KR20160040874A - Method for producing difluoroalkylated amromatics - Google Patents

Abstract

The present invention relates to a preparation method of an aromatic compound to which a difluoroalkyl group is introduced. The preparation method can effectively introduce a difluoroalkyl group to an aromatic compound at moderate conditions. According to an embodiment of the present invention, the preparation method comprises a step of emitting visible rays to a mixture including a iridium-based photocatalyst, an aromatic compound, halodifluoroacetate, a base, and a solvent.

Description

[0001] METHOD FOR PRODUCING DIFLUOROALKYLATED AMROMATICS [0002]

The present invention relates to a process for efficiently introducing a difluoroalkyl group into an aromatic compound under mild conditions.

The aromatic compounds into which the difluoroalkyl group is introduced have a large biological activity and have a structure that plays an important role in the functional material, and thus it is a substance which is attracted to the fields of life sciences and materials chemistry. Particularly, aromatic compounds into which a difluoroalkyl group is introduced have attracted attention as an important application in the development of new drugs because they have characteristics of bioisostere having the same biological activity as oxygen atoms or carbonyl groups in the human body.

Various methods have been introduced to synthesize aromatic compounds into which such difluoroalkyl groups have been introduced. As one of them, aromatic compounds are pre-treated to introduce -B (OH) ₂ or -I into an aromatic compound and reacted with silyl-CF ₂ CO ₂ Et or BrCF ₂ CO ₂ Et in the presence of Cu or Pd / Cu catalyst, A method of synthesizing an aromatic compound into which a fluoroalkyl group is introduced is known. The process involves a pretreatment step of introducing -B (OH) ₂ or -I to the aromatic compound to activate the reacting wholly aromatic compound introducing the difluoroalkyl group, wherein -B (OH) ₂ or -I The introduced aromatic compound must be reacted with silyl-CF ₂ CO ₂ Et or BrCF ₂ CO ₂ Et at a high temperature.

As another method, there is known a method in which a non-preprocessed aromatic compound is reacted with a compound containing a difluoroalkyl group under UV irradiation or at a high temperature. However, these methods also have the problem of irradiating the reactants with UV or with severe process conditions where the reaction takes place at high temperature. Therefore, there is a need for studies to synthesize aromatic compounds in which difluoroalkyl groups are introduced environmentally friendly under mild process conditions.

The present invention provides a process for producing an aromatic compound into which a difluoroalkyl group is introduced, which is capable of efficiently introducing a difluoroalkyl group into an aromatic compound under mild conditions.

One embodiment of the present invention provides a process for producing a difluoroalkyl group-introduced aromatic compound, which comprises irradiating a mixture containing an iridium-based photocatalyst, an aromatic compound, halodifluoroacetate, a base and a solvent with visible light do.

The aromatic compound may be a compound having at least one substituent selected from the group consisting of an alkyl group, a hydroxy group, an alkoxy group, an alkoxycarbonyl group, a mercapto group, an alkylthio group, an amino group and an alkylamino group, An aromatic compound which is linked to form a ring can be used. As the photocatalyst, fac - tris [2 - phenylpyridinate] iridium ( fac - Ir (ppy) ₃ ]) or iridium (Ir dFppy) ₃ ) can be used.

As the base, a tertiary amine, aprotic anion, or a mixture thereof may be used. The base may be used in an amount of 1 to 5 equivalents based on 1 equivalent of an aromatic compound.

As the solvent, an aprotic solvent may be used. The solvent may be used so that the concentration of the aromatic compound with respect to the solvent is 0.01 to 10M.

In one example, an arene may be used as the aromatic compound. At this time, an aprotic anion may be used as the base, and dimethyl sulfoxide (DMSO) may be used as the solvent.

According to one embodiment of the present invention, a difluoroalkyl group can be introduced not only in highly reactive heteroarenes but also in unactivated arenes under mild conditions, so that various fluorine-based compounds Can be easily provided. In addition, the production process according to an embodiment has the advantage that a difluoroalkyl group can be introduced at a desired position of an aromatic compound with high selectivity, and two or more difluoroalkyl groups are not introduced into an aromatic compound.

Hereinafter, a method for producing an aromatic compound into which a difluoroalkyl group is introduced according to a specific embodiment of the present invention will be described.

According to one embodiment of the present invention, there is provided a process for producing an aromatic compound having a difluoroalkyl group introduced thereinto, which comprises irradiating a mixture containing an iridium photocatalyst, an aromatic compound, halodifluoroacetate, a base and a solvent with visible light Is provided.

When the mixture is irradiated with visible light, a CF ₂ COOR radical is generated by an iridium-based photocatalyst activated by visible light, which can be introduced into an aromatic compound. The -CF ₂ COOR group can be converted to various difluoroalkyl groups such as -CHF ₂ , -CF ₂ CH ₂ OH, -CF ₂ C (CH ₃ ) ₂ OH, or -CF ₂ CONH ₂ , And thus it is possible to easily provide a compound required in various fields such as medicine and pesticide. In the present specification, two hydrogen atoms of the alkyl group are substituted with fluorine, and another hydrogen atom is substituted with a substituent other than fluorine, for example, -COOEt, -CH ₂ OH, -C (CH ₃ ) ₂ OH or -CONH ₂ The alkyl group is also referred to as a difluoroalkyl group. That is, when two of the substituents of the alkyl group are fluorine, they are referred to as a difluoroalkyl group irrespective of other substituents. The alkyl group in the difluoroalkyl group may be a straight or branched alkyl group having 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 5 carbon atoms.

The process for preparing an aromatic compound having a difluoroalkyl group according to an embodiment can introduce a difluoroalkyl group into an unactivated aromatic compound and has a high regioselectivity, The introduction of difluoroalkyl groups has the advantage that no further fluoroalkylation proceeds.

Aromatic compounds include heteroarenes and arenes, which are distinguished by the presence or absence of heteroatoms in the aromatic rings. Examples of the heteroarenes include furan, pyrrole, thiophene, indole, imidazole or pyridine, and examples of areenes include benzene and naphthalene. If the heteroatom is present at a moiety other than the ring showing directionality, such a compound is referred to as areene. For example, a compound in which oxygen, which is a heteroatom, is present in a moiety other than the aromatic ring, such as anisole, can be divided into arenes.

According to one embodiment of the present invention, there is provided an aromatic compound having 6 to 20 carbon atoms or 6 to 12 carbon atoms which is unsubstituted or substituted with an aromatic compound, or substituted or unsubstituted heteroarylene having 4 to 20 carbon atoms or 4 to 12 carbon atoms Can be used.

Through the preparation process according to this embodiment, it is possible to introduce a difluoroalkyl group into an unactivated allene as well as a highly reactive heteroarene without a pretreatment process. It is also possible to simultaneously introduce a difluoroalkyl group into the heteroarenes and allenes using the production method according to one embodiment, if necessary.

The aromatic compounds that can be used in the above-described preparation method may have at least one electro-donating group for easier reaction. Specifically, the aromatic compound may be an aromatic compound having at least one substituent selected from the group consisting of an alkyl group, a hydroxy group, an alkoxy group, an alkoxycarbonyl group, a mercapto group, an alkylthio group, an amino group and an alkylamino group have. In addition, an aromatic compound in which two or more substituents selected from the group consisting of an alkyl group, a hydroxy group, an alkoxy group, an alkoxycarbonyl group, a mercapto group, an alkylthio group, an amino group and an alkylamino group are linked together to form a ring may be used .

Wherein the alkyl group is a linear or branched alkyl group having 1 to 20 carbon atoms, 1 to 10 carbon atoms, and 1 to 5 carbon atoms; Or a cycloalkyl group having 3 to 20 carbon atoms or 3 to 12 carbon atoms. The alkoxy group is a straight chain or branched chain alkoxy group having 1 to 20 carbon atoms, 1 to 10 carbon atoms, and 1 to 5 carbon atoms; Or a cycloalkoxy group having 3 to 20 carbon atoms or 3 to 12 carbon atoms. The alkyl group or the alkoxy group contained in the alkoxycarbonyl group, alkylthio group and alkylamino group may be the above-mentioned alkyl group or alkoxy group. The alkylamino group may be a monoalkylamino group or a dialkylamino group.

The aromatic compound may have various substituents other than the substituents described above. However, in the case of having a reactive substituent such as a vinyl group, a reactive substituent of an aromatic compound may react with halodifluoroacetate, so that the yield of an aromatic compound in which a difluoroalkyl group is introduced at a desired position may be lowered.

Halodifluoroacetate is used as a compound that provides a difluoroalkyl group to the aromatic compound.

The halodifluoroacetate may be represented by the following formula (1).

[Chemical Formula 1]

CF ₂ XCOOR

In the above formula (1), R is an aliphatic hydrocarbon group having 1 to 12 carbon atoms or a (hetero) aryl group having 5 to 30 carbon atoms, and X is Cl or Br.

Specifically, the aliphatic hydrocarbon group may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, neopentyl or n-hexyl. The (hetero) aryl group means an aryl group or a heteroaryl group, and may be phenyl or naphthyl.

The halodifluoroacetate may be used alone or in combination of two or more.

The halodifluoroacetate may be used in an amount of 1 to 5 equivalents based on 1 equivalent of an aromatic compound. Specifically, when heteroarylene having good reactivity is used as the aromatic compound, halodifluoroacetate may be used in an amount of 1 to 3 equivalents based on 1 equivalent of heteroarene. On the other hand, in the case of using arenes whose reactivity is lower than that of heteroarenes as aromatic compounds, 2.5 to 4 equivalents of halodifluoroacetate can be used based on 1 equivalent of arenes. When halodifluoroacetate is used in the above-mentioned range, it is possible to synthesize an aromatic compound into which a difluoroalkyl group is introduced in a high yield.

The aromatic compound and halodifluoroacetate can produce an aromatic compound in which a difluoroalkyl group is introduced through a radical type reaction. According to one embodiment of the present invention, radicals can easily be generated by irradiating visible light under a photocatalyst. Specifically, when a visible ray is irradiated under a photocatalyst, a radical (CF ₂ COOR) can be formed from halodifluoroacetate (CF ₂ XCOOR) by a photocatalyst activated by visible light.

Particularly, in the manufacturing method according to an embodiment, the iridium-based photocatalyst containing iridium (Ir) as a photocatalyst can be used to introduce a difluoroalkyl group into arene and / or heteroaren. Referring to Experimental Example 1 to be described later, it is confirmed that when a ruthenium-based photocatalyst is used as a photocatalyst, a difluoroalkyl group is not introduced into the arene or is introduced at a very low rate. However, when an iridium-based photocatalyst is used, it is confirmed that even if a less reactive areene is used, it is possible to provide an isoform in which difluoroalkyl is introduced at a yield of about 81%.

As the iridium-based photocatalyst, fac -tris [2-phenylpyridinate] iridium ( fac- [Ir (ppy) ₃ ]) or iridium (2- (1,4-difluorophenyl) (Ir (dFppy) ₃ ), and the like. Among them, when fac- [Ir (ppy) ₃ ] is used as an iridium-based photocatalyst, a difluoroalkyl group can be introduced into arene and / or heteroarene with high selectivity and high yield.

The photocatalyst can be used in an amount of, for example, about 0.5 to 3.5 mol% (mol%) based on the aromatic compound, to provide an aromatic compound in which a difluoroalkyl group is introduced economically and efficiently. If the photocatalyst is used in excess of the above-mentioned range, the cost of the synthesized compound increases and the economical efficiency is lowered. On the other hand, if the photocatalyst is used within the above-mentioned range, the yield of the reaction may be lowered too much. In particular, when heteroarylene having good reactivity is used as the aromatic compound, the photocatalyst can be used in an amount of 0.5 to 1.5 mol% based on the heterolearene, which is more economical. On the other hand, in the case of using an arene whose reactivity is lower than that of heteroaren as the aromatic compound, the use of a photocatalyst at 1.5 to 3.5 mol% or 2.5 to 3.5 mol% relative to the arene yields a di-fluoroalkyl- can do.

The mixture containing the photocatalyst may be irradiated with visible light so that the photocatalyst is activated. As a source of the visible light, for example, a blue LED, a fluorescent lamp, or a sunlight may be used.

As described above, the production method according to one embodiment is expected to be useful in various fields such as medicine and pesticide because it can produce an aromatic compound in which a difluoroalkyl group is introduced by a gentle method of irradiating visible light under a photocatalyst.

A base is added to the mixture to regenerate the aromatic compound by removing hydrogen from the intermediate generated by the mild reaction using the photocatalyst and visible light as described above. As the base, an appropriate one may be used depending on the aromatic compound, photocatalyst and solvent to be used. In one example, the base may be a tertiary amine, an aprotic anion, or a mixture thereof.

The non-protonic anion is a base on which a negative charge is generated, and a base in which no hydrogen or protons bound to oxygen or nitrogen exist. Examples of the aprotic anion include a phosphate anion (PO ₄ ^{3 -} ); Carbonate anion (CO ₃ ^{2 -} ); Sulfuric anion (SO ₄ ^{2 -} ); Alkoxides such as methoxide, ethoxide, n-propoxide, isopropoxide, n-butoxide, iso-butoxide or t-butoxide; And a halide such as fluoride (F ^- ), chloride (Cl ^- ), bromide (Br ^- ) or iodide (I ^- ). The non-protonic anion may be used in an ion-bonded form with an alkali metal cation or an alkaline earth metal cation. Examples of the tertiary amine include at least one selected from the group consisting of tetramethylethylene diamine (TMEDA), trimethylamine, triethylamine (TEA), and 2,6-lutidine .

In the case of Experimental Example 1 to be described later, an aromatic compound into which a difluoroalkyl group is introduced is also formed when a protic anion (Ex. HPO ₄ ^{2 -} ) is used as a base (Production Example 5), but a tertiary amine or a bis When a protonic anion is used, an aromatic compound having a difluoroalkyl group introduced at a higher yield can be obtained. Further, referring to Production Examples 3 to 6, it is confirmed that when arenes are used as aromatic compounds, arenes having difluoroalkyl groups introduced at a higher yield than tertiary amines can be obtained by using aprotic anions .

The base may be used in an amount of 1 to 5 equivalents, 1 to 4 equivalents, 1 to 4 equivalents, 1 to 3 equivalents, or 1 to 2.5 equivalents based on 1 equivalent of an aromatic compound. When the base is used in the above-mentioned range, an aromatic compound having a difluoroalkyl group introduced at a high yield can be obtained while minimizing unwanted side reactions.

The solvent used in the mixture may also affect the synthesis yield of the aromatic compound into which the difluoroalkyl group is introduced, such as the base. The preparation method according to an embodiment may use aprotic solvent as the solvent. As with the aprotic base, the aprotic solvent means a solvent in which no hydrogen or protons bound to oxygen or nitrogen are present. The Applicant has found that difluoroalkylation of aromatic compounds is difficult when protic solvents such as alcohols are used. However, referring to Experimental Examples 1 to 4 to be described later, it is confirmed that when an aprotic solvent is used, the difluoroalkylation can be performed at a high yield.

Examples of the aprotic solvent include dimethylformamide (DMF), dimethylsulfoxide (DMSO), acetonitrile (MeCN), dichloromethane (DCM), tetrahydrofuran (THF) 1,4-dioxane, or mixtures thereof. Such an aprotic solvent may be used such that the concentration of the aromatic compound in the solvent is 0.01 to 10M, 0.01 to 5M, 0.01 to 3M, 0.01 to 1M, 0.1 to 0.5M or 0.2 to 0.4M. For example, when 1 mol of an aromatic compound is used, the use of 0.25 M of solvent means that the concentration of 1 mol of aromatic compound is 0.25 M, so that 4 L of solvent is used. The aprotic solvent can be used in the above-mentioned contents to provide an aromatic compound in which a difluoroalkyl group is introduced at a high yield.

The process according to one embodiment of the present invention can provide an aromatic compound in which a difluoroalkyl group is introduced at a high yield through a combination of a photocatalyst, a base and / or a solvent. In one example, if the aromatic compound is areene, an aprotic anion is used as the base, and dimethyl sulfoxide as the solvent is used, it is possible to provide the arene in which the difluoroalkyl group is introduced in high yield. Further, if the content of the photocatalyst, the content of halodifluoroacetate and the content of the solvent are adjusted to the above-mentioned range, it is possible to provide an areene in which a difluoroalkyl group is introduced at a higher yield.

On the other hand, in another example, when heteroarene is used as the aromatic compound, use of dimethylformamide as a solvent can provide heteroarenes in which a difluoroalkyl group is introduced in a high yield. The reaction conditions optimized for the arene and heteroarene can be referred to Experimental Examples 1 to 4 described later.

The irradiation of the mixture with visible light can proceed at room temperature and atmospheric pressure. As used herein, ambient temperature refers to a natural temperature that is not warmed or warmed, and may mean, for example, a temperature of about 15 ° C to 35 ° C, about 20 ° C to 25 ° C, or about 25 ° C. Also, the atmospheric pressure means a natural pressure which is not pressurized or depressurized, and may mean, for example, a pressure of 1 atm. Since the step of introducing -CF ₂ COOR group into the aromatic compound proceeds using visible light at room temperature and atmospheric pressure, it is not harmful to the human body and has excellent stability under mild process conditions.

The aromatic compound into which the -CF ₂ COOR group is introduced by irradiating the mixture with visible light as described above can be converted into a compound required in the fields of medicines and agrochemicals through various methods known in the technical field of the present invention.

As an example, Org. Lett. 2011, 13, 5560 discloses a method of converting a -CF ₂ COOR group of an aromatic compound into a -CHF ₂ group by hydrolysis and decarboxylation. Specifically, K ₂ CO ₃ , methanol and water are added to an aromatic compound into which a -CF ₂ COOR group is introduced to hydrolyze -CF ₂ COOR with -CF ₂ COOH, and then halide is added to add -CF ₂ COOH Lt; _{RTI ID} = 0.0 &_gt; -CHF2. ≪ / RTI >

As another example, by the addition of a hydride (hydride) in the said -CF ₂ COOR group introducing an aromatic compound by reducing the -CF ₂ COOR group to obtain an aromatic compound of the -CF ₂ CH ₂ OH group introduction. Specifically, NaBH ₄ , an example of hydride, is added to obtain an aromatic compound into which a -CF ₂ CH ₂ OH group is introduced.

As another example, when a carbon atom is added to an aromatic compound into which the -CF ₂ COOR group is introduced to reduce a -CF ₂ COOR group, an aromatic group into which CF ₂ C (R) ₂ OH (R is an alkyl group) Compound can be obtained. Specifically, an aromatic compound having -CF ₂ C (CH ₃ ) ₂ OH group introduced can be obtained by adding Grignard reagent (MeMgBr), which is an example of a carbon anion.

As another example, ammonia or the like may be added to the aromatic compound into which the -CF ₂ COOR group is introduced to obtain an aromatic compound into which -CF ₂ CONH ₂ group is introduced.

The method for converting the -CF ₂ COOR group is not limited to the above-described methods, and can be utilized for various applications by converting the -CF ₂ COOR group through various methods known in the art to which the present invention belongs.

BRIEF DESCRIPTION OF THE DRAWINGS The above and other objects, features and advantages of the present invention will be more apparent from the following detailed description taken in conjunction with the accompanying drawings, in which: FIG. However, this is provided as an example of the invention, and the scope of the invention is not limited thereto in any sense.

Experimental Example  One: Areen's Difluoroalkylation

( Manufacturing example  One)

In the reactor, 0.1 mmol of 1,4-dimethoxybenzene was placed, and after degassing, argon was charged. A solution of 0.002 mmol of [Ru (bpy) ₃ ] Cl ₂ in 0.4 mL of DMF and 0.2 mmol of TMEDA were then added to the reactor. And 0.3 mmol of ethyl bromodifluoroacetate (BrCF ₂ COOEt) were added to the reactor to prepare a reaction mixture. The reaction mixture was stirred in an argon atmosphere, and 7W of visible light was irradiated to the reaction mixture under agitation at room temperature using a blue LED.

Thereafter, the reaction mixture was continuously stirred to maintain the reaction, and the progress of the reaction was observed by TLC or gas chromatography. When after about 18 to 24 hours the reaction was complete, the reaction mixture was diluted with ethyl acetate, dried and washed with ammonium chloride solution and brine (brine), and the resulting organic layer with MgSO _4, and was vacuum-concentrated to obtain a product, the product Was purified by column chromatography to obtain an isomer having -CF ₂ CO ₂ Et introduced therein. The yields of isobutylene with -CF ₂ CO ₂ Et were determined by gas chromatography and ¹⁹ F NMR spectroscopy, and the results are shown in Table 1.

( Manufacturing example  2 to 23)

Except that the kind and content of the photocatalyst, the kind and content of the base, the kind and content of the solvent, the content of ethyl bromodifluoroacetate and the power of the visible light were adjusted as shown in Table 1 in Production Example 1, Was synthesized in the same manner as in Example ₁ except that -CF ₂ CO ₂ Et was introduced.

Manufacturing example Photocatalyst Base menstruum variable yield(%) One [Ru (bpy) ₃ ] Cl ₂ TMEDA DMF - 8 2 [Ru (phen) ₃ ] Cl ₂ TMEDA DMF - trace 3 fac - [Ir (ppy) ₃ ] TMEDA DMF - 20 4 fac - [Ir (ppy) ₃ ] K ₃ PO ₄ DMF - 36 5 fac - [Ir (ppy) ₃ ] K ₂ HPO ₄ DMF - 10 6 fac - [Ir (ppy) ₃ ] KO ^{t This} DMF - 35 7 fac - [Ir (ppy) ₃ ] K ₃ PO ₄ DMSO - 52 8 fac - [Ir (ppy) ₃ ] KO ^{t This} DMSO - 60 9 fac - [Ir (ppy) ₃ ] (0.003 mmol) KO ^{t This} DMSO - 80 10 fac - [Ir (ppy) ₃ ] (0.003 mmol) KO ^{t This} DMSO 15W fluorescent lamp 52 11 fac - [Ir (ppy) ₃ ] (0.003 mmol) KO ^{t This} DMSO BrCF ₂ COOEt (0.15 mmol) 10 12 fac - [Ir (ppy) ₃ ] (0.003 mmol) KO ^{t This} DMSO BrCF ₂ COOEt (0.2 mmol) 47 13 fac - [Ir (ppy) ₃ ] (0.003 mmol) KO ^{t This} DMSO BrCF ₂ COOEt (0.4 mmol) 78 14 fac - [Ir (ppy) ₃ ] (0.003 mmol) KO ^{t This}
(0.15 mmol) DMSO - 81 15 fac - [Ir (ppy) ₃ ] (0.003 mmol) KO ^{t This}
(0.3 mmol) DMSO - 64 16 fac - [Ir (ppy) ₃ ] KO ^{t This} DMSO
(1 mL) - 32 17 fac - [Ir (ppy) ₃ ] KO ^{t This} DMSO
(0.2 mL) - 44 18 fac - [Ir (ppy) ₃ ] KO ^{t This} DMSO no light trace 19 - KO ^{t This} DMSO - trace

* Photocatalyst : Use 0.002mmol if not otherwise specified.

[Ru (bpy) ₃ ] Cl ₂ : [Ru (2,2'-bipyridine) ₃ ] Cl ₂

[Ru (phen) ₃ ] Cl ₂ : [Ru (1, 10-phenanthroline) ₃ ] Cl ₂

fac - [Ir (ppy) ₃ ]: fac - [Ir (2-phenylpyridinato) ₃ ]

* Base : 0.2mmol is used unless otherwise specified.

TMEDA: tetramethylethylene diamine

KO ^t Bu: Potassium t-butoxide

* Solvent : Use 0.4 mL if not otherwise indicated.

DMF: dimethylformamide

DMSO: dimethylsulfoxide

Referring to Table 1, in Production Examples 2 and 3, a different photocatalyst was used in Production Example 1, and a difluoroalkyl group was introduced into the arene under the same conditions as in Production Example 1, The results were comparable. Referring to Production Examples 1 to 3, it was confirmed that when fac - [Ir (ppy) ₃ ] was used as a photocatalyst, arenes having a difluoroalkyl group introduced therein in the best yield.

In Production Examples 4 to 6, the results of the difluoroalkylation of arenes with respect to the base were compared by introducing a difluoroalkyl group in areene under the same conditions as in Production Example 3, except that a base different from Production Example 3 was used. Referring to Production Examples 3 to 6, it was confirmed that when an aprotic anion was used as a base, arenes having a difluoroalkyl group introduced therein could be synthesized with the best yield.

In Production Example 8, difluoroalkylation of areene was compared with that of solvent by introducing a difluoroalkyl group in areene under the same conditions as in Production Example 6 except that a solvent different from that of Production Example 6 was used. Referring to Production Examples 6 and 8, it was confirmed that when DMSO was used in place of DMF, isoleon introduced with a difluoroalkyl group in an excellent yield could be synthesized.

Comparing Production Examples 4 and 6, it was confirmed that Production Examples 7 and 8 in which K ₃ PO ₄ was used as a base had a slightly higher contrast yield when KO ^t Bu was used, but Production Examples 7 and 8 in which the solvents of Production Examples 4 and 6 were changed to DMSO , It is confirmed that the contrast yield is significantly higher when K ₃ PO ₄ is used as the base and KO ^t Bu is used as the base.

In Production Example 9, a difluoroalkyl group was introduced into the arene under the same conditions as in Production Example 8, except that the content of the photocatalyst in Production Example 8 was changed to 0.003 mmol. Referring to Production Examples 8 and 9, it was confirmed that the yield was improved when the content of the photocatalyst was 3 mol% as compared with the case where the content of the photocatalyst was 2 mol% with respect to the aromatic compound.

In Production Example 10, a difluoroalkyl group was introduced into the arene under the same conditions as in Production Example 9, except that the irradiation power of the visible light ray was changed to 15 W in Production Example 9. Referring to Production Examples 9 and 10, it was confirmed that when the irradiation power of the visible light ray was 15 W, the isoleucine having a difluoroalkyl group introduced therein at a yield of 7 W at a higher yield was obtained.

Preparation 11 to 13 The introduction of an alkyl group, the content of BrCF ₂ COOEt in Preparation 9-difluoro the arene in the same conditions as in the Preparation Example 9, except changing, as shown in Table 1 arenes according to the content of BrCF ₂ COOEt ≪ / RTI > could be compared. Referring to Production Examples 9 and 11 to 13, it was confirmed that when using about 2.5 to 4 equivalents of BrCF ₂ COOEt with respect to one equivalent of an aromatic compound, it is possible to synthesize a di-fluoroalkyl-substituted arene with a high yield.

In Production Examples 14 and 15, a difluoroalkyl group was introduced into allene under the same conditions as in Production Example 9, except that the content of the base was changed as shown in Table 1 in Production Example 9, The results of the alkylation were comparable. Referring to Production Examples 9, 14 and 15, it was confirmed that when the base is used in an amount of about 1 to 2 equivalents based on 1 equivalent of an aromatic compound, it is possible to synthesize a di-fluoroalkyl-introduced arene in a high yield.

In Production Examples 16 and 17, the difluoroalkylation results of arenes according to the content of the solvent were introduced into the allene by introducing a difluoroalkyl group in the same manner as in Production Example 8 while changing the solvent content of the production example 8 as shown in Table 1 I could compare. Referring to Production Examples 8, 16, and 17, the content of the solvent is adjusted so that the aromatic compound can be dissolved to about 0.25 M (= moles of the aromatic compound [0.1 mmol] / the volume of the solvent [0.4 mL] It is confirmed that the isoleucine in which the difluoroalkyl group is introduced at a high yield can be synthesized.

In Production Example 18, a difluoroalkyl group was introduced into arene under the same conditions as in Production Example 8, except that the visible ray was irradiated in Production Example 8. However, in Production Example 18, the arene with the difluoroalkyl group introduced therein was not synthesized. In Production Example 19, a di-fluoroalkyl group was introduced into the arene under the same conditions as in Production Example 8 without adding the photocatalyst of Production Example 8. Production Example 19 also did not synthesize a di-fluoroalkyl-introduced arene. Therefore, it has been confirmed that addition of a photocatalyst and irradiation of visible light are essential for introducing a difluoroalkyl group into arene.

Experimental Example  2: Various Areen's Difluoroalkylation

( Example  1 to 10)

Production Example 14 having the highest yield among the above production examples was defined as Example 1, and various arenes into which a difluoroalkyl group was introduced were prepared as in Example 1, except that the arene of Example 1 was changed to various arenes . The structure of the prepared arene and the yield of each synthesis reaction are shown in Table 2.

Experimental Example  3: Heteroarene Difluoroalkylation

( Manufacturing example  20)

The reactor was charged with 0.1 mmol of N-methylpyrrole, followed by degassing and then filled with argon. A solution of 0.001 mmol [Ru (bpy) ₃ ] Cl ₂ in 0.4 mL of acetonitrile and 0.2 mmol of TMEDA were then added to the reactor. And 0.2 mmol of ethyl bromodifluoroacetate (BrCF ₂ COOEt) were added to the reactor to prepare a reaction mixture. The reaction mixture was stirred in an argon atmosphere, and 7W of visible light was irradiated to the reaction mixture under agitation at room temperature using a blue LED.

Thereafter, the reaction mixture was continuously stirred to maintain the reaction, and the progress of the reaction was observed by TLC or gas chromatography. When after about 16 hours the reaction was complete, the reaction mixture was diluted with ethyl acetate, dried and washed with ammonium chloride solution and brine (brine), and the resulting organic layer with MgSO _4, and was vacuum-concentrated to obtain the product, the column and the product Chromatography was performed to obtain heteroarenes into which CF ₂ CO ₂ Et was introduced.

( Manufacturing example  21 to 40)

The type of the hetero arene in Preparative Example 20, of the photocatalyst types, the type of base, the exception that the control as a kind of solvent, and the content such as in Table 3, the same as in Preparation Example 20 to CF ₂ CO ₂ Et is introduced heteroaryl Were synthesized.

Manufacturing example Heteroaren Photocatalyst Base menstruum yield(%) 20 N-methylpyrole [Ru (bpy) ₃ ] Cl ₂ TMEDA MeCN 20 21 N-methylpyrole [Ru (phen) ₃ ] Cl ₂ TMEDA MeCN 27 22 N-methylpyrole fac - [Ir (ppy) ₃ ] TMEDA MeCN 33 23 N-methylpyrole Ir (dFppy) ₃ TMEDA MeCN 39 24 N-methylpyrole fac - [Ir (ppy) ₃ ] TEA MeCN 45 25 N-methylpyrole fac - [Ir (ppy) ₃ ] TEA DMF 95 26 N-methylpyrole fac - [Ir (ppy) ₃ ] TEA DCM 60 27 N-methylpyrole fac - [Ir (ppy) ₃ ] TMEDA DMF 68 28 N-methylpyrole fac - [Ir (ppy) ₃ ] TMEDA DCM 59 29 N-methylpyrole - TEA DMF trace 30 N-methylpyrole fac - [Ir (ppy) ₃ ]
(no light) TEA DMF trace 31 N-methylpyrole fac - [Ir (ppy) ₃ ] TEA DMF
(1 mL) 58 32 N-methylpyrole fac - [Ir (ppy) ₃ ] TEA DMF
(0.2 mL) 86 33 2-ethylfuran fac - [Ir (ppy) ₃ ] TEA DMF 30 34 2-ethylfuran fac - [Ir (ppy) ₃ ] 2,6-lutidine DMF 82 35 2-ethylfuran fac - [Ir (ppy) ₃ ] K ₃ PO ₄ DMF 83 36 2-ethylfuran fac - [Ir (ppy) ₃ ] 2,6-lutidine 1,4-dioxane 54 37 2-ethylfuran fac - [Ir (ppy) ₃ ] K ₃ PO ₄ 1,4-dioxane 36 38 2-ethylfuran fac - [Ir (ppy) ₃ ] 2,6-lutidine THF 54 39 2-ethylfuran fac - [Ir (ppy) ₃ ] K ₃ PO ₄ DMF
(0.2 mL) 60 40 2-ethylfuran fac - [Ir (ppy) ₃ ] K ₃ PO ₄ DMF
(1 mL) 72

* Photocatalyst : Use 0.001mmol if not otherwise specified.

Ir (dFppy) ₃ : Ir (2- (1,4-difluorophenyl) pyridinato) ₃

* Base : 0.2mmol is used unless otherwise specified.

TEA: Triethylamine

* Solvent : Use 0.4 mL if not otherwise indicated.

MeCN: acetonitrile

DCM: dichloromethane

THF: tetrahydrofuran

Referring to Table 3, in Production Examples 21 to 23, a difluoroalkylation of heteroarene according to the photocatalyst was carried out by introducing a difluoroalkyl group in heteroarene under the same conditions as in Production Example 20, except that a photocatalyst different from that of Production Example 20 was used. The results were compared. In Production Examples 20 to 23, it was confirmed that when an iridium-based catalyst is used as a photocatalyst, heterolearenes in which a difluoroalkyl group is introduced in an excellent yield can be synthesized.

Production Examples 24 to 28 were carried out in the same manner as in Production Example 22 except that the base and / or the solvent were changed as shown in Table 3, and the difluoroalkyl groups of the heteroarenes according to the base and / The results of the analysis were compared.

In Production Example 29, a difluoroalkyl group was introduced into the heteroarene under the same conditions as in Production Example 22, except that a photocatalyst was not used and Production Example 30 was irradiated with visible light. However, in Production Examples 29 and 30, heteroarenes into which a difluoroalkyl group was introduced were not synthesized.

In Production Examples 31 and 32, the solvent content of Production Example 25 was changed as shown in Table 3, and a difluoroalkyl group was introduced into the heteroarene under the same conditions as in Production Example 25 to obtain a difluoroalkylation of heteroarene The results were comparable. Referring to Production Examples 25, 31 and 32, the content of the solvent is adjusted so that the aromatic compound can be dissolved to about 0.25 M (= moles of aromatic compound [0.1 mmol] / volume of solvent [0.4 mL] It is confirmed that the isoleucine in which the difluoroalkyl group is introduced at a high yield can be synthesized.

In Production Example 33, difluoroalkyl groups were introduced into the heteroarenes under the same conditions as in Production Example 25, except that 2-ethylfuran was used as the heteroarenes in Production Example 25. [ In Production Examples 34 to 40, difluoroalkyl groups were introduced into the heteroarenes under the same conditions as in Production Example 33 except that the base and / or the solvent were changed as shown in Table 3, and the difluoro We were able to compare the results of Rochelle.

Experimental Example  4: Various Heteroarene Difluoroalkylation

( Example  11 to 17)

Production Example 35 having the highest yield among the production examples using 2-ethylfuran as Example 11 and Production Example 35 having the highest yield among the production examples using N-methyl pyrrole was defined as Example 11, A variety of heteroarenes having a difluoroalkyl group introduced as in Example 11 or 12 were prepared, except that 12 heteroarenes were changed to various heteroarenes. The structures of the prepared heteroarenes and their synthesis yields are shown in Table 4.

Claims (10)

A process for producing a difluoroalkyl group-introduced aromatic compound, which comprises irradiating a mixture containing an iridium-based photocatalyst, an aromatic compound, halodifluoroacetate, a base and a solvent with visible light.
The aromatic compound according to claim 1, wherein the aromatic compound has at least one substituent selected from the group consisting of an alkyl group, a hydroxy group, an alkoxy group, an alkoxycarbonyl group, a mercapto group, an alkylthio group, an amino group and an alkylamino group, A process for producing an aromatic compound into which a difluoroalkyl group is introduced using an aromatic compound in which two or more kinds of substituents are linked together to form a ring.
2. The method according to claim 1, wherein the iridium-based photocatalyst is fac -tris [2-phenylpyridinate] iridium ( fac- [Ir (ppy) ₃ ]) or (2- (1,4-difluorophenyl) (Ir (dFppy) ₃ ) is used as the dialkyl-substituted aromatic compound.
The process according to claim 1, wherein the base is a tertiary amine, an aprotic anion, or a mixture thereof, wherein the difluoroalkyl group is introduced.
The process for producing an aromatic compound according to claim 1, wherein the base is used in an amount of 1 to 5 equivalents based on 1 equivalent of the aromatic compound.
The process for producing an aromatic compound according to claim 1, wherein the solvent is an aprotic solvent and a difluoroalkyl group is introduced.
The process for producing an aromatic compound according to claim 1, wherein the solvent is used so that the concentration of the aromatic compound with respect to the solvent is 0.01 to 10 M.
The process for producing an aromatic compound according to claim 1, wherein the aromatic compound is an aromatic compound, wherein a difluoroalkyl group is introduced.
The process for producing an aromatic compound according to claim 8, wherein a dipolaroalkyl group is introduced into the base using an aprotic anion.
The process for producing an aromatic compound according to claim 9, wherein the solvent is dimethylsulfoxide, in which a difluoroalkyl group is introduced.