JP2009114078A - Method for producing cross-coupling compound - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for efficiently producing a cross-coupling compound by a reaction of a Grignard compound with an alkyl halide. <P>SOLUTION: This method for producing the cross-coupling compound represented by the following formula (3): R<SP>1</SP>-R<SP>2</SP>(wherein, R<SP>1</SP>is a 1-15C alkyl group; R<SP>2</SP>is a 1-30C alkyl group having a carboxy group) comprises reacting the Grignard compound represented by the following formula (1): R<SP>1</SP>MgX (wherein, X is a halogen atom) with an alkyl halide represented by the following formula (2): R<SP>2</SP>-X' (wherein, X' is a halogen atom) in the presence of a crown ether compound and a copper compound. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to a method for producing a cross-coupling compound using a crown ether compound and a copper compound.

Cross-coupling reactions between Grignard compounds and alkyl halides are used in many carbon-carbon production reactions.
In this carbon-carbon bond generation reaction, generally, a transition metal compound such as palladium, nickel, or copper is used as a catalyst. Furthermore, many improvements in the cross-coupling reaction yield by the combination of these transition metal compounds and various additives have been reported. So far, the yield is improved by using a nickel catalyst or palladium catalyst and phosphine (Non-patent Document 1), and the yield is improved by using a copper catalyst and olefins such as 1,3-butadiene. (Non-Patent Document 2) and the like are known.

Also in the method for producing fatty acids, a carbon-carbon bond forming reaction between two types of Grignard compounds and a halocarboxylic acid has been reported (Non-patent Document 3).
In this method, however, it is necessary to add a Grignard compound to a halocarboxylic acid to make a magnesium chloride salt, and then add dilithium tetrachlorocuprate. In this reaction, after making the magnesium chloride salt, the Grignard compound is again added. Because it is necessary to add, the operation is extremely roundabout, and there was a problem in manufacturing in the factory.

Moreover, the manufacturing method which produces | generates a carboxylic acid ester from a Grignard compound and a halocarboxylic acid ester in the presence of a copper compound and hydrolyzes it has been reported (Patent Document 1).
However, this method has a problem that the operation is detoured because it is necessary to hydrolyze the ester after the carbon-carbon bond formation reaction.

On the other hand, a crown ether compound is a cyclic polyether that has a property of trapping cations and is widely used as a phase transfer catalyst by utilizing the property.
However, it has not been known so far to improve the yield by using a crown ether compound and a copper compound in the carbon-carbon bond formation reaction.
Bull. Chem. Soc. Jpn., 1976, 49, 1958-1969 J. Am. Chem. Soc., 2003, 125, 5646-5647 Tetrahedron Lett., 1976, 51, 4697-4700 International Publication No. 2006/083030 Pamphlet

  The present invention relates to providing a method for efficiently performing a cross-coupling reaction between a Grignard compound and an alkyl halide in a simple and high yield.

  The present inventor examined an effective method for producing a cross-coupling compound in a factory, and by reacting a Grignard compound and an alkyl halide in the presence of a crown ether compound and a copper compound, a simple operation was achieved. And it discovered that a cross-coupling compound could be manufactured efficiently.

That is, in the present invention, in the presence of a crown ether compound and a copper compound, the following formula (1): R ¹ MgX (wherein R ¹ represents an alkyl group having 1 to 15 carbon atoms, and X represents a halogen atom) And a Grignard compound represented by the following formula (2): R ² -X ′ (wherein R ² represents a C 1-30 alkyl group having a carboxyl group, and X ′ represents a halogen atom. Of the cross-coupling compound represented by the following formula (3): R ¹ -R ² (wherein R ¹ and R ² are the same as described above). It relates to a manufacturing method.
In the present invention, in the presence of a crown ether compound and a copper compound, the following formula (1): R ¹ MgX (wherein R ¹ represents an alkyl group having 1 to 15 carbon atoms, and X represents a halogen atom) And a Grignard compound represented by the following formula (2): R ² -X ′ (wherein R ² represents a C 1-30 alkyl group having a carboxyl group, and X ′ represents a halogen atom. A cross-coupling reaction method represented by the following formula (3): R ¹ -R ² (wherein R ¹ and R ² are the same as described above). It is related to.

According to the present invention, a cross-coupling compound of a Grignard compound and an alkyl halide can be efficiently produced by a simple operation.
In particular, the present invention can produce a branched fatty acid such as 18-methyleicosanoic acid, which is useful as a hair care material, from a Grignard compound and a halocarboxylic acid efficiently by a simple operation, and is useful as an industrial production method.

Examples of the crown ether compound in the present invention include 18-crown-6, 15-crown-5, 12-crown-4, 30-crown-10 and the like; benzo-18-crown-6, dibenzo-18-crown- 6, tribenzo-18-crown-6, benzo-15-crown-5, dibenzo-15-crown-5, tribenzo-15-crown-5, benzo-12-crown-4, dibenzo-12-crown-4, Benzocrown series such as tribenzo-12-crown-4, benzo-30-crown-10, dibenzo-30-crown-10, tribenzo-30-crown-10; dicyclohexano-18-crown-6, dicyclohexano -15-crown-5, dicyclohexano-12-crown-4, dicyclohexano-30-crown Cyclohexanone Crown system such as 10, and the like, carbon - in terms of the efficiency of the carbon bond formation reaction, 18-crown-6,15-crown-5, dibenzo-18-crown-6 is preferable.
Moreover, you may use such a crown ether in mixture of 2 or more types.
These crown ethers can be obtained by a known ether synthesis method such as a reaction of sodium alkoxide with an alkyl halide, and commercially available products can also be used.

  Although the copper compound used in this invention is not specifically limited, The copper compound normally used for a carbon-carbon bond production | generation reaction can be used, A copper halide and a lithium copper compound are preferable, for example, a copper bromide (I ), Copper (II) bromide, copper (I) chloride, copper (II) chloride, copper (I) iodide, copper (II) iodide, dilithium tetrachlorocuprate and the like.

The alkyl group having 1 to 15 carbon atoms represented by R ¹ may be either a straight chain or branched chain, such as a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a 2-methylpropyl group, n -Butyl group, tert-butyl group, pentyl group, sec-butyl group, 2-methylbutyl group, 3-methylbutyl group, n-pentyl group, 2-methylpentyl group, 3-methylpentyl group, 4-methylpentyl group, An n-hexyl group and the like can be mentioned. Among these, a branched alkyl group having 3 to 6 carbon atoms is preferable, an isopropyl group, a 2-methylpropyl group, and a sec-butyl group are more preferable, and a sec-butyl group is further preferable.

  Examples of the halogen atom represented by X include a chlorine atom, a bromine atom, and an iodine atom, and a chlorine atom and a bromine atom are preferable.

As the Grignard compound represented by R ¹ MgX, isopropyl magnesium bromide, 2-methylpropyl magnesium bromide, and sec-butyl magnesium bromide are preferable, and sec-butyl magnesium bromide is more preferable.
The Grignard compound represented by R ¹ MgX can be synthesized from the corresponding alkyl halide by a known method, and a commercially available reagent can also be used.

The alkyl group having 1 to 30 carbon atoms and having a carboxyl group represented by R ² may be linear or branched, such as a carboxymethyl group, a carboxybutyl group, a carboxyhexyl group, a carboxyoctyl group, Examples thereof include a carboxydecyl group, a carboxyundecyl group, a carboxydodecyl group, a carboxytridecyl group, a carboxytetradecyl group, a carboxypentadecyl group, a carboxyhexadecyl group, and a carboxyheptadecyl group. Among these, a straight chain having 5 to 20 carbon atoms is preferable, and carboxyundecyl group, carboxydodecyl group, carboxytridecyl group, carboxytetradecyl group, carboxypentadecyl group, carboxyhexadecyl group, and carboxyheptadecyl group are preferable. More preferred is a carboxypentadecyl group.

  Examples of the halogen atom represented by X ′ include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom, and a bromine atom is preferable.

Examples of the alkyl halide represented by R ² —X ′ include 11-bromoundecanoic acid, 12-bromododecanoic acid, 13-bromotridecanoic acid, 14-bromotetradecanoic acid, 15-bromopentadecanoic acid, 16-bromohexadecane. An acid, 17-bromoheptadecanoic acid is preferable, and 15-bromopentadecanoic acid is more preferable.
The alkyl halide represented by R ² —X ′ is synthesized by a known method such as bromination of hydroxy fatty acid using hydrobromic acid or a mixture of hydrobromic acid and sulfuric acid. It is possible to use a commercial product.

  The reaction can be carried out by adding a crown ether compound and a copper compound to a Grignard compound and an alkyl halide in the presence or absence of a solvent.

  The amount of crown ether, copper compound and Grignard compound used may be appropriately selected in such an amount that the reaction time is not delayed and the reaction rate does not decrease, but 0.0001 to 10 equivalents to the alkyl halide, It is preferable to use 0.001-1 equivalent and 1.5-4 equivalent.

  The method of the present invention can be carried out in the presence or absence of a solvent. The solvent is not particularly limited. For example, ethers such as tetrahydrofuran, diethyl ether, dimethyl ether, methoxyethane, t-butyl methyl ether, isopropyl ether and dioxane; hydrocarbons such as hexane, cyclohexane, heptane, isooctane and decane. Aromatic hydrocarbons such as benzene, toluene and xylene; nitriles such as acetonitrile, and mixtures thereof.

  The reaction temperature is not particularly limited and is, for example, about -20 to 65 ° C.

  The reaction time is not particularly limited, and for example, the reaction time is about 30 minutes to 50 hours.

  The method of the present invention is preferably performed in an inert gas atmosphere from the viewpoint of promoting a smooth carbon-carbon bond formation reaction. The inert gas is not particularly limited, and examples thereof include argon gas, nitrogen gas, and helium gas.

  The target compound can be isolated and purified from the reaction system by appropriately combining ordinary means such as filtration, washing, drying, recrystallization, extraction with various solvents, and chromatography.

The details of the reaction will be described below using examples.
In addition, the confirmation of the product was compared with a separately synthesized standard by gas chromatography by a method known in the literature.

Example 1 Production of 16-methyloctadecanoic acid (1)

In a 50 mL four-necked flask equipped with a reflux condenser, a 10 mL dropping funnel, a magnetic stirrer, and a temperature sensor, 15-bromopentadecanoic acid 1.01 g (3.14 mmol) and 18-crown-6 were 823.3 mg (1. 0 eq) was added and dried under reduced pressure. Under an argon atmosphere, copper (I) bromide (13.3 mg, 0.03 eq), anhydrous tetrahydrofuran (6 ml)
Was added to dissolve the raw material. Under room temperature, sec-butylmagnesium bromide 7.85mL (2.5eq, tetrahydrofuran solution 1.0M) was dripped in 30 minutes. After stirring for 1 hour, 5 mL of 6N-sulfuric acid aqueous solution was added and extracted with 10 mL of hexane. After washing twice with 10 mL of ion exchange water, it was dried over magnesium sulfate. Filtration and concentration under reduced pressure gave 0.84 g of a crude product.
Yield 95 as a result of measurement by gas chromatography (column: Ultra-2 manufactured by Agilent, 30 m × 0.2 mm × 0.33 μm, DET 300 ° C., INJ 300 ° C., column temperature 100 ° C. → 300 ° C., 10 ° C./min) %Met.

Examples 2-6 Production of 16-methyloctadecanoic acid (2)
Using the copper compound and crown ether shown in Table 1 below, 16-methyloctadecanoic acid was produced in the same manner as in Example 1. The results are shown in Table 1.

Comparative Examples 1 to 3 Production of 16-methyloctadecanoic acid The title compound was produced in the same manner as in Example 1 except that the crown ether shown in Table 1 was not added.

<Discussion>
From the results of Examples 1 to 6 and Comparative Examples 1 to 3, the coupling reaction between sec-butylmagnesium bromide and 15-bromopentadecanoic acid was carried out in the presence of crown ether and copper (I) bromide, thereby allowing room temperature. The reaction proceeded well in the vicinity, and a remarkable yield improvement of the desired alkyl branched fatty acid was observed.
That is, it is shown that a desired cross-coupling compound can be produced in a good yield by performing the reaction in the presence of a crown ether compound and a copper compound in a carbon-carbon bond formation reaction between a Grignard compound and an alkyl halide. It was done.

Claims (4)

In the presence of a crown ether compound and a copper compound, it is represented by the following formula (1): R ¹ MgX (wherein R ¹ represents an alkyl group having 1 to 15 carbon atoms, and X represents a halogen atom). The Grignard compound is represented by the following formula (2): R ² —X ′ (wherein R ² represents a C 1-30 alkyl group having a carboxyl group, and X ′ represents a halogen atom). A method for producing a cross-coupling compound represented by the following formula (3): R ¹ -R ² (wherein R ¹ and R ² are the same as described above) is reacted. The process according to claim 1, wherein R ¹ is a branched alkyl group having 3 to 6 carbon atoms. R < ² > is a C5-C20 linear alkyl group which has a carboxyl group, The manufacturing method of any one of Claims 1-2. In the presence of a crown ether compound and a copper compound, it is represented by the following formula (1): R ¹ MgX (wherein R ¹ represents an alkyl group having 1 to 15 carbon atoms, and X represents a halogen atom). The Grignard compound is represented by the following formula (2): R ² —X ′ (wherein R ² represents a C 1-30 alkyl group having a carboxyl group, and X ′ represents a halogen atom). A cross-coupling reaction method represented by the following formula (3): R ¹ -R ² (wherein R ¹ and R ² are the same as described above).