JP7199664B2 - Method for producing chlorinated ketone compound - Google Patents

Description

TECHNICAL FIELD The present invention relates to a method for producing a chlorinated ketone compound, and more particularly to a method for producing a chlorinated ketone compound using an α,α-disubstituted allyl alcohol compound as a reaction raw material. Furthermore, the present invention relates to a method for producing an α-methylene ketone compound based on the chlorinated ketone compound produced by the above method.

α-methylene ketone compounds, specifically
General formula (3)

(wherein R ¹ and R ² are each an alkyl group, an aromatic hydrocarbon group, or an alicyclic hydrocarbon group, and R ¹ and R ² together form an aliphatic hydrocarbon ring; may form)
The compound represented by is widely found in natural products and is known as a biologically active substance (eg, Non-Patent Documents 1 to 3). Therefore, it would be very useful if the compound could be produced by organic synthesis, and various attempts have been made. For example, a method of oxidizing an α,α-disubstituted allyl alcohol compound as a raw material using a heavy metal oxidizing agent such as thallium (eg, Non-Patent Documents 4 and 5) and mercury (eg, Non-Patent Document 6),
A method of oxidation using hypervalent iodine (eg, Non-Patent Documents 7 to 9) is known.

Arch. Microbiol. 1981, 730, 223-227; Tetrahedron 2006, 62, 2370-2379 Sci. Transl. Med. 2015, 7, 286ra67 Tetrahedron Lett. 1996,37,3865-3866 J. Org. Chem. 1999, 64, 101-119 Tetrahedron Lett. 1992, 33, 4325-4328 J. Org. Chem. 1995, 60, 4439-4443 Org. Lett. 2008, 10, 1017-1020 Molecules. 2015, 20, 1475-1494

However, heavy metal oxidizing agents and hypervalent iodine oxidizing agents are difficult to say as general-purpose reagents and are expensive, and the former heavy metal oxidizing agent imposes a large environmental load. Therefore, it has been desired to develop a simpler production method, which is not a method that is sufficiently satisfactory as an industrial method.

In view of the above problems, the inventors of the present invention have continued earnest research. As a result, if the α,α-disubstituted allyl alcohol compound is oxidized in the presence of tetraalkylammonium hypochlorite, the chlorinated ketone, which is an intermediate for producing the α-methylene ketone compound, can be obtained. The inventors have found that the compound can be easily synthesized, and have completed the present invention.

That is, the present invention has the general formula (1)

(wherein R ¹ and R ² are each an alkyl group, an aromatic hydrocarbon group, or an alicyclic hydrocarbon group, and R ¹ and R ² together form an aliphatic hydrocarbon ring may be)
The α,α-disubstituted allyl alcohol compound represented by general formula (2), characterized by being oxidized in the presence of tetraalkylammonium hypochlorite

(Wherein, R ¹ and R ² are the same as above)
A method for producing a chlorinated ketone compound.

Furthermore, the present invention further dehydrochlorinates the chlorinated ketone compound represented by the general formula (2) produced above in the presence of a base,
General formula (3)

(Wherein, R ¹ and R ² are the same as above)
Also provided is a method for producing an α-methylene ketone compound represented by

According to the present invention, a corresponding chlorinated ketone compound can be easily organically synthesized by an oxidation reaction using tetraalkylammonium hypochlorite using an α,α-disubstituted allyl alcohol compound as a starting material. This chlorinated ketone compound can be converted to an α-methylene ketone compound by dehydrochlorination in the presence of a base. Therefore, the target compound can be efficiently obtained by a method with less environmental impact without using expensive oxidizing agents such as heavy metals, and is industrially extremely useful.

Embodiments of the present invention are described in detail below. However, the present invention is not limited to these forms.

In the production method of the present invention, as a raw material compound, the general formula (1)

(wherein R ¹ and R ² are each an alkyl group, an aromatic hydrocarbon group, or an alicyclic hydrocarbon group, and R ¹ and R ² together form an alicyclic hydrocarbon group; may form)
An α,α-disubstituted allyl alcohol compound represented by is used. Such α,α-disubstituted allyl alcohol compounds are readily prepared by nucleophilic addition of a vinyl Grignard reagent to the corresponding ketone compound.

Here, the alkyl groups for R ¹ and R ² may be linear or branched, and examples thereof include alkyl groups having 1 to 20 carbon atoms. Examples of such alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, neopentyl and tert-pentyl. group, isopentyl group, 2-methylbutyl group, 1-ethylpropyl group, hexyl group, isohexyl group, 4-methylpentyl group, 3-methylpentyl group, 2-methylpentyl group, 1-methylpentyl group, 3,3- dimethylbutyl group, 2,2-dimethylbutyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group, 1-ethylbutyl group, 2 -ethylbutyl group, heptyl group, octyl group, nonyl group, decyl group, cetyl group, stearyl group and the like. The alkyl group preferably has 1 to 12 carbon atoms, more preferably a lower alkyl group having 1 to 6 carbon atoms, and most preferably a methyl group.

Further, the aromatic hydrocarbon group includes, for example, an aryl group having 6 to 20 carbon atoms, and specific examples include a phenyl group, 1-naphthyl group, 2-naphthyl group, anthryl group, phenanthryl group, and 2-biphenyl group. , 3-biphenyl group, 4-biphenyl group, terphenyl group and the like, and phenyl group is particularly preferred.

Furthermore, the alicyclic hydrocarbon group may have, for example, 3 to 20 carbon atoms, preferably 5 to 15 carbon atoms, and more preferably 6 to 12 carbon atoms. Specifically, monocyclic groups such as cyclopropyl group, cyclobutyl group, cyclopentyl group, methylcyclopentyl group, cyclohexyl group, cycloheptyl group, cyclooctyl group, adamantyl group, bicyclo(2,2,1)heptyl group, etc. Among them, a cyclohexyl group is particularly preferred. These alicyclic groups may also be condensed alicyclic groups in which aromatic hydrocarbon rings or other aliphatic hydrocarbon rings are condensed.

Furthermore, these R ¹ and R ² may together form an aliphatic hydrocarbon ring. Aliphatic hydrocarbon rings formed by such R ¹ and R ² together include spiro rings corresponding to the alicyclic hydrocarbon groups represented by R ¹ and R ² above, particularly cyclo A condensed aliphatic ring obtained by condensing an alkyl ring, an aromatic ring, or another aliphatic ring is preferred.

These aromatic hydrocarbon groups or alicyclic hydrocarbon groups for R ¹ and R ² may have substituents, and such substituents include the above-described alkyl groups and halogen atoms (preferably , chlorine atom), a thio group, a hydroxyl group, and the like.

In the method of the present invention, such an α,α-disubstituted allyl alcohol compound is oxidized in the presence of tetraalkylammonium hypochlorite to obtain the compound represented by general formula (2).

(Wherein, R ¹ and R ² are the same as above)
to obtain a chlorinated ketone compound represented by Here, the tetraalkylammonium hypochlorite preferably has an alkyl group having 1 to 5 carbon atoms such as a methyl group and an ethyl group. Examples of such tetraalkylammonium hypochlorite include tetramethylammonium hypochlorite, tetraethylammonium hypochlorite, tetrapropylammonium hypochlorite, and tetrabutylammonium hypochlorite. Tetramethylammonium chlorate and tetraethylammonium hypochlorite are particularly preferred. These tetraalkylammonium hypochlorites can also be used in combination of two or more.

The above-mentioned tetraalkylammonium hypochlorite may be obtained by any production method. Specifically, chlorination is performed by blowing chlorine gas into a tetraalkylammonium hydroxide solution to produce the target compound. Alternatively, the target compound is eluted by passing a tetraalkylammonium hydroxide solution through an ion-exchange resin to replace it with a tetraalkylammonium and then passing it through a hypochlorite solution such as sodium hypochlorite. Those obtained by the ion-exchange resin method that allows the Due to these production methods, these tetraalkylammonium hypochlorites may contain tetraalkylammonium chlorides, tetraalkylammonium hydroxides, and the like.

The amount of tetraalkylammonium hypochlorite to be used is not particularly limited, but is preferably equimolar or more per 1 mol of the α,α-disubstituted allyl alcohol compound. From the viewpoint of obtaining the target chlorinated ketone compound in high yield, the amount is more preferably 1 to 6 mol, and particularly preferably 1.1 to 4 mol.

The solvent for carrying out the oxidation reaction of the α,α-disubstituted allyl alcohol compound is an organic solvent in which the raw material compound is dissolved, and the organic solvent itself is oxidized to tetraalkylammonium hypochlorite as an oxidizing agent. A difficult one is used. Specifically, polar protic solvents such as methanol, ethanol, and isopropyl alcohol; polar aprotic solvents such as acetonitrile, acetone, ethyl acetate, butyl acetate, N,N-dimethylformamide, dimethylsulfoxide, and nitrobenzene; dichloromethane and chloroform. , hexane, benzene, and toluene. These may be used in combination of two or more. For example, in the α,α-disubstituted allyl alcohol compound, in the general formula (1), when R ¹ is a lower alkyl group such as a methyl group and R ² is a monocyclic group such as a cyclohexyl group, methanol ( 10 to 90% by mass) and acetonitrile (10 to 50% by mass) are particularly preferred.

A suitable amount of the solvent to be used is an amount that dissolves 0.02 to 0.5 mmol, more preferably 0.03 to 0.4 mmol of the raw material compound in 1 ml of the solvent.

Such an oxidation reaction of the α,α-disubstituted allyl alcohol compound is preferably carried out in the presence of an acidic compound. That is, the acidic compound exerts the action of promoting halogen addition to the double bond, thereby enhancing the progress of the reaction. Such acidic compounds are not particularly limited as long as they are Bronsted acids whose aqueous solutions are acidic. Among them, acetic acid is particularly preferred.

If the amount of the acidic compound used is large enough to make the pH of the reaction solution strongly acidic, hypochlorous acid derived from tetraalkylammonium hypochlorite used as an oxidizing agent will decompose to generate chlorine gas. , Since there is a risk of leakage out of the system, it is sufficient if there is a necessary amount to achieve the above-mentioned purpose of blending, 1 to 6 equivalents, preferably 1.2 to 3 equivalents, relative to tetraalkylammonium hypochlorite Used in the equivalent range.

The above oxidation reaction is usually carried out at a reaction temperature of 0 to 50°C with stirring, preferably at a reaction temperature of 5 to 35°C with stirring. If the reaction temperature exceeds 50°C, the decomposition reaction and the oxidation reaction of tetraalkylammonium hypochlorite will be competing reactions, and the amount of tetraalkylammonium hypochlorite used will increase, which is not preferable. Lowering the temperature to a low temperature (less than 0° C.) at which the reaction system does not solidify requires special equipment measures and causes a decrease in the reaction rate.

The reaction time is generally selected from the range of 0.2-8 hours, more preferably 0.5-4 hours.

By the above oxidation reaction of the α,α-disubstituted allyl alcohol compound, the formula (2)

(Wherein, R ¹ and R ² are the same as above)
A chlorinated ketone compound represented by is produced. This chlorinated ketone compound can be used as a raw material for various reactions.

(Wherein, R ¹ and R ² are the same as above)
is preferably used as a raw material for producing the α-methylene ketone compound represented by

The α-methylene ketone compound represented by the above formula (3) can be easily produced by dehydrochlorinating the chlorinated ketone compound represented by the above formula (2) in the presence of a base. That is, after the oxidation reaction of the α,α-disubstituted allyl alcohol compound, a base may be added to the reaction solution containing the chlorinated ketone compound to produce the α-methylene ketone compound.

Incidentally, the compound represented by the above formula (3) may be converted to the above-mentioned The reaction may progress to dehydrochlorination, and may coexist with the compound represented by the formula (2).

Here, the base can be used without limitation as long as it is a substance that emits hydroxide ions (OH ⁻ ). Preferably, it is a basic compound exhibiting a pKa value of 5 or more, preferably 10 or more. Specifically, inorganic carbonates such as sodium carbonate, potassium carbonate, calcium carbonate, lithium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, lithium hydrogen carbonate; sodium hydroxide, potassium hydroxide, lithium hydroxide, magnesium hydroxide, Hydroxides such as calcium hydroxide; hydrides such as sodium hydride and potassium hydride; aliphatic tertiary amine compounds such as triethylamine and tributylamine; class amine compounds and the like.

Furthermore, as the base, a superstrong base comprising an organic base compound such as phosphazene, amidine, guanidine, or polycyclic polyamine can be suitably used. Such superbases include 1,4-diazabicyclo[2,2,2]octane (DABCO), 1,5-diazabicyclo[4.3.0]-5-nonene (DBN), 1,8-diazabicyclo[ 5.4.0]-7-undecene (DBU), 1,1,3,3-tetramethylguanidine (TMG), 7-methyl-1,5,7-triazabicyclo[4,4,0]deca -5-ene (MTBD), 1,5,7-triazabicyclo[4,4,0]dec-5-ene (TBD), tert-butylimino-tri(pyrrolidino)phosphorane (BTPP), 2-tert- butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine (BEMP), among which DBU is particularly preferred.

The amount of these bases to be used is not particularly limited, but from the viewpoint of obtaining the desired α-methylene ketone compound in high yield, it is preferably 1 to 4 equivalents relative to the chlorinated ketone compound, and more Preferably 2 to 3 equivalents.

The reaction temperature of the dehydrochlorination reaction is generally 0 to 50°C with stirring, preferably 5 to 35°C with stirring. The reaction time is generally 0.3 to 4 hours, preferably 0.5 to 3 hours.

EXAMPLES The present invention will be described in more detail below with reference to Examples, but the present invention is not limited to these Examples.

The compound names in Examples are summarized below.

Example 1
0.5 mmol of compound 1a, 1 mmol of tetramethylammonium hypochlorite, and 1 mmol of acetic acid were added to 6 ml of methanol, and the compound 1a and tetramethylammonium hypochlorite were mixed with each other by stirring at room temperature for 2 hours. reacted. The product of the obtained reaction solution was measured by proton nuclear magnetic resonance spectroscopy ( ¹ H-NMR) in deuterated chloroform. A peak of acetyl group hydrogen at around δ: 2.25 ppm and a hydrogen peak of trisubstituted carbon at around δ: 3.62 ppm were confirmed, confirming that this is compound 2a. The yield of compound 2a was 90%.

Example 2
Example 1 was carried out in the same manner as in Example 1, except that compound 1b was used instead of compound 1a as a raw material compound. The product of the resulting reaction solution was measured by ¹ H-NMR in deuterated chloroform and confirmed to be compound 2b. The yield of compound 2b was 45%. In addition, this reaction solution contained compound 3b at a yield of 12%.

Example 3
Example 1 was carried out in the same manner as in Example 1, except that compound 1b was used instead of compound 1a as the raw material compound, and tetraethylammonium hypochlorite was used instead of tetramethylammonium hypochlorite. The product of the resulting reaction solution was measured by ¹ H-NMR in deuterated chloroform and confirmed to be compound 2b. The yield of compound 2b was 26%. In addition, this reaction solution contained compound 3b at a yield of 36%.

Example 4
A mixed solvent of 4 ml of methanol and 2 ml of acetonitrile was charged with 0.5 mmol of compound 1c, 1 mmol of tetramethylammonium hypochlorite, and 1 mmol of acetic acid, and stirred at room temperature for 4 hours to give the above compound 1c and hypochlorous acid. It was reacted with tetramethylammonium acid. The product of the obtained reaction solution was measured by ¹ H-NMR in deuterated chloroform and confirmed to be compound 2c. The yield of compound 2c was 59%.

Example 5
Subsequently, 2 mmol of 1,8-diazabicyclo[5.4.0]-7-undecene (DBU) was added to the reaction solution containing compound 2a obtained by performing the same operation as in Example 1, and the mixture was allowed to cool to room temperature. and stirred for 3 hours. Regarding the obtained reaction solution, the product was measured by ¹ H-NMR in deuterated chloroform. A hydrogen peak of the group was confirmed, confirming that this was compound 3a. The yield of compound 3a was 68% based on compound 1a.

Claims (3)

General formula (1)

(wherein R ¹ and R ² are each an alkyl group, an aromatic hydrocarbon group, or an alicyclic hydrocarbon group, and R ¹ and R ² together form an aliphatic hydrocarbon ring; may form)
The α,α-disubstituted allyl alcohol compound represented by general formula (2), characterized by being oxidized in the presence of tetraalkylammonium hypochlorite

(Wherein, R ¹ and R ² are the same as above)
A method for producing a chlorinated ketone compound. 2. The method for producing a chlorinated ketone compound according to claim 1, wherein the tetraalkylammonium hypochlorite is tetramethylammonium hypochlorite. The chlorinated ketone compound represented by the general formula (2) produced by the method according to any one of claims 1 and 2 is dehydrochlorinated in the presence of a base,
General formula (3)

(Wherein, R ¹ and R ² are the same as above)
A method for producing an α-methylene ketone compound represented by