KR102007956B1 - Acylmethyl-substituted pyridine compound and its preparation method - Google Patents

Abstract

The present invention relates to an acylmethylpyridine compound and a method for manufacturing the same. More specifically, the present invention relates to the method for manufacturing the acylmethylpyridine compound through acylmethylation using an azirine compound, and a manufactured acylmethylpyridine compound. The acylmethylpyridine compound according to the present invention can be usefully used as an important raw material or intermediate in the field of natural materials or pharmaceuticals as well as in the field of electronic materials.

Description

Acylmethylpyridine compound and its preparation method {ACYLMETHYL-SUBSTITUTED PYRIDINE COMPOUND AND ITS PREPARATION METHOD}

The present invention relates to acylmethylpyridine compounds and methods for their preparation.

Heterocyclic compounds containing nitrogen have high physiological and pharmacological activity, are widely used as host materials in the field of electronic materials, and exist in various natural products, which are very important for biological activity research and pharmaceuticals, as well as electronic materials.

Methods for introducing various substituents into such compounds are of great importance in building a valuable heterocyclic compound library. Therefore, researches for introducing various substituents into heterocyclic compounds have been actively conducted. Among them, for the acylmethylation reaction, the developed method was very limited, and only one method was reported. This method is an inefficient method of synthesizing the reactants required for acylmethylation through several steps and has a limitation of the substrate.

On the other hand, controlling the chemical, positional and stereoselectivity of chemical reactions is generally important, but more particularly in organic chemistry. And, the carbon-hydrogen bond activation reaction is most preferably performed with high selectivity, and considerable research has been made in the past for coupling carbon-hydrogen activation with carbon-carbon and carbon-nitrogen bond formation modifications.

Among them, alkyl and aryl azide showed prominent characteristics as important reagents, and many carbon-nitrogen forming reagents based on carbon-hydrogen activation reactions have been developed. Acyl azide can form carbon-carbon bonds through isocyanates produced in situ within the framework of the Curtius rearrangement pathway.

Most notably, Professor Jang recently developed a method of forming carbon-nitrogen bonds using acyl azide through a carbon-hydrogen activation reaction using a ruthenium catalyst. Stable sulfonyl azides have also been used to form carbon-nitrogen bonds in carbon-hydrogen activation reactions and most recently dioxazolone has been identified as a substitute for azide to build carbon-nitrogen bonds under mild reaction conditions.

From this it can be seen that the choice of reagents that mediate the formation of carbon-nitrogen and / or carbon-carbon bonds is important.

On the other hand, azirin is a tricyclic compound containing nitrogen. In the past, azirin was widely used as a reactant to supply nitrogen. In addition, it has been widely used to synthesize heterocyclic compounds such as indole, pyridine, and pyrazine by inducing intermolecular or intramolecular cyclization reactions.

There is no research on the carbon-hydrogen activation reaction using azirin.

Therefore, the present inventors completed an efficient acylmethylation method by forming a selective carbon-carbon bond by extending the range of carbon-hydrogen activation reaction using azirin as a new starting material that can be applied to a wider substrate than the conventional acylmethylation reaction. Was intended.

 Angew. Chem. Int. Ed. 2017, 56, 13117  Org. Lett. 2017, 19, 5256  Org. Lett. 2018, 20, 1396  J. Org. Chem. 2018, 83, 4641  Org. Chem. Front. 2018, 5, 998  Org. Lett. 2018, 20, 5981  Chem. Rev. 2017, 117, 9247  Org. Lett. 2014, 16, 2022

An object of the present invention is to provide a novel acylmethylpyridine compound.

It is another object of the present invention to provide an acylmethylation reaction using azirin.

Another object of the present invention is to provide a method for preparing an acylmethylpyridine compound by reacting a pyridine compound and an aziline compound in the presence of a rhodium or ruthenium catalyst, a silver additive, acetic acid and water.

The present invention provides an acylmethylpyridine compound represented by the following formula (1).

[Formula 1]

In Chemical Formula 1,

L is -CR ^a = CR ^b- , NR ^c , O or S;

R ¹ , R ² , R ^a , R ^b and R ^c are each independently hydrogen, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, halogen, C 1 -C 10 alkylcarbonyl, C 1 -C 10 alkoxycarbonyl, C 6 -C 20 aryl , C6-C20 aryloxy, C6-C20 arylcarbonyl or C6-C20 aryloxycarbonyl, or may be linked with adjacent substituents to form a fused ring,

R ³ is hydrogen, C 1 -C 10 alkyl, halogen, C 1 -C 10 alkylcarbonyl, C 1 -C 10 alkoxycarbonyl, C 6 -C 20 aryl, C 6 -C 20 arylcarbonyl or C 6 -C 20 aryloxycarbonyl;

Ar is C6-C20 aryl or C3-C20 heteroaryl;

Alkyl, alkoxy, alkylcarbonyl, aryl, aryloxy or arylcarbonyl of R ¹ , R ² , R ^a , R ^b and R ^c , alkyl, alkylcarbonyl, alkoxycarbonyl of R ³ , aryl, arylcarbon Aryl or heteroaryl of aryl or aryloxycarbonyl and Ar is C1-C10 alkyl, halogen, C1-C10 alkoxy, haloC1-C10 alkyl, C6-C20 aryl, C6-C20 aryloxy, C1-C10 alkylcarbonyl, Further substituted with one or more selected from the group consisting of C1-C10 alkoxycarbonyl, C6-C20 arylcarbonyl, C6-C20 aryloxycarbonyl, nitro and cyano;

The heteroaryl includes 1 to 4 heteroatoms selected from N, O and S.

The present invention also prepares an acylmethylpyridine compound represented by Chemical Formula 1 by reacting a pyridine compound represented by Chemical Formula 4 and an azirin compound represented by Chemical Formula 5 in the presence of a rhodium or ruthenium catalyst, a silver additive, acetic acid, and water. Provides a way to:

[Formula 1]

[Formula 4]

[Formula 5]

In Chemical Formulas 1, 4, and 5,

L is -CR ^a = CR ^b- , NR ^c , O or S;

R ¹ , R ² , R ^a , R ^b and R ^c are each independently hydrogen, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, halogen, C 1 -C 10 alkylcarbonyl, C 1 -C 10 alkoxycarbonyl, C 6 -C 20 aryl , C6-C20 aryloxy, C6-C20 arylcarbonyl or C6-C20 aryloxycarbonyl, or may be linked with adjacent substituents to form a fused ring,

R ³ is hydrogen, C 1 -C 10 alkyl, halogen, C 1 -C 10 alkylcarbonyl, C 1 -C 10 alkoxycarbonyl, C 6 -C 20 aryl, C 6 -C 20 arylcarbonyl or C 6 -C 20 aryloxycarbonyl;

Ar is C6-C20 aryl or C3-C20 heteroaryl;

Alkyl, alkoxy, alkylcarbonyl, aryl, aryloxy or arylcarbonyl of R ¹ , R ² , R ^a , R ^b and R ^c , alkyl, alkylcarbonyl, alkoxycarbonyl of R ³ , aryl, arylcarbon Aryl or heteroaryl of aryl or aryloxycarbonyl and Ar is C1-C10 alkyl, halogen, C1-C10 alkoxy, haloC1-C10 alkyl, C6-C20 aryl, C6-C20 aryloxy, C1-C10 alkylcarbonyl, Further substituted with one or more selected from the group consisting of C1-C10 alkoxycarbonyl, C6-C20 arylcarbonyl, C6-C20 aryloxycarbonyl, nitro and cyano;

The heteroaryl includes 1 to 4 heteroatoms selected from N, O and S.

The acylmethylpyridine compound according to the present invention may be usefully used as an important raw material or intermediate in the field of natural materials or pharmaceuticals, as well as electronic materials.

In addition, the method for preparing an acylmethylpyridine compound according to the present invention is acyl methylated reaction of the pyridine compound of formula (4) in the presence of a rhodium or ruthenium catalyst, silver additives, acetic acid and water with the azirin compound as a starting material acyl methyl Methylpyridine compounds can be produced efficiently.

Hereinafter, the present invention will be described in detail.

At this time, if there is no other definition in the technical terms and scientific terms used, it has a meaning commonly understood by those of ordinary skill in the art. In addition, repeated description of the same technical configuration and operation as in the prior art will be omitted.

As used herein, the term “alkyl” refers to a monovalent straight or pulverized saturated hydrocarbon radical composed solely of carbon and hydrogen atoms. The alkyl may have 1 to 10 carbon atoms. The alkyl may have 1 to 7 carbon atoms. Examples of such alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl and the like.

As used herein, the term "alkoxy" refers to an -O-alkyl radical, where "alkyl" is as defined above. Specific examples include, but are not limited to, methoxy, ethoxy, isopropoxy, butoxy, isobutoxy, t-butoxy and the like.

As used herein, the term “aryl” refers to an organic radical derived from an aromatic hydrocarbon by one hydrogen removal, wherein each ring is a single or fused ring containing 4 to 7, preferably 5 or 6 ring atoms, as appropriate. It includes a system, including a form in which a plurality of aryl is connected by a single bond. Specific examples include, but are not limited to, phenyl, naphthyl, biphenyl, anthryl, fluorenyl, indenyl, and the like.

As used herein, the term "aryloxy" refers to an -O-aryl radical, where "aryl" is as defined above. Examples of such aryloxy radicals include, but are not limited to, phenoxy, naphthoxy and the like.

The term "halo" or "halogen" herein refers to a halogen group element and includes, for example, fluoro, chloro, bromo and iodo.

As used herein, the term "haloalkyl" refers to an alkyl radical substituted with at least one halogen, where "alkyl" is as defined above. Examples of such haloalkyl radicals include, but are not limited to, fluoromethyl, trifluoromethyl, bromomethyl, perfluoroethyl, and the like.

As used herein, the term “heteroaryl” refers to an aryl group containing 1 to 4 heteroatoms selected from N, O, and S as an aromatic ring skeleton atom, and the remaining aromatic ring skeleton atoms are carbon. Monocyclic heteroaryl and polycyclic heteroaryl condensed with one or more benzene rings. In addition, heteroaryl in the present invention also includes a form in which one or more heteroaryl is connected by a single bond. Specific examples include monocyclic heteroaryl such as furyl, thiophenyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, isoxazolyl, oxazolyl, pyridyl, benzofuranyl, dibenzofuranyl, di Polycyclic heteros such as benzothiofail, benzothiophenyl, isobenzofuranyl, benzoimidazolyl, benzothiazolyl, benzoisothiazolyl, benzoisoxazolyl, benzooxazolyl, quinolyl, isoquinolyl, carbazolyl and the like Aryl and the like, but are not limited thereto.

The present invention provides an acylmethylpyridine compound represented by Formula 1 below:

[Formula 1]

In Chemical Formula 1,

L is -CR ^a = CR ^b- , NR ^c , O or S;

R ¹ , R ² , R ^a , R ^b and R ^c are each independently hydrogen, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, halogen, C 1 -C 10 alkylcarbonyl, C 1 -C 10 alkoxycarbonyl, C 6 -C 20 aryl , C6-C20 aryloxy, C6-C20 arylcarbonyl or C6-C20 aryloxycarbonyl, or may be linked with adjacent substituents to form a fused ring,

R ³ is hydrogen, C 1 -C 10 alkyl, halogen, C 1 -C 10 alkylcarbonyl, C 1 -C 10 alkoxycarbonyl, C 6 -C 20 aryl, C 6 -C 20 arylcarbonyl or C 6 -C 20 aryloxycarbonyl;

Ar is C6-C20 aryl or C3-C20 heteroaryl;

Alkyl, alkoxy, alkylcarbonyl, aryl, aryloxy or arylcarbonyl of R ¹ , R ² , R ^a , R ^b and R ^c , alkyl, alkylcarbonyl, alkoxycarbonyl of R ³ , aryl, arylcarbon Aryl or heteroaryl of aryl or aryloxycarbonyl and Ar is C1-C10 alkyl, halogen, C1-C10 alkoxy, haloC1-C10 alkyl, C6-C20 aryl, C6-C20 aryloxy, C1-C10 alkylcarbonyl, Further substituted with one or more selected from the group consisting of C1-C10 alkoxycarbonyl, C6-C20 arylcarbonyl, C6-C20 aryloxycarbonyl, nitro and cyano;

The heteroaryl includes 1 to 4 heteroatoms selected from N, O and S.

Since the acylmethylpyridine compound of Formula 1 according to the present invention can be used as a starting material for preparing heterocycles used in a variety of natural products, such as pyridoisoindole and pyridoisoquinolinone, and pharmaceutical and electronic materials, It can be widely used as an important raw material or intermediate in the field of materials, materials and medicinal chemistry.

In one embodiment of the present invention, the acylmethylpyridine compound may be represented by the following formula (2) or (3):

[Formula 2]

[Formula 3]

In Chemical Formulas 2 and 3,

R ¹ and R ^a are each independently hydrogen, C 1 -C 10 alkyl, haloC 1 -C 10 alkyl, C 1 -C 10 alkoxy, haloC 1 -C 10 alkoxy, C 1 -C 10 alkoxyC 1 -C 10 alkoxy, C 1 -C 10 alkoxyC 1 -C 10 alkyl , C6-C20 arylC1-C10alkyl, halogen, C1-C10alkylcarbonyl, haloC1-C10alkylcarbonyl, C6-C20aryl, C1-C10alkylC6-C20aryl, (haloC1-C10alkyl) C6- C20 aryl, C6-C20 aryloxy or C6-C20 arylcarbonyl, or R ¹ and R ^a may be linked to each other to form a fused ring,

L ¹ is O or S;

R ³ is hydrogen, C1-C10 alkyl, halogen, haloC1-C10 alkyl, C6-C20 arylC1-C10 alkyl, C1-C10 alkylcarbonyl, C1-C10 alkoxycarbonyl, haloC1-C10 alkylcarbonyl, C6 -C20 aryl, C1-C10 alkylC6-C20 aryl, C6-C20 arylcarbonyl or C6-C20 aryloxycarbonyl;

Ar is C6-C20 aryl or C3-C20 heteroaryl, wherein the aryl or heteroaryl of Ar is C1-C10 alkyl, halogen, C1-C10 alkoxy, haloC1-C10 alkyl, C6-C20 aryl, C6-C20 aryloxy It may be further substituted with one or more selected from the group consisting of, C1-C10 alkoxycarbonyl, C6-C20 aryloxycarbonyl, nitro and cyano.

In one embodiment of the present invention, R ¹ and R ^a are each independently hydrogen, C ¹ -C 7 alkyl, haloC 1 -C 7 alkyl, C 1 -C 7 alkoxy, halogen, C 1 -C 7 alkylcarbonyl or C 6 -C 12 aryl Or R ¹ and R ^a may be linked to each other to form a fused ring; L ¹ is O or S; R ³ is hydrogen, C 1 -C 7 alkyl, halogen, haloC 1 -C 7 alkyl, C 1 -C 7 alkylcarbonyl, C 1 -C 7 alkoxycarbonyl, haloC 1 -C 7 alkylcarbonyl or C 6 -C 12 aryl; Ar is C6-C12 aryl or C3-C12 heteroaryl, wherein the aryl of Ar is C1-C7 alkyl, halogen, C1-C7 alkoxy, haloC1-C7 alkyl, C6-C12 aryl, C1-C7 alkoxycarbonyl, nitro And cyano may be further substituted with one or more selected from the group consisting of.

,

또는

으로 연결되어 융합고리를 형성할 수 있고, L¹은 C1-C10알킬렌이고, X¹ 및 X²는 각각 독립적으로 NR', O 또는 S이고, R'는 수소 또는 C1-C10알킬이고, R¹¹ 내지 R¹⁴는 각각 독립적으로 수소, C1-C10알킬 또는 C6-C20아릴이거나, 인접한 치환체와 연결되어 방향족 융합고리를 형성할 수 있고, X³는 O 또는 S이고, R''는 C1-C10알킬일 수 있다.In one embodiment of the present invention, R ^a and R ¹ are

,

or

Can be linked to form a fused ring, L ¹ is C1-C10 alkylene, X ¹ and X ² are each independently NR ', O or S, R' is hydrogen or C1-C10 alkyl, R ¹¹ to R ¹⁴ are each independently hydrogen, C 1 -C 10 alkyl or C 6 -C 20 aryl, or may be linked to adjacent substituents to form an aromatic fused ring, X ³ is O or S, and R '' is C 1 -C 10 It may be alkyl.

,

,

,

,

또는

로 연결되어 융합고리를 형성할 수 있다.In one embodiment according to the invention, R ^a and R ¹ are

,

,

,

,

or

Can be connected to form a fused ring.

In one embodiment according to the present invention, the acylmethylpyridine compound may be more specifically selected from the following compounds, but is not limited thereto.

Hereinafter, the manufacturing method of the acylmethylpyridine compound which concerns on this invention is demonstrated in detail.

The present invention is a method for preparing an acylmethylpyridine compound represented by the following Chemical Formula 1 by reacting a pyridine compound represented by the following Chemical Formula 4 and an azirin compound represented by the Chemical Formula 5 in the presence of a rhodium or ruthenium catalyst, a silver additive, acetic acid and water. Provides:

[Formula 1]

[Formula 4]

[Formula 5]

In Chemical Formulas 1, 4, and 5,

L is -CR ^a = CR ^b- , NR ^c , O or S;

R ¹ , R ² , R ^a , R ^b and R ^c are each independently hydrogen, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, halogen, C 1 -C 10 alkylcarbonyl, C 1 -C 10 alkoxycarbonyl, C 6 -C 20 aryl , C6-C20 aryloxy, C6-C20 arylcarbonyl or C6-C20 aryloxycarbonyl, or may be linked with adjacent substituents to form a fused ring,

R ³ is hydrogen, C 1 -C 10 alkyl, halogen, C 1 -C 10 alkylcarbonyl, C 1 -C 10 alkoxycarbonyl, C 6 -C 20 aryl, C 6 -C 20 arylcarbonyl or C 6 -C 20 aryloxycarbonyl;

Ar is C6-C20 aryl or C3-C20 heteroaryl;

Alkyl, alkoxy, alkylcarbonyl, aryl, aryloxy or arylcarbonyl of R ¹ , R ² , R ^a , R ^b and R ^c , alkyl, alkylcarbonyl, alkoxycarbonyl of R ³ , aryl, arylcarbon Aryl or heteroaryl of aryl or aryloxycarbonyl and Ar is C1-C10 alkyl, halogen, C1-C10 alkoxy, haloC1-C10 alkyl, C6-C20 aryl, C6-C20 aryloxy, C1-C10 alkylcarbonyl, Further substituted with one or more selected from the group consisting of C1-C10 alkoxycarbonyl, C6-C20 arylcarbonyl, C6-C20 aryloxycarbonyl, nitro and cyano;

The heteroaryl includes 1 to 4 heteroatoms selected from N, O and S.

The method for preparing the acylmethylpyridine compound of Chemical Formula 1 according to the present invention is prepared by reacting a pyridine compound of Chemical Formula 4 in the presence of a rhodium or ruthenium catalyst, a silver additive, acetic acid and water, using the aziline compound of Chemical Formula 5 as a starting material, Acylmethylation of the pyridine compound of formula 4 can be efficiently performed through carbon-hydrogen activation and selective carbon-carbon bond formation.

The method for preparing the acylmethylpyridine compound of Formula 1 according to the present invention can introduce a wider substrate than the conventional acylmethylation reaction, and also has excellent yield. In particular, the azirin compound of the formula (5) has never been used in the carbon-hydrogen activation reaction at all, and moreover, the present invention is the first case used in the acylmethylation reaction.

That is, the pyridine compound of formula 4 in the presence of a rhodium or ruthenium catalyst, a silver additive and acetic acid is subjected to a cyclometalated intermediate together with a catalyst and acetic acid to form an imine compound through oxidation of the azirin compound of formula 5, The resulting imine compound may be hydrolyzed by water to finally prepare a compound in which pyridine of formula 4 is acylmethylated by an aziline compound of formula 5, ie, acylmethylpyridine compound of formula 1. As an example, Scheme 1 is shown.

Scheme 1

In one embodiment according to the present invention, the pyridine compound of formula 4 is 0.8 to 5 moles, preferably 0.8 to 3 moles, more preferably 1.0 to 3 with respect to 1 mole of the azirin compound of formula 5 It can be used in a molar range, it is more preferable if the pyridine compound of the formula (4) within the above range can be further improved the yield and economics of the target compound.

In one embodiment, the rhodium catalyst is [Rh (C ₅ Me ₅ ) Cl ₂ ] ₂ (Dichloro (pentamethylcyclopentadienyl) rhodium (III) dimer), [(C ₅ Me ₅ ) Rh (MeCN) ₃ ] SbF ₆ ] ₂ (Tris (acetonitrile) pentamethylcyclopentadienylrhodium (III) hexafluoroantimonate), Rh (C ₅ Me ₅ ) (OAc) ₂ and RhCl (PPh ₃ ) ₃ (Tris (triphenylphosphine) rhodium (I) chloride) may be one or a mixture of two or more selected from the ruthenium catalyst is _{[Ru (p -cymene) Cl 2} ] 2 (Dichloro (p-cymene) ruthenium (II) dimer), Ru (PPh 3) 3 (CO) H ₂ (Carbonyldihydridotris (triphenylphosphine) ruthenium (II)), Ru ₃ (CO) ₁₂ (Triruthenium dodecacarbonyl), [RuCl ₂ (C ₆ H ₆ )] ₂ (Benzeneruthenium (II) chloride dimer) and [RuCl ₂ (cod) ] ₂ (cod = 1,5-cyclooctadiene) may be one or a mixture of two or more selected, preferably [Rh (C ₅ Me ₅ ) Cl ₂ ] ₂ or [Ru ( p -cymene) Cl ₂ ] ₂ .

In one embodiment of the present invention, in terms of better yield, preferably a rhodium catalyst may be used. More preferably [Rh (C ₅ Me ₅ ) Cl ₂ ] ₂ can be used.

The amount of the rhodium or ruthenium catalyst according to an embodiment of the present invention is 0.5 to 20 mol%, preferably 1.0 to 10.0 mol%, more preferably 3.0 to 7.0 mol% based on 1 mol of the azirin compound of Formula 5 When the rhodium or ruthenium catalyst is used within the above range, the acylmethylpyridine compound of Formula 1 may be prepared in a higher yield.

In one embodiment according to the invention, the silver additive is AgAsF ₆ (Silver hexafluoroarsenate), AgSbF ₆ (Silver hexafluoroantimonate), AgBF ₄ (Silver tetrafluoroborate), AgNTf ₂ (Silver bis (trifluoromethanesulfonyl) imide) and AgPF ₆ (Silver hexafluorophosphate), and may be one or two or more selected from the group consisting of hexafluorophosphate, and preferably AgSbF ₆ , AgNTf ₂ or AgPF ₆ in view of economical efficiency, reactivity and yield.

The amount of the silver additive according to an embodiment of the present invention is 5 to 50 mol%, preferably 10 to 30 mol%, more preferably 10 to 20 mol% with respect to 1 mol of the azirin compound of Formula 5, The use of silver additives within the range is more preferable in view of reactivity and yield.

In one embodiment according to the present invention, the amount of acetic acid may range from 0.8 to 5 moles, preferably from 0.8 to 2 moles, with respect to 1 mole of the azirin compound of Formula 5, and the amount of water may be It may be in the range of 0.8 to 5 moles, preferably in the range of 0.8 to 2 moles per mole of azirin compound. Use of acetic acid and water in the above range is more preferable in terms of reactivity and yield.

In one embodiment of the present invention, the reaction may be carried out under a conventional organic solvent, and there is no need to limit the organic solvent as long as it can dissolve the reactants. The organic solvent according to an embodiment of the present invention is specifically dichloromethane (DCM), dichloroethane (DCE), 1,4-dioxane, tetrahydrofuran (THF), methanol, ethanol, trifluoroethanol (TFE) , Hexafluoroisopropanol (HFIP), acetonitrile (MeCN), toluene, dimethylformamide (DMF), nitromethane and chloroform may be used one or two or more, and solubility and removal of the reactants Dichloroethane (DCE), tetrahydrofuran (THF), methanol, trifluoroethanol (TFE) or hexafluoroisopropanol (HFIP) may be used in consideration of the ease of use, more preferably trifluoroethanol (TFE). ) Can be used.

In one embodiment of the present invention, the reaction temperature for preparing the acylmethylpyridine compound of Formula 1 may be carried out at 50 to 100 ℃, the reaction time depends on the reactant, the type of solvent and the amount of solvent The azirin compound of Chemical Formula 5, which is a starting material, may be consumed through TLC, and the reaction may be completed after confirming the product. After the reaction is completed, the solvent is distilled off under reduced pressure, and the desired product can be separated and purified through conventional methods such as column chromatography.

Hereinafter, the configuration of the present invention in more detail through examples, the following examples are provided to help the understanding of the present invention, the scope of the present invention is not limited thereto.

Example  I: Acylmethylpyridine  Compound ( 1) of  Produce

Pyridine compound (4) (2.0 equiv), [Cp * RhCl ₂ ] ₂ (Cp *: pentamethylcyclopentadienyl) (4.0 mol%), AgSbF ₆ (16.0 mol%) and TFE under a nitrogen atmosphere in a dry test tube equipped with a magnetic stirrer (2,2,2-trifluoroethanol, 1.0 mL) was added. 2 H -azirine compound (5) (0.2 mmol, 1.0 equiv), TFE (1.0 mL), water (1.0 equiv) and AcOH (1.0 equiv) were added to the reaction mixture. After stirring at 80 ° C. for 3 hours, it was cooled to room temperature, filtered through a pad of celite and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography to obtain acylmethylpyridine compound (1) as a target compound.

Various acylmethylpyridine compounds (1) were prepared using the method described above.

Example 1 Preparation of 1- (4-Methoxyphenyl) -2- (2- (pyridin-2-yl) phenyl) ethan-1-one (Compound 1-1)

Yield: 52.4 mg (86%); R _f = 0.3 (EtOAc: Hexane = 1: 5); Yellow oil; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.47 (dq, J = 4.9 Hz, J = 0.9 Hz, 1H), 7.87 (dt, J = 9.7 Hz, J = 2.5 Hz, 2H), 7.68 (td, J = 11.6 Hz, J = 1.9 Hz, 1H), 7.48-7.46 (m, 1H), 7.44 (dt, J = 7.9 Hz, J = 1.0 Hz, 1H), 7.40-7.35 (m, 2H), 7.34-7.30 (m, 1H), 7.16 (ddd, J = 7.6 Hz, J = 4.9 Hz, J = 1.1 Hz, 1H), 6.88 (dt, J = 9.7 Hz, J = 2.5 Hz, 2H), 4.46 (s, 2H ), 3.85 (s, 3 H); ¹³ C { ¹ H} NMR (100 MHz, CDCl ₃ ) δ 196.7, 163.3, 159.7, 148.9, 140.2, 136.7, 133.7, 131.7, 130.7, 130.2, 130.0, 128.6, 127.2, 124.0, 121.8, 113.7, 55.5, 43.2 .

Example 2 Preparation of 1-Phenyl-2- (2- (pyridin-2-yl) phenyl) ethan-1-one (Compound 1-2)

Yield: 46.0 mg (84%); R _f = 0.3 (EtOAc: Hexane = 1: 5); Yellow oil; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.38 (dq, J = 4.8 Hz, J = 0.8 Hz, 1H), 7.90-7.88 (m, 2H), 7.67 (td, J = 11.6 Hz, J = 1.7 Hz , 1H), 7.53-7.48 (m, 2H), 7.45 (dt, J = 7.9 Hz, J = 0.9 Hz, 1H), 7.42-7.37 (m, 4H), 7.35-7.31 (m, 1H), 7.12 ( ddd, J = 7.5 Hz, J = 4.9 Hz, J = 0.9 Hz, 1H), 4.51 (s, 2H); ¹³ C { ¹ H} NMR (100 MHz, CDCl ₃ ) δ 198.0, 159.6, 148.7, 140.1, 137.2, 136.7, 133.4, 132.8, 132.0, 129.9, 128.7, 128.5, 128.3, 127.4, 123.9, 121.8, 43.7.

Example 3 Preparation of 2- (2- (Pyridin-2-yl) phenyl) -1- ( o -tolyl) ethanone (Compound 1-3)

Yield: 52.3 mg (89%); R _f = 0.3 (EtOAc: Hexane = 1: 5); Brown oil; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.40-8.39 (m, 1H), 7.67 (td, J = 11.6 Hz, J = 1.8 Hz, 1H), 7.52 (d, J = 7.8 Hz, 1H), 7.49 -7.47 (m, 1H), 7.45-7.38 (m, 3H), 7.36-7.30 (m, 2H), 7.21-7.12 (m, 3H), 4.45 (s, 2H), 2.37 (s, 3H); ¹³ C { ¹ H} NMR (100 MHz, CDCl ₃ ) δ 201.5, 159.7, 148.6, 140.1, 138.4, 138.3, 136.7, 133.5, 132.2, 131.8, 131.0, 130.0, 128.7, 128.3, 127.4, 125.6, 124.0, 121.8 , 46.7, 21.1; IR (film): 3063, 2968, 1688, 1587, 1426, 1321, 1216, 988, 751 cm ⁻¹ ; HRMS (EI) m / z : [M] ⁺ Calcd for C ₂₀ H ₁₇ NO 287.1310; Found 287.1307.

Example 4 Preparation of 2- (2- (Pyridin-2-yl) phenyl) -1- ( m- tolyl) ethan-1-one (Compound 1-4)

Yield: 50.7 mg (88%); R _f = 0.3 (EtOAc: Hexane = 1: 5); Brown oil; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.43 (dq, J = 4.8 Hz, J = 0.8 Hz, 1H), 7.71-7.66 (m, 3H), 7.49-7.47 (m, 1H), 7.45 (dt, J = 7.9 Hz, J = 0.9 Hz, 1H), 7.39-7.37 (m, 2H), 7.34-7.27 (m, 3H), 7.14 (ddd, J = 7.5 Hz, J = 4.9 Hz, J = 1.0 Hz, 1H), 4.51 (s, 2H), 2.37 (s, 3H); ¹³ C { ¹ H} NMR (100 MHz, CDCl ₃ ) δ 198.2, 159.7, 148.8, 140.2, 138.3, 137.3, 136.7, 133.6, 133.5, 131.9, 130.0, 128.9, 128.7, 128.4, 127.3, 125.6, 124.0, 121.8 , 43.6, 21.5; IR (film): 3058, 2918, 1685, 1586, 1426, 1245, 1157, 1024, 794, 752, 691 cm ⁻¹ ; HRMS (EI) m / z : [M] ⁺ Calcd for C ₂₀ H ₁₇ NO 287.1310; Found 287.1311.

Example 5 Preparation of 2- (2- (Pyridin-2-yl) phenyl) -1- ( p -tolyl) ethan-1-one (Compound 1-5)

Yield: 52.4 mg (91%); R _f = 0.3 (EtOAc: Hexane = 1: 5); Brown oil; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.43 (dq, J = 4.8 Hz, J = 0.9 Hz, 1H), 7.78 (dt, J = 8.5 Hz, J = 1.8 Hz, 2H), 7.67 (td, J = 11.6 Hz, J = 1.8 Hz, 1H), 7.49-7.47 (m, 1H), 7.44 (dt, J = 7.9 Hz, J = 1.0 Hz, 1H), 7.40-7.35 (m, 2H), 7.34-7.30 (m, 1H), 7.20 (d, J = 8.0 Hz, 2H), 7.14 (ddd, J = 7.6 Hz, J = 4.9 Hz, J = 1.1 Hz, 1H), 4.48 (s, 2H), 2.38 (s , 3H); ¹³ C { ¹ H} NMR (100 MHz, CDCl ₃ ) δ 197.7, 159.7, 148.9, 143.5, 140.2, 136.7, 134.7, 133.6, 131.9, 130.0, 129.2, 128.7, 128.5, 127.3, 124.0, 121.8, 43.5, 21.7 .

Example 6 Preparation of 1- (4- ( tert- Butyl) phenyl) -2- (2- (pyridin-2-yl) phenyl) ethan-1-one (Compound 1-6)

Yield: 47.9 mg (73%); R _f = 0.4 (EtOAc: Hexane = 1: 5); Red oil; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.46 (dq, J = 4.8 Hz, J = 0.8 Hz, 1H), 7.83 (dt, J = 9.1 Hz, J = 2.1 Hz, 2H), 7.67 (td, J = 11.6 Hz, J = 1.8 Hz, 1H), 7.50-7.42 (m, 3H), 7.41-7.39 (m, 1H), 7.38-7.34 (m, 2H), 7.33-7.29 (m, 1H), 7.15 ( ddd, J = 7.5 Hz, J = 4.9 Hz, J = 1.1 Hz, 1H), 4.50 (s, 2H), 1.32 (s, 9H); ¹³ C { ¹ H} NMR (100 MHz, CDCl ₃ ) δ 197.7, 159.7, 156.5, 148.9, 140.3, 136.6, 134.6, 133.5, 131.7, 130.0, 128.6, 128.4, 127.3, 125.5, 124.0, 121.8, 43.5, 35.2 , 31.2; IR (film): 3058, 2963, 1684, 1604, 1471, 1331, 1222, 995, 752 cm ⁻¹ ; HRMS (EI) m / z : [M] ⁺ Calcd for C ₂₃ H ₂₃ NO 329.1780; Found 329.1780.

Example 7 Preparation of 1- (4-Fluorophenyl) -2- (2- (pyridin-2-yl) phenyl) ethan-1-one (Compound 1-7)

Yield: 44.8 mg (77%); R _f = 0.3 (EtOAc: Hexane = 1: 5); Beige solid; Melting point: 63-65 ° C .; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.37 (dq, J = 4.8 Hz, J = 0.9 Hz, 1H), 7.94-7.89 (m, 2H), 7.68 (td, J = 11.6 Hz, J = 1.8 Hz , 1H), 7.51-7.48 (m, 1H), 7.45 (dt, J = 7.9 Hz, J = 0.9 Hz, 1H), 7.40-7.35 (m, 2H), 7.34-7.30 (m, 1H), 7.13 ( ddd, J = 7.5 Hz, J = 4.9 Hz, J = 1.1 Hz, 1H), 7.09-7.04 (m, 2H), 4.48 (s, 2H); ¹³ C { ¹ H} NMR (100 MHz, CDCl ₃ ) δ 196.5, 165.6 (d, J = 254.0 Hz), 159.5, 148.7, 139.9, 136.7, 133.6 (d, J = 2.9 Hz), 133.3, 131.9, 131.0 (d, J = 9.1 Hz), 130.0, 128.7, 127.4, 123.9, 121.9, 115.6 (d, J = 21.7 Hz), 43.6; ¹⁹ F NMR (376 MHz, CDCl ₃ ) δ −105.94; IR (film): 3063, 2911, 1687, 1597, 1331, 1220, 1156, 997, 835, 752 cm ⁻¹ ; HRMS (EI) m / z : [M] ⁺ Calcd for C ₁₉ H ₁₄ FNO 291.1059; Found 291.1062.

Example 8 Preparation of 1- (2-Chlorophenyl) -2- (2- (pyridin-2-yl) phenyl) ethan-1-one (Compound 1-8)

Yield: 35.2 mg (57%); R _f = 0.3 (EtOAc: Hexane = 1: 5); Brown oil; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.41 (dq, J = 4.9 Hz, J = 0.9 Hz, 1H), 7.68 (td, J = 11.6 Hz, J = 1.8 Hz, 1H), 7.47-7.45 (m , 1H), 7.43-7.37 (m, 4H), 7.36-7.29 (m, 3H), 7.26-7.22 (m, 1H), 7.15 (ddd, J = 7.5 Hz, J = 4.9 Hz, J = 1.1 Hz, 1H), 4.49 (s, 2H); ¹³ C { ¹ H} NMR (100 MHz, CDCl ₃ ) δ 200.5, 159.5, 148.6, 140.2, 139.7, 136.7, 132.7, 132.4, 131.4, 130.8, 130.4, 129.9, 129.4, 128.7, 127.6, 126.7, 123.9, 121.9 , 48.0; IR (film): 3062, 1699, 1587, 1427, 1324, 1211, 1066, 991, 753 cm ⁻¹ ; HRMS (EI) m / z : [M] ⁺ Calcd for C ₁₉ H ₁₄ ClNO 307.0764; Found 307.0765.

Example 9 Preparation of 1- (3-Chlorophenyl) -2- (2- (pyridin-2-yl) phenyl) ethan-1-one (Compound 1-9)

Yield: 40.7 mg (66%); R _f = 0.2 (EtOAc: Hexane = 1: 5); Beige solid; Melting point: 85-87 ° C .; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.34 (dq, J = 4.8 Hz, J = 0.9 Hz, 1H), 7.86 (t, J = 1.8 Hz, 1H), 7.77 (dt, J = 7.8 Hz, J = 1.3 Hz, 1H), 7.69 (td, J = 11.6 Hz, J = 1.8 Hz, 1H), 7.51-7.45 (m, 3H), 7.41-7.38 (m, 2H), 7.37-7.31 (m, 2H) , 7.14 (ddd, J = 7.5 Hz, J = 4.9 Hz, J = 1.1 Hz, 1H), 4.50 (s, 2H); ¹³ C { ¹ H} NMR (100 MHz, CDCl ₃ ) δ 196.7, 159.4, 148.6, 139.8, 138.9, 136.8, 134.8, 133.0, 132.7, 132.1, 130.0, 129.9, 128.8, 128.5, 127.6, 126.4, 123.8, 121.9 , 43.8; IR (film): 3064, 2923, 1692, 1587, 1425, 1329, 1211, 997, 788, 750 cm ⁻¹ ; HRMS (EI) m / z : [M] ⁺ Calcd for C ₁₉ H ₁₄ ClNO 307.0764; Found 307.0761.

Example 10 Preparation of 1- (4-Chlorophenyl) -2- (2- (pyridin-2-yl) phenyl) ethan-1-one (Compound 1-10)

Yield: 38.2 mg (62%); R _f = 0.3 (EtOAc: Hexane = 1: 5); Brown oil; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.35 (dq, J = 4.9 Hz, J = 0.9 Hz, 1H), 7.84 (dt, J = 9.1 Hz, J = 2.1 Hz, 2H), 7.69 (td, J = 11.6 Hz, J = 1.8 Hz, 1H), 7.51-7.48 (m, 1H), 7.46 (dt, J = 7.9 Hz, J = 0.9 Hz, 1H), 7.40-7.37 (m, 4H), 7.33-7.30 (m, 1 H), 7.14 (ddd, J = 7.6 Hz, J = 4.9 Hz, J = 1.1 Hz, 1H), 4.47 (s, 2H); ¹³ C { ¹ H} NMR (100 MHz, CDCl ₃ ) δ 196.8, 159.5, 148.7, 139.8, 139.1, 136.8, 135.6, 133.2, 132.0, 130.0, 129.8, 128.9, 128.8, 127.5, 123.9, 121.9, 43.7; IR (film): 3060, 2905, 1688, 1587, 1426, 1331, 1213, 1090, 996, 803, 753 cm ⁻¹ ; HRMS (EI) m / z : [M] ⁺ Calcd for C ₁₉ H ₁₄ ClNO 307.0764; Found 307.0766.

Example 11 Preparation of 1- (4-Bromophenyl) -2- (2- (pyridin-2-yl) phenyl) ethan-1-one (Compound 1-11)

Yield: 52.6 mg (75%); R _f = 0.3 (EtOAc: Hexane = 1: 5); Brown solid; Melting point: 86-88 ° C .; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.33 (dq, J = 4.9 Hz, J = 0.8 Hz, 1H), 7.76 (dt, J = 9.0 Hz, J = 2.1 Hz, 2H), 7.68 (td, J = 11.6 Hz, J = 1.8 Hz, 1H), 7.54 (dt, J = 9.0 Hz, J = 2.1 Hz, 2H), 7.51-7.48 (m, 1H), 7.45 (dt, J = 7.9 Hz, J = 0.9 Hz, 1H), 7.40-7.36 (m, 2H), 7.33-7.30 (m, 1H), 7.13 (ddd, J = 7.5 Hz, J = 4.9 Hz, J = 1.1 Hz, 1H), 4.46 (s, 2H ); ¹³ C { ¹ H} NMR (100 MHz, CDCl ₃ ) δ 197.0, 159.4, 148.7, 139.8, 136.8, 136.0, 133.2, 132.0, 131.8, 129.9 (2C), 128.8, 127.8, 127.5, 123.8, 121.9, 43.7.

Example 12 Preparation of 2- (2- (Pyridin-2-yl) phenyl) -1- (4- (trifluoromethyl) phenyl) ethan-1-one (Compound 1-12)

Yield: 36.6 mg (54%); R _f = 0.4 (EtOAc: Hexane = 1: 5); Beige solid; Melting point: 98-100 ° C .; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.28 (dq, J = 4.9 Hz, J = 0.9 Hz, 1H), 8.01 (d, J = 8.1 Hz, 2H), 7.73-7.67 (m, 3H), 7.54 -7.51 (m, 1H), 7.48 (dt, J = 7.9 Hz, J = 1.0 Hz, 1H), 7.43-7.38 (m, 2H), 7.36-7.32 (m, 1H), 7.13 (ddd, J = 7.6) Hz, J = 4.9 Hz, J = 1.1 Hz, 1H), 4.53 (s, 2H); ¹³ C { ¹ H} NMR (100 MHz, CDCl ₃ ) δ 197.0, 159.4, 148.6, 140.1, 139.6, 136.9, 134.0 (q, J = 32.6 Hz), 133.0, 132.2, 130.0, 128.9, 128.7, 127.7, 125.6 (q, J = 3.7 Hz), 123.82 (q, J = 272.4 Hz), 123.81, 122.0, 44.2; ¹⁹ F NMR (376 MHz, CDCl ₃ ) δ −63.02; IR (film): 3062, 2921, 1693, 1587, 1322, 1127, 1066, 834, 752 cm ⁻¹ ; HRMS (EI) m / z : [M] ⁺ Calcd for C ₂₀ H ₁₄ F ₃ NO 341.1027; Found 341.1030.

Example 13 Preparation of 1- (4-Nitrophenyl) -2- (2- (pyridin-2-yl) phenyl) ethan-1-one (Compound 1-13)

Yield: 26.9 mg (42%); R _f = 0.2 (EtOAc: Hexane = 1: 5); Orange solid; Melting point: 128-130 ° C .; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.27 (dt, J = 9.1 Hz, J = 2.1 Hz, 2H), 8.20 (dq, J = 4.8 Hz, J = 0.8 Hz, 1H), 8.07 (dt, J = 9.1 Hz, J = 2.1 Hz, 2H), 7.71 (td, J = 11.6 Hz, J = 1.8 Hz, 1H), 7.55-7.50 (m, 2H), 7.44-7.40 (m, 2H), 7.37-7.33 (m, 1 H), 7.12 (ddd, J = 7.5 Hz, J = 4.9 Hz, J = 1.1 Hz, 1H), 4.53 (s, 2H); ¹³ C { ¹ H} NMR (100 MHz, CDCl ₃ ) δ 196.4, 159.1, 150.1, 148.3, 142.1, 139.2, 137.0, 132.7, 132.3, 130.0, 129.3, 128.9, 127.8, 123.8, 123.7, 122.0, 44.5; IR (film): 2924, 1693, 1522, 1346, 1211, 999, 855, 750 cm ⁻¹ ; HRMS (EI) m / z : [M] ⁺ Calcd for C ₁₉ H ₁₄ N ₂ O ₃ 318.1004; Found 318.1008.

Example 14 Preparation of Methyl 4- (2- (2- (pyridin-2-yl) phenyl) acetyl) benzoate (Compound 1-14)

Yield: 33.2 mg (50%); R _f = 0.2 (EtOAc: Hexane = 1: 5); Ivory solid; Melting point: 63-65 ° C .; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.26 (dq, J = 4.9 Hz, J = 0.9 Hz, 1H), 8.08 (dt, J = 8.3 Hz, J = 1.7 Hz, 2H), 7.94 (dt, J = 8.3 Hz, J = 1.7 Hz, 2H), 7.68 (td, J = 11.6 Hz, J = 1.9 Hz, 1H), 7.53-7.49 (m, 1H), 7.47 (dt, J = 7.9 Hz, J = 1.0 Hz, 1H), 7.43-7.37 (m, 2H), 7.37-7.32 (m, 1H), 7.11 (ddd, J = 7.5 Hz, J = 4.9 Hz, J = 1.1 Hz, 1H), 4.52 (s, 2H ), 3.94 (s, 3 H); ¹³ C { ¹ H} NMR (100 MHz, CDCl ₃ ) δ 197.5, 166.5, 159.4, 148.6, 140.8, 139.7, 136.8, 133.5, 133.2, 132.2, 129.9, 129.8, 128.8, 128.2, 127.6, 123.8, 121.9, 52.5 , 44.2; IR (film): 3059, 2951, 1724, 1692, 1427, 1280, 1213, 1109, 997, 753 cm ⁻¹ ; HRMS (EI) m / z : [M] ⁺ Calcd for C ₂₁ H ₁₇ NO ₃ 331.1208; Found 331.1210.

Example 15 Preparation of 1-([1,1'-Biphenyl] -2-yl) -2- (2- (pyridin-2-yl) phenyl) ethan-1-one (Compound 1-15)

Yield: 58.0 mg (83%); R _f = 0.2 (EtOAc: Hexane = 1: 5); Ruby solid; Melting point: 101-103 ° C .; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.41 (dq, J = 4.8 Hz, J = 0.8 Hz, 1H), 7.63 (td, J = 11.6 Hz, J = 1.8 Hz, 1H), 7.42 (td, J = 11.1 Hz, J = 1.7 Hz, 1H), 7.38-7.33 (m, 4H), 7.32-7.31 (m, 1H), 7.30-7.23 (m, 7H), 7.14 (ddd, J = 7.6 Hz, J = 4.9 Hz, J = 1.1 Hz, 1H), 6.97-6.95 (m, 1H), 3.81 (s, 2H); ¹³ C { ¹ H} NMR (100 MHz, CDCl ₃ ) δ 204.7, 159.6, 148.7, 141.0, 140.7, 140.4, 139.9, 136.5, 132.8, 131.7, 130.2, 130.1, 129.8, 129.0, 128.7, 128.4, 128.0, 127.9 , 127.3, 127.2, 123.9, 121.7, 47.5; IR (film): 3058, 2919, 1693, 1587, 1471, 1426, 1209, 990, 749, 701 cm ⁻¹ ; HRMS (EI) m / z : [M] ⁺ Calcd for C ₂₅ H ₁₉ NO 349.1467; Found 349.1464.

Example 16 Preparation of 1- (Naphthalen-1-yl) -2- (2- (pyridin-2-yl) phenyl) ethan-1-one (Compound 1-16)

Yield: 54.3 mg (84%); R _f = 0.2 (EtOAc: Hexane = 1: 5); Orange oil; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.45-8.41 (m, 1H), 8.19 (dq, J = 4.9 Hz, J = 0.9 Hz, 1H), 7.92 (d, J = 8.2 Hz, 1H), 7.85 -7.81 (m, 1H), 7.75 (dd, J = 7.2 Hz, J = 1.1 Hz, 1H), 7.61 (td, J = 11.6 Hz, J = 1.8 Hz, 1H), 7.51-7.46 (m, 3H) , 7.45-7.37 (m, 5H), 7.03 (ddd, J = 7.5 Hz, J = 4.9 Hz, J = 1.1 Hz, 1H), 4.60 (s, 2H); ¹³ C { ¹ H} NMR (100 MHz, CDCl ₃ ) δ 201.4, 159.6, 148.6, 140.1, 136.65, 136.58, 134.0, 133.6, 132.3, 132.2, 130.3, 130.0, 128.7, 128.3, 127.7, 127.5, 127.0, 126.4 , 126.2, 124.4, 123.9, 121.8, 47.4; IR (film): 3049, 2922, 1689, 1587, 1426, 1231, 1093, 948, 779, 752 cm ⁻¹ ; HRMS (EI) m / z : [M] ⁺ Calcd for C ₂₃ H ₁₇ NO 323.1310; Found 323.1311.

Example 17 Preparation of 2- (2- (Pyridin-2-yl) phenyl) -1- (thiophen-2-yl) ethan-1-one (Compound 1-17)

Yield: 39.4 mg (71%); R _f = 0.1 (EtOAc: Hexane = 1: 5); Moss green solid; Melting point: 78-80 ° C .; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.48 (dq, J = 4.8 Hz, J = 0.9 Hz, 1H), 7.69 (td, J = 11.6 Hz, J = 1.8 Hz, 1H), 7.60 (dd, J = 3.8 Hz, J = 1.1 Hz, 1H), 7.56 (dd, J = 5.0 Hz, J = 1.1 Hz, 1H), 7.49-7.44 (m, 2H), 7.40-7.34 (m, 3H), 7.17 (ddd) , J = 7.6 Hz, J = 4.9 Hz, J = 1.1 Hz, 1H), 7.05 (dd, J = 4.9 Hz, J = 3.8 Hz, 1H), 4.44 (s, 2H); ¹³ C { ¹ H} NMR (100 MHz, CDCl ₃ ) δ 190.8, 159.6, 148.8, 144.3, 140.3, 136.7, 133.4, 133.0, 132.1, 131.8, 130.0, 128.7, 128.0, 127.5, 124.1, 121.9, 44.2.

Example 18 Preparation of 2- (4-Methyl-2- (pyridin-2-yl) phenyl) -1- ( p -tolyl) ethan-1-one (Compound 1-18)

Yield: 47.6 mg (79%); R _f = 0.4 (EtOAc: Hexane = 1: 5); Ivory solid; Melting point: 99-101 ° C .; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.46 (dq, J = 4.9 Hz, J = 0.8 Hz, 1H), 7.77 (d, J = 8.2 Hz, 2H), 7.65 (td, J = 11.6 Hz, J = 1.8 Hz, 1H), 7.43 (dt, J = 7.9 Hz, J = 0.9 Hz, 1H), 7.29 (s, 1H), 7.19-7.17 (m, 4H), 7.13 (ddd, J = 7.5 Hz, J = 4.9 Hz, J = 1.0 Hz, 1H), 4.42 (s, 2H), 2.382 (s, 3H), 2.375 (s, 3H); ¹³ C { ¹ H} NMR (100 MHz, CDCl ₃ ) δ 197.9, 159.8, 148.9, 143.5, 140.1, 136.8, 136.5, 134.7, 131.6, 130.7, 130.4, 129.4, 129.2, 128.5, 124.0, 121.8, 43.1, 21.7 , 21.2; IR (film): 3017, 2919, 1685, 1606, 1427, 1330, 1223, 1000, 779 cm ⁻¹ ; HRMS (EI) m / z : [M] ⁺ Calcd for C ₂₁ H ₁₉ NO 301.1467; Found 301.1465.

Example 19 Preparation of 2- (5-Methyl-2- (pyridin-2-yl) phenyl) -1- ( p -tolyl) ethan-1-one (Compound 1-19)

Yield: 53.0 mg (88%); R _f = 0.3 (EtOAc: Hexane = 1: 5); Yellow oil; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.40 (dq, J = 4.8 Hz, J = 0.9 Hz, 1H), 7.79 (dt, J = 8.4 Hz, J = 1.8 Hz, 2H), 7.65 (td, J = 11.6 Hz, J = 1.9 Hz, 1H), 7.42 (dt, J = 7.9 Hz, J = 1.0 Hz, 1H), 7.38 (d, J = 7.8 Hz, 1H), 7.20-7.16 (m, 3H), 7.13-7.09 (m, 2H), 4.46 (s, 2H), 2.383 (s, 3H), 2.375 (s, 3H); ¹³ C { ¹ H} NMR (100 MHz, CDCl ₃ ) δ 197.9, 159.7, 148.8, 143.5, 138.5, 137.4, 136.6, 134.8, 133.4, 132.6, 129.9, 129.2, 128.5, 128.1, 123.9, 121.6, 43.5, 21.7 , 21.3; IR (film): 3049, 2919, 1685, 1606, 1467, 1331, 1181, 1012, 780, 748 cm ⁻¹ ; HRMS (EI) m / z : [M] ⁺ Calcd for C ₂₁ H ₁₉ NO 301.1467; Found 301.1469.

Example 20 Preparation of 2- (5-Methoxy-2- (pyridin-2-yl) phenyl) -1- ( p -tolyl) ethan-1-one (Compound 1-20)

Yield: 56.4 mg (89%); R _f = 0.2 (EtOAc: Hexane = 1: 5); Brown solid; Melting point: 55-57 ° C .; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.38 (dq, J = 4.9 Hz, J = 0.8 Hz, 1H), 7.79 (dt, J = 8.5 Hz, J = 1.9 Hz, 2H), 7.64 (td, J = 11.6 Hz, J = 1.9 Hz, 1H), 7.44-7.40 (m, 2H), 7.20 (d, J = 7.9 Hz, 2H), 7.09 (ddd, J = 7.5 Hz, J = 4.9 Hz, J = 1.1 Hz, 1H), 6.90 (dd, J = 8.5 Hz, J = 2.6 Hz, 1H), 6.85 (d, J = 2.6 Hz, 1H), 4.49 (s, 2H), 3.38 (s, 3H), 2.39 ( s, 3H); ¹³ C { ¹ H} NMR (100 MHz, CDCl ₃ ) δ 197.6, 159.8, 159.4, 148.8, 143.5, 136.6, 135.2, 134.7, 132.9, 131.2, 129.3, 128.6, 123.7, 121.4, 117.3, 112.8, 55.4, 43.8 , 21.7; IR (film): 3004, 2922, 1685, 1607, 1466, 1241, 1181, 1045, 782 cm ⁻¹ ; HRMS (EI) m / z : [M] ⁺ Calcd for C ₂₁ H ₁₉ NO ₂ 317.1416; Found 317.1413.

Example 21 2- (6- (Pyridin-2-yl) benzo [d] [1,3] dioxol-5-yl) -1- ( p -tolyl) ethan-1-one (Compound 1-21 Manufacturing

Yield: 58.9 mg (89%); R _f = 0.3 (EtOAc: Hexane = 1: 5); Beige solid; Melting point: 119-121 ° C .; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.34 (dq, J = 4.8 Hz, J = 0.9 Hz, 1H), 7.84 (dt, J = 8.4 Hz, J = 1.8 Hz, 2H), 7.62 (td, J = 11.6 Hz, J = 1.8 Hz, 1H), 7.41 (dt, J = 7.9 Hz, J = 1.0 Hz, 1H), 7.22 (d, J = 8.0 Hz, 2H), 7.07 (ddd, J = 7.5 Hz, J = 4.9 Hz, J = 1.1 Hz, 1H), 7.02 (d, J = 8.0 Hz, 1H), 6.83 (d, J = 8.1 Hz, 1H), 5.99 (s, 2H), 4.50 (s, 2H) , 2.40 (s, 3 H); ¹³ C { ¹ H} NMR (100 MHz, CDCl ₃ ) δ 196.4, 159.0, 148.7, 147.7, 147.4, 143.6, 136.6, 134.7, 134.6, 129.3, 128.4, 123.60, 123.57, 121.5, 115.9, 107.2, 101.4, 37.2 , 21.8; IR (film): 3051, 2899, 1685, 1586, 1455, 1255, 1056, 932, 781 cm ⁻¹ ; HRMS (EI) m / z : [M] ⁺ Calcd for C ₂₁ H ₁₇ NO ₃ 331.1208; Found 331.1207.

Example 22 Preparation of 2- (5-Fluoro-2- (pyridin-2-yl) phenyl) -1- ( p -tolyl) ethan-1-one (Compound 1-22)

Yield: 50.7 mg (83%); R _f = 0.4 (EtOAc: Hexane = 1: 5); Ivory solid; Melting point: 88-90 ° C .; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.41 (dq, J = 4.8 Hz, J = 0.8 Hz, 1H), 7.77 (dt, J = 8.5 Hz, J = 1.8 Hz, 2H), 7.66 (td, J = 11.6 Hz, J = 1.8 Hz, 1H), 7.45 (dd, J = 8.3 Hz, J = 5.9 Hz, 1H), 7.40 (dt, J = 7.9 Hz, J = 1.0 Hz, 1H), 7.21 (d, J = 8.0 Hz, 2H), 7.13 (ddd, J = 7.5 Hz, J = 4.9 Hz, J = 1.0 Hz, 1H), 7.08-7.02 (m, 2H), 4.47 (s, 2H), 2.39 (s, 3H); ¹³ C { ¹ H} NMR (100 MHz, CDCl ₃ ) δ 197.0, 162.7 (d, J = 247.8 Hz), 158.8, 148.9, 143.8, 136.8, 136.4 (d, J = 3.4 Hz), 136.1 (d, J = 8.0 Hz), 134.5, 131.6 (d, J = 8.4 Hz), 129.3, 128.5, 123.9, 121.9, 118.7 (d, J = 21.6 Hz), 114.2 (d, J = 21.1 Hz), 43.4, 21.7; ¹⁹ F NMR (376 MHz, CDCl ₃ ) δ −113.82; IR (film): 3053, 2920, 1684, 1607, 1430, 1330, 1227, 1006, 782 cm ⁻¹ ; HRMS (EI) m / z : [M] ⁺ Calcd for C ₂₀ H ₁₆ FNO 305.1216; Found 305.1214.

Example 23 Preparation of 2- (4-Chloro-2- (pyridin-2-yl) phenyl) -1- ( p -tolyl) ethan-1-one (Compound 1-23)

Yield: 39.3 mg (61%); R _f = 0.4 (EtOAc: Hexane = 1: 5); Ivory solid; Melting point: 107-109 ° C .; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.43 (dq, J = 4.8 Hz, J = 0.8 Hz, 1H), 7.77 (d, J = 8.1 Hz, 2H), 7.68 (td, J = 11.6 Hz, J = 1.8 Hz, 1H), 7.48 (d, J = 2.2 Hz, 1H), 7.43 (dt, J = 7.9 Hz, J = 0.9 Hz, 1H), 7.35 (dd, J = 8.2 Hz, J = 2.2 Hz, 1H), 7.23-7.15 (m, 4H), 4.45 (s, 2H), 2.39 (s, 3H); ¹³ C { ¹ H} NMR (100 MHz, CDCl ₃ ) δ 197.2, 158.4, 149.0, 143.8, 141.8, 136.9, 134.5, 133.3, 133.0, 132.2, 129.9, 129.3, 128.6, 128.5, 123.9, 122.3, 42.9, 21.8 ; IR (film): 3053, 2919, 1683, 1606, 1427, 1329, 1222, 1000, 777 cm ⁻¹ ; HRMS (EI) m / z : [M] ⁺ Calcd for C ₂₀ H ₁₆ ClNO 321.0920; Found 321.0921.

Example 24 Preparation of 2- (5-Chloro-2- (pyridin-2-yl) phenyl) -1- ( p -tolyl) ethan-1-one (Compound 1-24)

Yield: 45.1 mg (70%); R _f = 0.4 (EtOAc: Hexane = 1: 5); Yellow solid; Melting point: 108-110 ° C .; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.40 (dq, J = 4.8 Hz, J = 0.9 Hz, 1H), 7.78 (dt, J = 8.5 Hz, J = 1.8 Hz, 2H), 7.67 (td, J = 11.6 Hz, J = 1.8 Hz, 1H), 7.43-7.40 (m, 2H), 7.36-7.31 (m, 2H), 7.21 (d, J = 7.9 Hz, 2H), 7.14 (ddd, J = 7.6 Hz , J = 4.9 Hz, J = 1.1 Hz, 1H), 4.47 (s, 2H), 2.39 (s, 3H); ¹³ C { ¹ H} NMR (100 MHz, CDCl ₃ ) δ 196.9, 158.6, 148.9, 143.8, 138.7, 136.8, 135.6, 134.5, 134.4, 132.0, 131.1, 129.3, 128.5, 127.5, 123.9, 122.1, 43.3, 21.8 ; IR (film): 3054, 2919, 1684, 1587, 1465, 1328, 1222, 1002, 808, 779 cm ⁻¹ ; HRMS (EI) m / z : [M] ⁺ Calcd for C ₂₀ H ₁₆ ClNO 321.0920; Found 321.0918.

Example 25 Preparation of 2- (2- (Pyridin-2-yl) -5- (trifluoromethyl) phenyl) -1- ( p -tolyl) ethan-1-one (Compound 1-25)

Yield: 46.2 mg (65%); R _f = 0.2 (EtOAc: Hexane = 1: 5); Beige solid; Melting point: 97-99 ° C .; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.42 (dq, J = 4.8 Hz, J = 0.8 Hz, 1H), 7.78 (dt, J = 8.5 Hz, J = 1.7 Hz, 2H), 7.70 (td, J = 11.6 Hz, J = 1.8 Hz, 1H), 7.63 (dd, J = 8.1 Hz, J = 1.2 Hz, 1H), 7.59 (d, J = 7.9 Hz, 2H), 7.46 (dt, J = 7.9 Hz, J = 0.9 Hz, 1H), 7.22 (d, J = 8.0 Hz, 2H), 7.17 (ddd, J = 7.6 Hz, J = 4.9 Hz, J = 1.1 Hz, 1H), 4.56 (s, 2H), 2.40 (s, 3H); ¹³ C { ¹ H} NMR (100 MHz, CDCl ₃ ) δ 196.7, 158.4, 149.0, 143.9, 143.7, 136.9, 134.7, 134.4, 130.6 (q, J = 32.5 Hz), 130.3, 129.4, 129.0 (q, J = 3.7 Hz), 128.4, 124.21 (q, J = 272.3 Hz), 124.19 (q, J = 3.8 Hz), 124.0, 122.5, 43.4, 21.8; ¹⁹ F NMR (376 MHz, CDCl ₃ ) δ −62.50; IR (film): 3054, 2920, 1685, 1607, 1468, 1334, 1124, 1002, 781 cm ⁻¹ ; HRMS (EI) m / z : [M] ⁺ Calcd for C ₂₁ H ₁₆ F ₃ NO 355.1184; Found 355.1188.

Example 26 Preparation of 2- (5-Acetyl-2- (pyridin-2-yl) phenyl) -1- ( p -tolyl) ethan-1-one (Compound 1-26)

Yield: 48.8 mg (74%); R _f = 0.1 (EtOAc: Hexane = 1: 5); Brown solid; Melting point: 100-102 ° C .; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.41 (dq, J = 4.8 Hz, J = 0.9 Hz, 1H), 7.96 (dd, J = 8.0 Hz, J = 1.8 Hz, 1H), 7.91 (d, J = 1.7 Hz, 1H), 7.79 (dt, J = 8.5 Hz, J = 1.8 Hz, 2H), 7.69 (td, J = 11.6 Hz, J = 1.8 Hz, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.48 (dt, J = 7.9 Hz, J = 1.0 Hz, 1H), 7.22 (d, J = 8.0 Hz, 2H), 7.16 (ddd, J = 7.6 Hz, J = 4.9 Hz, J = 1.1 Hz , 1H), 4.58 (s, 2H), 2.63 (s, 3H), 2.40 (s, 3H); ¹³ C { ¹ H} NMR (100 MHz, CDCl ₃ ) δ 197.9, 197.0, 158.6, 149.0, 144.6, 143.8, 136.93, 136.90, 134.5, 134.3, 132.2, 130.2, 129.3, 128.4, 127.3, 124.0, 122.4, 43.5 , 26.9, 21.7; IR (film): 3052, 2920, 1681, 1606, 1467, 1276, 1223, 1004, 841, 781, 693 cm ⁻¹ ; HRMS (EI) m / z : [M] ⁺ Calcd for C ₂₂ H ₁₉ NO ₂ 329.1416; Found 329.1418.

Example 27 2- (4- (Pyridin-2-yl)-[1,1'-biphenyl] -3-yl) -1- ( p- tolyl) ethan-1-one (Compound 1-27) Manufacture

Yield: 53.8 mg (74%); R _f = 0.3 (EtOAc: Hexane = 1: 5); Gray solid; Melting point: 120-122 ° C .; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.43 (dq, J = 4.8 Hz, J = 0.9 Hz, 1H), 7.81 (d, J = 8.2 Hz, 2H), 7.68 (td, J = 11.6 Hz, J = 1.8 Hz, 1H), 7.64-7.61 (m, 2H), 7.60-7.54 (m, 3H), 7.50 (dt, J = 8.0 Hz, J = 0.9 Hz, 1H), 7.43 (t, J = 7.5 Hz , 2H), 7.36-7.32 (m, 1H), 7.20 (d, J = 8.0 Hz, 2H), 7.14 (ddd, J = 7.5 Hz, J = 4.9 Hz, J = 1.0 Hz, 1H), 4.58 (s , 2H), 2.39 (s, 3H); ¹³ C { ¹ H} NMR (100 MHz, CDCl ₃ ) δ 197.6, 159.4, 148.9, 143.6, 141.4, 140.7, 139.1, 136.7, 134.7, 134.0, 130.8, 130.4, 129.3, 128.8, 128.5, 127.5, 127.4, 126.0 , 123.9, 121.8, 43.7, 21.7; IR (film): 3054, 2918, 1684, 1586, 1466, 1331, 1222, 1002, 761, 698 cm ⁻¹ ; HRMS (EI) m / z : [M] ⁺ Calcd for C ₂₆ H ₂₁ NO 363.1623; Found 363.1621.

Example 28 Preparation of 2- (3- (Pyridin-2-yl) naphthalen-2-yl) -1- ( p -tolyl) ethan-1-one (Compound 1-28)

Yield: 55.7 mg (83%); R _f = 0.4 (EtOAc: Hexane = 1: 5); Ivory solid; Melting point: 157-159 ° C .; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.42 (dq, J = 4.8 Hz, J = 0.8 Hz, 1H), 7.95 (s, 1H), 7.87-7.84 (m, 1H), 7.83-7.77 (m, 4H), 7.71 (td, J = 11.6 Hz, J = 1.8 Hz, 1H), 7.58 (dt, J = 7.9 Hz, J = 0.9 Hz, 1H), 7.50-7.44 (m, 2H), 7.20 (d, J = 8.0 Hz, 2H), 7.14 (ddd, J = 7.5 Hz, J = 4.9 Hz, J = 1.1 Hz, 1H), 4.68 (s, 2H), 2.38 (s, 3H); ¹³ C { ¹ H} NMR (100 MHz, CDCl ₃ ) δ 197.8, 159.8, 148.7, 143.5, 138.5, 136.8, 134.7, 133.4, 132.7, 131.6, 130.8, 129.5, 129.2, 128.5, 128.0, 127.5, 126.6, 126.2 , 124.2, 121.9, 43.9, 21.7; IR (film): 3054, 2919, 1683, 1606, 1426, 1326, 1221, 1008, 893, 746 cm ⁻¹ ; HRMS (EI) m / z : [M] ⁺ Calcd for C ₂₄ H ₁₉ NO 337.1467; Found 337.1464.

Example 29 Preparation of 2- (2- (Pyridin-2-yl) thiophen-3-yl) -1- ( p -tolyl) ethan-1-one (Compound 1-29)

Yield: 35.2 mg (60%); R _f = 0.5 (EtOAc: Hexane = 1: 5); Ruby oil; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.46 (dq, J = 4.8 Hz, J = 0.8 Hz, 1H), 7.93 (dt, J = 8.4 Hz, J = 1.8 Hz, 1H), 7.64 (td, J = 11.6 Hz, J = 1.8 Hz, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.31 (d, J = 5.1 Hz, 1H), 7.24 (d, J = 8.4 Hz, 2H), 7.11 ( ddd, J = 7.5 Hz, J = 4.9 Hz, J = 1.0 Hz, 1H), 7.00 (d, J = 5.1 Hz, 1H), 4.72 (s, 2H), 2.41 (s, 3H); ¹³ C { ¹ H} NMR (100 MHz, CDCl ₃ ) δ 197.5, 153.4, 149.4, 143.8, 138.5, 136.8, 134.8, 133.6, 131.8, 129.4, 128.8, 125.3, 122.1, 121.7, 39.8, 21.8; IR (film): 3106, 2919, 1683, 1606, 1470, 1329, 1181, 1007, 778 cm ⁻¹ ; HRMS (EI) m / z : [M] ⁺ Calcd for C ₁₈ H ₁₅ NOS 293.0874; Found 293.0871.

[Example 30] (8 S, 9 R , 13 R, 14 R) -13-Methyl-2- (2-oxo-2- (p -tolyl) ethyl) -3- (pyridin-2-yl) - Preparation of 6,7,8,9,11,12,13,14,15,16-decahydro-17H-cyclopenta [ a ] phenanthren-17-one (Compound 1-30)

Yield: 74.0 mg (80%); R _f = 0.4 (EtOAc: Hexane = 1: 5); Brown solid; Melting point: 172-174 ° C; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.42 (dq, J = 4.9 Hz, J = 0.8 Hz, 1H), 7.79 (dt, J = 8.5 Hz, J = 1.8 Hz, 2H), 7.64 (td, J = 11.6 Hz, J = 1.8 Hz, 1H), 7.43 (dt, J = 7.9 Hz, J = 0.9 Hz, 1H), 7.23 (d, J = 2.0 Hz, 2H), 7.20 (d, J = 8.0 Hz, 2H), 7.11 (ddd, J = 7.5 Hz, J = 4.9 Hz, J = 1.1 Hz, 1H), 4.45 (q, J = 15.8 Hz, 2H), 2.97-2.95 (m, 2H), 2.51 (q, J = 9.1 Hz, 1H), 2.46-2.42 (m, 1H), 2.38 (s, 3H), 2.36-2.33 (m, 1H), 2.22-2.12 (m, 1H), 2.10-2.01 (m, 2H) , 1.96 (dt, J = 12.5 Hz, J = 2.9 Hz, 1H), 1.69-1.57 (m, 3H), 1.55-1.42 (m, 3H), 0.92 (s, 3H); ¹³ C { ¹ H} NMR (100 MHz, CDCl ₃ ) δ 220.9, 197.9, 159.6, 148.8, 143.5, 140.1, 137.8, 136.5, 135.4, 134.7, 130.6, 130.5, 129.2, 128.9, 128.5, 123.7, 121.6, 50.6 , 48.1, 44.4, 43.3, 38.2, 36.0, 31.7, 29.2, 26.6, 25.8, 21.7 (2C), 14.0; IR (film): 2927, 2865, 1736, 1685, 1587, 1469, 1427, 1222, 808, 733 cm ⁻¹ ; HRMS (EI) m / z : [M] ⁺ Calcd for C ₃₂ H ₃₃ NO ₂ 463.2511; Found 463.2508.

Example 31 Preparation of 2- (2- (5-Methylpyridin-2-yl) phenyl) -1- ( p -tolyl) ethan-1-one (Compound 1-31)

Yield: 49.8 mg (83%); R _f = 0.3 (EtOAc: Hexane = 1: 5); Brown oil; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.29 (s, 1H), 7.78 (d, J = 8.2 Hz, 2H), 7.50-7.47 (m, 1H), 7.47-7.43 (m, 1H), 7.37- 7.31 (m, 3H), 7.30-7.28 (m, 1H), 7.19 (d, J = 8.2 Hz, 2H), 4.48 (s, 2H), 2.38 (s, 3H), 2.29 (s, 3H); ¹³ C { ¹ H} NMR (100 MHz, CDCl ₃ ) δ 197.8, 156.8, 149.2, 143.5, 140.2, 137.3, 134.7, 133.5, 131.7, 131.3, 129.9, 129.2, 128.5, 128.4, 127.2, 123.5, 43.5, 21.7 , 18.2; IR (film): 3027, 2920, 1685, 1605, 1478, 1330, 1222, 1000, 808, 746 cm ⁻¹ ; HRMS (EI) m / z : [M] ⁺ Calcd for C ₂₁ H ₁₉ NO 301.1467; Found 301.1464.

Example 32 Preparation of 2- (2- (5-Fluoropyridin-2-yl) phenyl) -1- ( p -tolyl) ethan-1-one (Compound 1-32)

Yield: 27.4 mg (45%); R _f = 0.4 (EtOAc: Hexane = 1: 5); Brown solid; Melting point: 77-79 ° C; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.25 (d, J = 2.8 Hz, 1H), 7.79 (d J = 8.2 Hz, 2H), 7.47-7.43 (m, 2H), 7.42-7.36 (m, 3H ), 7.32-7.29 (m, 1H), 7.21 (d, J = 8.0 Hz, 2H), 4.46 (s, 2H), 2.40 (s, 3H); ¹³ C { ¹ H} NMR (100 MHz, CDCl ₃ ) δ 197.5, 158.5 (d, J = 256.4 Hz), 155.9 (d, J = 4.2 Hz), 143.7, 139.2, 136.9 (d, J = 23.2 Hz) , 134.6, 133.7, 132.1, 129.9, 129.3, 128.8, 128.5, 127.4, 124.9 (d, J = 4.1 Hz), 123.6 (d, J = 18.3 Hz), 43.5, 21.8; ¹⁹ F NMR (376 MHz, CDCl ₃ ) δ −129.67; IR (film): 3027, 2920, 1684, 1606, 1476, 1330, 1224, 841, 744 cm ⁻¹ ; HRMS (EI) m / z : [M] ⁺ Calcd for C ₂₀ H ₁₆ FNO 305.1216; Found 305.1217.

Example 33 Preparation of Ethyl 6- (2- (2-oxo-2- (p-tolyl) ethyl) phenyl) nicotinate (Compound 1-33)

Yield: 48.1 mg (67%); R _f = 0.4 (EtOAc: Hexane = 1: 5); Brown oil; ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.015-9.008 (m, 1H), 8.28 (dd, J = 8.2 Hz, J = 2.2 Hz, 1H), 7.79 (d, J = 8.2 Hz, 2H), 7.55 (d, J = 8.2 Hz, 1H), 7.52-7.50 (m, 1H), 7.44-7.37 (m, 2H), 7.35-7.31 (m, 1H), 7.21 (d, J = 8.0 Hz, 2H), 4.54 (s, 2H), 4.39 (q, J = 7.1 Hz, 2H), 2.40 (s, 3H), 1.39 (t, J = 7.1 Hz, 3H); ¹³ C { ¹ H} NMR (100 MHz, CDCl ₃ ) δ 197.4, 165.4, 163.5, 150.1, 143.7, 139.4, 137.8, 134.6, 133.9, 132.2, 130.1, 129.3 (2C), 128.5, 127.5, 124.3, 123.5, 61.4, 43.6, 21.8, 14.4; IR (film): 3061, 2981, 1718, 1594, 1370, 1284, 1120, 1021, 810, 754 cm ^-1 ; HRMS (EI) m / z : [M] ⁺ Calcd for C ₂₃ H ₂₁ NO ₃ 359.1521; Found 359.1523.

Example 34 Preparation of 2- (2- (5-Acetylpyridin-2-yl) phenyl) -1- ( p -tolyl) ethan-1-one (Compound 1-34)

Yield: 44.9 mg (68%); R _f = 0.2 (EtOAc: Hexane = 1: 5); Brown oil; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.91 (dd, J = 2.3 Hz, J = 0.8 Hz, 1H), 8.22 (dd, J = 8.2 Hz, J = 2.3 Hz, 1H), 7.80 (dt, J = 8.5 Hz, J = 1.8 Hz, 2H), 7.59 (dd, J = 8.2 Hz, J = 0.8 Hz, 1H), 7.53-7.50 (m, 1H), 7.45-7.38 (m, 2H), 7.34-7.32 (m, 1 H), 7.22 (d, J = 7.9 Hz, 2H), 4.54 (s, 2H), 2.56 (s, 3H), 2.40 (s, 3H); ¹³ C { ¹ H} NMR (100 MHz, CDCl ₃ ) δ 197.3, 196.6, 163.7, 149.1, 143.8, 139.2, 136.3, 134.6, 134.0, 132.3, 130.2, 130.0, 129.4, 129.3, 128.4, 127.5, 123.8, 43.6 , 26.8, 21.7; IR (film): 3027, 2920, 1685, 1590, 1373, 1272, 1020, 810, 748 cm ⁻¹ ; HRMS (EI) m / z : [M] ⁺ Calcd for C ₂₂ H ₁₉ NO ₂ 329.1416; Found 329.1413.

[Examples 35 to 40 and Comparative Examples 1 to 4]

In order to determine whether the acylmethylpyridine compound was prepared according to the reaction conditions, the following experiment was carried out.

In a dry test tube equipped with a magnetic stirrer under a nitrogen atmosphere, pyridine compound 4a (0.2 mmol, 1.0 equiv), 2 H -azirine compound 5a (1.2 equiv), catalyst (4.0 mol%), additive (16.0 mol%) water, AcOH and solvent (2.0 mL) were added and stirred at 80 ° C. for 3 hours. Yield of the desired compound 1-1 was determined by NMR yield using dibromomethane as internal standard.

The reaction results according to the type of catalyst, the type and amount of the additive, the presence or absence of water, and the type of the solvent are shown in Table 1 below.

catalyst additive water
(equiv) AcOH
(equiv) menstruum Of compound 1-1
NMR yield (%) Example 35 [Cp ^* RhCl ₂ ] ₂ AgSbF ₆ 1.0 equiv 1.0 equiv DCE 35 Example 36 [Cp ^* RhCl ₂ ] ₂ AgSbF ₆ 1.0 equiv 1.0 equiv TFE 73 Example 37 [Cp ^* RhCl ₂ ] ₂ AgSbF ₆ 1.0 equiv 1.0 equiv HFIP 46 Example 38 [Cp ^* RhCl ₂ ] ₂ AgNTf ₂ 1.0 equiv 1.0 equiv THF 37 Example 39 [Cp ^* RhCl ₂ ] ₂ AgPF ₆ 1.0 equiv 1.0 equiv TFE 70 Example 40 [Ru ( p -cymene) Cl ₂ ] ₂ AgSbF ₆ 1.0 equiv 1.0 equiv TFE 65 Comparative Example 1 [Cp ^* RhCl ₂ ] ₂ AgSbF ₆ 1.0 equiv - DCE 0 Comparative Example 2 [Cp ^* IrCl ₂ ] ₂ AgSbF ₆ 1.0 equiv 1.0 equiv TFE 0 Comparative Example 3 [Cp ^* CoCl ₂ ] ₂ AgSbF ₆ 1.0 equiv 1.0 equiv TFE 0 Comparative Example 4 [Cp ^* RhCl ₂ ] ₂ AgSbF ₆ - 1.0 equiv TFE 17 DCE: 1,2-Dichloroethane
TFE: 2,2,2-Trifluoroethanol
HFIP: 1,1,1,3,3,3-Hexafluoro-2-propanol
THF: Tetrahydrofuran

Example  II: Acylmethylpyridine  Through cyclization of the compound Pyridoisoindole  And Pyridoisoquinolinone  Produce

Example 41 Preparation of (4-Chlorophenyl) (pyrido [2,1- a ] isoindol-6-yl) methanone (Compound A)

Compound 1-10 (1.0 equiv, 0.1 mmol, 31.0 mg), Cu (OAc) ₂ (50.0 mol%, 9.1 mg) and DCE (1.0 mL) in air were placed in a dry test tube equipped with a magnetic stirrer and heated to 100 ° C. Stir for 12 h. When stirring was complete, cooled to room temperature, filtered through a pad of celite and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography to obtain (4-Chlorophenyl) (pyrido [2,1- a ] isoindol-6-yl) methanone (Compound A) as a target compound.

Yield: 55.7 mg (91%); R _f = 0.3 (EtOAc: Hexane = 1: 5); Yellow solid; ¹ H NMR (400 MHz, CDCl ₃ ) δ 10.60 (d, J = 7.0 Hz, 1H), 8.24 (d, J = 8.5 Hz, 1H), 8.12 (d, J = 7.9 Hz, 1H), 7.65 (d , J = 8.3 Hz, 2H), 7.57 (t, J = 7.7 Hz, 1H), 7.50 (d, J = 8.3 Hz, 2H), 7.41-7.37 (m, 1H), 7.32-7.23 (m, 2H) , 6.92 (d, J = 8.3 Hz, 1H); ¹³ C { ¹ H} NMR (100 MHz, CDCl ₃ ) δ 181.6, 140.8, 136.3, 135.1, 132.4, 129.8, 129.5, 128.9, 128.5, 125.6, 121.5, 120.1, 119.9, 119.0, 118.6, 117.3, 114.0.

[Example 42] (4-Methoxyphenyl) ( pyrido [2,1- a] isoindol-6-yl) methanone ( compound B) and 7- (4-Methoxyphenyl) -6 H -pyrido [2,1- a] Preparation of isoquinolin-6-one (Compound C)

Compound 1-1 in test tube drying in air (1.0 equiv, 0.2 mmol, 60.6 mg) and tosyl azide (0.24 mmol, 1.2 equiv.) Were dissolved in MeCN (1.0 mL). After 5 minutes, DBU (0.3 mmol, 1.5 equiv.) Was added, stirred at 40 ° C. for 30 minutes, then Cu (OTf) ₂ (1.0 mol%) was added and stirred at 80 ° C. for 1 hour. The solvent is then removed under reduced pressure and the residue is purified by silica gel column chromatography to afford the desired (4-Methoxyphenyl) (pyrido [2,1- a ] isoindol-6-yl) methanone (Compound B) and 7 - a (4-Methoxyphenyl) -6 H -pyrido [2,1- a] isoquinolin-6-one ( compound C) was obtained.

(4-Methoxyphenyl) (pyrido [2,1- a ] isoindol-6-yl) methanone (Compound B) : yield: 27.1 mg (45%); R _f = 0.3 (EtOAc: Hexane = 1: 5); Yellow solid; ¹ H NMR (400 MHz, CDCl ₃ ) δ 10.51 (d, J = 7.0 Hz, 1H), 8.20 (d, J = 8.5 Hz, 1H), 8.10 (d, J = 8.0 Hz, 1H), 7.71 (d , J = 7.0 Hz, 2H), 7.50-7.46 (m, 1H), 7.35-7.20 (m, 4H), 7.08 (d, J = 8.4 Hz, 1H), 7.02 (d, J = 7.1 Hz, 2H) , 3.92 (s, 3 H); ¹³ C { ¹ H} NMR (100 MHz, CDCl ₃ ) δ 183.0, 161.6, 134.9, 134.4, 132.3, 130.5, 129.1, 128.0, 124.6, 121.1, 120.0, 119.4, 118.2, 117.3, 114.3, 113.7, 55.4.

7- (4-Methoxyphenyl) -6 H -pyrido [2,1- a] isoquinolin-6-one ( compound C): Yield: 24.1 mg (40%); R _f = 0.2 (EtOAc: Hexane = 3: 1); red solid; Melting point: 162-165 ° C; ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.97 (d, J = 7.0 Hz, 1H), 8.74 (d, J = 8.8 Hz, 1H), 8.38 (d, J = 8.6 Hz, 1H), 7.96-7.91 (m, 1H), 7.61-7.54 (m, 2H), 7.47-7.41 (m, 3H), 7.23-7.19 (m, 1H), 7.06 (d, J = 8.7 Hz, 2H), 3.89 (s, 3H ); ¹³ C { ¹ H} NMR (100 MHz, CDCl ₃ ) δ 158.6, 153.6, 141.5, 138.0, 132.6, 132.6, 131.0, 130.7, 129.1, 123.9, 123.7, 121.3, 120.8, 118.8, 114.1, 114.0, 109.7, 55.4 ; IR (neat) 2924, 2742, 2623, 1744, 1710, 1242, 1021, 842 cm ⁻¹ ; HRMS (EI) calcd for C ₂₀ H ₁₅ NO ₂ 301.1103, found 301.1105.

From Examples 41 and 42 above, acylmethylpyridine compounds are very useful for synthesizing biologically related heterocycles such as pyridoisoindole and pyridoisoquinolinone in one-pot via intramolecular cyclization It can be seen that it can be used.

The foregoing description of the present invention is intended for illustration, and it will be understood by those skilled in the art that the present invention may be easily modified in other specific forms without changing the technical spirit or essential features of the present invention. will be. Therefore, it should be understood that the embodiments described above are exemplary in all respects and not restrictive.

Claims (12)

delete delete delete delete One or more organic solvents selected from the group consisting of dichloroethane (DCE), tetrahydrofuran (THF), trifluoroethanol (TFE) and hexafluoroisopropanol (HFIP), rhodium or ruthenium catalyst, silver additives, acetic acid And reacting a pyridine compound represented by the following formula (4) and an aziline compound represented by the formula (5) in the presence of water to produce an acylmethylpyridine compound represented by the following formula (1).
[Formula 1]

[Formula 4]

[Formula 5]

In Chemical Formulas 1, 4, and 5,
L is -CR ^a = CR ^b- , NR ^c , O or S;
R ¹ , R ² , R ^a , R ^b and R ^c are each independently hydrogen, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, halogen, C 1 -C 10 alkylcarbonyl, C 1 -C 10 alkoxycarbonyl, C 6 -C 20 aryl , C6-C20 aryloxy, C6-C20 arylcarbonyl or C6-C20 aryloxycarbonyl, or may be linked with adjacent substituents to form a fused ring,
R ³ is hydrogen, C 1 -C 10 alkyl, halogen, C 1 -C 10 alkylcarbonyl, C 1 -C 10 alkoxycarbonyl, C 6 -C 20 aryl, C 6 -C 20 arylcarbonyl or C 6 -C 20 aryloxycarbonyl;
Ar is C6-C20 aryl or C3-C20 heteroaryl;
Alkyl, alkoxy, alkylcarbonyl, aryl, aryloxy or arylcarbonyl of R ¹ , R ² , R ^a , R ^b and R ^c , alkyl, alkylcarbonyl, alkoxycarbonyl of R ³ , aryl, arylcarbon Aryl or heteroaryl of aryl or aryloxycarbonyl and Ar is C1-C10 alkyl, halogen, C1-C10 alkoxy, haloC1-C10 alkyl, C6-C20 aryl, C6-C20 aryloxy, C1-C10 alkylcarbonyl, Further substituted with one or more selected from the group consisting of C1-C10 alkoxycarbonyl, C6-C20 arylcarbonyl, C6-C20 aryloxycarbonyl, nitro and cyano;
The heteroaryl includes 1 to 4 heteroatoms selected from N, O and S. The method of claim 5,
The pyridine compound of Formula 4 is used in the range of 0.8 to 5 moles with respect to 1 mole of the azirin compound of Formula 5 above. The method of claim 5,
The rhodium catalyst is [Rh (C ₅ Me ₅ ) Cl ₂ ] ₂ , [(C ₅ Me ₅ ) Rh (MeCN) ₃ ] [SbF ₆ ] ₂ , Rh (C ₅ Me ₅ ) (OAc) ₂ and RhCl ( PPh ₃ ) ₃ or one or more selected from the group consisting of
The ruthenium catalyst is [Ru ( p -cymene) Cl ₂ ] ₂ , Ru (PPh ₃ ) ₃ (CO) H ₂ , Ru ₃ (CO) ₁₂ , [RuCl ₂ (C ₆ H ₆ )] ₂ and [RuCl ₂ (cod)] ₂ (cod = 1,5-cyclooctadiene), one or two or more selected from the group consisting of. The method of claim 5,
The rhodium or ruthenium catalyst is used in the range of 0.5 to 20 mol% based on 1 mole of the aziline compound of Chemical Formula 5. The method of claim 5,
The silver additive is one or two or more selected from the group consisting of AgAsF ₆ , AgSbF ₆ , AgBF ₄ , AgNTf ₂ and AgPF ₆ . The method of claim 9,
The silver additive is used in the range of 5 to 50 mol% based on 1 mole of the aziline compound of Chemical Formula 5. The method of claim 5,
The acetic acid is used in the range of 0.8 to 5 moles per mole of the aziline compound of Formula 5, and the water is used in the range of 0.8 to 5 moles per mole of the azirin compound of Formula 5, . delete