JP2005255553A - Method for producing n-containing ring compound - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for producing compounds bearing an N-containing heterocyclic rings, for example, quinoline ring, pyridine ring or the like starting from a carbonyl compound and an aminoalcohol under mild conditions. <P>SOLUTION: In the presence of a compound of a group 9 element and a base, a carbonyl compound of formula (1) (wherein R<SP>1</SP>, R<SP>2</SP>, Y are identical or different and shows each H or an organic group; at least two of R<SP>1</SP>, R<SP>2</SP>and Y may bond to each other and together with adjoining one or two carbon atoms to form a chain ring) and an aminoalcohol represented by formula (2) (wherein A is a divalent organic group, R<SP>3</SP>is H or an organic group, A and R<SP>3</SP>may link to each other to form a ring together with adjacent carbon atoms) are allowed to react with each other to produce a N-including ring compound. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

  The present invention relates to a method for producing a nitrogen-containing cyclic compound using a group 9 element compound catalyst of a periodic table, and more specifically, a carbonyl compound having a hydrogen atom at the α-position and an amino alcohol using a group 9 element compound catalyst of the periodic table To a method for producing a nitrogen-containing cyclic compound having a nitrogen atom in the ring.

  A compound having a nitrogen-containing heterocycle such as a quinoline ring or a pyridine ring is useful as a physiologically active compound or a synthetic intermediate thereof. Recently, as a method for synthesizing quinolines in place of the conventional Friedlander reaction, a method using a ruthenium complex as a catalyst has been proposed (see Non-Patent Document 1).

Chemical Communication (Chem. Commun.), 2576 (2001)

  An object of the present invention is to provide a method for easily producing a compound having a nitrogen-containing heterocycle such as a quinoline ring or a pyridine ring from a carbonyl compound and an amino alcohol under mild conditions.

  As a result of diligent studies to achieve the above object, the present inventors have found that when a carbonyl compound having a hydrogen atom at the α-position is reacted with an amino alcohol using a specific catalyst, the nitrogen-containing cyclic compound is subjected to mild conditions. Thus, the present invention was completed.

（式中、Ｒ¹、Ｒ²、Ｙは、同一又は異なって、水素原子又は有機基を示す。Ｒ¹、Ｒ²及びＹのうち少なくとも２つが互いに結合して隣接する１又は２個の炭素原子と共に環を形成していてもよい）
で表されるカルボニル化合物と、下記式（２）

（式中、Ａは２価の有機基を示し、Ｒ³は水素原子又は有機基を示す。Ａ及びＲ³は互いに結合して隣接する炭素原子と共に環を形成していてもよい）
で表されるアミノアルコールとを反応させて、含窒素環状化合物を生成させることを特徴とする含窒素環状化合物の製造法を提供する。 That is, the present invention provides the following formula (1) in the presence of a group 9 element compound of the periodic table and a base.

(In the formula, R ¹ , R ² and Y are the same or different and each represents a hydrogen atom or an organic group. At least two of R ¹ , R ² and Y are bonded to each other and adjacent to one or two carbon atoms. (It may form a ring with atoms)
And a carbonyl compound represented by the following formula (2)

(In the formula, A represents a divalent organic group, R ³ represents a hydrogen atom or an organic group. A and R ³ may be bonded to each other to form a ring with an adjacent carbon atom)
A method for producing a nitrogen-containing cyclic compound is provided, wherein a nitrogen-containing cyclic compound is produced by reacting with an amino alcohol represented by the formula:

（式中、Ａは２価の有機基を示し、Ｒ¹、Ｒ²、Ｙは、同一又は異なって、水素原子又は有機基を示す。Ｒ¹、Ｒ²及びＹのうち少なくとも２つが互いに結合して隣接する１又は２個の炭素原子と共に環を形成していてもよい。Ｒ³は水素原子又は有機基を示す。Ａ及びＲ³は互いに結合して隣接する炭素原子と共に環を形成していてもよい）
で表される化合物、又は該化合物における含窒素環が脱水素化された化合物が挙げられる。好ましい含窒素環状化合物には、ピリジン誘導体、キノリン誘導体等が含まれる。 The carbonyl compound represented by the formula (1) includes ketone, aldehyde, ester, lactone, amide or lactam. The divalent organic group in A includes a divalent aliphatic hydrocarbon group, an alicyclic hydrocarbon group, an aromatic hydrocarbon group or a heterocyclic group, or a group in which two or more of these are bonded. . As the nitrogen-containing cyclic compound, the following formula (3a), (3b) or (3c)

(In the formula, A represents a divalent organic group, R ¹ , R ² and Y are the same or different and represent a hydrogen atom or an organic group. At least two of R ¹ , R ² and Y are bonded to each other. R ³ may be a hydrogen atom or an organic group, and A and R ³ may be bonded to each other to form a ring together with the adjacent carbon atoms. May be)
Or a compound in which the nitrogen-containing ring in the compound is dehydrogenated. Preferred nitrogen-containing cyclic compounds include pyridine derivatives and quinoline derivatives.

  In the present specification, the “carbonyl compound” includes a wide range of compounds having — (C═O) — groups such as esters, lactones, amides, lactams, carboxylic acids, carboxylates, in addition to ketones and aldehydes. Used for meaning. “Organic group” is used in a broad sense including not only carbon atom-containing groups but also non-metal atom-containing groups such as halogen atoms, hydroxyl groups, mercapto groups, amino groups, nitro groups, and sulfonic acid groups. .

  According to the production method of the present invention, a compound having a nitrogen-containing heterocycle such as a quinoline ring or a pyridine ring can be easily produced from a carbonyl compound and an amino alcohol under mild conditions.

[Group 9 element compound of the periodic table]
In the present invention, a Group 9 element compound (including a simple metal) is used as a catalyst. The periodic table group 9 element (metal) includes cobalt, rhodium, and iridium. The periodic table group 9 element compound includes a wide range of inorganic and organic compounds including the periodic table group 9 element. Examples of the inorganic compound include simple metals, oxides, sulfides, hydroxides, halides, sulfates, oxo acids containing Group 9 elements of the periodic table or salts thereof, and inorganic complexes. Examples of the organic compound include cyanide, organic acid salt (such as acetate), and organic complex. Among these, organic compounds such as organic complexes are preferable. The ligand of the complex includes a known ligand. The valence of the group 9 element in the group 9 element compound of the periodic table is about 0 to 6, preferably 0 to 3. In particular, in the case of an iridium compound, monovalent or trivalent is preferable. The periodic table group 9 element compounds may be used alone or in combination of two or more.

  For example, iridium is used as a representative example of the group 9 element compound of the periodic table. For example, metal iridium, iridium oxide, iridium sulfide, iridium hydroxide, iridium fluoride, iridium chloride, iridium bromide, iridium iodide, sulfuric acid Examples thereof include iridium, iridium acid or a salt thereof (for example, potassium iridate), an inorganic iridium complex [for example, hexaammineiridium (III) salt, chloropentammineiridium (III) salt, etc.] and the like.

As the organic iridium compound, for example, an organic iridium complex can be used in addition to iridium cyanide. Examples of the organic iridium complex include tris (acetylacetonato) iridium, dodecacarbonyltetrairidium (0), chlorotricarbonyliridium (I), di-μ-chlorotetrakis (cyclooctene) diiridium (I), di- μ-chlorotetrakis (ethylene) diiridium (I), di-μ-chlorobis (1,5-cyclooctadiene) diiridium (I) [IrCl (cod)] ₂ , di-μ-chlorodichlorobis (pentamethyl) Cyclopentadienyl) diiridium (III), trichlorotris (triethylphosphine) iridium (III), pentahydridobis (trimethylphosphine) iridium (V), chlorocarbonylbis (triphenylphosphine) iridium (I), chloroethylenebis (Triphenylphosphine) Lidium (I), (pentamethylcyclopentadienyl) dicarbonyliridium (I), bis {1,2-bis (diphenylphosphino) ethane} iridium (I) chloride, pentamethylcyclopentadienylbis (ethylene ) Iridium (I), carbonylmethylbis (triphenylphosphine) iridium (I), (1,5-cyclooctadiene) (diphosphine) iridium (I) halide, 1,5-cyclooctadiene (1,2- Bis (diphenylphosphino) ethane) iridium (I) hexafluorophosphate, (1,5-cyclooctadiene) bis (trialkylphosphine) iridium (I) halide, bis (1,5-cyclooctadiene) Iridium tetrafluoroborate, (1,5-cyclooctadiene) (a Cetonitrile) iridium tetrafluoroborate etc.] and the like.

  Preferred iridium compounds include iridium complexes. Among these, organic iridium complexes, in particular, unsaturated hydrocarbons such as cyclopentene, dicyclopentadiene, cyclooctene, 1,5-cyclooctadiene, ethylene, pentamethylcyclopentadiene, benzene, toluene; nitriles such as acetonitrile; Organic iridium complexes having ethers such as tetrahydrofuran as ligands [for example, di-μ-chlorotetrakis (cyclooctene) diiridium (I), di-μ-chlorotetrakis (ethylene) diiridium (I), di- μ-chlorobis (1,5-cyclooctadiene) diiridium (I), bis (1,5-cyclooctadiene) iridium tetrafluoroborate, (1,5-cyclooctadiene) (acetonitrile) iridium tetrafluoroborate, etc. ] Is preferred

  Examples of periodic table group 9 element compounds other than iridium compounds include compounds corresponding to the above iridium compounds [eg, dichlorobis (1,5-cyclooctadiene) dirhodium, etc.], literatures, etc. (eg, Chemical Society of Japan) , 4th edition experimental chemistry courses 17 and 18, published by Maruzen Co., Ltd.) and the like. Also in Group 9 element compounds other than iridium, for example, unsaturated hydrocarbons such as cyclopentene, dicyclopentadiene, cyclooctene, 1,5-cyclooctadiene, ethylene, pentamethylcyclopentadiene, benzene, toluene; acetonitrile, etc. Particularly preferred are organic complexes having ethers such as tetrahydrofuran as ligands.

  The group 9 element compound of the periodic table can be used as it is or in a form supported on a carrier. Examples of the carrier include conventional carriers for supporting a catalyst, for example, metal oxides such as silica, alumina, silica-alumina, zeolite, titania, and magnesia, and activated carbon. In the carrier-supported catalyst, the supported amount of the group 9 element compound of the periodic table is, for example, about 0.1 to 50% by weight, preferably about 1 to 20% by weight with respect to the carrier. The catalyst can be supported by a conventional method such as an impregnation method, a precipitation method, or an ion exchange method.

  The amount of the group 9 element compound in the periodic table can be appropriately selected depending on the type of raw material, the type of catalyst, and the like, but in general, for example, 0 parts per mole of the smaller component of the carbonyl compound and amino alcohol used as the raw material. 0.0001 to 1 mol, preferably 0.001 to 0.3 mol, more preferably about 0.005 to 0.1 mol.

  In the present invention, Group 9 element compounds of the periodic table such as organic complexes can be used in combination with an appropriate ligand. Examples of the ligand include a phosphorus atom-containing ligand, an oxygen atom-containing ligand, a nitrogen atom-containing ligand, and a carbon-carbon double bond-containing ligand. As the ligand, a phosphorus atom-containing ligand can be suitably used. Examples of the phosphorus atom-containing ligand include monocycloalkyl ligands such as tricycloalkylphosphine such as tricyclohexylphosphine, trialkylphosphine such as trimethylphosphine and tributylphosphine, and triarylphosphine such as triphenylphosphine; -Bis (diarylphosphino) ethane, 1,3-bis (diphenylphosphino) propane, 1,4-bis (diphenylphosphino) butane, 2,3-bis (diphenylphosphino) butane, etc. (Fino) bidentate ligands such as alkanes.

  The amount of the ligand used can be appropriately selected within the range that does not inhibit the reaction, but generally it is about 0.5 to 10 mol, preferably 1 to 5 mol, relative to 1 mol of the group 9 element compound of the periodic table. Degree.

  Moreover, the usage-amount of a ligand is about 0.001-1 mol with respect to 1 mol of the components (especially carbonyl compound) of the carbonyl compound used as a raw material, and an amino alcohol, for example, Preferably it is 0.005. You may select from the range of about -0.3 mol, More preferably, about 0.01-0.1 mol.

[base]
In the present invention, a base is used together with the group 9 element compound of the periodic table. The base may be any of an inorganic base, an organic base, a Lewis base and the like, and a base usually used for aldol condensation is preferable.

  Examples of the inorganic base include alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide, and cesium hydroxide; alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, and cesium carbonate; hydrogen carbonate Alkali metal hydrogen carbonates such as sodium, potassium hydrogen carbonate and cesium hydrogen carbonate; Alkaline earth metal hydroxides such as magnesium hydroxide, calcium hydroxide and barium hydroxide; Alkaline earth such as magnesium carbonate, calcium carbonate and barium carbonate Metal group carbonates; Group 3 element compounds of periodic table such as cerium carbonate (for example, carbonates) and the like.

  Examples of the organic base include alkali metal alkoxides such as sodium methoxide and sodium ethoxide; alkali metal organic acid salts such as sodium acetate; amines such as triethylamine, piperidine, N-methylpiperidine and pyridine (tertiary amine and the like) And nitrogen-containing heterocyclic compounds.

  Among these, in particular, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal carbonates such as sodium carbonate and cesium carbonate, alkali metal hydrogen carbonates such as sodium hydrogen carbonate, alkali metal alkoxides and alkali metals Alkali metal element-containing bases such as organic acid salts are preferred.

  The amount of base added varies depending on the type of raw material and the Group 9 element compound of the periodic table, etc., but is usually 0 with respect to 1 mol of the smaller component (particularly carbonyl compound) of the carbonyl compound and amino alcohol used as the raw material. About 0.01 to 0.5 mol, preferably about 0.05 to 0.3 mol.

[Carbonyl compound]
In the carbonyl compound represented by the formula (1), R ¹ , R ² and Y each represent a hydrogen atom or an organic group. The organic group may be a group that does not inhibit this reaction (for example, a group that is non-reactive under the reaction conditions in the present method), such as a halogen atom (fluorine, chlorine, bromine, iodine atom), carbonization, etc. Hydrogen group, heterocyclic group, substituted oxycarbonyl group (alkoxycarbonyl group, aryloxycarbonyl group, aralkyloxycarbonyl group, cycloalkyloxycarbonyl group, etc.), carboxyl group, substituted or unsubstituted carbamoyl group, cyano group, nitro group , Sulfur acid groups, sulfur acid ester groups, acyl groups (aliphatic acyl groups such as acetyl groups; aromatic acyl groups such as benzoyl groups), substituted oxy groups (C _1-6 alkoxy groups such as methoxy groups and ethoxy groups) alkoxy groups such as; vinyloxy group, alkenyloxy groups such as C _2-6 alkenyloxy groups such as allyloxy group; Shi A cycloalkyloxy group such as a cyclohexyloxy group; an aryloxy group such as a phenoxy group; an aralkyloxy group such as a benzyloxy group; an acyloxy group such as an acetoxy group), a hydroxyl group, a substituted or unsubstituted amino group (amino group; Mono- or di-C _1-6 alkyl-substituted amino groups such as N-methylamino group and N, N-dimethylamino group; cyclic amino groups such as 1-pyrrolidinyl group, piperidino group and morpholino group), etc. Examples include a bonded group. The carboxyl group, hydroxyl group, amino group and the like may be protected by a known or commonly used protecting group in the field of organic synthesis, and may be substituted with a metal.

  The hydrocarbon group and the heterocyclic group also include a hydrocarbon group and a heterocyclic group having a substituent. The hydrocarbon group includes an aliphatic hydrocarbon group, an alicyclic hydrocarbon group, an aromatic hydrocarbon group, and a group in which these are bonded. Examples of the aliphatic hydrocarbon group include 1 to 20 carbon atoms (preferably 1 to 1) such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, hexyl, decyl, and dodecyl groups. 10, more preferably an alkyl group of about 1 to 3); an alkenyl group of about 2 to 20 carbon atoms (preferably 2 to 10, more preferably 2 to 3) such as vinyl, allyl, 1-butenyl group; Examples thereof include alkynyl groups having about 2 to 20 carbon atoms (preferably 2 to 10, more preferably 2 to 3) such as propynyl groups.

As the alicyclic hydrocarbon group, a cycloalkyl group having about 3 to 20 members (preferably 3 to 15 members, more preferably 5 to 8 members) such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cyclooctyl groups; Cycloalkenyl groups of about 3 to 20 members (preferably 3 to 15 members, more preferably 5 to 8 members) such as pentenyl and cyclohexenyl groups; perhydronaphthalen-1-yl group, norbornyl, adamantyl, tetracyclo [4 4.0.1, ^2,5 . 1 ^7,10 ] bridged cyclic hydrocarbon groups such as dodecan-3-yl groups. Examples of the aromatic hydrocarbon group include aromatic hydrocarbon groups having about 6 to 14 (preferably 6 to 10) carbon atoms such as phenyl and naphthyl groups.

The hydrocarbon group in which an aliphatic hydrocarbon group and an alicyclic hydrocarbon group are bonded includes a cycloalkyl-alkyl group such as cyclopentylmethyl, cyclohexylmethyl, 2-cyclohexylethyl group (for example, C _3-20 cycloalkyl- C _1-4 alkyl group and the like). The hydrocarbon group in which an aliphatic hydrocarbon group and an aromatic hydrocarbon group are bonded to each other includes an aralkyl group (for example, a C _7-18 aralkyl group) and an alkyl-substituted aryl group (for example, about 1 to about 4). A phenyl group substituted with a C _1-4 alkyl group or a naphthyl group).

Preferred hydrocarbon groups include C _1-10 alkyl groups, C _2-10 alkenyl groups, C _2-10 alkynyl groups, C _3-15 cycloalkyl groups, C _6-10 aromatic hydrocarbon groups, C _3-15 A cycloalkyl-C _1-4 alkyl group, a C _7-14 aralkyl group and the like are included.

  The hydrocarbon group includes various substituents such as halogen atoms, oxo groups, hydroxyl groups, substituted oxy groups (for example, alkoxy groups, aryloxy groups, aralkyloxy groups, acyloxy groups, etc.), carboxyl groups, substituted oxycarbonyls. Group (alkoxycarbonyl group, aryloxycarbonyl group, aralkyloxycarbonyl group, etc.), substituted or unsubstituted carbamoyl group, cyano group, nitro group, substituted or unsubstituted amino group, sulfo group, heterocyclic group, etc. May be. The hydroxyl group and carboxyl group may be protected with a protective group commonly used in the field of organic synthesis. In addition, an aromatic or non-aromatic heterocycle may be condensed with the ring of the alicyclic hydrocarbon group or aromatic hydrocarbon group.

The heterocyclic ring constituting the heterocyclic group in R ^{1 and the} like includes an aromatic heterocyclic ring and a non-aromatic heterocyclic ring. Examples of such a heterocyclic ring include a heterocyclic ring containing an oxygen atom as a hetero atom (for example, 5-membered ring such as furan, tetrahydrofuran, oxazole, isoxazole, and γ-butyrolactone ring, 4-oxo-4H-pyran, tetrahydro 6-membered ring such as pyran, morpholine ring, condensed ring such as benzofuran, isobenzofuran, 4-oxo-4H-chromene, chroman, isochroman ring, 3-oxatricyclo [4.3.1.1 ^4,8 ] undecane 2-one ring, a bridged ring such as 3-oxatricyclo [4.2.1.0 ^4,8 ] nonan-2-one ring), a heterocycle containing a sulfur atom as a hetero atom (for example, thiophene, 5-membered ring such as thiazole, isothiazole, thiadiazole ring, 6-membered ring such as 4-oxo-4H-thiopyran ring, benzothiophene ring Any fused ring), heterocycles containing nitrogen atoms as heteroatoms (eg, 5-membered rings such as pyrrole, pyrrolidine, pyrazole, imidazole, triazole rings, 6-membered rings such as pyridine, pyridazine, pyrimidine, pyrazine, piperidine, piperazine rings) Ring, indole, indoline, quinoline, acridine, naphthyridine, quinazoline, a condensed ring such as a purine ring, etc.). In addition to the substituents that the hydrocarbon group may have, the heterocyclic group includes an alkyl group (eg, a C _1-4 alkyl group such as a methyl or ethyl group), a cycloalkyl group, an aryl group It may have a substituent such as (for example, phenyl, naphthyl group).

In the formula (1), at least two of R ¹ , R ² and Y may be bonded to each other to form a ring with adjacent 1 or 2 carbon atoms. Examples of such a ring include a hydrocarbon ring and a heterocyclic ring. Examples of the hydrocarbon ring include cyclopropane rings, cyclobutane rings, cyclopentane rings, cyclohexane rings, cycloheptane rings, cyclooctane rings, cyclodecane rings, cyclododecane rings and the like, and cyclopentene rings. And a cycloalkene ring having about 3 to 20 members such as a cyclohexene ring; a bridged hydrocarbon ring such as an adamantane ring, a norbornane ring and a norbornene ring. Examples of the heterocycle include a perhydroazole ring, a perhydroazine ring, a perhydroazepine ring, an oxolane ring, an oxane ring, an oxepane ring, a thiolane ring, a thiane ring, a thiene ring, and a 4- to 20-membered heterocycle (nitrogen atom, oxygen Heterocycles containing at least one heteroatom selected from atoms and sulfur atoms).

Preferred R ¹ includes a hydrogen atom and a hydrocarbon group (eg, C _1-10 alkyl group, C _2-10 alkenyl group, C _2-10 alkynyl group, C _3-15 cycloalkyl group, C _6-10 aromatic group) Hydrocarbon group, C _3-12 cycloalkyl-C _1-4 alkyl group, C _7-14 aralkyl group, etc.). R ¹ is particularly preferably a hydrogen atom.

Preferred R ² includes a hydrogen atom, a hydrocarbon group (for example, a C _1-10 alkyl group, a C _2-10 alkenyl group, a C _2-10 alkynyl group, a C _3-15 cycloalkyl group, a C _6-10 aromatic group). Hydrocarbon group, C _3-12 cycloalkyl-C _1-4 alkyl group, C _7-14 aralkyl group, etc.), substituted oxycarbonyl group (C _1-6 alkoxy-carbonyl group, C _6-14 aryloxy-carbonyl group) C _7-15 aralkyloxycarbonyl group, 3-8 membered cycloalkyloxycarbonyl group, etc.).

Preferred Y is a hydrogen atom, a hydrocarbon group (for example, a C _1-10 alkyl group, a C _2-10 alkenyl group, a C _2-10 alkynyl group, a C _3-15 cycloalkyl group, a C _6-10 aromatic carbonization). A hydrogen group, a C _3-12 cycloalkyl-C _1-4 alkyl group, a C _7-14 aralkyl group, etc.), a substituted oxy group (for example, an alkoxy group such as a C _1-6 alkoxy group, a C _2-6 alkenyloxy group) Alkenyloxy groups such as 3- to 8-membered cycloalkyloxy groups, C _6-14 aryloxy groups, C _7-15 aralkyloxy groups, etc., substituted amino groups (mono or di C _1-6 alkyl substituted amino groups; Cyclic amino group) and the like.

It is also preferred that R ² and Y together with two adjacent carbon atoms form a 3-20 membered hydrocarbon ring or a 4-20 membered heterocyclic ring.

  The carbonyl compound represented by the formula (1) is particularly preferably a ketone (chain ketone, cyclic ketone, β-ketoester, etc.), aldehyde, ester, lactone, amide or lactam.

  Among the carbonyl compounds represented by the formula (1), typical examples of ketones include acetone, ethyl methyl ketone, 3-methyl-2-butanone, 3,3-dimethyl-2-butanone, 2-pentanone, 3 -Pentanone, 4-methyl-2-pentanone, 3-methyl-2-pentanone, 2-hexanone, 4-heptanone, 2-octanone, 3-octanone, 2-nonanone, 5-nonanone, 2-decanone, 2-dodecanone Chain ketones such as cyclohexyl methyl ketone, 3-phenyl-2-propanone, 4-phenyl-2-butanone, acetophenone, propiophenone, acetylacetone; cyclopentanone, cyclohexanone, 2-methylcyclohexanone, cyclooctanone, etc. 5-15 membered cyclic ketone; methyl acetoacetate, ethyl acetoacetate , Β-ketoesters such as propylacetoacetate, phenylacetoacetate, ethyl propionylacetate, ethyl benzoylacetate, methyl cyclopentanone-2-carboxylate; pyruvate (methyl pyruvate, ethyl pyruvate, etc.), 2-oxosuccinic acid Examples include α-ketoesters such as dimethyl.

  Among the carbonyl compounds represented by the formula (1), typical examples of aldehydes include acetaldehyde, propanal, butanal, pentanal, decanal, 2-methylpropanal, 2-methylbutanal, 2-phenylacetaldehyde, 3 -Phenylpropanal and the like.

  Among the carbonyl compounds represented by the formula (1), typical examples of esters include methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, t-butyl acetate, vinyl acetate, allyl acetate, Phenyl acetate, methyl propionate, ethyl propionate, methyl butanoate, ethyl butanoate, ethyl pentanoate, ethyl hexanoate, ethyl heptanoate, ethyl octanoate, ethyl decanoate, methyl phenylacetate, ethyl phenylacetate, 3-phenylpropiate Examples include ethyl onate, ethyl cyclohexane acid, dimethyl malonate, and diethyl malonate. Among these, esters of aliphatic carboxylic acids having about 2 to 10 carbon atoms such as acetates and propionates, phenylacetates such as ethyl phenylacetate, and malonates such as diethyl malonate are particularly preferable.

  Among carbonyl compounds represented by the formula (1), typical examples of lactones include 5- to 16-membered compounds such as γ-butyrolactone, γ, γ-dimethyl-γ-butyrolactone, δ-valerolactone, and ε-caprolactone. Examples include lactones.

  Among the carbonyl compounds represented by the formula (1), typical examples of amides include N, N-dimethylacetamide, N, N-dimethylpropionamide, 1-acetylpyrrolidine, 1-acetylpiperidine and the like.

  Among the carbonyl compounds represented by the formula (1), typical examples of lactam include N-methyl-α-pyrrolidone and N-methyl-α-pyridone.

[Amino alcohol]
In the amino alcohol represented by the formula (2), A represents a divalent organic group, and R ³ represents a hydrogen atom or an organic group. A and R ³ may be bonded to each other to form a ring together with adjacent carbon atoms. The amino alcohol represented by the formula (2) is a primary alcohol or a secondary alcohol as an alcohol, and a primary amine as an amine.

The divalent organic group in A may be any group that does not inhibit this reaction (for example, a non-reactive group under the reaction conditions in this method). For example, a divalent aliphatic hydrocarbon group Examples thereof include a divalent alicyclic hydrocarbon group, a divalent aromatic hydrocarbon group, a divalent heterocyclic group, and a group in which two or more of these are bonded. As the divalent aliphatic hydrocarbon group, for example, a straight chain such as methylene, methylmethylene, dimethylmethylene, ethylene, methylethylene, propylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, octamethylene, nonamethylene, decamethylene Or a branched alkylene group (eg, a C _1-20 alkylene group, preferably a C _1-10 alkylene group, more preferably a C _1-4 alkylene group); a linear or branched chain such as vinylene or propynylene. And alkenylene groups (for example, C _2-20 alkenylene groups, preferably C _2-10 alkenylene groups, more preferably C _2-4 alkenylene groups).

  Examples of the divalent alicyclic hydrocarbon group include 3 to 20 members (preferably 3 to 10 members) such as cyclopentylidene, cyclohexylidene, 1,2-cyclopentylene, and 1,2-cyclohexylene groups. And more preferably a divalent alicyclic hydrocarbon group of about 5 to 6 members). Examples of the divalent aromatic hydrocarbon group (arylene group) include o-phenylene, 1,2-naphthylene, and 3,4-naphthylene group. Examples of the divalent heterocyclic group include nitrogen atoms such as pyridine-2,3-diyl, pyridine-3,4-diyl, furan-2,3-diyl, and thiophene-2,3-diyl groups, oxygen Examples thereof include a divalent heterocyclic group having a 3 to 15 membered heterocyclic ring containing at least one heteroatom selected from an atom and a sulfur atom.

Examples of the group in which two or more divalent aliphatic hydrocarbon groups, divalent alicyclic hydrocarbon groups, divalent aromatic hydrocarbon groups, or divalent heterocyclic groups are bonded include —CH ₂ —. Ph- (Ph represents a phenylene group) and the like.

Preferred examples of A include linear or branched C _1-4 alkylene groups such as methylene and ethylene groups, linear or branched C _2-4 alkenylene groups such as vinylene groups, and cyclohexylidene groups. About 3 to 10-membered cycloalkylidene group, about 3 to 10-membered 1,2-cycloalkylene group such as 1,2-cyclohexylene group, 1,2-arylene group such as o-phenylene group, pyridine-2 , 3-diyl groups and the like having a heterocyclic group having two bonds at adjacent positions (for example, a 3-15 membered heterocyclic ring containing at least one heteroatom selected from a nitrogen atom, an oxygen atom and a sulfur atom) And a group in which 2 to 3 of these are bonded.

The divalent aliphatic hydrocarbon group, alicyclic hydrocarbon group, aromatic hydrocarbon group, and heterocyclic group include those having a substituent. The substituent is not particularly limited as long as it does not inhibit the reaction, and examples thereof include the same substituents that the hydrocarbon group and heterocyclic group in R ¹ and the like may have.

The organic group in R ³ may be any group that does not inhibit this reaction (for example, a group that is non-reactive under the reaction conditions in the present method). For example, the same organic group as in R ¹ above Can be illustrated. Typical organic groups include hydrocarbon groups, heterocyclic groups, and the like. Examples of the hydrocarbon group and heterocyclic group are the same as the hydrocarbon group and heterocyclic group in R ¹ and the like. The hydrocarbon group and heterocyclic group also include a hydrocarbon group having a substituent and a heterocyclic group (including a case where a ring is condensed to these). The substituent is not particularly limited as long as it does not inhibit the reaction, and examples thereof include the same substituents that the hydrocarbon group and heterocyclic group in R ¹ and the like may have.

The ring formed by A and R ³ bonded to each other with an adjacent carbon atom is a ring formed with at least two of R ¹ , R ² and Y bonded to each other with one or two adjacent carbon atoms The same thing is illustrated.

Preferred R ³ is a hydrogen atom, a hydrocarbon group (for example, a C _1-10 alkyl group, a C _2-10 alkenyl group, a C _2-10 alkynyl group, a C _3-15 cycloalkyl group, a C _6-10 aromatic group). A hydrocarbon group, a C _3-12 cycloalkyl-C _1-4 alkyl group, a C _7-14 aralkyl group, etc.), a heterocyclic group (eg, at least one hetero selected from a nitrogen atom, an oxygen atom and a sulfur atom) Heterocyclic groups having about 3 to 15-membered heterocycles containing atoms) and the like. It is also preferred that A and R ³ together with adjacent carbon atoms form a 3-20 membered hydrocarbon ring or a 4-20 membered heterocyclic ring.

  Representative examples of the amino alcohol represented by the formula (2) include 2-aminoethanol (ethanolamine), 3-aminopropanol, 3-amino-2-methylpropanol, 4-aminobutanol, 6-aminohexanol and the like. Aliphatic alcohols such as 1-amino-1-hydroxymethylcyclohexane, 1-amino-2-hydroxymethylcyclohexane and the like; o-aminobenzyl alcohol, 2-amino-3-methylphenylmethyl alcohol, Aromatic amino alcohols such as 2-amino-4-methylphenylmethyl alcohol, 2-amino-5-methylphenylmethyl alcohol, 2-amino-6-methylphenylmethyl alcohol, o- (aminomethyl) benzyl alcohol, 2- Amino-3- (hydride Kishimechiru) and heterocyclic amino alcohols, such as pyridine.

[reaction]
The reaction of the carbonyl compound represented by the formula (1) and the amino alcohol represented by the formula (2) is performed in the presence or absence of a solvent. Examples of the solvent include aliphatic hydrocarbons such as hexane, heptane, and octane; alicyclic hydrocarbons such as cyclohexane; aromatic hydrocarbons such as benzene, toluene, xylene, and ethylbenzene; chloroform, dichloromethane, 1,2- Halogenated hydrocarbons such as dichloroethane; ethers such as diethyl ether, dimethoxyethane, tetrahydrofuran and dioxane; esters such as methyl acetate, ethyl acetate, isopropyl acetate and butyl acetate; N, N-dimethylformamide, N, N-dimethylacetamide and the like And nitriles such as acetonitrile, propionitrile, and benzonitrile. These solvents are used alone or in admixture of two or more.

  The ratio of the carbonyl compound represented by the formula (1) and the amino alcohol represented by the formula (2) can be appropriately selected in consideration of the reactivity, the raw material cost and the like. Usually, the usage-amount of the amino alcohol represented by Formula (2) is about 0.1-100 mol with respect to 1 mol of carbonyl compounds represented by Formula (1), Preferably it is about 0.2-10 mol. More preferably, it is about 0.3 to 5 mol.

A small amount of aminocarbonyl compound [R ³ —C (═O) —A—NH ₂ ] (aminoketone or aminoaldehyde) corresponding to the amino alcohol represented by the formula (2) may be added to the reaction system. . The reaction rate may be improved by adding the aminocarbonyl compound.

  The reaction may be performed in the presence of a polymerization inhibitor. When a hydrogen acceptor such as benzophenone is added to the reaction system, the yield of the target compound may be improved. The reaction temperature can be appropriately selected according to the reaction components and the type of catalyst, and is, for example, about 20 to 200 ° C, preferably about 50 to 150 ° C, and more preferably about 70 to 120 ° C. The reaction may be carried out at normal pressure or under reduced pressure or increased pressure. The atmosphere of the reaction is not particularly limited as long as the reaction is not inhibited, and may be any of an air atmosphere, a nitrogen atmosphere, an argon atmosphere, and the like. Further, the reaction can be carried out by any method such as batch, semi-batch and continuous methods.

In the method of the present invention, a compound represented by the formula (3a), (3b) or (3c), or a compound in which the nitrogen-containing ring in the compound is dehydrogenated (such as an aromatic cyclized compound) by the reaction. ) And other nitrogen-containing cyclic compounds. In the formula, A, R ¹ , R ² , R ³ and Y are the same as described above. At least two of R ¹ , R ² and Y may be bonded to each other to form a ring with adjacent 1 or 2 carbon atoms. A and R ³ may be bonded to each other to form a ring together with adjacent carbon atoms. In the amino alcohol represented by the formula (2) used as a reaction raw material, when the number of carbon atoms between the amino group and the hydroxyl group is 2, for example, a compound containing a 5-membered nitrogen-containing ring (pyrrole derivative, oxazolidine derivative, etc.) ), But when the number of carbon atoms between the amino group and the hydroxyl group is 3, compounds containing a 6-membered nitrogen-containing ring (pyridine derivatives, tetrahydropyridine derivatives, quinoline derivatives, perhydrooxazine derivatives, etc.) are usually produced. .

Although the reaction mechanism is not necessarily clear, the above-mentioned nitrogen-containing compounds are combined with a reaction such as an oxidative dehydrogenation reaction, an aldol-type condensation reaction, a dehydration condensation reaction (iminization reaction) between a carbonyl group and an amino group, or a hydrogenation reaction. It is considered that a cyclic compound is formed. More specifically, acetophenone [compound represented by formula (4)] is used as the carbonyl compound represented by formula (1), and 3-amino-1-propanol is used as the amino alcohol represented by formula (2). When [compound represented by formula (5)] is used, it is presumed that the reaction proceeds by a mechanism such as the following formula. In this case, 2-phenylpyridine represented by the formula (6), 6-phenyl-2,3,4,5-tetrahydropyridine represented by the formula (7), perhydroform represented by the formula (8) 2-methyl-2-phenyl-1,3-oxazine, 1-phenyl-2- (6-phenyl-2,3,4,5-tetrahydropyridin-4-yl) ethanone represented by formula (9) Produces. The production ratio of these products can be adjusted by appropriately selecting each reaction condition.

  After completion of the reaction, the reaction product can be separated and purified by separation means such as filtration, concentration, distillation, extraction, crystallization, recrystallization, column chromatography, etc., or a separation means combining these.

  The nitrogen-containing cyclic compound obtained by the method of the present invention can be used as, for example, a physiologically active compound or a synthetic intermediate thereof.

  Hereinafter, the present invention will be described in more detail based on examples, but the present invention is not limited to these examples. In addition, the use ratio (mol%) and yield (%) of each raw material are all values based on the amino alcohol used in the reaction.

Example 1
To the reactor, 2 mmol of o-aminobenzyl alcohol, 4 mmol of acetophenone, di-μ-chlorobis (1,5-cyclooctadiene) diiridium (I) [IrCl (cod)] ₂ (1 mol%), potassium hydroxide (10 mol) %) And triphenylphosphine (4 mol%) were added, and the reaction was performed at 100 ° C. for 3 hours in a nitrogen atmosphere. When the reaction solution was analyzed by gas chromatography after the reaction, 2-phenylquinoline was produced in a yield of 91%.

Example 2
When the same operation as in Example 1 was performed except that triphenylphosphine was not used, 2-phenylquinoline was produced in a yield of 23%.

Example 3
The reaction was conducted in the same manner as in Example 1 except that 4 mol% of diphenylphosphinopropane (dppp) was used instead of triphenylphosphine. When the reaction solution was analyzed by gas chromatography after the reaction, 2-phenylquinoline was produced in a yield of 88%.

Example 4
The reaction was performed in the same manner as in Example 1 except that 2 mmol of acetophenone was used. When the reaction solution was analyzed by gas chromatography after the reaction, 2-phenylquinoline was produced in a yield of 49%.

Example 5
The reaction was performed in the same manner as in Example 1 except that benzophenone was added as a hydrogen acceptor in 3 mmol system. When the reaction solution was analyzed by gas chromatography after the reaction, 2-phenylquinoline was produced in a yield of 93%.

Example 6
To the reactor, 2 mmol of o-aminobenzyl alcohol, 4 mmol of cyclohexanone, di-μ-chlorobis (1,5-cyclooctadiene) diiridium (I) [IrCl (cod)] ₂ (1 mol%), potassium hydroxide (10 mol) %) And triphenylphosphine (4 mol%) were added, and the reaction was performed at 100 ° C. for 4 hours in a nitrogen atmosphere. When the reaction solution was analyzed by gas chromatography after the reaction, 1,2,3,4-tetrahydroacridine was produced in a yield of 82%.

Example 7
The reaction was performed in the same manner as in Example 6 except that 2-octanone was used instead of cyclohexanone. When the reaction solution was analyzed by gas chromatography after the reaction, 2-hexylquinoline was produced in a yield of 72% and 3-hexylquinoline in a yield of 25%. Further, 9-methyl-7-pentadecanone was by-produced at 1% or less.

Example 8
In a reactor, 3-amino-1-propanol 2 mmol, acetophenone 6 mmol, di-μ-chlorobis (1,5-cyclooctadiene) diiridium (I) [IrCl (cod)] ₂ (1 mol%), potassium hydroxide (10 mol%) and triphenylphosphine (4 mol%) were added, and the reaction was performed at 100 ° C. for 4 hours in a nitrogen atmosphere. After the reaction, the reaction solution was analyzed by gas chromatography. As a result, 32% 2-phenylpyridine, 8% 6-phenyl-2,3,4,5-tetrahydropyridine, perhydro-2-methyl-2-phenyl- 1,3-Oxazine was produced in a yield of 5%, and 1-phenyl-2- (6-phenyl-2,3,4,5-tetrahydropyridin-4-yl) ethanone was produced in a yield of 12%.

Example 9
The reaction was conducted in the same manner as in Example 8 except that 1 ml of dioxane was added as a reaction solvent. After the reaction, the reaction solution was analyzed by gas chromatography. As a result, 18% 2-phenylpyridine, 10% 6-phenyl-2,3,4,5-tetrahydropyridine, perhydro-2-methyl-2-phenyl- 1,3-Oxazine was produced in 19%, and 1-phenyl-2- (6-phenyl-2,3,4,5-tetrahydropyridin-4-yl) ethanone was produced in a yield of 18%.

Example 10
In a reactor, 3-amino-1-propanol 2 mmol, acetophenone 6 mmol, di-μ-chlorobis (1,5-cyclooctadiene) diiridium (I) [IrCl (cod)] ₂ (1.3 mol%), water Potassium oxide (13 mol%) and triphenylphosphine (5.2 mol%) were added, and the reaction was performed at 100 ° C. for 4 hours in a nitrogen atmosphere. After the reaction, the reaction solution was analyzed by gas chromatography. As a result, 39% 2-phenylpyridine, 28% 6-phenyl-2,3,4,5-tetrahydropyridine, perhydro-2-methyl-2-phenyl- 1,3-Oxazine was produced in a yield of 1%, and 1-phenyl-2- (6-phenyl-2,3,4,5-tetrahydropyridin-4-yl) ethanone was produced in a yield of 2%.

Example 11
In a reactor, ethanolamine 2 mmol, acetophenone 4 mmol, di-μ-chlorobis (1,5-cyclooctadiene) diiridium (I) [IrCl (cod)] ₂ (1 mol%), potassium hydroxide (10 mol%), Triphenylphosphine (4 mol%) was added, and the reaction was performed at 100 ° C. for 3 hours in a nitrogen atmosphere. When the reaction solution was analyzed by gas chromatography after the reaction, 2-phenylpyrrole was produced in a yield of 25% and 2-methyl-2-phenyloxazolidine in a yield of 37%.

Example 12
To the reactor, 1 mmol of 1-amino-2-propanol, 4 mmol of propiophenone, di-μ-chlorobis (1,5-cyclooctadiene) diiridium (I) [IrCl (cod)] ₂ (1.3 mol%) Potassium hydroxide (13 mol%) and triphenylphosphine (5.2 mol%) were added, and the reaction was performed at 100 ° C. for 3 hours in a nitrogen atmosphere. When the reaction solution was analyzed by gas chromatography after the reaction, 3,4-dimethyl-2-phenyl-1H-pyrrole was produced in a yield of 49%.

Example 13
To the reactor, ethanolamine 2 mmol, propiophenone 4 mmol, di-μ-chlorobis (1,5-cyclooctadiene) diiridium (I) [IrCl (cod)] ₂ (1.3 mol%), potassium hydroxide ( 13 mol%) and triphenylphosphine (5.2 mol%) were added, and the reaction was performed at 100 ° C. for 3 hours in a nitrogen atmosphere. When the reaction solution was analyzed by gas chromatography after the reaction, 3-methyl-2-phenyl-1H-pyrrole was produced in a yield of 45%.

Example 14
In a reactor, 2 mmol of o-aminobenzyl alcohol, 4 mmol of methyl pyruvate, di-μ-chlorobis (1,5-cyclooctadiene) diiridium (I) [IrCl (cod)] ₂ (1.3 mol%), water Potassium oxide (13 mol%) and triphenylphosphine (5.2 mol%) were added, and the reaction was performed at 100 ° C. for 3 hours in a nitrogen atmosphere. When the reaction solution was analyzed by gas chromatography after the reaction, methyl quinoline-2-carboxylate was produced in a yield of 68%.

Claims (5)

In the presence of a group 9 element compound of the periodic table and a base, the following formula (1)

(In the formula, R ¹ , R ² and Y are the same or different and each represents a hydrogen atom or an organic group. At least two of R ¹ , R ² and Y are bonded to each other and adjacent to one or two carbon atoms. (It may form a ring with atoms)
And a carbonyl compound represented by the following formula (2)

(In the formula, A represents a divalent organic group, R ³ represents a hydrogen atom or an organic group. A and R ³ may be bonded to each other to form a ring with an adjacent carbon atom)
A method for producing a nitrogen-containing cyclic compound, which comprises reacting with an amino alcohol represented by the formula:   The method for producing a nitrogen-containing cyclic compound according to claim 1, wherein the carbonyl compound represented by the formula (1) is a ketone, aldehyde, ester, lactone, amide or lactam.   2. The divalent organic group in A is a divalent aliphatic hydrocarbon group, alicyclic hydrocarbon group, aromatic hydrocarbon group or heterocyclic group, or a group in which two or more of these are bonded. Of producing a nitrogen-containing cyclic compound. The nitrogen-containing cyclic compound is represented by the following formula (3a), (3b) or (3c)

(In the formula, A represents a divalent organic group, R ¹ , R ² and Y are the same or different and represent a hydrogen atom or an organic group. At least two of R ¹ , R ² and Y are bonded to each other. R ³ may be a hydrogen atom or an organic group, and A and R ³ may be bonded to each other to form a ring together with the adjacent carbon atoms. May be)
The method for producing a nitrogen-containing cyclic compound according to claim 1, wherein the compound is represented by the formula: or a compound in which the nitrogen-containing ring in the compound is dehydrogenated. The method for producing a nitrogen-containing cyclic compound according to claim 4, wherein the nitrogen-containing cyclic compound is a pyridine derivative or a quinoline derivative.