JPH11106377A - Oxidation of heterocyclic compound and production of heterocyclic carboxylic acid or heterocyclic ketone - Google Patents

Abstract

PROBLEM TO BE SOLVED: To efficiently produce the corresponding oxide from a heterocyclic compound by using an oxidation catalyst composed of a specific compound and a promoter. SOLUTION: A heterocyclic compound (e.g. 2,5-dimethylthiophene) is brought into contact with oxygen in the presence of an oxidation catalyst composed of an imide compound represented by the formula [R<1> and R<2> are each H, a halogen, an alkyl, an aryl or the like; X is O atom or hydroxyl; (n) is 1-3] (e.g. N-hydroxyophthalimide) and preferably a promoter (especially a transition metallic compound). The contact is preferably carried out in the presence of a protonic acid in a solvent such as acetic acid at 0-300 deg.C reactional temperature under atmospheric pressure or under an applied pressure for about 30 min to 48 hr.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a heterocyclic compound having a methyl group or a methylene group at a position adjacent to an aromatic heterocyclic ring or a non-aromatic heterocyclic compound, and a corresponding oxide (for example, heterocyclic carboxylic acid, Oxidation method useful for producing a heterocyclic ketone).

[0002]

2. Description of the Related Art Heterocyclic compounds having an oxygen atom, such as heterocyclic carboxylic acids and heterocyclic ketones, are used in medicines, flavors, dyes,
It is an important compound as an organic synthetic intermediate and a polymer resin raw material. As a method for producing a heterocyclic carboxylic acid or ketone, a method is known in which a heterocyclic compound having a side chain is oxidized with nitric acid, permanganate or dichromate.
For example, nicotinic acid is produced by oxidizing nicotine with nitric acid or oxidizing picoline with potassium permanganate. However, in the method using nitric acid, N
To treat ₂ O and NO _X , expensive exhaust gas treatment facilities are required. In addition, the method using permanganate or dichromate requires a large amount of expensive oxidizing agent, requires complicated post-treatment and metal recovery equipment, and is not economical. In addition, a method of producing a heterocyclic carboxylic acid or the like by subjecting a heterocyclic compound having a side chain to oxygen or air oxidation using a cobalt salt or a manganese salt as a catalyst is also known. However, this method requires a reaction at a relatively high temperature.

[0003]

SUMMARY OF THE INVENTION Accordingly, an object of the present invention is to provide a method for efficiently oxidizing a heterocyclic compound with oxygen.

Another object of the present invention is to oxidize an aromatic heterocyclic compound having a side chain or a non-aromatic heterocyclic compound with oxygen to efficiently produce a corresponding oxide. To provide a simple method. Still another object of the present invention is to provide a method capable of producing a corresponding heterocyclic carboxylic acid or ketone from an aromatic heterocyclic compound having a side chain with a simple operation in a good yield with oxygen under mild conditions. It is in.

[0005]

Means for Solving the Problems The present inventors have conducted intensive studies to achieve the above object, and as a result, have found that using an oxidation catalyst composed of an N-hydroxyphthalimide compound or an N-hydroxyphthalimide compound and a promoter. The present inventors have found that a corresponding oxide is efficiently produced from a heterocyclic compound and completed the present invention. That is, in the oxidation method of the present invention, the general formula (1)

[0006]

Embedded image (Wherein, R ¹ and R ² are the same or different and represent a hydrogen atom, a halogen atom, an alkyl group, an aryl group, a cycloalkyl group, a hydroxyl group, an alkoxy group, a carboxyl group, an alkoxycarbonyl group, an acyl group; R ¹
And R ² may combine with each other to form a double bond or an aromatic or non-aromatic ring. X represents an oxygen atom or a hydroxyl group, and n represents an integer of 1 to 3) in the presence of an oxidation catalyst composed of an imide compound represented by the following formula: The oxidation catalyst may be composed of an imide compound represented by the general formula (1) and a co-catalyst. The cocatalyst can be composed of a transition metal compound (for example, an oxide, an organic acid salt, an inorganic acid salt, a halide, an oxyacid or a salt thereof, a complex, and a heteropoly acid or a salt thereof). The heterocyclic compound includes a compound having an aromatic heterocyclic ring and having a methyl group or a methylene group at a position adjacent to the aromatic heterocyclic ring, a non-aromatic heterocyclic compound, and the like. The aromatic heterocyclic ring is, for example, an oxygen atom,
It contains 1 to 3 heteroatoms selected from a sulfur atom and a nitrogen atom. In the production method of the present invention, a heterocyclic compound having a methyl group or a methylene group at a position adjacent to an aromatic heterocyclic ring is brought into contact with oxygen in the presence of the oxidation catalyst to form a corresponding heterocyclic carboxylic acid or heterocyclic ketone. Is generated. In addition, in this specification, a "heterocyclic compound" may only be called a "substrate."

[0007]

BEST MODE FOR CARRYING OUT THE INVENTION

[Imide compound] In the compound represented by the general formula (1), a halogen atom among the substituents R ¹ and R ² includes:
Includes iodine, bromine, chlorine and fluorine. Examples of the alkyl group include a linear or branched chain having about C _1-10 such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, hexyl, heptyl, octyl, and decyl groups. Includes chain alkyl groups. Preferred alkyl groups include, for example, C
_{About 1-6} , especially about C _1-4 alkyl groups are exemplified.

The aryl group includes a phenyl group, a naphthyl group and the like, and the cycloalkyl group includes a cyclopentyl, cyclohexyl, cyclooctyl group and the like. Alkoxy groups include, for example, methoxy, ethoxy,
Propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, pentyloxy, hexyloxy groups and the like, about C _1-10 , preferably about C _1-6 , especially C _1-4
A degree of alkoxy groups are included.

The alkoxycarbonyl group includes, for example, an alkoxy moiety such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, t-butoxycarbonyl, pentyloxycarbonyl and hexyloxycarbonyl. _It contains about _1-10 alkoxycarbonyl groups. Preferred alkoxycarbonyl groups include those having an alkoxy moiety of about C _1-6 , especially about C _1-4 .

Examples of the acyl group include C _1-6 acyl groups such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, and pivaloyl groups.

The substituents R ¹ and R ² may be the same or different. In the general formula (1),
R ¹ and R ² may combine with each other to form a double bond or an aromatic or non-aromatic ring. Preferred aromatic or non-aromatic rings are 5 to 12 membered rings, especially 6 to 1
It is about a zero-membered ring, and may be a heterocyclic ring or a fused heterocyclic ring, but is often a hydrocarbon ring. Examples of such a ring include a non-aromatic alicyclic ring (a cycloalkene ring which may have a substituent such as a cyclohexane ring and a cycloalkene which may have a substituent such as a cyclohexene ring). Ring), a non-aromatic bridged ring (eg, a bridged hydrocarbon ring which may have a substituent such as a 5-norbornene ring), a benzene ring, a naphthalene ring or the like. And aromatic rings. The ring is often composed of an aromatic ring.

Preferred imide compounds include those represented by the following formula:

[0013]

Embedded image (Wherein, R ^{3 to} R ⁶ are the same or different and are each a hydrogen atom,
It represents an alkyl group, a hydroxyl group, an alkoxy group, a carboxyl group, an alkoxycarbonyl group, an acyl group, a nitro group, a cyano group, an amino group, and a halogen atom. R ¹ ,
R ² , X and n are the same as those described above. In the substituents R ^{3 to} R ⁶ , the alkyl group includes the same alkyl group as the above-described alkyl group, particularly an alkyl group having about C _1-6. the groups include the same alkoxy groups, especially C _1-4 about alkoxy groups, alkoxycarbonyl groups include the same alkoxycarbonyl groups, especially alkoxy moiety contains an alkoxycarbonyl group of about C _1-4 . Examples of the acyl group include the same acyl groups as described above, particularly, an acyl group of about C _{1-6, and} examples of the halogen atom include fluorine, chlorine, and bromine atoms. The substituents R ^{3 to} R ⁶ are usually a hydrogen atom, C
_It is often about _1-4 alkyl groups, carboxyl groups, nitro groups, and halogen atoms.

In the general formula (1), X represents an oxygen atom or a hydroxyl group, n is usually about 1 to 3,
Preferably it is 1 or 2. One or more compounds represented by the general formula (1) can be used in the oxidation reaction.

The acid anhydride corresponding to the imide compound represented by the general formula (1) includes, for example, saturated or unsaturated aliphatic dicarboxylic anhydrides such as succinic anhydride and maleic anhydride, and tetrahydrophthalic anhydride. And unsaturated non-aromatic cyclic polycarboxylic acids such as hexahydrophthalic anhydride (1,2-cyclohexanedicarboxylic anhydride) and 1,2,3,4-cyclohexanetetracarboxylic acid 1,2-anhydride Anhydrides (alicyclic polycarboxylic anhydrides), bridged cyclic polycarboxylic anhydrides such as hetic anhydride and hymic anhydride (alicyclic polycarboxylic anhydrides), phthalic anhydride, tetrabromo Phthalic anhydride, tetrachlorophthalic anhydride, nitrophthalic anhydride, trimellitic anhydride, methylcyclohexentricarboxylic anhydride, pyromellitic anhydride, none Mellitic acid, 1,8; 4,
Aromatic polycarboxylic anhydrides such as 5-naphthalenetetracarboxylic dianhydride are included. Preferred imide compounds include, for example, N-hydroxysuccinimide,
N-hydroxymaleimide, N-hydroxyhexahydrophthalimide, N, N'-dihydroxycyclohexanetetracarboxylic imide, N-hydroxyphthalimide, N-hydroxytetrabromophthalimide, N-hydroxytetrachlorophthalide Acid imide, N
-Hydroxyhetimide, N-hydroxyhymic imide, N-hydroxytrimellitic imide,
N, N'-dihydroxypyromellitic imide,
N'-dihydroxynaphthalenetetracarboxylic imide and the like. Particularly preferred compounds include N-hydroxyimide compounds derived from alicyclic polycarboxylic anhydrides, especially aromatic polycarboxylic anhydrides, such as N-hydroxyphthalimide.

The above imide compound is subjected to a conventional imidization reaction, for example, the corresponding acid anhydride and hydroxylamine N
It can be prepared by reacting with H ₂ OH to open the acid anhydride group and then closing the ring to imidize the ring.

[Co-catalyst] The catalyst may comprise an imide compound represented by the above formula (1) and a co-catalyst. The promoter includes a metal compound, for example, a Group 2A element of the periodic table (magnesium, calcium, strontium, barium, etc.),
Examples include transition metal compounds and compounds containing Group 3B elements of the periodic table (boron B, aluminum Al, etc.). The cocatalyst can be used alone or in combination of two or more.

Examples of the elements of the transition metal include Group 3A elements of the periodic table (for example, lanthanide elements such as lanthanum La, cerium Ce and samarium Sm, and actinoid elements such as actinoid Ac, in addition to scandium Sc and yttrium Y). Group 4A element (titanium Ti, zirconium Zr, hafnium Hf, etc.), group 5A element (vanadium V, niobium Nb, tantalum Ta, etc.), group 6A element (chromium Cr, molybdenum Mo, tungsten W, etc.), group 7A element (manganese) Mn, technetium Tc,
Group 8 elements (iron Fe, ruthenium R, etc.)
u, osmium Os, cobalt Co, rhodium Rh, iridium Ir, nickel Ni, palladium Pd, platinum P
t), group 1B elements (copper Cu, silver Ag, gold Au, etc.) and group 2B elements (zinc Zn, cadmium Cd, etc.).

Preferred elements constituting the cocatalyst include transition metal elements (for example, lanthanoid elements such as Ce, Group 3A elements such as actinoid elements, Group 4A elements such as Ti and Zr, V, Nb, etc.). Group 5A element, Cr, M
Group 6A elements such as o and W, and 7A such as Mn, Tc and Re
Group B elements such as Fe, Ru, Co, Rh, and Ni; Group 1B elements such as Cu); and Group 3B elements such as B. The oxidation number of the metal element constituting the co-catalyst is not particularly limited, and for example, 0, +2, +
3, +4, +5, +6, etc. As the cocatalyst, a divalent transition metal compound (for example, a divalent cobalt compound, a divalent manganese compound, or the like) is often used.

The co-catalyst may be a simple metal, a hydroxide or the like, but is usually a metal oxide containing the above-mentioned element (including a double oxide, an oxyacid or a salt thereof), an organic acid salt, and an inorganic acid. salt,
Halide, coordination compound (complex) containing the metal element
Or a polyacid (heteropolyacid or isopolyacid) or a salt thereof in many cases.

Examples of the boron compound include borohydride (eg, borane, diborane, tetraborane, pentaborane, decaborane, etc.), boric acid (eg, orthoboric acid, metaboric acid, tetraboric acid), borate (eg, , Nickel borate, magnesium borate, manganese borate, etc.), boron oxides such as B ₂ O ₃ , borazane,
Examples include nitrogen compounds such as borazene, borazine, boron amide, and boron imide, halides such as BF ₃ , BCl ₃ , and tetrafluoroborate, and borate esters (for example, methyl borate, phenyl borate, and the like).
Preferred boron compounds include boric acid such as borohydride and orthoboric acid or salts thereof, especially boric acid. One or more of these cocatalysts can be used.

The hydroxide includes, for example, Mn (OH)_Two ,
MnO (OH), Fe (OH)_Two, Fe (OH)_ThreeSuch
Is included. Metal oxides include, for example, Sm_TwoO_Three, T
iO _Two, ZrO_Two, V_TwoO_Three, V_TwoO_Five, CrO, Cr
_TwoO_Three, MoO_Three, MnO, Mn_Three O_Four , Mn_Two O_Three ,
MnO_Two , Mn_Two O₇ , FeO, Fe_TwoO_Three, Fe_Three O
_Four, RuO_Two, RuO_Four, CoO, CoO_Two, Co_TwoO
_Three, RhO_Two, Rh_Two O_Three, Cu_TwoO_ThreeEtc. are included,
As the double oxide or oxyacid salt, for example, MnAl_Two 
O_Four , MnTiO_Three , LaMnO_Three , K_Two Mn_Two O_Five ,
CaO xMnO_Two (X = 0.5,1,2,3,5),
Manganates [eg, Na_Three MnO _Four , Ba_Three [Mn
O_Four ]_Two Manganese (V) salts, such as K_Two MnO_Four , N
a_Two MnO_Four , BaMnO_Four Manganese (VI) acid such as
Salt, KMnO_Four , NaMnO_Four , LiMnO_Four , NH_Four 
MnO_Four , CsMnO_Four , AgMnO_Four , Ca (MnO
_Four)_Two , Zn (MnO_Four )_Two , Ba (MnO_Four )_Two , M
g (MnO_Four )_Two , Cd (MnO_Four )_Two Overmanga such as
Phosphate]. As the organic acid salt, for example, acetic acid
Cobalt, manganese acetate, cobalt propionate, pro
Manganese pionate, cobalt naphthenate, ma naphthenate
Ngan, cobalt stearate, manganese stearate
Such as C_2-20Fatty acid salts, manganese thiocyanate and the corresponding
Ce salt, Ti salt, Zr salt, V salt, Cr salt, Mo salt, F salt
e salt, Ru salt, Ni salt, Pd salt, Cu salt, Zn salt, etc.
Illustrative examples of inorganic acid salts include, for example, cobalt nitrate,
Nitric acid such as iron nitrate, manganese nitrate, nickel nitrate, copper nitrate
And corresponding sulfates, phosphates and carbonates
(For example, cobalt sulfate, iron sulfate, manganese sulfate, phosphorus
Cobaltate, iron phosphate, manganese phosphate, iron carbonate, carbonate
Manganese, iron perchlorate, etc.). Also halo
Examples of the genide include SmCl_Three, SmI_Two, T
iCl_Two, ZrCl_Two, ZrOCl_Two, VCl_Three, VO
Cl_Two, MnCl_Two , MnCl_Three , FeCl_Two, FeC
l_Three, RuCl_Three, CoCl_Two, RhCl_Two, RhCl
_Three, NiCl_Two, PdCl_Two, PtCl_Two, CuCl,
CuCl_TwoChlorides and the corresponding fluorides
, Bromide and iodide (eg, MnF_Two , MnBr
_Two , MnF_Three , FeF_Two, FeF _Three, FeBr_Two, Fe
Br_Three, FeI_Two, CuBr, CuBr_TwoEtc.)
Halide, M¹ MnCl_Three , M¹ _TwoMnCl_Four , M¹ _Two
MnCl_Five , M¹ _TwoMnCl ₆ (M¹ Represents a monovalent metal)
And the like.

The ligands forming the complex include alkoxy groups such as OH (hydroxo), methoxy, ethoxy, propoxy and butoxy groups, acyl groups such as acetyl and propionyl, and alkoxy groups such as methoxycarbonyl (acetato) and ethoxycarbonyl. Phosphorus such as carbonyl group, acetylacetonate, cyclopentadienyl group, halogen atom such as chlorine and bromine, CO, CN, oxygen atom, H ₂ O (aquo), phosphine (for example, triarylphosphine such as triphenylphosphine) Compound, NH
₃ (ammine), NO, NO ₂ (nitro), NO ₃ (nitrat), ethylenediamine, diethylenetriamine,
And nitrogen-containing compounds such as pyridine and phenanthroline. In the complex or complex salt, the same or different ligands may be coordinated by one kind or two or more kinds. The ligand is, for example, OH, an alkoxy group, an acyl group, an alkoxycarbonyl group, acetylacetonate, a halogen atom,
It is often a phosphorus compound such as CO, CN, H ₂ O (aquo), triphenylphosphine, or a nitrogen-containing compound including NH ₃ , NO ₂ , and NO ₃ .

The transition metal element and the ligand can be appropriately combined to form a complex. For example, an acetylacetonato complex (Ce, Sm, Ti, Zr, V, Cr, Mo,
Acetylacetonato complexes such as Mn, Fe, Ru, Co, Ni, Cu, and Zn, titanylacetylacetonato complexes TiO (AA) ₂ , zirconylacetylacetonato complexes ZrO (AA) ₂ , and vanadyl acetylacetonato complexes VO ( AA) ₂ ), cyano complexes (such as hexacyanomanganese (I) and hexacyanoferrate (II)), carbonyl complexes and cyclopentadienyl complexes (tricarbonylcyclopentadienylmanganese (I), biscyclopenta dienyl manganese (II), bis-cyclopentadienyl iron (II), Fe (CO) 5, Fe 2 (CO) 9, F
e ₃ (CO) ₁₂ ), nitrosyl compounds (Fe (N
O) ₄ , Fe (CO) ₂ (NO) ₂ ), thiocyanato complex (cobalt thiocyanate, manganese thiocyanate, iron thiocyanate, etc.), acetyl complex (cobalt acetate, manganese acetate, iron acetate, copper acetate, acetic acid) Zirconyl Z
rO (OAc) ₂ , titanyl acetate TiO (OAc) ₂ ,
Vanadyl acetate (VO (OAc) ₂ etc.).

Polyacids (isopolyacids and heteropolyacids)
For example, in many cases, the element is a group 5A or 6A element of the periodic table, for example, at least one of V (vanadic acid), Mo (molybdic acid) and W (tungstic acid). The central atom is not particularly limited. , Be, B, Al, S
i, Ge, Sn, Ti, Th, N, P, As, Sb,
V, Nb, Ta, Cr, Mo, W, S, Se, Te, M
n, I, Fe, Co, Ni, Rh, Os, Ir, Pt,
It may be Cu or the like. Specific examples of the heteropolyacid include, for example, cobalt molybdate, cobalt tungstate, molybdenum tungstate, manganese molybdate, manganese tungstate, manganese molybdenum tungstate, vanadomolybdophosphate,
Phosphorus molybdate, manganese vanadium molybdate, manganese vanadomolybdophosphate, vanadium molybdate, vanadium tungstate, silicomolybdate, silicotungstate, phosphomolybdate, phosphotungstic acid, phosphovanadomolybdate, phosphorus vanad Tungstic acid and the like can be mentioned.

The imide compound represented by the formula (1), or the catalyst composed of the imide compound and the cocatalyst, may be a homogeneous system or a heterogeneous system.
Further, the catalyst may be a solid catalyst in which a catalyst component is supported on a carrier. As the carrier, a porous carrier such as activated carbon, zeolite, silica, silica-alumina and bentonite is often used. The supported amount of the catalyst component in the solid catalyst is 0.1 to 50 parts by weight, preferably 0.5 to 30 parts by weight, more preferably 0.5 to 30 parts by weight, based on 100 parts by weight of the carrier. It is about 1 to 20 parts by weight. The amount of the cocatalyst supported is 0.1 to 30 parts by weight, preferably 0.5 to 30 parts by weight, per 100 parts by weight of the carrier.
It is about 25 parts by weight, more preferably about 1 to 20 parts by weight.

The amount of the imide compound represented by the general formula (1) can be selected in a wide range, for example, from 0.001 mol (0.1 mol%) to 1 mol (1 mol) relative to 1 mol of the substrate.
00 mol%), preferably about 0.001 mol (0.1 mol%) to 0.5 mol (50 mol%), more preferably about 0.01 to 0.30 mol, and 0.01 to 0.1 mol. 2
It is often about 5 moles. The amount of the co-catalyst (co-oxidizing agent) to be used can be appropriately selected within a range that does not decrease the reactivity and the selectivity.
0001 mol (0.01 mol%) to 1 mol (100 mol%), preferably about 0.0001 to 0.7 mol, and more preferably about 0.001 to 0.5 mol.
05 to 0.5 mol (for example, 0.005 to 0.5 mol)
Often around. The activity of the imide compound may decrease as the amount of the cocatalyst increases. Therefore, in order to maintain a high activity of the oxidation catalyst system, the ratio of the cocatalyst is an effective amount or more and 0.1 mol or less (for example, 0.001 to 1 mol) per 1 mol of the imide compound.
0.1 mol, preferably about 0.005 to 0.08 mol, and more preferably about 0.01 to 0.07 mol).

When a heteropolyacid or a salt thereof is used as a cocatalyst, 0.1 to 25 parts by weight, preferably 0.5 to 10 parts by weight, more preferably about 1 to 5 parts by weight, per 100 parts by weight of the substrate. It is.

By using such an oxidation catalyst, the oxidation reaction of the heterocyclic compound can be catalytically promoted even under mild conditions with high oxidation activity. Therefore, for example, a heterocyclic compound having a methyl group or a methylene group at a position adjacent to an aromatic heterocyclic ring can be efficiently oxidized, and a corresponding heterocyclic carboxylic acid or ketone can be produced. In addition, as for the non-aromatic heterocyclic compound, for example, the adjacent position of the hetero atom constituting the non-aromatic hetero ring can be efficiently oxidized to produce a compound having a hydroxy group or an oxo group at the adjacent position of the hetero atom. it can.

[Substrate] The heterocyclic compound as a substrate is not particularly limited as long as it has at least one heterocyclic ring, and may be any of a monocyclic heterocyclic compound and a condensed heterocyclic compound. In the condensed heterocyclic compound, a plurality of heterocycles may be condensed, or a heterocycle and a carbocycle may be condensed. In heterocyclic compounds, for example,
(A) a compound having an aromatic heterocyclic ring and having a methyl group or a methylene group at a site (α-position) adjacent to the aromatic heterocyclic ring, (b) a non-aromatic heterocyclic compound, etc. . The (b) non-aromatic heterocyclic compound may have a non-aromatic heterocyclic ring, and is used to mean, for example, a condensed cyclic hydrocarbon containing a non-aromatic heterocyclic ring. .

In the compound (a) having an aromatic heterocyclic ring and having a methyl group or a methylene group at a position adjacent to the aromatic heterocyclic ring, the aromatic heterocyclic ring includes, for example, a hetero atom Heterocycle containing an oxygen atom (eg,
5-membered ring such as furan, oxazole, isoxazole, furazane, etc., 6-membered ring such as 2H-2-oxopyran, 4H-4-oxopyran, benzofuran, isobenzofuran, dibenzofuran, 2H-2-oxochromene, 4H
Condensed ring such as -4-oxochromene, 1H-1-oxo-2-benzopyran), heterocycle containing sulfur atom as a hetero atom (for example, 5-membered ring such as thiophene, thiazole, isothiazole and thiadiazole, 2H-2- 6-membered rings such as oxothiopyran and 4H-4-oxothiopyran; condensed rings such as 1-benzothiophene and 2-benzothiophene); and heterocycles containing a nitrogen atom as a hetero atom (for example, 5 such as pyrrole, pyrazole, imidazole and triazole). 6-membered ring such as pyridine, pyridazine, pyrimidine, pyrazine, triazine, triazine, tetrazine, indole, isoindole, indolizine, indazole, quinoline, isoquinoline, quinoline quinoline, quinoxaline, quinazoline, cinnoline, phthalazine, purine, acridine Nafutokinorin, phenanthridine rosin, phenanthroline, naphthyridine, condensed rings such as benzo quinoline), and the like. Preferred aromatic heterocycles include those containing from 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen.
The number of members of the aromatic heterocycle is preferably about 5 or 6.

Various substituents such as a halogen atom (a fluorine atom, a chlorine atom, a bromine atom or an iodine atom), an oxo group, a hydroxyl group and a substituted oxy group (for example, an alkoxy group, an aryl group) An oxy group, an acyloxy group, etc.), a mercapto group, a substituted thio group (eg, an alkylthio group, an arylthio group, etc.), a carboxyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, an acyl group, a carbamoyl group, a substituted carbamoyl group, an amino group, Substituted amino group, cyano group, nitro group,
A heterocyclic group and the like may be substituted.

In the method of the present invention, the methyl group or methylene group at the adjacent site (α-position) of the aromatic heterocyclic ring can be efficiently oxidized. It can be selected from a wide range (for example, about 1 to 6, preferably about 1 to 5) depending on the type and size of the heterocyclic ring. As the heterocyclic compound substituted with a methyl group,
For example, a heterocyclic compound substituted with about 1 to 6 methyl groups, for example, 2-methylfuran, 3-methylfuran,
2,5-dimethylfuran, 3,4-dimethylfuran, 2
-Methyloxazole, 4-methyloxazole, 5-
Methyl oxazole, 3-methyl isoxazole, 4
-Methylisoxazole, 5-methylisoxazole, 3-methylfurazan, 2H-4-methyl-2-oxopyran, 2H-5-methyl-2-oxopyran, 2H
-6-methyl-2-oxopyran, 4H-2-methyl-
4-oxopyran, 4H-3-methyl-4-oxopyran, 4H-3,5-dimethyl-4-oxopyran, 4H
-2,6-dimethyl-4-oxopyran, 2-methylbenzofuran, 3-methylbenzofuran, 2,3-dimethylbenzofuran, 1-methylisobenzofuran, 2H-
3-methyl-2-oxochromene, 2H-4-methyl-
2-oxochromene, 4H-2-methyl-4-oxochromene, 4H-3-methyl-4-oxochromene, 1H
Heterocyclic compounds in which a heterocyclic group containing an oxygen atom as a hetero atom, such as -3-methyl-1-oxo-2-benzopyran, is substituted with a methyl group; 2-methylthiophene, 3-methylthiophene, 2,3-dimethyl Thiophene, 2,5
-Dimethylthiophene, 3,4-dimethylthiophene,
2-methylthiazole, 4-methylthiazole, 5-methylthiazole, 3-methylisothiazole, 4-methylisothiazole, 5-methylisothiazole, 2-methyl-1,3,5-thiadiazole, 2H-3-methyl -2-oxothiopyran, 2H-4-methyl-2-oxothiopyran, 2H-5-methyl-2-oxothiopyran, 2H-6-methyl-2-oxothiopyran, 4H-
2-methyl-4-oxothiopyran, 4H-3-methyl-4-oxothiopyran, 4H-3,5-dimethyl-4
-Oxothiopyran, 4H-2,6-dimethyl-4-oxothiopyran, 2-methyl-1-benzothiophene,
3-methyl-1-benzothiophene, 1-methyl-2-
Heterocyclic compounds in which a methyl group is substituted on a heterocyclic ring containing a sulfur atom as a hetero atom such as benzothiophene;
Methylpyrrole, 3-methylpyrrole, 2,3-dimethylpyrrole, 3,4-dimethylpyrrole, 2,5-dimethylpyrrole, 3-methylpyrazole, 4-methylpyrazole, 5-methylpyrazole, 2-methylimidazole, 4 -Methylimidazole, 3-methyl-1,2,4
-Picoline such as triazole, 2-methylpyridine, 3-methylpyridine, 4-methylpyridine, 2,3-dimethylpyridine, 2,4-dimethylpyridine, 2,5-
Dimethylpyridine, 2,6-dimethylpyridine, 3,5
-Lutidine such as dimethylpyridine, 2,3,4-trimethylpyridine, 2,3,5-trimethylpyridine,
Collidines such as 2,3,6-trimethylpyridine and 2,4,6-trimethylpyridine, 3-methylpyridazine,
4-methylpyridazine, 3,4-dimethylpyridazine,
2-methylpyrimidine, 4-methylpyrimidine, 5-methylpyrimidine, 2-methylpyrazine, 2,3-dimethylpyrazine, 2,6-dimethylpyrazine, 2-methyl-
1,3,5-triazine, 3-methyl-1,2,4-triazine, 5-methyl-1,2,4-triazine, 6-
Methyl-1,2,4-triazine, 3-methyl-1,
2,4,5-tetrazine, 2-methylindole, 3-
Methylindole, 2,3-dimethylindole, 1-
Methylisoindole, 1,3-dimethylisoindole, 1-methylindolizine, 2-methylindolizine, 6-methylindolizine, 7-methylindolizine, 3-methyl-1H-indazole, 2-methylquinoline, 3 -Methylquinoline, 4-methylquinoline, 2,
3-dimethylquinoline, 2,4-dimethylquinoline, 1
-Methylisoquinoline, 3-methylisoquinoline, 4-
Methyl isoquinoline, 2-methylquinoxaline, 2-methylquinazoline, 4-methylquinazoline, 3-methylcinnoline, 4-methylcinnoline, 1-methylphthalazine, 2-methylpurine, 6-methylpurine, 8-methylpurine , 9-methylacridine, 6-methylphenanthroline, 2-methylphenanthroline, 2-methylphenanthroline, 2-methyl-1,10-phenanthroline, 2-methyl-1,8-naphthyridine, 3-methyl-
Heterocyclic compounds in which a heterocyclic group containing a nitrogen atom as a hetero atom, such as 1,8-naphthyridine and 4-methyl-1,8-naphthyridine, are substituted with a methyl group can be exemplified.

In the preferred heterocyclic compound (a), the number of substitution of the methyl group is 1 to 4 (for example, 1 or 2) in the molecule.
) In many cases. In particular, many heterocyclic compounds containing a 5- or 6-membered heterocyclic ring substituted by about 1 to 4 methyl groups are industrially useful for producing a carboxylic acid.

In the compound having a methylene group at a position adjacent to the aromatic heterocyclic ring, the aromatic heterocyclic ring is substituted with an alkyl group having 2 or more carbon atoms (for example, about 2 to 6 carbon atoms) or a substituted alkyl group. Heterocyclic compounds and heterocyclic compounds having a condensed heterocyclic ring in which a non-aromatic carbon ring or a heterocyclic ring is condensed with an aromatic heterocyclic ring are included. As the heterocyclic compound having an alkyl group or a substituted alkyl group, for example,
Heterocyclic compounds in which a heterocyclic ring is substituted with an alkyl group having 2 or more carbon atoms or a substituted alkyl group (e.g., 2-ethylfuran, 3-propylfuran, -Ethylthiophene,
2,6-diethylthiophene, 2-ethylpyridine, 2
-Propylpyridine, 3-ethylpyridine, 3-butylpyridine, 4-ethylpyridine, etc.).

The fused heterocyclic ring obtained by condensing a non-aromatic carbon ring or a heterocyclic ring with the aromatic heterocyclic ring includes, for example, a 5- to 8-membered (preferably a 5- to 6-membered) ) Non-aromatic carbocyclic or heterocyclic rings (eg, oxygen atom,
A non-aromatic heterocyclic ring containing 1 to 3 heteroatoms selected from a sulfur atom and a nitrogen atom). As such a fused heterocyclic ring, for example,
A fused heterocycle in which a non-aromatic ring is fused to an aromatic heterocycle containing an oxygen atom as a hetero atom (for example, 4, 5, 6,
7-tetrahydrobenzofuran, 4,5,6,7-tetrahydroisobenzofuran, 5,6,7,8-tetrahydro-2-oxo-2H-chromene, 5,6,7,8-
Tetrahydro-4-oxo-4H-chromene, 5,6
7,8-tetrahydro-1-oxo-1H-2-benzopyran, 1,2,3,4-tetrahydro-9-oxoxanthene, 1,2,3,4,5,6,7,8-octahydro-9 -Oxoxanthene, etc.), a fused heterocyclic ring in which a non-aromatic ring is fused to an aromatic heterocyclic ring containing a sulfur atom as a hetero atom (for example, 4,5,6,7-tetrahydro-1-benzothiophene, 5,6,7-tetrahydro-2-benzothiophene), a condensed heterocyclic ring obtained by condensing a non-aromatic ring with an aromatic heterocyclic ring containing a nitrogen atom as a hetero atom (for example, 4,5,6,7- Tetrahydroindole, 4,5,6,7-tetrahydroisoindole, 5,6,7,8-tetrahydroindolizine, 1,
2,3,4-tetrahydrocarbazole, 5,6,7,
8-tetrahydroquinoline, 5,6,7,8-tetrahydroisoquinoline, 4,5,6,7-tetrahydrobenzimidazole, 4,5,6,7-tetrahydro-1H
-Indazole, 1,2,3,4-tetrahydro-1,
8-naphthyridine, 5,6,7,8-tetrahydroquinoxaline, 5,6,7,8-tetrahydroquinazoline,
5,6,7,8-tetrahydrocinnoline, 5,6
7,8-tetrahydrophthalazine, 1,2,3,4-tetrahydrophenanthrin, 1,2,3,4-tetrahydroacridine, 5,6-dihydro-1,10-phenanthroline and the like. .

The heterocyclic compound (a) may have a methylene group together with a methyl group at a site adjacent to the aromatic heterocyclic ring. As such a compound, for example, a heterocyclic compound having at least one methyl group and an alkyl group having 2 or more carbon atoms or a substituted alkyl group (for example, 2-ethyl-4-methylpyridine, 3-ethyl-4-methyl Pyridine, 4-ethyl-2-methylpyridine, etc.), a fused heterocycle wherein a non-aromatic carbocycle or heterocycle is fused to an aromatic heterocycle and at least one methyl group is substituted on the aromatic heterocycle. Heterocyclic compound having a ring (for example, 4,
5,6,7-tetrahydro-3-methylbenzofuran) and the like.

In the non-aromatic heterocyclic compound (b), the non-aromatic heterocyclic ring includes, for example, a heterocyclic ring containing a nitrogen atom as a hetero atom (for example, pyrrolidine, 2-pyrroline, imidazolidine, 5-membered ring such as imidazoline, pyrazolidine, 3-pyrazoline, oxazolidine, thiazolidine; 6-membered ring such as piperidine, piperazine, morpholine, perhydrothiazine, quinuclidine; condensed ring such as indoline, isoindoline); sulfur atom as a hetero atom (E.g., 5-membered rings such as thiolane and 2-thiolene; thiane, 2,3-dihydrothiin,
6-membered ring such as 1,4-dithiane; 2,3-dihydro-1
-A fused ring such as benzothiophene), a heterocyclic ring containing an oxygen atom as a hetero atom (for example, tetrahydrofuran,
A 5-membered ring such as dihydrofuran; a 6-membered ring such as oxane, 1,3-dioxane, 1,4-dioxane, and 2,3-dihydrooxin; a condensed ring such as chromone and isochromone). Preferred non-aromatic heterocycles include
1-3 selected from an oxygen atom, a sulfur atom and a nitrogen atom
And heterocycles containing two heteroatoms. The number of members of the non-aromatic heterocycle is preferably about 5 or 6.

The non-aromatic heterocycle includes various substituents such as a halogen atom (a fluorine atom, a chlorine atom, a bromine atom or an iodine atom), an oxo group, a hydroxyl group and an alkyl group (eg, methyl, ethyl, An alkyl group having about 1 to 6 carbon atoms such as an isopropyl group; an alkenyl group (such as an alkenyl group having about 2 to 6 carbon atoms such as an allyl group); and an alkynyl group (for example, having 2 to 6 carbon atoms such as a propynyl group). About 6 alkynyl groups, etc.), aryl groups (for example, phenyl group, naphthyl group, etc.), aralkyl groups (for example, aralkyl groups having about 7 to 15 carbon atoms, such as benzyl and phenylethyl groups), and substituted oxy groups (for example, , An alkoxy group, an aryloxy group, an acyloxy group, etc.), a mercapto group, a substituted thio group (for example, an alkylthio group, an aryl O, etc. groups), a carboxyl group, an alkoxycarbonyl group, an aryloxycarbonyl group,
An acyl group, carbamoyl group, substituted carbamoyl group, amino group, substituted amino group, cyano group, nitro group, heterocyclic group and the like may be substituted. Preferred (b) non-aromatic heterocyclic compounds include (b1) a compound having a methine carbon atom as an atom constituting the heterocyclic ring, and (b2) a methylene carbon atom or methyl at the position adjacent to the heteroatom constituting the heterocyclic ring. Compounds having carbon atoms are included.

An oxidation catalyst comprising the imide compound,
Alternatively, when such a heterocyclic compound is oxidized by contact with oxygen in the presence of an oxidation catalyst system composed of an imide compound and a cocatalyst, a corresponding oxide (eg, alcohol, ketone, aldehyde, carboxylic acid, etc.) Is generated efficiently. For example, when (a) a heterocyclic compound having an aromatic heterocyclic ring and having a methyl group or a methylene group at a position adjacent to the aromatic heterocyclic ring, a methyl group adjacent to the aromatic heterocyclic ring is used. Or can oxidize the methylene group with high efficiency,
Heterocyclic aldehydes or carboxylic acids, particularly heterocyclic carboxylic acids, can be obtained in high yield from methyl group-containing heterocyclic compounds, and ketones can be obtained in high yield from heterocyclic compounds having methylene groups. it can. In particular, even if the reaction is performed under mild conditions, the reaction proceeds smoothly within a short time, and a heterocyclic carboxylic acid or a heterocyclic ketone can be obtained in a high yield. Furthermore, when oxidizing a heterocyclic compound having a plurality of methyl groups, by controlling reaction conditions such as reaction time, it is possible to generate a heterocyclic carboxylic acid in which a methyl group remains as the reaction proceeds, When the reaction is further advanced, it is easy to obtain a heterocyclic polycarboxylic acid having two or more carboxyl groups. When a divalent transition metal compound (for example, a divalent cobalt compound or the like) is used as a cocatalyst, even under a low temperature condition,
The selectivity and yield of heterocyclic polycarboxylic acids and heterocyclic ketones can be improved.

When (b1) a compound having a methine carbon atom as an atom constituting a heterocyclic ring is used as a substrate among the (b) non-aromatic heterocyclic compounds, the methine carbon atom is efficiently oxidized. , The corresponding alcohol can be obtained. Further, when (b2) a compound having a methylene carbon atom or a methyl carbon atom at a position adjacent to a hetero atom constituting the heterocyclic ring is used as the substrate, among the (b) non-aromatic heterocyclic compounds, the methylene carbon atom or The methyl carbon atom is efficiently oxidized, and an oxo group can be introduced into the carbon atom. Further, depending on conditions, the methyl carbon atom can be oxidized to a carboxyl group.

[Oxidation reaction] The oxygen used for the oxidation of the substrate may be active oxygen, but it is economically advantageous to use molecular oxygen. The molecular oxygen is not particularly limited, and pure oxygen may be used, or oxygen diluted with an inert gas such as nitrogen, helium, argon, or carbon dioxide may be used. It is preferable to use air from the viewpoint of economy as well as operability and safety. The amount of oxygen used can be selected according to the type of the substrate, and is usually 0.5 mol or more (for example, 1 mol or more), preferably 1 to 100 mol, more preferably 2 to 50 mol per mol of the substrate. It is about a mole. In many cases, an excess molar amount of oxygen relative to the substrate is used, and it is particularly advantageous to carry out the reaction under an atmosphere containing molecular oxygen such as air or oxygen.

The oxidation method of the present invention is usually carried out in an organic solvent inert to the reaction. Examples of the organic solvent include organic carboxylic acids such as acetic acid and propionic acid; nitriles such as acetonitrile, propionitrile and benzonitrile; amides such as formamide, acetamide, dimethylformamide (DMF) and dimethylacetamide; hexane and octane. Aliphatic hydrocarbons such as benzene, aromatic hydrocarbons such as benzene, chloroform, dichloromethane, dichloroethane, carbon tetrachloride, halogenated hydrocarbons such as chlorobenzene, nitro compounds such as nitrobenzene, nitromethane, nitroethane, ethyl acetate, butyl acetate and the like Esters or a mixed solvent thereof are exemplified. In addition, by using an excess amount of the substrate,
A substrate may be used as a reaction solvent. As the solvent,
Organic carboxylic acids such as acetic acid and nitriles such as acetonitrile and benzonitrile are often used.

When the reaction is carried out in the presence of a protonic acid, the oxidation reaction can be carried out smoothly, and the desired compound can be obtained with high selectivity and yield. This protonic acid may be used as a solvent as described above. Examples of the protic acid include organic acids (organic carboxylic acids such as formic acid, acetic acid, and propionic acid; oxycarboxylic acids such as oxalic acid, citric acid, and tartaric acid; alkylsulfonic acids such as methanesulfonic acid and ethanesulfonic acid; benzenesulfonic acid; arylsulfonic acids such as p-toluenesulfonic acid) and inorganic acids (eg, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, etc.).

The method of the present invention is characterized in that the oxidation reaction proceeds smoothly even under relatively mild conditions. The reaction temperature can be appropriately selected depending on the type of the substrate and the like, and is, for example, 0 to 300 ° C, preferably 30 to 250 ° C.
° C, more preferably about 50 to 200 ° C, and usually reacts at about 70 to 150 ° C in many cases. Also,
The reaction can be performed under normal pressure or under pressure. When the reaction is performed under pressure, it is usually 1 to 100 atm (for example, 1.5 to 80 atm), preferably 2 to 70 atm.
m, more preferably about 5 to 50 atm. The reaction time can be appropriately selected depending on the reaction temperature and pressure, for example, from a range of 30 minutes to 48 hours, preferably 1 to 36 hours, more preferably 2 to 24 hours. The reaction may be performed by bringing the substrate and oxygen into contact with each other in the presence of the catalyst, and in the presence of molecular oxygen or under the flow of molecular oxygen, in a batch system, a semi-batch system, or a conventional system such as a continuous system. be able to. After the completion of the reaction, the reaction product is easily separated and purified by a conventional method, for example, separation means such as filtration, concentration, distillation, extraction, crystallization, recrystallization, column chromatography, or a combination thereof. it can.

In the method of the present invention, a heterocyclic compound is converted to a corresponding oxidized compound such as a heterocyclic carboxylic acid or a heterocyclic ketone which can be used as an intermediate compound for a medicine, a fragrance, a dye, food, an organic synthetic intermediate or a raw material of a polymer resin. You can get things.

[0047]

According to the oxidation method of the present invention, the imide compound represented by the general formula (1) or the oxidation catalyst composed of the imide compound and the cocatalyst is used. It can be oxidized efficiently. Also,
Even under mild conditions, the heterocyclic compound can be efficiently oxidized by oxygen. Therefore, it is useful for producing a heterocyclic compound containing oxygen such as a heterocyclic carboxylic acid or a heterocyclic ketone in a high yield.

[0048]

The present invention will be described in more detail with reference to the following Examples, which should not be construed as limiting the invention thereto. Example 1 1.12 g (10 mmol) of 2,5-dimethylthiophene, 0.16 g (1 mmol) of N-hydroxyphthalimide, cobalt (II) acetylacetonate Co (A
A) ₂ 0.015 g (0.05 mmol), acetic acid 25 m
The mixture was stirred at 100 ° C. for 6 hours under an oxygen atmosphere. The product in the reaction mixture was analyzed by gas chromatography to find that the conversion of 2,5-dimethylthiophene was 75%, and that 5-methyl-2-thiophenecarboxylic acid (yield 41%) and 2,5-dimethylthiophene were used. Thiophenedicarboxylic acid (30% yield) was obtained.

Example 2 The reaction was carried out in the same manner as in Example 1 except that 0.93 g (10 mmol) of 2-methylpyridine was used instead of 2,5-dimethylthiophene. At 82%, 2-pyridinecarboxylic acid (yield 77
%)was gotten.

Example 3 In place of 2,5-dimethylthiophene, 1.07 g (10 mmol) of 2,6-dimethylpyridine was used.
When the reaction was carried out in the same manner as in Example 1, 6-methyl-2-pyridinecarboxylic acid (yield 42%) and 2,6-pyridinedicarboxylic acid (78% conversion of 2,6-dimethylpyridine) (Yield 33%).

Example 4 Example 1 was repeated except that 0.82 g (10 mmol) of 2-methylfuran was used in place of 2,5-dimethylthiophene.
As a result, furfural (10% yield) and 2-furancarboxylic acid (72% yield) were obtained at a conversion rate of 2-methylfuran of 95%.

Example 5 The reaction was carried out in the same manner as in Example 4 except that the reaction temperature was changed to 80 ° C., and the conversion of 2-methylfuran was 82%.
Thus, furfural (yield 61%) and 2-furancarboxylic acid (yield 18%) were obtained.

Example 6 The reaction was carried out in the same manner as in Example 4 except that the reaction temperature was changed to 120 ° C., and the conversion of 2-methylfuran was 97%.
Thus, furfural (3% yield) and 2-furancarboxylic acid (90% yield) were obtained.

Example 7 Instead of 2,5-dimethylthiophene, morpholine 1
The reaction was carried out in the same manner as in Example 1 except that 0 mmol was used and acetonitrile was used as a solvent instead of acetic acid. The conversion of morpholine was 67%, and 3-oxomorpholine (yield 24%) and 2 -Oxomorpholine (27% yield) was obtained.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁶ Identification symbol FI C07D 307/68 C07D 307/68 // C07B 61/00 300 C07B 61/00 300 C07D 209/48 C07D 295/02 Z 295/02 333/40 333/40 209/48 Z

Claims (7)

[Claims] 1. A compound of the general formula (1) (Wherein, R ¹ and R ² are the same or different and represent a hydrogen atom, a halogen atom, an alkyl group, an aryl group, a cycloalkyl group, a hydroxyl group, an alkoxy group, a carboxyl group, an alkoxycarbonyl group, an acyl group; R ¹
And R ² may combine with each other to form a double bond or an aromatic or non-aromatic ring. X represents an oxygen atom or a hydroxyl group, and n represents an integer of 1 to 3) in the presence of an oxidation catalyst composed of an imide compound represented by the following formula: Method. 2. The method for oxidizing a heterocyclic compound according to claim 1, wherein the heterocyclic compound is contacted with oxygen in the presence of an oxidation catalyst composed of the imide compound represented by the general formula (1) and a promoter. 3. The co-catalyst is a transition metal compound.
The oxidation method as described. 4. The oxidation method according to claim 1, wherein the heterocyclic compound is a compound having an aromatic heterocyclic ring and having a methyl group or a methylene group at a position adjacent to the aromatic heterocyclic ring. 5. The oxidation method according to claim 4, wherein the aromatic heterocyclic ring contains 1 to 3 hetero atoms selected from an oxygen atom, a sulfur atom and a nitrogen atom. 6. The oxidation method according to claim 1, wherein the heterocyclic compound is a non-aromatic heterocyclic compound. 7. A corresponding heterocyclic carboxylic acid obtained by contacting a heterocyclic compound having a methyl group or a methylene group at a position adjacent to an aromatic heterocyclic ring with oxygen in the presence of the oxidation catalyst according to claim 1 or 2. A method for producing a heterocyclic carboxylic acid or ketone, which produces an acid or a heterocyclic ketone.