JP4902519B2 - Immobilized catalyst - Google Patents

Description

  The present invention relates to an immobilized catalyst. Specifically, the present invention relates to an immobilized catalyst in which a mercury triflate catalyst is immobilized on a solid phase carrier via a linker.

  Mercury triflate is known as a catalyst for excellent cyclization and the like, and is used for synthetic research of various natural products (for example, Non-Patent Document 1). For example, hydration reaction of terminal alkyne, biosynthesis-like tandem cyclization reaction, catalytic glycosylation reaction using alkinoate as a leaving group, enone synthesis by reaction of propargyl acetate and water are known. These have the advantage that there are many cases where the catalyst efficiency greatly exceeds that of conventional transition metal complex catalysts.

  However, mercury is converted into organic mercury compounds by microorganisms and the like in an aquatic environment, and is accumulated in large fish, deep sea fish, and marine animals through the food chain. In addition, when mercury is vaporized, it is easily absorbed from the lungs, and when absorbed in the body, it binds to hemoglobin and serum albumin and exhibits toxicity. As described above, since organic mercury compounds are concerned about environmental pollution problems and effects on the human body, there is a demand for a catalyst that is less discharged into the environment and excellent in recyclability when the compound is produced.

Journal of Synthetic Organic Chemistry, Vol. 64 744-751

  An object of the present invention is to provide an immobilized catalyst that reduces the burden on the environment, emits less environmentally hazardous substances in the case of compound production, and is excellent in recyclability.

The present invention relates to the following inventions.
1. An immobilized catalyst characterized in that a mercury triflate catalyst is immobilized on a solid phase carrier via a linker.
2. An immobilized catalyst in which the linker is a phenyl group.
3. A method for producing a mercury triflate-immobilized catalyst, comprising immobilizing mercury triflate on a solid phase carrier via a linker.
4). A method for producing a cyclized compound, comprising contacting an alkyne compound or an allyl alcohol compound with a mercury triflate-immobilized catalyst.
5. A method for producing a hydrated compound, comprising contacting an alkyne compound and a mercury triflate-immobilized catalyst.
6). A method for producing an enone compound, comprising contacting an alkyne compound and a mercury triflate-immobilized catalyst.

  In the present invention, by using mercury triflate as an immobilized catalyst, the discharge of environmentally hazardous substances is small and the recyclability can be improved. Surprisingly, the catalyst activity is lowered by fixing the catalyst as a normal catalyst, but the immobilized catalyst of the present invention does not decrease the catalyst activity, and exhibits the activity originally possessed by the catalyst. Can be made.

  In the present invention, a mercury triflate-immobilized catalyst can be obtained by immobilizing mercury triflate on a solid phase carrier such as silica gel via a linker.

As the silica gel used for the immobilized catalyst of the present invention, those having a particle diameter of 0.1 μm to 2000 μm can be used. Preferably 40-300 micrometers thing is good. (Example: Kanto Chemical, Silica gel 60, special)
Moreover, the solid phase carrier used for the immobilization catalyst can also use polystyrene instead of silica gel (e.g., Tokyo Chemical Industry, polystyrene resin Polystyrene Resin, cross-linked with 1% DVB 200-400 mesh, or 100-200 mesh).

  As a linker used in the immobilization catalyst of the present invention, a phenyl group, a diphenylphosphino group, a dialkylphosphino group, an alkyl group, a thiol group, a diol group, a carboxylic acid, a tosylic acid, a sulfonic acid, an amino group, a diamino group, Those having tosylhydrazine can be mentioned.

  Linkers with silica gel using a fixed catalyst of the present invention, Silicycle's SiliaBond Phenyl, SiliaBond Diphenylphosphine, SiliaBond Thiol, SiliaBond Diol, SiliaBond Carboxylic Acid, SiliaBond Tosic Acid, SiliaBond Propylsulfonic Acid, SiliaBond Ethylenediaminobenzyl, SiliaBond amine, SiliaBond Diamine Is mentioned. SiliaBond Phenyl is preferable.

The case where the solid phase carrier is silica gel will be described with the method for producing an immobilized catalyst of the present invention as a representative example.
First, as a manufacturing method (a), silica gel with a linker and Hg (OAc) ₂ are reacted in a solvent. Examples of the solvent include acetic acid, sulfuric acid, water, amide solvents such as N, N-dimethylformamide, sulfoxide solvents such as dimethyl sulfoxide, alcohol solvents such as methanol and ethanol, and nitrile solvents such as acetonitrile and propionitrile. be able to. The reaction temperature is 0 to 200 ° C, preferably 100 to 150 ° C. The reaction time is 0.5 to 48 hours, preferably 1 to 2 hours. Moreover, you may irradiate a microwave etc. The amount of silica gel with a linker and Hg (OAc) ₂ used is 0.5 to 10 equivalents, preferably 1 to 2 equivalents, of Hg (OAc) ₂ with respect to the silica gel with a linker. After completion of the reaction, filtration and washing can be performed to obtain a compound in which HgOAc is immobilized on silica gel via a linker.

  Next, the compound in which HgOAc is immobilized on silica gel through a linker is reacted with trifluoromethanesulfonic acid in a solvent. Solvents include nitrile solvents such as acetonitrile and propionitrile, aliphatic halogenated hydrocarbons such as dichloromethane, 1,2-chloroethane, chloroform and carbon tetrachloride, aromatic hydrocarbons such as benzene and toluene, hexane and cyclohexane. And ether solvents such as aliphatic hydrocarbons such as diethyl ether and diisopropio ether. The reaction temperature is -20 to 100 ° C, preferably 0 to room temperature (25 ° C). The reaction time is 1 minute to 2 hours, preferably 5 to 10 minutes. The amount of HgOAc immobilized on silica gel via a linker and the amount of trifluoromethane sulfonic acid used was 0.5-10 for trifluoromethane sulfonic acid relative to the compound immobilized on silica gel via a linker for HgOAc. Equivalents, preferably 1-2 equivalents are used. After completion of the reaction, filtration and washing can be performed to obtain a compound in which mercury triflate (HgOTf) is immobilized on silica gel through a linker.

Moreover, as a manufacturing method (b) of the fixed catalyst of this invention, the silica gel with a linker and Hg (OAc) ₂ are first made to react in a solvent. This reaction is the same as in the production method (a).

  Next, a compound in which HgOAc is immobilized on silica gel via a linker is reacted with an alkali metal halide such as sodium chloride in a solvent. Examples of the solvent include water, alcohol solvents such as methanol and ethanol, amide solvents such as N, N-dimethylformamide, sulfoxide solvents such as dimethyl sulfoxide, and mixed solvents thereof. The reaction temperature is 0 to 150 ° C, preferably 80 to 120 ° C. The reaction time is 1 to 48 hours, preferably 5 to 15 hours. The amount of the compound in which HgOAc is immobilized on the silica gel via the linker and the halide of the alkali metal is 1 to 50 times the amount of the alkali metal halide in the compound in which HgOAc is immobilized on the silica gel via the linker. Equivalents, preferably 2-10 equivalents are used. After completion of the reaction, filtration and washing can be performed to obtain a compound in which, for example, HgCl is immobilized on silica gel through a linker.

  Further, a compound in which HgCl is immobilized on silica gel through a linker is reacted with silver trifluoromethanesulfonic acid in a solvent. Solvents include: aliphatic halogenated hydrocarbons such as dichloromethane, 1,2-chloroethane, chloroform and carbon tetrachloride; aromatic hydrocarbons such as benzene and toluene; nitrile solvents such as acetonitrile and propionitrile; nitromethane and nitroethane. And nitro-based solvents such as The reaction temperature is 0 to 100 ° C, preferably room temperature (25 ° C) to 60 ° C. The reaction time is 10 minutes to 10 hours, preferably 0.5 to 1 hour. The amount of HgCl immobilized on silica gel via a linker and the amount of silver trifluoromethanesulfonic acid used were 0.5% of silver trifluoromethanesulfonic acid relative to the compound of HgCl immobilized on silica gel via a linker. -10 equivalents, preferably 1-2 equivalents are used. After completion of the reaction, filtration and washing can be performed to obtain a compound in which mercury triflate (HgOTf) is immobilized on silica gel through a linker.

Various reactions can be carried out using the immobilized catalyst of the present invention. For example, it can be used for the reaction described on pages 745 to 750 of Non-Patent Document 1. The reaction is, for example, as shown below.
(1) Alkyne hydration reaction. For example, 1-phenylpropan-2-one can be obtained by using an immobilization catalyst for the alkyne compound prop-2-nylbenzene.

(2) Arylin cyclization reaction of enyne compound. For example, if an immobilization catalyst is used for the enyne compound 1,3-dimethyl-5- (oct-3-ynyl) benzene, 4-butyl-5,7-dimethyl-1,2-dihydronaphthalene can be obtained.

(3) Tandem cyclization reaction of inene aryl compounds. For example, if an immobilized catalyst is used for the inenearyl compound (E) -1,3-dimethyl-5- (4-methylnon-3-en-7-nyl) benzene, 5,7-dimethyl-1,4a-dimethyl -3,4,4a, 9,10,10a-hexahydrophenanthrene can be obtained.

(4) Furan ring synthesis reaction of ketoalkyne compound. For example, 2,5-diphenylfuran can be obtained by using an immobilized catalyst for the ketoalkyne compound 1,4-diphenylbut-3-yn-1-one.

(5) Indole ring synthesis reaction of an alkynylaniline compound. For example, 1-tosyl-1H-indole can be obtained by using an immobilized catalyst on the alkynylaniline compound N- (2-ethylphenyl) -4-methylbenzensulfamide.

(6) Exomethylene lactone synthesis reaction of alkynyl carboxylic acid compound. For example, if an immobilization catalyst is used for the alkynylcarboxylic acid compound hex-5-ynoic acid, 6-methylenetetrahydro-2H-pyran-2-one can be obtained.

(7) Enone compound synthesis reaction of propargyl acetate compound. For example, if an immobilized catalyst is used for the propargyl acetate compound undec-3-yn-2-yl acetate, (E) -undec-2-en-4-one can be obtained.

  Examples of the alkyne compound include an enyne compound, an inene aryl compound, a ketoalkyne compound, an alkynylaniline compound, an alkynylcarboxylic acid compound, and a propargyl acetate compound. Specifically, prop-2-nylbenzene, 1,3-dimethyl-5- (oct-3-ynyl) benzene, (E) -1,3-dimethyl-5- (4-methylnon-3-en-7 -Nyl) benzone, 1,4-diphenylbut-3-yn-1-one, N- (2-ethylphenyl) -4-methylbenzenesulfonamide, hex-5-ynoic acid, undec-3-yn-2-yl acetate, etc. Can be mentioned.

  Even if it is an allyl alcohol compound instead of the alkyne compound, a similar cyclized compound can be obtained. The reaction is, for example, as shown below.

(1) Allyl alcohol compound (E) -6- (3,5-dimethylphenyl) hex-2-en-1-ol, if an immobilized catalyst is used, 6,8-dimethyl-1-vinyl-1,2,3 , 4-tetrahydronaphthalene can be obtained.

(2) If an immobilized catalyst is used for the allyl alcohol compound 1- (3,5-dimethylphenyl) but-3-en-2-ol, 5,7-dimethyl-1,4-dihydroxynaphthalene can be obtained.

(3) If an immobilized catalyst is used for the allyl alcohol compound (E) -6- (1-tosyl-1H-indol-2-yl) hex-2-en-1-ol, 9-tosyl-4-vinyl-2 , 3,4,9-tetrahydro-1H-carbazole.

  Specific examples of the allyl alcohol compound include (E) -6- (3,5-dimethylphenyl) hex-2-en-1-ol, 1- (3,5-dimethylphenyl) but-3-en-2- ol, (E) -6- (1-tosyl-1H-indol-2-yl) hex-2-en-1-ol, and the like.

  As an example of the reaction using the immobilized catalyst of the present invention, a production method of an alkyne compound to a cyclized compound is shown. A compound in which mercury triflate (HgOTf) is immobilized on a silica gel via a linker is combined with an alkyne compound. The method of making it react in a solvent can be mentioned. Solvents include nitrile solvents such as acetonitrile and propionitrile, nitro solvents such as nitromethane and nitroethane, aliphatic halogenated hydrocarbons such as dichloromethane, 1,2-chloroethane, chloroform and carbon tetrachloride, benzene, toluene, etc. Aromatic hydrocarbons, or mixed solvents thereof. The reaction temperature is -78 to 200 ° C, preferably 0 ° C to room temperature (25 ° C). The reaction time is 5 minutes to 48 hours, preferably 10 minutes to 6 hours. After completion of the reaction, filtration and washing can be performed to obtain a cyclized compound.

  In the present invention, a compound in which mercury triflate (HgOTf) is immobilized on silica gel via a linker is used as an immobilization catalyst. For example, an alkyne compound is reacted to obtain a cyclized compound. By using mercury triflate as the immobilized catalyst of the present invention, the discharge of environmentally hazardous substances is small and the recyclability can be improved. Surprisingly, the catalyst activity is lowered by fixing the catalyst as a normal catalyst, but the immobilized catalyst of the present invention does not decrease the catalyst activity, and exhibits the activity originally possessed by the catalyst. Can be made.

  EXAMPLES Hereinafter, although this invention is demonstrated concretely based on an Example, it is not limited to these at all.

Synthesis Example 1 (Preparation of silica gel-Phenyl-HgOAc)
Silica gel carrier (silica gel LICYCLE, silica gel-Phenyl Reversed Phase Silica Gel, 230-400 mesh, loading 1.62 mmol / g) (250 mg, 405 μmol) and Hg (OAc) ₂ (155 mg, 486 μmol) in 99.5% acetic acid ( 2.7 mL) was irradiated with microwaves (CEM, Discover System, MODEL No. 908015) at 140 ° C. for 1 hour. Thereafter, the mixture is cooled to room temperature (25 ° C.), the reaction solution is removed using filter paper, and the resulting residue is washed successively with 10% acetic acid, water, methanol, ethyl acetate, and ether, dried with a desiccator, and silica gel-phenyl. -HgOAc (248 mg, loading 0.20 mmol / g) was obtained. In addition, unreacted Hg (OAc) ₂ in the reaction filtrate and washing solvent was quantified (138 mg) by reducing vapor atomic absorption spectrophotometry (using NIPPON INSTRUMENTS, MERCURY ANALYZER RA-2), and mercury loading (loading) 0.20 mmol / g was calculated. The carrier diameter was 20 times magnified with an optical microscope (OLYMPUS, IX70) and a digital camera (OLYMPUS, DP70), and a total of 100 carriers using analysis software (Media Cybernetics, Image-Pro PLAS). The number was measured and it was confirmed that the main carrier diameter was 50 to 80 μm.

Synthesis Example 2 (Preparation of silica gel-Phenyl-HgCl)
Saturated saline (2.7 mL) was added to silica gel-Phenyl-HgOAc (248 mg, loading 0.20 mmol / g) prepared in Synthesis Example 1, and the mixture was stirred at 60 ° C. for 11 hours. After cooling to room temperature (25 ° C.), the reaction solution is removed using filter paper, and the resulting residue is washed with water, methanol, ethyl acetate, and ether successively, dried by a desiccator, and silica gel-phenyl-HgCl (yield 232 mg). Got. The carrier diameter was 20 times magnified with an optical microscope (OLYMPUS, IX70) and a digital camera (OLYMPUS, DP70), and a total of 100 carriers using analysis software (Media Cybernetics, Image-Pro PLAS). The number was measured and it was confirmed that the main carrier diameter was 6 to 15 μm.

Example 1 (Preparation of silica gel-Phenyl-HgOTf)
Anhydrous acetonitrile (0.3 mL) was added to silica gel-Phenyl-HgOAc (25.0 mg, 5 μmol, loading 0.20 mmol / g) prepared in Synthesis Example 1, and trifluoromethanesulfonic acid (1.50 mg, 10 μmol, 0.88 μL) was added dropwise, and the mixture was stirred at room temperature (25 ° C.) for 10 minutes. The reaction solution was removed using filter paper, and the resulting residue was washed successively with acetonitrile, dichloromethane and ether, and dried with a desiccator to obtain silica gel-Phenyl-HgOTf (yield 23.8 mg). The carrier diameter was 20 times magnified with an optical microscope (OLYMPUS, IX70) and a digital camera (OLYMPUS, DP70), and a total of 100 carriers using analysis software (Media Cybernetics, Image-Pro PLAS). The number was measured and it was confirmed that the main carrier diameter was 50 to 80 μm.

Example 2
Silica gel-Phenyl-HgOAc (25.0 mg, 5 μmol) and anhydrous acetonitrile (0.3 mL) were added to the dried reaction flask, and trifluoromethanesulfonic acid (1.50 mg, 10 μmol) was added dropwise with stirring. After stirring at room temperature (25 ° C.) for 10 minutes, the reaction solution was removed using filter paper, and the residue was washed successively with acetonitrile, dichloromethane and ether to prepare silica gel-Phenyl-HgOTf. Next, anhydrous dichloromethane (1 mL) and N- [2- (hex-1-ynyl) phenyl] -4-methylbenzensulfamide (32.7 mg, 100 μmol) were sequentially added to silica gel-Phenyl-HgOTf as solvents, and room temperature (25 ° C.). For 90 minutes. Thereafter, the catalyst was removed using filter paper, and the filtrate was concentrated. The obtained residue was purified by column chromatography (hexane / ethyl acetate 5: 1) to obtain cyclized 2-butyl-1-tosyl-1H-indole (32.5 mg, 99%).

IR (neat) 3051, 2958, 2930, 2871, 1596, 1454, 1376, 1218, 1179 cm ⁻¹ .
¹ H NMR (200 MHz, CDCl ₃ )
δ 0.96 (3H, t, J = 7.4 Hz), 1.48 (2H, m), 1.73 (2H, quintet, J = 7.4 Hz), 2.33 (3H, s), 2 .98 (2H, t, J = 7.4 Hz), 6.38 (1H, s), 7.15-7.29 (4H, m), 7.40 (1H, d, J = 7.8 Hz) 7.61 (2H, d, J = 7.8 Hz), 8.16 (1H, dd, J = 7.8, 0.8 Hz).

¹³ C NMR (50 MHz, CDCl ₃ )? 13.88, 21.44, 22.43, 28.69, 30.95, 108.56, 114.78, 120.00, 123.41, 123.71, 126.19, 129.71, 129.84, 136.22, 137.19, 142.49, 144.54.
MS (EI) m / z 327 (M ^<+> ).
_{HR-MS (EI) calcd for} C 19 H 21 NO 2 S (M +) 327.1293, found 327.1283.

Example 3
To the dried reaction flask, anhydrous acetonitrile (0.24 mL) was added to silica gel-Phenyl-HgOAc (20.0 mg, 4 μmol), and trifluoromethanesulfonic acid (1.20 mg, 8 μmol) was added dropwise with stirring. After stirring at room temperature (25 ° C.) for 10 minutes, the reaction solution was removed using a filter paper, and the residue was washed successively with acetonitrile, dichloromethane, and ether to prepare silica gel-Phenyl-HgOTf. Subsequently, anhydrous acetonitrile (0.8 mL) and 1- (hept-2-nyloxy) -3,5-dimethylbenzene (19.8 mg, 80 μmol) were sequentially added to silica gel-Phenyl-HgOTf as a solvent at room temperature (25 ° C.). The reaction was performed for 90 minutes. Thereafter, the catalyst was removed using filter paper, and the filtrate was concentrated. The obtained residue was purified by column chromatography (hexane / ethyl acetate 7: 1) to obtain cyclized 4-butyl-5,7-dimethyl-2H-chromene (19.7 mg, 99%).

IR (neat) 2956, 2856, 1201, 1157, 1128, 819 cm ⁻¹ .
¹ H NMR (600 MHz, CDCl ₃ )
δ 0.88 (3H, t, J = 7.1 Hz), 1.28-1.38 (4H, m), 2.56 (2H, dt, J = 1.1, 7.1 Hz), 3. 77 (3H, s), 3.78 (3H, s), 4.46 (2H, dt, J = 1.1, 4.4 Hz), 5.46 (1H, tt, J = 1.1, 4) .4 Hz), 6.09 (1 H, d, J = 2.5 Hz), 6.13 (1 H, d, J = 2.5 Hz).

¹³ C NMR (150 MHz, CDCl ₃ )
δ 14.00, 22.54, 31.20, 34.53, 55.26, 55.27, 64.88, 92.80, 93.88, 107.19, 114.86, 136.19, 157 .66, 157.83, 160.41.
MS (EI) m / z 248 (M ^<+> ).
_{HR-MS (EI) calcd for} C 15 H 20 O 3 (M +) 248.1412, found 248.1418.

Example 4
Silica gel-Phenyl-HgCl (25.1 mg, 5 μmol) and anhydrous dichloromethane (0.3 mL) were added to the dried reaction flask, and silver trifluoromethanesulfonate (2.57 mg, 10 μmol) was added with stirring. After stirring at room temperature (25 ° C.) for 10 minutes, N- [2- (hex-1-ynyl) phenyl] -4-methylbenzensulfonamide (32.7 mg, 100 μmol) was added. The mixture was reacted at room temperature (25 ° C.) for 2 hours, sodium hydrogen carbonate powder was added, the solid matter was removed using filter paper, and the filtrate was concentrated. The obtained residue was purified by column chromatography (hexane / ethyl acetate 5: 1) to obtain cyclized 2-butyl-1-tosyl-1H-indole (32.0 mg, 98%).

Claims (10)

An immobilized catalyst characterized in that a mercury triflate catalyst is immobilized on a solid phase carrier via a linker. The immobilized catalyst according to claim 1, wherein the linker is a phenyl group. A method for producing a mercury triflate-immobilized catalyst, comprising immobilizing mercury triflate on a solid phase carrier via a linker. A method for producing a cyclized compound, comprising contacting an alkyne compound or an allyl alcohol compound with a mercury triflate-immobilized catalyst. The alkyne compound is 1,3-dimethyl-5- (oct-3-ynyl) benzone, (E) -1,3-dimethyl-5- (4-methylnon-3-en-7-nyyl) benzene, 1,4 The method for producing a cyclized compound according to claim 4, which is -diphenylbut-3-yn-1-one, N- (2-ethylphenyl) -4-methylbenzensulfamide, hex-5-ynoic acid. The allyl alcohol compound is (E) -6- (3,5-dimethylphenyl) hex-2-en-1-ol, 1- (3,5-dimethylphenyl) but-3-en-2-ol, (E)- The method for producing a cyclized compound according to claim 4, which is 6- (1-tosyl-1H-indol-2-yl) hex-2-en-1-ol. A method for producing a hydrated compound, comprising contacting an alkyne compound and a mercury triflate-immobilized catalyst. The method for producing a hydrated compound according to claim 7, wherein the alkyne compound is prop-2-nylbenzene. A method for producing an enone compound, comprising contacting an alkyne compound and a mercury triflate-immobilized catalyst. The method for producing an enone compound according to claim 9, wherein the alkyne compound is undec-3-yn-2-yl acetate.