JP4576586B2 - Method for producing organic compound - Google Patents

Description

  The present invention relates to a method for producing an organic compound, which is carried out by reacting a reaction substrate or a reactant separated into an aqueous phase and an organic phase.

In organic synthetic chemistry, the development of new reaction media is one of the most important issues. In recent years, a fluorous solvent has attracted attention as such a new solvent. A fluorous solvent has a portion containing a large amount of fluorine such as a perfluoroalkyl group, has a higher density and a lower boiling point than saturated hydrocarbons, and is excellent in heat resistance and chemical resistance. Moreover, the intermolecular force is weak, and it shows a large solubility in gas. Furthermore, although it is difficult to mix with water or an organic solvent at room temperature, it has a property of being mixed with some organic solvents by heating. However, the examination of the two-phase reaction between the organic phase and the fluorous phase has been limited to esterification reaction, polymerization reaction, oxygen oxidation reaction, bromination reaction, enzyme reaction and the like.
Synthetic chemical researches are actively conducted by utilizing such properties of fluorous solvents. In addition, in the field of material chemistry and colloid science, an application example using a multi-component surfactant having a parent fluorous substituent (Non-patent Document 1) and an application example of a multi-component polymer having a parent fluorous substituent (non-patent document 1) Patent Document 2) has been studied.

Kondo, Y. et al. J. Am. Chem. Soc. 124, 66516-6517 (2002). hou, Z. et al. J. Am. Chem. Soc. 125, 10182- (2003).

By the way, in a two-phase reaction of an aqueous phase and an organic phase, a phase transfer catalyst is often used. However, in order to increase a contact area between phases, a special apparatus such as high-speed stirring, ultrasonic wave, microwave, or microreactor is not used. It is difficult to obtain a product with a high yield, and it is difficult to scale up and lack generality.
For this reason, the present invention provides a reaction of the reaction substrate and / or the reactant separated into an aqueous phase and an organic phase in a high yield without using a special apparatus, and an organic compound that can be easily scaled up. The object is to provide a manufacturing method.

That is, the present invention relates to a system containing a fluorous compound having a hydrophilic group and a perfluoroalkyl group in a three-phase solvent composed of water, an organic solvent immiscible with water, and a fluorous solvent, and a phase transfer catalyst. the reaction substrate及beauty reactant was separated into an aqueous phase and an organic phase are reacted, using the active methylene compound as a alkyl halide and a nucleophile as reaction substrate, using an inorganic base as the reactant, the alkylation reaction or causing, or the use of an olefin as a reaction substrate, using hypochlorite as the reactant, characterized Rukoto cause epoxidation reaction.

The fluorous solvent is preferably a compound in which all hydrogen atoms in a hydrocarbon compound having 6 to 10 carbon atoms or a halogenated hydrocarbon compound having 6 to 10 carbon atoms are substituted with fluorine atoms.
The fluoro compound is of the formula (I)
(R ¹ represents a perfluoroalkyl group having 4 to 10 carbon atoms, R ² represents a polyhydric alcohol group having 2 to 6 carbon atoms, X represents a methylene group, and n represents an integer of 0 to 3) It is preferable to be represented by
The fluoro compound is of the formula (II)
(R ³ is preferably a C 6-10 perfluoroalkyl group).

The phase transfer catalyst is preferably a quaternary ammonium salt. The quaternary ammonium salt is represented by the formula (III)
A compound represented by (R ⁴ represents an alkyl group having 4 to 8 carbon atoms, and Y represents a halogen atom) is preferable.

  According to this invention, the organic compound can be obtained by performing the reaction of the reaction substrate and / or the reactant separated into an aqueous phase and an organic phase in a high yield.

<Reaction system>
The method for producing an organic compound according to the present invention is carried out in a system containing a fluorous compound and a phase transfer catalyst in a three-phase solvent composed of water, an organic solvent immiscible with water, and a fluorous solvent.
The present inventors further added a fluorous solvent as a third phase to the conventional two-phase reaction of an aqueous phase-organic phase, so that the fluorous phase functions as a dispersion medium for the aqueous phase and the organic phase. -We considered it to affect the interface between the organic phases, and conducted intensive studies. As a result, a fluorous compound having a perfluoroalkyl group and a hydrophilic group is added together with a phase transfer catalyst (used in a conventional two-phase system) into a three-phase solvent of water-organic solvent-fluorus solvent. As a result, it was found that the reaction between the hydrophilic substance and the lipophilic substance is greatly promoted, and the present invention has been completed.

<Fluorous solvent>
The fluorous solvent has a portion containing a large amount of fluorine such as perfluorocarbon, and forms a third phase that is immiscible with water or an organic solvent. Such a fluorous solvent dissolves a compound having a portion containing a large amount of fluorine well. Examples of the portion containing a large amount of fluorine include a perfluoroalkyl group, a perfluoroaryl group, and a perfluoroaralkyl group. Examples of fluorous solvents include perfluoroalkanes and perfluorobenzene derivatives, and in particular, all hydrogen atoms in hydrocarbon compounds having 6 to 10 carbon atoms or halogenated hydrocarbon compounds having 6 to 10 carbon atoms are substituted with fluorine atoms. The compounds obtained are preferred.
Specific fluorous solvents include perfluoromethylcyclohexane, perfluorotoluene, perfluorobenzene, perfluorooctane, perfluoroheptane, perfluorohexane, perfluorodecalin and the like.

<Organic solvent>
Examples of the organic solvent include hydrocarbons such as hexane, benzene and toluene, esters such as ethyl acetate, halogenated hydrocarbons such as dichloroethane and chlorobenzene, and ether compounds such as diisopropyl ether.

  The mixing ratio of water, the organic solvent, and the fluorous solvent in the three-phase solvent is not particularly limited. Can be adjusted.

<Fluorous compound>
The fluoro compound has a hydrophilic group and a perfluoroalkyl group and functions as a parent fluorosurfactant. It is presumed that most of the fluorous compound is present in the fluorous phase and part is present at the interface with the aqueous phase. Although the action of the fluorous compound is not clear, it is conceivable that the fluorous phase expands the interface as a dispersion medium between the aqueous phase and the organic phase and promotes phase transfer at the interface.
Fluorous compounds include, for example, formula (I)
(R ¹ represents a perfluoroalkyl group having 4 to 10 carbon atoms, R ² represents a polyhydric alcohol group having 2 to 6 carbon atoms, X represents a methylene group, and n represents an integer of 0 to 3) The compound represented by these can be used.

Further, as a fluorous compound, the formula (II)
A compound represented by (R ³ is a C 6-10 perfluoroalkyl group) can be used.

Specific examples of the fluorous compound include 3-perfluorooctyl-1,2-propanediol, 3-perfluorohexyl-1,2-propanediol, and 3-perfluoroolodecyl-1,2-propanediol. Can be mentioned.
The addition ratio of the fluorous compound can be, for example, 0.1 to 10 mol%, preferably 0.5 to 2 mol% with respect to the phase transfer catalyst.

<Phase transfer catalyst>
As the phase transfer catalyst, the same one as used in the conventional two-phase reaction of an aqueous phase and an organic phase can be used. As the phase transfer catalyst, for example, a salt or a crown ether having a cation soluble in both water and an organic solvent can be used. Specific examples of the phase transfer catalyst include salts having a long-chain alkylammonium cation (tetrabutylammonium salt, trioctylmethylammonium salt, benzyldimethyloctadecylammonium salt, etc.). Examples of the tetrabutylammonium salt include tetrabutylammonium bromide.
In particular, the phase transfer catalyst is preferably a quaternary ammonium salt, preferably a quaternary ammonium salt of the formula (III)
A compound represented by (R ⁴ represents an alkyl group having 4 to 8 carbon atoms, and Y represents a halogen atom) is preferable.

  The addition ratio of a phase transfer catalyst can be 0.1-10 mol% with respect to the reaction substrate, for example.

<Reactants and reaction types>
In the present invention, the reaction substrate and / or the reactant separated into the aqueous phase and the organic phase are reacted in the reaction system. The combination of the reaction substrate and / or the reaction agent is not particularly limited. For example, the reaction substrate can be made hydrophobic and the reaction agent that reacts with it can be made water-soluble. Conversely, the reaction substrate can be made water-soluble and the reaction agent can be made hydrophobic. You may use 2 or more types as a reaction substrate and / or a reaction agent, respectively. Alternatively, the two reaction substrates may be separated into an aqueous phase and an organic phase, respectively. As a compound used as a reaction substrate and / or a reaction agent, for example, the same compounds as those used in a conventional two-phase reaction of an aqueous phase and an organic phase can be used.
The reaction can be applied to a nucleophilic reaction, an oxidation reaction, an alkylation reaction, an epoxidation, a hydrolysis reaction, etc., as in the conventional two-phase reaction of an aqueous phase and an organic phase.
Examples of hydrophilic substances include sugars, amino acids, low molecular weight alcohols, polar organic compounds such as amines or carboxylic acids, inorganic acids, inorganic bases, metal salts of organic acids, inorganic salts, and the like.
As the lipophilic substance, compounds such as hydrocarbons, halogenated hydrocarbons, esters and the like that generally have low solubility in water and are soluble in low-polar organic solvents can be widely used.

  As a reaction suitable for the present invention, a reaction substrate is a hydrophobic (lipophilic) organic compound, and the reaction agent is a water-soluble (hydrophilic) acid or a water-soluble base.

  Specific examples of the reaction suitable for the present invention include an alkylation reaction using an alkyl halide as a reaction substrate and an active methylene compound as a nucleophile, and an inorganic base as a reactant. Inorganic bases serve as catalysts for extracting active methylene protons.

  Specific examples of the reaction suitable for the present invention include an epoxidation reaction using olefin as a reaction substrate and hypochlorite as a reactant.

<Example>
The following examples illustrate the invention but are not intended to limit the invention.

In the following examples, the following measuring devices were used for analysis of solvents, reagents, products, and the like. ¹ H NMR and ¹³ C NMR use JEOL JNM-LA400, CDCl ₃ as solvent, tetramethylsilane (δ = 0, ¹ H NMR) or CDCl ₃ (δ = 77.0, ¹³ C NMR) as internal standard Measured as a substance. JASCO FT / IR-610 was used for IR spectrum measurement. For mass spectrometry, SHIMADZU GC-17A or SHIMADZU GCMS-QP5050A was used. For the melting point measurement, YAZAWA BY-1 was used. Silica gel 60 (Merck) was used for column chromatography, and Wakogel B-5F was used for preparative silica gel thin layer chromatography. All substrates used were commercially available products without any particular purification, and the solvents used were distilled according to a conventional method.
The reaction of each example was performed using a 10 ml flask while stirring with a magnetic stirrer.

  The following fluorous diols were used as the fluoro compound. Fluorous diol is obtained from the corresponding 3-perfluoroalkyl-1,2-epoxypropane (Daikin Industries) by a known method (Jew, S.-S .; Lee, J.-H .; Jeong, B.- S .; Yoo, M.-S .; Kim, M.-J .; Lee, J .; Choi, S.-H .; Lee, K .; Lah, MS; Park, H.-G. Angew. Chem. Int. Ed. 2005, 44, 1383.). The physical property values of each fluorous compound were as follows.

3-perfluorohexyl-1,2-propanediol (formula IV)
colorless prisms; mp 68-69 ° C; ¹ H NMR (CD ₃ OD) d 2.15-2.28 (1H, m), 2.39-2.49 (1H, m), 3.46 (1H, dd, J = 5.5, 11.0 Hz), 3.53 (1H, dd, J = 5.5, 11.0 Hz), 4.02-4.08 (1H, m); ¹⁹ F NMR (CD ₃ OD) d ・ -127.7 (2F, s), -125.1 (2F, s),- 124.3 (2F, s), -123.2 (2F, s), -115.0 (1F, d, J = 270.2 Hz), -113.7 (1F, d, J = 275.5 Hz), -82.8 (3F, s); IR (KBr): 3370, 2948, 1236, 1205, 1145, 705, 658, 530 cm ^-1 ; HRMS (ESI): Exact mass calcd for C ₉ H ₈ F ₁₃ O ₂ [M + H] ⁺ , 395.0311. 395.0293.
3-perfluorooctyl-1,2-propanediol (formula V)
colorless prisms; mp 110-113 ° C; ¹ H NMR (CD ₃ OD) d 2.16-2.28 (1H, m), 2.39-2.50 (1H, m), 3.47 (1H, dd, J = 5.5, 11.0 Hz), 3.54 (1H, dd, J = 5.5, 11.7 Hz), 4.03-4.08 (1H, m); ¹³ C NMR (CD ₃ OD, partially) d ・ 35.4 (t, J = 21.0 Hz), 66.8; ¹⁹ F NMR (CD ₃ OD) d ・ -127.7 (2F, s), -125.0 (2F, s), -124.1 (2F, s), -123.3 (4F, s), -123.0 (2F, s), -115.0 ( 1F, d, J = 270.2 Hz), -113.7 (1F, d, J = 275.5 Hz), -82.7 (3F, s); IR (KBr): 3362, 2938, 1204, 1148, 661, 528 cm ^-1 ; HRMS (ESI): Exact mass calcd for C ₁₁ H ₈ F ₁₇ O ₂ [M + H] ⁺ , 495.0247. Found 495.0259.
3-Perfluoroorodecyl-1,2-propanediol (formula VI)
colorless prisms; mp 155-157 ° C; ¹ H NMR (CD ₃ OD) d 2.15-2.28 (1H, m), 2.38-2.50 (1H, m), 3.47 (1H, dd, J = 5.5, 11.0 Hz), 3.53 (1H, dd, J = 5.5, 11.0 Hz), 4.03-4.07 (1H, m); ¹⁹ F NMR (CD ₃ OD) d ・ -127.7 (2F, s), -125.0 (2F, s),- 124.1 (2F, s), -123.3-123.0 (10F, m), -115.0 (1F, d, J = 270.2 Hz), -113.7 (1F, d, J = 270.2 Hz), -82.8 (3F, s) ; IR (KBr): 3364, 2943, 1203, 1146, 647, 557, 526 cm ^-1 ; HRMS (ESI): Exact mass calcd for C ₁₃ H ₈ F ₂₁ O ₂ [M + H] ⁺ , 595.0183. Found 595.0159.

Tetrabutylammonium bromide (phase transfer catalyst; Tokyo Kasei, 0.010 mmol) and 3-perfluorooctyl-1,2-propanediol (fluorus compound; 0.025 mmol) are dissolved in methanol (0.5 ml) and concentrated under reduced pressure. Vacuum dried for 10 minutes. Toluene (200 μL) was added to this, and 2-oxocyclopentanecarboxylic acid tert-butyl ester (lipophilic substance; 0.50 mmol), benzyl bromide (lipophilic substance; 0.75 mmol), perfluoromethylcyclohexane (fluorous) Solvent; Tokyo Kasei Co., Ltd., 2.0 mL) and aqueous potassium hydroxide solution (1 M, 0.60 mL) were sequentially added, and the mixture was stirred at room temperature at 800 rpm. After 40 minutes, a saturated aqueous ammonium chloride solution was added to stop the reaction, and the mixture was extracted three times with methylene chloride. The organic phases were combined and dried over anhydrous sodium sulfate, and then the desiccant was filtered off and concentrated under reduced pressure. The crude product was purified by preparative silica gel thin layer chromatography (developing solvent hexane / ethyl acetate = 10/1) to obtain the desired product. The yield was 94%.
On the other hand, when a similar reaction was carried out as a two-phase system of water-organic solvent without adding a fluorous solvent (perfluoromethylcyclohexane) and a fluorous compound (3-perfluorooctyl-1,2-propanediol), The rate was 66%.
The reaction formula is shown by the formula VII.
The physical properties of the obtained target product (tert-Butyl 1-benzyl-2-oxocyclopentanecarboxylate) were as follows.
¹ H NMR (CDCl ₃ ) δ = 1.43 (9H, s), 1.52-1.59 (1H, m), 1.85-1.99 (1H, m), 2.32-2.37 (2H, m), 3.12 (2H, s), 7.13-7.15 (2H, m), 7.18-7.27 (3H, m); ¹³ C NMR (CDCl ₃ ) d ・ 19.4, 27.7, 31.8, 38.2, 38.6, 61.8, 81.9, 126.6, 128.2, 130.2, 136.8, 170.2 , 215.2.

The reaction was conducted in the same manner as in Example 1 except that 1,2-diphenylethanone was used in place of 2-oxocyclopentanecarboxylic acid tert-butyl ester as the lipophilic substance. The desired product was obtained in a yield of 96%.
The reaction formula is shown by the formula VIII.
The physical properties of the obtained target product (1,2,3-Triphenylpropan-1-one) were as follows.
¹ H NMR (CDCl ₃ ) δ = 3.08 (1H, dd, J = 7.5, 13.7 Hz), 3.58 (1H, dd, J = 7.5, 13.7 Hz), 4.83 (1H, t, J = 7.2 Hz), 7.09 (2H, d, J = 7.6 Hz), 7.13-7.16 (1H, m), 7.19-7.22 (3H, m), 7.24-7.28 (4H, m), 7.35 (2H, t, J = 7.6 Hz), 7.44-7.45 (1H, m), 7.91 (2H, d, J = 8.2 Hz).

Use 1,2-diphenylethanone instead of 2-oxocyclopentanecarboxylic acid tert-butyl ester as the lipophilic substance, and use butyl iodide (2 eq) instead of benzyl bromide as the hydrophilic substance. The reaction was carried out in the same manner as in Example 1 except that a saturated aqueous solution of potassium hydroxide (0.2 ml) was used. The yield was 85%.
On the other hand, when a similar reaction was carried out as a two-phase system of water-organic solvent without adding a fluorous solvent (perfluoromethylcyclohexane) and a fluorous compound (3-perfluorooctyl-1,2-propanediol), The rate was 63%.
The physical properties of the obtained target product (1,2-Diphenylhexan-1-one) were as follows.
¹ H NMR (CDCl ₃ ) δ = 0.85 (3H, t, J = 7.2 Hz), 1.17-1.38 (4H, m), 1.80-1.86 (1H, m), 2.16-2.22 (1H, m), 4.54 ( 1H, t, J = 7.2 Hz), 7.16-7.19 (1H, m), 7.26-7.28 (2H, m), 7.31 (2H, d, J = 6.9 Hz), 7.36 (2H, t, J = 9.0 Hz ), 7.43-7.46 (1H, m), 7.95-7.98 (2H, m).

As a lipophilic substance, tert-butyl 2- (diphenylmethyleneamino) acetic acid was used instead of 2-oxocyclopentanecarboxylic acid tert-butyl ester, 4M aqueous potassium hydroxide solution (0.8 ml) was used as the base, and organic solvent was used as the organic solvent. The reaction was performed in the same manner as in Example 1 except that methylene chloride (0.8 ml) was used instead of toluene. The yield was 72%.
On the other hand, when a similar reaction was carried out as a two-phase system of water-organic solvent without adding a fluorous solvent (perfluoromethylcyclohexane) and a fluorous compound (3-perfluorooctyl-1,2-propanediol), The rate was 20%.
The physical properties of the obtained target product (tert-Butyl N- (diphenylmethylene) phenylalaninate) were as follows.
¹ H NMR (CDCl ₃ ) δ = 1.43 (9H, s), 3.17 (1H, dd, J = 9.3, 13.4 Hz), 3.23 (1H, dd, J = 4.1, 13.1 Hz), 4.12 (1H, dd, J = 4.5, 9.3 Hz), 6.60 (2H, d, J = 6.0 Hz), 7.04-7.06 (2H, m), 7.13-7.21 (3H, m), 7.26-7.38 (6H, m), 7.56-7.58 (2H, m).

Tetrabutylammonium bromide (phase transfer catalyst; Tokyo Kasei, 0.010 mmol) and 3-perfluorooctyl-1,2-propanediol (fluorus compound; 0.025 mmol) were dissolved in methanol (0.5 ml) and concentrated under reduced pressure. Vacuum dried for 10 minutes. Toluene (200 μL) was added as an organic solvent, trans-chalcone (lipophilic substance; 0.50 mmol), sodium hypochlorite (hydrophilic substance; 10%, 0.7 ml), perfluoromethylcyclohexane (fluorus) Solvent; Tokyo Kasei Co., Ltd., 2.0 mL) was sequentially added, and the mixture was stirred at room temperature at 800 rpm for 16 hours. Water was added and extracted three times with methylene chloride, and the organic phases were combined and dried over anhydrous sodium sulfate. The desiccant was filtered off and concentrated under reduced pressure, and the crude product was purified by preparative silica gel thin layer chromatography (developing solvent hexane / ethyl acetate = 10/1) to obtain the desired product. The yield was 93%.
The reaction formula is shown by the formula IX.
The physical properties of the obtained target product (trans-2,3-Epoxy-1,3-diphenylpropan-1-one) were as follows.
¹ H NMR (CDCl ₃ ) δ = 4.08 (1H, d, J = 1.4 Hz), 4.30 (1H, d, J = 2.1 Hz), 7.36-7.42 (5H, m), 7.47-7.51 (2H, m) , 7.61-7.63 (1H, m), 8.00-8.02 (2H, m); ¹³ C NMR (CDCl ₃ ) d ・ 59.4, 61.0, 125.8, 128.3, 128.7, 128.8, 129.0, 134.0, 135.4 (x2), 193.0 .

Claims (6)

In a system containing a fluorous compound having a hydrophilic group and a perfluoroalkyl group and a phase transfer catalyst in a three-phase solvent comprising water, an organic solvent immiscible with water, and a fluorous solvent, an aqueous phase and an organic phase reacting the reaction substrate及beauty reactant was separated into,
An alkyl halide is used as the reaction substrate and an active methylene compound as a nucleophile, an inorganic base is used as the reactant, and an alkylation reaction is generated, or an olefin is used as the reaction substrate, and the following as the reactant: using chlorite, characterized Rukoto cause epoxidation reaction, the method of manufacturing the organic compound. The organic compound according to claim 1, wherein the fluorous solvent is a compound in which all hydrogen atoms in a hydrocarbon compound having 6 to 10 carbon atoms or a halogenated hydrocarbon compound having 6 to 10 carbon atoms are substituted with fluorine atoms. Manufacturing method. The fluoro compound is of the formula (I)
(R ¹ represents a perfluoroalkyl group having 4 to 10 carbon atoms, R ² represents a polyhydric alcohol group having 2 to 6 carbon atoms, X represents a methylene group, and n represents an integer of 0 to 3) The manufacturing method of the organic compound of Claim 1 or 2 represented by these. The fluoro compound is of the formula (II)
The method for producing an organic compound according to claim 3, wherein R ³ represents a perfluoroalkyl group having 6 to 10 carbon atoms. The manufacturing method of the organic compound in any one of Claims 1-4 whose said phase transfer catalyst is a quaternary ammonium salt. The quaternary ammonium salt has the formula (III)
(R ⁴ represents an alkyl group of 4-8 carbon atoms, Y is a halogen atom) is a compound represented by the process for producing an organic compound according to claim 5.