JP2013043831A - TERTIARY α-TRIFLUOROMETHYL KETONE DERIVATIVE, AND METHOD FOR PRODUCING THE SAME - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a tertiary α-trifluoromethyl ketone derivative, and a method for producing the same.SOLUTION: This invention relates to a method for producing simply and highly efficiently a tertiary α-trifluoromethyl ketone derivative represented by general formula (1) (in the formula, Rand Reach represents substituted or unsubstituted alkyl, alkenyl, aralkyl, alkynyl, aryl or aryloxy. Further, Rand Rmay form together a part of an annular structure interposed or non-interposed by a heteroatom).

Description

The present invention relates to a tertiary α-trifluoromethyl ketone derivative and a method for producing the same.

α-Trifluoromethylcarbonyl compounds are of interest because of their characteristic physical and biological properties, and direct α-trifluoromethylation reaction to ketones has been studied for a long time. However, the synthesis of α-trifluoromethyl ketone derivatives is difficult in terms of synthesis because the defluorination reaction proceeds easily with the enolate or base of the starting material used in the reaction. Therefore, although the synthesis of α-trifluoromethyl ketone derivatives has been studied for a long time, there are problems such as low yield and side reactions. (Non-patent Documents 1, 2, and 3) Therefore, a method for synthesizing a tertiary α-trifluoromethyl ketone derivative more easily and efficiently is required.

Itoh, Y .; Mikami, K. Org. Lett., 2005, 7, 649. Itoh, Y .; Mikami, K. Org. Lett., 2005, 7, 4883. Kirij, N. V .; Pasenok, S. V .; Yagupolskii, Y. L .; Tyrra, W .; Naumann, D. J. Fluorine Chem. 2000, 106, 217.

In view of the above points, an object of the present invention is to develop a method for producing a tertiary α-trifluoromethyl ketone derivative in a simple and high yield.

  In order to achieve the above object, the inventors of the present invention represented by the following general formula (1) by decarboxylation of α-trifluoromethyl-β-ketoester represented by the following general formula (2) by hydrogenation reaction in the presence of a Pd / C catalyst. And succeeded in derivatization to a tertiary α-trifluoromethyl ketone represented by That is, the invention described in claim 1 resides in a tertiary α-trifluoromethyl ketone derivative represented by the following general formula (1).

(Wherein, R ¹ and R ² are a substituted or unsubstituted alkyl group, an alkenyl group, an aralkyl group, an alkynyl group, an aryl group, or an aryloxy group. In addition R ¹ and R ² together, hetero (A part of the cyclic structure may be formed with or without intervening atoms.)

The method for producing the tertiary α-trifluoromethyl ketone derivative of the present invention is a method for synthesizing the tertiary α-trifluoromethyl ketone derivative represented by the above general formula (1) as shown in claim 2. And a process for decarboxylation of α-trifluoromethyl-β-ketoester represented by the following general formula (2) by hydrogenation reaction in the presence of a Pd / C catalyst. .

(In the formula, R ¹ and R ² are as described in formula (1).)

In this specification, as the alkyl group represented by R ¹ and R ² , for example, an alkyl group having about 1 to 20 carbon atoms can be used. Specifically, methyl group, ethyl group, propyl group, butyl group, pentyl group, hexyl group, heptyl group, octyl group, nonyl group, decyl group, undecyl group, dodecyl group, tridecyl group, tetradecyl group, 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 and R ² is not particularly limited, but is preferably about 1 to 2. The alkenyl group or alkynyl group may be linear or branched.
Examples of the aralkyl group represented by R ¹ and R ² include benzyl group, pentafluorobenzyl group, o-methylbenzyl group, m-methylbenzyl group, p-methylbenzyl group, p-nitrobenzyl group, naphthylmethyl group, Examples include a furfuryl group and an α-phenethyl group.
The aryl group represented by R ¹ and R ² also includes a heteroaryl group, and specific examples include, for example, an aryl group having 2 to 30 carbon atoms, specifically a phenyl group, a naphthyl group, an anthranyl group, and a pyrenyl group. , Biphenyl group, indenyl group, tetrahydronaphthyl group, pyridyl group, pyrimidinyl group, pyrazinyl group, pyridanyl 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 and R ² also includes a heteroaryloxy group. Specific examples thereof include, for example, an aryl group having 2 to 30 carbon atoms, specifically, a phenyloxy group, a naphthyloxy group, an anthracite group. Nyloxy, pyrenyloxy, biphenyloxy, indenyloxy, tetrahydronaphthyloxy, pyridyloxy, pyrimidinyloxy, pyrazinyloxy, pyridanyloxy, piperazinyloxy, pyrazolyloxy, imidazolyloxy , Quinyloxy group, pyrrolyloxy group, indolyloxy group, furyloxy group, and the like.
Examples of the cyclic structure that can be formed by combining R ¹ and R ² can be a monocyclic, bicyclic, or higher polycyclic structure consisting of 3 to 20 members. These cyclic structures may have a hetero atom.
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 1 or 2 or more substituents selected from the group consisting of a group or a substituent containing an alkyl moiety (for example, an alkoxy group, an alkylthio group, an alkoxycarbonyl group, etc.) may be present. If substituted, they may be the same or different.
R ¹ and R ² each independently represent one of the substituents defined above, but all may be the same substituent.
Any stereoisomer such as an optical isomer or diastereoisomer of the compound of the present invention is included in the scope of the present invention. Further, any mixture of stereoisomers, racemates, and the like are also included in the scope of the present invention.
The tertiary α-trifluoromethyl ketone derivative of the present invention and the production method thereof are not particularly limited, but the α-trifluoromethyl-β-ketoester represented by the above formula (2) is subjected to Pd in a hydrogen atmosphere. The tertiary α-trifluoromethyl ketone derivative of the above formula (1) can be produced by reacting in a solvent using a / C catalyst.
The α-trifluoromethyl-β-ketoester represented by the formula (2) is not particularly limited, but α-trifluoromethyl-β-ketoester synthesized according to Non-Patent Documents 4 and 5 can be used. .
Noritake, S .; Shibata, N .; Nakamura, S .; Toru, T .; Shiro, M. Eur. J. Org. Chem. 2008, 3465. Matsnev, A .; Noritake, S .; Nomura, Y .; Tokunaga, E .; Nakamura, S .; Shibata, N. Angew. Chem. Int. Ed., 2010, 49, 572. Although not, 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; chloroform, carbon tetrachloride Halogenated hydrocarbon solvents such as benzene, toluene, xylene, cumene, cymene, mesitylene, diisopropylbenzene, pyridine, pyrimidine, pyrazine, pyridazine, etc .; esters such as ethyl acetate Solvents; ketone solvents such as acetone and methyl ethyl ketone; acetonitrile, dimethyl Solvents such as sulfoxide, dimethylformamide; alcohol solvents such as methanol, ethanol, propanol, i-propyl alcohol, aminoethanol, N, N-dimethylaminoethanol; water, supercritical carbon dioxide, ionic liquid Acetonitrile is most preferred. These can be used alone or in combination of two or more. The production of the formula (1) can be carried out under pressure, but is usually carried out at normal pressure. The reaction temperature can be between −80 ° C. and the boiling point of the solvent, but it is preferably −20 ° C. to around room temperature. After the reaction, the tertiary α-trifluoromethyl ketone derivative represented by the formula (1) can be isolated and purified from the reaction solution by a general method. For example, the reaction solution is concentrated and then purified by distillation or Examples include purification by column chromatography using an adsorbent such as silica gel and alumina, salting out, recrystallization, and the like. 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)
General production method of formula (1)
Add 10 wt% Pd / C (9.5 mg, 0.00897 mmol) to a 5.0 ml acetonitrile solution of α-trifluoromethyl-β-ketoester 2a (30 mg, 0.0897 mmol) synthesized according to Non-Patent Document 4 or 5, and add an aspirator. The reaction system was sufficiently purged with nitrogen, and then the reaction system was purged with hydrogen using an aspirator. After stirring at room temperature for 20 hours, the reaction solution was filtered through Celite, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (silica gel 4 g, hexane: ethyl acetate = 9: 1). The desired trifluoromethylated product 1a (17.0 mg, 95%) was obtained as a white solid.

Compound 1a: 2- (trifluoromethyl) -2,3-dihydroinden-1-one
¹ H NMR (200 MHz, CDCl ₃ ): δ 7.80 (d, J = 7.6 Hz, 1H), 7.65 (td, J = 7.8, 1.2 Hz, 1H), 7.53-7.38 (m, 2H), 3.53-3.23 (m, 3H) ppm; ¹⁹ F NMR (188 MHz, CDCl ₃ ): δ -67.7 (d, J = 8.9 Hz, 3F) ppm; ¹³ C NMR (150.9 Hz, CDCl ₃ ): δ 197.18, 152.42, 139.66 , 136.16, 128.55, 126.86, 125.29 (q, J = 278 Hz), 125.10, 50.11 (q, J = 27 Hz), 27.96 (q, 2.6 Hz) ppm;
(Second Embodiment)
Add 10 wt% Pd / C (8.8 mg, 0.00830 mmol) to a 5.0 ml acetonitrile solution of α-trifluoromethyl-β-ketoester 2b (32.7 mg, 0.0830 mmol) synthesized according to Non-Patent Document 4 or 5, and add an aspirator. The reaction system was sufficiently purged with nitrogen, and then the reaction system was purged with hydrogen using an aspirator. After stirring at room temperature for 20 hours, the reaction solution was filtered through Celite, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (silica gel 4 g, benzene: ethyl acetate = 7: 3). The desired trifluoromethylated compound 1b (21.6 mg, 99%) was obtained as a white solid.

Compound 1b: 2- (trifluoromethyl) -2,3-dihydro-5,6-dimethoxyinden-1-one
¹ H NMR (200 MHz, CDCl ₃ ): δ 7.19 (s, 1H), 6.90 (s, 1H), 3.98 (s, 3H), 3.91 (s, 3H), 3.47-3.14 (m, 3H) ppm; ¹⁹ F NMR (188 MHz, CDCl ₃ ): δ -67.9 (d, J = 8.9 Hz, 3F) ppm; ¹³ C NMR (150.9 Hz, CDCl ₃ ) δ 195.68, 156.80, 150.44, 148.14, 129.13, 125.45 (q , J = 279 Hz), 107.55, 105.15, 56.79, 56.58, 50.39 (q, J = 27 Hz), 27.71 ppm;
(Third embodiment)
Add 10 wt% Pd / C (9.2 mg, 0.00860 mmol) to a 5.0 ml acetonitrile solution of α-trifluoromethyl-β-ketoester 2c (30.0 mg, 0.0860 mmol) synthesized according to Non-Patent Document 4 or 5, and add an aspirator. The reaction system was sufficiently purged with nitrogen, and then the reaction system was purged with hydrogen using an aspirator. After stirring at room temperature for 20 hours, the reaction solution was filtered through Celite, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (silica gel 4 g, hexane: ethyl acetate = 95: 5). The desired trifluoromethylated compound 1c (15.7 mg, 85%) was obtained as a yellow oil.

Compound 1c: 2- (trifluoromethyl) -3,4-dihydronaphthalen-1 (2H) -one
¹ H NMR (200 MHz, CDCl ₃ ): δ 8.05 (d, J = 6.8 Hz, 1H), 7.51 (td, J = 7.6, 1.4 Hz, 1H), 7.37-7.25 (m, 2H), 3.38-3.16 (m, 1H), 3.12-2.97 (m, 2H), 2.57-2.43 (m, 1H), 2.37-2.17 (m, 1H) ppm; ¹⁹ F NMR (181 MHz, CDCl ₃ ): δ -67.5 (d , J = 8.9 Hz, 3F) ppm; ¹³ C NMR (150.9 Hz, CDCl ₃ ): δ 190.57, 143.41, 134.54, 132.31, 129.12, 128.25, 127.48, 125.41 (q, J = 280 Hz), 51.25 (q, J = 26 Hz), 27.89, 23.79 ppm;
(Fourth embodiment)
Add 10 wt% Pd / C (11.3 mg, 0.0106 mmol) to a 6.0 ml acetonitrile solution of α-trifluoromethyl-β-ketoester 2d (35.5 mg, 0.106 mmol) synthesized according to Non-Patent Document 4 or 5, and add an aspirator. The reaction system was sufficiently purged with nitrogen, and then the reaction system was purged with hydrogen using an aspirator. After stirring at room temperature for 20 hours, the reaction solution was filtered through Celite, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (silica gel 4 g, benzene: hexane = 5: 5). The target trifluoromethylated compound 1d (13.7 mg, 64%) was obtained as an oil.

Compound 1d: 2- (trifluoromethyl) -1-phenylprop-1-one
¹ H NMR (300 MHz, CDCl ₃ ) δ 7.96 (d, J = 8.7 Hz, 2H), 7.66-7.61 (m, 1H), 7.54-7.49 (m, 2H), 4.27 (m, 1H), 1.48 ( d, J = 7.2 Hz, 1H) ppm; ¹⁹ F NMR (282 MHz, CDCl ₃ ) δ -68.8 (d, J = 7.9 Hz, 3F) ppm; ¹³ C NMR (150.9 Hz, CDCl ₃ ) δ 194.77, 136.04 , 134.35, 129.27, 128.96, 125.66 (q, J = 279 Hz), 44.64 (q, J = 27 Hz), 12.04 (q, J = 2.9 Hz) ppm;

Claims (2)

A derivative derived from tertiary α-trifluoromethyl ketone represented by the following general formula (1).

(Wherein, R ¹ and R ² are a substituted or unsubstituted alkyl group, an alkenyl group, an aralkyl group, an alkynyl group, an aryl group, or an aryloxy group. In addition R ¹ and R ² together, hetero (A part of the cyclic structure may be formed with or without intervening atoms.)
The α-trifluoromethyl-β-keto ester represented by the following general formula (2) is decarboxylated by hydrogenation reaction in the presence of a Pd / C catalyst, and the tertiary α-trifluoro represented by the general formula (1). A method for producing a methyl ketone derivative.

(In the formula, R ¹ and R ² are as described in the general formula (1).)