mmol) in 10 ml of dry tetrahydrofuran was added added. The reaction mixture was twelve hours long refluxed, then was in 50 ml 2 η aqueous

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Hydrochloric acid avis poured. The solution was extracted several times with ether. The ether extracts were combined, washed with saturated aqueous sodium chloride solution, over magnesium sulfate dried and removed by removing the solvent in a rotary evaporator concentrated. The resulting residue was further purified by chromatography on silica gel. By eluting with Hexane, 1.15 g (85% yield) of Adaman ty Ii the adamant were obtained, based on its spectral properties (infrared spectrum, mass spectrum and nuclear magnetic resonance) as well as through its melting point, m.p. 185-186 °, was identified.

Example XIII

Beta-carotene, produced by the action of titanium tetrachloride and lithium borohydride on retinal

By dissolving titanium tetrachloride (1.10 ml, 10.0 mmol) in A solution was prepared 25 ml of dry tetrahydrofuran under an inert atmosphere. Lithium borohydride (110 mg, 5.0 mmol) was added and the resulting solution was stirred at 50 ° for two hours. A solution of retinal (1.42 g, 5.0 mmol) in 5 ml of dry tetrahydrofuran was added and the reaction mixture was refluxed for four hours treated. The solution was then poured into 50 ml of 2 η aqueous hydrochloric acid, and it was extracted several times with ether. The ether extracts were combined, washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate

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and by removing the solvent in a rotary evaporator concentrated. The residue was chromatographed on silica gel further cleaned. By eluting with hexane, 0.8 g (60%) of beta-carotene was obtained, which can be seen by comparison with an authentic ti Sample has been identified. 180-182 °.

Example XIV Beta-carotene, produced by the action of titanium tetrachloride

and calcium hydride on retinal

It was made by dissolving titanium tetrachloride (1.10 ml, 10.0 mmol) in 25 ml of dry tetrahydrofuran under an inert atmosphere Solution prepared. Calcium hydride (420 mg, 10.0 ml) and the resulting solution was stirred at room temperature for two hours. A solution of retinal (1.42 g, 5.0 mmol) in 5 ml of dry tetrahydrofuran was then added and the reaction mixture was refluxed for three hours. Thereafter, the solution in 50 ml of 2 η aqueous Hydrochloric acid poured out, and it was extracted several times with ether. The ether extracts were combined, washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate and concentrated by removing the solvent in a rotary evaporator. The residue was chromatographed on silica gel further cleaned. Elution with hexane yielded 1.0 g (75%) of beta-carotene, which was determined by thin-layer chromatography compared to an authentic comparison sample and based on the melting point, mp. 180-182 °.

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Claims (9)

- 21 PATENT CLAIMS 1. Process for the production of symmetrical olefins, characterized in that aldehydes and / or ketones are converted by means of special Ti (II). 2. The method according to claim 1, characterized in that the special Ti (II) by reducing one in a solvent dissolved, a higher oxidation state than II represents Ti pointing to Ti (II) and the resulting Ti (II) solution is reacted with an aldehyde or a ketone. 3. The method according to claim 2, characterized in that the reduction of the higher-valued Ti to Ti (II) with lithium aluminum hydride, Zn, Mg, CaH, or LiBH. is made as a reducing agent. 4. The method according to claim 1 to 3, characterized in that the reaction in a solution in which the Ti (II) in an inert dry solvent with an aldehyde or ketone is carried out, the resulting solution is acidified and the oils fin product extracted. -22-609809 / 1024 5. The method according to claim 4, characterized in that the Ti (II) containing solution by reducing a one higher oxidation state than II exhibiting Ti Ti (II) is formed. 6. The method according to claim 5, characterized in that used as the inert dry solvent tetrahydrofuran will. 7. The method according to claim 1 for the production of beta-carotene, characterized in that a Ti (II) containing solution reacted with retinal, the resulting solution acidified and extracting the beta-carotene product. 8. The method according to claim 1 for the production of dimestrol, characterized in that a Ti (II) containing solution reacted with para-methoxypropiophenone, the resulting solution acidified and the Dimes trol product is extracted. 9. The method according to claim 7 or 8, characterized in that the Ti (II) containing solution by reducing a one higher oxidation state exhibiting Ti under an inert atmosphere in an inert dry solvent Ti (II) is obtained. 609809/1024