GB1560895A - Process for producing symmetrical olefins - Google Patents

Description

(54) PROCESS FOR PRODUCING SYMMETRICAL OLEFINS (71) We, THE REGENTS OF THE UNIVERSITY OF CALIFORNIA, a corporation organised and existing under the laws of the State of California, of 2200 University Avenue, Berkeley, State of California 94720, United States of America, do hereby declare the invention for which we pray that a patent may be granted to us and the method by which it is to be performed, to be particularly described in and by the following statement: This invention relates to a process for the production of olefins. In particular, this invention relates to a method for the synthesis of symmetrical olefins which has particular application in the production of transss-caro- tene and dimestrol.

While the desirability of synthesizing olefins by addition reactions of aldehydes or ketones to form compounds containing a new C=C linkage instead of the C= 0 groups, of the starting aldehydes or ketones had been previously recognized, known processes for accomplishing such reactions are typically complex.

For example, the provitamin A-carotene, has typically been synthesized by multi-step processes such as that described in U.S. Patent 3,078,256, issued on February 19, 1963 to Wittig, et al, which comprises converting a quaternary phosphonium halide to the corresponding phosphonium ylide, and reacting this ylide with an appropriate aldehyde to form Scarotene.

In addition to the complexity of such known processes, many of the reactants employed in this and similar processes are themselves difficult to obtain. For example, the quaternary phosphonium halides employed in the process of the above-mentioned Wittig patent, as well as other related compounds employed as intermediate in similar processes for the production of sscarototene, such as those described in U.S. Patents, 3,622,633; 3,408,414; and 3,600,473 issued respectively on November 23, 1971; October 29, 1%8; and August 17, 1971 to Surmatis are typically produced by relatively complex processes.

Other processes for the synthesis of trans -carotene and related carotenoids characterized by their complexity are exemplified by those described in U.S. Patents 2,846,487 and 2,846,475, both issued to Isler, et al on August 5, 1968; 3,000,982 and 3,441,623 both issued to Surmatis on September 19, 1961 and April 29, 1969, respectively; 2,945,069, issued on July 12, 1960 to Stern; 3,007,976 issued on November 7, 1961 to Eiter, et al; and 3,408,406, issued on October 29, 1968 to Chechak, et al.

It is accordingly desirable to provide a method for synthesizing symmetrical olefins which is simple and which in many instances utilizes readily available reactants. It is in particular desirable to provide a simple method for synthesizing such commercially valuable compounds as ,ss-carotene and dimestrol from readily available precursors such as vitamin A aldehyde (retinal) and methoxy proniophenone, respectively.

The invention provides a method for the synthesis of symmetrical olefins, which has particular usefulness in the synthesis of trans ss-carotene and dimestrol. Broadly, the process comprises the reductive coupling of ketones or aldehvdes with reactive metallic titanium, i.e. Ti(O) to form the corresponding symmetrical olefins according to the following general reaction scheme:

The reactive Ti(O) may be obtained by reducing titanium in an oxidation state greater than (II) down to the finely divided active metaL The desired ketone or aldehyde precursor is then reacted with the active metal (in a suitable solvent medium such as an ether, e.g. tetrahydrofuran) to produce the corresponding symmetrical olefin. Reaction will desirablv be quenched, e.g. by addition of acid, preferably a mineral acid such as hydrochloric acid. The olefin produced may thereafter be separated from the solution by conventional extraction techniques, if desired, though a solution of the olefin may be required for further reaction.

As a consequence of this process a simple method for the synthesis of symmetrical olefins, especially employing readily-obtainable reactants is provided and it is possible to employ the method to provide processes for the reductive coupling of vitamin A aldehyde to form a translP-carotene and for the synthesis of dimestrol.

According to the method of this invention, the active titanium [O] reagent is reacted with an aldehyde or ketone to reductively couple the aldehyde or ketone molecules, replacing the C=O groups of the starting material with a C=C linkage. The reaction may be represented in the instance of benzophenone, for example, in the following manner

The "active" metallic titanium, i.e. Ti(O) is reacted with the aldehyde or ketone and is believed to produce the initial pinacol dialkoxide. During this initial reaction, the Ti(O) is oxidized to Ti(II). The Ti(II), thus produced, is then available to further react with the pinacol dialkoxide to yield the symmetrical olefin. The complete reaction may be briefly expressed as:

The procedure utilizing active titanium metal appears to proceed more readily than does the equivalent procedure utilizing Ti(II), which is described and claimed in our copending British Patent Specification No.

1,510,211.

It should be further understood that the titanium metal utilized in the process must be in the "active" form. Normally bulk titanium metal is quite unreactive since its surface is covered by a thin oxide coating. "Active" titanium metal can be prepared by reducing a titanium salt, such as titanium trichloride, with an alkali metal, i.e. sodium potassium or lithium, in a suitable dry organic solvent, e.g.

an ether such as dry tetrahydrofuran. The freshly prepared "active" titanium is preferably maintained as a slurry in the solvent, and the desired aldehyde or ketone is added thereto to initiate the pinacol dimerization.

The processes of this invention are useful for aldehydes and ketones broadly, including cyclic aldehydes and ketones since the reaction conditions do not tend to result in disruption of the ring formation of these cyclic compounds.

The following specific examples are provided merely to illustrate the processes of this invention: EXAMPLE I Cycloheptylidenecycloheptane Prepared by Action of Active Titanium Metal on Cycloheptanone A slurry of "active titanium metal was prepared in the following way: A slurry of titanium trichloride (1.23 g., 8.0 mmol) in 30 ml dry tetrahydrofuran was mixed under a nitrogen atmosphere, and potassium metal (0.94 g., 24 mmol) was then added. The resulting mixture was refluxed for one hour to produce active titanium metal slurried in the tetrahydrofuran. A solution of cycloheptanone (450 mg., 4.0 mmol) in 5 ml tetrahydrofuran was then added. The reaction was refluxed for ten hours, and then poured into 50 ml 2N aqueous hydrochloric acid. The solution was extracted several times with ether, and the extracts were combined, washed with water and with brine, then dried over magnesium sulfate and concentrated in a rotary evaporator. The resulting product (400 mg., 95% yield) was pure cycloheptylidene-cycloheptane as identified by its spectral properties (ir, NMR, mass spectrum).

Example II Beta-carotene Prepared by Action of Active Titanium Metal on Retinal Active titanium metal was prepared by placing titanium trichloride (1.23 g., 8.0 mmol) in 30 ml dry tetrahydrofuran under an inert atmosphere, adding either potassium metal 0.94 g., 24 mmol) or lithium metal (170 mg., 24 mmol), and then refluxing for one hour. A solution of retinal (1.15 g., 4.0 mmol) in 5 ml dry tetrahydrofuran was added, and the reaction was stirred two hours at 50 , then cooled to room temperature. The reaction mixture was quenched by cautious addition of 5 ml methanol, then poured into 5 ml 1N aqueous hydrochloric acid. The solution was extracted several times with ether, and the extracts were combined, dried over MgSO4, and concentrated by solvent removal.

After chromatographic purification on silica gel, 60% beta carotene was obtained and identified by its spectral properties 'ir, uv, nmr)." m.pt. 180--182"(3.

Claims (11)

WHAT WE CLAIM IS:

1. A process for the production of symmetrical olefins comprising reducing Ti in oxidation states greater than II to reactive Ti(O) metal in an inert solvent solution, and reacting the reactive Ti(O) metal with an aldehyde or ketone.

2. A process as claimed in claim 1 wherein Ti in the higher oxidation state is reduced to Ti(O) metal by an alkali metal reducing agent.

3. A process as claimed in claim 1 or claim 2 wherein the inert solvent is tetrahydrofuran.

4. A Drocess as claimed in any of claims 1-3 wherein the symmetrical olefin is p- carotene and the aldehyde is retinal.

5. A process as claimed in any of claims 1--3 wherein the symmetrical olefin is dimestrol and the ketone is paramethoxypropiophenone.

6. A process as claimed in any of claims 1--5 wherein the reaction solution is quenched and the symmetrical olefin separated from the reaction solution.

7. A process as claimed in any of claims 1--6 wherein the reactive Ti(O) metal is prepared by reducing a Ti salt having Ti in an oxidation state greater than (II) in a dry inert solvent medium, with an alkali metal reducing agent, to yield a slurry of reactive Ti(O) metal in said inert solvent.

8. A process as claimed in claim 7 wherein the alkali metal is sodium, potassium or lithium.

9. A process as claimed in claim 1 substantially as hereinbefore described.

10. A process for the preparation of sym metrical olefins substantially as hereinbefore described with reference to the Examples.

11. A symmetrical olefin whenever prepared by a process as claimed in any of claims 1-10.