Method for producing α-substituted β-diketone fluorinated at the α-position

Abstract

To fluorinate the α-position of an α-substituted β-diketone in high yield and with high enantioselectivity, providing a compound with the α-substituted β-diketone having the fluorinated α-position.SOLUTION: A method for producing a compound with an α-substituted β-diketone having a fluorinated α-position, including the step of mixing an α-substituted β-diketone and a fluorinating agent in the presence of at least one catalyst selected from the group consisting of β,β-diaryl substituted serine and a derivative thereof in an organic solvent, to fluorinate the α-position of the α-substituted β-diketone.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a method for producing a compound in which the α-position of an α-substituted β-diketone is fluorinated. [Background technology]

[0002] US Pat. No. 5,699,499 discloses the enantioselective transformation of α-branched β-ketocarbonyls and vinyl ketones using chiral primary amine catalysts.

[0003] US Pat. No. 5,699,233 discloses an enantioselective transformation for the asymmetric fluorination of β-ketocarbonyls using a chiral primary amine catalyst. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] Acc. Chem. Res. 2015, 48, 986-997 [Patent Document 2] Chem. Sci., 2017, 8, 621-626 Summary of the Invention [Problem to be solved by the invention]

[0005] An object of the present invention is to carry out a fluorination reaction at the α-position of an α-substituted β-diketone in high yield and with high enantioselectivity, thereby providing a compound in which the α-position of the α-substituted β-diketone is fluorinated. [Means for solving the problem]

[0006] The present inventors have conducted extensive research to solve the above-mentioned problems, and as a result have found that the α-position of an α-substituted β-diketone can be fluorinated in high yield and with high enantioselectivity by reacting an α-substituted β-diketone with a fluorinating agent such as 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) in an organic solvent in the presence of a catalyst such as β,β-diarylserine.

[0007] Based on this finding, the present inventors have conducted further research and have completed the present invention.

[0008] That is, the present invention includes the following method for producing a compound in which the α-position of an α-substituted β-diketone is fluorinated.

[0009] Section 1. A method for producing a compound in which the α-position of an α-substituted β-diketone is fluorinated, comprising the steps of: A production method comprising the step of mixing an α-substituted β-diketone with a fluorinating agent in an organic solvent in the presence of at least one catalyst selected from the group consisting of β,β-diaryl-substituted serine and derivatives thereof, and carrying out a fluorination reaction at the α-position of the α-substituted β-diketone.

[0010] Section 2. Item 2. The production method according to Item 1, wherein the fluorinating agent is at least one selected from the group consisting of N-fluorobenzenesulfonimide, 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate), 1-fluoro-2,4,6-trimethylpyridinium tetrafluoroborate, 2,6-dichloro-1-fluoropyridinium tetrafluoroborate, and 2,6-dichloro-1-fluoropyridinium triflate.

[0011] Section 3. 3. The method according to claim 1, wherein the organic solvent is at least one organic solvent selected from the group consisting of halogen-based solvents, ether-based solvents, ester-based solvents, hydrocarbon-based solvents, and aromatic solvents. [Effects of the Invention]

[0012] The present invention makes it possible to carry out a fluorination reaction at the α-position of an α-substituted β-diketone in high yield and with high enantioselectivity, thereby producing a compound in which the α-position of the α-substituted β-diketone is fluorinated. DETAILED DESCRIPTION OF THE INVENTION

[0013] The present invention will be described in detail below.

[0014] In this specification, the terms "comprise" and "contain" are concepts that encompass all of "comprise," "consist essentially of," and "consist only of."

[0015] In this specification, when a numerical range is expressed as "A to B," it means A or more and B or less.

[0016] [1] A method for producing a compound in which the α-position of an α-substituted β-diketone is fluorinated The method of the present invention for producing a compound in which the α-position of an α-substituted β-diketone is fluorinated (hereinafter also referred to as the "production method of the present invention") includes a step of mixing an α-substituted β-diketone with a fluorinating agent in a liquid phase in the presence of a catalyst (for example, a primary amine organic catalyst such as β,β-diaryl serine), and carrying out a fluorination reaction at the α-position of the α-substituted β-diketone.

[0017] The production method of the present invention makes it possible to produce a compound in which the α-position of an α-substituted β-diketone is fluorinated from the starting compound, an α-substituted β-diketone, in high yield (74% to 99% yield) and with high enantioselectivity (75% ee to 95% ee).

[0018] [1-1] α-substituted β-diketone (substrate) The production method of the present invention includes a step of using an α-substituted β-diketone as a substrate and fluorinating the α-position of the α-substituted β-diketone.

[0019] The α-substituted β-diketone preferably has a structure represented by the following general formula (1):

[0020] [ka]

[0021] In formula (1), R 1 is preferably an alkyl group, an alkoxy group, an aryl group, or the like, and more preferably an alkyl group, an aryl group, or the like.

[0022] In formula (1), R 2 (The moiety at the 2-position) is preferably an alkyl group, an aryl group, an aralkyl group, an alkenyl group, an alkynyl group, or the like.

[0023] In formula (1), R 3 is preferably an alkyl group, an alkoxy group, an aryl group, or the like, and more preferably an alkyl group, an aryl group, or the like.

[0024] The alkyl group is preferably a linear, branched, or cyclic alkyl group. Specific examples include linear or branched alkyl groups having 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and 1-ethylpropyl; linear or branched alkyl groups having 1 to 18 carbon atoms, such as n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, 3-methylpentyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, 5-propylnonyl, n-tridecyl, n-tetradecyl, n-pentadecyl, hexadecyl, heptadecyl, and octadecyl; and cyclic alkyl groups having 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0025] The alkoxy group is preferably a linear, branched or cyclic alkoxy group, and specific examples thereof include linear or branched alkoxy groups having 1 to 4 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropyloxy, n-butyloxy, isobutyloxy, sec-butyloxy, tert-butyloxy, and 1-ethylpropyloxy; n-pentyloxy, isopentyloxy, neopentyloxy, n-hexyloxy, isohexyloxy, 3-methylpentyloxy, n-heptyloxy, and n-octyloxy; linear or branched alkoxy groups having 1 to 18 carbon atoms, such as alkoxy, n-nonyloxy, n-decyloxy, n-undecyloxy, n-dodecyloxy, 5-propylnonyloxy, n-tridecyloxy, n-tetradecyloxy, n-pentadecyloxy, hexadecyloxy, heptadecyloxy, or octadecyloxy; and cyclic alkoxy groups having 3 to 8 carbon atoms, such as cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, and cyclooctyloxy.

[0026] The aryl group is preferably a phenyl, biphenyl, naphthyl, dihydroindenyl, 9H-fluorenyl group, or the like.

[0027] The aralkyl group is preferably a benzyl, phenethyl, trityl, 1-naphthylmethyl, 2-(1-naphthyl)ethyl, 2-(2-naphthyl)ethyl group, or the like.

[0028] The alkenyl group is preferably an ethenyl group (vinyl group), a 2-propenyl group (allyl group), an isopropenyl group, a butenyl group, an isobutenyl group, a tert-butenyl group, a pentenyl group, a hexenyl group, a heptenyl group, an octynyl group, an isooctynyl group, a nonenyl group, or the like.

[0029] The alkynyl group is preferably an ethynyl group, a propynyl group, an isopropynyl group, a butynyl group, an isobutynyl group, a tert-butynyl group, a pentynyl group, a hexynyl group, an octynyl group, or a nonynyl group.

[0030] [1-2] Organic solvents The production method of the present invention includes a step of fluorinating the α-position of an α-substituted β-diketone in an organic solvent.

[0031] The organic solvent is preferably at least one organic solvent selected from the group consisting of halogen-based solvents, ether-based solvents, ester-based solvents, hydrocarbon-based solvents, and aromatic-based solvents.

[0032] The halogen-based solvent is preferably dichloromethane (CH2Cl2), trichloromethane (CHCl3), or the like.

[0033] The ether solvent is preferably tetrahydrofuran (THF), dioxane, diethyl ether (Et2O), isopropyl ether (IPE), or the like.

[0034] The ester solvent is preferably ethyl acetate (AcOEt) or the like.

[0035] The hydrocarbon solvent is preferably n-hexane or the like.

[0036] The aromatic solvent is preferably toluene or the like.

[0037] The organic solvent is more preferably an ether solvent (polar solvent) such as THF, dioxane, or diethyl ether.

[0038] The amount of the organic solvent used is adjusted so that the concentration (M (mol / L)) of the α-substituted β-diketone (substrate) is preferably 0.005M to 5M, more preferably 0.05M to 2M.

[0039] [1-3] At least one catalyst selected from the group consisting of β,β-diaryl-substituted serine and its derivatives The production method of the present invention includes a step of fluorinating the α-position of an α-substituted β-diketone in the presence of at least one catalyst selected from the group consisting of β,β-diaryl-substituted serine such as β,β-diarylserine and derivatives thereof.

[0040] The catalyst preferably has a structure represented by the following general formula (2):

[0041] [ka] In formula (2), Ar represents an aryl group.

[0042] In the production method of the present invention, the CO2H group of β,β-diarylserine in particular contributes to high enantioselectivity.

[0043] The catalyst is preferably β,β-diphenylserine (C6), β,β-di(4-fluorophenyl)serine (C7), β,β-di(3,4,5-trifluorophenyl)serine (C8), β,β-di(3,5-ditrifluoromethylphenyl)serine (C9), β,β-di(3,5-dimethylphenyl)serine (C10), β,β-di(3,5-di-t-butylphenyl)serine (C11), β,β-bis(3,5-dimethyl-4-methoxyphenyl)serine (C12), β,β-bis(3,5-di-t-butyl-4-methoxyphenyl)serine (C13), more preferably β,β-di(3,5-dimethylphenyl)serine (C10), β,β-di(3,5-di-t-butylphenyl)serine (C11), β,β-bis(3,5-di-t-butyl-4-methoxyphenyl)serine (C13), still more preferably β,β-di(3,5-dimethylphenyl)serine (C10) and β,β-bis(3,5-di-t-butyl-4-methoxyphenyl)serine (C13), and particularly preferably β,β-bis(3,5-di-t-butyl-4-methoxyphenyl)serine (C13).

[0044] β,β-bis(3,5-di-t-butyl-4-methoxyphenyl)serine (C13) has the following structure:

[0045] [ka]

[0046] The amount of catalyst used in the fluorination reaction is, in terms of molar ratio, preferably 5 mol % to 40 mol %, more preferably 10 mol % to 30 mol %, and even more preferably 15 mol % to 25 mol %, relative to the α-substituted β-diketone (substrate) (when the substrate is taken as 100 mol %).

[0047] In the production method of the present invention, by using the above catalyst in the fluorination reaction, a compound in which the α-position of an α-substituted β-diketone is fluorinated can be produced in high yield and with high enantioselectivity.

[0048] [1-4] Fluorinating agents The production method of the present invention includes a step of mixing an α-substituted β-diketone with a fluorinating agent and carrying out a fluorination reaction at the α-position of the α-substituted β-diketone.

[0049] The fluorinating agent is preferably at least one selected from the group consisting of N-fluorobenzenesulfonimide (NFSI), 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (Selectfluor(R)), 1-fluoro-2,4,6-trimethylpyridinium tetrafluoroborate, 2,6-dichloro-1-fluoropyridinium tetrafluoroborate, and 2,6-dichloro-1-fluoropyridinium triflate, more preferably N-fluorobenzenesulfonimide (NFSI) or 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate), and particularly preferably 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate).

[0050] 1-Chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) has the following structure:

[0051] [ka]

[0052] The amount of catalyst used in the fluorination reaction is, in terms of molar ratio relative to the α-substituted β-diketone (substrate) (when the substrate is taken as 1 equivalent), preferably 0.1 to 20 equivalents, more preferably 0.9 to 5 equivalents, and even more preferably 1 to 3 equivalents.

[0053] In the production method of the present invention, by using the above-mentioned fluorinating agent in the fluorination reaction, a compound in which the α-position of an α-substituted β-diketone is fluorinated can be produced in high yield and with high enantioselectivity.

[0054] [1-5] Fluorination of the α-position of an α-substituted β-diketone The production method of the present invention makes it possible to produce a compound in which the α-position of an α-substituted β-diketone is fluorinated from the starting compound, an α-substituted β-diketone, in high yield (74% to 99% yield) and with high enantioselectivity (75% ee to 95% ee).

[0055] [ka]

[0056] The reaction temperature in the fluorination reaction step is preferably 0 to 90°C, more preferably 0 to 60°C, and further preferably 10 to 35°C.

[0057] The reaction time in the fluorination reaction step is preferably 0.5 to 70 hours, more preferably 10 to 60 hours, and further preferably 20 to 50 hours.

[0058] [2] Application example As an application example of the production method of the present invention, from a compound in which the α-position of an α-substituted β-diketone is fluorinated, it is possible to further produce diol compounds, aldol compounds, allyl compounds, etc. with high enantioselectivity.

[0059] Although the embodiments of the present invention have been described above, the present invention is not limited to these examples and can be embodied in various forms without departing from the spirit and scope of the present invention. [Example]

[0060] Hereinafter, the embodiments of the present invention will be described more specifically based on examples.

[0061] The present invention is not limited to these.

[0062] [1] Examination of fluorination reaction conditions As shown in Scheme 1 and Table 1, optimization of the conditions for the fluorination reaction at the α-position of α-substituted β-diketones was investigated. Organic solvent: Substrate concentration 0.5M / tetrahydrofuran (THF) Catalyst: 20 mol% / substrate Fluorinating agent: 1.5 equivalents / substrate Reaction conditions: room temperature, 48 hours

[0063] In Comparative Examples 1 to 5 and Examples 1 to 5, the fluorinating agent (F + N-fluorobenzenesulfonimide (NFSI, F1 compound) was used as a reagent to produce β-diketone 1a compound (R 1 is a methyl group, and R 2 is a methyl group, and R 3 The compound (which is a phenyl group) was subjected to a fluorination reaction.

[0064] [ka]

[0065] Comparative Examples 1-5 (Catalysts C1-C5) When β-diketone 1a compound was fluorinated using catalysts C1 to C5, the production of the target compound (fluorinated compound 2a) in which the α-position of the α-substituted β-diketone was fluorinated was not observed or was observed only in low yield, and the enantioselectivity of the obtained compound was also low.

[0066] Examples 1 to 3 (Catalysts C6 to C8) The α-position of α-substituted β-diketones was fluorinated using β,β-diphenylserine (catalyst C6). The fluorination of β-diketone 1a using catalyst C6, a basic catalyst for β,β-diarylserine with a phenyl substituent, resulted in an improved yield of fluorinated compound 2a, with good enantioselectivity (71% ee).

[0067] In the reaction systems using β,β-di(4-fluorophenyl)serine (C7) and β,β-di(3,4,5-trifluorophenyl)serine (C8) as catalysts, the yield of fluorinated compound 2a was improved and good enantioselectivity was observed.

[0068] Examples 4 and 5 (Catalysts C10 and C13) We screened various substituted β,β-diarylserines (β,β-di(3,5-dimethylphenyl)serine (C10) and β,β-bis(3,5-di-t-butyl-4-methoxyphenyl)serine (C13)) as catalysts, and both showed high enantioselectivity.

[0069] Example 6 (Combination of Catalyst C13 and Fluorinating Agent F3) By using β,β-bis(3,5-di-t-butyl-4-methoxyphenyl)serine (C13) as a catalyst and 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (Selectfluor®, F3 compound) as a fluorinating agent, the reaction time of the fluorination reaction was shortened, and the fluorinated compound 2a was produced in a higher yield and with a higher enantioselectivity (94% ee).

[0070] [Table 1]

[0071] [2] Scheme 2: Substrate considerations The substrate scope of the α-substituted β-diketones shown in Scheme 2 was explored. Organic solvent: Substrate concentration 0.5M / tetrahydrofuran (THF) Catalyst: β,β-bis(3,5-di-t-butyl-4-methoxyphenyl)serine (C13), 20 mol% / substrate Fluorinating agent: 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (Selectfluor®, F3 compound), 2 equivalents / substrate Reaction conditions: 40°C, 17 to 48 hours

[0072] [ka]

[0073] Even when α-substituted β-diketones represented by the substrates 2a to 2n were used as substrates, the enantioselectivity of the compounds in which the α-position of the α-substituted β-diketone was fluorinated was high, and the fluorinated compounds could be produced in excellent yields.

[0074] [3] Scheme 3: Reference Example Reference examples of synthetic applications of fluorinated compounds produced using the fluorination reaction of the present invention are shown below.

[0075] [ka] [Industrial Applicability]

[0076] According to the method of the present invention for producing a compound in which the α-position of an α-substituted β-diketone is fluorinated, it is possible to carry out a fluorination reaction of an α-substituted β-diketone, which is difficult to distinguish, in high yield and with high enantioselectivity.

[0077] The α-substituted β-diketones obtained by the production method of the present invention, which are fluorinated at the α-position, can be derived into special fluorinated amino acids, and are expected to have a wide range of industrial applications.

Claims

1. A method for producing a compound in which the α-position of an α-substituted β-diketone is fluorinated, comprising the steps of: the step of mixing an α-substituted β-diketone with a fluorinating agent in an organic solvent in the presence of at least one catalyst selected from the group consisting of β,β-diaryl-substituted serine and derivatives thereof, and fluorinating the α-position of the α-substituted β-diketone; The α-substituted β-diketone is a compound having a structure represented by the following general formula (1): 【Chemistry 1】 (In formula (1), R 1 is an alkyl group, an alkoxy group, or an aryl group; R2 is an alkyl group, an aryl group, an aralkyl group, an alkenyl group, or an alkynyl group; R3 is an alkyl group, an alkoxy group, or an aryl group. the catalyst is at least one selected from the group consisting of β,β-diphenylserine, β,β-di(4-fluorophenyl)serine, β,β-di(3,4,5-trifluorophenyl)serine, β,β-di(3,5-ditrifluoromethylphenyl)serine, β,β-di(3,5-dimethylphenyl)serine, β,β-di(3,5-di-t-butylphenyl)serine, β,β-bis(3,5-dimethyl-4-methoxyphenyl)serine, and β,β-bis(3,5-di-t-butyl-4-methoxyphenyl)serine; the fluorinating agent is at least one selected from the group consisting of N-fluorobenzenesulfonimide, 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate), 1-fluoro-2,4,6-trimethylpyridinium tetrafluoroborate, 2,6-dichloro-1-fluoropyridinium tetrafluoroborate, and 2,6-dichloro-1-fluoropyridinium triflate; enantioselectively fluorinating the α-position of the α-substituted β-diketone; Manufacturing method.

2. 2. The method according to claim 1, wherein the organic solvent is at least one organic solvent selected from the group consisting of halogen-based solvents, ether-based solvents, ester-based solvents, hydrocarbon-based solvents, and aromatic solvents.

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