WO2002048104A1

WO2002048104A1 - Method for producing indole derivative

Info

Publication number: WO2002048104A1
Application number: PCT/JP2001/010969
Authority: WO
Inventors: Yasuo Shirai; Tomohisa Utsunomiya; Norio Tanaka
Original assignee: Nissan Chemical Industries, Ltd.
Priority date: 2000-12-14
Filing date: 2001-12-14
Publication date: 2002-06-20
Also published as: AU2002222642A1

Abstract

A method for producing a novel indole derivative, characterized in that it comprises cyclizing a ß-nitrostyrene derivative having no substituent at least one ortho position under a reducing condition. The cyclization is preferably carried out by the use of a metal catalyst containing a Group VIII atom of the periodic table in a carbon monoxide containing atmosphere.

Description

Description Method for producing indole derivative

The present invention relates to a novel method for producing indole derivatives. Background art

Indole derivatives are a group of compounds useful as intermediates of fine chemicals, such as compounds having biological activity such as pharmaceuticals and agricultural chemicals described in JP-A-2001-187786, and include those derived from natural products. Many types are known. As a method for producing an indole derivative, for example, the following method is typically known.

(1) Method of cyclizing o, ω-dinitrostyrene derivative under catalytic reduction conditions to obtain indole (J. 0. (., 38, 3004, 1973)

(2) Method of obtaining indole by reducing ο-nitro styrene derivative with trivalent phosphorus (J. 0., 30, 3604, 1965)

(3) A method for obtaining indole by reductively cyclizing an ο-nitrostyrene derivative using a transition metal catalyst such as rhodium in the presence of carbon monoxide (J. C.S. Chem. Commun., P. 82, 1 98 1 year J. 0.C., 59, 3375, 1994)

(4) Method for obtaining indole by cyclizing o-aryluaniline using a palladium catalyst (J. Am. Chem. Soc., 98, 2674, 1976)

(5) Method of obtaining indole by treating o-methylacetanilide at high temperature in the presence of a strong base such as sodium amide (Org. Synthesis. Coll., Vol. 3, p. 597, 1955)

(6) A method of obtaining indole by reacting aniline with ethylene dalicol in the presence of a silver-based catalyst (European Patent (EP) 69242)

(7) A method of reacting an alkylaniline derivative with a solid catalyst such as silica or alumina to obtain indole (Hungarian Patent No. 16696, 1979) (8) Method of obtaining indole by treating j3-azidostyrene, azirine derivative, etc. at high temperature (Tetrahedron. Lett., P. 3499, 1968; Chem. Commun., P. 565, 1970, etc.) ·

An object of the present invention is to provide a novel method for producing an indole derivative having higher versatility than conventionally known production methods. Disclosure of the invention

The present inventors have thoroughly investigated a novel synthetic route for indole derivatives in order to solve the above problems. As a result, the _nitrostyrene derivative, which can be easily synthesized by various means, is treated under a reducing condition, for example, in a gas atmosphere containing carbon monoxide using a metal catalyst containing a group atom of the periodic table. The present inventors have found that the desired indole derivative can be obtained at a high yield, and completed the present invention.

That is, the present invention

As a first aspect, a method for producing an indole derivative, characterized in that at least one ortho position of an unsubstituted —ditorostyrene derivative is cyclized under reducing conditions. As a second aspect, the following formula: I)

[Where,

1 ^ Oyopi 1 ₂ are each independently a hydrogen atom, an alkyl group having 1 to ⁶ carbon atoms, an alkoxy force carbonyl groups of 1 to 4 carbon atoms or the same or different and one or more substituents, Represents an optionally substituted phenyl group;

The substituent is a halogen atom, an alkyl group having 1 to ⁶ carbon atoms, selected from the group consisting of alkoxy group and Shiano group having 1 to 6 carbon atoms, and

Χ 1 _Ν Χ ₂ , Χ ₃ and Χ ₄ are each independently a hydrogen atom, a fluorine atom, a chlorine atom, Represents a methyl group or a methoxy group. Cyclization of the j3-nitro derivative represented by the formula (1)

[Wherein R R ₂ , X X ₂ , X ₃ and X ₄ represent those defined above. The method for producing an indole derivative represented by

As a third aspect, in the above formula, X ₂ and X ₄ represent a hydrogen atom, The method for producing an indole derivative according to the second aspect,

According to a fourth aspect, the cyclization is performed in a carbon monoxide-containing gas atmosphere using a metal catalyst containing a group atom of the periodic table. A method for producing an indole derivative according to any one of the above,

According to a fifth aspect, the group atom is selected from the group consisting of iron, cobalt, nickel, ruthenium, rhodium, palladium, and platinum. The method for producing an indole derivative according to the fourth aspect,

As a sixth aspect, the method for producing an indole derivative according to the fifth aspect, wherein the vm group atom is selected from the group consisting of iron, cobalt, ruthenium, and rhodium.

As a seventh aspect, the method for producing an indole derivative according to any one of the fourth to sixth aspects, wherein the metal catalyst is a complex catalyst.

As an eighth aspect, the method for producing an indole derivative according to any one of the fourth to seventh aspects, further comprising adding a ligand in addition to the metal catalyst.

About.

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail.

J3-Nitro used in the method for producing the indole derivative of the present invention.

The body is J. Chera. Soc., 3531, 1954; J. Org. Chem., 15th volume, 8 pages, 1950 or Bull. Soc. Chim. Fr. According to the method described in, for example, pp. 884, 1949, the corresponding aromatic carbonyl compound and nitroal alkane can be obtained relatively inexpensively, for example, as shown in Scheme 1 below. It can be easily obtained by reacting in the presence of a base.

The above-mentioned] 3-nitrostyrene derivative is often obtained as a mixture of E- and Z-stereoisomers in general, but it is possible to isolate one stereoisomer by purification. . However, in the method for producing an indole derivative of the present invention, the same target indole derivative can be obtained regardless of whether a pure compound or a mixture is used as a starting material. Therefore, in the present specification,-a dinitrostyrene derivative is described without particular distinction of stereoisomerism, and both a pure compound and a mixture are assumed to be starting materials of the production method of the present invention.

The substituents and R ₂ in the _nitrostyrene derivative represented by the formula (I) and the indole derivative represented by the formula (Π) are each independently a hydrogen atom or an alkyl group having 1 to 6 carbon atoms. Represents

The alkyl group having 1 to 6 carbon atoms is a linear, branched or cyclic alkyl group, for example, methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group, i-butyl group , S-butyl, t-butyl, n-pentyl, i-amyl, s-amyl, t-amyl, neopentyl, siropentyl, n-hexyl, cyclohexyl, etc. No.

Examples of the alkoxycarbonyl group having 1 to 4 carbon atoms include methoxyl Carbonyl, ethoxycarbonyl, n-propyloxycarbonyl, i-propinoleoxycanolebonyl, n-butoxycarbinole, s-butoxycarbinole, t-butoxycarbonyl and the like. Can be

Examples of the phenyl group which may be substituted include a phenyl group, a 2-fluorophenyl group, a 3-fluorophenyl group, a 4-phenolelophenyl group, a 2-chlorophenyl group, and a 3-chlorophenyl group. , 4-chloropheno group, 2-bromophenyl group, 3-bromophenyl group, 4-promophenyl group, 4-phenylphenol group, 2,4-diphenyl group, 3,4 —Dichlorophenol group, 2,6-difluorophenyl group, 2,6-dichlorophenyl group, 2-fluoro-4-chlorophenyl group, 2,3,4,5,6-pentafluorophenyl group, 2-cyanophenyl group, 3-cyanophenyl group, 4-cyanophenyl group, 2-methylphenyl group, 3-methylphenyl group, 4-methynolephenyl group, 2,5-dimethylphenyl group, 4-methylinole 2,3,. · 5, 6-tetrafluoro Phenol, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2,6-dimethylphenyl, 3,4-dimethylphenyl, 3,4,5- Trimethoxyphenyl, 2-chloro-4- methyphenyl, 3-bromo-15-methylphenyl, 2-methynole-5-fluorophenyl, 2-chloro-13-cyanophenyl and the like. No. In view of the availability of starting materials and the ease of synthesis, 1 ^ ₂ is preferably each independently a hydrogen atom, a methyl group or an ethyl group, especially a hydrogen atom or Represents a methyl group.

The substituents X ₂ , X ₃ and X ₄ each independently represent a hydrogen atom, a fluorine atom, a chlorine atom, a methyl group or a methoxy group. In consideration of the availability of the substituted benzene derivative and the ease of synthesis, X ₂ , X _3, and X ₄ preferably represent a hydrogen atom, a fluorine atom or a chlorine atom, and particularly preferably represent a hydrogen atom or Represents a fluorine atom.

Also, from the gist and usefulness of the cyclization reaction of the present invention, when both X ₂ and X ₄ represent a hydrogen atom or the same substituent, even if represents a hydrogen atom, Since the structure is uniquely determined, it is particularly preferable that the intended indole derivative is a compound represented by this combination of substituents. The cyclization in the method for producing the indole derivative of the present invention can be carried out by a method using hydrogen gas, a method using a phosphite triester, or the like, but is preferably a carbon monoxide atmosphere or containing carbon monoxide. This method is performed in a gas atmosphere. And especially preferably, the cyclization is carried out in a carbon monoxide-containing gas atmosphere using a metal catalyst containing a Group III element of the periodic table. When using phosphite triester, a catalyst is not necessarily required.

The metal catalyst used in the cyclization of the present invention contains, inter alia, a Group VI atom selected from the group consisting of iron, cobalt, nickel, ruthenium, rhodium, palladium and platinum. Examples of the metal catalyst are shown below.

Examples of iron catalysts include ferrous iron, pentacarbonyl iron, phenylcarbonyldiiron, dodecacarbonyl triiron, dichlorobis (triphenylphosphine) iron, tetracarponinole (triphenylphosphine) iron, and tribonibis (triphenyl) Dinolephosphine) Iron, sodium cyclopentadienyldicarbonyliron, cyclopentadienyldicarbonyliron dimer, pentamethylcyclopentadiene / regicarbyliron dimer, cyclopentadientylcarbonyliron, cyclohexadientylcarbonyliron, butadiethylenedicarbonyliron , Sodium tetracarbonylferrate, bis (cyclopentageninole) iron [Hueguchisen], bis (tetramethinolecyclopentagenil) iron, bis (me, tylcyclopentagenenyl) iron [1,1 ' —Dimethyl fuectocene], complex catalysts such as acetyl fucetene, and acetyl acetonato iron; and salts such as iron acetate, iron chloride, and iron bromide.

Examples of the cobalt catalyst include Raney cobalt, octacarbonyl nicocobalt, dodecacarbonylcarbonyl, cobalt hydride, tetratetracarbonircone phenol, cyclopentadieninoresinolecanoleboninolecopanoleto, chlorotris (triphenylinolephosphine) konolenoate, Complex catalysts such as cobaltene are exemplified.

Nickel catalysts include supported catalysts such as Raney nickel, nickel-supported silica, nickel-supported alumina, nickel-supported carbon, tetracarbonylnickel, dichlorobis (triphenylphosphine) nickel, tetrakis (triphenylphosphine) Huckel, tetrakis (triff) (Enyl phosphite) Complex catalysts such as nickel, nickel chloride, nickel oxide and the like. Examples of the ruthenium catalyst include supported catalysts such as ruthenium-supported silica, ruthenium-supported alumina, ruthenium-supported carbon, pentacarbonylruthenium, dodecacarbonyltriruthenium, tetrahydrido-de-de-carbonyl tetraruthenium, dihydrido (dinitrogen) tris (triphenylphosphine) ) Ruthenium, dicarbonyl tris (triphenylphosphine) ruthenium, tetracarbonyl (trimethylphosphite) ruthenium, pentakis (trimethylphosphite) ruthenium, tris (acetylacetonato) ruthenium, diacetatodicarbonylbis (triphenylene) Norephosphine) Noletenium, dichlorobis (chlorotricanolevonyl) noretanium, canoleboninolechlorohydrido tris (trifeninolefos) Inlet) Noletenium, Tetrahydridotris (triphenylphosphine) ruthenium, 'acetatohydridotris (triphenyl ^^ phosphine) ruthenium, dichlorobis (acetonitrile) bis (triphenylphosphine) ruthenium, ruthenocene, bis (pentamethinolecyclopentane) Genil) luteuium, dichloro (pentamethinolecyclopentagenyl) noletenium, black mouth (cyclopentageninole) bis (tripheninolephosphine) noletenium, hydride (cyclopentageninole) bis (tripheninole phosphine) noretanium , Chlorocanoleboninole (cyclopentageninole) noretium, hydride (cyclopentagenenyl) (1,5-cyclooctadiene) ruthenium, (Cyclopentageninole) (1,5-cyclooctadiene) noletenium, dihydridotetrakis (triphenylphosphine) ruthenium, cyclootatatriene (cyclooctadiene) ruthenium, chlorohydrido dotris (triphenylenolephosphine) noretenium, Tricanoleponinolebis (triphenylinolephosphine) nortenium, tricarbonyl (cyclooctatetraene) ruthenium, tricarbonyl (1,5-cyclooctane) ruthenium, dichlorotris (triphenylphosphine) ruthenium, etc. Complex catalysts, ruthenium chloride, ruthenium oxide, ruthenium black and the like can be mentioned.

Examples of the palladium catalyst include Raney palladium, palladium-supported silica, palladium-supported anolemmina, palladium-supported carbon, palladium-supported barium sulfate, palladium-supported zeolite, palladium-supported silica and alumina, and supported catalysts such as dichlorobis (triphenyl Phosphine) palladium, dichlorobis (trimethylphosphine) In) palladium, dichlorobis (tributylphosphine) palladium, bis (tricyclohexylphosphine) palladium, tetrakis (triethylphosphite) palladium, bis (cycloocta-1,5-diene) palladium, tetrax (triphenylinophosphine) Complex catalysts such as palladium, dicanoleponinolebis (tripheninolephosphine) palladium, carbonyl tris (triphenylinolephosphine) palladium, dichlorobis (benzo-tolyl) palladium, dichloro (1,5-cyclooctane) palladium, palladium chloride, Examples include palladium acetate and palladium oxide.

Examples of the rhodium catalyst include supported catalysts such as rhodium-supported silica, rhodium-supported alumina, and rhodium-supported carbon; rhodium chlorotris (triphenylphosphine); Rhodium dodotetracarbonyl rhodium, hydridocarbonyltris (triphenylphosphine) rhodium, hydridotetrakis (triphenylinolephosphine) rhodium, dichlorobis (cyclooctadiene) dirhodium, dicanoleponinole (pentamethinolecyclopentageninole) Rhodium, cyclopentadienylbis (triphenylinolephosphine) Rhodium, dichlorotetrakis (arinole) Rhodium complex catalyst, rhodium chloride, rhodium oxide And the like.

Examples of the platinum catalyst include supported catalysts such as platinum-supported silica, platinum-supported alumina, and platinum-supported carbon; dichlorobis (triphenylphosphine) platinum; dichlorobis (trimethylphosphine) platinum; dichlorobis (tributylphosphine) platinum; and tetrax (triphenyl). (Phosphine) platinum, tetrakis (triphenylphosphite) platinum, tris (triphenylphosphine) platinum, dicarbonylbis (triphenylphosphine) platinum, carbonyltris (triphenylphosphine) platinum, cis-bis (benzonitrile) dichloro Complex catalysts such as platinum and bis (1,5-cyclooctadiene) platinum, platinum chloride, platinum oxide [Adams catalyst], platinum black, and the like are listed.

Among them, a metal catalyst containing a group atom selected from the group consisting of iron, cobalt, ruthenium and rhodium is preferable, and a complex catalyst can be suitably used as a catalyst form. Further, the metal catalyst may be used alone or in combination. Can be.

The amount of the metal catalyst to be used is generally in the range of 0.001 to 20 mol%, and preferably in the range of 0.001 to 20 mol%, based on the 0-nitrostyrene derivative represented by the formula (I). A range of 10 mol% is preferred.

In addition to the metal catalyst, a ligand can be added as needed. Examples of ligands include trimethylphosphine, tri'ethylphosphine, tributylphosphine, triphenylphosphine, tris (paratolyl) phosphine, tris (2,6-dimethinolepheninole) phosphine, and dipheninolephosphino. Sodium benzene-3-sonolephonate, bis (3-sulfonatophenyl) phosphinobenzenesodium salt, 1,2-bis (diphenylphosphino) ethane, 1,3-bis (diphenylinophosphino) Monodentate and polydentate tertiary phosphines such as pronon, 1,4-bis (diphenolenophosphino) butane, tris (3-sulfonatophenyl) phosphine sodium salt, triethyl phosphite, tributyl phosphite, Triphenylphosphite, tris (2,6-dimethylphenyl ) Phosphites such as phosphites, triphenylmethylphosphonimide, triphenylenomethylphosphonium bromide, triphenylenomethylphosphonamide bromide, Salts such as azide, triphenylenoleolinolephosphonium chloride, triphenylphenylphosphonium chloride, tetraphenylphosphonium chloride, tetraphenylphosphonium bromide, tetraphenylphosphonium chloride, etc. Phosphate esters such as triphenyl phosphate, trimethyl phosphate, triethyl phosphate, and triaryl phosphate; nitriles such as benzo-tolyl and acetonitrile; ketones such as acetylacetone; cyclopentagen; and pentamethinolecyclopen Genes such as 1,5-cyclopentyl, pyridine, 2-picoline, 3-picoline, 4-picoline, 2,2-bipyridinole, terpyridine, 1,10-phenanthroline, 8-Hydroxyquinoline, bisoxazolidinyl pyridine (Pybox), 1,4-dimethylvirazole, 1,3,5-trimethylpyrazole, pyrimidine, pyrimidine, etc. Nitrogen-containing heterocyclic ligands, maleic acid dimethyl Pyric acid ligands such as oleolester, dimethylenoestene fumanoleate, phenylenoleacetylene, difluoroacetylene, etc. And carbon.

The amount of the ligand, based on the metal catalyst, usually from 0.1 to 1 0 0 0 0 molar%, preferably in the range from 1 to 5 0 0 0 mole ^_0/0 are preferred.

The carbon monoxide-containing gas used in the cyclization of the present invention can be carbon monoxide gas or a gas containing carbon monoxide, and the carbon monoxide partial pressure is 0.001 to 5 OMPa, industrial Specifically, 0.01 to 2 OMPa is preferable. The total pressure can be freely selected as long as the partial pressure of carbon monoxide is maintained, but is preferably from 0.01 to 5 OMPa, particularly preferably from 0.05 to 3 OMPa. As the gas for diluting the carbon monoxide-containing gas, various gases can be used as long as they are not directly involved in the reaction. For example, inert gases such as nitrogen, argon, and helium are generally used. Gases that can be coexistent in the reaction system, such as carbon dioxide, can also be used.

The cyclization of the present invention is preferably carried out by diluting with a solvent in order to promote the reaction by promoting the dispersion and mixing of the components used in the reaction. The solvent is not particularly limited as long as it is a solvent inert to the reaction. Examples thereof include dimethyl ether, methyl-t-butyl ether, tetrahydrofuran, dimethyl ether, dimethoxymethane, diethoxymethane, and ethylene glycol resin. Ethenole, Ethyleneglyconolejete Noretheneo, Ethyleneglyconoresiebutinoeatenole, Diethyleneglycolenoresime Tinoleatenoe, Diethyleneglycolenoteinee Noethene, Diethyleneglyconelee Noetheneo Ethers such as 1,4-dioxane and aniso-mono-ole, methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butano-one, iso-butanol, 2-butane CHIRU 2-propanol, methinoreserosolove, ethinoreserosonoleb, i-propyl cellosonoleb, diethylene glycol monomethyl ether, diethylene glycol monoethylenoate ethere, diethylene glycolone monobutenoate ethere, cyclohexanoe monoleate, benzinole alcohol Alcohols such as acetone, methyl ethyl ketone, ethynole ketone, 2-bentanone, methinoleisobutynole ketone, cyclohexanone, etc., pentane, hexane, cyclohexane, meth ^ / cyclohexane, heptane , Octane, decane, etc., aliphatic hydrocarbons, carbon form, carbon tetrachloride, dichloroethane, tetrachloroethylene, etc., halogenated hydrocarbons, benzene, Aromatic hydrocarbons such as tonolenene, xylene, benzene, o-dichlorobenzene, m-dichlorobenzene, p-dichlorobenzene, nitrobenzene, tetrahydronaphthalene, etc., nitriles such as acetonitrile and propionitrile , Esters such as methyl acetate, ethyl acetate, butyl acetate, and ethyl propionate; amides such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone; 1 Ureas such as 3,3-dimethylimidazolidinone, N, N, Ν ', Ν, -tetramethylurea, and pyridines such as pyridine, 2-picoline, 3-picoline, 4_picoline, and 5-ethyl-2-picoline Or water. These can be used alone or in combination.

The cyclization of the present invention can be performed in a wide temperature range. However, in consideration of economic advantages including the amount of the reactant used, a suitable temperature range is usually 50 to 400 ° C, particularly 100 to 300 ° C.

The reaction time in the cyclization of the present invention varies depending on the amount, concentration, reaction temperature, etc. of the reagents used, but it is usually 0.1 to 20 hours, particularly preferably 0.5 to 10 hours. It is preferable to set conditions.

As a mode for carrying out the cyclization of the present invention, it is preferable to use a pressurized reaction vessel such as an autoclave. The reaction can be performed either in a batch system or a continuous system, and can be selected based on the required substrate concentration, conversion, productivity, and the like. After completion of the reaction, the desired indole derivative can be directly obtained by distilling off the solvent if necessary, followed by distillation or recrystallization. After adding water and a solvent immiscible with water to the obtained crude product and washing it sufficiently, the organic layer is purified and isolated by a conventional treatment such as distillation, column chromatography, etc. to obtain the indole derivative. It is also possible to get Example

Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited thereto. Reference Example 1: 4-((E)-2 ---- Tropropene-1-inole) Manufacture of Zen

To 48 ml of nitrethane, 24.8 g (0.2 mol) of 4-benzophenol and 0.2 g of benzinoleamine were added and reacted under reflux for 4 hours. After the reaction, excess nitroethane was recovered by distillation under reduced pressure, and the residue was recrystallized from ethanol to obtain 24.5 g of 4- (2-etropropene-11-yl) _1-fluorobenzene. Was obtained as yellow crystals. As a result of iH-NMR spectrum analysis, it was confirmed that the obtained product was an E-isomer. Yield: 67%. Reference example 2: Production of 4-((Z) -122-tropene-1 1-f)

14 g of 4-((E) -12-nitropropene-1-yl) _1-fluorobenzene produced in Reference Example 1 was dissolved in 100 ml of acetonitrile. The solution was irradiated with light from a high-pressure mercury lamp at room temperature for 16 hours while passing through nitrogen gas. The reaction mixture was concentrated under reduced pressure, and the obtained mixture of the E_ form and the Z form was separated and purified by silica gel column chromatography (form: hexane = 2: 1) to give 6.76 g of 4-((Z) 1-212 Tropropene-1-yl) 1-Fluorobenzene was obtained. ^X H-NM R spectrum analysis results, resulting product was confirmed to contain Z- body 9 9.6%. Reference Example 3: Production of (2-dipropene-1-yl) benzene

2.65 g (0.025 mol) of benzaldehyde and 0.53 g of benzylamine were added to 1 Om 1 of two-necked toluene, and the mixture was reacted under reflux conditions for 8 hours. After the reaction, excess nitroethane was collected by distillation under reduced pressure, and the residue was recrystallized from ethanol to give 1.45 (2-dipropene-11-yl) benzene as yellow crystals. Reference Example 4: 1- (2-dipropene-1-yl) -1 4-methoxybenzene troethane 1 Om I to 4-methoxybenzaldehyde 3.40 g (0.02 5 mol) and 0.53 g of benzylamine were added and reacted under reflux conditions for 4 hours. After the reaction, the excess nitroethane was recovered by distillation under reduced pressure, and the residue was recrystallized from ethanol to give 1.88 § of 1- (2-dipropene-1-yl) 14-methoxybenzene. Was obtained as yellow crystals. Example 1: Preparation of 6-fluoro-2-methylindole

In a 100 ml stainless steel autoclave, 1-fluoro 4- (2-ditropropene_1-yl) benzene as a starting material 1.81 g (1.0 mimol) of benzene, octacarbonylni as a catalyst cobalt 17 lmg (5. 0 mol ^_0/0) and 1, 4_ charged Jiokisan 40 m 1, was replaced in the reaction system 5 times with nitrogen then IMP a. Subsequently, carbon monoxide gas was injected under a pressure of 4 MPa, the temperature was raised while stirring, and the reaction was performed at a temperature of 200 ° C for 1 hour. After cooling, the reaction solution was taken out and analyzed. As a result, it was found that 6-fluoro-2-methylindole was obtained as a product in a yield of 30.5%. Example 2: Preparation of 6_fluoro-2-methylindole

In a 100 ml stainless steel autoclave, 1-fluoro 4-1-1 (2-nitropropene-1-inole) benzene as a starting material 1.81 g (10 mimol), iron pentacarbonyl 79 mg (4 . 0 mole ^_0/0) and charged pyridine 4 Om l, and the inside of the reaction system was replaced five times with nitrogen then IMP a. Subsequently, carbon monoxide gas was injected at a pressure of 4 MPa, the temperature was increased while stirring, and the reaction was carried out at a temperature of 220 ° C. for 1 hour. After cooling, the reaction solution was taken out and analyzed. As a result, it was found that 61-fluoro-2-methylindole was obtained as a product in a yield of 42%. Example 3: Preparation of 6-fluoro-2-methylindole

In Example 2, except for using Eniakarubo two Runi iron 146 mg (4.0 mol ^_0/0) as the catalyst performs the same operation, as product 6- Furuoro methyl Indoru was obtained in 39% yield. Example 4: Preparation of 6-Fluoro-2-methylindole

In Example 3, except for using Dodekakarubo sulfonyl ferric 20 Img (4.0 mole ^_0/0) as the catalyst performs the same operation, to give the 6 _ Furuoro methyl Indoru in 38% yield as product Was. Example 5: Preparation of 6-fluoro-2-methylindole

In Example 2, the same operation was carried out except that 144 mg (8.0 mol%) of 1,10-phenanthroline was added as a ligand to the reaction system, and 6-fluoro-2-methyl was used as a product. Indole was obtained in a yield of 61%. Example 6: Preparation of 6-fluoro-2-methylindole

In the same manner as in Example 2, except that 125 mg (8.0 mol%) of 2,2′-biviridyl was added as a ligand to the reaction system, 6-fluoro-2-methylindole was added as a product. % Yield. Example 7: Preparation of 6-fluoro-2-methylindole

In Example 1, the same operation was carried out except that 256 mg (4.0 mol%) of dodecacarbonyl triruthenium was used as a catalyst and 4 Oml of toluene as a solvent, and 6-fluor-2-methylindole was used as a product. Obtained in 26% yield. Example 8: Preparation of 6-fluoro-2-methylindole

In Example 7, 1 as a ligand in the reaction system, 10 Fuenanto port phosphate 144 mg (8. 0 mole ^_0/0) was added, the solvent as a 1, 4 a similar except for using an Jiokisan 40 m 1 The operation was performed, and 6-fluoro-2-methylindole was obtained as a product in a yield of 58%. Example 9: Preparation of 6-fluoro-2-methylindole

The same operation as in Example 7 was carried out except that 213 mg (2.0 mol%) of hexadecacarbonyl hexarhodium was used as a catalyst. -Methylindole was obtained in a yield of 20%. Example 10 Preparation of 6-Fluoro-2-methylindole

In Example 9, the same operation was carried out except that 137 mg (4.0 mol%) of octacarbonylnicocobalt was used as a catalyst, and 21% of 6-fluoro-2-methylindole was obtained as a product. Rate obtained. Example 11 1: Preparation of 6-fluoro-2-methylindole-The same operation as in Example 10 was carried out except that 40 ml of pyridine was used as a solvent, and 6-fluoro-2-methylindole was used as a product. Was obtained in 29% yield. Example 12: Preparation of 4,6-difluoroindole

In Example 2, the same operation was carried out except that 1.86 g (10 mmol) of 2,4-difluoro-1- (2-nitrobinyl) benzene was used as a starting material. 6-Difluoroindole was obtained in a yield of 45%. Example 13: Preparation of 2-methylindole.

In Example 2, the same operation was carried out except that 1.63 g (10 mmol) of (2-nitropropene-11-yl) benzene was used as a starting material, and 2-methylindole was used as a product. Was obtained in a yield of 61%. Example 14 Preparation of 6: 6-Methoxyindole

In Example 2, the same operation was carried out except that 1.79 g (10 mmol) of 1-methoxy4_ (2-nitrobul) benzene was used as a starting material, and 6-methoxyindole was used as a product. Was obtained in 57% yield. Example 15 Preparation of 6-chloro-2-methylindole

In Example 2, the starting material was 1-chloro-41- (2- The same operation was performed except that 1.98 g (10 mmol) of benzene was used to obtain 6-chloro-2-methylindole as a product in a yield of 53%. Example 16 to 37

Following the procedure of Example 1., and _c伹were produced Indoru derivative under the conditions shown in Table 1, the amount of solvent are all 30 m 1, symbols in Table 1 denote the following.

—Fluoro-41 (2-dipropene-1) Benzene 0.543

Π: 1-Methinole 4-one (2-dipropene-1-inole) Benzene 0 · 532 g ΙΠ: (2-Nitropropene-1-inole) Benzene 0.489 g

IV: 1-Methoxy 41- (2-dipropene-1-yl) Benzene 0 · 580 g

V: 1-Chloro-4_ (2-ditropropene_1-inore) 593 g VI: 1-Fluoro4-1- (2-nitro-1 1-butene-1-yl) Nsen (E-form) 0.585 g

A

B: cyclopentagenenyl dicarbonyl iron dimer 42 omg

a: 1, 10-phenanthroline monohydrate 47.6 mg

b: Tetramethinoleethylenediamine 27 · 8 mg

c: Methinolestenol maleate 54 · 7 mg

d: Methinoleestenole fumanolate 54.7 mg

e: Fuenorea acetylene 49. Omg

f: Trifenylphosphine 251.8 mg 1]

Example Starting material Catalyst Ligand Solvent / dish CO partial pressure Time Yield

\ I IV Γ d)

(h)

1 6 A rigid, 260 1.5 1 19

¹¹

1A A pyridine 200 4.5 1 45

¹¹

1 8 A b Pyridine 200 4.5 1 32

¹¹

1 9 B Toluene 120 3.0 5 47

¹¹

20 B Torzoleen 120 5.0 5 66

¹¹

21 B Toluene 120 7.0 5 77

¹¹

22 B Toluene 90 5.0 5 30

¹¹

23 B Black benzene 150 5.0 5 54

¹¹

24 B 1,4-dioxane 150 5.0 1 13

¹¹

25 B Anniversary 150 5.0 3 67

¹¹

26 B N-methylpyrrolidone 150 3.0 7 16

¹¹

27 B Pyridine 150 3.0 7 34

¹¹

28 B Toluene 150 5.0 5 24

¹¹

29 B c Trainen 120 5.0 7 66

¹¹

30 B d Toluene 120 5.0 7 66

¹¹

31 B e Toluene 120 5.0 5 69 o2 B f Torr _ ノ. Ί Ί 4o

33 Π B Toluene 120 5.0 5 68

34 ΙΠ B Toluene 150 5.0 3 38

35 IV B Toluene 150 5.0 7 41

36 V B Toluene 120 5.0 3 63

37 I * B Toluene 120 5.0 5 74

38 VI B Toluene 120 5.0 3 100

*: z-form When at least one of R and R ₂ represents an alkoxyl group having 1 to 6 carbon atoms, a substituted phenyl group or a substituted phenyl group, similarly, by appropriately changing the starting material, an indone derivative can also be obtained. Can be manufactured. Industrial applicability According to the production method of the present invention, an indole derivative can be obtained in a favorable yield under relatively mild reaction conditions. The indole derivative produced according to the production method of the present invention is a group of compounds that are important as intermediates of fine chemicals, such as pharmaceuticals and agricultural chemicals.

Claims

The scope of the claims

1. A method for producing an indole derivative, comprising cyclizing a j3-nitrostyrene derivative having at least one ortho position unsubstituted under reducing conditions.

2. The following equation (I)

[Where,

1 ^ and R ₂ are each independently substituted with a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxycarbonyl group having 1 to 4 carbon atoms, or one or more substituents which are the same or different Represents a phenyl group which may be

The substituent is selected from the group consisting of a halogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, and a cyano group, and

X x _2, ₃ Oyopi ₄ each independently represent a hydrogen atom, a fluorine atom, a chlorine atom, a methyl group or main butoxy group. The cyclization of a β-12-nitrostyrene derivative represented by the following formula under reducing conditions:

[Wherein, R ₂ , X, X ₂ , X ₃ and X ₄ represent those defined above. ] The manufacturing method of the indole derivative represented by these.

3. In the above formula, X ₂ and X ₄ represent a hydrogen atom. A method for producing the indole derivative described above.

4. The method according to any one of claims 1 to 3, wherein the cyclization is performed in a carbon monoxide-containing gas atmosphere using a metal catalyst containing a group atom of the periodic table.方法 A method for producing an indole derivative.

5. The method for producing an indole derivative according to claim 4, wherein the group-group atom is selected from the group consisting of iron, cobalt, nickel, ruthenium, rhodium, palladium and platinum.

6. The method for producing an indole derivative according to claim 5, wherein the Group VI atom is selected from the group consisting of iron, cobalt, ruthenium, and rhodium.

7. The method for producing an indole derivative according to any one of claims 4 to 6, wherein the metal catalyst is a complex catalyst.

8. The method for producing an indole derivative according to any one of claims 4 to 7, wherein a ligand is added in addition to the metal catalyst.