Method for producing compound having nitrogen-containing aromatic ring, and compound including nitrogen-containing aromatic ring

Abstract

To provide: a method for efficiently oxidizing a metal amide intermediate itself in a one-pot or flow reaction; and a method for using the same to efficiently introduce a substituent at the nitrogen α-position of a nitrogen-containing aromatic compound.SOLUTION: A method for producing a compound including a nitrogen-containing aromatic ring represented by general formula (III) comprises a step of reacting a metal amide compound represented by general formula (I) with an aromatic aldehyde or aromatic ketone represented by general formula (II).SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a method for producing a compound having a nitrogen-containing aromatic ring, and to a compound having a nitrogen-containing aromatic ring. [Background technology]

[0002] Nitrogen-containing aromatic rings include pyridine, quinoline, phenanthroline, etc., and compounds having this as part of their structure are used in a wide range of applications, such as ligands for metal catalysts, medicines, materials, etc. In order to utilize compounds having a nitrogen-containing aromatic ring, which is such a useful structural unit, it may be necessary to introduce an alkyl group or an optionally substituted aryl group or heteroaryl group to the α-position of the aromatic ring nitrogen, and many methods for this have been reported so far.

[0003] For example, a method in which a compound having a nitrogen-containing aromatic ring is reacted with an organometallic such as phenyllithium to obtain a metalamide intermediate, which is then post-treated with a protic solvent such as water to obtain a dihydro compound, which is then subjected to oxidative aromatization using an oxidizing agent such as manganese dioxide, nitrobenzene, chloranil, DDQ, air, or oxygen (e.g., paragraph 0063 of Patent Document 1). etc. are known. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] JP 2004-281390 A Summary of the Invention [Problem to be solved by the invention]

[0005] However, in the method described in Patent Document 1, in order to obtain an oxidatively aromatized compound from a metalamide intermediate, it is necessary to first convert the metalamide intermediate into a dihydro compound rather than directly oxidizing the metalamide intermediate, and a method for efficiently oxidizing the metalamide intermediate itself has not been disclosed or suggested.

[0006] An object of the present invention is to provide a method for efficiently oxidizing a metalamide intermediate itself in a one-pot or flow reaction, and to provide a method for efficiently introducing a substituent to the α-position of nitrogen in a nitrogen-containing aromatic ring compound by utilizing the same. [Means for solving the problem]

[0007] In order to solve the above problems, the present invention has the following configuration. (1) General formula (I)

[0008] [ka]

[0009] [In general formula (I), R 1 ~R 4 are each independently selected from the group consisting of a hydrogen atom, an alkyl group, and an optionally substituted aryl group or heteroaryl group. 1 ~R 4 R may be bonded to adjacent groups to form an optionally substituted fused aryl ring or fused heteroaryl ring. 5 represents an alkyl group, or an optionally substituted aryl group or heteroaryl group; M represents Li, Na, MgCl, or MgBr; and n is an integer of 1 to 2.] A metal amide compound represented by the formula: General formula (II)

[0010] [ka]

[0011] [In general formula (II), R represents a hydrogen atom or an optionally substituted aryl or heteroaryl group, and Ar represents an optionally substituted aryl or heteroaryl group.] With an aromatic aldehyde or aromatic ketone represented by the formula: General formula (III)

[0012] [ka]

[0013] [In general formula (III), R 1 ~R 4 are each independently selected from the group consisting of a hydrogen atom, an alkyl group, and an optionally substituted aryl group or heteroaryl group. 1 ~R 4 R may be bonded to adjacent groups to form an optionally substituted fused aryl ring or fused heteroaryl ring. 5 represents an alkyl group, or an optionally substituted aryl group or heteroaryl group, and n is an integer of 1 to 2.] A method for producing a compound having a nitrogen-containing aromatic ring represented by the formula: (2) A method for producing the compound having a nitrogen-containing aromatic ring according to (1), wherein M in general formula (I) is Li. (3) A method for producing a compound having a nitrogen-containing aromatic ring according to (1) or (2), wherein R in general formula (II) is a hydrogen atom or a phenyl group. (4) General formula (IV)

[0014] [ka]

[0015] [In general formula (IV), R 1 ~R 4 are each independently selected from the group consisting of a hydrogen atom, an alkyl group, and an optionally substituted aryl group or heteroaryl group. 1 ~R 4 adjacent groups may be linked to each other to form an optionally substituted fused aryl ring or fused heteroaryl ring. A compound containing a nitrogen-containing aromatic ring represented by the formula: General formula (V)

[0016] [ka]

[0017] [R 5 represents an alkyl group, or an optionally substituted aryl group or heteroaryl group; M represents Li, Na, MgCl, or MgBr; and n is an integer of 1 to 2.] By reacting the organometallic compound represented by General formula (I)

[0018] [ka]

[0019] [In general formula (I), R 1 ~R 4 are each independently selected from the group consisting of a hydrogen atom, an alkyl group, and an optionally substituted aryl group or heteroaryl group. 1 ~R 4 R may be bonded to adjacent groups to form an optionally substituted fused aryl ring or fused heteroaryl ring. 5 represents an alkyl group, or an optionally substituted aryl group or heteroaryl group; M represents Li, Na, MgCl, or MgBr; and n is an integer of 1 to 2.] The metal amide compound represented by the formula: General formula (II)

[0020] [ka]

[0021] [In general formula (II), R represents a hydrogen atom or an optionally substituted aryl or heteroaryl group, and Ar represents an optionally substituted aryl or heteroaryl group.] With an aromatic aldehyde or aromatic ketone represented by the formula: General formula (III)

[0022] [ka]

[0023] [In general formula (III), R 1 ~R 4 are each independently selected from the group consisting of a hydrogen atom, an alkyl group, and an optionally substituted aryl group or heteroaryl group. 1 ~R 4 R may be bonded to adjacent groups to form an optionally substituted fused aryl ring or fused heteroaryl ring. 5 represents an alkyl group, or an optionally substituted aryl group or heteroaryl group, and n is an integer of 1 to 2.] A method for producing a compound having a nitrogen-containing aromatic ring represented by the formula: (5) A method for producing the compound having a nitrogen-containing aromatic ring according to (4), wherein M in general formula (I) is Li. (6) A method for producing a compound having a nitrogen-containing aromatic ring according to (4) or (5), wherein R in general formula (II) is a hydrogen atom or a phenyl group. (7) General formula (VI)

[0024] [ka]

[0025] [In general formula (VI), R represents a hydrogen atom, or an optionally substituted aryl group or heteroaryl group, and Ar represents an optionally substituted aryl group or heteroaryl group] in an amount equal to or less than a certain threshold value in terms of HPLC area percentage. General formula (III)

[0026] [ka]

[0027] [In general formula (III), R 1 ~R 4 are each independently selected from the group consisting of a hydrogen atom, an alkyl group, and an optionally substituted aryl group or heteroaryl group. 1 ~R 4 R may be bonded to adjacent groups to form an optionally substituted fused aryl ring or fused heteroaryl ring. 5 represents an optionally substituted alkyl group, aryl group or heteroaryl group, and n is an integer of 1 to 2.] A compound containing a nitrogen-containing aromatic ring represented by the formula: Effect of the Invention

[0028] According to the present invention, when a substituent is introduced into the α-position of the nitrogen of a nitrogen-containing aromatic ring compound, the oxidation of the metalamide intermediate itself can be efficiently carried out in a one-pot or flow reaction. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0029] The method for producing a compound containing a nitrogen-containing aromatic ring according to the present invention uses a specific aromatic aldehyde or aromatic ketone in the oxidation step in introducing a substituent into a nitrogen-containing aromatic ring compound by an addition-oxidation reaction.

[0030] (Embodiment 1) The method for producing a compound containing a nitrogen-containing aromatic ring according to embodiment 1 of the present invention is a method for producing a compound containing a nitrogen-containing aromatic ring represented by general formula (III), comprising a step of reacting a metal amide compound represented by general formula (I) with an aromatic aldehyde or aromatic ketone represented by general formula (II).

[0031] [ka]

[0032] The production method according to the first embodiment includes a step of reacting a metal amide compound represented by general formula (I) with an aromatic aldehyde or aromatic ketone represented by general formula (II).

[0033] R in general formula (I) 1 ~R 4 are each independently selected from the group consisting of a hydrogen atom, an alkyl group, and an optionally substituted aryl group or heteroaryl group. Among these, a hydrogen atom, a methyl group, an ethyl group, an isopropyl group, a t-butyl group, an optionally substituted phenyl group, an optionally substituted naphthyl group, an optionally substituted pyridyl group, an optionally substituted quinolyl group, and the like are preferred. 1 ~R 4 may be bonded to adjacent groups to form an optionally substituted fused aryl ring or fused heteroaryl ring, and particularly preferably to form an optionally substituted benzene ring, naphthalene ring, pyridine ring, or quinoline ring.

[0034] R 5 represents an alkyl group, or an optionally substituted aryl group or heteroaryl group. Among these, a methyl group, a t-butyl group, a phenyl group, a naphthyl group, a pyridyl group, and a quinolyl group are preferred, a phenyl group and a naphthyl group are more preferred, and a phenyl group is particularly preferred.

[0035] M is Li, Na, MgCl or MgBr, with Li being particularly preferred. n is an integer of 1 to 2.

[0036] Specific examples of the compound represented by the general formula (I) include lithium 2-phenyl-2H-quinolin-1-ide, lithium 8-methyl-2-phenyl-2H-quinolin-1-ide, lithium 6-methyl-2-phenyl-2H-quinolin-1-ide, lithium 2-phenyl-2H-1,10-phenanthroline-1-ide, lithium 2-methyl-2H-1,10-phenanthroline-1-ide, lithium 2-(t-butyl)-2H-1,10-phenanthroline-1-ide, lithium 2-(naphthalene-1-yl)-2H-1,10-phenanthroline-1-ide, lithium 2-(naphthalene-2-yl)-2H-1,10-phenanthroline-1-ide, lithium 2-(p-tolyl)-2H-1,10-phenanthroline-1-ide, and lithium 2-(4-(t-butyl)phenyl)-2H-1,10-phenanthroline-1-ide, lithium 2,2'-(1,3-phenylene)bis(2H-quinolin-1-ide), lithium 2,2'-(1,3-phenylene)bis(8-methyl-2H-quinolin-1-ide), lithium 2,2'-(1,3-phenylene)bis(6-methyl-2H-quinolin-1-ide), lithium 2,2'-(1,4-phenylene)bis(2H-quinolin-1-ide), lithium 2,2'-(naphthalene-1,7-diyl)bis(2H-quinolin-1-ide), lithium 2,2'-(naphthalene-2,7-diyl)bis(2H-quinolin-1-ide), lithium 2,2'-(naphthalene-2,6-diyl)bis(2H-quinolin-1-ide), lithium 2,2'-(1,3-phenylene)bis(2H-benzo[h]quinolin-1-ide), lithium 2,2'-(1,3-phenylene)bis(9-methyl-2H-benzo[h]quinolin-1-ide), lithium 2,2'-(1,3-phenylene)bis(9-phenyl-2H-benzo[h]quinolin-1-ide), lithium 2,2'-(1,3-phenylene)bis(2H-1,10-phenanthroline-1-ide), lithium 2,2'-(1,3-phenylene)bis(9-methyl-2H-1,10-phenanthroline-1-ide), lithium 2,2'-(1,3-phenylene)bis(9-phenyl-2H-1,10-phenanthroline-1-ide), lithium 2,2'-(1,3-phenylene)bis(9-(naphthalene-1-yl)-2H-1,10-phenanthroline-1-ide), lithium 2,2'-(1,3-phenylene)bis(9-(naphthalene-2-yl)-2H-1,10-phenanthroline-1-ide), lithium 2,2'-(1,3-phenylene)bis(9-(p-tolyl)-2H-1,10-phenanthroline-1-ide), lithium 2,2'-(1,3-phenylene)bis(9-(4-(t-butyl)phenyl)-2H-1,10-phenanthroline-1-ide), lithium 2,2'-(1,4-phenylene)bis(2H-1,10-phenanthroline-1-ide), lithium 2,2'-(1,4-phenylene)bis(9-methyl-2H-1,10-phenanthroline-1-ide), lithium 2,2'-(1,4-phenylene)bis(9-phenyl-2H-1,10-phenanthroline-1-ide), lithium 2,2'-(1,7-naphthalene-diyl)bis(2H-1,10-phenanthroline-1-ide), lithium 2,2'-(1,7-naphthalene-diyl)bis(9-phenyl-2H-1,10-phenanthroline-1-ide), lithium 2,2'-(2,7-naphthalene-diyl)bis(9-phenyl-2H-1,10-phenanthroline-1-ide), lithium Examples include, but are not limited to, 2,2'-(2,6-naphthalene-diyl)bis(9-phenyl-2H-1,10-phenanthroline-1-ide).

[0037] In the general formula (II), R is a hydrogen atom or an optionally substituted aryl or heteroaryl group, and is preferably a hydrogen atom or a phenyl group.

[0038] Ar is an optionally substituted aryl or heteroaryl group, preferably an optionally substituted phenyl, pyridyl or naphthyl group, with an optionally substituted phenyl or pyridyl group being particularly preferred.

[0039] Specific examples of the compound represented by general formula (II) include benzaldehyde, 2-methylbenzaldehyde, 3-methylbenzaldehyde, 4-methylbenzaldehyde, 2-methoxybenzaldehyde, 3-methoxybenzaldehyde, 4-methoxybenzaldehyde, 2-chlorobenzaldehyde, 3-chlorobenzaldehyde, 4-chlorobenzaldehyde, picolinaldehyde, nicotinaldehyde, isonicotinaldehyde, benzophenone, di-p-tolylmethanone, bis(4-methoxyphenyl)methanone, and bis(4-chlorophenyl)methanone, but are not limited thereto.

[0040] The compound represented by the general formula (III) is a compound represented by the general formula (I) in which the -N(M)-position is converted to -N=. Therefore, the explanation of each group and n in the general formula (III) is the same as the explanation of each group and n in the general formula (I).

[0041] Specific examples of the compound represented by the general formula (III) include 2-phenylquinoline, 8-methyl-2-phenylquinoline, 6-methyl-2-phenylquinoline, 2-phenyl-1,10-phenanthroline, 2-methyl-1,10-phenanthroline, 2-(t-butyl)-1,10-phenanthroline, 2-(naphthalene-1-yl)-1,10-phenanthroline, 2-(naphthalene-2-yl)-1,10-phenanthroline, 2-(p-tolyl)-1,10-phenanthroline, 2-(4-(t-butyl)-1,10-phenanthroline, 1,3-Di(quinolin-2-yl)benzene, 1,3-bis(8-methylquinolin-2-yl)benzene, 1,3-bis(6-methylquinolin-2-yl)benzene, 1,4-di(quinolin-2-yl)benzene, 2,2'-(naphthalene-1,7-diyl)diquinoline, 2,7-di(quinolin-2-yl)naphthalene, 2,6-di(quinolin-2-yl)naphthalene, 1,3-bis(benzo[h]quinolin-2-yl)benzene, 1,3-bis(9-methyl benzo[h]quinolin-2-yl)benzene, 1,3-bis(9-phenylbenzo[h]quinolin-2-yl)benzene, 1,3-di(1,10-phenanthroline-2-yl)benzene, 1,3-bis(9-methyl-1,10-phenanthroline-2-yl)benzene, 1,3-bis(9-phenyl-1,10-phenanthroline-2-yl)benzene, 1,3-bis(9-phenyl-1,10-phenanthroline-2-yl)benzene, 1,3-bis(9-(naphthalen-1-yl)-1,10-phenanthroline-2-yl)benzene, 1,3-bis(9-(naphthalen-2-yl)-1 ,10-phenanthroline-2-yl)benzene, 1,3-bis(9-(p-tolyl)-1,10-phenanthroline-2-yl)benzene, 1,3-bis(9-(4-t-butyl)phenyl)-1,10-phenanthroline-2-yl)benzene, 1,4-di(1,10-phenanthroline-2-yl)benzene, 1,4-bis(9-methyl-1,10-phenanthroline-2-yl)benzene, 1,4-bis(9-phenyl-1,10-phenanthroline-2-yl)benzene, 2,2'-(naphthalene-1,7-diyl)bis(1,10-phenanthroline), 9,9'-(naphthalene-1,7-diyl)bis(2-phenyl-1,10-phenanthroline), 2,Examples of the naphthalene include, but are not limited to, 7-bis(9-phenyl-1,10-phenanthroline-2-yl)naphthalene and 2,6-bis(9-phenyl-1,10-phenanthroline-2-yl)naphthalene.

[0042] The equivalent of the aromatic aldehyde or aromatic ketone represented by general formula (II) relative to the metal amide compound represented by general formula (I) is preferably 0.5 to 3.0 equivalents, more preferably 0.8 to 1.5 equivalents, and even more preferably 0.9 to 1.1 equivalents when n is 1 in general formula (I). When n is 2, the equivalent is preferably 1.0 to 6.0 equivalents, more preferably 1.6 to 3.0 equivalents, and even more preferably 1.8 to 2.2 equivalents.

[0043] The solvent to be used is not particularly limited as long as it does not interfere with the reaction, but preferred are saturated hydrocarbons having 5 to 8 carbon atoms, such as pentane, hexane, heptane, octane, and cyclohexane; and ether solvents, such as diethyl ether, t-butyl methyl ether, cyclopentyl methyl ether, tetrahydrofuran, 1,4-dioxane, and dimethoxyethane, or mixed solvents thereof.

[0044] The reaction can be carried out at a temperature in the range of -70 to 100°C, preferably -40 to 40°C, and more preferably -30 to 30°C.

[0045] The reaction time is not particularly limited and can be appropriately selected depending on the reaction temperature, but the reaction is completed in about 5 minutes to 24 hours.

[0046] According to the first embodiment, by reacting a metalamide compound with an aromatic aldehyde or aromatic ketone, the step of converting the metalamide compound to a dihydro form, which was previously required, becomes unnecessary, and the metalamide compound can be efficiently oxidized in a one-pot or flow reaction.

[0047] When a metalamide compound is reacted with an aliphatic aldehyde or an aliphatic ketone, the metalamide compound abstracts the proton at the α-position of the aldehyde or ketone, deactivating it, making it difficult to oxidize it.

[0048] (Embodiment 2) The method for producing a compound containing a nitrogen-containing aromatic ring according to the second embodiment of the present invention is a method for producing a compound containing a nitrogen-containing aromatic ring represented by general formula (III), which comprises reacting a compound containing a nitrogen-containing aromatic ring represented by general formula (IV) with an organometallic represented by general formula (V) to obtain a metal amide compound represented by general formula (I), which is then reacted, without post-treatment, with an aromatic aldehyde or aromatic ketone represented by general formula (II).

[0049] [ka]

[0050] The manufacturing method according to the second embodiment includes (A) a first step of reacting a compound containing a nitrogen-containing aromatic ring represented by general formula (IV) with an organometallic represented by general formula (V) to obtain a metalamide compound represented by general formula (I), and (B) a second step of reacting the metalamide compound represented by general formula (I) with an aromatic aldehyde or aromatic ketone represented by general formula (II). Of these, the second step is the same as in the manufacturing method according to the first embodiment. Therefore, the description of the compounds represented by general formulas (I) to (III) in the second embodiment is the same as in the first embodiment.

[0051] Moreover, the compound represented by the general formula (IV) and the compound represented by the general formula (V) are raw material compounds for synthesizing the compound represented by the general formula (I). Therefore, the explanation of each group and n in the general formulas (IV) and (V) is the same as the explanation of each group in the general formula (I).

[0052] Specific examples of the compound represented by general formula (IV) include quinoline, 8-methylquinoline, 6-methylquinoline, benzo[h]quinoline, 9-methylbenzo[h]quinoline, 9-phenylbenzo[h]quinoline, 1,10-phenanthroline, 2-methyl-1,10-phenanthroline, 2-phenyl-1,10-phenanthroline, 2-(naphthalene-1-yl)-1,10-phenanthroline, 2-(naphthalene-2-yl)-1,10-phenanthroline, 2-(p-tolyl)-1,10-phenanthroline, and 2-(4-(t-butyl)phenyl)-1,10-phenanthroline, but are not limited thereto.

[0053] Specific examples of the compound represented by general formula (V) include phenyllithium, methyllithium, t-butyllithium, naphthalene-1-yllithium, naphthalene-2-yllithium, p-tolyllithium, (4-(t-butyl)phenyl)lithium, 1,3-dilithiobenzene, 1,4-dilithiobenzene, 1,7-dilithionaphthalene, and 2,7-dilithionaphthalene, but are not limited to these.

[0054] The equivalent of the organometallic compound represented by general formula (V) used in the first step relative to the compound containing a nitrogen-containing aromatic ring represented by general formula (IV) is preferably 0.5 to 3.0 equivalents, more preferably 0.8 to 1.5 equivalents, and even more preferably 0.9 to 1.1 equivalents when n in general formula (V) is 1. When n is 2, the equivalent is preferably 0.25 to 1.50 equivalents, more preferably 0.40 to 0.75 equivalents, and even more preferably 0.45 to 0.55 equivalents.

[0055] The solvent to be used is not particularly limited as long as it does not interfere with the reaction, but preferred are saturated hydrocarbons having 5 to 8 carbon atoms, such as pentane, hexane, heptane, octane, and cyclohexane; and ether solvents, such as diethyl ether, t-butyl methyl ether, cyclopentyl methyl ether, tetrahydrofuran, 1,4-dioxane, and dimethoxyethane, or mixed solvents thereof.

[0056] The reaction can be carried out at a temperature in the range of -70 to 100°C, preferably -40 to 40°C, and more preferably -30 to 0°C.

[0057] The reaction time is not particularly limited and can be appropriately selected depending on the reaction temperature, but the reaction is completed in about 5 minutes to 24 hours.

[0058] The second step can be carried out in the same manner as in the manufacturing method according to the above-mentioned embodiment 1. Here, after the first step is completed, the obtained metalamide compound represented by general formula (I) can be directly subjected to the second step without post-treatment.

[0059] According to the second embodiment, by reacting a metal amide compound with an aromatic aldehyde or aromatic ketone, the step of converting the metal amide compound into a dihydro compound, which was previously required, becomes unnecessary. By utilizing this, the reaction of introducing a substituent into the α-position of the nitrogen of the nitrogen-containing aromatic ring compound, which is the raw material compound, can be efficiently carried out in a one-pot or flow reaction.

[0060] (Compounds containing nitrogen-containing aromatic rings) The compound containing a nitrogen-containing aromatic ring according to the embodiment of the present invention is a compound containing a nitrogen-containing aromatic ring represented by general formula (III) containing a compound represented by general formula (VI) in an amount equal to or less than a certain threshold value. Here, containing an amount equal to or less than a certain threshold value means that the amount is preferably more than 0% and less than 1%, more preferably less than 0.5%, and even more preferably less than 0.1% by HPLC area percentage.

[0061] [ka]

[0062] The compound represented by the general formula (III) is the same as that shown in the first embodiment, and therefore the description thereof is the same as that in the first embodiment.

[0063] In the general formula (VI), R is a hydrogen atom or an optionally substituted aryl or heteroaryl group, preferably a hydrogen atom or a phenyl group, more preferably a hydrogen atom.Ar is an optionally substituted aryl or heteroaryl group, preferably an optionally substituted phenyl group, pyridyl group or naphthyl group, particularly preferably an optionally substituted phenyl group or pyridyl group.

[0064] Specific examples of the compound represented by general formula (VI) include benzyl alcohol, 2-methylbenzyl alcohol, 3-methylbenzyl alcohol, 4-methylbenzyl alcohol, 2-methoxybenzyl alcohol, 3-methoxybenzyl alcohol, 4-methoxybenzyl alcohol, 2-chlorobenzyl alcohol, 3-chlorobenzyl alcohol, 4-chlorobenzyl alcohol, pyridin-2-ylmethanol, pyridin-3-ylmethanol, pyridin-4-ylmethanol, diphenylmethanol, di-p-tolylmethanol, bis(4-methoxyphenyl)methanol, and bis(4-chlorophenyl)methanol, but are not limited to these.

[0065] When the method for producing a compound containing a nitrogen-containing aromatic ring according to the embodiment of the present invention is used, the compound represented by general formula (II) is reduced to produce an equivalent amount of a compound represented by general formula (VI) as a process by-product, which coexists with the target compound represented by general formula (III). A certain amount of the compound represented by general formula (VI) can be removed by a general purification method such as recrystallization or chromatography. Here, the degree of purification varies depending on the application of the compound represented by general formula (III), for example, if it is a pharmaceutical product, impurities exceeding 0.1% in terms of HPLC area percentage require structural determination, and if it is an electronic material, a specification of 99.9% or more in terms of HPLC area percentage may be required. In either case, exceeding a certain threshold leads to a decrease in quality, so a compound whose process by-product is below a certain threshold is useful. EXAMPLES

[0066] The present invention will be described in more detail with reference to the following examples, but the present invention is not limited thereto.

[0067] For compounds used in the synthesis of the compounds in the examples and comparative examples without a description of the synthesis method, commercially available compounds were used. 400MHz NMR spectra were measured using a JNM-ECZ400S nuclear magnetic resonance spectrometer (manufactured by JEOL Ltd.). The solvent names shown in the NMR data indicate the solvents used in the measurements. Chemical shifts were expressed as δ (unit: ppm) based on tetramethylsilane, and signals were expressed as s (singlet), d (doublet), t (triplet), q (quadruple), m (multiplet), and br (broad), respectively. ESI-MS spectra were measured using an Agilent 1260 Infinity II LC / single quadrupole MSD (manufactured by Agilent Technologies). HPLC was measured using the following method.

[0068] <Measurement conditions> Detector: Photodiode array detector (measurement wavelength: 254 nm) Column: (inner diameter: 4.6 mm, length: 250 mm, particle size: 5.0 μm) (YMC) Column temperature: 45℃ Mobile phase A: 20 mM dipotassium hydrogen phosphate in water Mobile phase B: Methanol Gradient conditions: Time after injection (min) 0 Mobile phase A (%) 40 Mobile phase B (%) 60 Time after injection (min) 15 Mobile phase A (%) 40 Mobile phase B (%) 60 Time after injection (min) 30 Mobile phase A (%) 10 Mobile phase B (%) 90 Time after injection (min) 45 Mobile phase A (%) 10 Mobile phase B (%) 90 Flow rate: 1.0mL / min Injection volume: 2.0μL Sample cooler temperature: 5.0℃ Injector cleaning solution: acetonitrile / water (6 / 4).

[0069] Example 1 Synthesis of 2-phenylquinoline To a solution of 0.49 mL (4.6 mmol) of bromobenzene in dibutyl ether (1.1 mL), 3.0 mL (4.7 mmol) of n-butyl lithium (1.6 M hexane solution) was added at -20 to -15 °C, and the mixture was reacted for 1 hour at 5 to 10 °C to obtain a phenyllithium solution. The solution was added to a solution of 0.46 mL (3.9 mmol) of quinoline in THF (15 mL) cooled to -20 °C, and stirred for 1 hour at -20 °C. To the resulting reaction solution, 0.40 mL (3.0 mmol) of benzaldehyde was added at -10 °C, and the mixture was reacted for 1 hour at 20 °C to obtain 2-phenylquinoline with an HPLC purity of 88.1%. 1 H-NMR (400MHz, CDCl3)δppm 8.23(d, J=8.4Hz, 1H), 8.19-8.15(m, 3H), 7.89(d, J=8.8Hz, 1H), 7.84(d, J=8.0Hz, 1H) , 7.73(dt, J=6.8, 1.2Hz, 1H), 7.54(t, J=7.6Hz, 3H), 7.47(tt, J=6.4, 2.8.1.2Hz, 1H). ESI-MS: 206.1 (M+1).

[0070] Example 2 In the same manner as in Example 1, 2-phenylquinoline was obtained with an HPLC purity of 87.5%, except that 2-pyridinecarboxaldehyde was used instead of benzaldehyde.

[0071] Example 3 In the same manner as in Example 1, 2-phenylquinoline was obtained with an HPLC purity of 87.7%, except that o-anisaldehyde was used instead of benzaldehyde.

[0072] Example 4 In the same manner as in Example 1, 2-phenylquinoline was obtained with an HPLC purity of 99.0%, except that benzophenone was used instead of benzaldehyde.

[0073] Comparative Example 1 When acetone was used in place of benzaldehyde in the same manner as in Example 1, the HPLC purity of 2-phenylquinoline was 12.6%.

[0074] Example 5 Synthesis of 2-phenyl-1,10-phenanthroline To a solution of 0.35 mL (3.3 mmol) of bromobenzene in dibutyl ether (1.2 mL), 2.1 mL (3.3 mmol) of n-butyl lithium (1.6 M hexane solution) was added at -20 to -15 °C, and the mixture was reacted at 5 to 10 °C for 4 hours to obtain a phenyllithium solution. The solution was added to a solution of 0.5 g (2.8 mmol) of phenanthroline in THF (10.2 mL) cooled to -20 °C, and stirred at -20 °C for 1 hour. To the resulting reaction solution, 0.28 mL (3.3 mmol) of benzaldehyde was added at -10 °C, and the mixture was reacted at 20 °C for 1 hour to obtain 2-phenyl-1,10-phenanthroline with an HPLC purity of 86.6%. 1 H-NMR (400MHz, CHCl3)δppm 9.25(dd, J=4.0,1.6Hz, 1H), 8.34(t, J=8.0Hz, 3H), 8.27(dd, J=7.6, 3.6Hz, 1H), 8.12(d, J=8.0Hz, 1H), 7.81(q, J=8.4Hz, 2H), 7.65(m, 1H), 7.57-7.54(m, 2H), 7.50-7.48(m, 1H). ESI-MS: 257.1 (M+1) Example 6 In the same manner as in Example 5, except that 2-pyridinecarboxaldehyde was used instead of benzaldehyde, 2-phenyl-1,10-phenanthroline was obtained with an HPLC purity of 82.3%.

[0075] Example 7 The procedure of Example 5 was repeated except that o-anisaldehyde was used instead of benzaldehyde to obtain 2-phenyl-1,10-phenanthroline with an HPLC purity of 86.5%.

[0076] Example 8 In the same manner as in Example 5, except that benzophenone was used instead of benzaldehyde, 2-phenyl-1,10-phenanthroline was obtained with an HPLC purity of 87.0%.

[0077] Comparative Example 2 When acetone was used in place of benzaldehyde in the same manner as in Example 5, the HPLC purity of 2-phenyl-1,10-phenanthroline was 9.6%.

[0078] Comparative Example 3 When the reaction was carried out in the same manner as in Example 5, but using p-benzoquinone instead of benzaldehyde, the HPLC purity of 2-phenyl-1,10-phenanthroline was 70.0%. [Industrial Applicability]

[0079] The production method of the present invention is useful for introducing a substituent into the α-position of nitrogen in a nitrogen-containing aromatic ring compound by an addition-oxidation reaction.

Claims

1. General formula (I) 【Chemistry 1】 [In general formula (I), R １ ~R ４ Each is independently selected from the group consisting of a hydrogen atom, an alkyl group, and an optionally substituted aryl group or heteroaryl group. １ ~R ４ The adjacent groups may be linked to each other to form a fused aryl ring or a fused heteroaryl ring, which may be substituted. ５ represents an alkyl group or an optionally substituted aryl or heteroaryl group. M represents Li, Na, MgCl, or MgBr. n is an integer between 1 and 2. A metalamide compound represented by, General formula (II) 【Chemistry 2】 [In general formula (II), R represents a hydrogen atom or an optionally substituted aryl or heteroaryl group, and Ar represents an optionally substituted aryl or heteroaryl group.] The process comprises reacting an aromatic aldehyde or aromatic ketone represented by [formula] with [another form of aromatic aldehyde]. General formula (III) 【Transformation 3】 [In general formula (III), R １ to R ４ are each independently selected from the group consisting of a hydrogen atom, an alkyl group, and an aryl group or heteroaryl group which may be substituted. R １ to R ４ may be such that adjacent groups are linked to each other to form a condensed aryl ring or condensed heteroaryl ring which may be substituted. R ５ represents an alkyl group or an aryl group or heteroaryl group which may be substituted. n is an integer of 1 to 2.] A method for producing a compound containing a nitrogen-containing aromatic ring, represented by [the formula shown].

2. A method for producing a compound containing a nitrogen-containing aromatic ring according to claim 1, wherein M in general formula (I) is Li.

3. A method for producing a compound containing a nitrogen-containing aromatic ring according to claim 1 or 2, wherein R in general formula (II) is a hydrogen atom or a phenyl group.

4. General formula (IV) 【Chemistry 4】 [In general formula (IV), R １ ~R ４ Each is independently selected from the group consisting of a hydrogen atom, an alkyl group, and an optionally substituted aryl group or heteroaryl group. １ ~R ４ The adjacent groups may be linked to each other to form a fused aryl ring or a fused heteroaryl ring, which may be substituted. Compounds containing a nitrogen-containing aromatic ring, represented by the following: General formula (V) 【Transformation 5】 [R ５ represents an alkyl group or an optionally substituted aryl or heteroaryl group. M represents Li, Na, MgCl, or MgBr. n is an integer between 1 and 2. By reacting organometallic compounds represented by, General formula (I) 【Transformation 6】 [In general formula (I), R １ ~R ４ Each is independently selected from the group consisting of a hydrogen atom, an alkyl group, and an optionally substituted aryl group or heteroaryl group. １ ~R ４ The adjacent groups may be linked to each other to form a fused aryl ring or a fused heteroaryl ring, which may be substituted. ５ represents an alkyl group or an optionally substituted aryl or heteroaryl group. M represents Li, Na, MgCl, or MgBr. n is an integer between 1 and 2. Let the metalamide compound be represented by this, General formula (II) 【Transformation 7】 [In general formula (II), R represents a hydrogen atom or an optionally substituted aryl or heteroaryl group, and Ar represents an optionally substituted aryl or heteroaryl group.] The process comprises reacting an aromatic aldehyde or aromatic ketone represented by [formula] with [another form of aromatic aldehyde]. General formula (III) 【Transformation 8】 [In general formula (III), R １ ~R ４ Each is independently selected from the group consisting of a hydrogen atom, an alkyl group, and an optionally substituted aryl group or heteroaryl group. １ ~R ４ The adjacent groups may be linked to each other to form a fused aryl ring or a fused heteroaryl ring, which may be substituted. ５ n represents an alkyl group or an optionally substituted aryl or heteroaryl group. n is an integer between 1 and 2. A method for producing a compound containing a nitrogen-containing aromatic ring, represented by [the formula shown].

5. A method for producing a compound containing a nitrogen-containing aromatic ring according to claim 4, wherein M in general formula (I) is Li.

6. A method for producing a compound containing a nitrogen-containing aromatic ring according to claim 4 or 5, wherein R in general formula (II) is a hydrogen atom or a phenyl group.

7. General formula (VI) 【Chemistry 9】 [In general formula (VI), R represents a hydrogen atom or an optionally substituted aryl or heteroaryl group, and Ar represents an optionally substituted aryl or heteroaryl group.] The compound represented by is contained in an amount below a certain threshold in terms of HPLC area percentage. General formula (III) 【Chemistry 10】 [In general formula (III), R １ ~R ４ Each is independently selected from the group consisting of a hydrogen atom, an alkyl group, and an optionally substituted aryl group or heteroaryl group. １ ~R ４ The adjacent groups may be linked to each other to form a fused aryl ring or a fused heteroaryl ring, which may be substituted. ５ [where n is an integer between 1 and 2] A compound containing a nitrogen-containing aromatic ring represented by [the formula shown].

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