JPH0519553B2 - - Google Patents

Description

[Detailed description of the invention]

(Industrial Application Field) The present invention relates to a method for producing a specific fluorine-containing heterocyclic compound, and particularly an industrially advantageous method for producing a fluorine-containing heterocyclic compound in which a perfluoroalkyl is introduced into a furan or thiophene ring. Regarding. BACKGROUND ART Compounds in which perfluoroalkyl groups are introduced into organic compounds have recently attracted attention as they exhibit useful properties such as physiological activity. In particular, furan or thiophene derivatives in which a perfluoroalkyl group is introduced into the furan or thiophene ring are useful for pharmaceuticals,
It is useful as a synthetic intermediate for agricultural chemicals, etc. (Prior art) Conventionally, as a method for introducing a perfluoroalkyl group into furan or thiophene, a method of treating furan or thiophene and iodized perfluorodecane at a high temperature of 170°C or higher [Journal of
The Fluorine Chemistry (J.Fluorine
Chem.), 17, 345 (1981)], or a method of reacting perfluorooctyl phenyl iodonium _{trifluoromethanesulfonate} [ _C8F17I (Ph) _OSO2CF3 ] with furan or _thiophene [Chemistry Letters (Chem. Lett.), 1663 (1981)]
It has been known. (Problems to be Solved by the Invention) However, the above conventional method has the following problems. That is, in the method using perfluoroalkyl iodide, perfluoroalkyl iodide is expensive and the reaction temperature is as high as 170°C or higher.
Moreover, the yield of the desired reaction product is low. On the other hand, in the method using perfluoroalkyl phenyl iodonium trifluoromethanesulfonate, it is not easy to synthesize the above reagent, and furthermore, there are drawbacks such as the need to use special equipment because fluorine gas etc. are used for the synthesis. However, in both cases, it was not an industrially advantageous manufacturing method. Therefore, there is no industrially advantageous method for producing fluorine-containing furan or thiophene derivatives by introducing a perfluoroalkyl group into a heterocycle, particularly a furan or thiophene ring, and there is a strong need for the development of such a method. Therefore, the present inventors conducted intensive research to develop a method that meets the above requirements, and as a result, a perfluoroalkyl group was introduced by reacting a specific aliphatic di(haloacyl)peroxide with a substituted furan or a substituted thiophene. The present invention was completed based on the knowledge that fluorine-containing furan and thiophene derivatives can be selectively obtained in high yield and easily in a short period of time. (Means for Solving the Problems of the Invention) That is, the present invention provides the general formula () (In the formula, X ₁ represents a fluorine, chlorine or hydrogen atom. n ₁ is an integer from 1 to 10.) A di(haloacyl) peroxide represented by

[Formula] or (In _{the formula ,} (represents an integer. _R2 represents an alkylene group having 3 to 6 carbon atoms.) is reacted with a heterocyclic compound represented by

[Formula] or This is a method for producing a fluorine-containing heterocyclic compound represented by The present invention is characterized by the use of a specific di(haloacyl)peroxide, that is, the di(haloacyl)peroxide represented by the general formula (). This di(haloacyl)peroxide is preferably diluted in a solvent for handling and reaction purposes. Specifically, the concentration of di(haloacyl)peroxide in the solvent is usually about 2 to 30%, and The solvent is preferably a halogenated aliphatic solvent that does not contain hydrogen atoms. The solubility in these solvents should be good, and therefore n ₁ in the general formula () needs to be an integer of 1 to 10. Specific examples of the di(haloacyl) peroxide represented by the general formula () used in the present invention include bis(trifluoroacetyl) peroxide, bis(pentafluoropropionyl) peroxide, bis(heptafluorobutyryl) peroxide, and bis(heptafluorobutyryl) peroxide. (Nonafluoropentanoyl)
Peroxide, bis(undecafluorohexanoyl) peroxide, bis(tridecafluoroheptanoyl) peroxide, bis(pentadecafluorooctanol) peroxide, bis(heptadecafluoroperargonyl) peroxide, bis(nonadecafluorodecanoyl) peroxide,
Bis(heneicosafluoroundecanoyl) peroxide, bis(chlorodifluoroacetyl)
Peroxide, bis(3-chlorotetrafluoropropionyl) peroxide, bis(4-chlorohexafluorobutyryl) peroxide, bis(5-chlorooctafluoropentanoyl) peroxide, bis(6-chlorodecafluorohexanoyl) peroxide, bis (7-chlorododecafluorooctanoyl)peroxide, bis(9
-chlorohexadecafluoroperargonyl) peroxide, bis(10-chlorooctadecafluorodecanoyl) peroxide, bis(11-chloroeicosafluoroundecanoyl) peroxide,
Bis(difluoroacetyl) peroxide, bis(3-H-tetrafluoropropionyl) peroxide, bis(4-H-hexafluorobutyryl) peroxide, bis(5-H-octafluoropentanoyl) peroxide, bis(6-H −
decafluorohexanoyl) peroxide, bis(7-H-dodecafluoroheptanoyl) peroxide, bis(8-H-tetradecafluorooctanoyl) peroxide, bis(9-H-hexadecafluoroperargonyl) peroxide, bis( 10-H-octadecafluorodecanoyl) peroxide, bis(11-H-eicosafluoroundecanoyl) peroxide, and the like. Preferred halogenated aliphatic solvents for dissolving this di(haloacyl)peroxide include:
2-chloro-1,2-dibromo-1,1,2-trifluoroethane, 1,2-dibromohexafluoropropane, 1,2-dibromotetrafluoroethane, 1,1-difluorotetrachloroethane, 1,2- Difluorotetrachloroethane, fluorotrichloromethane, heptafluoro-2,
3,3-trichlorobutane, 1,1,1,3-tetrachlorotetrafluoropropane, 1,1,1
-trichloropentafluoropropane, 1,1,
1-trichlorotrifluoroethane etc. can be used, among which industrially preferred are 1,
1,2-trichlorotrifluoroethane. The substituted furan or substituted thiophene used in the present invention is a compound represented by the above general formulas () and ()'. Examples of the substituted furan or substituted thiophene, which is a heterocyclic compound represented by the general formulas () and ()', used in the present invention include furan, 2
-Methylfuran, 2-chlorofuran, 2-bromofuran, 2-fluorofuran, 2-iodofuran, 2-methoxycarbonylfuran, 2-nitrofuran, 2-cyanofuran, 3-methylfuran,
3-chlorofuran, 3-bromofuran, 3-fluorofuran, 3-iodofuran, 3-methoxycarbonylfuran, 2-ethylfuran, 2-n-propylfuran, 2-t-butylfuran, 2,3-
dimethylfuran, 2,3-dichlorofuran, 2,
3-dibromofuran, 2,5-dimethylfuran,
2,5-dichlorofuran, 2,5-dibromofuran, 2,3-diethylfuran, 2,5-diethylfuran, 4,5,6,7-tetrahydrobenzo[b]furan, 4,5,6,7 -tetrahydrobenzo[b]thiophene, 2-methyl-4,5,
6,7-tetrahydrobenzo[b]furan, 2-
Methyl-4,5,6,7-tetrahydrobenzo[b]thiophene, 4,5,6,7-tetrahydro-8-H-cyclohepta[b]furan, 4,
5,6,7-tetrahydro-8-H-cyclohepta[b]furan, 4,5,6,7-tetrahydro-8-H-cyclohepta[b]thiophene, 2,
5-dimethyl-4,5,6,7-tetrahydro-
8-H-cyclohepta[b]furan, 2,5-dimethyl-4,5,6,7-tetrahydro-8-H
-cyclohepta[b]thiophene, 4,5,6,
7,8,9-hexahydrocycloocta[b]furan, 4,5,6,7,8,9-hexahydrocycloocta[b]thiophene, 2-methyl-4,
5,6,7,8,9-hexahydrocycloocta[b]furan, 2-methyl-4,5,6,7,8,
9-hexahydrocycloocta[b]thiophene, 3-iodo-4,5,6,7-tetrahydrobenzo[b]thiophene, 3-iodo-4,5,
6,7-tetrahydro-8-H-cyclohepta[b]-thiophene, 4,5,6,7,8,9-hexahydrocycloocta[b]thiophene, 4,
5,6,7,8,9-hexahydro-3-iodo-cycloocta[b]-thiophene, thiophene,
2-methylthiophene, 2-chlorothiophene,
2-bromothiophene, 2-fluorothiophene, 2-iodothiophene, 2-methoxycarbonylthiophene, 2-nitrothiophene, 2-cyanothiophene, 3-methylthiophene, 3-chlorothiophene, 3-bromothiophene, 3-fluorothiophene, 3- Methoxycarbonylthiophene, 2-ethylthiophene, 2-n-propylthiophene, 2-t-butylthiophene, 2,
3-dimethylthiophene, 2,3-dichlorothiophene, 2,3-dibromothiophene, 2,5-
Dimethylthiophene, 2,5-dichlorothiophene, 2,5-dibromothiophene, 2,3-diethylthiophene, 2,5-diethylthiophene,
2,3,4-trimethylthiophene, 2,3,5
-trimethylfuran, 2,3,4-trimethylthiophene, 2,3,5-trimethylthiophene, and the like. Next, the reaction conditions of the di(haloacyl)peroxide and the substituted furan or substituted thiophene are as follows. When reacting di(haloacyl)peroxide with substituted furan or substituted thiophene, the charging molar ratio is preferably 1:1 to 10, more preferably 1:2.
-5 is more preferable. If the molar ratio is less than 1, the yield of the fluorine-containing furan or thiophene derivative produced tends to decrease, and if it exceeds 10, there will be a large amount of unreacted substituted furan or substituted thiophene after the reaction is completed, and the desired product will not be produced. The yield of the fluorine-containing compound becomes low. Note that the reaction can be carried out under normal pressure,
The reaction temperature is also usually in the range of 0 to 50°C, preferably in the range of 10 to 40°C. If the reaction temperature is less than 0℃, the reaction time tends to be longer;
If it exceeds 20%, the pressure during the reaction becomes high and the reaction operation tends to become difficult. Reaction time is usually 30 minutes ~
Although the duration is in the range of 20 hours, it is practically preferable to set the conditions so that the duration is 3 to 10 hours. The reaction product is purified by appropriate means. In the above manner, the fluorine-containing heterocyclic compounds represented by the general formulas () and ()', which are fluorine-containing furan and thiophene derivatives, are produced. These compounds are usually colorless or pale yellow in appearance and are liquid or solid at room temperature. And these are gas chromatograph, IR, 1H
The structure can be fixed by -NMR, 13C-NMR, GC-MS, etc. (Effects of the Invention) The features of the present invention are listed below. (1) By reacting a specific di(haloacyl)peroxide with substituted furan or substituted thiophene, a fluorine-containing aliphatic group can be easily introduced into the furan or thiophene ring in a short time, with high yield, and achieve the desired purpose. A fluorine-containing heterocyclic compound that is a fluorine-containing furan or thiophene derivative containing a perfluoroalkyl group can be produced,
Furthermore, no reaction catalyst or special equipment is required. (2) In the present invention, unlike conventional methods, fluorine-containing aliphatic groups are introduced even in furans and thiophenes substituted with reactive halogen atoms such as bromine and chlorine atoms. Therefore, fluorine-containing furan and thiophene derivatives having such reactive substituents are useful as synthetic intermediates for various useful compounds. (3) In the production method of the present invention, fluorine-containing fatty acids are produced as reaction by-products in approximately the same molar amount as the fluorine-containing furan and thiophene derivatives. This fatty acid is expensive and has various uses, but
Moreover, by chlorinating this to form an acid chloride and further forming a di(haloacyl)peroxide, it can be effectively used as a raw material in the present invention. (4) Although a fluorine-containing peroxide is used in the reaction, the desired fluorine-containing furan and thiophene derivatives can be produced safely. (5) The fluorine-containing furan and thiophene derivatives produced by the method of the present invention are useful as synthetic intermediates for pharmaceuticals, agricultural chemicals, water and oil repellents, and the like. (Examples), (Comparative Examples) The present invention will be specifically described below based on Examples and Comparative Examples. The raw materials, reaction conditions, and reaction products of Examples and Comparative Examples are summarized in a table. Example 1 Bis(heptafluorobutyryl) peroxide
Add 0.47 g (4 mmol) of 2-chlorothiophene to 30 g of 1,1,2-trichlorotrifluoroethane solution containing 0.85 g (2 mmol), and add
℃ for 3 hours. After the reaction is complete, add 30ml of the reaction product.
After washing with water and drying with magnesium sulfate, the reaction product was analyzed by gas chromatography. As a result, 2-chloro-5-heptafluoropropylthiophene was obtained in a yield of 95%. Further analysis of the aqueous layer revealed that heptafluorobutyric acid was obtained with a yield of 102%. In addition, by scaling up experiments under the same reaction conditions, the product was isolated and analyzed by IR, 1H-NMR, 13C-NMR, and MASS.
The structure was determined by IR (cm ^-1 ) 1350 (CF ₃ ), 1230 (CF ₂ ); ¹ H-NMR (CDCl ₃ ) 7.20 (1H), 7.46 (1H); ¹³ C-NMR (CDCl ₃ ) 126.6, 129.9 ( t, J _CCCF =
6.1Hz135.9; MASS m/e 288, 286 (M ⁺ ), 169, 167,
69; Exact MASS m/e 285.9447 (theoretical value C _{7
H2F7SCl285.9453} ) Examples 2 to 9 2-chlorothiophene to 2-bromothiophene, 2-methoxycarbonylfuran, 2-methylfuran, 2 _- methylthiophene, 2,5-dimethylthiophene, 3-bromothiophene, 2 -Methyl-4,5,6-tetrahydrobenzo[b]thiophene and 2-methyl-4,5,6,7-tetrahydro-8-H-cyclohepta[b]thiophene, respectively, and carried out under the conditions shown in the table. Reactions were carried out according to Example 1. The respective products obtained by conducting the same analysis as in Example 1 and their yields are shown in the table. Examples 10-12 Replacement of bis(heptafluorobutyryl) peroxide with bis(pentadecafluorooctanoyl) peroxide, bis(4-chlorohexafluorobutyryl) peroxide or bis(4-H-hexafluorobutyryl) peroxide Further, reactions were carried out according to Example 1 under the conditions shown in the table. The respective products obtained by conducting the same analysis as in Example 1 and their yields are shown in the table. Comparative Example 1 A reaction was carried out according to Example 1, except that 2-chlorothiophene was replaced with thiophene and bis(heptafluorobutyryl) peroxide was replaced with benzoyl peroxide. As a result, the yield of a product in which the phenyl group was substituted with a thiophene ring was 2%. Therefore, it was confirmed that when a diacyl peroxide not substituted with fluorine is used, a product substituted on a thiophene ring is hardly obtained.

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[Table] In other words, the comparative example shows that even when a peroxide such as benzoyl peroxide which is not substituted with fluorine is reacted with thiophene, the phenyl group is substituted with the thiophene ring (in the present invention, the dihydrogen group represented by the general formula ()) is (corresponding to the substitution of the fluorine-containing aliphatic group of the haloacyl)peroxide) is hardly produced, and in the present invention, by using the di(haloacyl)peroxide represented by the general formula (), It was clear that he had achieved his goal for the first time.

Claims (1)

[Claims] 1 General formula () (In the formula, X ₁ represents a fluorine, chlorine, or hydrogen atom. n ₁ is an integer from 1 to 10.) A di(haloacyl) peroxide represented by (In _{the formula ,} (represents an integer. R ₂ represents an alkylene group having 3 to 6 carbon atoms.) is reacted with a heterocyclic compound represented by [Formula] or A method for producing a fluorine-containing heterocyclic compound represented by: