Method for producing aryl compound containing perfluoroalkyl group

Abstract

To provide a novel production method for synthesizing an aryl compound in which a tetrafluorosulfanyl group bonded to a perfluoroalkyl group is introduced.SOLUTION: There is provided a method for producing an aryl compound containing a perfluoroalkyl group in which a compound represented by the following general formula (1) is synthesized by conducting a reaction in which a thioaryl compound represented by the following general formula (2) is added to tetrafluoroethylene in the presence of tetraiodomethane and a radical initiator, and the compound represented by the general formula (1) is fluorinated by a fluorinating agent to synthesize an aryl compound containing a perfluoroalkyl group represented by the following general formula (3). In the formula, A1 is an aryl group which may have a substituent or a heteroaryl group which may have a substituent.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a method for producing an aryl compound having a tetrafluorosulfanyl group bonded to a perfluoroalkyl group. [Background technology]

[0002] Fluorine-containing compounds exhibit unique material properties and biological activity. For example, by introducing fluorine atoms or trifluoromethyl groups into organic compounds, hydrophobicity is improved in addition to metabolic stability. For this reason, the use of compounds having fluorine atoms is prominent, particularly in the development of medicines and agrochemicals. In recent years, from the viewpoint of improving the functionality of fluorine-containing compounds, the focus of research has shifted to functional groups that have a greater effect of improving hydrophobicity. For example, sulfur-fluorine functional groups having a structure in which multiple fluorine atoms are bonded to hexavalent sulfur have attracted attention as they confer higher hydrophobicity than the corresponding carbon-fluorine functional groups (Non-Patent Document 1).

[0003] On the other hand, it is difficult to introduce sulfur-fluorine functional groups into existing compounds. For this reason, despite their great appeal, the use of sulfur-fluorine functional groups in the active ingredients of pharmaceuticals and pesticides, organic materials, etc. has not progressed very much. Research that has progressed so far has focused on the use of pentafluoro-λ as a sulfur-fluorine functional group. 6 -sulfanyl (SF5) group. A practical method for the synthesis of aromatic SF5 compounds is the introduction of chlorotetrafluoro-lamellar 6 A two-step synthesis using a tetrafluorosulfanyl (SF4Cl) compound as an intermediate has been developed (Patent Document 1). In addition, an aromatic SF4CF3 compound has been synthesized, and it has been revealed that it has greater hydrophobicity than an aromatic SF5 compound (Non-Patent Document 2). Furthermore, a method has been reported in which a tetrafluorosulfanyl group-containing aryl compound can be synthesized in a single step by reacting an SF4Cl compound with a fluorine-substituted olefin in the presence of a radical initiator (Patent Document 2). [Prior art documents] [Patent documents]

[0004] [Patent Document 1] International Publication No. 2010 / 014665 [Patent Document 2] International Publication No. 2023 / 048244 [Non-patent literature]

[0005] [Non-Patent Document 1] Savoie and Welch, Chemical Reviews, 2015, vol.115, p.1130-1190. [Non-Patent Document 2] Kirsch and Hahn, Eur. J. Org. Chem. 2006, vol.2006(5), p.1125-1131. Summary of the Invention [Problem to be solved by the invention]

[0006] An aryl compound having a tetrafluorosulfanyl group bonded to a chlorotetrafluoroethyl group introduced therein can be synthesized relatively easily by the method described in Patent Document 2. However, this method cannot synthesize an aryl compound having a tetrafluorosulfanyl group bonded to a perfluoroethyl group introduced therein.

[0007] An object of the present invention is to provide a novel process for efficiently synthesizing an aryl compound having a tetrafluorosulfanyl group bonded to a perfluoroalkyl group. [Means for solving the problem]

[0008] The present inventors have discovered that an aryl compound having a tetrafluorosulfanyl group bonded to a perfluoroalkyl group can be easily synthesized under relatively mild conditions by reacting an SF4Cl compound with tetrafluoroethylene in the presence of tetraiodomethane and a radical initiator and fluorinating the resulting iodine compound, thereby completing the present invention.

[0009] That is, the present invention is as follows. [1] In the presence of tetraiodomethane and a radical initiator, a reaction represented by the following general formula (2)

[0010] [ka]

[0011] [In the formula, A 1 is an optionally substituted aryl group or an optionally substituted heteroaryl group. To tetrafluoroethylene, a thioaryl compound represented by the following general formula (1) is added to the tetrafluoroethylene.

[0012] [ka]

[0013] [In the formula, A 1 is the same as above] A compound represented by the formula: The compound represented by the general formula (1) is fluorinated with a fluorinating agent to obtain a compound represented by the following general formula (3):

[0014] [ka]

[0015] [In the formula, A 1 is the same as above] The present invention relates to a method for producing a perfluoroalkyl group-containing aryl compound, comprising synthesizing a perfluoroalkyl group-containing aryl compound represented by the following formula: [2] The above A 1 is an aryl group which may have one or more substituents selected from the group consisting of a halogen atom, an alkyl group, an alkenyl group, an aryl group, an alkoxy group, a hydroxy group, a carboxy group, an acyl group, a cyano group, an amino group, and a nitro group, and the method for producing the perfluoroalkyl group-containing aryl compound according to the above [1]. [3] The method for producing the perfluoroalkyl group-containing aryl compound according to the above [1] or [2], wherein the reaction is carried out at -40 to 130 °C. [4] The following general formula (3)

[0016] [Chemical formula]

[0017] [In the formula, A 1 is an aryl group which may have a substituent or a heteroaryl group which may have a substituent.] The perfluoroalkyl group-containing aryl compound represented by [Advantages of the Invention]

[0018] According to the method of the present invention, an aryl compound into which a tetrafluorosulfanyl group bonded to a perfluoroalkyl group is introduced can be easily synthesized under relatively mild conditions. [Embodiments for Carrying Out the Invention]

[0019] In the present invention and this specification, "C p1-p2 "(p1 and p2 are positive integers satisfying p1 < p2) means a group having 1 to p2 carbon atoms.

[0020] In the present invention and this specification, "C 1-6 alkyl group" is an alkyl group having 1 to 6 carbon atoms, which may be linear or branched. C 1-6Examples of the alkyl group include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, an isopentyl group, a neopentyl group, a tert-pentyl group, and a hexyl group.

[0021] In the present invention and the present specification, "C 1-6 "Alkoxy group" means C 1-6 A group in which an oxygen atom is bonded to the bond terminal of an alkyl group. 1-6 The alkoxy group may be linear or branched. 1-6 Examples of the alkoxy group include a methoxy group, an ethoxy group, a propoxy group, a butoxy group, a tert-butoxy group, a pentyloxy group, and a hexyloxy group.

[0022] In the present invention and the present specification, "C 2-6 The term "alkenyl group" refers to an alkyl group having 2 to 6 carbon atoms in which at least one carbon-carbon bond is unsaturated. 2-6 The alkenyl group may be a straight chain or a branched chain. 2-6 Examples of the alkenyl group include a vinyl group, an allyl group, a butenyl group, a pentenyl group, and a hexenyl group.

[0023] In the present invention and the present specification, "C 2-7 An "acyl group" is an acyl group whose hydrocarbon group is formed by removing the carbonyl group. 1-6 Alkyl group, C 2-6 The acyl group is an alkenyl group, a 5- or 6-membered aryl group, or a 5- or 6-membered heteroaryl group. The hydrocarbon portion of the acyl group may be linear or branched. 2-7 Examples of the acyl group include a formyl group, an acetyl group, a propanoyl group, a propenoyl group, and a benzoyl group.

[0024] In the present invention and in this specification, the "halogen atom" refers to a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom. The "halogen atom other than fluorine atom" refers to a chlorine atom, a bromine atom, or an iodine atom. As an example of the "halogen atom other than fluorine atom", a chlorine atom or a bromine atom is preferable, and a chlorine atom is particularly preferable.

[0025] Also, hereinafter, "compound (n)" means a compound represented by formula (n).

[0026] <Addition Reaction of <SF4Cl Compound and Tetrafluoroethylene>> The method for producing a perfluoroalkyl group-containing aryl compound (hereinafter, "aryl compound containing R FP ") according to the present invention is to add the sulfur atom in the SF4Cl group in the SF4Cl group-containing aryl compound to tetrafluoroethylene in the presence of tetraiodomethane and a radical initiator, and then fluorinate the obtained iodide compound. The chloride obtained by adding the sulfur atom in the SF4Cl group in the SF4Cl group-containing aryl compound to tetrafluoroethylene cannot be fluorinated only by treatment with a fluorinating agent. By performing the radical addition reaction with tetrafluoroethylene in the presence of tetraiodomethane and then treating with a fluorinating agent, the desired aryl compound containing R FP can be obtained for the first time.

[0027] The method for producing the aryl compound containing R according to the present invention FP specifically comprises performing a reaction of adding a thioaryl compound represented by the following general formula (2) to tetrafluoroethylene in the presence of tetraiodomethane and a radical initiator to synthesize a compound represented by the following general formula (1). Then, the compound represented by the general formula (1) is fluorinated with a fluorinating agent to synthesize a perfluoroalkyl group-containing aryl compound represented by the following general formula (3).

[0028]

Chemical Formula

[0029] In general formulas (1) to (3), A 1 is an aryl group which may have a substituent or a heteroaryl group which may have a substituent. The aryl group is not particularly limited, and examples thereof include a phenyl group, a naphthyl group, an anthryl group, and a 9-fluorenyl group, with a phenyl group being particularly preferred. The heteroaryl group is not particularly limited, and examples thereof include a pyridyl group, a pyrazinyl group, a pyrimidinyl group, a pyridazinyl group, a pyrazolyl group, a quinolyl group, an isoquinolyl group, a pyrrolyl group, an imidazolyl group, an indolyl group, a furyl group, a benzofuryl group, a thienyl group, a benzothienyl group, an oxazolyl group, an isoxazolyl group, a thiazolyl group, and an isothiazolyl group.

[0030] An "optionally substituted aryl group" is a group in which one or more, preferably 1 to 3, hydrogen atoms bonded to a carbon atom of an aryl group are substituted with other functional groups. Similarly, an "optionally substituted heteroaryl group" is a group in which one or more, preferably 1 to 3, hydrogen atoms bonded to a carbon atom of a heteroaryl group are substituted with other functional groups. When the heteroaryl group has two or more substituents, the substituents may be the same or different.

[0031] A 1 The aryl and heteroaryl groups may have one or more substituents in addition to the sulfur atom to be fluorinated. The substituents include halogen atoms, alkyl groups, alkenyl groups, alkoxy groups, aryl groups, acyl groups, hydroxy groups, carboxy groups, alkyloxycarbonyl groups, aryloxycarbonyl groups, cyano groups, amino groups, and nitro groups. The alkyl groups include C 1-6 Alkyl groups are preferred, and C 2-6 The alkyl group is preferred, and the alkoxy group is C 1-6 Alkoxy groups are preferred, and the acyl groups are C 2-7 An acyl group is preferred. As the alkyloxycarbonyl group, the alkyl group portion is C1-6 The alkyl group is preferred, and the alkyl group moiety is C 1-3 More preferably, the aryloxycarbonyl group is an alkyl group. As the aryloxycarbonyl group, a phenyl group is preferred.

[0032] The amount of the thioaryl compound (2) added to the reaction system may be equal to or greater than the stoichiometric amount. From the viewpoints of reaction efficiency and cost, the amount of the thioaryl compound (2) used is preferably 1 to 10 equivalents of tetrafluoroethylene, more preferably 1 to 6 equivalents.

[0033] The addition reaction of the thioaryl compound (2) with tetrafluoroethylene is carried out in the presence of tetraiodomethane and a radical initiator. As the radical initiator, a conventionally known initiator can be used. Specifically, for example, a radical initiator such as an azo compound or a peroxide can be used. The radical initiator used in the addition reaction of the thioaryl compound represented by the general formula (2) with tetrafluoroethylene preferably contains an azo compound.

[0034] Examples of the radical initiator of the azo compound include azobisisobutyronitrile (hereinafter also referred to as "AIBN"), 2,2'-azobis-2-methylbutyronitrile, 2,2'-azobis-2,4-dimethylvaleronitrile (ADVN), 2,2'-azobis-N-butyl-2-methylpropionamide, dimethyl-2,2'-azobis-2-methylpropionamide, 1,1'-azobis-cyclohexane-1-carbonitrile, etc. From the viewpoint of solubility in the reaction system, AIBN, 2,2'-azobis-2-methylbutyronitrile, and 2,2'-azobis-2,4-dimethylvaleronitrile are preferred.

[0035] Examples of the peroxide radical initiator include benzoyl peroxide, t-butyl peroxide, acetyl peroxide, diisopropyl peroxydicarbonate, t-butyl peroxy-2-ethylhexanate, 2-hexyl-peroxy-2-ethylhexanate, 1,1,3,3-tetramethylbutylperoxy-2-ethylhexanoate, etc. Benzoyl peroxide, t-butyl peroxide, t-butyl peroxy-2-ethylhexanate, and 2-hexyl-peroxy-2-ethylhexanate are preferred from the viewpoint of ease of controlling the reaction.

[0036] The addition reaction of the thioaryl compound (2) with tetrafluoroethylene can be carried out in a solvent inert to the reaction. The inert solvent is not particularly limited, but is preferably an aprotic polar solvent. Examples of the aprotic polar solvent include acetonitrile (MeCN), N,N'-dimethylformamide (DMF), N,N-dimethylacetamide, dimethylsulfoxide (DMSO), tetrahydrofuran (THF), dichloromethane (DCM), 1,2-dichloroethane (DCE), and diethyl ether. The solvent used in the reaction may be a mixed solvent of two or more solvents.

[0037] The addition reaction is carried out by reacting a reaction solution obtained by mixing a thioaryl compound (2), tetrafluoroethylene, tetraiodomethane, and a radical initiator in a reaction solvent at an appropriate temperature and time. The addition reaction proceeds under mild conditions. For example, the reaction temperature is not particularly limited as long as the reaction solvent is in a liquid state, and the reaction can be carried out at -40 to 130°C, preferably at 0 to 80°C, more preferably at 20 to 50°C, and can also be carried out at room temperature (0 to 30°C). For example, the addition reaction can be carried out at 20 to 50°C for less than 3 hours to obtain a compound represented by general formula (1) (compound (1)) in essentially quantitative yield.

[0038] Next, the synthesized compound (1) is treated with a fluorinating agent to replace the iodine atom with a fluorine atom to obtain the desired R FPA fluorinating agent containing aryl compounds (compounds represented by general formula (3)) is synthesized. A divalent or higher metal fluoride can be used as the fluorinating agent used in the fluorination reaction. Examples of the divalent or higher metal fluorides include fluorides of the first transition element, the second transition element, or the third transition element. Specific examples of the fluorinating agent used in the present invention include divalent or higher fluorides of silver, niobium, manganese, cobalt, copper, hafnium, tantalum, or cerium, and examples of the fluorinating agent include AgF2, manganese (III) fluoride (MnF3), cobalt (III) fluoride (CoF3), copper (II) fluoride (CuF2), niobium (V) fluoride (NbF5), hafnium (V) fluoride (HfF5), tantalum fluoride (TaF5), and cerium (IV) fluoride (CeF4). As the divalent or higher metal fluoride used as the fluorinating agent in the present invention, AgF2 is particularly preferred because of its good reactivity.

[0039] The oxidative fluorination reaction is carried out by reacting a reaction solution in which compound (1) and a fluorinating agent are mixed in a reaction solvent at an appropriate temperature for an appropriate time. The fluorination reaction proceeds under mild conditions. For example, the reaction temperature is not particularly limited as long as the reaction solvent is in a liquid state, and the reaction can be carried out at -40 to 130°C, preferably at 0 to 80°C, or can also be carried out at room temperature (0 to 30°C). For example, the fluorination reaction can be carried out at room temperature for less than 1 hour to give the desired R FP The aryl-containing compound (3) can be obtained in essentially quantitative yield.

[0040] The fluorination reaction can be carried out in a solvent inert to the reaction. The inert solvent is not particularly limited, but is preferably an aprotic polar solvent. As the aprotic polar solvent, those listed above can be used. The solvent used in the reaction may be a mixed solvent of two or more solvents. EXAMPLES

[0041] The present invention will be described below with reference to examples, but the present invention is not limited to these examples.

[0042] The NMR apparatus used in the analysis of the Examples and Comparative Examples was a JNM-ECZ400S (400 MHz) manufactured by JEOL Ltd. 1 H NMR showed tetramethylsilane at 0 ppm, 19 For F NMR, C6F6 was used as the reference value of -162 PPM.

[0043] [Example 1] An aryl compound was synthesized in which the chlorine atom of a chlorotetrafluorosulfanyl group-containing aryl compound was replaced with a perfluoroethyl group.

[0044] (1) Tetrafluoro(1,1,2,2-tetrafluoro-2-iodoethyl)(phenyl)-λ 6 Synthesis of sulfan

[0045] [ka]

[0046] Compound (1) (110.3 mg, 0.50 mmol) and EtOAc (5.0 mL) were placed in an oven-dried microwave vial. To this mixture, ADVN (37.3 mg, 0.15 mmol, 30 mol%) and tetraiodomethane (520 mg, 1.0 mmol, 2.0 equiv.) were added at ambient temperature. The reaction vial was sealed, cooled to 0° C., and charged with tetrafluoroethylene (1.0 atm) by bubbling. The resulting reaction mixture was stirred on an oil bath at 40° C. for 24 hours. Upon completion of the reaction, the crude mixture was cooled, poured into water, and extracted into EtOAc. The combined organic layers were washed with saturated aqueous Na2S2O3 and brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification by silica gel column chromatography (n-hexane) afforded compound (2) (130 mg, 63% yield) as a colorless oil.

[0047] 1H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 8.2 Hz, 2H), 7.51-7.43 (m, 3H) 19 F NMR (376 MHz, CDCl3) δ 50.0-49.8 (m, 4F), -57.2--57.3 (m, 2F), -83.5--83.7 (m, 2F) MS (CI) m / z (%): 285 (51) [MI] + , 393 (100) [MF] + .

[0048] (2) Tetrafluoro(perfluoroethyl)(phenyl)-λ 6 -Synthesis of sulfane

[0049] [ka]

[0050] To a solution of compound (2) (61.8 mg, 0.15 mmol) synthesized above in MeCN (1.5 mL) was added AgF2 (438 mg, 3.0 mmol, 20 equiv.), and the reaction mixture was stirred at ambient temperature for 2 days. Upon completion of the reaction, the crude mixture was poured into water and extracted into Et2O. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification by silica gel column chromatography (n-pentane) afforded compound (3) (10.2 mg, 22% yield) as a colorless oil.

[0051] 1 H NMR (400 MHz, CDCl3) δ 7.80-7.77 (m, 2H), 7.53-7.45 (m, 3H) 19 F NMR (376 MHz, CDCl3) δ 46.2-46.1 (m, 4F), -79.9--80.0 (m, 3F), -95.6--95.7 (m, 2F) MS (CI) m / z (%): 304 (100) [M] ·+.

[0052] [Comparative Example 1] In the synthesis reaction of Example 1, tetrabromomethane was used instead of tetraiodomethane to obtain tetrafluoro(perfluoroethyl)(phenyl)-λ 6 -Attempts were made to synthesize sulfane.

[0053] (1) (2-Bromo-1,1,2,2-tetrafluoroethyl)tetrafluoro(phenyl)-λ 6 Synthesis of sulfan Compound (1) (88.2 mg, 0.40 mmol) and EtOAc (4.0 mL) were placed in an oven-dried microwave vial. To this mixture, ADVN (29.8 mg, 0.12 mmol, 30 mol%) and tetrabromomethane (1.33 g, 4.0 mmol, 10.0 equiv.) were added at ambient temperature. The reaction vial was sealed, cooled to 0° C., and charged with tetrafluoroethylene (1.0 atm) by bubbling. The resulting reaction mixture was stirred on an oil bath at 40° C. for 24 hours. Upon completion of the reaction, the crude mixture was cooled, poured into water, and extracted into EtOAc. The combined organic layers were washed with saturated aqueous Na2S2O3 and brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification by silica gel column chromatography (n-hexane) afforded compound (4) (51.1 mg, 35% yield) as a colorless oil.

[0054] 1 H NMR (400 MHz, CDCl3) δ 7.80-7.77 (m, 2H), 7.52-7.44 (m, 3H) 19 F NMR (376 MHz, CDCl3) δ 49.1-48.9 (m, 4F), -62.3--62.4 (m, 2F), -87.4--87.6 (m, 2F).

[0055] Next, in the same manner as in Example 1, an attempt was made to fluorinate the obtained compound (4) with AgF2. However, the reaction of replacing the bromine atom with a chlorine atom did not proceed, and the fluorination product was tetrafluoro(perfluoroethyl)(phenyl)-λ 6 - No sulfane was obtained. [Industrial Applicability]

[0056] The present invention provides a method for synthesizing perfluoroalkyl SF4-containing aryl compounds under relatively mild conditions. The present invention is useful for introducing SF4 groups into active ingredients of pharmaceuticals and agricultural chemicals, organic materials, etc.

Claims

1. In the presence of tetraiodomethane and a radical initiator, a compound represented by the following general formula (2) is reacted with 【Chemistry 1】 [In the formula, A １ is an optionally substituted aryl group or an optionally substituted heteroaryl group. To tetrafluoroethylene, a thioaryl compound represented by the following general formula (1) is added to the tetrafluoroethylene. 【Chemistry 2】 [In the formula, A １ is the same as above. A compound represented by the formula: The compound represented by the general formula (1) is fluorinated with a fluorinating agent to obtain a compound represented by the following general formula (3): 【Chemistry 3】 [In the formula, A １ is the same as above. The present invention relates to a method for producing a perfluoroalkyl group-containing aryl compound, comprising synthesizing a perfluoroalkyl group-containing aryl compound represented by the following formula:

2. The above A １ is an aryl group which may have one or more substituents selected from the group consisting of a halogen atom, an alkyl group, an alkenyl group, an aryl group, an alkoxy group, a hydroxyl group, a carboxyl group, an acyl group, a cyano group, an amino group, and a nitro group.

3. The method for producing a perfluoroalkyl group-containing aryl compound according to claim 1 or 2, wherein the reaction is carried out at -40 to 130°C.

4. The following general formula (3) 【Chemistry 4】 [In the formula, A １ represents an optionally substituted aryl group or an optionally substituted heteroaryl group. The perfluoroalkyl group-containing aryl compound is represented by the following formula:

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