KR101654109B1 - Process for preparing aurone derivatives using Ag catalyst - Google Patents

Abstract

Provided is a manufacturing method of aurone derivative. The manufacturing method of aurone derivative comprises a step of making o-hydroxylaryl phenylethynyl ketone react under the presence of an Ag catalyst and a dimethylformamide solvent. The manufacturing method of aurone derivative using Ag catalyst is quick and efficient, and is useful in fields requiring synthesis of aurone derivative having various structures.

Description

BACKGROUND OF THE INVENTION 1. Field of the Invention [0001] The present invention relates to a process for preparing an aurone derivative,

The present invention relates to a process for preparing an orion derivative, and more particularly to a process for preparing an orion derivative comprising the step of reacting under silver catalyst.

Aurone and flavone are compounds that are found in many natural products. They are structurally isomeric with each other and function as pigments that show yellow in flowers and fruits. Among these compounds, flavon has been reported to exhibit physiological activities such as anticancer and antiviral (Mayuri M. Naik ,; Santosh G. Tilve, Vijatendra P. Kamat. Tetrahedron Letters. 2014, 55. 3340 ).

Unlike flavone, although Oron exhibits a variety of physiological activities, it has not been long since the study began. Sulfuretin exhibits anti-inflammatory activity, and aureusidin and bracteatin exhibit antioxidative activity. In addition, they have been reported to exhibit various physiological activities such as antibacterial and antifungal agents have. Oron derivatives showing various physiological activities as described above can be commercially highly potent compounds in the pharmaceutical field.

It has been reported that oron is produced by oxidation and cyclization reaction in plants and synthesized by rearrangement of chalcone by aureusidin synthase (Toru Nakayama J. Biosci. Bioeng., 2002, 94, 487) (see Scheme 1 below).

[Reaction Scheme 1]

Accordingly, the oron can be isolated from natural products, but the oron and its derivatives can also be synthesized through an organic reaction. As a classical synthesis method, the orion derivatives can be prepared through condensation. As shown in Reaction Scheme 2 below, the oron derivative can be prepared from coumaranone and aldehyde using alumina, but it is difficult to synthesize the starting material, quorumanone, and it is difficult to introduce various functional groups .

[Reaction Scheme 2]

The general method for synthesizing the oron is oxidative cyclization of 2'-hydroxychalcone as shown in Reaction Scheme 3 below. In the prior art, although the above-mentioned method has been used to synthesize oron derivatives, there is a disadvantage in that the use and yield of the mercury catalyst, which is highly toxic, are not good (Venkateswarlu, S .; Panchagnula, G. K., Gottumukkala, A. L, Subbaraju GV Tetrahedron 2007, 63, 6909).

[Reaction Scheme 3]

Transition metal catalysts are usually used in the synthesis of the o-ron compounds. A catalyst is a substance that maintains the properties of a substance itself and increases or decreases a chemical reaction rate. Depending on the nature of the catalyst, a stable result can be obtained with a high efficiency in the synthesis method. Therefore, it is very important to find a suitable catalyst for a specific reaction system in order to synthesize a compound with a consistent reaction in a short time in the field of organic chemistry.

As a representative example, when producing a cyclic compound from an alkyne compound, it is a catalyst that plays an important role in activating the alkyne. Conventionally, transition metal catalysts such as gold (Au), platinum (Pt) and rhodium (Rh) have been used as catalysts for activating alkane to produce ring compounds. However, the reaction in which such transition metal catalysts are used is costly and limited for use in commercial large scale synthesis.

In the transition metal catalyst, a silver catalyst is often used in an organic compound synthesis reaction. The silver (Ag) has an electron configuration [Kr] 4d ¹⁰ 5s ¹ , a melting point of 961.78 ° C, a density of 10.49 g / cm < ³ > and an atomic weight of 107.87 g / mol, which is a material having high thermal conductivity and electrical conductivity in the metal, In general, the oxidation state of silver in ordinary compounds is +1 and +2. Many researchers have reported that silver is an environmentally friendly, non-toxic, and easy-to-handle organotin in the organic reaction, and many studies have been conducted as catalysts for the cyclization reaction (Yancheng Hu, Ruxia Yi, Fan Wu ,; Boshun Wan J. Org. Chem., 2013, 78, 7714).

To the Prior Art (Hassina Harkat ,; Aure'lien Blanc ,; Jean -Marc Weibel ,; Patrick Pale. J. Org. Chem. 2008, 73, 1620) as shown in Scheme 4, using a metal catalyst 2- ( (1-hydroxyprop-2-ynyl) phenol] was synthesized by cyclization and oxidation. However, this reaction is disadvantageous in that it requires the use of expensive gold catalysts and other additives.

[Reaction Scheme 4]

In another prior art (Min Yu, Mingdeng Lin, Chengyan Han, and Li Zhu, Chao-Jun Li, Xiaoquan Yao. Tetrahedron. 2010, 51, 6722) -Hydroxypropyl-2-nyl) phenol, the use of a cosolvent and the synthesis of stereoisomers of E / Z form in the synthesized oron ) Can not be selectively controlled completely.

[Reaction Scheme 5]

When the cyclization reaction is carried out by activating the alkane with a transition metal catalyst, the ring form of the resulting compound is changed as the nucleophile attacks the inside of the alkene or attacks the outside. In general, both types of cyclization reactions forming a 5- exo- dig and 6- endo- dig are preferred reactions, so that one ring It is very important in organic reactions to produce only the form of the compound. According to the conventional method for synthesizing the orion derivative by a cyclization reaction, flavone, which is a cyclic compound in the form of a hexagonal ring in addition to the oron derivative, may be produced as a by-product, depending on the attack position of the nucleophile on the alkane (see Reaction Schemes 6 and 7 below) ).

[Reaction Scheme 6]

[Reaction Scheme 7]

As described above, various methods for obtaining Oron derivatives have been reported in the past, but problems such as low reaction yield, toxic use of a transition metal catalyst, and low position selectivity remain to be solved.

Korean Patent Publication No. 1983-0001919 (September 23, 1983) Chinese Patent Disclosure CN 103936701 A (Jul. 23, 2014)

Min Yu, et al., Tetrahedron. 2010, 51, 6722. Ting-Ting Jong, et al., J. Chem. Soc. Perkin Trans. 1. 1990, 423.

The inventors of the present invention have studied on a method of synthesizing oron derivatives having high selectivity at a high reaction yield without using a toxic transition metal catalyst and have found that o -hydroxyarylphenylethynyl It has been found that when the ketone ring is reacted, the reaction proceeds effectively, so that the Oron derivative which exhibits very high position selectivity in a short time can be synthesized.

Accordingly, it is an object of the present invention to provide a process for preparing an orion derivative, which comprises the step of reacting o -hydroxyarylphenyl ethynyl ketone with a silver catalyst and a dimethylformamide solvent.

According to one aspect of the present invention, there is provided a process for preparing a compound of the formula (I) or a salt thereof, comprising the step of reacting a compound represented by the formula (2) below in the presence of a silver catalyst and a dimethylformamide solvent.

≪ Formula 1 >

(2)

Wherein R ¹ is one or more substituents selected from the group consisting of hydrogen, C ₁ to C ₆ alkyl, C ₁ to C ₆ alkoxy and halogen.

In one embodiment, R ¹ may be one or more substituents selected from the group consisting of hydrogen, C ₁ to C ₄ alkyl, C ₁ to C ₄ alkoxy, and halogen.

In one embodiment, R < ¹ > may be one or more substituents selected from the group consisting of hydrogen, methyl, butyl, methoxy, chlorine and bromine.

In one embodiment, the compound of Formula 1 may be any one selected from the group consisting of the following compounds.

1) ( Z ) -Orone

2) Synthesis of ( Z ) -5-methylolone

3) Synthesis of ( Z ) -7-methoxhorone

4) Synthesis of ( Z ) -5-methoxhorone

5) ( Z ) -5-Bromorone

6) ( Z ) -5-chlororone

7) ( Z ) -5- t -Butylon.

In one embodiment, the silver catalyst may be any one selected from the group consisting of trifluoromethanesulfonic acid, silver carbonate, acetic acid silver, hexafluoroantimonic acid silver, silver oxide and mixtures thereof.

In one embodiment, the silver catalyst may be used in an amount of greater than 0 to 10 mole percent relative to the compound of formula (2).

In one embodiment, the reaction of the compound of formula 2 may be carried out at a temperature of 50 ° C or lower.

By using the o -hydroxyarylphenyl ethynyl ketone of the present invention in the presence of a silver catalyst and a dimethylformamide solvent, an expensive transition metal or a transition metal catalyst having toxicity is used It is possible to produce ozonic derivatives in an environmentally friendly manner and also to synthesize ozonic derivatives into which various substituents have been introduced by highly effective cyclization of terminal alkynes with high position selectivity with minimal occurrence of flavon, It is possible to synthesize oron derivatives with a high yield.

Accordingly, the process for preparing an orion derivative comprising the step of reacting o -hydroxyarylphenylethynyl ketone in the presence of silver catalyst and dimethylformamide solvent is a rapid and efficient method for preparing the oron derivative Will be useful.

The present invention provides a process for preparing a compound of the formula (I) or a salt thereof, which comprises the step of reacting a compound of the formula (2) in the presence of a silver catalyst and a dimethylformamide (DMF) solvent.

≪ Formula 1 >

(2)

Wherein R ¹ is one or more substituents selected from the group consisting of hydrogen, C ₁ to C ₆ alkyl, C ₁ to C ₆ alkoxy and halogen.

In one embodiment, R ¹ may be one or more substituents selected from the group consisting of hydrogen, C ₁ to C ₄ alkyl, C ₁ to C ₄ alkoxy and halogen, more preferably hydrogen, methyl, butyl , Methoxy, chlorine, and bromine.

In one embodiment, the compound of Formula 1 may be any one selected from the group consisting of the following compounds.

1) (Z) - ohron [(Z) -Aurone]

2) ( Z ) -5-Methylolone [( Z ) -5-Methylaurone]

3) ( Z ) -7-methoxyuron [( Z ) -7-Methoxyaurone]

4) (Z) -5- methoxy Please Rhone [(Z) -5-Methoxyaurone]

5) ( Z ) -5-Bromorone [( Z ) -5-Bromoaurone]

6) ( Z ) -5-Chloro [( Z ) -5-Chloroaurone]

7) (Z) -5- t - butyl ohron [(Z) -5- t -Butylaurone] .

In one embodiment, the silver catalyst is silver trifluoromethanesulfonate (AgOTf), silver carbonate (Ag ₂ CO ₃ ), silver acetate (AgOAc), hexafluoroantimonic acid silver hexafluoroantimonate, AgSbF ₆ ), silver oxide (Ag ₂ O), and a mixture thereof. Preferably, acetic acid may be used, but the present invention is not limited thereto.

In one embodiment, the silver catalyst may be used in an amount of from greater than 0 to 10 mol%, preferably from 1 to 5 mol%, more preferably from 2 to 4 mol% But are not limited thereto.

In one embodiment, the reaction of the compound of Formula 2 can be carried out at a temperature of 50 ° C or lower, preferably 0 to 30 ° C, but is not limited thereto.

The above reaction can be represented by the following reaction formula (8).

[Reaction Scheme 8]

Specifically, the reaction may be carried out by adding DMF solvent in the presence of a silver catalyst (for example, AgOAc), mixing o -hydroxyarylphenyl ethynyl ketone, and then stirring at mild conditions, for example, at room temperature. When the reaction is completed, the solvent is removed and the compound is separated by an appropriate compound separation method (for example, tube chromatography) to obtain the compound of formula (1).

Hereinafter, the present invention will be described in more detail through examples and test examples. However, the following examples and test examples are provided for illustrating the present invention, and the scope of the present invention is not limited thereto.

Example  One. ( Z ) - Of Oron (1a)  Produce

The nuclear magnetic resonance spectrum was observed using an NMR analyzer (Bruker ADVANCE III 400 NMR) and the δ value (ppm) was calculated using CDCl ₃ using TMS (tetramethylsilane) as an internal standard . For analytical thin layer chromatography (TLC), silica gel 60 (silica gel 60, 230-400 mesh ASTM, E. Merck) was used. All reagents used in the experiments were purchased from companies such as Sigma Aldrich, Alfa Aesar, TCI. The DMF used as solvent was distilled using Ca ₂ Cl ₂ and all reactions were performed under nitrogen unless otherwise noted.

To the test tube was added DMF (3 mL) in the presence of AgOAc (2.25 mg, 0.013 mmol), o -hydroxyphenylphenyl ethynyl ketone (100 mg, 0.45 mmol) was mixed and stirred at room temperature. After 1 hour, the reaction was terminated. The solvent was removed and the product was isolated by column chromatography (eluent: EtOAc / Hx = 1/5) to obtain the title compound, Oron (94.8 mg, 95%).

Yellow solid (94.8 mg, 95%). ^{1 H NMR (400 MHz, CDCl} 3): δ 7.90 (dd, J = 1.32 Hz, J = 1.32 Hz, 2H), 7.80 (dd, J = 0.72 Hz, J = 0.72 Hz, 1H), 7.64 (td, J = 1.36 Hz, J = 0.96 Hz, J = 1.36 Hz, 1H), 7.47-7.37 (m, 3H), 7.31 (d, J = 8.28 Hz, 1H), 7.20 (t, J = 7.4 Hz, J = 7.53 Hz, 1 H), 6.88 (s, 1 H). ¹³ C NMR (100 MHz, CDCl ₃ ): δ 184.8, 166.1, 146.9, 136.9, 132.3, 131.5, 129.9, 128.9, 124.7, 123.5, 121.6, 113.0, 112.9.

Example  2. ( Z ) -5- Of methylorone (1b)  Produce

The title compound was synthesized in the same manner as in Example 1, except that 2-hydroxy-5-methylphenyl phenyl ethynyl ketone was used instead of o -hydroxyphenyl phenyl ethynyl ketone.

Yellow solid (96 mg, 96%). ^{1 H NMR (400 MHz, CDCl} 3): δ 7.94 (d, J = 7.08 Hz, 1H), 7.60 (s, 1H), 7.48-7.38 (m, 4H), 7.23 (d, J = 8.4 Hz, 1H ), 6.88 (s, 1 H), 2.41 (s, 3 H). ¹³ C NMR (100 MHz, CDCl ₃ ): δ 184.9, 164.6, 147.3, 138.0, 133.2, 132.4, 129.8, 128.4, 128.2, 124.3, 121.5, 112.7, 112.5, 20.8.

Example  3. ( Z ) -7- Of methoxhiron (1c)  Produce

The title compound was synthesized by following the procedure of Example 1 while using 2-hydroxy-3-methoxyphenyl phenyl ethynyl ketone instead of o -hydroxyphenyl phenyl ethynyl ketone.

Yellow solid (115 mg, 90%). ^{1 H NMR (400 MHz, CDCl} 3): δ 7.96 (dd, J = 1.52 Hz, J = 5.24 Hz, 2H), 7.64 (td, J = 1.28 Hz, J = 1.52 Hz, J = 1.28 Hz, 2H) , 7.43-7.39 (m, 2H), 7.20-7.13 (m, 2H), 6.93 (s, 1H), 4.05 (s, 3H). ^{13 C NMR (100 MHz, CDCl} 3): δ 184.9, 155.8. 146.8, 146.0, 132.2, 131.7, 129.9, 128.9, 123.9, 123.0, 118.7, 115.8, 113.6, 56.4.

Example  4. ( Z ) -5- Of methoxhiron (1d)  Produce

The title compound was synthesized in the same manner as in Example 1, except that 2-hydroxy-5-methoxyphenyl phenyl ethynyl ketone was used in place of o -hydroxyphenyl phenyl ethynyl ketone.

Yellow solid (51.8 mg, 91%). ¹ H NMR (400 MHz, CDCl ₃ ):? 7.93 (dd, J = 1.52 Hz, J = 1.52 Hz, 2H), 7.48-7.41 (m, 3H), 7.26-7.23 , ≪ / RTI > 1H), 3.85 (s, 3H). ¹³ C NMR (100 MHz, CDCl ₃ ): δ 185.0, 161.3, 156.1, 147.7, 132.3, 131.5, 129.8, 128.9, 126.2, 121.7, 113.8, 113.1, 105.2, 55.9.

Example  5. ( Z ) -5- Of bromoaurane (1e)  Produce

The title compound was synthesized by following the procedure of Example 1 while using 2-hydroxy-5-bromophenylphenyl ethynyl ketone instead of o -hydroxyphenyl phenyl ethynyl ketone.

Yellow solid (146 mg, 97%). ¹ H NMR (400 MHz, CDCl ₃ ):? 7.94-7.91 (m, 3H), 7.76 (dd, J = 2.16 Hz, J = 2.16 Hz, 1H), 7.49-7.43 , J = 8.73 Hz, 1 H), 6.93 (s, 1 H). ¹³ C NMR (100 MHz, CDCl ₃ ):? 183.3, 164.7, 146.8, 139.4, 131.9, 131.7, 130.3, 129.0, 127.3, 123.3, 116.3, 114.7, 114.1.

Example  6. ( Z ) -5- Of chloroorone (1f)  Produce

The title compound was synthesized in the same manner as in Example 1, using 2-hydroxy-5-chlorophenylphenyl ethynyl ketone instead of o -hydroxyphenyl phenyl ethynyl ketone.

Yellow solid (97 mg, 94%). ^{1 H NMR (400 MHz, CDCl} 3): δ 7.91 (dd, J = 1.64 Hz, J = 1.0 Hz, 2H), 7.78 (dd, J = 0.36 Hz, J = 0.36 Hz, 1H), 7.62 (dd, J = 2.32 Hz, J = 2.28 Hz, 1H), 7.48-7.43 (m, 3H), 7.31 (dd, J = 0.36 Hz, J = 0.36 Hz, 1H), 6.93 (s, 1H). ¹³ C NMR (100 MHz, CDCl ₃ ):? 183.4, 164.3, 146.9, 136.7, 131.9, 131.7, 130.3, 129.2, 129.0, 124.3, 122.8, 114.3, 114.2, 114.1.

Example  7. ( Z ) -5- t - Of butylolone (1 g)  Produce

The title compound was synthesized in the same manner as in Example 1, using 2-hydroxy-5- t -butylphenylphenylethynylketone instead of o -hydroxyphenylphenylethynylketone.

Yellow solid (132 mg, 95%). ^{1 H NMR (400 MHz, CDCl} 3): δ 7.92 (d, J = 7.76 Hz, 2H), 7.82 (d, J = 1.92 Hz, 1H), 7.74 (dd, J = 2.20 Hz, J = 2.20 Hz, 1H), 7.49-7.38 (m, 3H), 7.28-7.26 (m, IH), 6.89 (s, IH), 1.36 (s, 9H). ¹³ C NMR (100 MHz, CDCl ₃ ): δ 185.2, 164.5, 147.5, 146.8, 134.8, 132.4, 131.5, 129.8, 128.8, 121.1, 120.8, 112.7, 112.3, 34.7, 31.4.

Comparative Example  One. ( Z )-2-( Cyclohexylmethylene ) Benzofuran -3 ( 2H ) -One (lh) and 2- Cyclohexyl - 4H -Chromen-4-one (3h)

The title compound was synthesized in the same manner as in Example 1, except that o -hydroxyphenylcyclohexylethynylketone was used in place of o -hydroxyphenylphenylethynylketone.

( Z ) -2- (cyclohexylmethylene) benzofuran-3 ( 2H ) -one (1h): yellow solid (35.2 mg, 64%). ^{1 H NMR (400 MHz, CDCl} 3): δ 7.76 (dddd, J = 0.6 Hz, J = 0.56 Hz, J = 0.6 Hz, J = 0.6 Hz, 1H), 7.62 (dtd, J = 1.44 Hz, J = 1.24 Hz, J = 1.28 Hz, J = 1.44 Hz, 1H), 7.22 (d, J = 8.32 Hz, 1H), 7.18-7.15 (m, 1H), 6.07 (d, J = 9.76 Hz, 1H), 1.84 -1.76 (m, 4H), 1.72-1.68 (m, 1H), 1.45-1.22 (m, 6H).

2-Cyclohexyl- 4H -chromen-4-one (3h): yellow liquid (36 mg, 31%). ^{1 H NMR (400 MHz, CDCl} 3): δ 8.17 (dd, 1H, J = 1.32 Hz, J = 1.32 Hz), 7.64 (t, 1H, J = 8.0 Hz), 7.43 (d, 1H, J = 8.0 1H), 7.37 (t, 1H, J = 8.0 Hz), 6.17 (s, 1H), 2.53 (tt, 1H, J = 11.4, 3.4 Hz), 1.26-2.06 (m, 10H). ¹³ C NMR (100 MHz, CDCl ₃ ): δ 178.6, 173.4, 156.4, 133.3, 125.6, 124.7, 123.7, 117.8, 107.8, 42.8, 30.4, 25.9, 25.8, 25.7.

Comparative Example  2. 2-Butyl- 4H - Kromen (3i) < / RTI >

o-ethynyl ketone instead of o-hydroxyphenyl-phenyl-hydroxyphenyl-n-butyl ethynyl ketone using, was prepared the title compound in the same manner as in Example 1.

Yellow liquid (55.6 mg, 55%). ^{1 H NMR (400 MHz, CDCl} 3): δ 8.19 (dd, J = 1.44 Hz, J = 1.48 Hz, 1H), 7.67-7.62 (m, 1H), 7.44-7.36 (m, 1H), 6.18 (s , 1H), 2.63 (t, J = 7.52 Hz, J = 7.72 Hz, 2H), 1.47-1.41 (m, 2H), 0.97 (t, J = 7.32 Hz, J = 7.37 Hz, 3H). ¹³ C NMR (100 MHz, CDCl ₃ ):? 178.3, 169.7, 156.4, 133.3, 125.6, 124.8, 123.7, 117.8, 109.7, 34.0, 28.8, 22.0, 13.7.

Test Example  1. Yield analysis of products according to catalyst, solvent, reaction temperature and reaction time

In order to confirm the optimum conditions of the reaction, the reaction was carried out under various conditions as described below. First, 10 mol% of various metal catalysts, that is trifluoromethane sulfonic acid metal [M (OTf)] using a catalyst results a reaction in CH ₃ NO ₂ solvent, TLC in the reaction with Cu (OTf) ₂ as a catalyst Two spots with similar concentrations expected to be cyclized products were visually identified. As a result of analyzing the compounds corresponding to the two spots by tube chromatography, the pentagon ring compound, Oron, and the hexagon ring compound flavone, respectively, were obtained in a yield of 33% and 29%, respectively (see Scheme 9 below).

[Reaction Scheme 9]

From the above reaction results, the reaction was carried out to find the optimization conditions for selectively obtaining only the O-RON compound (see Reaction Scheme 10 below) by using different catalysts, solvents, and temperatures, Are shown in Table 1 below.

[Reaction Scheme 10] ^a

number Catalyst (mol%) menstruum Temperature (℃) Reaction time (h) 1a yield (%) ^b 3a yield (%) ^b One Bi (OTf) ₃ (10) CH ₃ NO ₂ 100 21 0 8 2 Fe (OTf) ₃ (10) CH ₃ NO ₂ 100 21 0 6 3 Cu (OTf) ₂ (10) CH ₃ NO ₂ 100 21 33 29 4 In (OTf) ₃ (10) CH ₃ NO ₂ 100 21 0 9 5 AgOTf (10) CH ₃ NO ₂ 100 21 32 25 6 Hf (OTf) ₄ (10) CH ₃ NO ₂ 100 21 0 11 7 Cu (OTf) ₂ (10) DMF 100 One 93 4 8 Cu (OTf) ₂ (10) CH ₃ CN 100 24 Trace grain 9 Cu (OTf) ₂ (10) 1,4-Dioxane 100 24 0 8 10 Cu (OTf) ₂ (10) PhCl 100 24 14 2 11 Cu (OTf) ₂ (10) DMF Room temperature 30 0 grain 12 AgOTf (10) DMF Room temperature One 83 2 13 Ag ₂ CO ₃ (10) DMF Room temperature One 96 3 14 AgOAc (10) DMF Room temperature One 99 <1 15 AgOAc (3) DMF Room temperature One 99 (95) ^c <1 16 AgSbF ₆ (10) DMF Room temperature 4 65 2 17 Ag ₂ O (10) DMF Room temperature One 99 One 18 AgOAc (10) DMA Room temperature One 95 3 19 AgOAc (10) DMSO Room temperature One 96 3 20 ^d AgNO ₃ (10) MeOH Room temperature 3 95 5

a: Reaction conditions [2a (0.225 mmol), solvent (2.5 mL) under nitrogen atmosphere].

b: The yields were calculated on the basis of 1a and 3a, and measured by crude ¹ H NMR using dibromomethane as an internal standard.

c: separation yield

d: J. Chem . Soc . Perkin Trans. 1 , 1990,423.

As shown in Table 1, only a small amount of flavone (3a) in the form of a hexagonal ring was produced in small quantities in most cases when the reaction was carried out by fixing CH ₃ NO ₂ at a temperature of 100 ° C (No. 1-6) ) ₂ (No. 3) and AgOTf (No. 5) were used as catalysts, respectively.

To investigate the conditions for producing only Oron, additional reactions were carried out on Cu (OTf) ₂ and AgOTf catalysts with similar reactivity as follows. First, holding the Cu (OTf) ₂ as the catalyst and N, N - dimethylformamide (N, N -dimethylformamide, DMF), acetonitrile _{(acetonitrile, CH 3 CN),} 1,4- dioxane (4-Dioxane ) Or chlorobenzene (PhCl) as a solvent, respectively. As a result, when DMF was used as a solvent, Oon (1a) was produced in a high yield of 93% in 1 hour and only 4% of flavone was produced High position selectivity (No. 7).

Next, using Cu (OTf) ₂ as a catalyst and DMF as a solvent, the reaction was carried out by lowering the temperature at 100 ° C to room temperature. As a result, even after 30 hours of reaction time, only spot traces appeared on TLC, (No. 11).

Next, AgOTf was used as a catalyst, DMF was used as a solvent, and the reaction was carried out at room temperature. As a result, it was found that oon was produced at a yield of 83% even at room temperature (No. 12). As a result, it was found that when the reaction was carried out using AgOAc as a catalyst, the yield of oon was 99% and the flavone was less than 1% at a reaction time of 1 hour (No. 14).

Next, when AgOAc was used as a catalyst and the reaction was carried out at various temperatures using a variety of solvents, dimethylamine (DMA) and dimethylsulfoxide (DMSO) (Numbers 18-19).

As a result, it was found that even when the amount of catalyst was reduced at the same reaction time, it was found that the amount of the catalyst was changed from 10 mol% to 3 mol% The yield of the flavone was obtained in the same manner as in the case of using the catalyst in an amount of 10 mol% (NMR yield [oron: 99%: less than 1% .

In addition, o -hydroxyphenylphenylethynyl ketone as a starting material, which is a reaction condition described in the prior art (Ting-Ting Jong, et al., J. Chem . Soc . Perkin Trans. 10 mol% of AgNO ₃ , and methanol as a solvent, respectively. As a result, 95% of Oron and 5% of flavone were obtained in the yield of separation. It was confirmed that the amount of the catalyst was required more than the condition of the present invention, the reaction time was long, and the oon had a lower position selectivity.

Test Example  2. Reactant o - Hydroxyaryl Phenylethynyl  Product synthesis and yield analysis by ketone

3 mol% of AgOAc as a catalyst and DMF as a solvent were subjected to a cyclization reaction using a reaction product ([r ² ] introduced o -hydroxyarylethynyl ketone) into which various substituents were introduced (See Reaction Scheme 11 below), and the results are shown in Table 2 below.

[Reaction Scheme 11] ^a

a: Reaction conditions [Reaction (0.45 mmol), AgOAc (0.013 mmol), solvent (2.0 mL) under nitrogen atmosphere].

b: The yield was calculated based on the two materials in Scheme 11 and was determined by crude ¹ H NMR using dibromomethane as an internal standard.

c: separation yield.

As shown in Table 2 above, o -hydroxyphenylphenyl ethynyl ketone was used. As a result, oon was produced in a yield of 95% in 1 hour after the reaction was proceeded, and the NMR yields of the oon and flavone derivatives were 99% 1% (No.1).

Next, the electron donating group and the electron withdrawing group were introduced at various positions. As a result, it was found that the substitution of the methyl group at the carbon position 5 ( Z ) -5-methylolone was produced at a NMR yield of 99%: 1% and a separation yield of 96% for the Orone derivative and the flavone derivative in 30 minutes (No.2).

Then, when the methoxyl group was substituted with the methoxyl group at the 3-carbon position, it was found that the prodrug of the orion derivative [( Z ) -3-methoxhiorone] and the flavone derivative The NMR yield was 99%: 1% and the separation yield was 91%. When the methoxyl group was substituted at the 5th carbon position, the reaction was completed within 30 minutes much faster than that at the 3th carbon position, The NMR yields of the orion derivatives [( Z ) -5-methoxyionone] and flavone derivatives were 95%: 2% and the separation yield of the oron derivatives was 91% (No. 3-4). Thus, it can be seen that there is no difference in the yield of the final product when the electron donating group is introduced at different positions, and the position selectivity with respect to the auro derivative and the flavone derivative.

Next, the reactivity when the halogen element was substituted in the reactants was examined. When the electron withdrawing bromine was introduced at position 5, ( Z ) -5-bromorone was produced at a high yield of 97% in 30 minutes. NMR yields of the O and E fractions were 97% : 3%. When chlorine, a more powerful electron attracting moiety, was introduced at the same position, the Oron derivative [( Z ) -5-chloroion] and the flavone derivative were obtained at a yield of 95%: 5 %, And the separation yield of the oron derivative was 94% (No. 5-6). Thus, when a halogen element, which is an electron withdrawing group, is introduced into the reactant, the generation of the oron derivative progresses with high reactivity in a short time.

Next, the volume of the 5-carbon of the reactants in a large bulky (bulky) a tertiary butyl (t -butyl) group ohron derivative to determine the reactivity when the substituted result, the isolated yield of 95% in only 30 minutes reaction time ( Z ) -5- t -butylolone was produced, and the NMR yields of the oron and flavone derivatives were 96%: 2% (No. 7). As a result, it can be seen that even when a bulky alkyl group is introduced into the reactant, the generation of the auron derivative is produced with high selectivity.

To evaluate the reactivity of ohron generated when the R ² position in non-aromatic rings therein alkyne (internal alkyne) in the Scheme 11 is cyclo-hexyl (cyclohexyl) group and n-butyl group, such as (n -butyl) group and substituted. As a result, it was found that when the cyclohexyl group was introduced into the internal alkene, the pentagonal ring forming compound (Oron analog) [( Z ) -2- (cyclohexylmethylene) benzofuran-3 ( 2H ) The formation compound (flavone analog) [2-cyclohexyl- 4H -chromen-4-one] was produced in a yield of 64% and 31%, respectively. When the aromatic ring was substituted for the internal alkene, the selectivity of the position was decreased and the reaction time was 2 hours and 30 minutes (Reference 8).

Next, as a result of reacting with a reactant having a butyl group introduced into the R ² position of the internal alkane, no oval analog form of the pentagonal ring form was produced at all, and a flavone analogue (2-butyl- 4H- Chromene-4-one) was produced with a yield of 55% (No. 9). Thus, it can be seen that when a linear alkyl group is substituted at the R ² position of the internal alkane, only a flavone analogue in hexagonal ring form is produced.

Claims (7)

A process for producing a compound of the formula (1) or a salt thereof, which comprises the step of reacting a compound of the formula (2) in the presence of acetic acid silver or silver silver oxide and a dimethylformamide solvent:
&Lt; Formula 1 >

(2)

Wherein R ¹ is a substituent selected from the group consisting of hydrogen, C ₁ to C ₆ alkyl, C ₁ to C ₆ alkoxy and halogen. The process according to claim 1, wherein R ¹ is a substituent selected from the group consisting of hydrogen, C ₁ to C ₄ alkyl, C ₁ to C ₄ alkoxy and halogen. The process according to claim 1, wherein R ¹ is a substituent selected from the group consisting of hydrogen, methyl, butyl, methoxy, chlorine and bromine. The method according to claim 1, wherein the compound of formula (1) is any one selected from the group consisting of the following compounds:
1) ( Z ) -Orone
2) Synthesis of ( Z ) -5-methylolone
3) Synthesis of ( Z ) -7-methoxhorone
4) Synthesis of ( Z ) -5-methoxhorone
5) ( Z ) -5-Bromorone
6) ( Z ) -5-chlororone
7) ( Z ) -5- t -Butylon. delete The process according to claim 1, wherein the silver catalyst is used in an amount of more than 0 to 10 mol% based on the compound of formula (2). The process according to claim 1, wherein the reaction of the compound of formula (2) is carried out at a temperature of 50 ° C or lower.