JPH0819018B2 - Process for producing 1,1-disubstituted ethylene derivative - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to a novel method for producing a 1,1-disubstituted ethylene derivative, and more particularly to a method for reacting a ketone or aldehyde with an organic compound containing a halogen. 1,1
-A method for producing a disubstituted ethylene derivative.

Conventional technology and problems Conventional formula [Wherein R ¹ and R ² represent hydrogen or a chain or cyclic alkyl, alkenyl, alkynyl group, aralkyl group, aryl group, or heterocyclic group, which may be the same or different, and may be a carbon chain or a heterocyclic group. A carbon chain containing atoms may form a ring. Further, these may have a substituent. ] And a general formula CXmYn (II) [wherein m is 2 or 3, n is an integer of 1 or 2 and m + n = 4]
And X is fluorine, chlorine, bromine, or iodine, and Y
Includes fluorine, chlorine, bromine or iodine, and X and Y are the same. When m is 3, Y includes any of hydrogen, a carboxyl group, a protected carboxyl group, an amide group and a cyano group. ] The compound represented by the general formula [Wherein R ¹ , R ² , X, Y, m, and n are as defined above. ]]
A method for producing a 1,1-disubstituted ethylene derivative is represented by the formula (I)
From the compound of formula (II) and the compound of formula (II) [Wherein R ¹ , R ² , X, Y, m, and n are as defined above. A two-step reaction system is generally used in which a carbinol derivative represented by the formula [1] is produced, and a 1,1-disubstituted ethylene derivative represented by the formula (III) is produced by a 1,2-elimination reaction. For example, a method using zinc in a stoichiometric amount or more (JP-A-59-93089, JP-B-60-30301), an electrolytic method [Angew.Chem.Int.Ed.Engl., 16 ,
57 (1977), JP-A-58-52236, JP-A-58-144487] and the like are known. However, these methods inevitably produce a reaction by-product, which causes a reduction in the reaction selectivity, and thus adversely affects the purification of the target 1,1-disubstituted ethylene derivative. Further, the former method requires a heavy metal in a stoichiometric amount or more, and thus involves a serious problem in terms of pollution, and is problematic to carry out on an industrial scale. Further, the latter electrolysis method has drawbacks such as lack of versatility because it requires a special device and that maintenance of equipment is not easy. In addition, since each of them is a two-step reaction system, it is necessary to separate and purify the product at each step, and the complexity of the operation is unavoidable. Furthermore, the yield of the target 1,1-disubstituted ethylene derivative is reduced. It is also a cause.

OBJECT OF THE INVENTION The object of the present invention is to provide a method for producing a 1,1-disubstituted ethylene derivative represented by the above general formula (III) in a high yield by a safe and simple operation without relying on the above conventional method. Especially.

SUMMARY OF THE INVENTION Characterized by reacting a ketone or aldehyde represented by the formula with a compound represented by the general formula CXmYn (II) in a polar solvent in the presence of a lead compound, a metal having a higher ionization tendency than lead, and an acid anhydride or an acid halide. General formula The present invention relates to a method for producing a 1,1-disubstituted ethylene derivative represented by R ¹ , R ² , X, Y, m and n are the same as above.

The 1,1-disubstituted ethylene derivative represented by the general formula (III) obtained in the present invention is an important compound as an intermediate for synthesizing drugs, agricultural chemicals and the like. For example, it is derived from the chrysanthemic acid derivative, which is a raw material of pyrethroid insecticide. Also R ¹
Is an aryl group and X and Y are halogens, the compound (II)
Aryl acetic acid derivative useful as a raw material for antibiotics, β-blockers, antiphlogistics, etc. can be easily synthesized by hydrolyzing.

In the present invention, R ¹ and R ² represent hydrogen or a chain or cyclic alkyl, alkenyl, alkynyl group, aralkyl group, aryl group, or heterocyclic group, which may be the same or different, carbon chain or A carbon chain containing a hetero atom may form a ring. Further, these may have a substituent.

Preferred chain alkyl groups include methyl, ethyl,
Examples thereof include C _{1 to} C ₂₀ linear or branched alkyl groups such as propyl, isopropyl, butyl, isobutyl, t-butyl, amyl, isoamyl, hexyl, octyl, decyl and dodecyl.

Preferred as a cyclic alkyl group is cyclopropyl,
Cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, alicyclic group, and a 1-methylcyclopropyl of C ₃ -C _16, such as a cyclodecyl, 2,2-dimethyl-cyclopropyl, 3-methyl-cyclobutyl, 1-methylcyclopentyl, 3
C having at least one C _{1 to} C ₂₀ side chain such as -ethylcyclopentyl, 3-t-butylcyclopentyl, 4-isopropylcyclohexyl, and 4-t-butylcyclohexyl
It can be mentioned alicyclic group ₃ -C _16.

Preferred chain alkenyl and alkynyl groups are vinyl, ethynyl, 1-propenyl, 2-methyl-1-propenyl, propynyl, 3-butenyl, butynyl, pentenyl, pentadienyl, pentynyl, hexenyl, hexynyl, heptenyl, heptynyl, octenyl, Examples thereof include C _{2 to} C ₂₀ straight chain or branched unsaturated hydrocarbon groups such as octynyl, 9-decenyl, prenyl, and geranyl.

Preferred cyclic alkenyl groups include cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclooctadienyl and the like.
It can be mentioned alicyclic unsaturated hydrocarbon radical of C ₃ -C _16.

Specific examples of preferable aralkyl groups include benzyl, phenethyl, phenylbutyl, diphenylmethyl, triphenylmethyl, naphthylmethyl, naphthylethyl and the like.

The preferred aryl group is a phenyl group or a polynuclear aromatic hydrocarbon group, and specific examples of the polynuclear aromatic hydrocarbon group include α-naphthyl, β-naphthyl, anthranyl and pyrenyl groups.

Preferred heterocyclic groups include cyclic groups containing oxygen, nitrogen, sulfur atoms and the like, and specific examples thereof include tetrahydrofuryl, furyl, tetrahydropyranyl, pyranyl, pyrrolyl, piperidinyl, pyridyl, oxazolyl, morpholinyl, tetrahydro. Examples thereof include thienyl, thienyl, thiadiazolyl, toluazolyl, thiazolyl, triazolyl and tetrazolyl groups.

In the case of forming a ring with carbon chain containing a carbon chain or heteroatom [- (CH ₂₎ k -], k is -CH ₂ is a 2 to 13 - instead of oxygen based, nitrogen, sulfur heteroatom such It may enter.

The substituents of R ¹ and R ² are a hydroxyl group, a protected hydroxyl group, an acyloxy group, a halogen, a C _{1 to} C ₅ linear or branched alkyl group, and a C _{2 to} C ₆ linear or branched group. Unsaturated hydrocarbon group, aralkyl group, amino group, C _{1 to} C ₅
An amino group substituted with a linear or branched alkyl group of,
Protected amino group, nitro group, protected thiol group, carboxyl group, protected carboxyl group, sulfonic acid group, protected sulfonic acid group, cyano group,
The number of the substituents is 1 to 5, and these may be the same or different. Examples of the hydroxyl-protecting group include lower alkyl groups such as methyl, ethyl, propyl, isopyr, and butyl groups, or greene (Theodora W. Green
e) "Protective Groups in Organic Synthesis"
Second of (A Weiley-Interscience Publication.1981)
Mention may be made of the hydroxyl-protecting groups described in the chapter. Specific examples of the acyloxy group include formyloxy, acetyloxy, propionyloxy, valeryloxy, benzoyloxy, toluoyloxy and furoyloxy groups. Examples of halogen include fluorine, chlorine, bromine and iodine. Examples of the C _{1 to} C ₅ linear or branched alkyl group include methyl, ethyl, propyl, isopropyl, butyl, 1-butyl, amyl and isoamyl groups. Examples of the C _{2 to} C ₆ linear or branched unsaturated hydrocarbon group include vinyl, ethynyl, propenyl,
Examples of the aralkyl group include butenyl and hexenyl groups, and examples of the aralkyl group include benzyl, phenethyl, phenylpropyl, phenylbutyl and diphenylmethyl groups. Examples of C ₁ -C ₅ linear or branched alkyl groups substituted with amino groups include methyl, ethyl, propyl, isopropyl, butyl, t-butyl, amyl, isoamyl groups and the like. No. 7 of the same book as the protecting group for amino group
Mention may be made of the amino-protecting groups described in the chapter. Methyl, ethyl, propyl, as a protecting group for the thiol group,
Examples thereof include C _{1 to} C ₅ alkyl groups such as isopropyl, butyl, t-butyl, amyl and isoamyl groups, phenyl, benzyl and phenethyl groups. Examples of the carboxyl-protecting group include the carboxyl-protecting groups described in Chapter 5 of the same book. Examples of the protecting group for the sulfonic acid group include alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, amyl and isoamyl groups, and aralkyl groups such as phenyl, benzyl and phenethyl groups.

Further, specific examples of the above-mentioned substituents substituted with these groups include general formulas A group represented by the formula [wherein R ⁴ is hydrogen or the above-mentioned carboxylic acid-protecting group] can be given as an example.

Further, X in the general formula CXmYn (II) is any one of fluorine, chlorine, bromine and iodine, and Y is any one of fluorine, chlorine, bromine and iodine. Specific examples thereof are CCl ₄ , CBr ₄ and CCl. ₃ Br, CCl ₂ Br ₂ , CClBr ₃ , CC
l ₃ F, CCl ₂ F ₂ , CClF ₃ , CBr ₃ F, CBr ₂ F ₂ , CBrF ₃ , CCl ₃ I and the like can be mentioned. When m is 3, Y is hydrogen, a carboxyl group, a protected carboxyl group, an amido group or a cyano group, and specific examples thereof include CHCl ₃ and CCl _{3
COOH, CBr 3 COOH, CCl 3} COOCH 3, CF 3 COOCH 3, CCl 3 COOPh, CCl 3 C
OOCH ₂ Ph, CCl ₃ CONH ₂ , CCl ₃ CON (CH ₃ ) ₂ , CCl ₃ CN and the like can be mentioned.

In the present invention, the compound of the general formula (II) is a compound of the general formula (I)
It suffices to use an equivalent amount with respect to the ketone or aldehyde represented by the formula (1), but it is possible to obtain a good result by using a slight excess, and the preferred range of use is 1 to 4 equivalents with respect to the ketone or aldehyde.

Next, the solvent used in the present invention is preferably a polar solvent, for example, alcohols, ethers, nitriles, amides and the like, specifically, methanol, tetrahydrofuran, dioxane, acetonitrile, dimethylformamide, N-methyl-2-pyrrolidone. , 1,3-dimethyl-2-imidazolidinone, dimethyl sulfoxide and the like,
These are used alone or as a mixture. Water may be contained as needed. Particularly preferred is dimethylformamide, and its use amount is not particularly limited, but is preferably at least an amount in which the raw material is completely dissolved. However, even if it is less than that, there is no problem because the reaction proceeds, but it may be difficult to perform the operation, or there may be problems such as a decrease in yield.

The lead compound used in the present invention may have a lead valence of 0, 2, or 4, and these compounds may be in the form of a hydrate. As the lead compound used, conventionally known compounds can be widely used. For example, lead halides such as lead fluoride, lead chloride, lead bromide, lead iodide, lead nitrate, lead sulfate, lead perchlorate, lead borate, lead carbonate, lead phosphate, and other inorganic acid lead acetate. The fatty acid lead such as lead oxalate and lead stearate can be used. These lead compounds can be used alone or in combination of two or more. Particularly preferred are lead halides such as lead fluoride, lead chloride, lead bromide and lead iodide. The amount of these lead compounds used is preferably 0.001 to 0.5 equivalents relative to the ketone or aldehyde of the general formula (I) usually used as a starting material,
If it is less than 0.001 equivalent, the effect is small, and if it is more than 0.5 equivalent, the effect is inevitable, but it is not economical.

The metal having a greater ionization tendency than lead used in the present invention includes any one of aluminum, iron, nickel, tin, cobalt and magnesium, or a mixture thereof, with aluminum being particularly preferred.
The shape of these metals used is not particularly limited, and various shapes such as powder, plate, foil, lump or needle can be used. The amount used is preferably in the range of 0.7 to 6 equivalents relative to the ketone or aldehyde of the general formula (I). If the amount is less than 0.7 equivalents, the reaction will slow down or the reaction will stop. In addition to being uneconomical, side reactions occur and the yield decreases.

As the acid anhydride or acid halide used in the present invention, for example, an acid anhydride of C _{1 to} C ₁₂ monocarboxylic acid or an acid halide thereof can be used, but particularly preferable ones are acetic anhydride, propionic anhydride, Lactic anhydride is mentioned, and the amount thereof is preferably in the range of 1 to 4 equivalents relative to the ketone or aldehyde of the general formula (I).

In the present method, the presence of the above solvent and catalyst system is essential, and even if any of them is lacking, the object of the present invention cannot be achieved.

The reaction temperature in the present invention is preferably about 0 to 100 ° C, preferably 0 to 40 ° C, though the preferable range varies depending on the starting materials, the solvent and the like.

[Examples] The present invention will be described more specifically below with reference to Examples.

Example 1 In a round-bottomed flask, 18 mg (0.05 mmol) of lead bromide and 270 mg (10 mmol) of finely cut aluminum foil were placed, and 10 ml of dimethylformamide and benzaldehyde (1) 53
0 mg (5 mmol), carbon tetrachloride (2) 1.15 g (7.5 mmol) and acetic anhydride 1.02 g (10 mmol) were added,
The reaction was carried out by stirring at 5 ° C for 2 hours. After completion of the reaction, 10 ml of water was added to the reaction solution and extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give a yellow oil (900 mg).
Obtained. By refining this using a silica gel column, 870 mg (yield 90%) of colorless liquid compound (3) was obtained.
%) Obtained. The by-product of the compound (4) was 1% or less.

The NMR spectrum of compound (3) was in good agreement with its structure. ¹ H-NMR (CDCl ₃ ) δ6.75 (s, 1H, -CH =), 7.1 to 7.6 (m, 5H, Ph). Examples 2-9 The starting materials shown in Table 1 were reacted in the same manner as in Example 1 to obtain the products shown in Table 1 in high yield and high selectivity.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display area C07C 22/04 25/24 67/343 69/747 E 9546-4H F 9546-4H 253/30 255 / 35 // B01J 31/04 X C07B 61/00 300 (56) Reference JP 62-207233 (JP, A) JP 56-140936 (JP, A) JP 54-90103 (JP, A) JP-A-63-211242 (JP, A) JP-A-59-25350 (JP, A) JP-A-61-246149 (JP, A)

Claims (2)

[Claims] 1. A general formula [Wherein R ¹ and R ² represent hydrogen or a chain or cyclic alkyl, alkenyl, alkynyl group, aralkyl group, aryl group, or heterocyclic group, which may be the same or different, carbon chain or A carbon chain containing a hetero atom may form a ring. Further, these may have a substituent. ] In the presence of a lead compound in a polar solvent in the presence of a lead compound, a metal having a greater ionization tendency than lead, and an acid anhydride or an acid halide, a compound of the general formula CXmYn (II) [wherein m is 2 or 3, n is An integer of 1 or 2 and m + n = 4
And X is fluorine, chlorine, bromine, or iodine, and Y
Includes fluorine, chlorine, bromine or iodine, and X and Y are the same. When m is 3, Y includes any of hydrogen, a carboxyl group, a protected carboxyl group, an amide group and a cyano group. ] A general formula characterized by reacting with a compound represented by [Wherein R ¹ , R ² , X, Y, m, and n are as defined above. ]]
Process for producing 1,1-disubstituted ethylene derivative. 2. The method according to claim 1, wherein the metal having a higher ionization tendency than lead is any one of aluminum, iron, nickel, tin, cobalt, magnesium or a mixture thereof.