KR102483278B1 - Trifluoromethylated Hydroquinone Derivatives and Method for Preparing the Same - Google Patents

Abstract

The present invention relates to a method for producing a trifluoromethylated hydroquinone derivative comprising the step of irradiating and reacting a benzoquinone derivative with light having a wavelength of 380 nm to 500 nm in a solvent in the presence of a trifluoromethylation reagent. it's about In addition, the present invention relates to a trifluoromethylated hydroquinone derivative having a novel structure substituted with alkyl or alkoxy.

Description

Trifluoromethylated Hydroquinone Derivatives and Method for Preparing the Same

The present invention relates to trifluoromethylated hydroquinone derivatives and methods for their preparation. Specifically, it relates to novel trifluoromethylated hydroquinone derivatives and methods for preparing trifluoromethylated hydroquinone derivatives from benzoquinone derivatives.

Hydroquinone is a phenol-based aromatic organic compound that is well soluble in water and has strong reducing power, so it has been used as an antioxidant in foods, rubber, etc. or as a polymerization inhibitor using these properties. In addition, since hydroquinone is a strong melanin production inhibitor, its utilization and marketability are high, such as being used in functional cosmetics such as skin whitening agents and freckles removal agents. Such hydroquinone can be produced by various methods such as hydroperoxideizing 1,4-diisopropylbenzene and hydroxylating phenol.

On the other hand, the trifluoromethyl group (-CF ₃ ) is a substituent with a larger van der Waals radius than the methyl group (-CH ₃ ) and the same electronegativity as oxygen. Since it often changes biochemical properties, introduction of substituents in compounds in various fields such as electronic materials, pharmaceuticals, and agricultural chemicals has been tried and studied (Jing-Jing Yang et al., J. Org. Chem. 1998 , 63, 2656-2660).

Even in the case of hydroquinone, introduction of various substituents such as a trifluoromethyl group may be considered for the purpose of improving or changing at least some of the various properties, but optionally substituted hydroquinone is directly prepared from the starting material for the production of hydroquinone. It's not easy to do. Accordingly, a separate synthesis step of introducing a substituent after preparing hydroquinone was required, and even in the synthesis process, severe conditions were required or the synthesis yield was low, typically 30 to 50%.

One object of the present invention is to provide a method for preparing a trifluoromethylated hydroquinone derivative from a benzoquinone derivative as a starting material without having to perform a separate step of substituting a trifluoromethyl group after preparing hydroquinone. .

Another object of the present invention is to provide a trifluoromethylated hydroquinone derivative having a novel structure.

According to one aspect of the present invention, a trifluoromethylated hydroquinone derivative comprising the step of reacting by irradiating light with a wavelength of 380 nm to 500 nm to the benzoquinone derivative in a solvent in the presence of a trifluoromethylation reagent. A manufacturing method is provided.

According to one embodiment of the present invention, the benzoquinone derivative is 1,4-benzoquinone substituted or unsubstituted by at least one substituent selected from alkyl having 1 to 10 carbon atoms, alkoxy having 1 to 10 carbon atoms, and halogen. It can be a rice field.

According to another embodiment of the present invention, the trifluoromethylation reagent may be Langlois reagent (CF ₃ SO ₂ Na).

According to another embodiment of the present invention, the benzoquinone derivative may form a quinhydrone derivative by irradiation with light, and the quinhydrone derivative may react with the trifluoromethylation reagent.

According to another embodiment of the present invention, the benzoquinone derivative may be used in an amount of 2 to 3 equivalents to the trifluoromethylation reagent.

According to another embodiment of the present invention, the solvent may be selected from water, methanol, ethanol, dimethyl sulfoxide, acetonitrile, and 2,2,2-trifluoroethanol.

According to another embodiment of the present invention, the solvent may include water, acetonitrile or 2,2,2-trifluoroethanol.

According to another embodiment of the present invention, the solvent may be a mixed solvent obtained by mixing water and an organic solvent in a ratio of 1:2 to 2:1 (by volume).

According to another embodiment of the present invention, the reaction may be carried out at room temperature.

According to another embodiment of the present invention, the trifluoromethylated hydroquinone derivative may be represented by Formula 1 below:

[Formula 1]

In Formula 1,

R ₁ , R ₂ , R _{3 ,} and R ₄ are each independently selected from hydrogen, alkyl having 1 to 10 carbon atoms, alkoxy having 1 to 10 carbon atoms, halogen, and -CF ₃ , provided that R ₁ , R ₂ , R _{3 ,} and R ₄ is -CF ₃ .

According to another aspect of the present invention, a trifluoromethylated hydroquinone derivative represented by Formula 2 below is provided.

[Formula 2]

In Formula 2,

R ₁₁ , R ₁₂ , R _{13 ,} and R ₁₄ are each independently selected from hydrogen, alkyl having 1 to 10 carbon atoms, alkoxy having 1 to 10 carbon atoms, and -CF ₃ ;

However, any one of R ₁₁ , R ₁₂ , R _{13 ,} and R ₁₄ is -CF ₃ , and any one or two or more of the others are selected from alkyl having 1 to 10 carbon atoms and alkoxy having 1 to 10 carbon atoms.

According to one embodiment of the present invention, the trifluoromethylated hydroquinone derivative represented by Chemical Formula 2 may be represented by any one of Chemical Formulas 3 to 12:

[Formula 3] [Formula 4]

[Formula 5] [Formula 6]

[Formula 7] [Formula 8]

[Formula 9] [Formula 10]

[Formula 11] [Formula 12]

According to the production method of the present invention, a trifluoromethylated hydroquinone derivative can be directly prepared from a benzoquinone derivative without performing a separate trifluoromethyl group introduction step, and the process yield is high. Therefore, there is an advantage that the manufacturing method is simple and efficient. In addition, it does not require strong energy light such as UV light or 300 W xenon lamp, which was mainly used in the conventional hydroquinone derivative manufacturing method, and can be performed at room temperature using a low energy light source such as 18 W blue LED. And, since the benzoquinone derivative used as a starting material is inexpensive and readily available, the manufacturing method of the present invention is simple, economical, and applicable to mass production. The alkyl or alkoxy or halogen substituted trifluoromethylated hydroquinone derivatives of the present invention can be used for various uses of hydroquinone such as antioxidants and the like.

1 is a graph showing the absorbance of benzoquinone (BQ), quinhydrone, and Langlois reagent according to light wavelength, measured by UV-Vis spectroscopy.
2 is a graph showing absorbance measured according to light wavelength using UV-Vis spectroscopy while changing the amount of Langlois reagent for quinhydrone.

Hereinafter, the present invention will be described in detail.

The terms used in this application are only used to describe specific embodiments and are not intended to limit the present invention. Unless defined otherwise, all terms used herein, including technical or scientific terms, have the same meaning as commonly understood by one of ordinary skill in the art to which the present invention belongs.

In the present specification, when a part “includes”, “includes”, or “has” a certain component, it means that it may further include other components unless otherwise specifically defined.

In the present specification, “substitution” in the expression “substituted or unsubstituted” means that a hydrogen atom in a functional group is replaced with another atom or other functional group (ie, a substituent).

In this specification, “alkyl” may be straight-chain or branched-chain, and may be substituted or unsubstituted. The number of carbon atoms of the alkyl is not particularly limited, but may be specifically, straight-chain or branched-chain alkyl having 1 to 10 carbon atoms, and more specifically, straight-chain or branched-chain alkyl having 1 to 4 carbon atoms. Specific examples of the alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl.

In the present specification, the "alkoxy" may be a straight chain, branched chain, or cyclic chain, and may be substituted or unsubstituted. The number of carbon atoms of the alkoxy is not particularly limited, but may be specifically, straight-chain or branched-chain alkoxy having 1 to 10 carbon atoms, and more specifically, straight-chain or branched-chain alkoxy having 1 to 4 carbon atoms. Specific examples of the alkoxy include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy and the like.

In this specification, “halogen” includes F, Cl, Br, and I atoms, and may specifically be F, Cl, or Br atoms.

1. Method for producing trifluoromethylated hydroquinone derivatives

A method for preparing a trifluoromethylated hydroquinone derivative according to one aspect of the present invention includes reacting a benzoquinone derivative by irradiating light having a wavelength of 380 nm to 500 nm in the presence of a trifluoromethylation reagent in a solvent. .

According to the present invention, benzoquinone derivatives form quinhydrone derivatives while absorbing the corresponding light by irradiation with light having a wavelength of 380 nm to 500 nm. As the quinhydrone derivative reacts with the trifluoromethylation reagent, promotes the formation of the trifluoromethylated hydroquinone derivatives of the present invention. According to the formation of a quinhydroquinone derivative by irradiation of light with a wavelength of 380 nm to 500 nm, one-stop synthesis of a substituted hydroquinone derivative, which has been difficult in the prior art, may be possible. An example of a probable mechanism for the formation of a quinhydrone derivative and the formation of a reactant by light irradiation according to the present invention is shown in [Scheme 1] below.

[Scheme 1]

A light source for light irradiation is not particularly limited as long as it can supply light having a wavelength of 380 nm to 500 nm, and for example, a general blue light emitting lamp, specifically a blue light emitting LED, may be used regardless of intensity.

Conventionally, benzoquinone derivatives have been mainly used as oxidizing agents in the manufacturing process of compounds. According to the present invention, the benzoquinone derivative contributes to the one-stop production of trifluoromethylated hydroquinone derivative through the formation of a quinhydrone derivative by serving as a starting material and a photosensitizer.

The benzoquinone derivative may be a 1,4-benzoquinone derivative. The benzoquinone derivative may specifically be 1,4-benzoquinone substituted or unsubstituted by at least one substituent selected from alkyl, alkoxy, and halogen, and more specifically, unsubstituted 1,4-benzo quinone, or 1,4-benzoquinone substituted by one or two substituents selected from straight-chain or branched-chain alkyl having 1 to 10 carbon atoms, straight-chain or branched-chain alkoxy having 1 to 10 carbon atoms, and halogen. .

The amount of the benzoquinone derivative used is not particularly limited, but considering the manufacturing cost, reaction efficiency, etc., specifically, it may be used in an amount of 2 to 3 equivalents to the trifluoromethylation reagent.

Since the production method of the present invention directly prepares a trifluoromethylated hydroquinone derivative using a benzoquinone derivative as a starting material without proceeding with a separate trifluoromethylation step, the step of irradiating the benzoquinone derivative with light It is performed in the presence of a fluoromethylation reagent.

The trifluoromethylation reagent is not particularly limited as long as it is commonly used in organic synthesis reactions as a source of trifluoromethyl groups. Commonly used trifluoromethylation reagents include Togni reagent, Umemoto reagent, and Langlois reagent. Togni reagent and Umemoto reagent have the advantage of being stable and easy to handle even if left at room temperature for a long time, but have the disadvantage of being expensive. Langlois reagent (CF ₃ SO ₂ Na) is inexpensive, and when used in the production method of the present invention, the reaction can proceed smoothly in conjunction with the starting material, so according to one embodiment of the present invention, trifluoro As a methylation reagent, Langlois reagent is used.

The amount of the trifluoromethylation reagent used is not particularly limited, but when used in excess compared to the benzoquinone derivative, it may be undesirable from an economic point of view.

Light irradiation and reaction of the benzoquinone derivative according to one aspect of the present invention are performed in a solvent. The solvent may be water, an organic solvent, or a mixed solvent obtained by mixing water and an organic solvent. The organic solvent is not particularly limited as long as it does not react with the reactants, and examples thereof include methanol, ethanol, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), acetonitrile (MeCN), 2,2,2 -Trifluoroethanol (TFE) and the like, and these may be used alone or in combination of two or more. Considering the solubility of reactants, solubility of elimination, reaction efficiency, yield, etc., one selected from water, methanol, ethanol, dimethyl sulfoxide, acetonitrile, and 2,2,2-trifluoroethanol as the solvent more can be used. In terms of production yield, the solvent is preferably a mixed solvent of water and an organic solvent, specifically a mixed solvent of water and acetonitrile or 2,2,2-trifluoroethanol. When water and organic solvent are mixed, the mixing ratio thereof is 1:2 to 2:1 (by volume), specifically 1:1.5 to 1.5:1 (by volume), more specifically 1 :1 (by volume).

Light irradiation and reaction of the benzoquinone derivative according to one aspect of the present invention may be performed under mild conditions. For example, it may be performed at 20 to 60 ° C. under normal pressure, and specifically, it may be performed at room temperature and normal pressure. The light irradiation and reaction may be performed in an inert atmosphere such as argon (Ar). The reaction time may vary depending on the amount of the reactant, the type of the solvent, the amount of the solvent, etc., and is not particularly limited. For example, the reaction time may be 1 to 6 hours.

According to the production method of the present invention, a trifluoromethylated hydroquinone derivative represented by Formula 1 can be obtained:

[Formula 1]

In Formula 1, R ₁ , R ₂ , R _{3 ,} and R ₄ are each independently selected from hydrogen, alkyl having 1 to 10 carbon atoms, alkoxy having 1 to 10 carbon atoms, halogen, and -CF ₃ , provided that, Any one of R ₁ , R ₂ , R _{3 ,} and R ₄ is -CF ₃ .

Specifically, any one of R ₁ , R ₂ , R _{3 ,} and R ₄ is -CF ₃ , and the others are hydrogen or straight-chain or branched-chain alkyl having 1 to 10 carbon atoms, or hydrogen or linear chain having 1 to 10 carbon atoms. or branched chain alkoxy, or hydrogen or halogen.

Specific examples of the compound represented by Chemical Formula 1 include Chemical Formulas 1a to 1d and Chemical Formulas 2 and 3 to 12 described below:

[Formula 1a] [Formula 1b]

[Formula 1c] [Formula 1d]

2. Trifluoromethylated Hydroquinone Derivatives

According to one aspect of the present invention, a novel trifluoromethylated hydroquinone derivative represented by Formula 2 can be obtained:

[Formula 2]

In Formula 2, R ₁₁ , R ₁₂ , R _{13 ,} and R ₁₄ are each independently selected from hydrogen, alkyl having 1 to 10 carbon atoms, alkoxy having 1 to 10 carbon atoms, and -CF ₃ , provided that R ₁₁ , any one of R ₁₂ , R _{13 ,} and R ₁₄ is —CF ₃ , and any one or two or more of the others are selected from alkyl having 1 to 10 carbon atoms and alkoxy having 1 to 10 carbon atoms.

Specific examples of the compound of Formula 2 include those represented by Formulas 3 to 12 below:

[Formula 3] [Formula 4]

[Formula 5] [Formula 6]

[Formula 7] [Formula 8]

[Formula 9] [Formula 10]

[Formula 11] [Formula 12]

Hereinafter, the present invention will be described in more detail based on examples. However, the present invention is not limited to these examples.

3, Examples

[Experimental Example 1] Evaluation of Optimization of Reaction Conditions

In order to evaluate the optimization of the reaction conditions, 0.1 mmol of Langlois reagent and 2 equivalents of 1,4-benzoquinone relative to the reagent were mixed in various solvents (0.2 M) and reacted for 1 hour while irradiating light with a blue LED (18 W) to obtain 2-(trifluoromethyl)benzene-1,4-diol. The yield of the product obtained by the above reaction was measured separately or measured using a nuclear magnetic resonance spectrum.

The types of solvents used in this reaction, changes in the above-described reaction conditions, and yields are shown in [Table 1] below.

sample number menstruum change of reaction conditions transference number (%) One MeCN - 59 2 MeCN [Ru(bpy) ₃ ]Cl ₂ 52 3 MeCN fac -Ir(ppy) ₃ 40 4 MeCN darkroom - 5 MeCN 365 nm LEDs (18 W) - 6 TFE - 50 7 methanol - 17 8 DMF - 8 9 DMSO - 27 10 benzene - - 11 THF - - 12 H ₂ O - 20 13 MeCN/H ₂ O (1/1) - 69 14 TFE/H ₂ O (1/1) - 79 15 TFE/H ₂ O (1/1) Benzoquinone 3 equivalents 88

(a) Samples 1 to 5: Effect on light irradiation

As shown in [Table 1], it can be seen that the yield is rather reduced in Samples 2 and 3 using a photoreduction catalyst, compared to Sample 1 in which only light irradiation was performed on benzoquinone without using any additional catalyst. . This can be seen as meaning that the reaction according to the present invention can be promoted by light irradiation itself without the help of any catalyst.

In addition, it can be seen that no reaction occurs in Sample 4 in which light irradiation was not performed in a dark room and in Sample 5 in which a 365 nm wavelength LED was used outside the light wavelength range of the present invention. This can be seen as demonstrating that the reaction of the present invention can be initiated by irradiation with light having a wavelength of 380 nm to 500 nm according to the present invention.

(b) Samples 1 and 6 to 14: Effects of types of solvents

As shown in [Table 1], the reaction did not occur when benzene and THF were used as solvents (Samples 10 and 11), and when MeCN, TFE, methanol (MeOH), DMF, DMSO, and H ₂ O were used It can be seen that the reaction occurs in In particular, it can be seen that the yield is remarkably high in the case of using MeCN or TFE alone (Samples 1 and 6) and in the case of using a mixed solvent in which water and MeCN are mixed (Samples 13 and 14).

(c) Samples 14 and 15: Effects of Use of Benzoquinone

It can be seen that the yield was improved in Sample 15 using 3 equivalents of benzoquinone compared to Sample 14 using 2 equivalents of benzoquinone under the same conditions. Accordingly, the optimum amount of benzoquinone used can be estimated as 2 to 3 equivalents.

[Experimental Example 2] Effect of light irradiation

From Samples 1 to 5 of Experimental Example 1 above, it was confirmed that the reaction of the present invention occurs by irradiating benzoquinone with light having a wavelength of 380 nm to 500 nm. Benzoquinone used as a starting material in the present invention and quinhydrone formed by light irradiation of the benzoquinone absorb light with a wavelength of 380 nm to 500 nm, that is, react only with light in the corresponding wavelength range In order to further confirm, the absorbances of benzoquinone, quinhydrone, and Langlois reagent were measured according to light wavelengths by UV-Vis spectroscopy, and these are shown in [Figure 1]. It can be seen from [Figure 1] that benzoquinone and quinhydrone specifically exhibit absorbance only for light in the wavelength range of 380 nm to 500 nm, that is, they are photosensitizers for light in the corresponding wavelength range.

[Experimental Example 3-(1)] Effect of amount of trifluoromethylation reagent (1)

In order to examine the effect of the amount of tpifluoromethylation reagent, the absorbance according to the light wavelength was measured using UV-Vis spectroscopy while varying the amount of Langlois reagent for quinhydrone, which is shown in [FIG. 2]. showed up It can be seen from [Figure 2] that the sensitivity to light in the wavelength range of 380 nm to 500 nm increases as the amount of Langlois reagent increases.

[Experimental Example 3-(2)] Effect of amount of trifluoromethylation reagent (2)

In order to further investigate the effect of the amount of trifluoromethylation reagent, the interaction between the two molecules was confirmed using ¹ H NMR while varying the amount ^of Langlois reagent for quinhydrone. The H NMR spectrum is shown in [Fig. 3]. From [Figure 3], it was confirmed that the -OH peak moved to a down field as the interaction between the two molecules became stronger as the amount of Langlois reagent increased.

[Example 1] Preparation of 2-(trifluoromethyl)benzene-1,4-diol

Dissolving 1 mmol of Langlois reagent and 3 mmol of 1,4-benzoquinone in TFE/H ₂ O (1/1, 0.2 M) under an argon (Ar) atmosphere at room temperature and irradiating light with a blue LED (18 W) Reacted for 6 hours. This gave 2-(trifluoromethyl)benzene-1,4-diol as a white solid.

[Example 2] Preparation of 3,5-dimethoxy-2-(trifluoromethyl)benzene-1,4-diol

The reaction was conducted in the same manner as in Example 1, except that 2,6-dimethoxybenzoquinone was used instead of 1,4-benzoquinone as a starting material. This gave 3,5-dimethoxy-2-(trifluoromethyl)benzene-1,4-diol as a white solid.

[Example 3] Preparation of 3,5-dimethyl-2-(trifluoromethyl)benzene-1,4-diol

The reaction was conducted in the same manner as in Example 1, except that 2,6-dimethylbenzoquinone was used instead of 1,4-benzoquinone as a starting material. This gave 3,5-dimethyl-2-(trifluoromethyl)benzene-1,4-diol as a white solid.

[Example 4] Preparation of 2,5-dimethyl-2-(trifluoromethyl)benzene-1,4-diol

The reaction was conducted in the same manner as in Example 1, except that 2,5-dimethylbenzoquinone was used instead of 1,4-benzoquinone as a starting material. This gave 2,5-dimethyl-2-(trifluoromethyl)benzene-1,4-diol as a white solid.

[Example 5] Preparation of 2-methyl-3-(trifluoromethyl)benzene-1,4-diol

The reaction was conducted in the same manner as in Example 1, except that 2-methylbenzoquinone was used instead of 1,4-benzoquinone as a starting material. This gave 2-methyl-3-(trifluoromethyl)benzene-1,4-diol (in mixed form with 2-methylhydroquinone) as a white solid.

[Example 6] Preparation of 2-methyl-5-(trifluoromethyl)benzene-1,4-diol

The reaction was conducted in the same manner as in Example 1, except that 2-methylbenzoquinone was used instead of 1,4-benzoquinone as a starting material. This gave a mixture of 2-methyl-5-(trifluoromethyl)benzene-1,4-diol and 2-methyl-6-(trifluoromethyl)benzene-1,4-diol as a white solid.

[Example 7] Preparation of 2-chloro-3-(trifluoromethyl)benzene-1,4-diol

The reaction was conducted in the same manner as in Example 1, except that 2-chlorobenzoquinone was used instead of 1,4-benzoquinone as a starting material. This gave 2-chloro-3-(trifluoromethyl)benzene-1,4-diol as a white solid.

[Example 8] Preparation of 3,5-dichloro-4- (trifluoromethoxy) phenol

The reaction was conducted in the same manner as in Example 1, except that 2,5-dichlorobenzoquinone was used instead of 1,4-benzoquinone as a starting material. This gave 3,5-dichloro-4-(trifluoromethoxy)phenol as a white solid.

Although the above has been described with reference to preferred embodiments of the present invention, those skilled in the art can variously modify and change the present invention without departing from the spirit and scope of the present invention described in the claims below. You will understand that you can.

Claims (12)

A step of reacting a benzoquinone derivative in a solvent in the presence of a trifluoromethylation reagent by irradiating light with a wavelength of 380 nm to 500 nm,
In the reacting step, the benzoquinone derivative forms a quinhydrone derivative by the light irradiation, and the quinhydrone derivative reacts with the trifluoromethylation reagent. Method for producing hydroquinone derivatives. The benzoquinone derivative according to claim 1, wherein the benzoquinone derivative is 1,4-benzoquinone unsubstituted or substituted by at least one substituent selected from alkyl having 1 to 10 carbon atoms, alkoxy having 1 to 10 carbon atoms, and halogen. How to. The method of claim 1, wherein the trifluoromethylation reagent is Langlois reagent (CF ₃ SO ₂ Na). delete The method according to claim 1, wherein the benzoquinone derivative is used in an amount of 2 to 3 equivalents to the trifluoromethylation reagent. 2. The method of claim 1, wherein the solvent is selected from water, methanol, ethanol, dimethyl sulfoxide, acetonitrile, and 2,2,2-trifluoroethanol. 7. The method of claim 6, wherein the solvent comprises water and acetonitrile or 2,2,2-trifluoroethanol. The method according to claim 1, wherein the solvent is a mixed solvent obtained by mixing water and an organic solvent in a ratio of 1:2 to 2:1 (by volume). The method of claim 1, wherein the reaction is carried out at room temperature. The method of claim 1, wherein the trifluoromethylated hydroquinone derivative is represented by Formula 1:
[Formula 1]

In Formula 1,
R ₁ , R ₂ , R _{3 ,} and R ₄ are each independently selected from hydrogen, alkyl having 1 to 10 carbon atoms, alkoxy having 1 to 10 carbon atoms, halogen, and -CF ₃ , provided that R ₁ , R ₂ , R _{3 ,} and R ₄ is -CF ₃ . delete delete

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