JP2015063500A - Catalytic asymmetric fluorination method of tertiary 1,3-dicarbonyl compound using hypervalent iodine reagent - Google Patents

Abstract

PROBLEM TO BE SOLVED: To develop an efficient synthesis method of a quaternary 2-fluoro-1,3-dicarbonyl compound using a reaction to a nucleophilic site using a nucleophilic fluorination agent.SOLUTION: By using a hypervalent iodine reagent of a catalyst amount, a nucleophilic fluorination reagent is reacted in polarity inversion to a nucleophilic site to be fluorinated and an efficient synthesis method of a quaternary 2-fluoro-1,3-dicarbonyl compound is developed.

Description

The present invention generates a hypervalent iodine species in a reaction system by using a catalytic amount of an iodine reagent together with an oxidizing agent, and is used for medical and agricultural chemicals and materials for tertiary 1,3-dicarbonyl compounds. The present invention relates to a method for synthesizing a fluorine-containing organic compound that is noted in (1) using a nucleophilic fluorinating agent.

Fluorine-containing organic compounds have been widely used not only in the fields of medicine and agricultural chemicals but also in the field of materials in recent years because of their unique properties, such as fluorine atoms having the greatest electronegativity among all atoms. Fluorine atoms tend to take the form of fluoride ions, which are anions, due to their high electronegativity, and exist in this form with few exceptions in nature. For this reason, when synthesizing a fluorine-containing organic compound, it is effective from the viewpoint of cost to perform a fluorination reaction using fluoride ions as a fluorine source. However, in order to synthesize fluorine-containing organic compounds using fluoride ions in the fluorination reaction, a nucleophilic substitution reaction is mainly used, so a leaving group that is substituted with fluorine is introduced at the desired position on the substrate in advance. It was necessary to keep it. For this reason, there is a problem that an extra step for introducing a substituent is required, and it is difficult to introduce the substituent at a position where steric hindrance is large. Therefore, the fluorine introduction method using a hypervalent iodine reagent has come to be used. By using this method, the C—H bond at the α-position of the secondary 1,3-dicarbonyl compound can be obtained. It has become possible to directly convert to a C—F bond (non-patent document). However, there is a problem with these methods as well, and an expensive hypervalent iodine reagent must be used in a stoichiometric amount or more, and the α-position of a tertiary 1,3-dicarbonyl compound is fluorinated. For example, the method has not been reported. Therefore, development of a method that overcomes these problems is required.

Hara, S .; Sekiguchi, M .; Ohmori, A .; Fukuhara, T .; Yoneda, N. Chem. Commun. 1996, 1899. Yoshida, M .; Fujikawa, K .; Sato, S .; Hara, S. ARKIVOC 2003, 6, 36-42. Kitamura, T .; Kuriki, S .; Morshed, M. H .; Hori, Y. Org. Lett. 2011, 13, 2392. Gondo, K .; Kitamura, T. Molecules 2012, 17, 6625-6632.

In view of the above points, the present invention uses hydrogen fluoride as an inexpensive fluorine source and oxidizes a catalytic amount of an iodobenzene derivative in the reaction system instead of using a hypervalent iodine reagent having an equivalent amount or more of the substrate. It is an object of the present invention to provide a method for performing a fluorination reaction while changing the polarity with respect to the α-position of a tertiary 1,3-dicarbonyl compound by using the generated hypervalent iodine.

In order to achieve the above object, the inventors have used a catalytic amount of an iodobenzene derivative represented by the following general formula (2), an oxidant, and a fluoride ion source with respect to the carbonyl compound represented by the following general formula (1). It was found that a 2-fluoro-1,3-dicarbonyl compound represented by the following general formula (3) can be synthesized by stirring in a solvent in the presence of.
That is, the invention described in claim 1 is the presence of a catalytic amount of an iodobenzene derivative represented by the following general formula (2), an oxidant, and a fluoride ion source with respect to the dicarbonyl compound represented by the following general formula (1). Under the method, a 2-fluoro-1,3-dicarbonyl compound represented by the following general formula (3) is synthesized by stirring in a solvent.

(In the formula, R ¹ , R ² and R ³ are each independently a substituted or unsubstituted alkyl group, alkoxy group, aralkyl group, optionally substituted amino group, alkylthio group, carbonyl group, substituent group. A carbamoyl group, an aryl group, an aryloxy group, an alkenyl group, or an alkynyl group, which may have an aryl group, wherein two adjacent groups of R ¹ , R ² , and R ³ are combined together to form a heteroatom. 5 to 7-membered ring which may have a substituent may be formed with or without intervening)

(In the formula, R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ may each independently have a hydrogen atom, a substituted or unsubstituted alkyl group, an alkoxy group, an aralkyl group, a halogen atom, or a substituent. Good amino group, hydroxyl group, alkylthio group, carbonyl group, carbamoyl group which may have a substituent, cyano group, nitro group, aryl group, aryloxy group, alkenyl group, alkynyl group, silyl group or sulfonyl group Of the R ⁴ , R ⁵ , R ⁶ , R ⁷ , and R ⁸ , two adjacent groups may be combined with or without a heteroatom, and may have a substituent. A member ring may be formed.)

(In the formula, R ¹ , R ² and R ³ are as described in formula (1).)
The type of the oxidizing agent is not particularly limited. For example, peracetic acid, hydrogen peroxide solution, urea / hydrogen peroxide, sodium percarbonate, sodium hypochlorite, sodium chlorite, potassium bromate, sodium periodate , Sodium perborate, potassium perborate, sodium tetraborate, disodium peroxodisulfate, dipotassium peroxodisulfate, Oxone®, tetrabutylammonium persulfate, chromium trioxide, manganese dioxide, permanganese Potassium acid, potassium dichromate, 3-chloroperbenzoic acid, Selectfluor (registered trademark), oxygen, fluorine, chlorine, bromine, dimethyldioxirane, nitric acid, fuming nitric acid, tert-butyl hydroperoxide, hypochlorite tert- Butyl, bis (monoperoxyphthalic acid) ■ Magnesium hexahydrate, N-bromosuccinimide, N-hydride Kishifutaruimido, include one or more substances which Bareru independently from the group, such as silicon dioxide, and particularly preferably 3-chloroperbenzoic acid. The amount used is generally 1.0 to 10 equivalents, preferably 1.3 equivalents, relative to formula (1) (claims 2 and 3).
The fluoride ion source is not particularly limited. For example, hydrofluoric acid, triethylamine trihydrofluoride, triethylamine pentahydrofluoride, triethylamine hexahydrofluoride, pyridine trihydrofluoride, Pyridine hexahydrofluoride, pyridine nonhydrofluoride, pyridine polyhydrofluoride, potassium fluoride, potassium hydrogen fluoride, cesium fluoride, silver (I) fluoride, tetramethylammonium fluoride, tetra One or more substances selected from the group such as butylammonium fluoride, tetrabutylammonium bifluoride, tetrabutylammonium difluorotriphenyl silicate, tetrabutylammonium difluorotriphenyltin, tetrabutylammonium difluoride trifluoride And particularly preferably It is a Npori hydrofluoric acid salt. The amount used is generally 1.0 to 100 equivalents, preferably 10 equivalents, relative to formula (1) (claims 4 and 5).
The type of the solvent is not particularly limited, but ether solvents such as diethyl ether, diisopropyl ether, n-butyl methyl ether, tert-butyl methyl ether, tetrahydrofuran and dioxane; hydrocarbon solvents such as heptane, hexane, cyclopentane and cyclohexane Halogenated hydrocarbon solvents such as chloroform, carbon tetrachloride, methylene chloride, dichloroethane, and trichloroethane; aromatic solvents such as benzene, toluene, xylene, cumene, cymene, mesitylene, diisopropylbenzene, pyridine, pyrimidine, pyrazine, and pyridazine Ester solvents such as ethyl acetate; ketone solvents such as acetone and methyl ethyl ketone; solvents such as dimethyl sulfoxide and dimethylformamide; methanol, ethanol, propanol, i-propyl alcohol Alcohol solvents such as alcohol, aminoethanol, N, N-dimethylaminoethanol; nitrile solvents such as acetonitrile; 1,1,1,3,3-pentafluorobutane, 1,1,1,2,3,3 And fluorocarbon solvents such as 3-heptafluoropropane; supercritical carbon dioxide and ionic liquid. These can be used alone or in combination of two or more (claim 6).
In addition, the present invention resides in a novel substance of the following general formula (4) obtained by the state group method (claim 7).
That is, N, N-diethyl-2-fluoro-2,3-dihydro-1-oxo-1H-indene-2-carboxamide represented by the following general formula (4).

In this specification, as the alkyl group represented by R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ , for example, an alkyl group having about 1 to 20 carbon atoms may be used. it can. Specifically, methyl, ethyl, propyl, butyl, propyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, A pentadecyl group, a hexadecyl group, a heptadecyl group, an octadecyl group, a nonadecyl group, an icosyl group, or a cyclic alkyl group or a branched alkyl group thereof can be used. The alkyl group may be substituted with a substituent such as a halogen atom, a cyano group, a nitro group, an aryl group, an acyl group, an alkoxy group, an aryloxy group, and an acyloxy group.
The number of unsaturated bonds contained in the alkenyl group or alkynyl group represented by R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ is not particularly limited, but preferably 1 to 2 Degree. The alkenyl group or alkynyl group may be linear or branched.
Examples of the aralkyl group represented by R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ include a benzyl group, a pentafluorobenzyl group, an o-methylbenzyl group, and an m-methylbenzyl group. , P-methylbenzyl group, p-nitrobenzyl group, naphthylmethyl group, furfuryl group, α-phenethyl group and the like.
The aryl group represented by R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ also contains a heteroaryl group. Specific examples thereof include aryl having 2 to 30 carbon atoms. Group, specifically phenyl group, naphthyl group, anthranyl group, pyrenyl group, biphenyl group, indenyl group, tetrahydronaphthyl group, pyridinyl group, pyrimidinyl group, pyrazinyl group, pyridinyl group, piperazinyl group, pyrazolyl group, imidazolyl group, quinylyl Group, pyrrolyl group, indolyl group, furyl group and the like.
The aryloxy group represented by R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ also contains a heteroaryloxy group. Specific examples thereof include, for example, 2 to 30 carbon atoms. Aryl groups such as phenyloxy, naphthyloxy, anthranyloxy, pyrenyloxy, biphenyloxy, indenyloxy, tetrahydronaphthyloxy, pyridyloxy, pyrimidinyloxy, pyrazinyloxy, pyridyloxy Examples thereof include a Danidyloxy group, a piperazinyloxy group, a pyrazolyloxy group, an imidazolyloxy group, a quinyloxy group, a pyrrolyloxy group, an indolyloxy group, and a furyloxy group.
As the alkoxy group represented by R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ , for example, an alkoxy group having about 1 to 6 carbon atoms can be used. More specifically, methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, sec-butoxy group, tert-butoxy group, cyclopropylmethyloxy group, n-pentoxy group, n-hexoxy Group, triethyleneglycosyl group and the like.
The halogen atom represented by R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ may be a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
When the amino group represented by R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ has a substituent, examples of the substituent include about 1 to 10 carbon atoms described above. May have an alkyl group or a halogenated alkyl group. More specifically, a monoalkylamino group substituted with an alkyl group having about 1 to 6 carbon atoms, or a dialkylamino group substituted with two alkyl groups having about 1 to 6 carbon atoms (two alkyl groups May be the same or different.
As the alkylthio group represented by R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ , the alkylthio group having about 1 to 10 carbon atoms described above can be used. Examples thereof include a methylthio group and an ethylthio group.
Examples of the sulfonyl group represented by R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ include a sulfonyl group having an aryl group including an alkyl group, an alkoxy group, an alkenyl group, an alkynyl group, or a heteroaryl group. Can be used. Specific examples include a methanesulfonyl group, an ethanesulfonyl group, a trifluoromethanesulfonyl group, a benzenesulfonyl group, a paratoluenesulfonyl group, and a 2-nitrobenzenesulfonyl group.
Examples of the carbonyl group represented by R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ include a carbonyl group having an alkyl group, an alkoxy group, an alkenyl group, an alkynyl group, or an aryl group. Groups can be used. Specific examples include an acetoxy group, a propionoxy group, a butanoxy group, a pentanoxy group, a hexanoxy group, a methoxycarbonyl group, and an ethoxycarbonyl group.
When the carbamoyl group represented by R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ has a substituent, examples of the substituent include about 1 to 10 carbon atoms described above. May have an alkyl group or a halogenated alkyl group. When the carbamoyl group has two substituents, they may be the same or different.
Examples of the silyl group represented by R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ include two or three alkyl groups having about 1 to 10 carbon atoms and heteroaryl groups described above. An aryl group to be contained, or a silyl group substituted with an alkoxy group having about 1 to 6 carbon atoms (two or three substituents may be the same or different) can be used. Specific examples include trimethylsilyl group, triethylsilyl group, triisopropylsilyl group, tert-butyldimethylsilyl group, tert-butyldiphenylsilyl group, trimethoxysilyl group, triethoxysilyl group, and the like.
The alkyl moiety of an alkyl group or a substituent containing an alkyl moiety (eg, an alkoxy group, an alkylthio group, an alkoxycarbonyl group, etc.), an aryl moiety of an aryl group or a substituent containing an aryl moiety (eg, an aryloxy group) is fluorine 1 or 2 or more halogen atoms selected from the group consisting of an atom, a chlorine atom, a bromine atom, and an iodine atom may be present, and when two or more halogen atoms are substituted, they are the same But it can be different.
The alkyl moiety of an alkyl group or a substituent containing an alkyl moiety (eg, an alkoxy group, an alkylthio group, an alkoxycarbonyl group, etc.), an aryl moiety of an aryl group or a substituent containing an aryl moiety (eg, an aryloxy group) is an alkyl Group consisting of a group, an alkoxy group, an optionally substituted amino group, a hydroxyl group, an alkylthio group, a sulfonyl group, a carbonyl group, a cyano group, a nitro group, a silyl group, an aryl group, an alkenyl group, or an alkynyl group 1 or 2 or more substituents selected from the above, and when having 2 or more substituents, they may be the same or different.
R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ each independently represent any of the substituents defined above, but all are the same substituents Also good.
The type of oxidizing agent is not particularly limited. For example, peracetic acid, hydrogen peroxide solution, urea / hydrogen peroxide, sodium percarbonate, sodium hypochlorite, sodium chlorite, potassium bromate, sodium periodate, Sodium perborate, potassium perborate, sodium tetraborate, disodium peroxodisulfate, dipotassium peroxodisulfate, Oxone (registered trademark), tetrabutylammonium persulfate, chromium trioxide, manganese dioxide, permanganate Potassium, potassium dichromate, 3-chloroperbenzoic acid, Selectfluor (registered trademark), oxygen, fluorine, chlorine, bromine, dimethyldioxirane, nitric acid, fuming nitric acid, tert-butyl hydroperoxide, tert-butyl hypochlorite , Bis (monoperoxyphthalic acid) ■ Magnesium hexahydrate, N-bromosuccinimide, N-hydroxy Phthalimide, silicon dioxide, one or more substances which Bareru independently from the group, such as mentioned, particularly preferably 3-chloroperbenzoic acid. The amount used is generally 1.0 to 10 equivalents, preferably 1.3 equivalents, relative to formula (1).
The fluoride ion source is not particularly limited. For example, hydrofluoric acid, triethylamine trihydrofluoride, triethylamine pentahydrofluoride, triethylamine hexahydrofluoride, pyridine trihydrofluoride, pyridine Hexahydrofluoride, pyridine nonhydrofluoride, pyridine polyhydrofluoride, potassium fluoride, potassium hydrogen fluoride, cesium fluoride, silver (I) fluoride, tetramethylammonium fluoride, tetrabutyl Examples include one or more substances selected from the group consisting of ammonium fluoride, tetrabutylammonium bifluoride, tetrabutylammonium difluorotriphenyl silicate, tetrabutylammonium difluorotriphenyltin, tetrabutylammonium difluoride trifluoride, and the like. Particularly preferably pyridine It is a re-hydrofluoric acid salt. The amount used is generally 1.0 to 100 equivalents, preferably 10 equivalents, relative to formula (1).
The type of the solvent is not particularly limited, but ether solvents such as diethyl ether, diisopropyl ether, n-butyl methyl ether, tert-butyl methyl ether, tetrahydrofuran and dioxane; hydrocarbon solvents such as heptane, hexane, cyclopentane and cyclohexane Halogenated hydrocarbon solvents such as chloroform, carbon tetrachloride, methylene chloride, dichloroethane, and trichloroethane; aromatic solvents such as benzene, toluene, xylene, cumene, cymene, mesitylene, diisopropylbenzene, pyridine, pyrimidine, pyrazine, and pyridazine Ester solvents such as ethyl acetate; ketone solvents such as acetone and methyl ethyl ketone; solvents such as dimethyl sulfoxide and dimethylformamide; methanol, ethanol, propanol, i-propyl alcohol Alcohol solvents such as alcohol, aminoethanol, N, N-dimethylaminoethanol; nitrile solvents such as acetonitrile; 1,1,1,3,3-pentafluorobutane, 1,1,1,2,3,3 And fluorocarbon solvents such as 3-heptafluoropropane; supercritical carbon dioxide and ionic liquid. These can be used alone or in combination of two or more.
The absolute configuration of the 2-fluoro-1-carbonyl compound of the present invention may be either the (S) or (R) configuration, and any stereoisomer such as an optical isomer or a diastereoisomer may be of the present invention. Included in the range. Optically pure forms of isomers are a preferred embodiment of the invention. Further, any mixture of stereoisomers, racemates, and the like are also included in the scope of the present invention. The 2-fluoro-1,3-dicarbonyl compound of the present invention may form a salt depending on the type of substituent, and may exist as a hydrate or solvate. Both are included in the scope of the present invention.
The production of the formula (3) can be carried out under pressure, but is usually carried out at normal pressure. The reaction temperature can be from −80 ° C. to the boiling point of the solvent, but is preferably room temperature to around 40 ° C. The reaction time is not particularly limited, but the reaction is usually completed in 10 minutes to 5 days.
After the reaction, the 2-fluoro-1,3-dicarbonyl compound represented by the above formula (3) can be isolated and purified from the reaction solution by a general method. For example, the reaction solution is concentrated and purified by distillation. Alternatively, purification by column chromatography using an adsorbent such as silica gel and alumina, salting out, recrystallization and the like can be mentioned.
Hereinafter, the present invention will be described more specifically with reference to embodiments, but the scope of the present invention is not limited to the following embodiments.
(First embodiment)
Methyl 2,3-dihydro-1-oxo-1H-indene-2-carboxylate (0.20 mmol), iodobenzene (0.015 mmol), pyridine polyhydrofluoride (2.0 mmol), mCPBA (0.065 mmol) ) Was dissolved in 2.0 ml of 1,2-dichloroethane and the reaction solution was heated to 40 ° C. The progress of the reaction was confirmed by thin layer chromatography, mCPBA (0.065 mmol) was added again, and the mixture was stirred for 1 hour. The reaction solution was cooled to room temperature, water was added, extracted with dichloromethane, and the organic layer was washed with saturated brine. Thereafter, the solution was dried using Na ₂ SO ₄ and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography to obtain methyl 2-fluoro-2,3-dihydro-1-oxo-1H-indene-2-carboxylate 1a in 71% yield.

Compound 1a: Methyl 2-fluoro-2,3-dihydro-1-oxo-1H-indene-2-carboxylate
¹ H NMR (CDCl ₃ , 300 MHz) δ 3.45 (dd, J = 23.1, 18.0 Hz, 1H), 3.76-3.86 (m, 1H), 3.82 (s, 3H), 7.46-7.53 (m, 2H), 7.72 (t, J = 7.5 Hz, 1H), 7.85 (d, J = 7.5 Hz, 1H); ¹⁹ F NMR (CDCl ₃ , 282 MHz) δ -165.0 (dd, J = 23.1, 11.8 Hz); MS ( ESI, m / z) 231 (M + Na ⁺ ).
(Second Embodiment)
Methyl 5-chloro-2,3-dihydro-1-oxo-1H-indene-2-carboxylate (0.20 mmol), 4-methyliodobenzene (0.015 mmol), pyridine polyhydrofluoride (2.0 mmol) ), MCPBA (0.13 mmol) was dissolved in 2.0 ml of 1,2-dichloroethane, and the reaction solution was heated to 40 ° C. The progress of the reaction was confirmed by thin layer chromatography, mCPBA (0.13 mmol) was added again, and the mixture was stirred for 1 hour. The reaction solution was cooled to room temperature, water was added, extracted with dichloromethane, and the organic layer was washed with saturated brine. Thereafter, the solution was dried using Na ₂ SO ₄ and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography to obtain methyl 5-chloro-2-fluoro-2,3-dihydro-1-oxo-1H-indene-2-carboxylate 1b in 59% yield.

Compound 1b: Methyl 5-chloro-2-fluoro-2,3-dihydro-1-oxo-1H-indene-2-carboxylate
¹ H NMR (CDCl ₃ , 300 MHz) δ 3.43 (dd, J = 23.1, 18.9 Hz, 1H), 3.74-3.87 (m, 1H), 3.84 (s, 3H), 7.46 (d, J = 8.4 Hz, 1H), 7.52 (s, 1H), 7.78 (d, J = 7.8 Hz, 1H); ¹⁹ F NMR (CDCl ₃ , 282 MHz) δ -164.6 (dd, J = 22.8, 11.0 Hz); MS (ESI, m / z) 265 (M + Na ⁺ ).
(Third embodiment)
L-menthyl 2,3-dihydro-1-oxo-1H-indene-2-carboxylate (0.20 mmol), iodobenzene (0.015 mmol), pyridine polyhydrofluoride (2.0 mmol), mCPBA (0 0.065 mmol) was dissolved in 2.0 ml of 1,2-dichloroethane and the reaction solution was heated to 40 ° C. The progress of the reaction was confirmed by thin layer chromatography, mCPBA (0.065 mmol) was added again, and the mixture was stirred for 1 hour. The reaction solution was cooled to room temperature, water was added, extracted with dichloromethane, and the organic layer was washed with saturated brine. Thereafter, the solution was dried using Na ₂ SO ₄ and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography to obtain L-menthyl 2-fluoro-2,3-dihydro-1-oxo-1H-indene-2-carboxylate 1c in 59% yield.

Compound 1c: L-menthyl 2-fluoro-2,3-dihydro-1-oxo-1H-indene-2-carboxylate
¹ H NMR (CDCl ₃ , 300 MHz) δ 0.70-1.80 (m, 17H), 2.02 (d, J = 12.0 Hz, 1H), 3.44 (dd, J = 22.8, 17.7 Hz, 1H), 3.76 (dd, J = 17.4, 11.4 Hz, 1H), 4.74-4.84 (m, 1H), 7.45-7.52 (m, 2H), 7.71 (t, J = 7.5 Hz, 1H), 7.85 (d, J = 9.0 Hz, 1H ); ¹⁹ F NMR (CDCl ₃ , 282 MHz) major; δ -164.7 (dd, J = 23.5, 13.0 Hz), minor; δ -165.2 (dd, J = 22.7, 10.2 Hz) dr = 57:43; MS (ESI, m / z) 355 (M + Na ⁺ ).
(Fourth embodiment)
1. Benzyl 2-methyl-3-oxopentanolate (0.20 mmol), iodobenzene (0.015 mmol), pyridine polyhydrofluoride (2.0 mmol), mCPBA (0.065 mmol) in 1,2-dichloroethane Dissolved in 0 ml, the reaction solution was heated to 40 ° C. The progress of the reaction was confirmed by thin layer chromatography, mCPBA (0.065 mmol) was added again, and the mixture was stirred for 1 hour. The reaction solution was cooled to room temperature, water was added, extracted with dichloromethane, and the organic layer was washed with saturated brine. Thereafter, the solution was dried using Na ₂ SO ₄ and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography to obtain benzyl 2-fluoro-2-methyl-3-oxopentanolate 1d in a yield of 46%.

Compound 1d: benzyl 2-fluoro-2-methyl-3-oxopentanolate
¹ H NMR (CDCl ₃ , 300 MHz) δ 1.04 (t, J = 7.2 Hz, 3H), 1.70 (d, J = 22.2 Hz, 3H), 2.56-2.76 (m, 2H), 5.23 (s, 2H) , 7.34-7.40 (m, 5H); ¹⁹ F NMR (CDCl ₃ , 282 MHz) δ -159.7 (dd, J = 44.0, 22.8 Hz); MS (ESI, m / z) 261 (M + Na ⁺ ).
(Fifth embodiment)
Benzyl 2-oxocyclopentanecarboxylate (0.20 mmol), iodobenzene (0.015 mmol), pyridine polyhydrofluoride (2.0 mmol), mCPBA (0.065 mmol) in 2.0 ml of 1,2-dichloroethane Once dissolved, the reaction solution was heated to 40 ° C. The progress of the reaction was confirmed by thin layer chromatography, mCPBA (0.065 mmol) was added again, and the mixture was stirred for 1 hour. The reaction solution was cooled to room temperature, water was added, extracted with dichloromethane, and the organic layer was washed with saturated brine. Thereafter, the solution was dried using Na ₂ SO ₄ and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography to obtain benzyl 1-fluoro-2-oxocyclopentanecarboxylate 1e in a yield of 25%.

Compound 1e: Benzyl 1-fluoro-2-oxocyclopentanecarboxylate
¹ H NMR (CDCl ₃ , 300 MHz) δ 2.10-2.18 (m, 2H), 2.25-2.38 (m, 1H), 2.46-2.60 (m, 3H), 5.26 (dd, J = 15.0, 12.3 Hz, 2H ), 7.35 (m, 5H); ¹⁹ F NMR (CDCl ₃ , 282 MHz) δ -164.5 (t, J = 20.0 Hz); MS (ESI, m / z) 259 (M + Na ⁺ ).
(Sixth embodiment)
N, N-diethyl-2,3-dihydro-1-oxo-1H-indene-2-carboxamide (0.20 mmol), iodobenzene (0.015 mmol), pyridine polyhydrofluoride (2.0 mmol), mCPBA (0.065 mmol) was dissolved in 2.0 ml of 1,2-dichloroethane and the reaction solution was heated to 40 ° C. The progress of the reaction was confirmed by thin layer chromatography, mCPBA (0.065 mmol) was added again, and the mixture was stirred for 1 hour. The reaction solution was cooled to room temperature, water was added, extracted with dichloromethane, and the organic layer was washed with saturated brine. Thereafter, the solution was dried using Na ₂ SO ₄ and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography to obtain the novel substance N, N-diethyl-2-fluoro-2,3-dihydro-1-oxo-1H-indene-2-carboxamide 1f in 79% yield. It was.

Compound 1f: N, N-diethyl-2-fluoro-2,3-dihydro-1-oxo-1H-indene-2-carboxamide
¹ H NMR (CDCl ₃ , 300 MHz) δ 1.13 (t, J = 7.2 Hz, 3H), 1.28 (t, J = 7.2 Hz, 3H), 3.27-3.46 (m, 4H), 4.07 (dd, J = 16.7, 9.0 Hz, 2H), 7.41 (t, J = 7.2 Hz, 1H), 7.47 (d, J = 7.5 Hz, 1H), 7.65 (t, J = 7.2 Hz, 1H), 7.79 (d, J = 7.5 Hz, 1H); ¹⁹ F NMR (CDCl ₃ , 282 MHz) δ -159.0 (dd, J = 22.8, 8.5 Hz); MS (ESI, m / z) 272 (M + Na ⁺ ).

Claims (7)

Stirring in a solvent in the presence of a catalytic amount of an iodobenzene derivative represented by the following general formula (2), an oxidizing agent, and a fluoride ion source with respect to the 1,3-dicarbonyl compound represented by the following general formula (1) To synthesize a 2-fluoro-1,3-dicarbonyl compound represented by the following general formula (3).

(In the formula, R ¹ , R ² and R ³ are each independently a substituted or unsubstituted alkyl group, alkoxy group, aralkyl group, optionally substituted amino group, alkylthio group, carbonyl group, substituent group. A carbamoyl group, an aryl group, an aryloxy group, an alkenyl group, or an alkynyl group, which may have an aryl group, wherein two adjacent groups of R ¹ , R ² , and R ³ are combined together to form a heteroatom. 5 to 7-membered ring which may have a substituent may be formed with or without intervening)

(In the formula, R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ may each independently have a hydrogen atom, a substituted or unsubstituted alkyl group, an alkoxy group, an aralkyl group, a halogen atom, or a substituent. Good amino group, hydroxyl group, alkylthio group, carbonyl group, carbamoyl group which may have a substituent, cyano group, nitro group, aryl group, aryloxy group, alkenyl group, alkynyl group, silyl group or sulfonyl group Of the R ⁴ , R ⁵ , R ⁶ , R ⁷ , and R ⁸ , two adjacent groups may be combined with or without a heteroatom, and may have a substituent. A member ring may be formed.)

(In the formula, R ¹ , R ² and R ³ are as described in formula (1).) The oxidizing agent is peracetic acid, hydrogen peroxide solution, urea / hydrogen peroxide, sodium percarbonate, sodium hypochlorite, sodium chlorite, potassium bromate, sodium periodate, sodium perborate, perborate. Potassium phosphate, sodium tetraborate, dipotassium peroxodisulfate, Oxone (registered trademark), tetrabutylammonium persulfate, chromium trioxide, potassium permanganate, potassium dichromate, 3-chloroperbenzoic acid, Selectfluor (registered) Trademark), oxygen, fluorine, chlorine, bromine, dimethyldioxirane, nitric acid, fuming nitric acid, tert-butyl hydroperoxide, tert-butyl hypochlorite, bis (monoperoxyphthalic acid) Magnesium hexahydrate, N- One or more substances selected from the group of bromosuccinimide, N-hydroxyphthalimide, and silicon dioxide The method of claim 1, wherein the door. The method according to claim 1 or 2, wherein the amount of the oxidizing agent used is 1.0 to 10 equivalents relative to the general formula (1). The fluoride ion source is hydrofluoric acid, triethylamine trihydrofluoride, triethylamine pentahydrofluoride, triethylamine hexahydrofluoride, pyridine trihydrofluoride, pyridine hexahydrofluoride Salt, pyridine nonhydrofluoride, pyridine polyhydrofluoride, potassium fluoride, potassium hydrogen fluoride, cesium fluoride, silver fluoride (I), tetramethylammonium fluoride, tetrabutylammonium fluoride, tetra It is one or more substances selected from the group of butylammonium bifluoride, tetrabutylammonium difluorotriphenyl silicate, tetrabutylammonium difluorotriphenyltin, and tetrabutylammonium dihydrogen trifluoride. A method according to any one of claims 1 to 3 5. The method according to claim 1, wherein the amount of the fluoride ion source used is 1.0 to 100 equivalents relative to the general formula (1). The solvent is an ether solvent such as diethyl ether, diisopropyl ether, n-butyl methyl ether, tert-butyl methyl ether, tetrahydrofuran or dioxane; a hydrocarbon solvent such as heptane, hexane, cyclopentane or cyclohexane; chloroform, tetrachloride Halogenated hydrocarbon solvents such as carbon, methylene chloride, dichloroethane, trichloroethane; aromatic solvents such as benzene, toluene, xylene, cumene, cymene, mesitylene, diisopropylbenzene, pyridine, pyrimidine, pyrazine, pyridazine; ethyl acetate, etc. Ester solvents; Ketone solvents such as acetone and methyl ethyl ketone; Solvents such as dimethyl sulfoxide and dimethylformamide; Methanol, ethanol, propanol, i-propyl alcohol, aminoethanol Alcohol solvents such as diol, N, N-dimethylaminoethanol; nitrile solvents such as acetonitrile; 1,1,1,3,3-pentafluorobutane, 1,1,1,2,3,3,3- 6. A fluorocarbon solvent such as heptafluoropropane; a mixture of one or two or more substances selected from the group of supercritical carbon dioxide and ionic liquids. the method of. N, N-diethyl-2-fluoro-2,3-dihydro-1-oxo-1H-indene-2-carboxamide represented by the following general formula (4):