JP5093798B2 - Α, β-Unsaturated carbonyl compound having perfluoroalkyl group and process for producing the same - Google Patents

Description

  The present invention relates to an α, β-unsaturated carbonyl compound having a perfluoroalkyl group and a method for producing the same.

An α, β-unsaturated carbonyl compound having a perfluoroalkyl group at the α-position and a hydroxyl group at the β-position is a useful precursor for the synthesis of heterocyclic compounds in the field of medicine and agrochemicals. In particular, the perfluoroalkyl group is a trifluoromethyl group. These compounds are important because of their high physiological activity. In addition, α, β-unsaturated carbonyl compounds having an amino group at the β-position are also useful compounds as synthetic intermediates for medical and agricultural chemicals, such as herbicides and 3-aminoacrylates using 3-aminoacrylic acid derivatives. Synthesis of pharmaceutical intermediates using 2-cyclohexen-1-one derivatives is known.
As a direct production method of an α, β-unsaturated carbonyl compound having a perfluoroalkyl group at the α-position and a hydroxyl group at the β-position using a trifluoromethylating agent, a trifluoromethyl group can be obtained by electrode reaction using trifluoroacetic acid. A method of introducing a trifluoromethyl group using a (4-fluorophenyl) (3-nitrophenyl) (trifluoromethyl) sulfonium salt (Patent Document 1) is disclosed. Yes. However, the former requires the reaction at −40 ° C., and the latter uses a special reaction reagent.
Further, a compound in which a trifluoromethyl group is introduced at the α-position of an α, β-unsaturated carbonyl compound having an unsubstituted or monosubstituted amino group at the β-position of the present invention is not known.
Chemistry Letters, 853 pages, 1998 US Pat. No. 6,215,021

  An object of the present invention is to provide an α, β-unsaturated carbonyl compound having a perfluoroalkyl group and a simple and efficient method for producing the compound.

As a result of intensive studies to solve the above-mentioned problems, the present inventors have found that α, β-- can be obtained by halogenated perfluoroalkyls in the presence of sulfoxides, peroxides, iron compounds and optionally acids. It has been found that an α, β-unsaturated carbonyl compound having a perfluoroalkyl group can be produced from an unsaturated carbonyl compound in one step, and the present invention has been completed.
That is, the present invention relates to the general formula (1)

[Wherein, R ¹ represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms or an alkoxy group having 1 to 8 carbon atoms, and R ² represents an alkyl group having 1 to 4 carbon atoms or a phenyl group. R ¹ and R ² may be combined with the atoms to be bonded to form a ring. Rf represents a perfluoroalkyl group having 1 to 6 carbon atoms. Y ^a represents ^a nitrogen atom which may be substituted. ] The α, β-unsaturated carbonyl compound having a perfluoroalkyl group represented by the formula (hereinafter also referred to as “α, β-unsaturated carbonyl compound (1) having a perfluoroalkyl group” or “compound (1)”). ).
Further, the present invention provides a compound represented by the general formula (2)

[Wherein R ¹ and R ² have the same contents as above. Y represents an oxygen atom or an optionally substituted nitrogen atom. ], An α, β-unsaturated carbonyl compound (hereinafter also referred to as “α, β-unsaturated carbonyl compound (2)”) represented by the general formula (3): R ^3a S (═O) R ^3b [Formula In the formula, R ^3a and R ^3b represent an alkyl group having 1 to 12 carbon atoms or an optionally substituted phenyl group. ] In the presence of a peroxide, an iron compound and optionally an acid in the presence of an acid represented by general formula (4): Rf-X [wherein Rf Represents a C 1-6 perfluoroalkyl group, and X represents a halogen atom. And a halogenated perfluoroalkyl (hereinafter also referred to as “halogenated perfluoroalkyl (4)”) represented by the general formula (1a)

[Wherein, Rf, R ¹ , R ² and Y have the same contents as described above. ] The α, β-unsaturated carbonyl compound having a perfluoroalkyl group represented by the formula (hereinafter also referred to as “α, β-unsaturated carbonyl compound (1a) having a perfluoroalkyl group” or “compound (1a)”). ).

  The α, β-unsaturated carbonyl compound having a perfluoroalkyl group of the present invention is useful as a medical pesticide and a synthetic intermediate thereof, and the production method of the present invention uses the α, β-unsaturated carbonyl compound. It is industrially effective as a production method obtained with a high yield.

The present invention is described in further detail below.
In the general formulas (1), (1a) and (2), the alkyl group having 1 to 8 carbon atoms represented by R ¹ is specifically a methyl group, ethyl group, propyl group, isopropyl group, cyclopropyl Group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, cyclobutyl group, cyclopropylmethyl group, 2,2-dimethylpropyl group, 2-methylbutyl group, 2-methyl-2-butyl group, 3- Methylbutyl group, 3-methyl-2-butyl group, pentyl group, 2-pentyl group, 3-pentyl group, cyclopentyl group, cyclopentyl group, 2,3-dimethyl-2-butyl group, 3,3-dimethylbutyl group, 3,3-dimethyl-2-butyl group, 2-ethylbutyl group, hexyl group, 2-hexyl group, 3-hexyl group, 2-methylpentyl group, 2-methyl-2- Nethyl group, 2-methyl-3-pentyl group, 3-methylpentyl group, 3-methyl-2-pentyl group, 3-methyl-3-pentyl group, 4-methylpentyl group, 4-methyl-2-pentyl group Cyclohexyl group, 2,2-dimethyl-3-pentyl group, 2,3-dimethyl-3-pentyl group, 2,4-dimethyl-3-pentyl group, 4,4-dimethyl-2-pentyl group, 3- Ethyl-3-pentyl group, heptyl group, 2-heptyl group, 3-heptyl group, 2-methyl-2-hexyl group, 2-methyl-3-hexyl group, 5-methylhexyl group, 5-methyl-2- Hexyl group, 2-ethylhexyl group, 6-methyl-2-heptyl group, 4-methyl-3-heptyl group, octyl group, 2-octyl group, 3-octyl group, 2-propylpentyl group, 2,4,4 -Trimethyl Examples thereof include a pentyl group and a cyclooctyl group.

Specific examples of the alkoxy group having 1 to 8 carbon atoms represented by R ¹ include a methoxy group, an ethoxy group, a propoxy group, an isopropyloxy group, a cyclopropyloxy group, a butoxy group, an isobutyloxy group, and a sec-butyloxy group. Tert-butyloxy group, cyclobutyloxy group, cyclopropylmethyloxy group, 2,2-dimethylpropyloxy group, 2-methylbutyloxy group, 2-methyl-2-butyloxy group, 3-methylbutyloxy group, 3 -Methyl-2-butyloxy group, pentyloxy group, 2-pentyloxy group, 3-pentyloxy group, cyclopentyloxy group, cyclopentyloxy group, 2,3-dimethyl-2-butyloxy group, 3,3-dimethylbutyloxy Group, 3,3-dimethyl-2-butyloxy group, 2-ethylbutyl Xyl group, hexyloxy group, 2-hexyloxy group, 3-hexyloxy group, 2-methylpentyloxy group, 2-methyl-2-pentyloxy group, 2-methyl-3-pentyloxy group, 3-methylpentyl Oxy group, 3-methyl-2-pentyloxy group, 3-methyl-3-pentyloxy group, 4-methylpentyloxy group, 4-methyl-2-pentyloxy group, cyclohexyloxy group, 2,2-dimethyl- 3-pentyloxy group, 2,3-dimethyl-3-pentyloxy group, 2,4-dimethyl-3-pentyloxy group, 4,4-dimethyl-2-pentyloxy group, 3-ethyl-3-pentyloxy Group, heptyloxy group, 2-heptyloxy group, 3-heptyloxy group, 2-methyl-2-hexyloxy group, 2-methyl-3-hexyloxy group Si group, 5-methylhexyloxy group, 5-methyl-2-hexyloxy group, 2-ethylhexyloxy group, 6-methyl-2-heptyloxy group, 4-methyl-3-heptyloxy group, octyloxy group, Examples include 2-octyloxy group, 3-octyloxy group, 2-propylpentyloxy group, 2,4,4-trimethylpentyloxy group, cyclooctyloxy group and the like.

In (1), (1a) and (2), the alkyl group having 1 to 4 carbon atoms represented by R ² is specifically a methyl group, an ethyl group, a propyl group, an isopropyl group, or cyclopropyl. Examples thereof include a group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a cyclobutyl group, and a cyclopropylmethyl group.

Furthermore, in the general formula (3), specific examples of the alkyl group having 1 to 12 carbon atoms represented by R ^3a and R ^3b include a methyl group, a butyl group, and a dodecyl group. Specific examples of the optionally substituted phenyl group represented by R ^3a and R ^3b include a phenyl group, a p-tolyl group, an m-tolyl group, and an o-tolyl group. R ^3a and R ^3b are preferably a methyl group, a butyl group, a dodecyl group, a phenyl group or a p-tolyl group, and more preferably a methyl group, in terms of a good yield.

  Further, in the general formulas (1), (1a) and (4), specific examples of the perfluoroalkyl group having 1 to 6 carbon atoms represented by Rf include trifluoromethyl group, perfluoroethyl group, perfluoropropyl group. Group, perfluoroisopropyl group, perfluorocyclopropyl group, perfluorobutyl group, perfluoroisobutyl group, perfluoro-sec-butyl group, perfluoro-tert-butyl group, perfluorocyclobutyl group, perfluorocyclopropylmethyl Group, perfluoropentyl group, perfluoro-1,1-dimethylpropyl group, perfluoro-1,2-dimethylpropyl group, perfluoroneopentyl group, perfluoro-1-methylbutyl group, perfluoro-2-methylbutyl group Perfluoro-3-methylbutyl group, Fluorocyclobutylmethyl group, perfluoro-2-cyclopropylethyl group, perfluorocyclopentyl group, perfluorohexyl group, perfluoro-1-methylpentyl group, perfluoro-2-methylpentyl group, perfluoro-3-methyl Pentyl group, perfluoroisohexyl group, perfluoro-1,1-dimethylbutyl group, perfluoro-1,2-dimethylbutyl group, perfluoro-2,2-dimethylbutyl group, perfluoro-1,3-dimethyl Butyl group, perfluoro-2,3-dimethylbutyl group, perfluoro-3,3-dimethylbutyl group, perfluoro-1-ethylbutyl group, perfluoro-2-ethylbutyl group, perfluoro-1,1,2- Trimethylpropyl group, perfluoro-1,2,2-trimethylpropyl group Perfluoro-1-ethyl-1-methylpropyl group, etc. perfluoro-1-ethyl-2-methylpropyl group or a perfluoroalkyl cyclohexyl group can be exemplified. Trifluoromethyl group, perfluoroethyl group, perfluoropropyl group, perfluoroisopropyl group, perfluorobutyl group, perfluoroisobutyl group, perfluoro- in terms of being useful as a pharmaceutical / agricultural chemical / electronic material and synthetic intermediates thereof. A sec-butyl group, a perfluoro-tert-butyl group or a perfluorohexyl group is desirable, and a trifluoromethyl group or a perfluoroethyl group is more desirable.

  Furthermore, in the general formula (4), as X, specifically, a chlorine atom, a bromine atom or an iodine atom can be exemplified, and a bromine atom or an iodine atom is desirable in terms of a good yield, and an iodine atom is further desirable.

Further, in the general formulas (1), (1a) and (2), the nitrogen atom represented by Y ^a or Y is an acetyl group, propionyl group, pivaloyl group, propargyl group, benzoyl group, p-phenylbenzoyl group, benzyl Group, p-methoxybenzyl group, trityl group, 4,4′-dimethoxytrityl group, methoxyethoxymethyl group, phenyloxycarbonyl group, benzyloxycarbonyl group, tert-butoxycarbonyl group, 9-fluorenylmethoxycarbonyl group, Allyl group, p-methoxyphenyl group, trifluoroacetyl group, methoxymethyl group, 2- (trimethylsilyl) ethoxymethyl group, allyloxycarbonyl group, trichloroethoxycarbonyl group, methyl group, ethyl group, propyl group, isopropyl group, butyl Group, isobutyl group, sec Butyl group, may be substituted with such tert- butyl group.

  Here, specific examples of the α, β-unsaturated carbonyl compound (2) represented by the general formula (2) include ethyl acetoacetate, ethyl 4-methyl-3-oxopentanoate, 4-hydroxy-3- Penten-2-one, 5-hydroxy-4-hepten-3-one, octyl acetoacetate, ethyl 3-hydroxy-3-phenyl-2-propenoate, 2-hydroxy-2-nonen-4-one, 3- (Methyl (N-tert-butoxycarbonylamino) crotonate, 3-amino-2-cyclohexen-1-one, etc.).

  Specific examples of the sulfoxides (3) represented by the general formula (3) include dimethyl sulfoxide, dibutyl sulfoxide, di-sec-butyl sulfoxide, methylphenyl sulfoxide, (R)-(+)-methyl-p. -Tolyl sulfoxide, (S)-(-)-methyl-p-tolyl sulfoxide, diphenyl sulfoxide and the like. As the sulfoxides, dimethyl sulfoxide, dibutyl sulfoxide, and diphenyl sulfoxide are preferable, and dimethyl sulfoxide is more preferable in terms of good yield and low cost.

The α, β-unsaturated carbonyl compounds (1) and (1a) having a perfluoroalkyl group of the present invention are the above α, β-unsaturated carbonyl compounds (2), sulfoxides (3), and peroxides. It is obtained by reacting with a perfluoroalkyl halide (4) in the presence of an iron compound and optionally an acid.
Specific examples of the α, β-unsaturated carbonyl compounds (1) and (1a) having a perfluoroalkyl group of the present invention include ethyl 3-oxo-2-trifluoromethylbutanoate and 4-methyl-3-oxo. Ethyl 2-trifluoromethylpentanoate, 4-hydroxy-3-trifluoromethyl-3-penten-2-one, 5-hydroxy-4-trifluoromethyl-4-hepten-3-one, 3-oxo- Octyl 2-trifluoromethylbutanoate, ethyl 3-hydroxy-3-phenyl-2-trifluoromethyl-2-propenoate, 2-hydroxy-3-trifluoromethyl-2-nonen-4-one, 3- ( N-tert-butoxycarbonyl) amino-2-trifluoromethylcrotonate, 3-amino-2-trifluoromethyl-2-cyclo Hexene-1-one and the like.

The structure of the α, β-unsaturated carbonyl compound (1), (1a) having a perfluoroalkyl group of the present invention is determined by the nuclear magnetic resonance spectrum ( ¹⁹ F-NMR) of trifluoromethyl around −50 to −65 ppm. It can be confirmed by a peak derived from the group.

Next, the production method of the present invention will be described in detail.
The α, β-unsaturated carbonyl compound (1), (1a) having a perfluoroalkyl group of the present invention is obtained by converting the α, β-unsaturated carbonyl compound (2) into a sulfoxide (3), a peroxide, iron. It is obtained by reacting with perfluoroalkyl halides (4) in the presence of a compound and optionally an acid.
In the present invention, the sulfoxides (3) may be used as a solvent as they are, but a solvent that does not harm the reaction can also be used. Specifically, water, N, N-dimethylformamide, acetic acid, trifluoroacetic acid, tetrahydrofuran, diethyl ether, ethyl acetate, acetone, 1,4-dioxane, tert-butyl alcohol, ethanol, methanol, isopropyl alcohol, trifluoro Ethanol, hexamethylphosphoric triamide, N-methyl-2-pyrrolidone, N, N, N ′, N′-tetramethylurea or N, N′-dimethylpropyleneurea can be mentioned, and these are combined as appropriate It may be used. From the viewpoint of good yield, it is desirable to use water, sulfoxides (3), or a mixed solvent of water and sulfoxides (3).

The molar ratio of the α, β-unsaturated carbonyl compound (2) and the sulfoxides (3) is preferably 1: 1 to 1: 200, and more preferably 1:10 to 1: 100 in terms of a good yield.
The molar ratio of the α, β-unsaturated carbonyl compound (2) and the perfluoroalkyl halide (4) is preferably 1: 1 to 1: 100, and 1: 1.5 to 1 in terms of good yield. : 10 is more desirable.

Examples of the peroxide include hydrogen peroxide, hydrogen peroxide-urea complex, tert-butyl peroxide, and peracetic acid, and these may be used in combination as necessary. Hydrogen peroxide or hydrogen peroxide-urea complex is desirable in terms of good yield.
Hydrogen peroxide may be diluted with water. The concentration at that time may be 3 to 70% by weight, but a commercially available 35% by weight may be used as it is. In view of good yield and safety, it is more desirable to dilute with water to 10 wt% to 30 wt%.
The molar ratio of α, β-unsaturated carbonyl compound (2) and peroxide is preferably 1: 0.1 to 1:10, and more preferably 1: 1.5 to 1: 3 in terms of good yield. .

The iron compound is preferably an iron (II) salt in terms of a good yield. For example, iron (II) sulfate, iron (II) ammonium sulfate, iron (II) tetrafluoroborate, iron (II) chloride, bromide Inorganic acid salts such as iron (II) or iron (II) iodide, iron (II) acetate, iron (II) oxalate, iron (II) bisacetylacetonate, ferrocene or bis (η ⁵ -pentamethylcyclo An example of the organometallic compound such as (pentadienyl) iron may be used, and these may be used in appropriate combination. In addition, iron (II) salt can be generated in the system by combining iron powder, iron (0) salt or iron (I) salt and an oxidizing reagent such as peroxide. In this case, hydrogen peroxide used for the reaction can be used as it is as an oxidizing reagent. It is desirable to use iron (II) sulfate, iron (II) ammonium sulfate, iron (II) tetrafluoroborate, ferrocene or iron powder in terms of good yield.
These iron compounds may be used as solids, but can also be used as solutions. When used as a solution, the solvent may be any of the above-mentioned solvents, but water is particularly preferable. In this case, the concentration of the iron compound solution is preferably from 0.1 mol / L to 10 mol / L, and more preferably from 0.5 mol / L to 5 mol / L in terms of good yield.
The molar ratio of the α, β-unsaturated carbonyl compound (2) and the iron compound is preferably 1: 0.01 to 1:10, and more preferably 1: 0.1 to 1: 1 in terms of a good yield.

The reaction temperature can be carried out at a temperature appropriately selected from the range of 20 ° C to 100 ° C. 20 ° C to 70 ° C is desirable in terms of good yield.
The reaction time is usually about 1 to 300 minutes, preferably about 10 to 60 minutes.
When the reaction is performed in a closed system, the reaction can be performed at a pressure appropriately selected from the range of atmospheric pressure (0.1 MPa) to 1.0 MPa, but the reaction proceeds sufficiently even at atmospheric pressure. The atmosphere during the reaction may be an inert gas such as argon or nitrogen, but proceeds sufficiently even in air.
When the perfluoroalkyl halides (4) of the general formula (4) are gaseous at room temperature, they may be used as they are. At that time, it may be diluted with a gas such as argon, nitrogen, air, helium, oxygen, or the like, and may be used as a mixed gas, or a gas having a mole fraction of the perfluoroalkyl halide (4) of 1% to 100%. it can. When the reaction is carried out in a closed system, perfluoroalkyl halides (4) or a mixed gas can be used as the reaction atmosphere. The pressure at that time can be carried out at a pressure appropriately selected from the range of atmospheric pressure (0.1 MPa) to 1.0 MPa, but the reaction proceeds sufficiently even at atmospheric pressure. Alternatively, perfluoroalkyl halides (4) or a mixed gas may be bubbled and introduced into the reaction solution in an open system. The introduction rate of the perfluoroalkyl halides (4) or mixed gas at that time depends on the scale of the reaction, the amount of catalyst, the reaction temperature, and the mole fraction of the perfluoroalkyl halides (4) in the mixed gas. A rate selected from the range of 1 mL to 200 mL per minute is sufficient.

In the production method of the present invention, the yield of the target product can be improved by adding an acid. Examples of the acid include inorganic acids such as sulfuric acid, hydrochloric acid, hydrogen bromide, hydrogen iodide, nitric acid, phosphoric acid, hexafluorophosphoric acid and tetrafluboroboric acid, formic acid, acetic acid, propionic acid, oxalic acid and p-toluene. Organic acids such as sulfonic acid, trifluoromethanesulfonic acid and trifluoroacetic acid can be exemplified, and these may be used in combination as appropriate. Sulfuric acid is desirable because of its good yield.
Further, an acidic salt of sulfuric acid may be used. Examples of the acid salt include tetramethylammonium hydrogensulfate, tetraethylammonium hydrogensulfate, tetrabutylammonium hydrogensulfate, and tetraphenylphosphonium hydrogensulfate.
These acids may be used after diluting. The solvent in that case should just be said solvent, and water or sulfoxide (3) is desirable especially.
The molar ratio of the α, β-unsaturated carbonyl compound (2) and the acid is preferably 1: 0.001 to 1: 5, and more preferably 1: 0.01 to 1: 2 in terms of a good yield.

  The method for isolating the target product from the solution after the reaction is not particularly limited, but may be a general-purpose method such as solvent extraction, column chromatography, preparative thin layer chromatography, preparative liquid chromatography, recrystallization or sublimation. The object can be obtained.

The compound (1) of the present invention represented by the general formula (1) and the compound (1a) represented by the general formula (1a) are an equilibrium mixture of imino-amino tautomers depending on the solvent and pH. However, the present invention includes all of them.
In addition, in the compound of the general formula (1), (1a) or (2), when Y is a nitrogen atom which may be substituted, an equilibrium mixture of imino-amino tautomers is formed depending on the solvent and pH. However, the present invention includes all of these.
Furthermore, in the compound of the general formula (1a) or (2), when Y is an oxygen atom, an equilibrium mixture of keto-enol tautomers is formed depending on the solvent and pH, but the present invention includes all of them. .

  EXAMPLES Next, although an Example demonstrates this invention in detail, this invention is not limited to these.

Example 1
Based on the following reaction formula, compound (1a) was produced.

The inside of the two-necked flask was replaced with argon. 4.0 mL of dimethyl sulfoxide, 0.126 mL (1.0 mmol) of ethyl acetoacetate, 1.0 mL of a 3.0 mol / L dimethyl sulfoxide solution of trifluoromethyl iodide, 0.3 mL of a 1.0 mol / L iron (II) sulfate aqueous solution And 0.2% of 30% hydrogen peroxide water was added. After stirring at 40 to 50 ° C. for 20 minutes, the reaction solution was cooled to room temperature. The production of ethyl 3-oxo-2-trifluoromethylbutanoate was confirmed by ¹⁹ F-NMR using 2,2,2-trifluoroethanol as an internal standard substance (production rate 47%).
¹⁹ F-NMR (heavy dimethyl sulfoxide): δ-63.7.
MS (m / z): 198 [M] ⁺

(Example 2)
Based on the following reaction formula, compound (1a) was produced.

The inside of the two-necked flask was replaced with argon. 4.0 mL of dimethyl sulfoxide, 0.161 mL (1.0 mmol) of ethyl 4-methyl-3-oxopentanoate, 1.0 mL of a 3.0 mol / L dimethyl sulfoxide solution of trifluoromethyl iodide, 1.0 mol / L iron sulfate (II) 0.3 mL of an aqueous solution and 0.2 mL of 30% hydrogen peroxide water were added. After stirring at 40 to 50 ° C. for 20 minutes, the reaction solution was cooled to room temperature. Formation of ethyl 4-methyl-3-oxo-2-trifluoromethylpentanoate was confirmed by ¹⁹ F-NMR using 2,2,2-trifluoroethanol as an internal standard substance (production rate 20%).
¹⁹ F-NMR (heavy dimethyl sulfoxide): δ-63.7.
MS (m / z): 226 [M] ⁺

(Example 3)
Based on the following reaction formula, compound (1a) was produced.

The inside of the two-necked flask was replaced with argon. 4.0 mL of dimethyl sulfoxide, 0.043 mL (0.042 mmol) of 2,4-pentanedione and 0.060 mL (0.58 mmol) of 4-hydroxy-3-penten-2-one, 3 of trifluoromethyl iodide A 1.0 mol / L dimethyl sulfoxide solution (1.0 mL), a 1.0 mol / L iron (II) sulfate aqueous solution (0.3 mL) and a 30% aqueous hydrogen peroxide solution (0.2 mL) were added. After stirring at 40 to 50 ° C. for 20 minutes, the reaction solution was cooled to room temperature. The formation of 3-trifluoromethyl-2,4-pentanedione was confirmed by ¹⁹ F-NMR using 2,2,2-trifluoroethanol as an internal standard substance (production rate: 64%). It was also confirmed by ¹⁹ F-NMR that 4-hydroxy-3-trifluoromethyl-3-penten-2-one was produced in a trace amount.
3-trifluoromethyl-2,4-pentanedione
¹⁹ F-NMR (heavy dimethyl sulfoxide): δ-62.7.
MS (m / z): 168 [M] ⁺
4-Hydroxy-3-trifluoromethyl-3-penten-2-one
¹⁹ F-NMR (heavy dimethyl sulfoxide): δ-51.3.

Example 4
Based on the following reaction formula, compound (1a) was produced.

The inside of the two-necked flask was replaced with argon. A mixture of 4.0 mL of dimethyl sulfoxide, 0.074 mL (0.055 mmol) of 3,5-heptanedione and 0.061 mL (0.045 mmol) of 5-hydroxy-4-hepten-3-one, 3 of trifluoromethyl iodide A 1.0 mol / L dimethyl sulfoxide solution (1.0 mL), a 1.0 mol / L iron (II) sulfate aqueous solution (0.3 mL) and a 30% aqueous hydrogen peroxide solution (0.2 mL) were added. After stirring at 40 to 50 ° C. for 20 minutes, the reaction solution was cooled to room temperature. The formation of 4-trifluoromethyl-3,5-heptanedione was confirmed by ¹⁹ F-NMR using 2,2,2-trifluoroethanol as an internal standard substance (production rate 66%). In addition, it was confirmed by ¹⁹ F-NMR that a trace amount of 5-hydroxy-4-trifluoromethyl-4-hepten-3-one was also produced.
4-trifluoromethyl-3,5-heptanedione
¹⁹ F-NMR (heavy dimethyl sulfoxide): δ-62.5.
MS (m / z): 196 [M] ⁺
5-Hydroxy-4-trifluoromethyl-4-hepten-3-one
¹⁹ F-NMR (heavy dimethyl sulfoxide): δ-50.7.

(Example 5)
Based on the following reaction formula, compound (1a) was produced.

The inside of the two-necked flask was replaced with argon. 4.0 mL of dimethyl sulfoxide, 0.228 mL (1.0 mmol) of octyl acetoacetate, 1.0 mL of a 3.0 mol / L dimethylsulfoxide solution of trifluoromethyl iodide, 0.3 mL of a 1.0 mol / L iron (II) sulfate aqueous solution And 0.2% of 30% hydrogen peroxide water was added. After stirring at 40 to 50 ° C. for 20 minutes, the reaction solution was cooled to room temperature. The production of octyl 3-oxo-2-trifluoromethylbutanoate was confirmed by ¹⁹ F-NMR using 2,2,2-trifluoroethanol as an internal standard substance (production rate 33%).
¹ H-NMR (deuterated dimethyl sulfoxide): δ 0.87 (t, 3H, J = 6.9 Hz), 1.22-1.35 (m, 10H), 1.61 (tt, 2H, J = 6. 7 Hz, 6.7 Hz) 2.34 (s, 3 H), 4.21 (t, 2 H, J = 6.7 Hz), 5.38 (q, 1 H, J _HF = 9.0 Hz).
¹⁹ F-NMR (deuterated dimethyl sulfoxide): δ-63.7 (d, J _FH = 9.0 Hz).
MS (m / z): 281 [M-1] ⁺

(Example 6)
Based on the following reaction formula, compound (1a) was produced.

The inside of the two-necked flask was replaced with argon. 4.0 mL of dimethyl sulfoxide, a mixture of 0.157 mL (0.091 mmol) of ethyl 3-oxo-3-phenylpropionate and 0.015 mL (0.009 mmol) of ethyl 3-hydroxy-3-phenyl-2-propenoate, iodine 1.0 mL of a 3.0 mol / L dimethyl sulfoxide solution of trifluoromethyl iodide, 0.3 mL of a 1.0 mol / L iron (II) sulfate aqueous solution and 0.2 mL of 30% aqueous hydrogen peroxide were added. After stirring at 40 to 50 ° C. for 20 minutes, the reaction solution was cooled to room temperature. Formation of ethyl 3-oxo-3-phenyl-2-trifluoromethylpropionate was confirmed by ¹⁹ F-NMR using 2,2,2-trifluoroethanol as an internal standard substance (production rate 49%). Further, it was confirmed by ¹⁹ F-NMR that a small amount of ethyl 3-hydroxy-3-phenyl-2-trifluoromethyl-2-propenoate was produced.
Ethyl 3-oxo-3-phenyl-2-trifluoromethylpropionate
¹ H-NMR (deuterated dimethyl sulfoxide): δ 1.09 (t, 3H, J = 7.1 Hz), 4.17 (q, 2H, J = 7.1 Hz), 6.31 (q, 1H, J _HF = 8.5 Hz), 7.58-7.63 (m, 2H), 7.71-7.77 (m, 1H), 8.05-8, 09 (m, 2H).
¹⁹ F-NMR (deuterated dimethyl sulfoxide): δ-63.4 (d, J _FH = 8.5 Hz).
MS (m / z): 260 [M] ⁺
3-hydroxy-3-phenyl-2-trifluoromethyl-2-propenoic acid ethyl ester
¹⁹ F-NMR (heavy dimethyl sulfoxide): δ-57.1.

(Example 7)
Based on the following reaction formula, compound (1a) was produced.

In a two-neck flask, a mixture of 0.066 g (0.042 mmol) of 2,4-nonanedione and 0.090 g (0.058 mmol) of 2-hydroxy-2-nonen-4-one was weighed, and the inside of the container was replaced with argon. . Add 4.0 mL of dimethyl sulfoxide, 1.0 mL of a 3.0 mol / L dimethyl sulfoxide solution of trifluoromethyl iodide, 0.3 mL of a 1.0 mol / L aqueous iron (II) sulfate solution and 0.2 mL of 30% hydrogen peroxide solution. It was. After stirring at 40 to 50 ° C. for 20 minutes, the reaction solution was cooled to room temperature. The formation of 3-trifluoromethyl-2,4-nonanedione was confirmed by ¹⁹ F-NMR using 2,2,2-trifluoroethanol as an internal standard substance (production rate 52%). Further, it was confirmed by ¹⁹ F-NMR that trace amounts of 2-hydroxy-3-trifluoromethyl-2-nonen-4-one were also produced.
3-trifluoromethyl-2,4-nonanedione
¹ H-NMR (deuterated dimethyl sulfoxide): δ 0.85 (t, 3H, J = 7.1 Hz), 1.17-1.31 (m, 4H), 1.49 (tt, 2H, J = 7. 2 Hz, 7.2 Hz) 2.28 (s, 3 H), 2.65 (t, 2 H, J = 7.2 Hz), 5.45 (q, 1 H, J _HF = 9.3 Hz).
¹⁹ F-NMR (deuterated dimethyl sulfoxide): δ-62.6 (d, J _FH = 9.3 Hz).
MS (m / z): 224 [M] ⁺
2-Hydroxy-3-trifluoromethyl-2-nonen-4-one
¹⁹ F-NMR (heavy dimethyl sulfoxide): δ-50.7.

(Example 8)
Compound (1) was produced based on the following reaction formula.

In a two-necked flask, 0.056 g (0.3 mmol) of ferrocene was weighed, and the inside of the container was replaced with argon. Methyl 3- (N-tert-butoxycarbonylamino) crotonate 0.215 g (1.0 mmol), 4.0 mL of dimethyl sulfoxide, 1.0 mL of a 3.0 mol / L dimethyl sulfoxide solution of trifluoromethyl iodide and 30% excess 0.2 mL of hydrogen oxide water was added. After stirring at 40 to 50 ° C. for 20 minutes, the reaction solution was cooled to room temperature. The production of methyl 3- (N-tert-butoxycarbonyl) amino-2-trifluoromethylcrotonate was confirmed by ¹⁹ F-NMR using 2,2,2-trifluoroethanol as an internal standard substance (production rate 67 %). Column chromatography gave methyl 3- (N-tert-butoxycarbonylamino) -2-trifluoromethylcrotonate as a pale yellow oil (0.214 g, 50% yield).
¹ H-NMR (deuterated chloroform): δ 1.50 (s, 9H), 2.60 (q, J _HF = 2.45 Hz, 3H), 3.81 (s, 3H), 11.22 (brs, 1H) ).
¹³ C-NMR (deuterated chloroform): δ 17.1 (q, J _CF = 4.4 Hz), 27.3, 52.0, 82.2, 98.3 (q, J _CF = 32.1 Hz), 124 .5 (q, J _CF = 269.5 Hz), 146.7, 161.4 (q, J _CF = 1.88 Hz), 167.3.
¹⁹ F-NMR (deuterated chloroform): δ-52.3 (d, J _HF = 2.45 Hz).
MS (m / z): 283 [M] ⁺

Example 9
Compound (1) was produced based on the following reaction formula.

0.11 g (1.0 mmol) of 3-amino-2-cyclohexen-1-one was weighed into a two-necked flask, and the inside of the container was replaced with argon. Add 4.0 mL of dimethyl sulfoxide, 1.0 mL of a 3.0 mol / L dimethyl sulfoxide solution of trifluoromethyl iodide, 0.3 mL of a 1.0 mol / L aqueous iron (II) sulfate solution and 0.2 mL of 30% hydrogen peroxide solution. It was. After stirring at 40 to 50 ° C. for 20 minutes, the reaction solution was cooled to room temperature. The production of 3-amino-2-trifluoromethyl-2-cyclohexen-1-one was confirmed by ¹⁹ F-NMR using 2,2,2-trifluoroethanol as an internal standard substance (production rate 88%). Column chromatography gave 3-amino-2-trifluoromethyl-2-cyclohexen-1-one as a white solid (0.152 g, 85% yield).
¹ H-NMR (deuterated methanol): δ 1.89 (tt, J = 6.5, 6.0 Hz, 2H), 2.32 (t, J = 6.5 Hz, 2H), 2.58 (t, J = 6.0 Hz, 2H).
¹³ C-NMR (deuterated methanol): δ 21.4, 31.9, 38.1 (q, J _CF = 1.3 Hz), 99.8 (q, J _CF = 26.3 Hz), 127.2 (q , J _CF = 272.7 Hz), 168.9, 195.6.
¹⁹ F-NMR (deuterated methanol): δ-57.4.
MS (m / z): 179 [M] ⁺

Example 10 (Production of Compound (1))
0.11 g (1.0 mmol) of 3-amino-2-cyclohexen-1-one was weighed into a two-necked flask, and the inside of the container was replaced with argon. 2.0 mL of dimethyl sulfoxide, 1.0 mL of a 1N dimethyl sulfoxide solution of sulfuric acid, 1.0 mL of a 3.0 mol / L dimethyl sulfoxide solution of trifluoromethyl iodide, 0.3 mL and 30 mL of a 1.0 mol / L aqueous iron (II) sulfate solution A 0.2% aqueous hydrogen peroxide solution was added. After stirring at 40 to 50 ° C. for 20 minutes, the reaction solution was cooled to room temperature. The production of 3-amino-2-trifluoromethyl-2-cyclohexen-1-one was confirmed by ¹⁹ F-NMR using 2,2,2-trifluoroethanol as an internal standard substance (production rate 56%).

Example 11 (Production of Compound (1))
In a two-necked flask, 0.11 g (1.0 mmol) of 3-amino-2-cyclohexen-1-one and 0.056 g (0.3 mmol) of ferrocene were weighed, and the inside of the container was replaced with argon. 2.0 mL of dimethyl sulfoxide, 1.0 mL of a 1N dimethyl sulfoxide solution of sulfuric acid, 1.0 mL of a 3.0 mol / L dimethyl sulfoxide solution of trifluoromethyl iodide and 0.2 mL of 30% aqueous hydrogen peroxide were added. After stirring at 40 to 50 ° C. for 20 minutes, the reaction solution was cooled to room temperature. The production of 3-amino-2-trifluoromethyl-2-cyclohexen-1-one was confirmed by ¹⁹ F-NMR using 2,2,2-trifluoroethanol as an internal standard substance (production rate 49%).

  The α, β-unsaturated carbonyl compound having a perfluoroalkyl group of the present invention is a synthetic precursor of a useful compound in the field of medical and agrochemicals, and is useful as an application for synthetic intermediates such as medical and agricultural chemicals.

Claims (17)

General formula (1)
[ Wherein , R ¹ represents an alkyl group having 1 to 8 carbon atoms or an alkoxy group having 1 to 8 carbon atoms, and R ² represents an alkyl group having 1 to 4 carbon atoms. R ¹ and R ² may be combined with the atoms to be bonded to form a ring. Rf represents a perfluoroalkyl group composed of a trifluoromethyl group or a perfluoroethyl group. Y ^a is an acetyl group, propionyl group, pivaloyl group, propargyl group, benzoyl group, p-phenylbenzoyl group, benzyl group, p-methoxybenzyl group, trityl group, 4,4′-dimethoxytrityl group, methoxyethoxymethyl group, Phenyloxycarbonyl group, benzyloxycarbonyl group, tert-butoxycarbonyl group, 9-fluorenylmethoxycarbonyl group, allyl group, p-methoxyphenyl group, trifluoroacetyl group, methoxymethyl group, 2- (trimethylsilyl) ethoxymethyl A nitrogen atom which may be substituted with a group, allyloxycarbonyl group, trichloroethoxycarbonyl group, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, or tert-butyl group Show. An α, β-unsaturated carbonyl compound having a perfluoroalkyl group represented by the formula: ^{2. The} perfluoro of claim 1, wherein R ^{1 in the} general formula (1) is an alkoxy group having 1 to 8 carbon atoms, R ² is an alkyl group having 1 to 4 carbon atoms, and Rf is a trifluoromethyl group. An α, β-unsaturated carbonyl compound having an alkyl group. The α, β- having a perfluoroalkyl group according to claim 1, wherein R ¹ and R ^{2 in} the general formula (1) form a cyclohexene ring integrally with the atom to which R ¹ is bonded, and R f is a trifluoromethyl group. Unsaturated carbonyl compounds. General formula (2)
[In the formula, R ¹ represents an alkoxy group having 8 alkyl group or a C 1 -C 8 1 -C, R ² represents an alkyl group having 1 to 4 carbon atoms. R ¹ and R ² may be combined with the atoms to be bonded to form a ring. Y is acetyl group, propionyl group, pivaloyl group, propargyl group, benzoyl group, p-phenylbenzoyl group, benzyl group, p-methoxybenzyl group, trityl group, 4,4'-dimethoxytrityl group, methoxyethoxymethyl group, phenyl Oxycarbonyl group, benzyloxycarbonyl group, tert-butoxycarbonyl group, 9-fluorenylmethoxycarbonyl group, allyl group, p-methoxyphenyl group, trifluoroacetyl group, methoxymethyl group, 2- (trimethylsilyl) ethoxymethyl group , An allyloxycarbonyl group, a trichloroethoxycarbonyl group, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, or a nitrogen atom optionally substituted with a tert-butyl group . An α, β-unsaturated carbonyl compound represented by general formula (3): R ^3a S (═O) R ^3b [wherein R ^3a and R ^3b are alkyl groups having 1 to 12 carbon atoms or The phenyl group which may be substituted is shown. ] In the presence of sulfoxides, peroxides, iron compounds and optionally acids represented by the general formula (4): Rf-X [wherein Rf is a trifluoromethyl group or a perfluoroethyl group. And X represents a halogen atom. And a halogenated perfluoroalkyl compound represented by the general formula (1a)
[Wherein, Rf, R ¹ , R ² and Y have the same contents as described above. ] The manufacturing method of the alpha, beta-unsaturated carbonyl compound which has the perfluoroalkyl group represented by these. The α, β- having a perfluoroalkyl group according to claim 4, wherein R ^{1 in the} general formula (2) is an alkoxy group having 1 to 8 carbon atoms, and R ² is an alkyl group having 1 to 4 carbon atoms. A method for producing an unsaturated carbonyl compound. The method for producing an α, β-unsaturated carbonyl compound having a perfluoroalkyl group according to claim 4, wherein the cyclohexene ring is formed integrally with an atom to which R ¹ and R ^{2 in} the general formula (2) are bonded. .   The method for producing an α, β-unsaturated carbonyl compound having a perfluoroalkyl group according to any one of claims 4 to 6, wherein X in the general formula (4) is an iodine atom or a bromine atom. The iron compound is iron (II) sulfate, iron (II) sulfate, iron (II) tetrafluoroborate, iron (II) chloride, iron (II) bromide, iron (II) iodide, iron acetate (II) ), iron oxalate (II), bis acetylacetonato iron (II), ferrocene, bis (eta ⁵ - par according to claim 4 is a pentamethylcyclopentadienyl) iron or an iron powder 7 A method for producing an α, β-unsaturated carbonyl compound having a fluoroalkyl group. The method for producing an α, β-unsaturated carbonyl compound having a perfluoroalkyl group according to any one of claims 4 to 8 , wherein the iron compound is iron (II) sulfate or ferrocene. The α, β-unsaturated carbonyl having a perfluoroalkyl group according to claim 4 , wherein the peroxide is hydrogen peroxide, hydrogen peroxide-urea complex, tert-butyl peroxide or peracetic acid. Compound production method. The method for producing an α, β-unsaturated carbonyl compound having a perfluoroalkyl group according to any one of claims 4 to 10 , wherein the peroxide is hydrogen peroxide. Acid is sulfuric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, phosphoric acid, hexafluorophosphoric acid, tetrafluoroboric acid, formic acid, acetic acid, propionic acid, oxalic acid, p-toluenesulfonic acid, trifluoromethane The method for producing an α, β-unsaturated carbonyl compound having a perfluoroalkyl group according to any one of claims 4 to 11 , which is sulfonic acid or trifluoroacetic acid. The method for producing an α, β-unsaturated carbonyl compound having a perfluoroalkyl group according to any one of claims 4 to 12 , wherein the acid is sulfuric acid. The method for producing an α, β-unsaturated carbonyl compound having a perfluoroalkyl group according to any one of claims 4 to 13 , wherein R ^3a and R ^{3b in} the general formula (3) are methyl groups. The method for producing an α, β-unsaturated carbonyl compound having a perfluoroalkyl group according to any one of claims 4 to 14 , wherein the reaction temperature is a temperature selected from the range of 20 ° C to 100 ° C. The production of an α, β-unsaturated carbonyl compound having a perfluoroalkyl group according to any one of claims 4 to 15 , wherein the reaction pressure is a pressure selected from the range of atmospheric pressure (0.1 MPa) to 1.0 MPa. Method. The molar ratio of the α, β-unsaturated carbonyl compound represented by the general formula (2) and the halogenated perfluoroalkyl compound represented by the general formula (4) is 1: 1 to 1: 100, and the α, β The molar ratio of the unsaturated carbonyl compound to the sulfoxide represented by the general formula (3) is 1: 1 to 1: 200, and the molar ratio of the α, β-unsaturated carbonyl compound to the peroxide is 1: 0. 1 to 1:10, the molar ratio of the α, β-unsaturated carbonyl compound to the iron compound is 1: 0.01 to 1:10, and the molar ratio of the α, β-unsaturated carbonyl compound to the acid is 1: The method for producing an α, β-unsaturated carbonyl compound having a perfluoroalkyl group according to any one of claims 4 to 16, which is 0.001 to 1: 5.