KR101199178B1 - Method for the preparation of chiral beta-fluoroalkylated carbonyl compounds using chiral catalyst - Google Patents

Abstract

A method of preparing a beta-fluoroalkylated carbonyl compound is disclosed by reacting an alpha, beta-unsaturated ketone compound with 1-fluorobis (phenylsulfonyl) methane in the presence of a chiral catalyst. In the above production method, an optically active material having high optical purity can be efficiently produced using a chiral catalyst.

Chiral catalyst, 1-fluorobis (phenylsulfonyl) methane, alpha, beta-unsaturated ketones, optically active, beta-fluoroalkylated carbonyl compounds

Description

Method for preparing chiral beta-fluoroalkylated carbonyl compound using a chiral catalyst {METHOD FOR THE PREPARATION OF CHIRAL BETA-FLUOROALKYLATED CARBONYL COMPOUNDS USING CHIRAL CATALYST}

The present invention relates to a method for preparing a beta-fluoroalkylated carbonyl compound using a chiral catalyst.

Optical isomers have almost the same physical properties such as density, melting point, and boiling point. However, since the degree of absorption of polarized light is different, the polarization plane rotates when the linearly polarized light is irradiated. This phenomenon is called optical activity.

The optical activity of the material is measured using a polarimeter. Optical activity occurs in molecules that do not have symmetrical elements such as symmetry centers, symmetry planes, or rotational axes. These molecules can exist as two isomers with enantiomers that change left and right and do not overlap each other, such as the left or right hand, and a molecule having this property is called a chiral compound.

Chiral compounds are commonly found in carbon compounds with all four asymmetric (chiral center) carbons linked to carbon, or transition metal complexes with bidentate ligands.

It is an object of one embodiment of the present invention to provide a method for preparing a chiral beta-fluoroalkylated carbonyl compound.

The production process according to the invention is characterized in that an alpha, beta-unsaturated ketone compound is reacted with 1-fluorobis (phenylsulfonyl) methane in the presence of a chiral catalyst to produce a beta-fluoroalkylated carbonyl compound. It is done.

The method for producing a beta-fluoroalkylated carbonyl compound according to the present invention can efficiently produce an optically active material having high optical purity using a chiral catalyst.

In the method for producing a beta-fluoroalkylated carbonyl compound according to an embodiment of the present invention, the alpha, beta-unsaturated ketone compound is substituted with 1-fluorobis (phenylsulfonyl) in the presence of a chiral catalyst. Reaction with methane produces beta-fluoro alkylated carbonyl compounds. The above production method is for efficiently producing an optically active substance with high optical purity using a chiral catalyst.

In one embodiment of the present invention, the chiral catalyst may be a chiral bifunctional organic catalyst to which chiral primary amines and tertiary amine groups are combined. Asymmetric alkylation using chiral bifunctional organic catalysts in which chiral primary amines and tertiary amine groups are combined is a very simple and useful reaction that can yield optically pure chiral beta-fluoroalkylated carbonyl compounds in high yield.

In one embodiment of the present invention, the content of the chiral catalyst is 5 to 20 mol%, specifically 7 to 15 mol%, more specifically 9 to 12 mol%, based on the total moles of the reactants. The above range is for efficiently producing beta-fluoroalkylated carbonyl compounds having high optical purity. When the content of the chiral catalyst is lower than the above range, the optical purity of the synthesized beta-fluoroalkylated carbonyl compound is lowered, and when higher than the above range, the efficiency due to the addition of the catalyst may be lowered.

In one embodiment, the chiral catalyst, has a structure of formula (1).

In Chemical Formula 1 or Chemical Formula 2,

R is hydrogen, hydroxyl or alkoxy of C ₁ to C ₆ , preferably hydrogen, hydroxyl or methoxy.

Preferred specific examples of the catalyst, 9-amino-9-deoxyepiquinine, 9-amino-9-deoxyepiquinidine, 9 -Amino-9-deoxyepicinchonine (9-amino-9-deoxyepicinchonine) or 9-amino-9-deoxyepicinchonidine (9-amino-9-deoxyepicinchonidine) and the like can be used, more preferably 9-amino-9-deoxyepiquinine may be used.

In one embodiment of the present invention, the reaction of the alpha, beta-unsaturated ketone compound with 1-fluorobis (phenylsulfonyl) methane may occur in the presence of an acid additive or a base additive.

The acid additive may be benzoic acid, formic acid or paranitrobenzoic acid, and the base additive may be sodium acetate, sodium benzoate or Lithium acetate.

In one embodiment of the present invention, the alpha, beta-unsaturated ketone compound has the structure of Formula 3 below.

In Formula 3,

R ¹ and R ² are selected from the group consisting of: i) C ₁ -C ₄₀ alkyl group, ii) C ₁ -C ₄₀ alkylene group, and iii) C ₁ -C ₆ alkyl group, halogen or C ₁ -C ₆ alkoxy. Substituted or unsubstituted, it is selected from the group consisting of C ₁ ~ C ₄₀ aryl group, preferably iii) C ₁ ~ C ₂₀ Alkyl group, ii) C ₁ ~ C ₂₀ Alkylene group, and iii) C ₁ ~ alkyl group of C _6, halogen or C ₁ ~ C is substituted by alkoxy of _six or unsubstituted, is selected from the group consisting of an aryl group of C ₁ ~ C _20, more preferably ⅰ) C alkyl group of ₁ ~ C _10, Ii) a C ₁ to C ₁₀ alkylene group, and iii) a C ₁ to C ₃ alkyl group, a C ₁ to C ₁₀ aryl group which is unsubstituted or substituted by halogen or C ₁ to C ₃ alkoxy. And even more preferably iii) C ₁ -C ₃ alkyl group, ii) C ₁ -C ₃ alkylene group, and iii) C ₁ -C ₃ alkyl group, halogen or C ₁ -C ₃ alkoxy. Phenyl or naph, unsubstituted or substituted by It is selected from the group consisting of a group. In addition, R ¹ and R ² are the same as or different from each other, R ¹ and R ² May be connected to each other to form part of a ring system.

In one embodiment of the present invention, the 1-fluorobis (phenylsulfonyl) methane is a compound having a structure of formula (4).

In one embodiment of the present invention, the beta-fluoroalkylated carbonyl compound may be a compound having a structure of Formula 5 or Formula 6.

R ¹ and R ² are selected from the group consisting of: i) C ₁ -C ₄₀ alkyl group, ii) C ₁ -C ₄₀ alkylene group, and iii) C ₁ -C ₆ alkyl group, halogen or C ₁ -C ₆ alkoxy. Substituted or unsubstituted, it is selected from the group consisting of C ₁ ~ C ₄₀ aryl group, preferably iii) C ₁ ~ C ₂₀ Alkyl group, ii) C ₁ ~ C ₂₀ Alkylene group, and iii) C ₁ ~ alkyl group of C _6, halogen or C ₁ ~ C is substituted by alkoxy of _six or unsubstituted, is selected from the group consisting of an aryl group of C ₁ ~ C _20, more preferably ⅰ) C alkyl group of ₁ ~ C _10, Ii) a C ₁ to C ₁₀ alkylene group, and iii) a C ₁ to C ₃ alkyl group, a C ₁ to C ₁₀ aryl group which is unsubstituted or substituted by halogen or C ₁ to C ₃ alkoxy. And even more preferably iii) C ₁ -C ₃ alkyl group, ii) C ₁ -C ₃ alkylene group, and iii) C ₁ -C ₃ alkyl group, halogen or C ₁ -C ₃ alkoxy. Phenyl or naph, unsubstituted or substituted by It is selected from the group consisting of a group. In addition, R ¹ and R ² are the same as or different from each other, R ¹ and R ² May be connected to each other to form part of a ring system.

The beta-fluoroalkylated carbonyl compound according to one embodiment of the present invention is 5-fluoro-4- ( p -methylphenyl) -5,5-bis (phenylsulfonyl) pentan-2-one, 5-fluoro Rho-4- ( p -methoxyphenyl) -5,5-bis (phenylsulfonyl) pentan-2-one, 5-fluoro-4- ( p -fluorophenyl) -5,5-bis (phenyl Sulfonyl) pentan-2-one, 5-fluoro-4- (1-naphthyl) -5,5-bis (phenylsulfonyl) pentan-2-one, 6-fluoro-5-phenyl-6, 6-bis (phenylsulfonyl) hexan-3-one, 6-fluoro-5-methyl-6,6-bis (phenylsulfon) hexan-3-one, 3- [fluoro (bisphenylsulfonyl) methyl ] Cyclohexanone, 3- [fluoro (bisphenylsulfonyl) methyl] cyclopentanone, and 5-fluoro-4-phenyl-pentan-2-one.

Hereinafter, a method of preparing a beta-fluoroalkylated carbonyl compound according to an embodiment of the present invention will be described in more detail.

In one embodiment, the alpha, beta-unsaturated ketone compound (Formula 3) is reacted with 1-fluorobis (phenylsulfonyl) methane (Formula 4) in the presence of a chiral catalyst to form a beta-fluoroalkylated carbonyl compound (Formula 4) 5) can be prepared. Specific reaction formula is the same as that of Scheme 1 below.

In Scheme 1, R ¹ to R ² is as defined above.

Formula 5 may be synthesized through the desulfonation reaction to the compound of Formula 6.

In Scheme 2, R ¹ to R ² is as defined above.

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples and the like are intended to illustrate the present invention, but the scope of the present invention is not limited thereto.

Comparative Example 1 5-Fluoro-4-phenyl-5,5-bis (phenylsulfonyl) pentan-2-one:

10 mol% of the chiral cationic catalyst was added to the flask, and 0.1 mL of dichloromethane (CH ₂ Cl ₂ ) and methanol (MeOH) were added at a ratio of 9: 1, followed by stirring at room temperature. Subsequently, 0.0073 g (0.05 mmol) of 4-phenyl-3-buten-2-one and 0.0314 g (0.1 mmol) of 1-fluorobis (phenylsulfonyl) methane (Formula 4) were added sequentially, followed by 5 days at room temperature. Stirred. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to purify the solvent, and then purified by column chromatography (SiO ₂ , EA: Hex = 1: 5) to give 5-fluoro-4-phenyl-5,5-bis (phenylsulfonyl). Pentan-2-one was obtained in 82% yield, 9% ee. Where ee means enantiomeric excess.

Comparative Example 2 5-Fluoro-4-phenyl-5,5-bis (phenylsulfonyl) pentan-2-one:

10 mol% of the chiral cationic catalyst was added to the flask, and 0.1 mL of dichloromethane (CH ₂ Cl ₂ ) and methanol (MeOH) were added at a ratio of 9: 1, followed by stirring at room temperature. Subsequently, 0.0073 g (0.05 mmol) of 4-phenyl-3-buten-2-one and 0.0314 g (0.1 mmol) of 1-fluorobis (phenylsulfonyl) methane (Formula 4) were added sequentially, followed by 5 days at room temperature. Stirred. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to purify the solvent, and then purified by column chromatography (SiO ₂ , EA: Hex = 1: 5) to give 5-fluoro-4-phenyl-5,5-bis (phenylsulfonyl). Pentan-2-one was obtained in 79% yield, 5% ee.

Example 1 5-Fluoro-4-phenyl-5,5-bis (phenylsulfonyl) pentan-2-one:

10 mol% of the chiral cationic catalyst (Formula 1, R = OMe) was added to the flask, and 0.1 mL of MTBE was added thereto, followed by stirring at room temperature. Subsequently, 0.0073 g (0.05 mmol) of 4-phenyl-3-buten-2-one and 0.0314 g (0.1 mmol) of 1-fluorobis (phenylsulfonyl) methane (Formula 4) were added sequentially, followed by 5 days at room temperature. Stirred. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to purify the solvent, and then purified by column chromatography (SiO ₂ , EA: Hex = 1: 5) to give 5-fluoro-4-phenyl-5,5-bis (phenylsulfonyl). Pentan-2-one was obtained in 87% yield, 91% ee.

[a] ²⁵ _D = -130.66 (c = 0.25, CHCl ₃ ); ¹ H NMR (200 MHz, CDCl ₃ ) δ = 2.20 (s, 3H), 3.88 to 3.93 (m, 2H), 4.52 to 4.60 (m, 1H), 7.00 to 7.05 (m, 2H), 7.14 to 7.18 ( m, 3H), 7.42-7.50 (m, 2H), 7.57-7.69 (m, 3H), 7.75-7.82 (m, 3H), 7.88-7.73 (m, 2H); ¹³ C NMR (50 MHz, CDCl ₃ ) δ = 30.4, 42.1, 43.0 (d, J = 19.3), 115.0 (d, J = 264.5), 127.9, 128.0, 128.4, 129.2, 130.5, 131.1, 131.3, 133.6 ( d, J = 4.6), 134.0, 134.9, 135.4, 136.3, 208.0; Chiralpak AS, n-Hexane / i-PrOH = 90:10, flow rate 1.0 mL / min, λ = 254 nm, t _R = 21.6 min (minor), t _R = 24.1 min (major), 91% ee.

[Examples 2 to 8]

In the same manner as in Example 1, 5-fluoro-4-phenyl-5,5-bis (phenylsulfonyl) pentan-2-one was synthesized. Specific reaction conditions and yields are shown in Table 1 below.

In Table 1, rt is room temperature, DMSO is dimethylsulfoxide, DMF is dimethylformamide, DCM is dichloromethane, and MTBE is methyl tert-butyl ether. tert-butyl ether).

[Examples 9 to 12]

Different catalysts were used to synthesize 5-fluoro-4-phenyl-5,5-bis (phenylsulfonyl) pentan-2-one in the same manner as in Example 1.

In Table 2, rt is room temperature, DCM is dichloromethane, OH is hydroxyl, H is hydrogen, and OMe is methoxy.

[Examples 13 to 18]

Another acid or base was added as an additive, and 5-fluoro-4-phenyl-5,5-bis (phenylsulfonyl) pentan-2-one was synthesized in the same manner as in Example 1. Specific reaction conditions and yields are shown in Table 3 below.

Example 19 5-Fluoro-4- ( p -methylphenyl) -5,5-bis (phenylsulfonyl) pentan-2-one:

In the same manner as in Example 1, 5-fluoro-4- ( p -methylphenyl) -5,5-bis (phenylsulfonyl) pentan-2-one was obtained in 90% yield and 90% ee.

[α] ²⁵ _D = -130.1 (c = 0.22, CHC1 ₃ ); ¹ H NMR (200 MHz, CDCl ₃ ) δ = 2.19 (s, 3H), 2.25 (s, 3H), 3.86 to 3.89 (m, 2H), 4.47 to 4.52 (m, 1H), 6.88 to 6.99 (m, 4H), 7.41-7.49 (m. 2H), 7.55-7.69 (m, 3H), 7.73-7.90 (m, 5H); ¹³ C NMR (50 MHz) δ = 20.9, 30.3, 42.2, 42.7 (d, J = 19.0 Hz), 128.4, 128.7,129.1,130.2, 131.0, 131.2, 134.8, 135.3, 192.0 Chiralpak AD-H, n-Hexane / i-PrOH = 90:10, flow rate 1.0 mL / min, λ = 254 nm, t _R = 17.7 min (major), t _R = 21.6 min (minor), 90% ee.

Example 20 5-Fluoro-4- ( p -methoxyphenyl) -5,5-bis (phenylsulfonyl) pentan-2-one:

In the same manner as in Example 1, 5-fluoro-4- ( p -methoxyphenyl) -5,5-bis (phenylsulfonyl) pentan-2-one was obtained in 92% yield and 93% ee.

[a] ²⁵ _D = -150.2 (c = 0.22, CHC1 ₃ ); ¹ H NMR (200 MHz, CDCl ₃ ) δ = 2.19 (s, 3H), 3.73 (s, 3H), 3.85 (d, J = 6.4 Hz), 4.45 to 4.53 (m, 1H), 6.66 to 6.70 (m , 2H), 6.93-6.97 (m, 2H), 7.42-7.49 (m, 2H), 7.56-77.6 (m, 3H), 7.73-7.82 (m, 3H), 7.87-7.90 (m, 2H); ¹³ C NMR (50 MHz, CDCl ₃ ) δ = 30.2, 42.3 (d, J = 19.2 Hz), 54.9, 113.2, 114.9 (d, J = 264.3 Hz), 125.2, 125.3, 128.3, 130.0, 130.9, 131.1, 131.4, 134..0, 134.7, 135.2, 136.2, 159.0, 203.9; Chiralpak AD-H, n-Hexane / i-PrOH = 90:10, flow rate 1.0 mL / min, λ = 254 nm, t _R = 29.1 (major), min, t _R = 32.7 min (minor), 93% ee .

Example 21 5-Fluoro-4- ( p -fluorophenyl) -5,5-bis (phenylsulfonyl) pentan-2-one:

In the same manner as in Example 1, 5-fluoro-4- ( p -fluorophenyl) -5,5-bis (phenylsulfonyl) pentan-2-one was obtained in 90% yield and 86% ee.

[a] ²⁵ _D = -104.6 (c = 0.21, CHC1 ₃ ); ¹ H NMR (200 MHz, CDCl ₃ ) δ = 2.20 (s, 3H). 3.86-3.89 (m, 2H), 4.45-5.59 (m, 1H), 6.80-6.89 (m, 2H), 6.97-7.04 (m, 2H), 7.44-7.51 (m, 2H), 7.44-7.51 (m , 2H), 7.57-7.71 (m, 3H), 7.75-7.90 (m, 5H); ¹³ C NMR (50 MHz, CDCl ₃ ) δ = 30.3, 42.2 (d, J = 6.2 Hz), 42.4 (d, J = 11.0 Hz), 114.7 (d, J = 265.3 Hz), 114.9 (d, J = 21.8 Hz), 128.5, 129.2, 129.3 (t, J = 3.9 Hz), 131.0, 131.2, 132.1 (d, J = 8.4 Hz), 133.9, 135.0, 135.5, 136.1, 162.3 (d, J = 264.2 Hz), 203.8; Chiralcel OD-H, n-Hexane / i-PrOH = 90:10, flow rate 1.0 mL / min, λ = 254 nm, t _R = 13.0 min (minor), t _R = 14.4 min (major), 81% ee.

Example 22 5-Fluoro-4- (1-naphthyl) -5,5-bis (phenylsulfonyl) pentan-2-one:

In the same manner as in Example 1, 5-fluoro-4- (1-naphthyl) -5,5-bis (phenylsulfonyl) pentan-2-one was obtained in 75% yield and 86% ee.

[a] ²⁵ _D = -210.2 (c = 0.44, CHC1 ₃ ); ¹ H NMR (200 MHz, CDCl ₃ ) δ = 2.18 (s, 3H), 4.06-4.17 (m, 2H), 5.40-5.47 (m, 1H), 6.71-6.75 (m, 1H), 6.93-7.01 ( m, 1H), 7.30-7.46 (m, 4H), 7.55-7.77 (m, 8H), 7.95-7.98 (m, 3H) ¹³ C NMR (50 MHz, CDCl ₃ ) δ = 30.3, 37.2 (d, J = 19.6 Hz), 43.2, 116.6 (d, J = 260 Hz), 122.8, 124.9, 125.1, 126.1, 128.3, 128.4, 128.6, 129.1, 129.5, 129.6, 130.2, 131.0, 131.7, 133.5, 134.0, 134.7, 134.8 , 135.5, 135.6, 136.5, 204.0; Chiralpak AD-H, n-Hexane / EtOH = 90:10, flow rate 1.0 mL / min, λ = 254 nm, t _R = 22.2 min (major), t _R = 34.1 min (minor), 86% ee.

Example 23 6-Fluoro-5-phenyl-6,6-bis (phenylsulfonyl) hexan-3-one:

In the same manner as in Example 1, 6-fluoro-5-phenyl-6,6-bis (phenylsulfonyl) hexan-3-one was obtained in 82% yield and 75% ee.

[a] ²⁵ _D = -153.16 (c = 0.24, CHC1 ₃ ); ¹ H NMR (200 MHz, CDCl ₃ ) δ = 1.00 (t, 3H), 2.26 to 2.66 (m, 2H), 3.85 to 3.89 (m, 2H), 4.54-4.62 (m, 1H), 6.99 to 7.01 ( m, 2H), 7.12-7.14 (m, 3H), 7.41-7.45 (m, 2H), 7.56-77.6 (m, 3H), 7.73-7.82 (m, 3H), 7.92-8.10 (m, 2H); ¹³ C NMR (50 MHz, CDCl ₃ ) δ = 7.76, 32.9 (d, J = 18.2), 36.4, 43.1 (d, J = 4.9), 116.3 (d, J = 264.7), 128.8, 129.0, 131.0, 135.0 , 135.1, 135.2, 136.0, 208.0; Chiralpak AD-H, n-Hexane / EtOH = 90:10, flow rate 1.0 mL / min, λ = 254 nm, t _R = 15.1 min (major), t _minor = 17.9 min (minor), 75% ee.

Example 24 6-Fluoro-5-methyl-6,6-bis (phenylsulfon) hexan-3-one:

In the same manner as in Example 1, 6-fluoro-5-methyl-6,6-bis (phenylsulfonyl) hexan-3-one was obtained in 85% yield and 80% ee.

[α] ²⁰ _D = -88.5 (c = 0.04, CHC1 ₃ ); ¹ H NMR (200 MHz, CDCl ₃ ) δ = 1.04-1.11 (m, 3H), 1.27-1.31 (m, 3H), 2.35-2.60 (m, 2H), 2.90-3.04 (m, 1H), 3.15- 3.26 (m, 2H), 3.43-3.53 (m, 1H), 7.50-7.60 (m, 4H), 7.65-7.77 (m, 2H), 7.93-7.96 (m, 2H) ¹³ C NMR (50 MHz) δ = 7.8, 14.7, 32.9 (d, J = 18.0 Hz), 36.4, 43.0, 113.6 (d, J = 350 Hz). 1128., 129.0, 129.5, 130.2, 131.0, 135.1, 135.7, 136.0, 205.4; Chiralpak AD-H, n-Hexane / i-PrOH = 90:10, flow rate 1.0 mL / min, λ = 254 nm, t _R = 14.5 min (major), t _R = 18.8 min (minor), 80% ee.

Example 25 3- [fluoro (bisphenylsulfonyl) methyl] cyclohexanone:

In the same manner as in Example 1, 3- [fluoro (bisphenylsulfonyl) methyl] cyclohexanone was obtained in 93% yield and 89% ee.

[a] ²⁰ _D = -98.3 (c = 0.03, CHCl ₃ ); ¹ H NMR (200 MHz, CDCl ₃ ) δ = 1.41-1.57 (m, 1H), 2.16-2.26 (m, 1H), 2.33-2.48 (m, 3H), 2.53-2.75 (m, 3H), 2.99- 3.12 (m, 1H) ¹³ C NMR (50 MHz, CDCl ₃ ) δ = 20.5, 25.2, 41.2, 41.5 (d, J = 6.7 Hz), 111.0 (d, J = 145 Hz), 128.9, 129.1, 130.7, 130.9, 135.2, 135.3, 209.3 Chiralcel OD-H, n-Hexane / i-PrOH = 90:10, flow rate 1.0mL / min, λ = 254nm, t _R = 27.9 min (major), t _R = 31.0 min ( minor), 89% ee.

Example 26 3- [fluoro (bisphenylsulfonyl) methyl] cyclopentanone:

In the same manner as in Example 1, 3- [fluoro (bisphenylsulfonyl) methyl] cyclopentanone was obtained in 87% yield and 86% ee.

[a] ²⁰ _D = -27.00 (c = 0.08, CHC1 ₃ ); ¹ H NMR (200 MHz, CDCl ₃ ) δ = 2.03-2.26 (m 2H), 2.45-2.72 (m, 3H), 2.88-3.03 (m, 1H), 3.12-3.27 (m, 1H), 7.73-7.45 (m, 4H), 7.66-7.82 (m, 6H); ¹³ C NMR (50 MHz, CDCl ₃ ) δ = 23.8 (d, J = 4.6), 37.5, 39.4 (d, J = 3.1), 39.7 (d, J = 10.9), 116.4 (d, J = 265.7), 129.0, 129.1, 130.7, 135.30, 215.2; Chiralcel OD-H, n-Hexane / i-PrOH = 90:10, flow rate 1.0 mL / min, λ = 254 nm, t _R = 10.4 min (major), t _R = 12.5 min (minor), 86% ee.

Example 27 5-Fluoro-4-phenyl-pentan-2-one:

In one embodiment, 5-fluoro-4-phenyl-5,5-bis (phenylsulfonyl) pentan-2-one is desulfonated to yield 5-fluoro-4-phenyl-pentan-2-one. It can manufacture. The specific reaction formula is the same as the following scheme 3.

The product having an enantiomeric excess of 91% was reduced using NaBH ₄ and then the sulfone substrate was removed in 99% yield using Mg and I ₂ activated. The carbonyls were then oxidized using PCC to restore the beta fluoroalkylated ketone product in 90% yield. The reaction proceeded in three stages, yielding 5-fluoro-4-phenyl-pentan-2-one at 91% with constant enantiomeric excess.

[a] ²⁰ _D = -25.60 (c = 0.04, CHC1 ₃ ); ¹ H NMR (200 MHz, CDCl ₃ ) δ = 2.12 (s 3H), 2.76 to 3.07 (m, 2H), 3.45 to 3.68 (m, 1H), 4.33 to 4.50 (m, 1H), 4.56 to 4.71 (m , 1H), 7.22-7.36 (m, 5H); ¹³ C NMR (50 MHz, CDCl ₃ ) δ = 30.4, 41.3 (d, J = 18.7), 45.1 (d, J = 4.1), 86.1 (d, J = 3.4), 127.2, 127.8, 128.7, 130.8, 206.5 ; Astec Chiraldex ^™ G-TA (50 ^o C), t _R = 59.5 min (major), t _R = 66.1 min (minor), 91% ee.

Claims (11)

A method for preparing a beta-fluoroalkylated carbonyl compound using a chiral catalyst comprising reacting an alpha, beta-unsaturated ketone compound with 1-fluorobis (phenylsulfonyl) methane in the presence of a chiral catalyst, The chiral catalyst is a chiral bifunctional organic catalyst to which a chiral primary amine and a tertiary amine group are bonded, and have a structure of the following Chemical Formula 1 or Formula 2, ≪ Formula 1 >

<Formula 2>

(In Formula 1 or Formula 2, R is hydrogen, hydroxyl or alkoxy of C ₁ to C ₆ . The alpha, beta-unsaturated ketone compound has a structure of Formula 3, Method for producing a beta-fluoroalkylated carbonyl compound using a chiral catalyst, characterized in that the beta-fluoroalkylated carbonyl compound has a structure of Formula 5 <Formula 3>

&Lt; Formula 5 >

(In Formula 3 or Formula 5, R ¹ and R ² are selected from (i) C ₁ -C ₄₀ alkyl group, ii) C ₂ -C ₄₀ alkylene group, and (iii) C ₁ -C ₆ alkyl group, halogen or C ₁ -C ₆ alkoxy. Selected from the group consisting of a substituted or unsubstituted C ₆ -C ₄₀ aryl group, the same or different from each other, and R ¹ and R ² may be connected to each other to form part of a ring system.) delete The method of claim 1, The content of the chiral catalyst is 5 to 20 mol% based on the total number of moles of the reaction materials, the method for producing a beta-fluoroalkylated carbonyl compound using a chiral catalyst. delete The method according to claim 1 or 3, The chiral catalyst is 9-amino-9-deoxyepiquinine, 9-amino-9-deoxyepiquinidine, 9-amino-9 Beta-fluoro using a chiral catalyst characterized in that it is 9-amino-9-deoxyepicinchonine or 9-amino-9-deoxyepicinchonidine Process for the preparation of alkylated carbonyl compounds. The method of claim 1, The reaction is a method for producing a beta-fluoroalkylated carbonyl compound using a chiral catalyst, characterized in that in the presence of an acid additive or a base additive. The method of claim 6, The acid is benzoic acid, formic acid or paranitrobenzoic acid, and the base is sodium acetate, sodium benzoate or lithium acetate. A method for producing a beta-fluoroalkylated carbonyl compound using a chiral catalyst, characterized in that). delete delete Beta-fluoroalkylation using a chiral catalyst comprising desulfonating a beta-fluoroalkylated carbonyl compound prepared by claim 1 to produce a beta-fluoroalkylated carbonyl compound having the structure Process for preparing carbonyl compound: (6)

(In Chemical Formula 6, R ¹ and R ² are selected from (i) C ₁ -C ₄₀ alkyl group, ii) C ₂ -C ₄₀ alkylene group, and (iii) C ₁ -C ₆ alkyl group, halogen or C ₁ -C ₆ alkoxy. Selected from the group consisting of a substituted or unsubstituted C ₆ -C ₄₀ aryl group, the same or different from each other, and R ¹ and R ² may be connected to each other to form part of a ring system.) The method of claim 1, The beta-fluoroalkylated carbonyl compound is 5-fluoro-4- ( p -methylphenyl) -5,5-bis (phenylsulfonyl) pentan-2-one, 5-fluoro-4- ( p -meth Methoxyphenyl) -5,5-bis (phenylsulfonyl) pentan-2-one, 5-fluoro-4- ( p -fluorophenyl) -5,5-bis (phenylsulfonyl) pentan-2-one , 5-fluoro-4- (1-naphthyl) -5,5-bis (phenylsulfonyl) pentan-2-one, 6-fluoro-5-phenyl-6,6-bis (phenylsulfonyl) Hexane-3-one, 6-fluoro-5-methyl-6,6-bis (phenylsulfon) hexan-3-one, 3- [fluoro (bisphenylsulfonyl) methyl] cyclohexanone and 3- [ A method for producing a beta-fluoroalkylated carbonyl compound using a chiral catalyst, characterized in that it is selected from the group consisting of fluoro (bisphenylsulfonyl) methyl] cyclopentanone.