阅读说明：本技术 一种2-氟代苯乙腈衍生物及其制备方法与应用 (2-fluorobenzonitrile derivative and preparation method and application thereof ) 是由 李亚 陈德银 于 2020-12-16 设计创作，主要内容包括：本发明涉及一种2-氟代苯乙腈衍生物及其制备方法与应用。在水或有机溶剂中,2-氟代苯乙腈、α,β-不饱和化合物以及有机碱在-20℃～60℃温度下,反应0.5～12小时,得到2-氟代苯乙腈衍生物。本发明使用的原料经济易得,制备的工艺条件温和,方法高效,普适性强。本发明制备得到的2-氟代苯乙腈衍生物,为一种潜在的活性分子合成砌块,能够进行丰富的化学转化,有望在含氟精细化学品以及含氟生物活性分子研发领域得到应用。(The invention relates to a 2-fluorobenzonitrile derivative and a preparation method and application thereof. In water or an organic solvent, reacting 2-fluorobenzonitrile, an alpha, beta-unsaturated compound and an organic base for 0.5 to 12 hours at the temperature of between 20 ℃ below zero and 60 ℃ to obtain the 2-fluorobenzonitrile derivative. The raw materials used in the invention are economical and easily available, the preparation process conditions are mild, the method is efficient, and the universality is strong. The 2-fluorobenzonitrile derivative prepared by the invention is a potential active molecule synthesis block, can carry out abundant chemical transformation, and is expected to be applied in the research and development fields of fluorine-containing fine chemicals and fluorine-containing bioactive molecules.)

1. A method for preparing 2-fluorobenzonitrile derivatives is characterized in that 2-fluorobenzonitrile and alpha, beta-unsaturated compounds are subjected to addition reaction in a reaction solvent under the action of alkali to obtain the 2-fluorobenzonitrile derivatives.

2. The method of claim 1, wherein the 2-fluorobenzonitrile derivative has the following formula:

wherein: r is hydrogen, C_1-8Alkoxy, halogen, nitrile or nitro.

3. The method of claim 1, wherein the α, β -unsaturated compounds include α, β -unsaturated nitriles, α, β -unsaturated ketones, α, β -unsaturated esters and α, β -unsaturated sulfones;

the alpha, beta-unsaturated nitrile has the following structural formula:

wherein: r is hydrogen or C_1-4Alkyl groups of (a); the alpha, beta-unsaturated ketone has the following structural formula:

wherein: r is hydrogen, halogen, alkoxy or nitro; r¹Is hydrogen, phenyl or substituted phenyl;

the substituted phenyl is nitro-substituted phenyl or C_1-4Alkyl of (2)A substituted phenyl group;

the alpha, beta-unsaturated ester has the following structural formula:

wherein: r is phenyl, C_1-10Alkyl of (C)_1-10An alkyl substituent containing an ether bond structure;

the alpha, beta-unsaturated sulfone has the following structural formula:

wherein: r is C_1-4Alkyl group of (1).

4. The method of claim 1, wherein the base is one or more selected from the group consisting of sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, triethylamine, diisopropylethylamine, 1, 8-diazabicycloundecen-7-ene, 1,5, 7-triazabicyclo [4.4.0] dec-5-ene, 1,3, 3-tetramethylguanidine, and 2-tert-butyl-1, 1,3, 3-tetramethylguanidine.

5. The method of claim 1, wherein the molar ratio of the 2-fluorobenzonitrile to the α, β -unsaturated compound to the base is 1: (0.8-3) and (0.05-1).

6. The method for preparing 2-fluorobenzonitrile derivative according to claim 1, wherein the reaction solvent is one or more selected from water, diethyl ether, tetrahydrofuran, toluene, dichloromethane, N-dimethylformamide, acetonitrile and dimethylsulfoxide.

7. The method for preparing 2-fluorobenzonitrile derivatives according to claim 1, wherein the reaction conditions are as follows: reacting for 0.5-12 hours at the temperature of minus 20-60 ℃.

8. A2-fluorophenylacetonitrile derivative according to any one of claims 1 to 7, characterized by the following structural formula:

wherein in the formula (6a), R is hydrogen or C_1-8Alkoxy, halogen, nitrile or nitro of R₁Is hydrogen or C_1-4Alkyl groups of (a);

in the formula (6b), R is hydrogen or C_1-8Alkoxy, halogen, nitrile or nitro of R₂Is hydrogen, halogen, alkoxy or nitro; r₁Is hydrogen, phenyl or substituted phenyl, and the substituted phenyl is: nitro-substituted phenyl, C_1-4Alkyl-substituted phenyl of (a);

in the formula (6C), R is hydrogen or C_1-8Alkoxy, halogen, nitrile or nitro of R¹Is phenyl, C_1-10Alkyl of (C)_1-10An alkyl substituent containing an ether bond structure;

in the formula (6d), R is hydrogen or C_1-8Alkoxy, halogen, nitrile or nitro of R¹Is C_1-4Alkyl group of (1).

9. The 2-fluorobenzonitrile derivative according to claim 8, which is selected from the following structures:

10. use of the 2-fluorobenzonitrile derivatives according to claim 8, wherein the 2-fluorobenzonitrile derivatives are used as building blocks for the synthesis of biologically active molecules, in the preparation of fluorine-containing fine chemicals and fluorine-containing biologically active molecules.

Technical Field

The invention belongs to the technical field of organic matter synthesis, and particularly relates to a 2-fluorobenzonitrile derivative and a preparation method and application thereof.

Background

The introduction of fluorine atoms often increases the lipophilicity of the bioactive molecule, enhances its metabolic stability, and improves its bioavailability. Tetrasubstituted Fluorine-containing chiral Carbon structures are present in many biologically active molecules (Zhu, Y.; Han, J.; Wang, J.; Shibata, N.; Sodeoka, M.; Solosonok, V.A.; Coelho, J.A.S.; Toste, F.D.model applications for asymmetry Construction of Carbon-Fluorine quick chiral Centers: Synthetic channels and Pharmaceutical chemicals.chem.Rev.2018, 118, 3887-3964). Therefore, the development of a method for efficiently synthesizing the tetra-substituted fluorine-containing chiral carbon structure has important significance for drug research and development.

2-Fluorophenylacetonitrile is a convenient and readily available fluorine-containing reagent, and a condensation reaction of 2-fluorophenylacetonitrile with imine has been reported as (a) Ding, R.; De los Santos, Z.A.; Wolf, C.ACS. Cat.2019, 9, 2169-. However, no reports have been made on the method for preparing 2-fluorophenylacetonitrile derivatives containing tetrafluoro fluorine-containing chiral carbon structures by the addition reaction of 2-fluorophenylacetonitrile and active olefin.

Considering the importance of the tetra-substituted fluorine-containing chiral carbon structure and the fact that the 2-fluorophenylacetonitrile derivative can be subjected to diversified transformation, the development of a simple and efficient preparation method has important significance for the development of fluorine-containing bioactive molecules.

Disclosure of Invention

The invention aims to provide a 2-fluorobenzonitrile derivative and a preparation method and application thereof. The raw materials used in the method are easy to prepare, the reaction is easy to operate, the method is efficient, water can be used as a reaction solvent even, the reaction is green, and the purity of the prepared 2-fluorobenzonitrile derivative is high.

The purpose of the invention can be realized by the following technical scheme:

a method for preparing 2-fluorobenzonitrile derivatives is characterized in that 2-fluorobenzonitrile and alpha, beta-unsaturated compounds are subjected to addition reaction in a reaction solvent under the action of alkali to obtain the 2-fluorobenzonitrile derivatives.

Wherein, the 2-fluorobenzonitrile has the following structural formula (formula 1):

wherein: r is C_1-8Alkoxy, halogen, nitrile or nitro.

The alpha, beta-unsaturated compounds include alpha, beta-unsaturated nitriles, alpha, beta-unsaturated ketones, alpha, beta-unsaturated esters, and alpha, beta-unsaturated sulfones.

The alpha, beta-unsaturated nitrile has the following structural formula (formula 2):

wherein: r is hydrogen, or C_1-4Alkyl group of (1).

The alpha, beta-unsaturated ketone has the following structural formula (formula 3):

wherein: r is hydrogen, halogen, alkoxy or nitro; r¹Is hydrogen, phenyl or substituted phenyl; the substituted phenyl is nitro-substituted phenyl C_1-4Alkyl-substituted phenyl of (a).

The alpha, beta-unsaturated ester has the following structural formula:

wherein: r is phenyl, C_1-10Alkyl of (C)_1-10An alkyl substituent containing an ether linkage structure.

The alpha, beta-unsaturated sulfone has the following structural formula:

wherein: r is C_1-4Alkyl group of (1).

The base is selected from sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, triethylamine (NEt)₃) Diisopropylethylamine (iPr)₂NEt), 1, 8-diazabicycloundec-7-ene (DBU), 1,5, 7-triazabicyclo [4.4.0]One or more of deca-5-ene (TBD), 1,3, 3-Tetramethylguanidine (TMG) or 2-tert-butyl-1, 1,3, 3-tetramethylguanidine.

The molar ratio of the 2-fluorobenzonitrile to the alpha, beta-unsaturated compound to the base is 1: (0.8-3) and (0.05-1).

The reaction solvent is one or more selected from water, diethyl ether, tetrahydrofuran, toluene, dichloromethane, N-dimethylformamide, acetonitrile or dimethyl sulfoxide.

The reaction conditions are as follows: reacting for 0.5-12 hours at the temperature of minus 20-60 ℃.

A typical reaction is as follows (formula 6):

the 2-fluorobenzonitrile of the above formula (1) can be prepared by fluorination using the corresponding alcohol (Turkmann.; Shavrin, A.; Ivanov, R.A.; Rabinovich, B.; Volgin, A.; Gelovani, J.G.; Alauddin, M.M.Fluorinated cannabinoid CB2 receivers ligands: Synthesis and in vitro binding characteristics of 2-oxoquinoneine derivatives.Bioorg.Med.chem.2011,19, 5698-.

The activated unsaturated olefins described in the above formulas (2) to (5) are basically commercially available and can be prepared by a well-established method.

The invention also provides a 2-fluorobenzonitrile derivative prepared by the preparation method, which has the following structural formula:

wherein in the formula (6a), R is hydrogen or C_1-8Alkoxy, halogen, nitrile or nitro of R₁Is hydrogen or C_1-4Alkyl groups of (a);

in the formula (6b), R is hydrogen or C_1-8Alkoxy, halogen, nitrile or nitro of R₂Is hydrogen, halogen, alkoxy or nitro; r₁Is hydrogen, phenyl or substituted phenyl, and the substituted phenyl is: nitro-substituted phenyl, C_1-4Alkyl-substituted phenyl of (a);

in the formula (6C), R is hydrogen or C_1-8Alkoxy, halogen, nitrile or nitro of R¹Is phenyl, C_1-10Alkyl of (C)_1-10An alkyl substituent containing an ether bond structure;

in the formula (6d), R is hydrogen or C_1-8Alkoxy, halogen, nitrile or nitro of R¹Is C_1-4Alkyl group of (1).

In some embodiments of the invention, the 2-fluorobenzonitrile derivative is selected from the following structures:

the invention also provides application of the 2-fluorobenzonitrile derivative. The 2-fluorobenzonitrile derivative is used as a bioactive molecule synthesis building block and is applied to preparation of fluorine-containing fine chemicals and fluorine-containing bioactive molecules.

The 2-fluorobenzonitrile and active olefin are used as starting materials, and the 2-fluorobenzonitrile derivative is obtained by the Michael addition reaction. The method is simple and efficient, has high universality, and can use water as a reaction solvent. The 2-fluorobenzonitrile derivative prepared by the invention is a potential bioactive molecule synthesis building block, can carry out abundant chemical transformation, and is expected to be applied in the field of medicine research and development.

Detailed Description

The present invention will be described in detail with reference to specific examples.

In the following examples, the yield of the reaction refers to the isolation yield.

Example 1

2-fluorobenzonitrile (135 mg, 1.0mmol) represented by the formula (1a), an olefin (106 mg, 2mmol) represented by the formula (2a), water (3.0ML) and sodium carbonate (1mmol) were successively charged into a 20ML reaction flask at 27 ℃. The reaction was carried out at this temperature for 2 hours. After completion of the reaction, the reaction mixture was transferred to a separatory funnel and extracted with ethyl acetate (10 ml. times.3). The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Flash column chromatography over ethyl acetate/petroleum ether (1:4) gave product 3aa in 92% yield (173 mg).

Characterization data for compound 3 aa:

a colorless liquid.¹H NMR(500MHz,CDCl₃)δ7.53(s,5H),2.83–2.43(m,4H).¹⁹F NMR(376MHz,CDCl₃)δ-150.71(s).¹³C NMR(126MHz,CDCl₃)δ134.11(d,J＝22.5Hz),130.77(s),129.44(s),124.48(d,J＝6.3Hz),117.29(s),115.98(d,J＝33.9Hz),90.15(d,J＝186.9Hz),37.27(d,J＝25.9Hz),12.51(d,J＝4.3Hz).HRMS(ESI)m/z:calcd for C₁₁H₁₀FN₂ ⁺[M+H]⁺189.0828,found 189.0831.

Example 2

2-Fluorophenylacetonitrile (135 mg, 1.0mmol) represented by the formula (1a), olefin (58 mg, 0.8mmol) represented by the formula (2b), tetrahydrofuran (3.0ML) and triethylamine (NEt) were successively added at 27 ℃₃) (0.05mmol) was added to a 20ML reaction flask. The reaction was carried out at this temperature for 12 hours. After completion of the reaction, the reaction mixture was transferred to a separatory funnel and extracted with ethyl acetate (10 ml. times.3). The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Flash column chromatography over ethyl acetate/petroleum ether (1:4) gave the product 3ab in 72% yield (145 mg).

Characterization data for compound 3 ab:

a colorless liquid.¹H NMR(400MHz,CDCl₃)δ7.51–7.44(m,5H),2.71–2.53(m,2H),2.39(ddd,J＝26.9,16.7,10.1Hz,2H),1.26(dd,J＝21.3,6.8Hz,3H).¹⁹F NMR(376MHz,CDCl₃)δ-150.61(d,J＝13.7Hz),-155.25(d,J＝16.3Hz).¹³C NMR(126MHz,CDCl₃)δ133.16(d,J＝22.8Hz),130.70(d,J＝1.6Hz),129.30(s),124.94(d,J＝6.7Hz),116.77(s),115.69(d,J＝32.9Hz),93.34(d,J＝98.7Hz),40.94(d,J＝25.9Hz),20.20(d,J＝5.1Hz),13.73(d,J＝3.5Hz).HRMS(ESI)m/z:calcd for C₁₂H₁₂FN₂ ⁺[M+H]⁺203.0985,found 203.0981.

Example 3

2-fluorobenzylacetonitrile (165 mg, 1.0mmol) represented by the formula (1b), an olefin (53 mg, 1mmol) represented by the formula (1a), toluene (3.0ML) and sodium hydroxide (1mmol) were successively charged into a 20ML reaction flask at 60 ℃. The reaction was carried out at this temperature for 2 hours. After completion of the reaction, the reaction mixture was transferred to a separatory funnel and extracted with ethyl acetate (10 ml. times.3). The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Flash column chromatography with ethyl acetate/petroleum ether (1:2) gave the product 3ba in 89% yield (184 mg).

Characterization data for Compound 3ba

A colorless liquid.¹H NMR(500MHz,CDCl₃)δ7.43(t,J＝8.2Hz,1H),7.10–7.06(m,1H),7.03(d,J＝6.8Hz,2H),3.87(s,3H),2.69–2.56(m,4H).¹⁹F NMR(471MHz,CDCl₃)δ-150.95(s).¹³C NMR(126MHz,CDCl₃)δ160.28(s),135.47(d,J＝22.4Hz),130.66(s),117.32(s),116.49(d,J＝6.3Hz),116.02(d,J＝1.4Hz),115.99(d,J＝115.8Hz),110.34(d,J＝7.1Hz),89.94(d,J＝187.3Hz),55.54(s),37.22(d,J＝25.8Hz),12.46(d,J＝4.4Hz).HRMS(ESI)m/z:calcd for C₁₂H₁₂FN₂O₂ ⁺[M+H]⁺235.0883,found 235.0889.

Example 4

2-fluorobenzeneacetonitrile of the formula (1c) (213 mg, 1.0mmol), an olefin of the formula (1a) (53 mg, 1mmol), dimethyl sulfoxide (3.0ML), 1, 8-diazabicycloundecen-7-ene (1mmol) were added to a 20ML reaction flask in this order at 0 ℃. The reaction was carried out at this temperature for 3 hours. After completion of the reaction, the reaction mixture was transferred to a separatory funnel and extracted with ethyl acetate (10 ml. times.3). The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Flash column chromatography using ethyl acetate/petroleum ether (1:5) gave product 3ca in 78% yield (207 mg).

Characterization data for Compound 3ca

A colorless liquid.¹H NMR(500MHz,CDCl₃)δ7.66(d,J＝8.4Hz,2H),7.40(d,J＝8.6Hz,2H),2.70–2.51(m,4H).¹⁹F NMR(376MHz,CDCl₃)δ-168.43(s).¹³C NMR(126MHz,CDCl₃)δ133.19(d,J＝22.9Hz),132.71(s),126.19(d,J＝6.3Hz),125.28(d,J＝1.7Hz),117.11(s),115.53(d,J＝33.9Hz),89.74(d,J＝187.7Hz),37.11(d,J＝25.7Hz),12.52(d,J＝4.2Hz).HRMS(ESI)m/z:calcd for C₁₁H₉BrFN₂ ⁺[M+H]⁺266.9933,found 266.9938.

Example 5

2-fluorobenzonitrile (160 mg, 1.0mmol) represented by the formula (1d), an olefin (80 mg, 1.5mmol) represented by the formula (1a), N-dimethylformamide (3.0ML) and diisopropylethylamine (1mmol) were sequentially added to a 20ML reaction flask at 0 ℃. The reaction was carried out at this temperature for 1 hour. After completion of the reaction, the reaction mixture was transferred to a separatory funnel and extracted with ethyl acetate (10 ml. times.3). The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Flash column chromatography over ethyl acetate/petroleum ether (1:3) gave product 3da in 80% yield (170 mg).

Characterization data for Compound 3da

A colorless liquid.¹H NMR(500MHz,CDCl₃)δ7.85(d,J＝8.5Hz,2H),7.68(d,J＝8.5Hz,2H),2.75–2.70(m,2H),2.68–2.58(m,2H).¹⁹F NMR(471MHz,CDCl₃)δ-153.66(s).¹³C NMR(126MHz,CDCl₃)δ138.82(d,J＝22.9Hz),133.29(s),125.38(d,J＝6.8Hz),117.07(d,J＝77.3Hz),115.08(s),115.05(d,J＝16.9Hz),89.45(d,J＝189.5Hz),37.21(d,J＝25.2Hz),12.52(d,J＝4.1Hz).HRMS(ESI)m/z:calcd for C₁₂H₉FN₃ ⁺[M+H]⁺214.0781,found 214.0781.

Example 6

2-fluorobenzeneacetonitrile (180 mg, 1.0mmol) represented by the formula (1e), an olefin (106 mg, 2mmol) represented by the formula (1b), acetonitrile (3.0ML), 1,5, 7-triazabicyclo [4.4.0] dec-5-ene (1mmol) were sequentially added to a 20ML reaction flask at 50 ℃. The reaction was carried out at this temperature for 4 hours. After completion of the reaction, the reaction mixture was transferred to a separatory funnel and extracted with ethyl acetate (10 ml. times.3). The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Flash column chromatography over ethyl acetate/petroleum ether (1:4) gave 3eb, 95% yield (171 mg).

Characterization data for Compound 3eb

Colorless solid, M.p.93.7-95.8 ℃.¹H NMR(500MHz,CDCl₃)δ8.40(d,J＝8.7Hz,2H),7.76(d,J＝8.8Hz,2H),2.78–2.72(m,2H),2.71–2.61(m,2H).¹⁹F NMR(471MHz,CDCl₃)δ-153.35(s).¹³C NMR(126MHz,CDCl₃)δ149.29(s),140.47(d,J＝22.9Hz),125.83(d,J＝6.8Hz),124.71(s),116.72(s),114.99(d,J＝33.8Hz),89.39(d,J＝189.8Hz),37.28(d,J＝25.2Hz),12.53(d,J＝4.2Hz).HRMS(ESI)m/z:calcd for C₁₁H₉FN₃O₂ ⁺[M+H]⁺234.0679,found 234.0679.

Example 7

2-fluorobenzonitrile (135 mg, 1.0mmol) represented by the formula (1a), an olefin (520 mg, 2.5mmol) represented by the formula (2c), diethyl ether (3.0ML) and 1,1,3, 3-tetramethylguanidine (1mmol) were successively charged into a 20ML reaction flask at 40 ℃. The reaction was carried out at this temperature for 0.5 hour. After completion of the reaction, the reaction mixture was transferred to a separatory funnel and extracted with ethyl acetate (10 ml. times.3). The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Flash column chromatography over ethyl acetate/petroleum ether (1:4) gave product 3ac in 92% yield (173 mg). .

Characterization data for Compound 3ac

Colorless solid, M.p.153.8-155.2 ℃.¹H NMR(400MHz,CDCl₃)δ7.94(d,J＝8.5Hz,1H),7.91(d,J＝7.2Hz,1H),7.58(t,J＝7.3Hz,1H),7.48(d,J＝3.7Hz,1H),7.46(d,J＝7.5Hz,1H),δ7.36(d,J＝5.0Hz,5H),7.22(d,J＝6.8Hz,5H),4.25(ddd,J＝22.5,10.2,3.4Hz,1H),3.92(ddd,J＝23.5,17.6,9.8Hz,1H),3.64(ddd,J＝55.8,17.6,3.5Hz,1H).¹⁹F NMR(376MHz,CDCl₃)δ-153.82(d,J＝21.6Hz).¹³C NMR(101MHz,CDCl₃)δ195.66(s),136.49(s),135.26(s),134.72(d,J＝23.0Hz),133.44(s),129.83(s),129.59(s),128.68(s),128.55(s),128.27(s),128.02(s),125.19(d,J＝6.3Hz),117.02(d,J＝33.3Hz),94.38(d,J＝189.7Hz),50.85(d,J＝24.1Hz),39.29(d,J＝2.2Hz).HRMS(ESI)m/z:calcd for C₂₃H₁₉FNO⁺[M+H]⁺344.1451,found 344.1448.

Example 8

2-fluorobenzonitrile (135 mg, 1.0mmol) represented by the formula (1a), an olefin (400 mg, 1.8mmol) represented by the formula (2d), water (3.0ML), and 2-tert-butyl-1, 1,3, 3-tetramethylguanidine (1mmol) were sequentially added to a 20ML reaction flask at 25 ℃. The reaction was carried out at this temperature for 0.5 hour. After completion of the reaction, the reaction mixture was transferred to a separatory funnel and extracted with ethyl acetate (10 ml. times.3). The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Flash column chromatography with ethyl acetate/petroleum ether (1:6) gave product 3ad in 85% yield (303 mg).

Characterization data for Compound 3ad

Colorless solid, M.p.123.5-124.7 ℃.¹H NMR(400MHz,CDCl₃)δ7.96–7.88(m,2H),7.57(ddd,J＝4.6,4.1,1.2Hz,1H),7.47(dt,J＝13.8,6.1Hz,2H),7.43–7.35(m,5H),7.10(t,J＝7.2Hz,2H),7.04(d,J＝7.9Hz,1H),4.29–4.17(m,1H),3.97–3.80(m,1H),3.68(dd,J＝17.5,3.8Hz,1H),2.28(s,3H).¹⁹F NMR(376MHz,CDCl₃)δ-152.48(s).¹³C NMR(126MHz,CDCl3)δ196.01(d,J＝66.0Hz),137.76(s),136.53(d,J＝13.1Hz),134.75(d,J＝23.0Hz),133.42(d,J＝4.3Hz),132.14(s),129.85(s),129.39(d,J＝1.0Hz),129.21(s),129.06(d,J＝7.4Hz),128.67(s),128.57(s),128.05(d,J＝2.5Hz),125.29(d,J＝6.2Hz),117.03(d,J＝33.2Hz),94.45(d,J＝189.2Hz),50.40(d,J＝24.4Hz),39.93–37.93(m),21.07(s).HRMS(ESI)m/z:calcd for C₂₄H₂₁FNO⁺[M+H]⁺358.1607,found 358.1609.

Example 9

2-fluorobenzonitrile (135 mg, 1.0mmol) represented by the formula (1a), an olefin (253 mg, 1mmol) represented by the formula (2e), water (3.0ML) and sodium carbonate (1mmol) were successively charged into a 20ML reaction flask at 15 ℃. The reaction was carried out at this temperature for 0.5 hour. After completion of the reaction, the reaction mixture was transferred to a separatory funnel and extracted with ethyl acetate (10 ml. times.3). The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Flash column chromatography using ethyl acetate/petroleum ether (1:4) gave product 3ae in 84% yield (326 mg).

Characterization data for compound 3ae

Colorless solid, m.p.164.8 ℃.¹H NMR(500MHz,CDCl₃)δ8.11(d,J＝8.8Hz,1H),8.08(d,J＝8.8Hz,1H),7.92(d,J＝7.4Hz,2H),7.61(t,J＝7.4Hz,1H),7.49(t,J＝7.8Hz,2H),7.45–7.35(m,7H),4.35(ddd,J＝23.4,10.6,2.9Hz,1H),4.00(dd,J＝17.9,10.6Hz,1H),3.69(dd,J＝17.9,3.0Hz,1H).¹⁹F NMR(471MHz,CDCl₃)δ-155.11(s).¹³C NMR(126MHz,CDCl₃)δ195.04(s),147.58(s),142.90(s),135.94(s),133.93(s),130.50(d,J＝1.6Hz),130.33(d,J＝1.4Hz),128.96(s),128.86(s),128.04(s),124.89(s),124.84(s),123.40(s),116.49(d,J＝33.2Hz),93.78(d,J＝190.8Hz),50.82(d,J＝23.9Hz),39.33(d,J＝2.1Hz).HRMS(ESI)m/z:calcd for C₂₃H₁₈FN₂O₃ ⁺[M+H]⁺389.1301,found 389.1302.

Example 10

2-fluorobenzylacetonitrile (135 mg, 1.0mmol) represented by the formula (1a), an olefin (253 mg, 0.8mmol) represented by the formula (2f), acetonitrile (3.0ML) and sodium carbonate (1mmol) were successively charged into a 20ML reaction flask at 5 ℃. The reaction was carried out at this temperature for 2 hours. After completion of the reaction, the reaction mixture was transferred to a separatory funnel and extracted with ethyl acetate (10 ml. times.3). The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Flash column chromatography over ethyl acetate/petroleum ether (1:4) gave the product 3af in 75% yield (291 mg).

Characterization data for Compound 3af

Colorless solid, M.p.147.4-148.5 ℃.¹H NMR(500MHz,CDCl₃)δ8.31(d,J＝8.6Hz,2H),8.08(d,J＝8.7Hz,1H),8.05(d,J＝8.6Hz,1H),7.40–7.35(m,3H),7.33(d,J＝7.5Hz,2H),7.24(t,J＝7.5Hz,3H),7.17(t,J＝7.0Hz,2H),4.21(ddd,J＝23.5,10.0,3.3Hz,1H),3.95(dd,J＝17.7,9.9Hz,1H),3.67(dd,J＝17.6,3.4Hz,1H).¹⁹F NMR(471MHz,CDCl₃)δ-147.37(s),-155.18(s).¹³C NMR(126MHz,CDCl₃)δ194.46(s),150.54(s),140.76(s),134.71(s),134.35(d,J＝22.9Hz),129.96(s),129.49(d,J＝1.3Hz),129.09(d,J＝1.6Hz),128.63(s),128.42(s),128.29(s),125.07(d,J＝6.4Hz),116.95(d,J＝33.2Hz),94.10(d,J＝190.2Hz),50.87(d,J＝24.1Hz),40.01(d,J＝2.6Hz).HRMS(ESI)m/z:calcd for C₂₃H₁₈FN₂O₃ ⁺[M+H]⁺389.1301,found 389.1301.

Example 11

2-fluorobenzonitrile (135 mg, 1.0mmol) represented by the formula (1a), an olefin (238 mg, 1mmol) represented by the formula (2f), dimethyl sulfoxide (3.0ML) and potassium carbonate (1mmol) were sequentially added to a 20ML reaction flask at-20 ℃. The reaction was carried out at this temperature for 1 hour. After completion of the reaction, the reaction mixture was transferred to a separatory funnel and extracted with ethyl acetate (10 ml. times.3). The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Flash column chromatography with ethyl acetate/petroleum ether (1:4) gave 3ag in 90% yield (214 mg).

Characterization data for Compound 3ag

Colorless solid, M.p.68.3-77.8 deg.C.¹H NMR(500MHz,CDCl₃)δ7.47(dd,J＝7.2,5.2Hz,1H),7.45–7.41(m,1H),7.39–7.35(m,5H),7.26–7.19(m,3H),7.15(dd,J＝8.9,5.3Hz,2H),6.98(t,J＝7.0Hz,1H),6.93(t,J＝7.5Hz,1H),4.22–4.11(m,1H),3.94(s,3H),3.92–3.77(m,1H),3.66(dd,J＝17.7,3.7Hz,1H).¹⁹F NMR(471MHz,CDCl₃)δ-152.92(s).¹³C NMR(126MHz,CDCl₃)δ197.98(s),158.43(s),135.47(s),134.93(d,J＝23.0Hz),133.84(s),130.51(s),129.73(d,J＝1.3Hz),128.46(d,J＝1.9Hz),128.29(s),128.11(s),127.86(s),127.56(s),125.28(d,J＝6.3Hz),120.74(s),117.02(d,J＝33.2Hz),111.45(s),94.45(d,J＝189.4Hz),55.58(s),51.12(d,J＝24.1Hz),44.45(d,J＝2.6Hz).HRMS(ESI)m/z:calcd for C₂₄H₂₁FNO₂ ⁺[M+H]⁺374.1556,found 374.1552.

Example 12

2-fluorobenzonitrile (135 mg, 1.0mmol) represented by the formula (1a), an olefin (396 mg, 3mmol) represented by the formula (2f), water (3.0ML) and potassium hydroxide (1mmol) were successively charged into a 20ML reaction flask at 25 ℃. The reaction was carried out at this temperature for 3 hours. After completion of the reaction, the reaction mixture was transferred to a separatory funnel and extracted with ethyl acetate (10 ml. times.3). The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Flash column chromatography with ethyl acetate/petroleum ether (1:4) afforded the product 3ah in 92% yield (246 mg).

Characterization data for Compound 3ah

Colorless solid, M.p.57.9-60.5 ℃.¹H NMR(500MHz,CDCl₃)δ8.00–7.95(m,2H),7.62(d,J＝7.4Hz,1H),7.60(d,J＝2.6Hz,2H),7.58(d,J＝0.7Hz,1H),7.52(s,1H),7.51(s,1H),7.50(s,1H),7.50(s,1H),7.50(s,1H),7.49(s,1H),3.43–3.26(m,2H),2.85–2.62(m,2H).¹⁹F NMR(471MHz,CDCl₃)δ-147.63(s).¹³C NMR(126MHz,CDCl₃)δ197.03(s),136.26(s),135.69(d,J＝22.7Hz),133.56(s),130.22(d,J＝1.8Hz),129.13(s),128.76(s),128.05(s),124.68(d,J＝6.2Hz),117.07(d,J＝34.4Hz),91.41(d,J＝184.2Hz),35.89(d,J＝25.4Hz),33.01(d,J＝2.3Hz).HRMS(ESI)m/z:calcd for C₁₇H₁₅FNO⁺[M+H]⁺268.1138,found 268.1135.

Example 13

The same procedure was used as in example 6, in which:

the olefin employed was 2i, the 2-fluorophenylacetonitrile employed was 1 a: the yield was 89%.

Characterization data for Compound 3ai

Colorless solid, M.p.67.9-68.8 ℃.¹H NMR(500MHz,CDCl₃)δ8.02(dd,J＝8.8,5.4Hz,2H),7.59(d,J＝2.0Hz,2H),7.58(s,1H),7.51(s,1H),7.50(d,J＝1.4Hz,2H),7.18(t,J＝8.6Hz,2H),3.41–3.23(m,2H),2.85–2.61(m,2H).¹⁹F NMR(471MHz,CDCl₃)δ-104.28(s),-147.52–-148.09(m).¹³C NMR(126MHz,CDCl₃)δ195.40(s),166.01(d,J＝255.6Hz),135.53(s),132.70(d,J＝3.1Hz),130.73(d,J＝9.4Hz),130.26(d,J＝1.8Hz),129.15(s),124.66(d,J＝6.0Hz),117.01(d,J＝34.3Hz),115.91(d,J＝22.0Hz),91.35(d,J＝184.2Hz),35.86(d,J＝25.4Hz),32.94(d,J＝2.3Hz).HRMS(ESI)m/z:calcd for C₁₇H₁₄F₂NO⁺[M+H]⁺286.1043,found 286.1039.

Example 14

The same procedure was used as in example 7, in which:

the olefin employed was 2j, the 2-fluorophenylacetonitrile employed was 1 a: the yield was 81%.

Characterization data for Compound 3aj

A colorless liquid.¹H NMR(500MHz,CDCl₃)δ7.56–7.47(m,5H),3.70(s,3H),2.68–2.52(m,4H).¹⁹F NMR(376MHz,CDCl₃)δ-148.93(s).¹³C NMR(126MHz,CDCl₃)δ171.75(s),135.32(d,J＝22.6Hz),130.22(d,J＝1.7Hz),129.10(s),124.62(d,J＝6.2Hz),116.75(d,J＝34.2Hz),90.98(d,J＝185.0Hz),52.05(s),36.72(d,J＝25.7Hz),28.62(d,J＝3.5Hz).HRMS(ESI)m/z:calcd for C₁₂H₁₃FNO₂ ⁺[M+H]⁺222.0930,found 222.0930.

Example 15

The same procedure was used as in example 8, in which:

the olefin employed was 2k, the 2-fluorophenylacetonitrile employed was 1 a: the yield was 92%.

Characterization data for Compound 3ak

A colorless liquid.¹H NMR(400MHz,CDCl₃)δ7.60(d,J＝3.9Hz,2H),7.58(d,J＝1.5Hz,3H),7.55–7.51(m,2H),7.44–7.39(m,1H),7.31–7.24(m,2H),7.12(d,J＝1.1Hz,1H),7.10(d,1H),2.95–2.89(m,2H),2.83–2.62(m,2H).¹⁹F NMR(376MHz,CDCl₃)δ-150.61(d,J＝13.7Hz),-155.25(d,J＝16.3Hz).¹³C NMR(126MHz,CDCl₃)δ169.94(s),150.45(s),135.65–134.84(m),130.28(d,J＝12.7Hz),129.28(t,J＝24.8Hz),129.02–128.30(m),126.09(s),124.65(d,J＝6.2Hz),121.38(s),116.76(d,J＝34.1Hz),91.00(d,J＝185.2Hz),36.69(d,J＝25.6Hz),28.95(dd,J＝22.4,3.3Hz).HRMS(ESI)m/z:calcd for C₁₇H₁₅FNO₂ ⁺[M+H]⁺284.1087,found 284.1086.

Example 16

The same procedure was used as in example 1, in which:

the olefin employed was 2l, the 2-fluorophenylacetonitrile employed was 1 a: the yield was 78%. .

Characterization data for Compound 3al

A colorless liquid.¹H NMR(500MHz,CDCl₃)δ7.55–7.46(m,5H),4.21–4.16(m,1H),4.16–4.09(m,1H),4.03(dd,J＝11.1,6.9Hz,1H),3.90(dd,J＝14.9,6.9Hz,1H),3.82(dd,J＝14.4,7.3Hz,1H),2.70–2.53(m,4H),2.08–1.98(m,1H),1.97–1.87(m,2H),1.64–1.57(m,1H).¹⁹F NMR(471MHz,CDCl₃)δ-148.92(d,J＝84.3Hz).¹³C NMR(126MHz,CDCl₃)δ171.32(s),135.30(d,J＝22.7Hz),130.20(s),129.10(s),124.62(d,J＝6.1Hz),116.76(d,J＝34.1Hz),90.95(d,J＝185.0Hz),68.46(s),67.04(s),36.77(s),36.57(s),28.72(s),27.96(s),25.64(s).HRMS(ESI)m/z:calcd for C₁₆H₁₉FNO₃ ⁺[M+H]⁺292.1349,found 292.1353.

Example 17

The same procedure was used as in example 3, in which:

the olefin employed was 2m, the 2-fluorophenylacetonitrile employed was 1 a: the yield was 93%.

Characterization data for Compound 3am

Colorless solid, M.p.67.2-67.8 ℃.¹H NMR(500MHz,CDCl₃)δ7.56–7.51(m,5H),3.35–3.28(m,2H),3.01(s,3H),2.86–2.69(m,2H).¹⁹F NMR(376MHz,CDCl₃)δ-148.43(s).¹³C NMR(126MHz,CDCl₃)δ134.32(d,J＝22.6Hz),130.77(s),129.43(s),124.51(d,J＝6.2Hz),116.10(d,J＝34.2Hz),90.05(d,J＝186.8Hz),49.40(d,J＝2.1Hz),41.33(s),34.12(d,J＝26.3Hz).HRMS(ESI)m/z:calcd for C₁₁H₁₃FNO₂S⁺[M+H]⁺242.0651,found 242.0648.

Example 18

The 2-fluorophenylacetonitrile derivative (3aa,1mmol,188mg) obtained in example 1 was dissolved in DMSO at room temperature. Under ice-water bath, potassium carbonate (1mmol) and hydrogen peroxide (30%, 3mmol) were added. The reaction was carried out at this temperature for 5 h. The reaction solution was then transferred to a separatory funnel and extracted with ethyl acetate (10 ml. times.3). The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Flash column chromatography using ethyl acetate/petroleum ether (1:1) gave product 4a in 75% yield (155 mg).

Characterization data for Compound 4a

Colorless solid, M.p.79-82.8 ℃.¹H NMR(500MHz,CDCl₃)δ7.55(d,J＝7.3Hz,2H),7.42(t,J＝7.1Hz,3H),6.31(d,J＝154.2Hz,2H),2.73(ddd,J＝24.4,14.8,7.8Hz,1H),2.55(ddd,J＝29.3,14.7,7.4Hz,1H),2.47–2.41(m,2H).¹⁹F NMR(376MHz,CDCl₃)δ-163.90(s).¹³C NMR(126MHz,CDCl₃)δ171.76(d,J＝23.3Hz),136.43(d,J＝21.7Hz),129.15(d,J＝1.2Hz),128.82(d,J＝1.7Hz),124.19(d,J＝10.0Hz),118.61(s),98.06(d,J＝192.1Hz),34.07(d,J＝22.0Hz),11.98(d,J＝4.5Hz).HRMS(ESI)m/z:calcd for C₁₁H₁₂FN₂O⁺[M+H]⁺207.0934,found 207.0938.

Example 19

The 2-fluorobenzonitrile derivative (3ah,1mmol,267mg) obtained in example 12 was dissolved in methanol in an ice water bath. Then, sodium borohydride (1.0mmol) was added. The reaction was carried out at this temperature for 1 h. The reaction solution was then transferred to a separatory funnel and extracted with ethyl acetate (10 ml. times.3). The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Flash column chromatography using ethyl acetate/petroleum ether (1:1) gave product 4b in 95% yield (256 mg). .

Characterization data for Compound 4b

Colorless solid, M.p.94.5-95.4 ℃.¹H NMR(500MHz,CDCl₃)δ7.51(t,J＝5.3Hz,2H),7.47(dd,J＝4.2,1.8Hz,3H),7.39(dd,J＝11.2,3.8Hz,5H),7.34(dd,J＝7.0,4.9Hz,3H),4.76(t,J＝6.4Hz,1H),2.52–2.20(m,2H),2.11–2.00(m,2H).¹⁹F NMR(471MHz,CDCl₃)δ-146.55(s),-147.35(s).¹³C NMR(126MHz,CDCl₃)δ143.59(s),136.09(d,J＝3.2Hz),129.98(s),129.00(s),128.73(s),128.03(s),125.71(s),124.69(d,J＝1.9Hz),117.39(d,J＝9.7Hz),92.51(d,J＝21.7Hz),73.39(s),37.97(d,J＝8.1Hz),33.03(d,J＝2.8Hz).HRMS(ESI)m/z:calcd for C₁₇H₁₇FNO⁺[M+H]⁺270.1294,found 270.1293.

Example 20

The 2-fluorobenzonitrile derivative (3aa,1mmol,188mg) obtained in example 1 and concentrated hydrochloric acid (3.0ml) were heated at 100 ℃ for 12 hours. The reaction solution was then transferred to a separatory funnel and extracted with ethyl acetate (10 ml. times.3). The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Flash column chromatography using ethyl acetate/petroleum ether (1:1) gave product 4c in 65% yield (135 mg).

Characterization data for Compound 4c

A colorless liquid.¹H NMR(400MHz,CDCl₃)δ7.55–7.52(m,2H),7.51(t,J＝2.0Hz,2H),7.49(d,J＝2.5Hz,1H),2.74–2.65(m,2H),2.65–2.52(m,2H).¹⁹F NMR(471MHz,CDCl₃)δ-149.31(s).¹³C NMR(126MHz,CDCl₃)δ177.40(s),135.17(d,J＝22.6Hz),130.32(s),129.17(s),124.59(d,J＝6.2Hz),116.66(d,J＝34.0Hz),90.83(d,J＝185.2Hz),36.40(d,J＝25.7Hz),28.61(d,J＝2.8Hz).HRMS(ESI)m/z:calcd for C₁₁H₁₁FNO₂ ⁺[M+H]⁺208.0774,found 208.0776.

The embodiments described above are described to facilitate an understanding and use of the invention by those skilled in the art. It will be readily apparent to those skilled in the art that various modifications to these embodiments may be made, and the generic principles described herein may be applied to other embodiments without the use of the inventive faculty. Therefore, the present invention is not limited to the above embodiments, and those skilled in the art should make improvements and modifications within the scope of the present invention based on the disclosure of the present invention.