WO2015160125A1

WO2015160125A1 - Novel preparation method of quinoline n-oxide derivative with amide group

Info

Publication number: WO2015160125A1
Application number: PCT/KR2015/003364
Authority: WO
Inventors: Sukbok CAHNG; Heejun HWANG; Jinwoo Kim; Jisu Jeong
Original assignee: Institute For Basic Science; Korea Advanced Institute Of Science And Technology
Priority date: 2014-04-18
Filing date: 2015-04-03
Publication date: 2015-10-22
Also published as: KR101578504B1; KR20150120772A

Abstract

Provided are a preparation method of a quinoline N-oxide derivative with an amide group capable of easily introducing the amide group into the quinoline N-oxide derivative by simplified processes and mild reaction conditions, and a quinoline N-oxide derivative with an amide group prepared by using the same.

Description

NOVEL PREPARATION METHOD OF QUINOLINE N-OXIDE DERIVATIVE WITH AMIDE GROUP

The present invention relates to a novel preparation method of a quinoline N-oxide derivative with an amide group, and more specifically, to a preparation method of a quinoline N-oxide derivative with an amide group obtained by selectively introducing the amide group at a C-8 position of a quinoline N-oxide derivative, and a quinoline N-oxide derivative with an amide group prepared by using the same.

Since heteroaryl compounds including at least one heteroatom, more specifically, quinoline is capable of being variously utilized in the pharmaceutical industry and material industry, a preparation method of a derivative thereof has been dveloped in various ways.

However, most preparation methods of the quinoline derivative need complicated steps, and therefore, more simplified processes have been required.

Accordingly, methods of activating a C-H bond of quinoline and quinoline N-oxide which is easily convertible into quinoline to directly form a carbon-carbon bond and a carbon-halogen bond have been recently suggested.

However, these methods are to introduce a functional group at a C-2 position of the quinoline or the quinoline N-oxide (Wu, J. L.; Cui, X. L.; Chen, L. M.; Jiang, G. J.; Wu, Y. J. J. Am. Chem. Soc. 2009, 131, 13888; Campeau, L.-C.; Stuart, D. R.; Leclerc, J.-P.; Bertrand-Laperle, M.; Villemure, E.; Sun, H.-Y.; Lasserre, S.; Guimond, N.; Lecavallier, M.; Fagnou, K. J. Am. Chem. Soc. 2009, 131, 3291).

However, compounds with an amide group at a C-8 position of quinoline as shown below have been used in various fields, such that a simple and effective method in which an amide group is regioselectively introduced at the C-8 position rather than a C-2 position is required:

[Related Art Document]

(Non-Patent Document 1) J. Am. Chem. Soc. 2009, 131, 13888

(Non-Patent Document 2) J. Am. Chem. Soc. 2009, 131, 3291

An object of the present invention is to provide a preparation method of a quinoline N-oxide derivative with an amide group obtained by introducing the amide group at a C-8 position of a quinoline N-oxide derivative, and a quinoline N-oxide derivative with an amide group prepared by using the same.

The present inventors found that an amide group is regioselectively introduced at a C-8 position at the time of reacting a quinoline N-oxide derivative with an azide compound in the presence of an iridium catalyst and an acid, and completed the present invention.

That is, the present invention provides a preparation method of a quinoline N-oxide derivative with an amide group which can be used as an intermediate or a raw material of various pharmaceutical products and materials, and a quinoline N-oxide derivative with an amide group. More specifically, in one general aspect, a preparation method of a quinoline N-oxide derivative with an amide group, represented by Chemical Formula 1 below, includes: performing a reaction of a quinoline N-oxide derivative represented by Chemical Formula 3 below with an azide compound represented by Chemical Formula 4 below in the presence of an iridium catalyst and an acid.

[Chemical Formula 1]

[Chemical Formula 3]

[Chemical Formula 4]

in Chemical Formulas 1, 3, and 4,

A1 and A2 are each independently N or CR, R is hydrogen, halogen, nitro, formyl, (C1-C10)alkyl, (C1-C10)alkoxy, (C1-C10)alkoxycarbonyl, (C6-C12)aryl, (C6-C12)aryloxycarbonyl, (C3-C12)heterocycloalkyl, (C3-C12)heteroaryl, -OSi(R11)(R12)(R13) or -N(R14)(R15);

R1 to R4 are each independently hydrogen, halogen, nitro, formyl, (C1-C10)alkyl, (C1-C10)alkoxy, (C1-C10)alkoxycarbonyl, (C6-C12)aryl, (C6-C12)aryloxycarbonyl, (C3-C12)heterocycloalkyl, (C3-C12)heteroaryl, -OSi(R11)(R12)(R13) or -N(R14)(R15);

R11 to R15 are each independently hydrogen or (C1-C10)alkyl;

Z is -S(O)2- or -CO-;

T is (C1-C10)alkylene, (C6-C12)arylene or (C6-C12)heteroarylene;

R10 is hydrogen, halogen, nitro, (C1-C10)alkyl, (C1-C10)alkoxy, (C1-C10)alkoxycarbonyl, (C6-C12)aryl, (C6-C12)aryloxycarbonyl, (C3-C12)heterocycloalkyl or (C3-C12)heteroaryl;

R1 to R4 and R may be each independently linked with an adjacent substituent via (C3-C12)alkylene or (C3-C12)alkenylene with or without a fused ring to form an alicyclic ring and a monocyclic or polycyclic aromatic ring; and

the alkyl, alkoxy, alkoxycarbonyl, aryl, aryloxycarbonyl, heterocycloalkyl, heteroaryl, alicyclic ring, and aromatic ring of R1 to R4 and R, and the alkyl of R11 to R15 may be further substituted with at least one selected from the group consisting of halogen, hydroxy, amino, nitro, carboxy, (C1-C10)alkyl, halo(C1-C10)alkyl, (C6-C12)aryl, (C3-C12)heteroaryl, 5- to 7-membered heterocycloalkyl, (C3-C12)cycloalkyl, (C2-C10)alkenyl, (C2-C10)alkynyl, cyano, (C6-C12)ar(C1-C10)alkyl and (C1-C10)alkyl(C6-C12)aryl.

In addition, in another general aspect, a preparation method of a quinoline N-oxide derivative with an amide group represented by Chemical Formula 2 below, includes: performing a reaction of a quinoline N-oxide derivative represented by Chemical Formula 5 below with an azide compound represented by Chemical Formula 4 below in the presence of an iridium catalyst and an acid:

[Chemical Formula 2]

[Chemical Formula 5]

[Chemical Formula 4]

in Chemical Formulas 2, 4, and 5,

A1 and A3 are each independently N or CR, R is hydrogen, halogen, nitro, formyl, (C1-C10)alkyl, (C1-C10)alkoxy, (C1-C10)alkoxycarbonyl, (C6-C12)aryl, (C6-C12)aryloxycarbonyl, (C3-C12)heterocycloalkyl, (C3-C12)heteroaryl, -OSi(R11)(R12)(R13) or -N(R14)(R15);

R1 to R8 are each independently hydrogen, halogen, nitro, formyl, (C1-C10)alkyl, (C1-C10)alkoxy, (C1-C10)alkoxycarbonyl, (C6-C12)aryl, (C6-C12)aryloxycarbonyl, (C3-C12)heterocycloalkyl, (C3-C12)heteroaryl, -OSi(R11)(R12)(R13) or -N(R14)(R15);

R11 to R15 are each independently hydrogen or (C1-C10)alkyl;

Z is -S(O)2- or -CO-;

T is (C1-C10)alkylene, (C6-C12)arylene or (C6-C12)heteroarylene;

R1 to R8 and R may be each independently linked with an adjacent substituent via (C3-C12)alkylene or (C3-C12)alkenylene with or without a fused ring to form an alicyclic ring and a monocyclic or polycyclic aromatic ring; and

the alkyl, alkoxy, alkoxycarbonyl, aryl, aryloxycarbonyl, heterocycloalkyl, heteroaryl, alicyclic ring, and aromatic ring of R1 to R8 and R, and the alkyl of R11 to R15 may be further substituted with at least one selected from the group consisting of halogen, hydroxy, amino, nitro, carboxy, (C1-C10)alkyl, halo(C1-C10)alkyl, (C6-C12)aryl, (C3-C12)heteroaryl, 5- to 7-membered heterocycloalkyl, (C3-C12)cycloalkyl, (C2-C10)alkenyl, (C2-C10)alkynyl, cyano, (C6-C12)ar(C1-C10)alkyl and (C1-C10)alkyl(C6-C12)aryl.

In the preparation method of the quinoline N-oxide derivative with the amide group according to the present invention, the amide group is introduced at a C-8 position by performing an amidation reaction in the presence of an iridium catalyst and an acid to regioselectively activate C-H bond at the C-8 position rather than a C-2 position.

The preparation method of the quinoline N-oxide derivative with the amide group according to the present invention is significantly effective in that a product with an amide group regioselectively introduced at the C-8 position is capable of being obtained in high yield by simplified processes and mild reaction conditions.

As a result obtained from comparative experiment with a compound 1a substituted with heavy hydrogen as shown in Reaction Formula 1 below for mechanistic study of the present invention, it was confirmed that there was no significant difference in a reaction rate, and therefore, this step was not a rate-determining step. It was demonstrated that a crystal (8) was capable of being obtained by reaction of iridium and quinoline N-oxide as a reaction intermediate as shown in Reaction Formula 2, and a final compound was capable of being obtained by using the crystal (8) as a catalyst as shown in Reaction Formula 3. Based on the above description, it is expected that according to the mechanism of the present invention, reaction intermediate II and III are produced by a reaction with an azide compound after a C-H activation reaction (I), and a final catalytic reaction is completed with an acid as shown in Reaction Formula 4 below.

[Reaction Formula 1]

[Reaction Formula 2]

[Reaction Formula 3]

[Reaction Formula 4]

Preferably, Chemical Formula 1 in the present invention may be represented by Chemical Formulas 6 to 9 below:

[Chemical Formula 6]

[Chemical Formula 7]

[Chemical Formula 8]

[Chemical Formula 9]

in Chemical Formulas 6 to 9,

R11 to R15 are each independently hydrogen or (C1-C10)alkyl;

Z is -S(O)2- or -CO-;

T is (C1-C10)alkylene, (C6-C12)arylene or (C6-C12)heteroarylene;

R10 is hydrogen, halogen, nitro, (C1-C10)alkyl, (C1-C10)alkoxy, (C1-C10)alkoxycarbonyl, (C6-C12)aryl, (C6-C12)aryloxycarbonyl, (C3-C12)heterocycloalkyl or (C3-C12)heteroaryl; and

R21 to R25 are each independently hydrogen, halogen, hydroxy, amino, nitro, carboxy, (C1-C10)alkyl, halo(C1-C10)alkyl, (C6-C12)aryl, (C3-C12)heteroaryl, 5- to 7-membered heterocycloalkyl, (C3-C12)cycloalkyl, (C2-C10)alkenyl, (C2-C10)alkynyl, cyano, (C6-C12)ar(C1-C10)alkyl or (C1-C10)alkyl(C6-C12)aryl.

Preferably, in Chemical Formula 1 or 2 according to an exemplary embodiment of the present invention, T may be phenylene, naphthalene or anthracene.

More specifically, the quinoline N-oxide derivative with an amide group according to an exemplary embodiment of the present invention may be selected from the following compounds, but the present invention is not limited thereto:

The term 「alkyl」, 「alkoxy」, and other substituents including 「alkyl」 part described in the present invention include all linear or branched types. In addition, the term 「aryl」 described in the present invention, which is an organic radical derived from aromatic hydrocarbon by removal of one hydrogen, includes single or fused ring system including ring atoms of 4 to 7, preferably, 5 or 6 in each ring, and includes a form in which a plurality of aryls are linked by a single bond. Specific examples of the aryl include phenyl, naphthyl, biphenyl, anthryl, indenyl, fluorenyl, and the like, but the present invention is not limited thereto.

Further, the term 「heteroaryl」 described in the present invention, which means an aryl group containing 1 to 4 heteroatoms selected from B, N, O, S, P(=O), Si and P as an aromatic ring backbone atom and carbon as the remaining aromatic ring backbone atom, may include 5- to 6-membered monocyclic heteroaryl and polycyclic heteroaryl condensed with at least one benzene ring, and may also be partially saturated. In addition, heteroaryl in the present invention includes a form in which one or more heteroaryls are linked by a single bond.

The term 「alkenyl」 defined in the present invention means a linear-, branched-, or a cyclic hydrocarbon radical containing 2 to 12 carbon atoms and at least one carbon to carbon double bond.

The term 「cycloalkyl」 used alone or as a portion of other groups in the above description means a completely saturated and partially unsaturated hydrocarbon ring including 3 to 9 carbon atoms, and includes fused aryl or heteroaryl. For example,

of the present invention is included in the cycloalkyl.

The term 「heterocycloalkyl」 described in the present invention means a completely saturated and partially unsaturated hydrocarbon ring including oxygen, sulfur, or nitrogen as a heteroatom in a ring, and the number of heteroatoms is 1 to 4, preferably, 1 to 2. The cycloalkyl in the heterocycloalkyl is preferably monocycloalkyl or bicycloalkyl, and may be fused with aryl or heteroaryl which is an aromatic ring, and may also be linked by a double bond or a triple bond.

The iridium catalyst according to an exemplary embodiment of the present invention may be at least any one selected from the group consisting of [IrCp*Cl₂]₂, [IrCl(COD)]₂(Chloro-1,5-cyclooctadiene iridium(I) dimer), Ir(acac)₃(Ir(acetylacetonate)₃)(Iridium(III)acetylacetonate), [Ir(OMe)(COD)]₂(1,5-Cyclooctadiene)(methoxy)iridium(I) dimer), IrCl(CO)(PPh₃)₂ (Bis(triphenylphosphine)iridium(I) carbonyl chloride) and IrCl₃(Iridium(III) chloride), and preferably, may be at least any one selected from the group consisting of [IrCp*Cl₂]₂, [IrCl(COD)]₂ and [Ir(OMe)(COD)]₂ in view of reaction efficiency.

The iridium catalyst according to an exemplary embodiment of the present invention may be used in an amount of 0.01 to 0.5 mol, preferably, 0.02 to 0.1 mol, based on 1 mol of the quinoline N-oxide derivative represented by Chemical Formula 3 or 5.

The reaction according to an exemplary embodiment of the present invention may be performed by further including a silver catalyst. Specific examples of the silver catalyst may include AgNTf₂, AgSbF₆, AgPF₆, AgBF₄, Ag₂O or mixed catalysts thereof, but the present invention is not limited thereto.

The silver catalyst according to an exemplary embodiment of the present invention may be preferably at least any one selected from the group consisting of AgNTf₂, AgSbF₆, AgPF₆ and AgBF₄ in view of reaction efficiency, and may be used in an amount of 0.04 to 2 mol, preferably, 0.08 to 0.16 mol, based on 1 mol of the quinoline N-oxide derivative represented by Chemical Formula 3 or 5.

The acid of the present invention may be at least any one selected from the group consisting of an acetic acid, a pivalic acid, a benzoic acid and a sulfonic acid, preferably, may be an acetic acid, a pivalic acid, a benzoic acid or mixed acids thereof, and may be used in an amount of 0.1 to 3 mol, preferably, 0.2 to 1 mol, based on 1 mol of the quinoline N-oxide derivative represented by Chemical Formula 3 or 5.

The quinoline N-oxide derivative and the azide compound used in the present invention may be prepared by using methods which are generally used in an organic synthesis field.

The azide compound represented by Chemical Formula 4 according to an exemplary embodiment of the present invention may be used in an amount of 1.1 to 2 mol based on 1 mol of quinoline N-oxide derivative represented by Chemical Formula 3 or 5.

The reaction according to an exemplary embodiment of the present invention may be performed in the presence of an organic solvent, wherein the organic solvent is not limited as long as it dissolves reaction materials. The organic solvent may be selected from the group consisting of dioxane, tetrahydrofuran, dimethylformamide, dichloromethane, dichloroethane, benzene, toluene, and mixtures thereof. Among them, chloroform is more preferred in consideration of solubility of the reaction materials, easiness of removal or reaction efficiency.

A temperature for the reaction (hereinafter, referred to as a reaction temperature) has a range of 30 to 100℃, and preferably, has a range of 50 to 80℃. The reaction time is 4 to 24 hours, preferably, 8 to 15 hours. The reason is because the reaction time is excessively long or by-products are generated, which may deteriorate a reaction yield.

The reaction according to an exemplary embodiment of the present invention is allowed to be completed after confirming that all of the quinoline N-oxide derivative represented by Chemical Formula 3 or 5 which is a starting material is consumed, by TLC, and the like. After the reaction is completed, the solvent is removed under reduced pressure, and a target material may be separated and purified by general methods such as column chromatography, and the like.

In addition, in another general aspect, there is provided the quinoline N-oxide derivative with an amide group represented by Chemical Formula 1 or 2 above, prepared by using the preparation method of the present invention.

Preferably, the quinoline N-oxide derivative with an amide group represented by Chemical Formula 1 may be represented by Chemical Formulas 6 to 9 above.

The quinoline N-oxide derivative with an amide group of the present invention may be selected from the following structural formulas, but the present invention is not limited thereto:

The quinoline N-oxide derivative with an amide group of the present invention can be effectively used as a raw material or an intermediate for various fields such as a pharmaceutical industry, and the like.

In the preparation method of a quinoline N-oxide derivative with an amide group according to the present invention, the amide group may be regioselectively introduced into a C-8 position rather than a C-2 position, unlike methods according to the related art.

In addition, the preparation method of the quinoline N-oxide derivative with the amide group according to the present invention is significantly effective in that the quinoline N-oxide derivative with the amide group introduced into the C-8 position is capable of being obtained in high yield by simplified processes under mild reaction conditions.

Further, in the preparation method of the quinoline N-oxide derivative with the amide group according to the present invention, the amide group may be easily and regioselectively introduced into the C-8 position, and therefore, the preparation method of the present invention may be effectively applied to synthesize intermediates for various fields.

The quinoline N-oxide derivative with the amide group prepared according to the preparation method of the present invention may be used as a framework of natural products, and may also be effectively used for development of new medicine, various pharmaceutical products, and the like.

Hereinafter, a configuration of the present invention will be described in detail with reference to Examples. These Examples are only for exemplifying the present invention, and it will be obvious to those skilled in the art that the scope of the present invention is not construed to be limited to these Examples.

[Preparation Example 1] Preparation of Azide Compound

30.0 mmol of NaN₃ was dissolved in 10 mL of distilled water, a temperature was reduced to be 0 ℃, and 20.0 mmol of sulfonyl chloride (

) dissolved in 20 mL of acetone was slowly added thereto and the reaction mixture was stirred at room temperature for 11 hours. Then, the acetone, an organic solvent, was removed under reduced pressure, and the reaction mixture was extracted with 30 mL of ethyl acetate three times. The combined organic layer was dried over MgSO₄, then a solid was filtered, and the organic solvent was removed under reduced pressure to obtain sulfonyl azide. The obtained sulfonyl azide was used without further purification.

[Preparation Example 2] Preparation of Azide Compound

5.0 mmol of 4-nitrobenzoyl chloride was dissolved in 2.5 mL of acetone, and 8.1 mmol of sodium azide dissolved in 2.5 mL of distilled water was slowly added thereto at 0 ℃. A solid precipitate was immediately produced and the reaction mixture was stirred at room temperature for 30 minutes. After stirring, 2.5 mL of distilled water was added thereto and the reaction mixture was stirred for 30 minutes. The produced solid was collected and dried to obtain 4-nitrobenzoyl azide as a colorless solid in 90% yield.

[Preparation Example 3] Preparation of Quinoline Compound

A THF solution of 1.9 M NaHMDS (sodium hexamethyldisilazide) (2.67 mL) was added to 2.5 mmol of 6-aminoquinoline dissolved in 3 mL of THF at room temperature and the reaction mixture was stirred for 30 minutes. After stirring, 5.0 mmol of di-tert-butyl dicarbonate dissoved in 2 mL of THF was added thereto at room temperature and the reaction mixture stirred at room tempearture for 12 hours. After stirring, 10 mL of water was added thereto and the reaction was allowed to be completed, and 50 mL of saturated aqueous NaHCO₃ solution was added thereto. The reaction mixture was extracted with 20 mL of ethyl acetate three times. The combined organic layer was dried over MgSO₄, then a solid was filtered off, and an organic solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/n-hexane, 2/1) to obtain 6-[bis(tert-butoxycarbonyl)amino]quinoline as a white solid in 34% yield.

m.p. 148~149 ℃

¹H NMR (600 MHz, CDCl₃) δ 8.93 (dd, J = 4.2, 1.7 Hz, 1H), 8.14 (d, J = 8.4 Hz, 1H), 8.10 (d, J = 8.9 Hz, 1H), 7.61 (d, J = 2.3 Hz, 1H), 7.50 (dd, J = 9.0, 2.3 Hz, 1H), 7.42 (dd, J = 8.3, 4.2 Hz, 1H), 1.42 (s, 18H)

¹³C NMR (150 MHz, CDCl₃) δ 151.7, 150.8, 147.2, 137.3, 136.0, 130.1, 130.0, 128.1, 126.0, 121.3, 83.1, 27.9;

IR (diamond) 2979, 2934, 1748, 1712, 1367, 1273, 1249, 1151, 1097, 858

HRMS (EI) m/z calcd. for C₁₉H₂₄N₂O₄ [M]+: 344.1736, found: 344.1738.

[Preparation Example 4] Preparation of Quinoline Compound

3.75 equivalent of imidazole and 1.5 equivalent of triisopropylsilyl chloride were added to 1.5 mmol of 5-hydroxyquinoline dissolved in 10 mL of dimethylformamide and the reaction mixture was stirred at room temperature for 24 hours. After stirring, 20 mL of distilled water was added thereto, and the reaction mixture was extracted with 20 mL of dichloromethane three times. The combined organic layer was dried over MgSO₄, then a solid was filtered off, and an organic solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/n-hexane, 1/5) to obtain 5-(triisopropylsilyloxy)quinoline as a colorless liquid in 90 % yield.

¹H NMR (600 MHz, CDCl₃) δ 8.93-8.86 (m, 1H), 8.58 (d, J = 8.4 Hz, 1H), 7.71 (d, J = 8.5 Hz, 1H), 7.54 (t, J = 8.1 Hz, 1H), 7.42-7.33 (m, 1H), 6.92 (d, J = 7.6 Hz, 1H), 1.46-1.36 (m, 3H), 1.15 (d, J = 7.6 Hz, 18H)

¹³C NMR (150 MHz, CDCl₃) δ 151.8, 150.5, 149.5, 131.3, 129.3, 122.9, 122.0, 120.2, 112.2, 18.0, 13.0;

IR (diamond) 2943, 2865, 1466, 1393, 1269, 1085, 915, 881, 795, 676

HRMS (EI) m/z calcd. for C₁₈H₂₇NOSi [M]+: 301.1862, found: 301.1864

[Preparation Example 5] Preparation of Quinoline Compound

2.2 mmol of benzoyl chloride was added to 2.0 mmol of 4-quinolinol dissolved in 5 mL of dichloromethane at room temeprature and the reaction mixture was stirred for 3 hours. After stirring, 5 mL of distilled water was added thereto, the reaction was allowed to be completed, and the reaction mixutre was added to 30 mL of saturated aqueous NaHCO₃ solution. An organic layer was separated and an aqueous layer was extracted with 30 mL of dichloromethane three times. The combined organic layer was dried over MgSO₄, then a solid was filtered off, and an organic solvent was removed under reduced pressure. The obtained 4-(benzyloxy)quinoline was used to prepare corresponding N-oxide without further purification.

[Preparation Example 6] Preparation of Quinoline Compound

4.0 mmol of 3-quinolinecarboxaldehyde and 0.4 mmol of p-toluenesulfonic acid monohydrate were added to a two-neck round bottom flask equipped with a Dean-Stark trap, and 40 mL of benzene and 8.0 mmol of ethylene glycol were added thereto. The reaction mixture was refluxed until the reaction was completed by confirmation through TLC and cooled to room temperature, and an organic solvent was removed under reduced pressure. The reaction mixture was added to a saturated aqueous NaHCO₃ solution, and the reaction mixture was extrated with 20 mL of dichloromethane three times. The combined organic layer was dried over MgSO₄, then a solid was filtered off, an organic solvent was removed under reduced pressure. to obtain a reaction mixture, The residue was purified by silica gel column chromatography (EtOAc/n-hexane, 1/4) to obtain 3-(1,3-dioxolan-2-yl)quinoline as a white solid in 91% yield.

[Preparation Example 7] Preparation of Quinoline Compound

6.0 mmol of thionyl chloride was slowly added to 2.0 mmol of 6-quinolinecarboxylic acid dissolved in 5 mL of methanol at 0 ℃ and the reaction mixture was stirred at 50 ℃ for 12 hours. 30 mL of saturated aqueous NaHCO₃ solution was added thereto, and the reaction was allowed to be completed. The reaction mixture was extracted with 30 mL of dichloromethane three times. The reaction mixture was dried over MgSO₄, then a solid was filtered off, and an organic solvent was removed under reduced pressure 6-(methoxycarbonyl)quinoline as a white solid in 98 % yield.

[Preparation Example 8] Preparation of Quinoline Compound

5 mL of 2.0 M sodium carbonate aqueous solution was added to 5.0 mmol of 2-chloroquinoline, 7.5 mmol of naphthalen-1-ylboronic acid, 0.25 mmol of tetrakis(triphenylphosphine)palladium dissolved in 25 mL of toluene, and the reaction mixture was stirred at 80 ℃ for 24 hours. After stirring, the reaction mixture was cooled to room temperature, and passed through a celite and a silica, and extracted with 20 mL of ethyl acetate three times. The combined organic layer was dried over MgSO₄, then a solid was filtered off, and an organic solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/EtOAc, 3/1, Rf = 0.5) to obtain 2-(naphthalen-1-yl)quinoline in 76 % yield.

General Preparation of Quinoline N-oxide Derivative

2.5 equivalent of m-chloroperoxybenzoic acid(mCPBA) was added to 3.0 mmol of quinoline dissolved in 5 mL of chloroform and the reaction mixture was refluxed for 4 hours. The reaction mixture was cooled to room temperature and a saturated aqueous NaHCO₃ solution was added thereto. An organic layer was separated and an aqueous layer was extracted with 10 mL of dichloromethane three times. The combined organic layer was dried over MgSO₄, then a solid was filtered off, and an organic solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to obtain each N-oxide.

Each quinoline N-oxide prepared as described above is as follows.

[Preparation Example 9] Preparation of 6-Bromo-2-methylquinoline N-oxide (1i)

White solid; m.p. 151~152 ℃: ¹H NMR (600 MHz, CDCl₃) δ 8.64 (d, J = 9.2 Hz, 1H), 7.97 (d, J = 2.0 Hz, 1H), 7.79 (dd, J = 9.2, 2.1 Hz, 1H), 7.53 (d, J = 8.6 Hz, 1H), 7.33 (d, J = 8.6 Hz, 1H), 2.69 (s, 3H); ¹³C NMR (150 MHz, CDCl₃) δ 146.0, 140.4, 133.4, 130.3, 129.9, 124.2, 123.5, 122.0, 121.6, 18.7; IR (diamond) 3034, 2981, 1557, 1326, 1243, 1186, 886, 806, 766, 644; HRMS (EI) m/z calcd. for C₁₀H₈BrNO [M]+: 236.9789, found: 236.9792.

[Preparation Example 10] Preparation of 3-(1,3-Dioxolan-2-yl)quinoline N-oxide (1m)

White solid; m.p. 79~80 ℃: ¹H NMR (600 MHz, CDCl₃) δ 8.72 (d, J = 8.7 Hz, 1H), 8.66 (s, 1H), 7.87 (d, J = 8.2 Hz, 1H), 7.81 (s, 1H), 7.76 (t, J = 8.8 Hz, 1H), 7.65 (t, J = 7.6 Hz, 1H), 5.95 (s, 1H), 4.11 (d, J = 20.8 Hz, 4H); ¹³C NMR (150 MHz, CDCl₃) δ 141.5, 134.2, 132.7, 130.7, 129.8, 129.0, 128.5, 123.7, 119.7, 101.0, 65.5; IR (diamond) 3059, 2957, 2886, 1579, 1364, 1212, 1079, 997, 852, 767; HRMS (EI) m/z calcd. for C₁₂H₁₁NO₃ [M]+: 217.0739, found: 217.0738.

[Preparation Example 11] Preparation of 5-(Triisopropylsilyloxy)quinoline N-oxide (1o)

Yellow solid; m.p. 63~65 ℃: ¹H NMR (600 MHz, CDCl₃) δ 8.52 (d, J = 5.9 Hz, 1H), 8.32 (d, J = 8.9 Hz, 1H), 8.12 (d, J = 8.0 Hz, 1H), 7.58 (t, J = 8.2 Hz, 1H), 7.29?7.21 (m, 1H), 7.01 (d, J = 7.6 Hz, 1H), 1.49?1.32 (m, 3H), 1.15 (d, J = 7.5 Hz, 18H); ¹³C NMR (150 MHz, CDCl₃) δ 152.5, 142.9, 135.8, 130.4, 125.5, 121.2, 119.6, 114.5, 112.0, 18.0, 12.9; IR (diamond) 3081, 2944, 2866, 1510, 1401, 1291, 980, 882, 786, 688; HRMS (EI) m/z calcd. for C₁₈H₂₇NO₂Si [M]+: 317.1811, Found: 317.1811.

[Preparation Example 12] Preparation of 6-[Bis(tert-butoxycarbonyl)amino]quinoline N-oxide (1p)

White solid; m.p. 188~189 ℃: ¹H NMR (600 MHz, CDCl₃) δ 8.76 (d, J = 9.2 Hz, 1H), 8.54 (d, J = 6.0 Hz, 1H), 7.73 (d, J = 8.5 Hz, 1H), 7.69 (s, 1H), 7.55 (d, J = 9.5 Hz, 1H), 7.41?7.25 (m, 1H), 1.43 (s, 18H); ¹³C NMR (150 MHz, CDCl₃) δ 151.2, 140.4, 139.6, 135.8, 130.8, 130.6, 126.4, 125.6, 121.6, 120.7, 83.5, 27.8; IR (diamond) 2979, 2935, 1750, 1571, 1369, 1275, 1153, 1115, 847, 749; HRMS (EI) m/z calcd. for C₁₉H₂₄N₂O₅ [M]+: 360.1685, found: 360.1683.

[Preparation Example 13] Preparation of 3-Formylquinoline N-oxide(1q)

1.5 mL of 37 wt% formaldehyde aqueous solution and 0.7 mmol of p-toluenesulfonic acid monohydrate (p-TSA) were added to 0.7 mmol of 3-(1,3-dioxolan-2-yl)quinoline N-oxide dissolved in 3 mL of tetrahydrofuran and the reaction mixture was stirred at room temperature for 36 hours. After stirring, 20 mL of saturated aqueous NaHCO₃ solution was added thereto, then the reaction was allowed to be completed. The reaction mixture was extracted with 20 mL of dichloromethane three times. The combined organic layer was dried over MgSO₄, then a solid was filtered off,and an organic solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/n-hexane, 3/1) to obtain 3-formylquinoline N-oxide as a yellow solid in 80% yield.

m.p. 205~206 ℃

¹H NMR (600 MHz, CDCl₃) δ 10.09 (s, 1H), 8.92 (s, 1H), 8.80 (d, J = 8.7 Hz, 1H), 8.20 (s, 1H), 8.07 (d, J = 8.1 Hz, 1H), 7.93 (t, J = 7.9 Hz, 1H), 7.78 (t, J = 7.6 Hz, 1H)

¹³C NMR (150 MHz, CDCl₃) δ 188.1, 143.9, 133.2, 132.9, 130.1, 129.9, 129.9, 129.3, 129.1, 120.3;

IR (diamond) 3008, 2861, 1692, 1576, 1357, 1331, 1219, 993, 775, 573;

HRMS (EI) m/z calcd. for C₁₀H₇NO₂ [M]+: 173.0477, found: 173.0476.

[Preparation Example 14] Preparation of benzo[c]cinnoline N-oxide (6e)

1.2 mmol of acetophenone was added to a mixture of 25 mL of 40% NaOH aqueous solution and 1.0 mmol of 2,2’-dinitrobiphenyl and the reaction mixture was refluxed at 155 ℃ for 4 hours and 30 minutes. After the reflux, the reaction mixture was cooled to room temperature, slowly diluted with 100 mL of distilled water and 50 mL of ethyl acetate, and passed through a celite to remove a black solid. The reaction mixture was extracted with 20 mL of ethyl acetate three times. The combined organic layer was dried over Na₂SO₄, then a solid was filtered off, and an organic solvent was removed under reduced pressure. The reseidue was purified by silica gel column chromatography (CH₂Cl₂/acetone, 30/1, Rf = 0.5) to obtain benzo[c]cinnoline N-oxide as a white solid in 95% yield.

[Example] Preparation Method of Quinoline N-oxide Derivative with Amide Group

0.2 mmol of quinoline N-oxide, 0.22 mmol of azide, 0.004 mmol of [IrCp*Cl₂]₂, 0.016 mmol of AgNTf₂, 0.06 mmol of AcOH, and 0.5 mL of 1,2-dichloroethane were added to a 1 mL of reaction vial and the reaction mixture was stirred at 50 ℃ for 12 hours. After the stirring, the reaction mixture was passed through a celite and washed with 10 mL of dichloromethane three times, and an organic solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to obtain a product.

The following quinoline N-oxides with an amide group were prepared by the same method as described above.

[Example 1] Preparation of 8-(4-Methylphenylsulfonamido)quinoline N-oxide (3a)

Yield 89 %; yellow solid; m.p. 171~173 ℃; ¹H NMR (600 MHz, CDCl₃) δ 14.40 (s, 1H), 8.28 (d, J = 4.9 Hz, 1H), 7.86-7.79 (m, 3H), 7.70 (d, J = 8.3 Hz, 1H), 7.45 (t, J = 8.0 Hz, 1H), 7.40 (dd, J = 8.2, 1.4 Hz, 1H), 7.23 (dd, J = 8.4, 6.1 Hz, 1H), 7.19 (d, J = 8.1 Hz, 2H), 2.32 (s, 3H); ¹³C NMR (150 MHz, CDCl₃) δ 143.6, 137.0, 136.7, 133.8, 132.4, 131.1, 129.5, 129.1, 128.9, 127.3, 122.2, 120.9, 117.9, 21.5; IR (diamond) 3083, 2869, 1394, 1319, 1160, 1090, 817, 750, 654, 562; HRMS (EI) m/z calcd. for C₁₆H₁₄N₂O₃S [M]+: 314.0725, found: 314.0722.

[Example 2] Preparation of 6-Methyl-8-(4-methylphenylsulfonamido)quinoline N-oxide (3b)

Yield 90 %; pale brown solid; m.p 159~161 ℃; ¹H NMR (600 MHz, CDCl₃) δ 14.34 (s, 1H), 8.21 (dd, J = 6.1, 1.2 Hz, 1H), 7.83 (d, J = 8.3 Hz, 2H), 7.69 (d, J = 1.8 Hz, 1H), 7.60 (d, J = 9.2 Hz, 1H), 7.24-7.12 (m, 4H), 2.43 (s, 3H), 2.32 (s, 3H); ¹³C NMR (150 MHz, CDCl₃) δ 143.6, 139.7, 136.7, 136.2, 133.2, 132.4, 129.6, 129.5, 128.5, 127.3, 121.5, 120.9, 119.7, 21.7, 21.4; IR (diamond) 3067, 2920, 1584, 1394, 1329, 1160, 1091, 750, 668, 573; HRMS (EI) m/z calcd. for C₁₇H₁₆N₂O₃S [M]+: 328.0882, found: 328.0879.

[Example 3] Preparation of 2,6-Dimethyl-8-(4-methylphenylsulfonamido)quinoline N-oxide (3c)

Yield 88 %; light yellow solid; m.p 205~207 ℃; ¹H NMR (600 MHz, CDCl₃) δ 14.72 (s, 1H), 7.82 (d, J = 7.9 Hz, 2H), 7.63 (s, 1H), 7.48 (d, J =8.6 Hz, 1H), 7.21-7.15 (m, 3H), 7.12 (s, 1H), 2.57 (s, 3H), 2.40 (s, 3H), 2.32 (s, 3H); ¹³C NMR (150 MHz, CDCl₃) δ 146.1, 143.3, 138.6, 137.0, 133.1, 131.1, 129.7, 129.4, 127.4, 127.3, 123.0, 121.4, 119.7, 21.5, 21.4, 18.6; IR (diamond) 3046, 2919, 1604, 1357, 1163, 1090, 764, 665, 573, 546; HRMS (EI) m/z calcd. for C₁₈H₁₈N₂O₃S [M]+: 342.1038, found: 342.1036.

[Example 4] Preparation of 3-Methyl-8-(4-methylphenylsulfonamido)quinoline N-oxide (3d)

Yield 86 %; light brown solid; m.p 181~183 ℃; ¹H NMR (600 MHz, CDCl₃) δ 14.36 (s, 1H), 8.18 (s, 1H), 7.82 (d, J = 8.4 Hz, 2H), 7.76 (d, J = 7.9 Hz, 1H), 7.48 (s, 1H), 7.40 (t, J = 8.0 Hz, 1H), 7.30 (d, J = 8.2 Hz, 1H), 7.19 (d, J = 8.0 Hz, 2H), 2.39 (s, 3H), 2.32 (s, 3H); ¹³C NMR (150 MHz, CDCl₃) δ 143.5, 138.2, 136.7, 133.6, 132.1, 131.3, 129.5, 129.3, 129.1, 128.4, 127.3, 121.5, 116.8, 21.5, 18.3; IR (diamond) 3063, 2926, 1590, 1328, 1285, 1156, 1094, 749, 656, 551; HRMS (EI) m/z calcd. C₁₇H₁₆N₂O₃S [M]+: 328.0882, found: 328.0885.

[Example 5] Preparation of 5-Chloro-8-(4-methylphenylsulfonamido)quinoline N-oxide (3e)

Yield 72 %; yellow solid; m.p 186~188 ℃; ¹H NMR (600 MHz, CDCl₃) δ 14.29 (s, 1H), 8.35 (d, J = 6.0 Hz, 1H), 8.14 (d, J = 8.8 Hz, 1H), 7.88-7.76 (m, 3H), 7.55 (d, J = 8.6 Hz, 1H), 7.35 (dd, J = 8.8, 6.1 Hz, 1H), 7.21 (d, J = 8.0 Hz, 2H), 2.33 (s, 3H); ¹³C NMR (150 MHz, CDCl₃) δ 143.8, 137.5, 136.5, 133.1, 132.0, 130.0, 129.7, 129.4, 127.3, 125.6, 125.1, 121.7, 117.4, 21.5; IR (diamond) 3083, 2733, 1576, 1455, 1386, 1346, 1159, 1090, 862, 805; HRMS (EI) m/z calcd. for C₁₆H₁₃ClN₂O₃S [M]+: 348.0335, found: 348.0333.

[Example 6] Preparation of 6-Chloro-8-(4-methylphenylsulfonamido)quinoline N-oxide (3f)

Yield 73 %(0.2 mmol of AcOH at 80 ℃); pale yellow solid; m.p 174~176 ℃; ¹H NMR (600 MHz, CDCl₃) δ 14.52 (s, 1H), 8.26 (d, J = 6.0 Hz, 1H), 7.84 (d, J = 7.9 Hz, 2H), 7.78 (s, 1H), 7.61 (d, J = 8.5 Hz, 1H), 7.35 (s, 1H), 7.29-7.21 (m, 3H), 2.35 (s, 3H); ¹³C NMR (150 MHz, CDCl₃) δ 144.1, 137.0, 136.4, 135.4, 135.2, 132.8, 129.8, 129.6, 127.9, 127.4, 122.0, 120.4, 117.3, 21.5; IR (diamond) 3077, 1575, 1383, 1321, 1160, 1091, 749, 657, 571, 544; HRMS (EI) m/z calcd. for C₁₆H₁₃ClN₂O₃S [M]+: 348.0335, found: 348.0337.

[Example 7] Preparation of 4-Chloro-8-(4-methylphenylsulfonamido)quinoline N-oxide (3g)

Yield 60 %(0.2 mmol of AcOH at 80 ℃); yellow solid; m.p 189~190 ℃; ¹H NMR (600 MHz, CDCl₃) δ 14.39 (s, 1H), 8.21 (d, J = 6.6 Hz, 1H), 7.94 (dd, J = 8.0, 1.2 Hz, 1H), 7.83 (d, J = 8.3 Hz, 2H), 7.78 (dd, J = 8.4, 1.3 Hz, 1H), 7.57 (t, J = 8.2 Hz, 1H), 7.34 (d, J = 6.6 Hz, 1H), 7.21 (d, J = 8.1 Hz, 2H), 2.33 (s, 3H); ¹³C NMR (150 MHz, CDCl₃) δ 143.8, 136.6, 136.2, 134.5, 133.1, 131.5, 130.2, 129.7, 129.7, 127.8, 121.1, 119.0, 118.7, 21.5; IR (diamond) 3087, 3005, 1382, 1315, 1161, 1090, 749, 655, 587, 561; HRMS (EI) m/z calcd. for C₁₆H₁₃ClN₂O₃S [M]+: 348.0335, found: 348.0337.

[Example 8] Preparation of 6-Bromo-8-(4-methylphenylsulfonamido)quinoline N-oxide (3h)

Yield 61 %(0.2 mmol of AcOH at 80 ℃); pale yellow solid; m.p 190~192 ℃; ¹H NMR (600 MHz, CDCl₃) δ 14.46 (s, 1H), 8.28 (d, J = 6.0 Hz, 1H), 7.93 (s, 1H), 7.85 (d, J = 7.9 Hz, 2H), 7.59 (d, J = 8.4 Hz, 1H), 7.53 (d, J = 2.1 Hz, 1H), 7.29-7.18 (m, 3H), 2.35 (s, 3H); ¹³C NMR (150 MHz, CDCl₃) δ 144.0, 137.1, 136.3, 135.0, 133.1, 129.8, 129.7, 127.8, 127.4, 123.7, 123.4, 121.9, 119.9, 21.5; IR (diamond) 3070, 1574, 1379, 1320, 1160, 1090, 819, 656, 569, 545; HRMS (EI) m/z calcd. for C₁₆H₁₃BrN₂O₃S [M]+: 391.9830, found: 391.9832.

[Example 9] Preparation of 6-Bromo-2-methyl-8-(4-methylphenylsulfonamido)quinoline N-oxide (3i)

Yield 78 %; light yellow solid; m.p 227~228 ℃; ¹H NMR (600 MHz, CD₂Cl₂) δ 15.07 (s, 1H), 7.84 (d, J = 2.0 Hz, 1H), 7.81 (d, J = 8.0Hz, 2H), 7.54-7.49 (m, 2H), 7.28 (d, J = 8.6 Hz, 1H), 7.25 (d, J = 8.0 Hz, 2H), 2.56 (s, 3H), 2.34 (s,3H); ¹³C NMR (150 MHz, CD₂Cl₂) δ 148.2, 144.5, 136.9, 135.3, 132.4, 130.4, 130.1, 127.7, 127.1, 124.7, 124.3, 122.2, 120.1, 21.6, 18.9; IR (diamond) 3065, 1594, 1355, 1325, 1163, 1089, 810, 657, 571, 544; HRMS (EI) m/z calcd. for C₁₇H₁₅BrN₂O₃S [M]+: 405.9987, found: 405.9991.

[Example 10] Preparation of 8-(4-Methylphenylsulfonamido)-5-nitroquinoline N-oxide (3j)

Yield 64 %(0.2 mmol of AcOH at 80 ℃); orange solid; m.p 162~163 ℃; ¹H NMR (600 MHz, CDCl₃) δ 15.41 (s, 1H), 8.77 (d, J = 9.1 Hz, 1H), 8.43 (d, J = 6.0 Hz, 1H), 8.34 (d, J = 9.1 Hz, 1H), 7.89 (d, J = 8.0 Hz, 2H), 7.79 (d, J = 9.1 Hz, 1H), 7.55-7.45 (m, 1H), 7.29 (d, J = 7.9 Hz, 2H), 2.38 (s, 3H); ¹³C NMR (150 MHz, CDCl₃) δ 144.7, 140.5, 138.5, 137.8, 136.0, 130.2, 123.0, 128.7, 127.5, 126.5, 124.7, 123.9, 112.7, 21.6; IR (diamond) 3126, 3087, 1575, 1527, 1310, 1161, 1088, 808, 656, 546; HRMS (EI) m/z calcd. for C₁₆H₁₃N₃O₅S [M]+: 359.0576, found: 359.0573.

[Example 11] Preparation of 6-(Methoxycarbonyl)-8-(4-methylphenylsulfonamido)quinoline N-oxide (3k)

Yield 63 %; pale yellow solid; m.p 240~242 ℃; ¹H NMR (600 MHz, CD₂Cl₂) δ 14.45 (s, 1H), 8.36 (d, J = 6.1 Hz, 1H), 8.30 (s, 1H), 8.12 (s, 1H), 7.85-7.79 (m, 3H), 7.32 (dd, J = 8.5, 6.2 Hz, 1H), 7.23 (d, J = 8.0 Hz, 2H), 3.97 (s, 3H), 2.32 (s, 3H); ¹³C NMR (150 MHz, CD₂Cl₂) δ 165.6, 144.6, 139.0, 136.9, 134.8, 133.2, 132.5, 131.1, 130.2, 130.1, 127.8, 124.6, 122.4, 116.7, 53.2, 21.6; IR (diamond) 3126, 3087, 1575, 1527, 1310, 1161, 1088, 808, 656, 546; HRMS (EI) m/z calcd. for C₁₈H₁₆N₂O₅S [M]+: 372.0780, found: 372.0782.

[Example 12] Preparation of 4-(Benzoyloxy)-8-(4-methylphenylsulfonamido)quinoline N-oxide (3l)

Yield 56 %; light yellow solid; m.p 205~207 ℃; ¹H NMR (600 MHz, CDCl₃) δ 13.73 (s, 1H), 8.21 (d, J = 7.7 Hz, 2H), 7.82 (d, J = 7.9 Hz, 2H), 7.79 (t, J = 7.4 Hz, 1H), 7.67-7.54 (m, 3H), 7.47 (d, J = 8.1 Hz, 1H), 7.41 (t, J = 8.3 Hz, 1H), 7.22 (d, J = 7.9 Hz, 2H), 6.83 (d, J = 8.4 Hz, 1H), 6.20 (d, J = 8.1 Hz, 1H), 2.35 (s, 3H); ¹³C NMR (150 MHz, CDCl₃) δ 180.8, 163.5, 143.7, 141.4, 139.8, 139.1, 136.7, 135.8, 133.9, 130.4, 129.7, 129.4, 127.3, 124.6, 113.1, 111.3, 109.1, 105.6, 21.5; IR (diamond) 3076, 2922, 2742, 1777, 1619, 1493, 1233, 1161, 992, 704; HRMS (EI) m/z calcd. for C₂₃H₁₈N₂O₅S [M]+: 434.0936, found: 434.0939.

[Example 13] Preparation of 3-(1,3-Dioxolan-2-yl)-8-(4-methylphenylsulfonamido)quinoline N-oxide (3m)

Yield 67 %; yellow solid; m.p 159~161 ℃; ¹H NMR (600 MHz, CDCl₃) δ 14.33 (s, 1H), 8.40 (s, 1H), 7.85 (d, J = 7.8 Hz, 1H), 7.80 (d, J = 8.0 Hz, 2H), 7.75 (s, 1H), 7.45 (t, J = 8.0 Hz, 1H), 7.40 (d, J = 8.3 Hz, 1H), 7.17 (d, J = 8.0 Hz, 2H), 5.86 (s, 1H), 4.15-4.03 (m, 4H), 2.31 (s, 3H); ¹³C NMR (150 MHz, CDCl₃) δ 143.7, 136.6, 135.7, 133.8, 132.7, 131.7, 130.9, 129.6, 129.4, 127.3, 126.6, 122.7, 118.6, 100.4, 65.6, 21.5; IR (diamond) 3081, 2956, 2892, 1593, 1328, 1160, 1160, 1091, 655, 544; HRMS (EI) m/z calcd. for C₁₉H₁₈N₂O₅S [M]+: 386.0936, found: 386.0940.

[Example 14] Preparation of 6-Methoxy-8-(4-methylphenylsulfonamido)quinoline N-oxide (3n)

Yield 69 %(0.2 mmol of AcOH at 80 ℃); white solid; m.p 205~207 ℃; ¹H NMR (600 MHz, CDCl₃) δ 14.55 (s, 1H), 8.13 (d, J = 6.0 Hz, 1H), 7.85 (d, J = 8.3 Hz, 2H),7.57 (d, J = 8.4 Hz, 1H), 7.47 (d, J = 2.6 Hz, 1H), 7.22 (d, J = 8.0 Hz, 2H), 7.16 (dd, J = 8.5, 6.1 Hz, 1H), 6.67 (d, J = 2.6 Hz, 1H), 3.86 (s, 3H), 2.34 (s, 3H); ¹³C NMR (150 MHz, CDCl₃) δ 159.2, 143.6, 136.7, 135.2, 134.9, 133.7, 129.6, 127.9, 127.4, 127.1, 121.2, 108.7, 100.9, 55.7, 21.5; IR (diamond) 3087, 2837, 1616, 1333, 1159, 1089, 730, 669, 575, 546; HRMS (EI) m/z calcd. for C₁₇H₁₆N₂O₄S [M]+: 344.0831, found: 344.0830

[Example 15] Preparation of 8-(4-Methylphenylsulfonamido)-5-(triisopropylsilyloxy)quinoline N-oxide (3o)

Yield 86 %; yellow solid; m.p 136~137 ℃; ¹H NMR (600 MHz, CDCl₃) δ 13.53 (s, 1H), 8.25 (d, J = 5.5 Hz, 1H), 8.10 (d, J = 8.5 Hz, 1H), 7.78 (d, J = 8.6 Hz, 1H), 7.70 (d, J = 8.2 Hz, 2H), 7.18 (dd, J = 8.6, 6.0 Hz, 1H), 7.10 (d, J = 8.0 Hz, 2H), 6.91 (d, J = 8.7 Hz, 1H), 2.28 (s, 3H), 1.35 (hept, J = 7.5 Hz, 3H), 1.10 (d, J = 7.5 Hz, 18H); ¹³C NMR (150 MHz, CDCl₃) δ 148.0, 143.2, 137.4, 136.7, 132.7, 129.3, 127.3, 126.4, 126.1, 123.8, 120.9, 119.8, 114.9, 21.4, 18.0, 12.9; IR (diamond) 2944, 2866, 1461, 1396, 1305, 1161, 970, 783, 654, 547; HRMS (EI) m/z calcd. for C₂₅H₃₄N₂O₄SSi [M]+: 486.2009, found: 486.2011.

[Example 16] Preparation of 6-[Bis(tert-butoxycarbonyl)amino]-8-(4-methylphenylsulfonamido)quinoline N-oxide (3p)

Yield 55 %, white solid; m.p 171~173 ℃; ¹H NMR (600 MHz, CDCl₃) δ 14.39 (s, 1H), 8.27 (d, J = 6.0 Hz, 1H), 7.82 (d, J = 8.1 Hz, 2H), 7.72 (d, J = 2.1 Hz, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.26-7.22 (m, 2H), 7.19 (d, J = 8.0 Hz, 2H), 2.32 (s, 3H), 1.43 (s, 18H); ¹³C NMR (150 MHz, CDCl₃) δ 151.1, 143.7, 139.7, 137.2, 136.6, 134.5, 132.3, 130.0, 129.6, 128.8, 127.3, 121.3, 120.4, 118.0, 83.7, 27.8, 21.4; IR (diamond) 3080, 2980, 2933, 1751, 1338, 1272, 1157, 1092, 730, 537; HRMS (EI) m/z calcd. for C26H31N3O7S [M]+: 529.1883, found: 529.1886.

[Example 17] Preparation of 3-Formyl-8-(4-methylphenylsulfonamido)quinoline N-oxide (3q)

Yield 87 %; yellow solid; m.p 188~189 ℃; ¹H NMR (600 MHz, CD₂Cl₂) δ 14.15 (s, 1H), 10.00 (s, 1H), 8.65 (s, 1H), 8.16 (s, 1H), 7.97 (dd, J = 7.8, 1.5 Hz, 1H), 7.79 (d, J = 8.5 Hz, 2H), 7.68?7.54 (m, 2H), 7.23 (d, J = 7.9 Hz, 2H), 2.32 (s, 3H); ¹³C NMR (150 MHz, CD₂Cl₂) δ 187.5, 144.2, 136.4, 134.4, 134.3, 132.5, 132.0, 131.4, 130.2, 129.6, 129.6, 127.2, 124.1, 120.5, 21.2; IR (diamond) 3064, 2845, 1703, 1592, 1466, 1359, 1160, 1090, 655, 558; HRMS (EI) m/z calcd. for C₁₇H₁₄N₂O₄S [M]+: 342.0674, found: 342.0678.

[Example 18] Preparation of 8-(Methylsulfonamido)quinoline N-oxide (5a)

Yield 82 %; light yellow solid; m.p 151~153 ℃; ¹H NMR (600 MHz, CDCl₃) δ 14.04 (s, 1H), 8.38 (d, J = 5.5 Hz, 1H), 7.91 (dd, J = 7.8, 1.5 Hz, 1H), 7.80 (d, J = 1.2 Hz, 1H), 7.58 (t, J = 8.0 Hz, 1H), 7.54 (d, J = 6.9 Hz, 1H), 7.32 (dd, J = 8.4, 6.1 Hz, 1H), 3.08 (s, 3H); ¹³C NMR (150 MHz, CDCl₃) δ 137.3, 133.9, 132.6, 131.0, 129.4, 129.2, 122.6, 121.2, 117.9, 39.5; IR (diamond) 3083, 2929, 1582, 1394, 1316, 1149, 1053, 967, 819, 749; HRMS (EI) m/z calcd. for C₁₀H₁₀N₂O₃S [M]+: 238.0412, found: 238.0410.

[Example 19] Preparation of 8-(Phenylmethylsulfonamido)quinoline N-oxide (5b)

Yield 78 %; yellow solid; m.p 123~125 ℃; ¹H NMR (600 MHz, CDCl₃) δ 14.09 (s, 1H), 8.26 (d, J = 6.0 Hz, 1H), 7.73 (d, J = 8.4 Hz, 1H), 7.65 (d, J = 7.4 Hz, 1H), 7.45-7.35 (m, 2H), 7.29-7.24 (m, 1H), 7.22 (d, J = 7.2 Hz, 2H), 7.17 (t, J = 7.1 Hz, 1H), 7.11 (t, J = 7.8 Hz, 2H), 4.42 (s, 2H); ¹³C NMR (150 MHz, CDCl₃) δ 137.0, 134.2, 132.3, 130.9, 130.6, 129.1, 129.0, 128.6, 128.4, 128.3, 122.4, 121.0, 118.0, 58.8; IR (diamond) 3084, 3031, 1581, 1317, 1149, 1051, 818, 696, 537, 483; HRMS (EI) m/z calcd. for C₁₆H₁₄N₂O₃S [M]+: 314.0725, found: 314.0727.

[Example 20] Preparation of 8-[(7,7-Dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methylsulfonamido]quinoline N-oxide (5c)

Yield 87 %; light yellow solid; m.p 143~145 ℃; ¹H NMR (600 MHz, CDCl₃) δ 14.26 (s, 1H), 8.34 (d, J = 5.9 Hz, 1H), 8.00 (d, J = 7.9 Hz, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.57 (t, J = 8.0 Hz, 1H), 7.50 (d, J = 8.1 Hz, 1H), 7.31 (dd, J = 8.4, 6.0 Hz, 1H), 3.71 (d, J = 14.9 Hz, 1H), 3.08 (d, J = 14.9 Hz, 1H), 2.65-2.48 (m, 1H), 2.33 (dt, J = 18.6, 3.9 Hz, 1H), 2.11-2.08 (m, 1H), 2.07-2.02 (m, 1H), 1.91 (d, J = 18.5 Hz, 1H), 1.84-1.74 (m, 1H), 1.51-1.38 (m, 1H), 1.11 (s, 3H), 0.83 (s, 3H); ¹³C NMR (150 MHz, CDCl₃) δ 215.1, 137.1, 134.2, 132.5, 130.8, 129.4, 129.3, 122.0, 121.0, 116.8, 58.5, 48.6, 48.1, 42.7, 42.5, 26.9, 25.0, 19.8, 19.7; IR (diamond) 3080, 2957, 1741, 1317, 1144, 1049, 908, 817, 726, 482; HRMS (EI) m/z calcd. for C₁₉H₂₂N₂O₄S [M]+: 374.1300, found: 374.1298.

[Example 21] Preparation of 8-(2-Bromophenylsulfonamido)quinoline N-oxide (5d)

Yield 53 %; light yellow solid; m.p 190~192 ℃; ¹H NMR (600 MHz, CD₂Cl₂) δ 15.24 (s, 1H), 8.35 (d, J = 6.0 Hz, 1H), 8.30 (d, J = 8.4 Hz, 1H), 7.74 (t, J = 7.5 Hz, 1H), 7.66 (d, J = 7.8 Hz, 1H), 7.59-7.55 (m, 1H), 7.48 (t, J = 7.7 Hz, 1H), 7.43-7.35 (m, 3H), 7.32-7.26 (m, 1H); ¹³C NMR (150 MHz, CD₂Cl₂) δ 138.7, 137.4, 135.9, 134.4, 133.7, 133.0, 132.8, 131.0, 129.4, 129.3, 127.9, 122.2, 121.6, 120.6, 115.9; IR (diamond) 3088, 3072, 1579, 1348, 1318, 1160, 1052, 816, 746, 572; HRMS (EI) m/z calcd. for C₁₅H₁₁BrN₂O₃S [M]+: 377.9674, found: 377.9674.

[Example 22] Preparation of 8-(4-Methoxyphenylsulfonamido)quinoline N-oxide (5e)

Yield 87 %; yellow solid; m.p 179~181 ℃; ¹H NMR (600 MHz, CDCl₃) δ 14.31 (s, 1H), 8.28 (d, J = 6.1 Hz, 1H), 7.87 (d, J = 8.5 Hz, 2H), 7.84 (d, J = 7.8 Hz, 1H), 7.70 (d, J = 8.4 Hz, 1H), 7.46 (t, J = 8.1 Hz, 1H), 7.41 (d, J = 8.1 Hz, 1H), 7.26-7.19 (m, 1H), 6.85 (d, J = 8.5 Hz, 2H), 3.78 (s, 3H); ¹³C NMR (150 MHz, CDCl₃) δ 162.9, 137.0, 133.8, 132.4, 131.3, 131.2, 129.5, 129.1, 128.9, 122.2, 120.9, 118.0, 114.1, 55.5; IR (diamond) 3078, 2969, 1594, 1318, 1260, 1155, 1092, 1052, 819, 564; HRMS (EI) m/z calcd. for C₁₆H₁₄N₂O₄S [M]+: 330.0674, found: 330.0675.

[Example 23] Preparation of 8-(Naphthalene-1-sulfonamido)quinoline N-oxide (5f)

Yield 55 %(0.2 mmol of AcOH at 80 ℃); light yellow solid; m.p 202~203 ℃; ¹H NMR (600 MHz, CDCl₃) δ 15.00 (s, 1H), 8.84 (d, J = 8.6 Hz, 1H), 8.44 (d, J = 7.3 Hz, 1H), 8.25 (d, J = 6.1 Hz, 1H), 8.00 (d, J = 8.2 Hz, 1H), 7.85 (d, J = 8.2 Hz, 1H), 7.76-7.66 (m, 2H), 7.62 (d, J = 8.4 Hz, 1H), 7.58-7.47 (m, 2H), 7.37 (t, J = 8.1 Hz, 1H), 7.29 (d, J = 8.2 Hz, 1H), 7.20-7.12 (m, 1H); ¹³C NMR (150 MHz, CDCl₃) δ 136.7, 134.5, 134.4, 134.2, 133.8, 132.3, 130.6, 130.4, 129.0, 128.8, 128.7, 128.4, 128.2, 126.9, 124.7, 123.8, 121.5, 120.8, 116.3; IR (diamond) 3082, 2970, 1738, 1581, 1318, 1160, 1134, 1053, 770, 588; HRMS (EI) m/z calcd. for C₁₉H₁₄N₂O₃S [M]+: 350.0725, found: 350.0729.

[Example 24] Preparation of 8-(4-Nitrobenzamido)quinoline N-oxide (5g)

Yield 62 %; yellow solid; m.p 260~265 ℃; ¹H NMR (600 MHz, CD₂Cl₂) δ 15.78 (s, 1H), 9.22 (d, J = 7.8 Hz, 1H), 8.43 (d, J = 6.0 Hz, 1H), 8.35 (d, J = 8.8 Hz, 2H), 8.24 (d, J = 8.7 Hz, 2H), 7.88 (d, J = 8.4 Hz, 1H), 7.67 (t, J = 8.0 Hz, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.36 (dd, J = 8.4, 5.9 Hz, 1H); ¹³C NMR (150 MHz, CD₂Cl₂) δ 162.9, 149.7, 140.8, 137.6, 134.3, 132.4, 131.0, 129.5, 129.3, 128.4, 123.8, 122.8, 121.0, 119.2; IR (diamond) 3102, 2910, 1674, 1521, 1415, 1344, 1162, 815, 747, 712; HRMS (EI) m/z calcd. for C₁₆H₁₁N₃O₄ [M]+: 309.0750, found: 309.0748.

[Example 25] Preparation of 4-(4-Methylphenylsulfonamido)acridine 10-oxide (7a)

Yield 73 %; orange solid; m.p. 196~198 ℃; ¹H NMR (600 MHz, CDCl₃) δ 14.70 (s, 1H), 8.69 (d, J = 9.1 Hz, 1H), 8.20 (s, 1H), 7.89 (d, J = 8.4 Hz, 1H), 7.84 (d, J = 8.3 Hz, 2H), 7.81-7.74 (m, 2H), 7.58 (t, J = 7.5 Hz, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.35 (t, J = 8.0 Hz, 1H), 7.13 (d, J = 8.1 Hz, 2H), 2.25 (s, 3H); ¹³C NMR (150 MHz, CDCl₃) δ 143.4, 139.6, 136.8, 133.1, 131.9, 131.0, 129.4, 129.0, 128.2, 127.8, 127.4, 127.2, 127.1, 126.9, 122.6, 119.3, 117.2, 21.4; IR (diamond) 3046, 2698, 1620, 1573, 1540, 1452, 1328, 1219, 1156, 1090, 888, 755, 651; HRMS (EI) m/z calcd. for C₂₀H₁₆N₂O₃S [M]+: 364.0882, found: 364.0879.

[Example 26] Preparation of 5-(4-Methylphenylsulfonamido)benzo[f]quinoline 4-oxide (7b)

Yield 78 %; yellow solid; m.p. 230~232 ℃; ¹H NMR (600 MHz, DMSO-d6) δ 15.10 (s, 1H), 8.97 (dd, J = 8.5, 1.0 Hz, 1H), 8.69 (d, J = 8.4 Hz, 1H), 8.67 (dd, J = 6.4, 0.9 Hz, 1H), 7.98 (dd, J = 7.8, 1.4 Hz, 1H), 7.97 (s, 1H), 7.73 (d, J = 8.3 Hz, 2H), 7.70 (t, J = 7.4 Hz, 2H), 7.64 (ddd, J = 8.3, 7.0, 1.4 Hz, 1H), 7.23 (d, J = 8.0 Hz, 2H), 2.20 (s, 3H); ¹³C NMR (150 MHz, DMSO-d6) δ 144.1, 139.3, 136.4, 131.7, 131.7, 130.6, 130.2, 130.2, 130.0, 128.4, 127.6, 127.4, 125.7, 125.5, 124.4, 123.5, 117.4, 21.3; IR (diamond) 3064, 2661, 1619, 1595, 1449, 1332, 1227, 1156, 1091, 897, 773, 754 cm-1; HRMS (EI) m/z calcd. for C₂₀H₁₆N₂O₃S [M]+: 364.0882, found: 364.0878.

[Example 27] Preparation of 4-(4-Methylphenylsulfonamido)phenanthridine 5-oxide (7c)

Yield 77 %; yellow solid; m.p. 235~237 ℃; ¹H NMR (600 MHz, DMSO-d6) δ 15.42 (s, 1H), 9.19 (s, 1H), 8.67 (d, J = 8.3 Hz, 1H), 8.46 (d, J = 7.8 Hz, 1H), 8.02 (d, J = 7.9 Hz, 1H), 7.84 (t, J = 7.4 Hz, 1H), 7.80?7.64 (m, 5H), 7.27 (d, J = 8.2 Hz, 2H), 2.22 (s, 3H); ¹³C NMR (150 MHz, DMSO-d6) δ 144.2, 137.9, 136.5, 134.5, 131.8, 130.4, 130.3, 130.2, 128.9, 127.6, 127.4, 127.3, 126.6, 126.0, 123.5, 118.5, 118.3, 21.3; IR (diamond) 3076, 2649, 1596, 1534, 1465, 1334, 1307, 1153, 1093, 983, 954, 806, 750 cm-1; HRMS (EI) m/z calcd. for C₂₀H₁₆N₂O₃S [M]+: 364.0882, found: 364.0885.

[Example 28] Preparation of 4-(4-Methylphenylsulfonamido)phenazine 5-oxide (7d)

Yield 93 %; orange solid; m.p. 189~191 ℃; ¹H NMR (600 MHz, CDCl₃) δ 12.94 (s, 1H), 8.51 (d, J = 8.9 Hz, 1H), 8.05 (d, J = 8.6 Hz, 1H), 7.87-7.69 (m, 6H), 7.61 (t, J = 8.2 Hz, 1H), 7.14 (d, J = 8.0 Hz, 2H), 2.24 (s, 3H); ¹³C NMR (150 MHz, CDCl₃) δ 146.4, 144.9, 144.0, 136.2, 134.1, 132.2, 131.9, 131.2, 131.1, 130.0, 129.6, 127.4, 126.0, 124.5, 118.7, 116.2, 21.4; IR (diamond) 3094, 2892, 1620, 1596, 1568, 1466, 1331, 1161, 1107, 1050, 828, 736; HRMS (EI) m/z calcd. for C₁₉H₁₅N₃O₃S [M]+: 365.0834, found: 364.0830.

[Example 29] Preparation of 4-(4-Methylphenylsulfonamido)benzo[c]cinnoline 5-oxide (7e)

Yield 66 %(at 80 ℃); yellow solid; m.p. 240~242 ℃; ¹H NMR (600 MHz, CDCl₃) δ 12.96 (s, 1H), 8.27 (d, J = 8.1 Hz, 1H), 8.08 (d, J = 8.1 Hz, 1H), 8.03 (d, J = 8.2 Hz, 1H), 7.95 (d, J = 7.7 Hz, 1H), 7.84 (d, J = 8.3 Hz, 2H), 7.76 (t, J = 8.0 Hz, 2H), 7.71 (t, J = 8.1 Hz, 1H), 7.20 (d, J = 8.4 Hz, 2H), 2.31 (s, 3H); ¹³C NMR (150 MHz, CDCl₃) δ 144.2, 141.6, 136.2, 134.7, 133.1, 131.2, 131.0, 130.2, 129.8, 127.4, 127.0, 126.7, 121.7, 118.7, 118.5, 116.1, 21.5; IR (diamond) 3088, 3046, 1595, 1562, 1470, 1440, 1334, 1293, 1218, 1159, 1088, 853, 739; HRMS (EI) m/z calcd. for C₁₉H₁₅N₃O₃S [M]+: 365.0834, found:365.0833

[Example 30] Preparation of 8,8'-Bis(4-methylphenylsulfonamido)-2,2'-biquinoline 1,1'-dioxide (7f)

Yield 83 %(0.44 mmol of azide, 0.008 mmol of [IrCp*Cl₂]₂, 0.032 mmol of AgNTf₂ at 80 ℃ for 24 hours); yellow solid; m.p. 187~189 ℃; ¹H NMR (600 MHz, CDCl₃) δ 13.90 (s, 2H), 7.86-7.79 (m, 6H), 7.70 (d, J = 8.6 Hz, 2H), 7.50-7.44 (m, 4H), 7.41 (d, J = 8.1 Hz, 2H), 7.22 (d, J = 8.0 Hz, 4H), 2.30 (s, 6H); ₁₃C NMR (150 MHz, CDCl₃) δ 143.9, 139.6, 136.3, 133.9, 132.4, 131.3, 129.8, 129.8, 128.1, 127.3, 122.8, 122.6, 118.4, 21.5; IR (diamond) 2921, 2730, 1596, 1570, 1440, 1351, 1305, 1157, 1089, 1053, 826, 752; HRMS (FAB) m/z calcd. for C₃₂H₂₆N₄O₆S₂ [M+H+]+: 627.1372, found: 627.1375.

[Example 31] Preparation of 8-(4-Methylphenylsulfonamido)-2-phenylquinoline N-oxide (7g)

Yield 71 %; yellow solid; m.p. 167~169 ℃; ¹H NMR (600 MHz, CDCl₃) δ 14.57 (s, 1H), 7.83 (dd, J = 7.8, 1.4 Hz, 1H), 7.81 (d, J = 8.3 Hz, 2H), 7.79-7.76 (m, 2H), 7.69 (d, J = 8.7 Hz, 1H), 7.54-7.46 (m, 3H), 7.43 (t, J = 8.0 Hz, 1H), 7.38 (dd, J = 8.1, 1.3 Hz, 1H), 7.36 (d, J = 8.7 Hz, 1H), 7.17 (d, J = 8.2 Hz, 2H), 2.30 (s, 3H); ¹³C NMR (150 MHz, CDCl₃) δ 146.4, 143.4, 136.9, 134.2, 132.7, 131.5, 131.5, 130.0, 129.4, 129.4, 128.9, 128.4, 128.2, 127.4, 123.4, 122.2, 118.4, 21.5; IR (diamond) 3068, 3033, 2683, 1597, 1568, 1452, 1436, 1350, 1282, 1158, 1089, 1051, 842, 774 cm-1; HRMS (EI) m/z calcd. for C₂₂H₁₈N₂O₃S [M]+: 390.1038, found: 390.1036.

[Example 32] Preparation of 8-(4-Methylphenylsulfonamido)-2-(naphthalen-1-yl)quinoline N-oxide (7h)

Yield 82 %; yellow solid; m.p. 203~205 ℃; ¹H NMR (600 MHz, CDCl₃) δ 14.37 (s, 1H), 8.00 (d, J = 8.3 Hz, 1H), 7.96-7.89 (m, 2H), 7.79 (d, J = 8.3 Hz, 2H), 7.75 (d, J = 8.5 Hz, 1H), 7.62-7.57 (m, 1H), 7.55 (d, J = 7.9 Hz, 1H), 7.52-7.43 (m, 4H), 7.36-7.31 (m, 2H), 7.18 (d, J = 8.1 Hz, 2H), 2.34 (s, 3H); ¹³C NMR (150 MHz, CDCl₃) δ 146.9, 143.4, 136.9, 134.1, 133.5, 132.0, 131.6, 131.2, 130.4, 130.3, 129.5, 129.1, 128.8, 127.9, 127.4, 126.9, 126.4, 125.4, 125.1, 124.5, 122.6, 118.7, 21.5; IR (diamond) 3053, 2667, 1596, 1568, 1442, 1351, 1305, 1157, 1089, 1050, 772, 655; HRMS (EI) m/z calcd. for C₂₆H₂₀N₂O₃S [M]+: 440.1195, found: 440.1194.

[Comparative Example 1] Preparation of Quinoline N-oxide Derivative with Amide Group

A quinoline N-oxide derivative with an amide group was prepared by the same method as Example 1 except for using [RhCp*Cl₂]₂instead of using [IrCp*Cl₂]₂in Example 1.

As a result thereof, the yield of the quinoline N-oxide derivative with an amide group was less than 1%.

[Comparative Example 2] Preparation of Quinoline N-oxide Derivative with Amide Group

A quinoline N-oxide derivative with an amide group was prepared by the same method as Example 1 except for using [Ru(p-cymene)Cl₂]₂ instead of using [IrCp*Cl₂]₂ in Example 1.

[Comparative Example 3] Preparation of Quinoline N-oxide Derivative with Amide Group

A quinoline N-oxide derivative with an amide group was prepared by the same method as Example 1 except for using Pd(OAc)₂ instead of using [IrCp*Cl₂]₂ in Example 1.

As a result thereof, the quinoline N-oxide derivative with an amide group had a yield less than 1%.

[Comparative Example 4] Preparation of Quinoline N-oxide Derivative with Amide Group

A quinoline N-oxide derivative with an amide group was prepared by the same method as Example 1 except for using CHCOONa instead of using the acetic acid in Example 1.

As a result thereof, the quinoline N-oxide derivative with an amide group was obtained in 24% yield.

[Comparative Example 5] Preparation of Quinoline N-oxide Derivative with Amide Group

A quinoline N-oxide derivative with an amide group was prepared by the same method as Example 1 except for using camphorsulfonic acid (CSA) instead of using the acetic acid in Example 1.

As a result thereof, the quinoline N-oxide derivative with an amide group was obtained in 18% yield.

[Example 33] Preparation of Zinquin Ethyl Ester

(1) Preparation of Ethyl 2-[(2-methylquinolin-6-yl)oxy]acetate (9)

K₂CO₃ (460 mg, 3.3 mmol) and 2-methyl-6-hydroxyquinoline (318.4 mg, 2.0 mmol) were added to DMF (20 mL), and ethyl bromoacetate (367 mg, 2.2 mmol) was slowly added dropwise thereto and the reaction mixture was stirred at room temperature for 12 hours. H₂O (20 mL) was added to the reaction mixture and the reaction mixture was extracted with ethyl acetate (20 mL x 3). The combined organic layer was washed with saturated brine, dried over Na₂SO₄, then a solid was filtered off, and an organic solvent was removed under reduced pressure. The residue was separated by column chromatography (CH₂Cl₂/acetone, 10/1, Rf = 0.3) to obtain ethyl 2-[(2-methylquinolin-6-yl)oxy]acetate. (461 mg, 94%); yellow solid; m.p. 44~46 ℃; ¹H NMR (600 MHz, CDCl₃) δ 7.97-7.90 (m, 2H), 7.41 (dd, J = 9.2, 2.8 Hz, 1H), 7.24 (d, J = 8.4 Hz, 1H), 7.00 (d, J = 2.8 Hz, 1H), 4.73 (s, 2H), 4.29 (q, J = 7.1 Hz, 2H), 2.70 (s, 3H), 1.30 (t, J = 7.2 Hz, 3H); ¹³C NMR (150 MHz, CDCl₃) δ 168.6, 157.0, 155.3, 144.3, 135.1, 130.4, 127.0, 122.4, 121.7, 106.8, 65.7, 61.5, 25.1, 14.2; IR (diamond) 3043, 2984, 2947, 2911, 2869, 1747, 1620, 1598, 1499, 1446, 1377, 1201, 1164, 1074, 1021, 832; HRMS (EI) m/z calcd. for C₁₄H₁₅NO₃ [M+H+]+: 246.1125, found: 246.1129.

(2) Preparation of 6-(2-ethoxy-2-oxoethoxy)-2-methyl-8-(4-methylphenylsulfonamido) quinoline N-oxide (11)

Ethyl 2-(2-methylquinolin-6-yloxy)acetate (123 mg, 0.5 mmol) was dissolved in chloroform (10 mL), then m-chloroperbenzoic acid (168 mg, 0.75 mmol) was added in small portions thereto and the reaction mixture was stirred at 50 ℃ for 5 hours. 50 mL of chloroform was added thereto and the reaction mixture was washed with a saturated aqueous solution of sodium bicarbonate (10 mL x 3). The reaction mixture was dried over MgSO₄, then a solid was filtered off, and an organic solvent was removed under reduced pressure to obtain 6-(2-ethoxy-2-oxoethoxy)-2-methylquinoline N-oxide(10), which was used for next reaction without further purification. 6-(2-ethoxy-2-oxoethoxy)-2-methylquinoline N-oxide (10) (129.8 mg, 5.0 mmol), [IrCp*Cl2]2 (15.9 mg, 0.02 mmol), AgNTf₂ (31.0 mg, 0.08 mmol) and an acetic acid (9.0 mg, 0.15 mmol) were added to 1,2-dichloroethane (2.0 mL) and p-toluenesulfonyl azide (108 mg, 0.55 mmol) was added thereto, and the reaction mixture was stirred at 50 ℃ for 5 hours. The reaction mixture was passed through a celite and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH₂Cl₂/acetone, 10/1, Rf = 0.5) to obtain 6-(2-ethoxy-2-oxoethoxy)-2-methyl-8-(4-methylphenylsulfonamido)quinoline N-oxide (11). (164 mg, 76%); 10 : ¹H NMR (600 MHz, CDCl₃) δ 8.72 (d, J = 9.4 Hz, 1H), 7.51 (d, J = 8.5 Hz, 1H), 7.44 (dd, J = 9.5, 2.7 Hz, 1H), 7.27 (d, J = 8.6 Hz, 1H), 7.05 (d, J = 2.7 Hz, 1H), 4.74 (s, 2H), 4.30 (q, J = 7.1 Hz, 2H), 2.68 (s, 3H), 1.30 (t, J = 7.1 Hz, 3H); ¹³C NMR (150 MHz, CDCl₃) δ 168.2, 156.9, 144.1, 137.8, 130.3, 124.0, 123.7, 122.0, 121.7, 107.5, 65.6, 61.6, 18.5, 14.1; 11 : yellow solid; m.p. 155~157 ℃; ¹H NMR (600 MHz, CDCl3) δ 14.91 (s, 1H), 7.85 (d, J = 8.2 Hz, 2H), 7.51 (d, J = 2.7 Hz, 1H), 7.44 (d, J = 8.6 Hz, 1H), 7.21 (d, J = 8.2 Hz, 2H), 7.17 (d, J = 8.6 Hz, 1H), 6.63 (d, J = 2.6 Hz, 1H), 4.65 (s, 2H), 4.28 (q, J = 7.2 Hz, 2H), 2.56 (s, 3H), 2.33 (s, 3H), 1.30 (t, J = 7.1 Hz, 3H); ¹³C NMR (150 MHz, CDCl₃) δ 168.0, 156.6, 145.2, 143.5, 136.9, 135.1, 132.0, 129.5, 127.3, 127.1, 123.5, 107.9, 102.5, 65.4, 61.6, 21.4, 18.4, 14.1; IR (diamond) 3084, 2981, 2922, 2643, 1760, 1609, 1578, 1418, 1369, 1325, 1283, 1155, 1077, 841, 657; HRMS (EI) m/z calcd. for C₂₁H₂₂N₂O₆S [M]+: 430.1199, found: 430.1199.

(3) Preparation of zinquin ethyl ester (12)

6-(2-ethoxy-2-oxoethoxy)-2-methyl-8-(4-methylphenylsulfonamido)-quinoline N-oxide (43.1 mg, 0.1 mmol) was added to THF (1.5 mL) and 30% aqueous ammonium chloride solution (1.5 mL) and zinc powder (59 mg, 0.9 mmol) were sequentially added thereto and the reaction mixture was stirred at room temperature for 1 hour. Water (20 mL) was added thereto, the reaction mixture was extracted with ethyl acetate (20 mL x 3). The combined orgenic layer was dried over MgSO_4,then a solid was filtered off, and an organic solvent was removed under reduced pressure. The residue was purified by column chromatography (CH₂Cl₂/MeOH, 20/1, Rf = 0.3) to obtain zinquin ethyl ester. (32 mg, 76%); white solid; m.p. 106~108 ℃; ¹H NMR (600 MHz, CDCl₃) δ 9.27 (s, 1H), 7.83-7.79 (m, 3H), 7.50 (d, J = 2.6 Hz, 1H), 7.22 (d, J = 8.4 Hz, 1H), 7.18 (d, J = 8.1 Hz, 2H), 6.63 (d, J = 2.6 Hz, 1H), 4.66 (s, 2H), 4.28 (q, J = 7.1 Hz, 2H), 2.64 (s, 3H), 2.31 (s, 3H), 1.30 (t, J = 7.1 Hz, 3H); ¹³C NMR (150 MHz, CDCl₃) δ 168.5, 155.6, 155.5, 143.7, 136.5, 135.2, 134.5, 134.4, 129.5, 127.2, 126.8, 123.3, 106.8, 101.2, 65.7, 61.5, 24.8, 21.4, 14.1; IR (diamond) 3271, 2980, 2916, 1765, 1627, 1605, 1577, 1501, 1424, 1378, 1340, 1203, 1157, 1089, 840; HRMS (EI) m/z calcd. for C₂₁H₂₂N₂O₅S [M]+: 414.1249, found: 414.1248.

As described in Example 33, zinquin ethyl ester which is a dye for detecting zinc could be easily prepared by the preparation method of the quinoline N-oxide with an amide group according to the present invention.

Claims

A preparation method of a quinoline N-oxide derivative with an amide group represented by Chemical Formula 1 below, comprising:

performing a reaction of a quinoline N-oxide derivative represented by Chemical Formula 3 below with an azide compound represented by Chemical Formula 4 below, in the presence of an iridium catalyst and an acid:

[Chemical Formula 1]

[Chemical Formula 3]

[Chemical Formula 4]

in Chemical Formulas 1, 3, and 4,

A1 and A2 are each independently N or CR, R is hydrogen, halogen, nitro, formyl, (C1-C10)alkyl, (C1-C10)alkoxy, (C1-C10)alkoxycarbonyl, (C6-C12)aryl, (C6-C12)aryloxycarbonyl, (C3-C12)heterocycloalkyl, (C3-C12)heteroaryl, -OSi(R11)(R12)(R13) or -N(R14)(R15);

R1 to R4 are each independently hydrogen, halogen, nitro, formyl, (C1-C10)alkyl, (C1-C10)alkoxy, (C1-C10)alkoxycarbonyl, (C6-C12)aryl, (C6-C12)aryloxycarbonyl, (C3-C12)heterocycloalkyl, (C3-C12)heteroaryl, -OSi(R11)(R12)(R13) or -N(R14)(R15);

R11 to R15 are each independently hydrogen or (C1-C10)alkyl;

Z is -S(O)₂- or -CO-;

T is (C1-C10)alkylene, (C6-C12)arylene or (C6-C12)heteroarylene;

R10 is hydrogen, halogen, nitro, (C1-C10)alkyl, (C1-C10)alkoxy, (C1-C10)alkoxycarbonyl, (C6-C12)aryl, (C6-C12)aryloxycarbonyl, (C3-C12)heterocycloalkyl or (C3-C12)heteroaryl;

R1 to R4 and R may be each independently linked with an adjacent substituent via (C3-C12)alkylene or (C3-C12)alkenylene with or without a fused ring to form an alicyclic ring and a monocyclic or polycyclic aromatic ring; and

the alkyl, alkoxy, alkoxycarbonyl, aryl, aryloxycarbonyl, heterocycloalkyl, heteroaryl, alicyclic ring, and aromatic ring of R1 to R4 and R, and the alkyl of R11 to R15 may be further substituted with at least one selected from the group consisting of halogen, hydroxy, amino, nitro, carboxy, (C1-C10)alkyl, halo(C1-C10)alkyl, (C6-C12)aryl, (C3-C12)heteroaryl, 5- to 7-membered heteroc℃ycloalkyl, (C3-C12)cycloalkyl, (C2-C10)alkenyl, (C2-C10)alkynyl, cyano, (C6-C12)ar(C1-C10)alkyl and (C1-C10)alkyl(C6-C12)aryl.
A preparation method of a quinoline N-oxide derivative with an amide group represented by Chemical Formula 2 below, comprising:

performing a reaction of a quinoline N-oxide derivative represented by Chemical Formula 5 below with an azide compound represented by Chemical Formula 4 below in the presence of an iridium catalyst and an acid:

[Chemical Formula 2]

[Chemical Formula 5]

[Chemical Formula 4]

in Chemical Formulas 2, 4, and 5,

A1 and A3 are each independently N or CR, R is hydrogen, halogen, nitro, formyl, (C1-C10)alkyl, (C1-C10)alkoxy, (C1-C10)alkoxycarbonyl, (C6-C12)aryl, (C6-C12)aryloxycarbonyl, (C3-C12)heterocycloalkyl, (C3-C12)heteroaryl, -OSi(R11)(R12)(R13) or -N(R14)(R15);

R1 to R8 are each independently hydrogen, halogen, nitro, formyl, (C1-C10)alkyl, (C1-C10)alkoxy, (C1-C10)alkoxycarbonyl, (C6-C12)aryl, (C6-C12)aryloxycarbonyl, (C3-C12)heterocycloalkyl, (C3-C12)heteroaryl, -OSi(R11)(R12)(R13) or -N(R14)(R15);

R11 to R15 are each independently hydrogen or (C1-C10)alkyl;

Z is -S(O)₂- or -CO-;

T is (C1-C10)alkylene, (C6-C12)arylene or (C6-C12)heteroarylene;

R10 is hydrogen, halogen, nitro, (C1-C10)alkyl, (C1-C10)alkoxy, (C1-C10)alkoxycarbonyl, (C6-C12)aryl, (C6-C12)aryloxycarbonyl, (C3-C12)heterocycloalkyl or (C3-C12)heteroaryl;

R1 to R8 and R may be each independently linked with an adjacent substituent via (C3-C12)alkylene or (C3-C12)alkenylene with or without a fused ring to form an alicyclic ring and a monocyclic or polycyclic aromatic ring;

the alkyl, alkoxy, alkoxycarbonyl, aryl, aryloxycarbonyl, heterocycloalkyl, heteroaryl, alicyclic ring, and aromatic ring of R1 to R8 and R, and the alkyl of R11 to R15 may be further substituted with at least one selected from the group consisting of halogen, hydroxy, amino, nitro, carboxy, (C1-C10)alkyl, halo(C1-C10)alkyl, (C6-C12)aryl, (C3-C12)heteroaryl, 5- to 7-membered heteroc℃ycloalkyl, (C3-C12)cycloalkyl, (C2-C10)alkenyl, (C2-C10)alkynyl, cyano, (C6-C12)ar(C1-C10)alkyl and (C1-C10)alkyl(C6-C12)aryl.
The preparation method of claim 1, wherein Chemical Formula 1 is represented by Chemical Formulas 6 to 9 below:

[Chemical Formula 6]

[Chemical Formula 7]

[Chemical Formula 8]

[Chemical Formula 9]

in Chemical Formulas 6 to 9,

A1 and A2 are each independently N or CR, R is hydrogen, halogen, nitro, formyl, (C1-C10)alkyl, (C1-C10)alkoxy, (C1-C10)alkoxycarbonyl, (C6-C12)aryl, (C6-C12)aryloxycarbonyl, (C3-C12)heterocycloalkyl, (C3-C12)heteroaryl, -OSi(R11)(R12)(R13) or -N(R14)(R15);

R1 to R4 are each independently hydrogen, halogen, nitro, formyl, (C1-C10)alkyl, (C1-C10)alkoxy, (C1-C10)alkoxycarbonyl, (C6-C12)aryl, (C6-C12)aryloxycarbonyl, (C3-C12)heterocycloalkyl, (C3-C12)heteroaryl, -OSi(R11)(R12)(R13) or -N(R14)(R15);

R11 to R15 are each independently hydrogen or (C1-C10)alkyl;

Z is -S(O)₂- or -CO-;

T is (C1-C10)alkylene, (C6-C12)arylene or (C6-C12)heteroarylene;

R10 is hydrogen, halogen, nitro, (C1-C10)alkyl, (C1-C10)alkoxy, (C1-C10)alkoxycarbonyl, (C6-C12)aryl, (C6-C12)aryloxycarbonyl, (C3-C12)heterocycloalkyl or (C3-C12)heteroaryl; and

R21 to R25 are each independently hydrogen, halogen, hydroxy, amino, nitro, carboxy, (C1-C10)alkyl, halo(C1-C10)alkyl, (C6-C12)aryl, (C3-C12)heteroaryl, 5- to 7-membered heterocycloalkyl, (C3-C12)cycloalkyl, (C2-C10)alkenyl, (C2-C10)alkynyl, cyano, (C6-C12)ar(C1-C10)alkyl or (C1-C10)alkyl(C6-C12)aryl.
The preparation method of claim 1 or 2, wherein T is phenylene, naphthalene or anthracene.
The preparation method of claim 1 or 2, wherein Chemical Formula 1 is selected from the following compounds:

.
The preparation method of claim 1 or 2, wherein the iridium catalyst is at least any one selected from the group consisting of [IrCp*Cl₂]₂, [IrCl(COD)]₂, Ir(acac)₃, [Ir(OMe)(COD)]₂, IrCl(CO)(PPh₃)₂ and IrCl₃.
The preparation method of claim 1 or 2, wherein the reaction is performed by further including a silver catalyst.
The preparation method of claim 7, wherein the silver catalyst is at least one selected from the group consisting of AgNTf₂, AgSbF₆, AgPF₆, AgBF₄, and Ag₂O.
The preparation method of claim 1 or 2, wherein the acid is at least any one selected from the group consisting of an acetic acid, a pivalic acid, a benzoic acid and a sulfonic acid.
The preparation method of claim 1 or 2, wherein the iridium catalyst is used in an amount of 0.01 to 0.5 mol based on 1 mol of the quinoline N-oxide derivative represented by Chemical Formula 3 or 5.
The preparation method of claim 1 or 2, wherein the acid is used in an amount of 0.1 to 3 mol based on 1 mol of the quinoline N-oxide derivative represented by Chemical Formula 3 or 5.
A quinoline N-oxide derivative with an amide group represented by Chemical Formula 1 or 2 below:

[Chemical Formula 1]

[Chemical Formula 2]

in Chemical Formula 1,

A1, A2 and A3 are each independently N or CR, R is hydrogen, halogen, nitro, formyl, (C1-C10)alkyl, (C1-C10)alkoxy, (C1-C10)alkoxycarbonyl, (C6-C12)aryl, (C6-C12)aryloxycarbonyl, (C3-C12)heteroc℃ycloalkyl, (C3-C12)heteroaryl, -OSi(R11)(R12)(R13) or -N(R14)(R15);

R1 to R8 are each independently hydrogen, halogen, nitro, formyl, (C1-C10)alkyl, (C1-C10)alkoxy, (C1-C10)alkoxycarbonyl, (C6-C12)aryl, (C6-C12)aryloxycarbonyl, (C3-C12)heterocycloalkyl, (C3-C12)heteroaryl, -OSi(R11)(R12)(R13) or -N(R14)(R15);

R11 to R15 are each independently hydrogen or (C1-C10)alkyl;

Z is -S(O)₂- or -CO-;

T is (C1-C10)alkylene, (C6-C12)arylene or (C6-C12)heteroarylene;

R10 is hydrogen, halogen, nitro, (C1-C10)alkyl, (C1-C10)alkoxy, (C1-C10)alkoxycarbonyl, (C6-C12)aryl, (C6-C12)aryloxycarbonyl, (C3-C12)heterocycloalkyl or (C3-C12)heteroaryl;

R1 to R8 and R may be each independently linked with an adjacent substituent via (C3-C12)alkylene or (C3-C12)alkenylene with or without a fused ring to form an alicyclic ring and a monocyclic or polycyclic aromatic ring; and

the alkyl, alkoxy, alkoxycarbonyl, aryl, aryloxycarbonyl, heterocycloalkyl, heteroaryl, alicyclic ring, and aromatic ring of R1 to R8 and R, and the alkyl of R11 to R15 may be further substituted with at least one selected from the group consisting of halogen, hydroxy, amino, nitro, carboxy, (C1-C10)alkyl, halo(C1-C10)alkyl, (C6-C12)aryl, (C3-C12)heteroaryl, 5- to 7-membered heterocycloalkyl, (C3-C12)cycloalkyl, (C2-C10)alkenyl, (C2-C10)alkynyl, cyano, (C6-C12)ar(C1-C10)alkyl and (C1-C10)alkyl(C6-C12)aryl.
The quinoline N-oxide derivative with an amide group of claim 12, wherein Chemical Formula 1 is represented by Chemical Formulas 6 to 9 below:

[Chemical Formula 6]

[Chemical Formula 7]

[Chemical Formula 8]

[Chemical Formula 9]

in Chemical Formulas 6 to 9,

A1 and A2 are each independently N or CR, R is hydrogen, halogen, nitro, formyl, (C1-C10)alkyl, (C1-C10)alkoxy, (C1-C10)alkoxycarbonyl, (C6-C12)aryl, (C6-C12)aryloxycarbonyl, (C3-C12)heterocycloalkyl, (C3-C12)heteroaryl, -OSi(R11)(R12)(R13) or -N(R14)(R15);

R1 to R4 are each independently hydrogen, halogen, nitro, formyl, (C1-C10)alkyl, (C1-C10)alkoxy, (C1-C10)alkoxycarbonyl, (C6-C12)aryl, (C6-C12)aryloxycarbonyl, (C3-C12)heteroc℃ycloalkyl, (C3-C12)heteroaryl, -OSi(R11)(R12)(R13) or -N(R14)(R15);

R11 to R15 are each independently hydrogen or (C1-C10)alkyl;

Z is a single bond, -S(O)₂- or -CO-;

T is (C1-C10)alkylene, (C6-C12)arylene or (C6-C12)heteroarylene;

R10 is hydrogen, halogen, nitro, (C1-C10)alkyl, (C1-C10)alkoxy, (C1-C10)alkoxycarbonyl, (C6-C12)aryl, (C6-C12)aryloxycarbonyl, (C3-C12)heterocycloalkyl or (C3-C12)heteroaryl; and

R21 to R25 are each independently hydrogen, halogen, hydroxy, amino, nitro, carboxy, (C1-C10)alkyl, halo(C1-C10)alkyl, (C6-C12)aryl, (C3-C12)heteroaryl, 5- to 7-membered heterocycloalkyl, (C3-C12)cycloalkyl, (C2-C10)alkenyl, (C2-C10)alkynyl, cyano, (C6-C12)ar(C1-C10)alkyl or (C1-C10)alkyl(C6-C12)aryl.
The quinoline N-oxide derivative with an amide group of claim 12, wherein T is phenylene, naphthalene or anthracene.
The quinoline N-oxide derivative with an amide group of claim 12, wherein Chemical Formula 1 or 2 is selected from the following compounds:

.