JP2003252859A - Method for producing pyridine derivative - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for regioselectively and simply obtaining a pyridine derivative substituted with many different substituent groups. <P>SOLUTION: An azametalacyclopentadiene (2) is reacted with an alkyne (3) to provide the pyridine derivative represented by formula (1) [wherein R<SP>1</SP>to R<SP>4</SP>are same or different and they are each hydrogen atom, a hydrocarbon group or the like; M is a transition metal; L<SP>1</SP>and L<SP>2</SP>are each a ligand; X is a leaving group]. <P>COPYRIGHT: (C)2003,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for producing a pyridine derivative, and more particularly to a method for producing a polysubstituted pyridine derivative using a copper salt.

[0002]

BACKGROUND OF THE INVENTION Pyridines are important as intermediates and final chemical products for many chemical products such as pharmaceuticals, agricultural chemicals and cross-linking agents. It is possible to develop a method for producing such pyridines by using easily available raw materials, by simple steps (less steps), and by allowing the reaction to proceed selectively functional groups and regioselectively. Has been desired.

Conventionally, as a method for synthesizing pyridine, there is a method in which azazirconacyclopentadiene is obtained from one molecule of alkyne and one molecule of nitrile, and then pyridine is obtained by further reacting with one molecule of alkyne in the presence of nickel complex. It is known (Japanese Patent Laid-Open No. 2000-256321).
However, according to this method, a symmetric alkyne (for example, 3-hexyne) can be efficiently introduced, but there is a problem that it is difficult to regioselectively introduce an asymmetric alkyne.

Therefore, it has been desired to regioselectively and conveniently obtain polysubstituted pyridine derivatives having different substituents.

[0005]

The inventor of the present invention has found that the Zr-C bond and Zr in azazirconacyclopentadiene.
Focusing on the difference in the -N bond and conducting diligent studies on introducing asymmetric alkynes by utilizing this difference, as a result, by using a copper salt in place of the nickel complex, it is possible to regioselectively nucleophile. We have succeeded in introducing an asymmetric alkyne using an attack, and have found that a polysubstituted pyridine can be obtained selectively and in high yield, and have completed the present invention.

That is, the present invention provides a method for producing a pyridine derivative represented by the following formula (1):

[Chemical 4] [In the formula, R ¹ , R ² , R ³ and R ⁴ are each independently, the same or different, a hydrogen atom; a C ₁ -C ₂₀ hydrocarbon group which may have a substituent; A C ₁ -C ₂₀ alkoxy group which may have a group; a C ₆ -C ₂₀ aryloxy group which may have a substituent; an amino group which may have a substituent; Optionally a silyl group,
Or a hydroxyl group, provided that, R ¹ and R ² may form a C ₄ -C _{2 0} saturated or unsaturated ring crosslinked to each other,
The ring is an oxygen atom, a sulfur atom, a silicon atom, a tin atom,
Germanium atom or a group represented by the formula —N (B) — (wherein, B is a hydrogen atom or a C _{1 to} C ₂₀ hydrocarbon group).
It may be interrupted by and may have a substituent. ] In the presence of a copper salt, an azametallacyclopentadiene represented by the following formula (2),

[Chemical 5] [Wherein R ¹ , R ² and R ³ have the above-mentioned meanings. M
Represents a transition metal, and L ¹ and L ² each independently represent the same or different and represent an anionic ligand. However, L ¹ and L ² may be crosslinked. ] With an alkyne represented by the following formula (3)

[Chemical 6] [In the formula, R ⁴ has the above meaning. X represents a leaving group. ] The method of manufacturing the pyridine derivative characterized by making it react is provided.

In the present invention, the copper salt is preferably copper chloride or copper cyanide.

Further, in the present invention, R ¹ , R ² and R ³
Are each independently the same or different and are a C _{1 to} C ₂₀ hydrocarbon group which may have a substituent or a silyl group which may have a substituent, and R ⁴ is a hydrogen atom. Is preferred.

In the present invention, X is a halogen source.
Child, tosylate group (--OS (= O) ₂-C₆H_Four-C
H₃), A triflate group (—O—S (═O))₂-CF₃)
Or C₁~ C₂₀It is preferably an alkoxy group.

Further, in the present invention, M is preferably a transition metal of Groups 4 to 6 of the periodic table, and more preferably M is zirconium.

Further, in the present invention, the anionic ligand is a delocalized cyclic η ⁵ -coordination system ligand, which may be substituted cyclopentadienyl group, indenyl group, It is preferably a fluorenyl group or an azulenyl group.

In the present invention, the pyridine derivative represented by the formula (1) is 2- (4-t-butylphenyl) -6-methyl-3,4-dipropylpyridine, 3,
4-diethyl-6-methyl-2-phenylpyridine, 2
-Ethyl-6-methyl-3,4-dipropylpyridine,
2- (4-t-butylphenyl) -6-methyl-3,4
-Diphenylpyridine, 6-methyl-3,4-diphenyl-2-propylpyridine, 3-butyl-6-methyl-
2-phenyl-4- (trimethylsilyl) pyridine, 3
-Butyl-6-methyl-2-propyl-4- (trimethylsilyl) pyridine, or 2-ethyl-6-methyl-3
It is preferably -phenyl-4- (triethylsilyl) pyridine.

[0013]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention is characterized by reacting an azametallacyclopentadiene represented by the following formula (2) with an alkyne represented by the following formula (3) in the presence of a copper salt. A method for producing a pyridine derivative represented by the formula (1) is provided.

[0014]

[Chemical 7] [Wherein R ¹ , R ² , R ³ , R ⁴ , M, L ¹ , L ² and X are
It has the above meaning. ]

R ¹ , R ² , R ³ and R ⁴ are each independently, the same or different, a hydrogen atom; a C ₁ -C ₂₀ hydrocarbon group which may have a substituent; a substituent A C ₁ -C ₂₀ alkoxy group which may have a C ₆ -C ₂₀ aryloxy group which may have a substituent; an amino group which may have a substituent; Optionally a silyl group or a hydroxyl group.

In the present specification, C₁~ C₂₀The hydrocarbon group is
It may be saturated or unsaturated, acyclic, or saturated.
It may be unsaturated or cyclic. C₁~ C₂₀Carbonized water
When the base group is acyclic, it may be linear or branched.
Good. C₁~ C₂₀The hydrocarbon group includes C₁~ C₂₀Alkyl
Base, C₂~ C₂₀Alkenyl group, C₂~ C₂₀An alkynyl group,
C₃~ C₂₀Allyl group, C_Four~ C₂₀Alkyldienyl group, C
_Four~ C₂₀Polyenyl group, C₆~ C₁₈Aryl group, C₆~ C
₂₀Alkylaryl group, C₆~ C₂₀Arylalkyl
Base, C_Four~ C₂₀Cycloalkyl group, C_Four~ C₂₀Cycloal
Kenyl group, (C ₃~ C_TenCycloalkyl) C₁~ C_TenAl
Includes a kill group.

C₁~ C₂₀Alkyl group, C₂~ C₂₀Archeni
Lu group, C₂~ C₂₀Alkynyl group, C₃~ C₂₀Allyl group, C
_Four~ C₂₀Alkyldienyl group and C_Four~ C₂₀Polyeni
Each of the ru groups is C₁~ C_TenAlkyl group, C₂~ C_TenA
Lucenyl group, C₂~ C_TenAlkynyl group, C₃~ C_TenAllyl
Base, C_Four~ C_TenAlkyldienyl group and C_Four~ C_{1 0}Po
It is preferably a renyl group, each of which is C₁~ C₆
Alkyl group, C₂~ C ₆Alkenyl group, C₂~ C₆Alkini
Lu group, C₃~ C₆Allyl group, C_Four~ C₆Alkyldienyl
Group and C_Four~ C₆More preferably it is a polyenyl group.
Good

C ₆ -C ₁₈ aryl group, C ₆ -C ₂₀ alkylaryl group, C ₆ -C ₂₀ arylalkyl group, C ₄ -C ₂₀
Cycloalkyl group, and, C ₄ -C ₂₀ cycloalkenyl group, each, C ₆ -C ₁₀ aryl group, C ₆ -C ₁₂ alkylaryl group, C ₆ -C ₁₂ arylalkyl group, C ₄ ~
It may be a C ₁₀ cycloalkyl group or a C _{4 to} C ₁₀ cycloalkenyl group.

Examples of optionally substituted alkyl groups useful herein include, but are not limited to, methyl, ethyl, propyl, n-butyl, t-.
There are butyl, dodecanyl, trifluoromethyl, perfluoro-n-butyl, 2,2,2-trifluoroethyl, benzyl, 2-phenoxyethyl and the like.

Examples of optionally substituted aryl groups useful herein include, but are not limited to, phenyl, 2-tolyl, 3-tolyl, 4-tolyl, naphthyl, biphenyl. , 4-phenoxyphenyl,
4-fluorophenyl, 3-carbomethoxyphenyl,
4-carbomethoxyphenyl and the like.

Examples of optionally substituted alkoxy groups useful herein include, but are not limited to, methoxy, ethoxy, 2-methoxyethoxy, t-butoxy, and the like.

Examples of optionally substituted aryloxy groups useful herein include, but are not limited to, phenoxy, naphthoxy, phenylphenoxy, 4-methylphenoxy, 2-tolyloxy, Three
-Tolyloxy, 4-tolyloxy, naphthyloxy,
Biphenyloxy, 4-phenoxyphenyloxy, 4
-Fluorophenyloxy, 3-carbomethoxyphenyloxy, 4-carbomethoxyphenyloxy and the like.

Examples of optionally substituted amino groups useful herein include, but are not limited to, amino, dimethylamino, methylamino, methylphenylamino, phenylamino, and the like. .

The silyl group which may have a substituent and is useful in the present specification includes, but is not limited to, trimethylsilyl, triethylsilyl, trimethoxysilyl, triethoxysilyl, diphenylmethylsilyl and triphenyl. Examples include silyl, triphenoxysilyl, dimethylmethoxysilyl, dimethylphenoxysilyl, and methylmethoxyphenyl.

A substituent may be introduced into the C ₁ -C ₂₀ hydrocarbon group, C ₁ -C ₂₀ alkoxy group, C ₆ -C ₂₀ aryloxy group, amino group, and silyl group. Examples thereof include C _{1 to} C ₁₀ hydrocarbon groups, C _{1 to} C ₁₀ alkoxy groups, C _{6 to} C ₁₀ aryloxy groups, amino groups, hydroxyl groups and silyl groups.

However, R ¹ and R ² are crosslinked with each other to form C.
₄ -C ₂₀ saturated or unsaturated ring may be formed. The ring formed by these substituents is preferably a 4-membered ring to a 16-membered ring, more preferably a 4-membered ring to a 12-membered ring. This ring may be an aromatic ring such as a benzene ring or an aliphatic ring. Further, the ring formed by these substituents may further have a single ring or a plurality of rings.

The saturated ring or unsaturated ring is an oxygen atom,
Even if it is interrupted by a sulfur atom, a silicon atom, a tin atom, a germanium atom or a group represented by the formula —N (B) — (wherein B is a hydrogen atom or a C _{1 to} C ₂₀ hydrocarbon group). Good. That is, the saturated ring or unsaturated ring may be a heterocycle. Moreover, it may have a substituent. The unsaturated ring may be an aromatic ring such as a benzene ring.

B is preferably a hydrogen atom or a C _{1 to} C ₁₀ hydrocarbon group, more preferably a hydrogen atom or a C _{1 to} C ₇ hydrocarbon group, and B is a hydrogen atom or C ₁
More preferably, it is a C ₃ alkyl group, a phenyl group or a benzyl group.

[0029] The saturated or unsaturated ring may have a substituent, for example, C ₁ -C _{2 0} hydrocarbon group, C ₁ ~
Substituents such as C ₂₀ alkoxy group, C _{6 to} C ₂₀ aryloxy group, amino group, hydroxyl group or silyl group may be introduced.

In the present invention, R ¹ , R ² and R ³ are each independently, the same or different, and have a C _{1 to} C ₂₀ hydrocarbon group which may have a substituent or a substituent. It is preferably a silyl group which may be substituted, and is preferably a methyl group, an ethyl group, a propyl group, a butyl group, a phenyl group, p
It is more preferably -t-butylphenyl group, trimethylsilyl group or triethylsilyl group.

In the present invention, R ⁴ is preferably a hydrogen atom.

In the method for producing a pyridine derivative of the present invention,
Azametallacyclopentadiene represented by the following formula (2) is used.

[0033]

[Chemical 8] [Wherein R ¹ , R ² and R ³ have the above-mentioned meanings. ]

M represents a transition metal. M is preferably a transition metal of Group 4 to Group 6 of the periodic table, more preferably a metal of Group 4 of the periodic table, that is, titanium, zirconium and hafnium, and particularly preferably zirconium. preferable.

L ¹ and L ² are independent of each other,
The same or different, the anionic ligand is shown. However, L ¹ and L ² may be crosslinked. The anionic ligand is a delocalized cyclic η ⁵ -coordination system ligand, C _1-
It is preferably a C ₂₀ alkoxy group, a C ₆ -C ₂₀ aryloxy group or a dialkylamido group, and more preferably a delocalized cyclic η ⁵ -coordination system ligand. Examples of the delocalized cyclic η ⁵ -coordination ligand include an optionally substituted cyclopentadienyl group, an indenyl group, a fluorenyl group or an azulenyl group, and an unsubstituted cyclopentadienyl group. A group and a substituted cyclopentadienyl group are preferred.

This substituted cyclopentadienyl group is, for example, methylcyclopentadienyl, ethylcyclopentadienyl, isopropylcyclopentadienyl, n-butylcyclopentadienyl, t-butylcyclopentadienyl, dimethylcyclopentadienyl. Pentadienyl, diethylcyclopentadienyl, diisopropylcyclopentadienyl, di-t-butylcyclopentadienyl, tetramethylcyclopentadienyl, indenyl group, 2-methylindenyl group, 2-methyl-4-phenyl An indenyl group,
And tetrahydroindenyl group, benzoindenyl group, fluorenyl group, benzofluorenyl group, tetrahydrofluorenyl group, octahydrofluorenyl group and azulenyl group.

In the delocalized cyclic η ⁵ -coordination system ligand, one or more atoms of the delocalized cyclic π system may be substituted with a hetero atom. 1 in addition to hydrogen, such as elements of group 14 of the periodic table and / or elements of groups 15, 16 and 17 of the periodic table
It can contain one or more heteroatoms.

Delocalized ring η^Five-Coordinating ligands, eg
For example, a cyclopentadienyl group has a central metal and a cyclic
May be bridged by one or more bridging ligands.
It may be. Examples of the bridging ligand include C
H₂, CH₂CH₂, CH (CH₃) CH₂, CH (C
_FourH₉) C (CH₃)₂, C (CH₃)₂, (CH₃)₂Si,
(CH₃) ₂Ge, (CH₃)₂Sn, (C₆H_Five)₂Si,
(C₆H_Five) (CH₃) Si, (C₆H _Five)₂Ge, (C
₆H_Five)₂Sn, (CH₂)_FourSi, CH₂Si (CH₃)₂,
o-C₆H_FourOr 2, 2 '-(C₆H_Four)₂Is mentioned.

The azametallacyclopentadiene represented by the above formula (2) has two or more metallocene moieties (moiety).
Also included are compounds having Such compounds are known as polynuclear metallocenes. The polynuclear metallocene may have any substitution pattern and any bridged morphology. The independent metallocene moieties of the polynuclear metallocene are:
Each may be the same or different. Examples of the polynuclear metallocene include EP-A-632063 and JP-A-4-8.
0214, JP-A-4-85310, EP-A-654.
476.

In the method for producing a pyridine derivative of the present invention,
An alkyne represented by the following formula (3) is used.

[0041]

[Chemical 9] [In the formula, R ⁴ has the above meaning. ]

X represents a leaving group. Examples of the leaving group include a halogen atom such as F, Cl, Br and I, a tosylate group (—O—S (═O) ₂ —C ₆ H ₄ —CH ₃ ), a triflate group (—O—S). (= O) ₂ -CF ₃₎ or C ₁ -C
₂₀ alkoxy groups and the like. The leaving group is preferably a halogen atom, an alkoxy group or a tosylate group, and C
More preferred are l, Br, I, tosylate groups.

The amount of alkyne represented by the above formula (3) is
Each is 0.1 mol to 100 mol, preferably 0.5 mol to 3 mol, and more preferably 0.8 mol to 2.0 mol, relative to 1 mol of azametallacyclopentadiene (2). .

In the method for producing a pyridine derivative of the present invention, the above reaction is carried out in the presence of a copper salt.

The copper salt is not particularly limited as long as it is a salt containing copper ions, and CuX [wherein X represents a halogen atom such as a chlorine atom or a bromine atom]. ], Copper cyanide is preferable, and CuCl is more preferable.

The amount of the copper salt is 0.1 mol to 100 mol per 1 mol of azametallacyclopentadiene (2).
It is mol, preferably 0.5 mol to 3 mol, and more preferably 0.5 mol to 2.0 mol.

In the present invention, the pyridine derivative is typically produced by adding the alkyne (3) and a copper salt to a solution of the azametallacyclopentadiene represented by the above formula (2) and stirring the mixture. Azametallacyclopentadiene (2)
Does not have to be isolated, and azametallacyclopentadiene prepared in a solution may be used as it is.

In the present invention, in sp ² -C in the metallacycle in the azametallacyclopentadiene (2), the metal exchange reaction from the metal M to copper is immediately caused by the presence of the copper salt. Selectively attacking (3), the intermediate (4a) as shown below,
It is considered that the polysubstituted pyridine derivative (1) is selectively produced via the intermediate (4b).

[0049]

[Chemical 10] [Wherein R ¹ , R ² , R ³ , R ⁴ , M, L ¹ , L ² and X are
It has the above meaning. M ¹ represents a complex containing copper or metal M. The above reaction mechanism is only a hypothesis, and the present invention is not limited to these reaction mechanisms.

The reaction is preferably -100 ° C to 300 ° C.
Temperature range of 80 to 200 ° C.
It is carried out in the temperature range of ℃, more preferably in the temperature range of -80 ℃ ~ 60 ℃. The pressure is, for example, 0.1 bar to 25 bar.
Within the range of 00 bar, preferably 0.5 bar to 10
Within the bar range.

As the solvent, a solvent capable of dissolving the azametallacyclopentadiene represented by the above formula (2) is preferable. As the solvent, an aliphatic or aromatic organic solvent is used. Ethereal solvents such as tetrahydrofuran or diethyl ether; halogenated hydrocarbons such as methylene chloride; halogenated aromatic hydrocarbons such as o-dichlorobenzene; amides such as N, N-dimethylformamide, sulfoxides such as dimethylsulfoxide; Aromatic hydrocarbons such as benzene and toluene are used.

The azametallacyclopentadiene represented by the above formula (2) is obtained by reacting 1 mol of metallocene such as biscyclopentadienyl metal dialkyl with 1 mol of alkyne and 1 mol of nitrile. be able to. In the present invention, when azazirconacyclopentadiene is used as the azametallacyclopentadiene represented by the above formula (2), it can be synthesized using, for example, the following zirconocene.

Bis (cyclopentadienyl) diethylzirconium; Bis (methylcyclopentadienyl) diethylzirconium; Bis (butylcyclopentadienyl) diethylzirconium; Bis (isopropylcyclopentadienyl) diethylzirconium; Bis (n- Butyl (cyclopentadienyl) diethylzirconium; bis (t-butylcyclopentadienyl) diethylzirconium; bis (dimethylcyclopentadienyl) diethylzirconium; bis (diethylcyclopentadienyl) diethylzirconium; bis (diisopropylcyclopentadi) (Enyl) diethyl zirconium; bis (di-
t-butylcyclopentadienyl) diethylzirconium; bis (tetramethylcyclopentadienyl) diethylzirconium.

Bis (cyclopentadienyl) dichlorozirconium; bis (methylcyclopentadienyl) dichlorozirconium; bis (butylcyclopentadienyl) dichlorozirconium; bis (isopropylcyclopentadienyl) dichlorozirconium; bis ( n-butylcyclopentadienyl) dichlorozirconium; bis (t-butylcyclopentadienyl) dichlorozirconium; bis (dimethylcyclopentadienyl) dichlorozirconium; bis (diethylcyclopentadienyl) dichlorozirconium; bis (diisopropylcyclo) Pentadienyl) dichlorozirconium; bis (di-t-butylcyclopentadienyl) dichlorozirconium; bis (tetramethylcyclopentadienyl) dichlorozirconium For what dichloro body, an alkali metal such as sodium, or reduction with a strong base such as an alkaline earth metal such as magnesium, or, convert the dialkyl body, to produce aza zirconacyclopenta cyclopentadiene.

[0055]

EXAMPLES The present invention will be described below based on examples.
However, the present invention is not limited to the following examples.

All reactions were carried out under a dry nitrogen atmosphere unless otherwise stated. Tetrahydrofuran (THF) used as a solvent was distilled under a nitrogen stream with sodium metal and benzophenone to be anhydrous. Zirconocene dichloride used was purchased from Nichia Chemical Industry. The alkyne used was purchased from Aldrich Chemical. Further, n-butyllithium (1.6 M hexane solution) and EtMgBr (1.0 M THF solution) used were those purchased from Kanto Kagaku. As for the other reagents, commercially available products were purchased and used as they were.

¹ H and ¹³ C NMR spectra show CDC at 25 ° C.
l ₃ using (1% TMS-containing) solution, Bruker ARX-400 or JEO
It was measured on a L JNM-AL 300 NMR spectrometer. Silica glass capillary column SHIMADZU CBP1-M25-O25 and
SHI with SHIMADZU C-R6A-Chromatopac integrator
It was measured with a MADZU GC-14A gas chromatograph.

Example 1 2- (4-t-Butylphenyl) -6-methyl-3,4-dipropylpyridinebis (cyclopentadienyl) dichlorozirconium (Cp ₂ ZrCl ₂ ) (365 mg, 1.25 mmol) EtMgBr (2.5 mmol) was added to the THF (5 mL) solution of the above at -78 degreeC. After stirring at the same temperature for 1 hour, 4-octyne (1.0 mmol) was added, and the reaction mixture was warmed to 0 ° C over 3 hours. Subsequently, p-t-butylbenzonitrile (1.0 mmol) was added to the reaction mixture, and the mixture was stirred at 50 ° C for 1 hr. After cooling to 0 ° C,
Propargyl bromide (1.5 mmol) and CuCl (1.0 mm
ol) was added to the reaction mixture and stirred at 50 ° C. for 1 hour.
The reaction mixture was quenched with saturated sodium hydrogen carbonate and extracted with ether. The extract was washed with water and saturated brine and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography to obtain the title compound.
GC yield 93%. Isolated yield 81%. Orange liquid.

¹ H NMR (CDCl ₃ , Me ₄ Si) δ 0.78 (t, J = 7.
5 Hz, 3H), 1.00 (t, J = 7.5 Hz, 3H), 1.34-1.46 (m,
11H), 1.63 (q, J = 7.5 Hz, 2H), 2.50-2.62 (m, 7H),
6.93 (s, 1H), 7.30 (d, J = 8.1 Hz, 2H), 7.40 (d,
J = 8.4Hz, 2H); ¹³ C NMR (CDCl ₃ , Me ₄ Si) δ 14.31, 1
4.39, 23.81, 24.18, 24.31, 30.63, 31.38, 34.33, 3
4.53, 122.39, 124.95, 128.32, 130.87, 139.06, 150.
03, 150.33, 154.45, 159.15; IR (neat) 2961, 2934, 2
872, 1591, 1553, 1466, 1433, 1399, 1379, 1364, 126
7, 1109, 1020, 839 cm ^-1 ; High-resolution mass spectrometer calculated C ₂₂ H ₃₀ N 308.2378, found 308.2354.

Example 2 3,4-Diethyl-6-methyl-2-phenylpyridine The procedure was as in Example 1. However, 3-hexyne was used instead of 4-octyne, and benzonitrile was used instead of p-t-butylbenzonitrile. GC yield 98
%, Isolated yield 77%. Orange liquid.

¹ H NMR (CDCl ₃ , Me ₄ Si) δ 0.96 (t, J =
7.5 Hz, 3H), 1.25 (t, J = 7.5 Hz, 3H), 2.52-2.61
(m, 5H), 2.65 (q, J = 7.5 Hz, 2H), 6.98 (s, 1H),
7.32-7.40 (m, 5H); ¹³ C NMR (CDCl3, Me4Si) δ 14.6
5, 15.20, 21.45, 24.21, 25.02, 121.98, 127.37, 12
8.08, 128.68, 132.01, 141.92, 151.69, 154.75, 158.
90; f IR (neat) 2969, 2934, 2876, 1591, 1555, 149
7, 1464, 1449, 1429, 1387, 1339, 1055, 1028, 872,
764, 700 cm ^-1 ; High resolution mass spectrometer Calculated value C ₁₆ H ₁₈ N 22
4.1439, found 224.1443.

Example 3 2-Ethyl-6-methyl-3,4-dipropylpyridine The procedure was as in Example 1. However, propiononitrile was used instead of p-t-butylbenzonitrile. GC yield 57%, isolation yield 43%. Orange liquid.

[0063]¹H NMR (CDCl₃, Me_FourSi) δ 0.97 (t, J =
7.5 Hz, 3H), 1.00 (t, J = 7.5 Hz, 3H), 1.24 (t, J
 = 7.5 Hz, 3H), 1.43-1.67 (m, 4H), 2.45 (s, 3H),
2.49-2.59 (m, 4H), 2.75 (q, J = 7.5 Hz, 2H), 6.77
(s, 1H);¹³C NMR (CDCl₃, Me _FourSi) δ 14.26, 14.64,
14.70, 23.78, 24.07, 24.34, 28.50, 30.00, 34.44, 1
21.42, 130.14, 149.79, 154.42, 160.89; IR (neat) 2
961, 2934, 2874, 1593, 1559, 1456, 1379, 1256, 123
3, 1090, 1051, 949, 845 cm^-1; High resolution mass spectrometer
Calculated value C₁₄H_{twenty three}N 205.1830, Found 205.1820.

Example 4 2- (4-t-Butylphenyl) -6-methyl-3,4-diphenylpyridine The procedure was as in Example 1. However, 1,2-diphenylacetylene was used instead of 4-octyne. GC
Yield 73%, isolation yield 50%. Orange solid: melting point 159 ° C.

¹ H NMR (CDCl ₃ , Me ₄ Si) δ1.24 (s, 9H),
2.67 (s, 3H), 6.85-6.88 (m, 2H), 7.01-7.07 (m, 5H),
7.18-7.19 (m, 8H); ¹³ C NMR (CDCl ₃ , Me ₄ Si) δ 24.
45,31.25, 34.42, 122.97, 124.56, 126.29, 127.13, 1
27.54, 127.78, 129.29, 129.48, 131.38, 131.52, 13
8.00, 138.05, 139.80, 149.92, 149.99, 156.81, 157.
78; IR (KBr) 2963, 2867, 1584, 1537, 1474, 1429, 1
364, 1271, 1113, 841, 770, 700 cm ^-1 ; High resolution mass spectrometer Calc. C ₂₈ H ₂₆ N 376.2065, Found 376.2057.

Example 5 6-Methyl-3,4-diphenyl-2-propylpyridine The procedure was as in Example 1. However, 1,2-diphenylacetylene was used instead of 4-octyne, and p-t
-Butyronitrile was used instead of butylbenzonitrile. GC yield 66%, isolation yield 57%. Orange solid: melting point 67
° C.

¹ H NMR (CDCl ₃ , Me ₄ Si) δ 0.79 (t, J =
7.2 Hz, 3H), 1.55-1.68 (m, 2H), 2.60-2.65 (m, 5H),
7.01-7.04 (m, 5H), 7.12-7.25 (m, 6H); ¹³ C NMR (CD
Cl ₃ , Me ₄ Si) δ 14.20, 23.57, 24.36, 38.14, 121.66,
126.70, 127.05, 127.69, 127.81, 129.20, 130.59, 13
2.11, 138.32, 139.78, 149.35, 156.48, 159.93; IR (K
Br) 2957, 2901, 2870, 1586, 1541, 1499, 1462, 143
9, 1381, 1358, 1201, 1074, 868, 771, 700 cm ^-1 ; High resolution mass spectrometer Calculated value C ₂₁ H ₂₁ N 287.1674, Measured value 28
7.1667.

Example 6 3-Butyl-6-methyl-2-phenyl-4- (trimethylsilyl)
Pyridinebis (cyclopentadienyl) dichlorozirconium (Cp ₂ ZrCl ₂ ) (365 mg, 1.25 mmol) in THF (5 mL)
N-butyllithium (2.5 mmol) was added thereto at -78 ° C.
After stirring at the same temperature for 1 hour, 1-trimethylsilyl-1-hexyne (2.0 mmol) was added, and the reaction mixture was warmed to room temperature over 1 hour. Subsequently, benzonitrile (1.0 mmol) was added to the reaction mixture, and the mixture was stirred at 50 ° C for 1 hr. 0 ° C
After cooling to propargyl bromide (1.5 mmol)
And CuCl (1.0 mmol) were added to the reaction mixture, and the mixture was stirred at 50 ° C for 1 hr. The reaction mixture was quenched with saturated sodium hydrogen carbonate and extracted with ether. The extract was washed with water and saturated brine and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography to obtain the title compound. GC yield 54%, isolation yield 46%. Orange liquid.

¹ H NMR (CDCl ₃ , Me ₄ Si) δ 0.36 (s, 9H),
0.63 (t, J = 7.2 Hz, 3H), 1.06-1.20 (m, 4H), 2.54
(s, 3H), 2.65 (t, J = 7.2 Hz, 2H), 7.18 (s, 3H),
7.33-7.41 (m, 5H); ¹³ C NMR (CDCl ₃ , Me ₄ Si) δ 0.35,
13.48, 22.78, 24.17, 32.39, 33.51, 127.38, 127.7
7, 128.10, 128.82, 137.69, 141.85, 149.20, 153.72,
158.44; IR (neat) 2957, 2930, 2874, 1570, 1524, 1
495, 1460, 1447, 1416, 1368, 1298, 1252, 1092, 91
8, 855, 839, 754, 700 cm ^-1 ; High-resolution mass spectrometer calculated C ₁₉ H ₂₇ N 297.1913, found 297.1894.

Example 7 3-Butyl-6-methyl-2-propyl-4- (trimethylsilyl)
Pyridine Same procedure as in Example 6. However, butyronitrile was used instead of benzonitrile. GC yield 34%, isolation yield 27%. Orange liquid.

[0071]¹H NMR (CDCl₃, Me_FourSi) δ 0.32 (s, 9H),
0.95-1.04 (m, 6H), 1.43-1.49 (m, 4H), 1.68-1.76 (m,
 2H), 2.47 (s, 3H), 2.63-2.75 (m, 4H), 7.01 (s, 1
H); ¹³C NMR (CDCl₃, Me_FourSi) δ 0.31, 13.90, 14.46, 2
3.33, 23.87, 24.13, 32.60, 34.29, 37.01, 126.41, 1
37.29, 148.33, 153.75, 159.05; IR (neat) 2959,293
4, 2874, 1574, 1530, 1433, 1373, 1252, 1148, 1084,
 860, 839, 756, 689cm^-1; High-resolution mass spectrometer calculation
Value C₁₆H₂₉NSi 263.2069, Found 263.2076.

Example 8 2-Ethyl-6-methyl-3-phenyl-4- (triethylsilyl)
Pyridinebis (cyclopentadienyl) dichlorozirconium (Cp ₂ ZrCl ₂ ) (365 mg, 1.25 mmol) in THF (5 mL)
N-butyllithium (2.5 mmol) was added thereto at -78 ° C.
After stirring at the same temperature for 1 hour, triethylsilylphenylacetylene (1.0 mmol) was added, and the reaction mixture was warmed to room temperature over 3 hours. Subsequently, propiononitrile (1.0 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 3 hours. After cooling to 0 ° C, propargyl bromide (1.
5 mmol) and CuCl (1.0 mmol) were added to the reaction mixture and 5
The mixture was stirred at 0 ° C for 3 hours. The reaction mixture was quenched with saturated sodium hydrogen carbonate and extracted with ether. The extract was washed with water and saturated brine and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography to obtain 253 mg (81%) of the title compound as an orange solid. GC yield 94%: melting point 60 ° C.

¹ H NMR (CDCl ₃ , Me ₄ Si) δ 0.43 (q, J =
7.8 Hz, 6H), 0.76 (t, J = 7.8 Hz, 9H), 1.32 (t, J
= 7.5 Hz, 3H), 2.51 (s, 3H), 2.92 (q, J = 7.5 Hz, 2
H), 6.77 (s, 1H), 7.20-7.23 (m, 2H), 7.32-7.36 (m,
3H); ¹³ C NMR (CDCl ₃ , Me ₄ Si) δ 5.39, 8.04, 15.2
6, 24.13, 32.37, 122.09, 124.10, 127.64, 127.70,12
8.90, 143.81, 156.76, 159.10, 168.96; IR (neat) 29
57, 2874, 1574, 1520, 1493, 1466, 1441, 1375, 135
0, 1073, 1001, 880, 768, 733, 700 cm ^-1 ; High resolution mass spectrometer Calculated value C ₂₀ H ₂₉ NSi 311.2069, Measured value 311.205
9.

The starting materials, products and yields of Examples 1 to 8 are shown in Table 1. In the table, the yield shows the GC yield, and the parentheses show the isolated yield.

[0075]

[Table 1]

[0076]

INDUSTRIAL APPLICABILITY A polysubstituted pyridine derivative can be regioselectively and conveniently obtained by the method of the present invention.

Continued front page    F-term (reference) 4C055 AA01 BA03 BA06 BA08 CA02                       CA06 CA08 DA06 DA08 FA03                       FA23 FA34 FA37                 4H039 CA42 CH70                 4H049 VN01 VP01 VR24 VS01 VT04                       VU36 VV06

Claims (8)

[Claims] 1. A method for producing a pyridine derivative represented by the following formula (1), wherein: [In the formula, R ¹ , R ² , R ³ and R ⁴ are each independently, the same or different, a hydrogen atom; a C ₁ -C ₂₀ hydrocarbon group which may have a substituent; A C ₁ -C ₂₀ alkoxy group which may have a group; a C ₆ -C ₂₀ aryloxy group which may have a substituent; an amino group which may have a substituent; Optionally a silyl group,
Or a hydroxyl group, provided that R ¹ and R ² may be cross-linked with each other to form a C _{4 to} C ₂₀ saturated ring or an unsaturated ring, and the ring is an oxygen atom, a sulfur atom, a silicon atom, tin. Atom, a germanium atom, or a group represented by the formula —N (B) — (wherein B is a hydrogen atom or a C _{1 to} C ₂₀ hydrocarbon group), and may be interrupted. You may have. ] In the presence of a copper salt, an azametallacyclopentadiene represented by the following formula (2): [Wherein R ¹ , R ² and R ³ have the above-mentioned meanings. M
Represents a transition metal, and L ¹ and L ² each independently represent the same or different and represent an anionic ligand. However, L ¹ and L ² may be crosslinked. ] An alkyne represented by the following formula (3) and [In the formula, R ⁴ has the above meaning. X represents a leaving group. ] The method of manufacturing the pyridine derivative characterized by making it react. 2. The method for producing a pyridine derivative according to claim 1, wherein the copper salt is copper chloride or copper cyanide. 3. R ¹ , R ² and R ³ each independently have the same or different C ₁ -C ₂₀ hydrocarbon group optionally having a substituent or a substituent. 3. The method for producing a pyridine derivative according to claim 1, which is a silyl group which may be present, and R ⁴ is a hydrogen atom. 4. X is a halogen atom or a tosylate group (—O
_{-S (= O) 2 -C 6} H 4 -CH 3), triflate group (-
The method for producing a pyridine derivative according to claim 1, wherein the pyridine derivative is OS (= O) ₂ —CF ₃ ) or a C _{1 to} C ₂₀ alkoxy group. 5. The method for producing a pyridine derivative according to claim 1, wherein M is a transition metal of Groups 4 to 6 of the periodic table. 6. The method according to claim 1, wherein M is zirconium.
A method for producing the pyridine derivative according to any one of 1. 7. The anionic ligand is a delocalized cyclic η ⁵ -coordination system ligand, which may be substituted cyclopentadienyl group, indenyl group, fluorenyl group or azulenyl group. It is a group, The manufacturing method of the pyridine derivative in any one of Claims 1-6. 8. The pyridine derivative represented by the formula (1) is 2- (4-t-butylphenyl) -6-methyl-
3,4-dipropylpyridine, 3,4-diethyl-6-
Methyl-2-phenylpyridine, 2-ethyl-6-methyl-3,4-dipropylpyridine, 2- (4-t-butylphenyl) -6-methyl-3,4-diphenylpyridine, 6-methyl-3 , 4-diphenyl-2-propylpyridine, 3-butyl-6-methyl-2-phenyl-4-
(Trimethylsilyl) pyridine, 3-butyl-6-methyl-2-propyl-4- (trimethylsilyl) pyridine, or 2-ethyl-6-methyl-3-phenyl-4-
The method for producing a pyridine derivative according to any one of claims 1 to 7, which is (triethylsilyl) pyridine.