CN115043807B - Monofluorinated 4H-pyran compounds and methods of synthesizing the same - Google Patents

Monofluorinated 4H-pyran compounds and methods of synthesizing the same Download PDF

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CN115043807B
CN115043807B CN202210816049.9A CN202210816049A CN115043807B CN 115043807 B CN115043807 B CN 115043807B CN 202210816049 A CN202210816049 A CN 202210816049A CN 115043807 B CN115043807 B CN 115043807B
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CN115043807A (en
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常宏宏
马智广
张娟
任凡
闫庆芳
高文超
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Shanxi Tianhong Daan Pharmaceutical Technology Co ltd
Taiyuan University of Technology
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Taiyuan University of Technology
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/32—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/74—Benzo[b]pyrans, hydrogenated in the carbocyclic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

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Abstract

The invention belongs to the technical field of synthesis and application of organic compounds, and provides a monofluorinated 4H-pyran compound and a synthesis method thereof, wherein a beta-trifluoromethyl-1, 3-eneyne compound I reacts with acetylacetone II-a, acetoacetic acid ethyl ester II-b or 5, 5-dimethyl-1, 3-cyclohexanedione II-c respectively in alkali and a solvent, and a series of monofluorinated 4H-pyran compounds 3 are synthesized under the same reaction condition. The synthesis method does not need transition metal catalysis, the raw materials are cheap and easy to obtain, the reaction conditions are mild, the operation is simple and easy, the yield is higher, and the functional group tolerance is better. The construction of the method enriches the synthesis method of the fluorinated tetrahydropyran compound, and lays a synthesis foundation for the application of the high-activity fluorinated 4H-pyran derivative in the fields of medicines, materials and the like.

Description

Monofluorinated 4H-pyran compounds and methods of synthesizing the same
Technical Field
The invention belongs to the technical field of synthesis and application of organic compounds, and particularly relates to a monofluorinated 4H-pyran compound and a synthesis method thereof.
Background
The 4H-pyran has a typical unsaturated six-membered heterocyclic structure, and derivatives having a parent structure of 4H-pyran are widely found in natural products. In the biomedical field, 4H-pyran is an important skeleton for synthesizing drug-related molecules (such as 1, 4-dihydropyridine, pyridine, 2-pyridone, pyranopyrimidine and oxazine), and 4H-pyran derivatives have antibacterial, antiviral, anticancer and diuretic actions, and 4H-pyran derivatives are also widely used in the field of neurodegenerative diseases such as Parkinson's disease, huntington's disease and Alzheimer's disease. In recent years, it has been found that a 4H-pyran compound having a structure similar to that of 1, 4-dihydropyridine also exhibits calcium channel antagonistic activity. Therefore, it is of great importance to study the synthesis of 4H-pyran compounds.
It is well known that fluorochemicals tend to have higher reactivity, lipophilicity, and bioactivity than non-fluorochemicals. Among fluorine-containing compounds, a heterocycle containing only one fluorine atom (monofluorocyclic ring) is an important class of organic compounds, and few reports have been made so far about the synthesis of monofluorocyclic 4H-pyran compounds.
Disclosure of Invention
The invention aims to provide a monofluorinated 4H-pyran compound and a synthesis method thereof, which are used for efficiently constructing a series of monofluorinated 4H-pyran compounds by utilizing beta-trifluoromethyl-1, 3-eneyne compounds and acetylacetone, ethyl acetoacetate and 5, 5-dimethyl-1, 3-cyclohexanedione under the same reaction conditions. The synthesis method is simple and feasible, transition metal catalysis is not needed, the raw materials are cheap and easy to obtain, the universality of the substrate is wide, and the yield is high.
The invention is realized by the following technical scheme, and the synthesis method of the monofluorinated 4H-pyran compound is characterized by comprising the following steps: beta-trifluoromethyl-1, 3-eneyne compound I reacts with acetylacetone II-a, ethyl acetoacetate II-b or 5, 5-dimethyl-1, 3-cyclohexanedione II-c respectively in alkali and solvent to synthesize a series of monofluorinated 4H-pyran compounds 3 under the same reaction conditions, wherein the reaction process is shown in the following reaction formula:
；
Wherein: r 1 is any one of phenyl, 4-methoxyphenyl, 3-methylphenyl, 4-fluorophenyl, 3-fluorophenyl, 2-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-aminophenyl, 4-cyanophenyl, 3-pyridyl, 4-dimethylthiochroman, phenyl (S) -2- (4-isobutylphenyl) propionate or (R) -2- (4-isobutylphenyl) -N-amphetamine;
The alkali is any one of 1, 8-diazabicyclo [5.4.0] undec-7-ene, potassium phosphate, cesium carbonate, potassium carbonate, sodium bicarbonate, lithium carbonate, sodium acetate, triethylamine, triethylene diamine, 4-dimethylaminopyridine or N-methylmorpholine;
The molar ratio of the dosage of the beta-trifluoromethyl-1, 3-eneyne compound I to the dosage of the acetylacetone II-a, the acetoacetic ester II-b and the 5, 5-dimethyl-1, 3-cyclohexanedione II-c is 1 (1-10);
the molar amount of the alkali is 100-200mol% of the beta-trifluoromethyl-1, 3-eneyne compound I;
The ratio of the beta-trifluoromethyl-1, 3-eneyne compound I to the solvent used is 1mmol (1-15) mL;
The reaction temperature is 25-100 ℃; the reaction time is 1-6h.
R 1 may be, but is not limited to, the above substituents.
Further, the alkali is potassium phosphate K 3PO4, and the molar amount of the potassium phosphate is 150mol percent of the raw material beta-trifluoromethyl-1, 3-eneyne compound I.
The reaction solvent is any one of N, N-dimethylformamide, tetrahydrofuran, dimethyl sulfoxide, 1, 4-dioxane, toluene or acetonitrile.
Further, the reaction solvent is N, N-dimethylformamide.
Further, the molar ratio of the dosage of the beta-trifluoromethyl-1, 3-eneyne compound I to the dosage of the acetylacetone II-a, the acetoacetate II-b and the 5, 5-dimethyl-1, 3-cyclohexanedione II-c is 1:1.5; the ratio of beta-trifluoromethyl-1, 3-eneyne compound I to the solvent used was 1mmol:2mL; the reaction temperature is 50 ℃; the reaction time was 4h.
The reaction principle of the present invention will be described below by taking the reaction of a beta-trifluoromethyl-1, 3-eneyne compound with acetylacetone in the presence of a base potassium phosphate and a solvent N, N-dimethylformamide: firstly, acetyl acetone is deprotonated under the action of alkali to generate carbanion A, carbanion nucleophilic attacks beta-trifluoromethyl-1, 3-eneyne to form B, trifluoromethyl is easy to generate beta-F elimination to form gem-difluoro C under the induction of intermediate B carbanion, meanwhile, C is easy to enol interconversion to form D, then enol oxygen nucleophilic attacks the gem-difluoro center, and finally defluorination and cyclization are carried out to generate a target product 3. The specific reaction is as follows:
。
The beneficial effects of the invention are as follows: the synthesis method is simple and feasible, transition metal is not needed to participate, raw materials are cheap and easy to obtain, reaction conditions are mild, the yield is high, and the functional group tolerance is good; the construction of the method enriches the synthesis method of the mono-fluorinated tetrahydropyran compound, and lays a synthesis foundation for the application of the high-activity mono-fluorinated 4H-pyran derivative in the fields of medicines, materials and the like.
Drawings
FIG. 1 is a structural formula of the compound shown in example 1-example 12;
FIG. 2 is a structural formula of the compound shown in example 13-example 23;
FIG. 3 is a structural formula of the compound shown in example 24-example 35;
FIG. 4 is a nuclear magnetic resonance spectrum of the compound 3aa obtained in example 1;
FIG. 5 is a nuclear magnetic resonance spectrum of compound 3da obtained in example 4;
FIG. 6 is a nuclear magnetic resonance spectrum of the compound 3ga obtained in example 7;
FIG. 7 is a nuclear magnetic resonance spectrum of the compound 3bb obtained in example 14;
FIG. 8 is a nuclear magnetic resonance spectrum of compound 3ic obtained in example 32;
FIG. 9 is a nuclear magnetic resonance spectrum of the compound 3nc obtained in example 35.
Detailed Description
For the purpose of making the objects, technical solutions and advantages of the embodiments of the present invention more clear, the technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is apparent that the described embodiments are some embodiments of the present invention, but not all embodiments; all other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs, the disclosure of which is incorporated herein by reference as is commonly understood by reference.
Those skilled in the art will recognize that equivalents of the specific embodiments described, as well as those known by routine experimentation, are intended to be encompassed within the present application.
The experimental methods in the following examples are conventional methods unless otherwise specified. The instruments used in the following examples are laboratory conventional instruments unless otherwise specified; the experimental materials used in the examples described below, unless otherwise specified, were purchased from conventional biochemical reagent stores. The data presented in the examples below include specific operations and reaction conditions and products; the purity of the product was identified by nuclear magnetism.
Example 1: synthesis of compound 3 aa: in a 15 mL reaction tube, (3- (trifluoromethyl) -3-en-1-yn-1-yl) benzene (19.6 mg,0.1 mmol), acetylacetone (15.4. Mu.L, 0.15 mmol), potassium phosphate (31.8 mg, 0.15 mmol), DMF (2 mL) were added and stirred at 50℃for 4 hours, after completion of the reaction, quenched, extracted, concentrated and separated by column chromatography to give 3aa (21.0 mg, yield: 78%) as a yellow oily liquid.
Nuclear magnetism identification result ：1H NMR (400 MHz, CDCl3): δ7.46-7.42 (m, 2H), 7.33-7.30 (m, 3H), 3.31 (dd, J = 4.8, 1.2 Hz, 2H), 2.27 (s, 3H), 2.22 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ 198.0 (d, 4JCF = 1.3 Hz), 157.0 (d, 3JCF = 2.3 Hz), 156.1 (d, 1JCF = 262.4 Hz), 131.3, 128.3, 128.3, 122.9 (d, 4JCF = 1.1 Hz), 110.5 (d, 5JCF = 0.7 Hz), 93.7 (d, 3JCF = 4.6 Hz), 81.2 (d, 3JCF = 3.1 Hz), 72.0 (d, 2JCF = 15.8 Hz), 29.9, 28.0 (d, 4JCF = 1.8 Hz), 18.6 ppm; 19F NMR (376 MHz, CDCl3): δ -88.8 (s, 1F) ppm.
Example 2: synthesis of Compound 3 ba: 1-methoxy-4- (3- (trifluoromethyl) -3-en-1-yn-1-yl) benzene (22.6 mg, 0.1 mmol), acetylacetone (15.4. Mu.L, 0.15 mmol), potassium phosphate (31.8 mg, 0.15 mmol), DMF (2 mL) were added to a 15 mL reaction tube and stirred at 50℃for 4 hours, after completion of the reaction, quenched, extracted, concentrated, and separated by column chromatography to give 3ba (24.3 mg, yield: 85%) as a yellow oil.
Nuclear magnetism identification result ：1H NMR (400 MHz, CDCl3): δ 7.38 (dt, J = 8.8, 2.0 Hz, 2H), 6.84 (dt, J = 8.8, 2.0 Hz, 2H), 3.80 (s, 3H), 3.29 (dd, J = 4.8, 1.2 Hz, 2H), 2.25 (s, 3H), 2.21 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ 198.1 (d, 4JCF= 1.3 Hz), 159.6, 157.0 (d, 3JCF = 2.3 Hz), 155.8 (d, 1JCF = 261.8 Hz), 132.8, 115.0 (d, 4JCF = 1.0 Hz), 113.9, 110.4 (d, 5JCF = 0.9 Hz), 93.6 (d, 3JCF = 4.6 Hz), 79.8 (d, 3JCF = 3.0 Hz), 72.2 (d, 2JCF = 15.9 Hz), 55.2, 29.9, 28.1 (d, 4JCF = 1.7 Hz), 18.6 ppm; 19F NMR (376 MHz, CDCl3): δ -89.6 (s, 1F) ppm.
Example 3: synthesis of Compound 3 ca: 1-methyl-3- (3- (trifluoromethyl) -3-en-1-yn-1-yl) benzene (21.0 mg, 0.1 mmol), acetylacetone (15.4. Mu.L, 0.15 mmol), potassium phosphate (31.8 mg, 0.15 mmol), DMF (2 mL) were added to a 15 mL reaction tube, stirred at 50℃for 4 hours, after completion of the reaction, quenched, extracted, concentrated, and separated by column chromatography to give 3ca (22.1 mg, yield82%) as a yellow oil.
Nuclear magnetism identification result ：1H NMR (400 MHz, CDCl3): δ 7.28 (s, 1H), 7.24-7.18 (m, 2H), 7.12 (d, J = 1.8 Hz, 1H), 3.30 (dd, J = 4.8, 1.2 Hz, 2H), 2.33 (s, 3H), 2.26 (s, 3H), 2.22 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ 198.1 (d, 4JCF = 1.0 Hz), 157.0 (d, 3JCF = 2.2 Hz), 156.0 (d, 1JCF = 262.2 Hz), 138.0, 131.8, 129.2, 128.4, 122.7, 110.4, 93.9 (d, 3JCF = 4.6 Hz), 80.8 (d, 3JCF = 3.0 Hz), 72.0 (d, 2JCF = 15.8 Hz), 29.9, 28.0 (d, 4JCF = 1.7 Hz), 21.2, 18.6 ppm; 19F NMR (376 MHz, CDCl3): δ -89.0 (s, 1F) ppm.
Example 4: synthesis of compound 3 da: 1-fluoro-4- (3- (trifluoromethyl) -3-en-1-yn-1-yl) benzene (21.4 mg, 0.1 mmol), acetylacetone (15.4. Mu.L, 0.15 mmol), potassium phosphate (31.8 mg, 0.15 mmol), DMF (2 mL) were added to a 15mL reaction tube and stirred at 50℃for 4 hours, after completion of the reaction, quenched, extracted, concentrated, and separated by column chromatography to give 3da (22.7 mg, yield83%) as a yellow oil.
Nuclear magnetism identification result ：1H NMR (400 MHz, CDCl3): δ7.44-7.39 (m, 2H), 7.01 (tt, J= 8.8, 2.0 Hz, 2H), 3.29 (dd, J = 5.2, 1.6 Hz, 2H), 2.26 (s, 3H), 2.22 (t, J= 1.2 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ 197.9, 162.4 (d, 1JCF = 249.6 Hz), 156.9 (d, 3JCF = 2.0 Hz), 156.2 (d, 1JCF = 262.3 Hz), 133.2 (d, 3JCF = 8.0 Hz), 119.0 (d, 3JCF = 3.4 Hz), 115.6 (d, 2JCF = 2.2 Hz), 110.5 (d, 4JCF = 0.9 Hz), 92.6 (d, 3JCF = 4.2 Hz), 80.9 (d, 4JCF = 1.5 Hz), 71.8 (d, 2JCF = 15.3 Hz), 29.9, 28.0, 18.5 ppm; 19F NMR (376 MHz, CDCl3): δ -88.7 (s, 1F), -110.8 (s, 1F) ppm.
Example 5: synthesis of compound 3 ea: 1-fluoro-3- (3- (trifluoromethyl) -3-en-1-yn-1-yl) benzene (21.4 mg, 0.1 mmol), acetylacetone (15.4. Mu.L, 0.15 mmol), potassium phosphate (31.8 mg, 0.15 mmol), DMF (2 mL) were added to a 15 mL reaction tube, stirred at 50℃for 4 hours, after completion of the reaction, quenched, extracted, concentrated, and separated by column chromatography to give 3ea (22.2 mg, yield: 81%) as a yellow oil.
Nuclear magnetism identification result ：1H NMR (400 MHz, CDCl3): δ7.31-7.27 (m, 1H), 7.21 (dt, J= 7.6, 1.2 Hz, 1H), 7.13 (ddd, J = 9.6, 2.8, 1.2 Hz, 1H), 7.02 (tdd, J = 8.8, 2.8, 1.2 Hz, 1H), 3.30 (dd, J = 4.8, 1.2 Hz, 2H), 2.27 (s, 3H), 2.23 (t, J = 1.2 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ 197.9 (d, 4JCF = 2.1 Hz), 162.3 (d, 1JCF = 245.2 Hz), 156.9, 156.4 (d, 1JCF = 263.4 Hz), 129.9(d, 3JCF = 8.5 Hz), 127.2, 124.8(d, 3JCF = 10.4 Hz), 118.0(d, 2JCF = 23.0 Hz), 115.6(d, 2JCF = 21.1 Hz),110.6, 92.4 (d, 4JCF = 3.3 Hz), 82.2 (d, 4JCF = 2.5 Hz), 71.7 (d, 2JCF= 15.9 Hz), 29.9, 27.8, 18.6 ppm; 19F NMR (376 MHz, CDCl3): δ -87.9 (s, 1F), -112.9 (s, 1F) ppm.
Example 6: synthesis of Compound 3 fa: 1-fluoro-2- (3- (trifluoromethyl) -3-en-1-yn-1-yl) benzene (21.4 mg, 0.1 mmol), acetylacetone (15.4. Mu.L, 0.15 mmol), potassium phosphate (31.8 mg, 0.15 mmol), DMF (2 mL) were added to a 15 mL reaction tube, stirred at 50℃for 4 hours, after completion of the reaction, quenched, extracted, concentrated, and separated by column chromatography to give 3fa (22.5 mg, yield82%) as a yellow oil.
Nuclear magnetism identification result ：1H NMR (400 MHz, CDCl3): δ 7.43 (td, J = 7.6, 1.6 Hz, 1H), 7.32-7.26 (m, 1H),7.11-7.04 (m, 2H), 3.32 (dd, J = 4.8, 1.6 Hz, 2H), 2.26 (s, 3H), 2.22 (t, J = 1.2 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ 197.9 (d, 4JCF = 0.4 Hz), 162.4 (d, 1JCF = 250.1 Hz), 156.9, 156.4 (d, 1JCF = 263.2 Hz), 133.1, 130.0 (d, 3JCF = 7.9 Hz), 123.9 (d, 3JCF = 3.5 Hz), 115.4 (d, 2JCF = 20.8 Hz), 111.6 (d, 2JCF = 15.7 Hz), 110.6, 87.0 (d, 3JCF = 4.5 Hz), 86.3 (d, 3JCF = 2.6 Hz), 71.9 (d, 2JCF = 15.9 Hz), 29.9, 27.9, 18.5 ppm; 19F NMR (376 MHz, CDCl3): δ -87.8 (s, 1F), -110.0 (s, 1F) ppm.
Example 7: synthesis of Compound 3 ga: 1-chloro-4- (3- (trifluoromethyl) -3-en-1-yn-1-yl) benzene (23.0 mg, 0.1 mmol), acetylacetone (15.4. Mu.L, 0.15 mmol), potassium phosphate (31.8 mg, 0.15 mmol), DMF (2 mL) were added to a 15 mL reaction tube, stirred at 50℃for 4 hours, after completion of the reaction, quenched, extracted, concentrated, and separated by column chromatography to give 3ga (25.5 mg, yield: 88%) as a yellow oil.
Nuclear magnetism identification result ：1H NMR (400 MHz, CDCl3): δ 7.36 (dt, J = 8.8, 2.0 Hz, 2H), 7.29 (dt, J = 8.8 2.0 Hz, 2H), 3.29 (dd, J = 4.8, 1.2 Hz, 2H), 2.27 (s, 3H), 2.22 (t, J = 1.6 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ 198.0 (d, 4JCF = 1.0 Hz), 157.0 (d, 3JCF = 1.7 Hz), 156.3 (d, 1JCF = 262.8 Hz), 134.2, 132.5, 128.6, 121.4, 110.5, 92.6 (d, 3JCF = 4.5 Hz), 82.2 (d, 3JCF = 3.1 Hz), 71.8 (d, 2JCF = 16.0 Hz), 30.0, 27.9 (d, 4JCF = 1.0 Hz), 18.6 ppm; 19F NMR (376 MHz, CDCl3): δ -88.2 (s, 1F) ppm.
Example 8: synthesis of Compound 3 ha: 1-bromo-4- (3- (trifluoromethyl) -3-en-1-yn-1-yl) benzene (27.3 mg, 0.1 mmol), acetylacetone (15.4. Mu.L, 0.15 mmol), potassium phosphate (31.8 mg, 0.15 mmol), DMF (2 mL) were added to a 15 mL reaction tube, stirred at 50℃for 4 hours, after completion of the reaction, quenched, extracted, concentrated, and separated by column chromatography to give 3ha (27.7 mg, yield83%) as a yellow oil.
Nuclear magnetism identification result ：1H NMR (400 MHz, CDCl3): δ 7.45 (dt, J = 8.8, 2.0 Hz, 2H), 7.29 (dt, J = 8.4, 2.0 Hz, 2H), 3.29 (dd, J = 4.8, 1.2 Hz, 2H), 2.26 (s, 3H), 2.22 (t, J = 1.6 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ 198.0 (d, 4JCF = 1.3 Hz), 157.0 (d, 3JCF = 2.3 Hz), 156.3 (d, 1JCF = 262.9 Hz), 132.7, 131.6, 122.5, 121.9, 110.5 (d, 4JCF = 0.9 Hz), 92.6 (d, 3JCF = 4.5 Hz), 82.4 (d, 3JCF = 3.1 Hz), 71.8 (d, 2JCF = 15.8 Hz), 30.0, 27.9 (d, 4JCF = 1.6 Hz), 18.6 ppm; 19F NMR (376 MHz, CDCl3): δ -88.1 (s, 1F) ppm.
Example 9: synthesis of compound 3 ia: 4- (trifluoromethyl) -3-en-1-yn-1-yl) aniline (21.1 mg, 0.1 mmol), acetylacetone (15.4. Mu.L, 0.15 mmol), potassium phosphate (31.8 mg, 0.15 mmol), DMF (2 mL) were added to a 15mL reaction tube and stirred at 50℃for 4 hours, after completion of the reaction, quenched, extracted, concentrated and separated by column chromatography to give 3ia (19.2 mg, yield: 71%) as a yellow oil.
Nuclear magnetism identification result ：1H NMR (400 MHz, CDCl3): δ 7.24 (d, J= 8.0 Hz, 2H), 6.58 (d, J = 8.4 Hz, 2H), 3.81 (s, 2H), 3.27 (d, J = 4.0 Hz, 2H), 2.24 (s, 3H), 2.20 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ 198.2 (d, 4JCF = 1.3 Hz), 156.9 (d, 3JCF = 2.3 Hz), 155.6 (d, 1JCF = 261.3 Hz), 146.7, 132.7, 114.6, 112.1, 110.4 (d, 4JCF = 0.7 Hz), 94.3 (d, 3JCF = 4.6 Hz), 78.9 (d, 3JCF = 3.1 Hz), 72.4 (d, 2JCF = 16.0 Hz), 29.9, 28.2 (d, 4JCF = 1.7 Hz), 18.5 ppm; 19F NMR (376 MHz, CDCl3): δ -90.2 (s, 1F) ppm.
Example 10: synthesis of Compound 3 ja: 3- (3- (trifluoromethyl) -3-en-1-yn-1-yl) pyridine (19.7 mg, 0.1 mmol), acetylacetone (15.4. Mu.L, 0.15 mmol), potassium phosphate (31.8 mg, 0.15 mmol), DMF (2 mL) were added to a 15 mL reaction tube, stirred at 50℃for 4 hours, after completion of the reaction, quenched, extracted, concentrated, and isolated as a yellow oily liquid 3ja (18.0 mg, yield: 70%) by column chromatography.
Nuclear magnetism identification result ：1H NMR (400 MHz, CDCl3): δ 8.67 (s, 1H), 8.52 (d, J = 2.8 Hz, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.27-7.24 (m, 1H), 3.31 (d, J = 4.0 Hz, 2H), 2.27 (s, 3H), 2.23 (s, 3H) ppm;13C NMR (100 MHz, CDCl3): δ 197.8, 156.9 (d, 3JCF = 1.8 Hz), 156.6 (d, 1JCF = 263.3 Hz), 151.9, 148.5, 138.1, 123.0, 120.2, 110.6, 90.3 (d, 3JCF = 4.4 Hz), 84.7 (d, 3JCF = 2.8 Hz), 71.6 (d, 2JCF = 15.7 Hz), 29.9, 27.8, 18.5 ppm; 19F NMR (376 MHz, CDCl3): δ -87.3 (s, 1F) ppm.
Example 11: synthesis of Compound 3 ka: 4, 4-dimethyl-6- (3- (trifluoromethyl) -3-en-1-yn-1-yl) chromium sulfate (29.6 mg, 0.1 mmol), acetylacetone (15.4. Mu.L, 0.15 mmol), potassium phosphate (31.8 mg, 0.15 mmol), DMF (2 mL) were added to a 15 mL reaction tube and stirred at 50℃for 4 hours, after the completion of the reaction, quenched, extracted, concentrated, and separated by column chromatography to give yellow oily liquid 3ka (28.5 mg, yield: 80%).
Nuclear magnetism identification result ：1H NMR (400 MHz, CDCl3): δ 7.42 (d, J = 1.2 Hz, 1H), 7.09 (dd, J = 8.0, 1.6 Hz, 1H), 7.01 (d, J = 8.0 Hz, 1H), 3.30 (dd, J = 4.8, 1.2 Hz, 2H), 3.02 (t, J = 6.0 Hz, 2H), 2.26 (s, 3H), 2.22 (s, 3H),1.93 (t, J = 6.0 Hz, 2H), 1.31 ppm; 13C NMR (100 MHz, CDCl3): δ 198.1 (d, 4JCF = 1.2 Hz), 157.0 (d, 3JCF = 2.3 Hz), 155.9 (d, 1JCF = 262.0 Hz), 141.9, 133.0, 129.3, 128.6, 126.4, 118.1, 110.4 (d, 4JCF = 0.6 Hz), 94.0 (d, 3JCF = 4.6 Hz), 80.3 (d, 3JCF = 3.1 Hz), 72.1 (d, 2JCF = 15.8 Hz), 37.1, 32.9, 29.9, 29.9, 28.1 (d, 4JCF = 1.7 Hz), 23.1, 18.6 ppm; 19F NMR (376 MHz, CDCl3): δ -89.2 (s, 1F) ppm.
Example 12: synthesis of compound 3 la: in a 15 mL reaction tube, (R) -2- (4-isobutylphenyl) -N- (4- (3- (trifluoromethyl) -3-en-1-yn-1-yl) phenyl) propylamine (39.9 mg, 0.1 mmol), acetylacetone (15.4. Mu.L, 0.15 mmol), potassium phosphate (31.8 mg, 0.15 mmol) and DMF (2 mL) were added, and after completion of the reaction, the mixture was quenched, extracted and concentrated to give a yellow oily liquid 3la (30.8 mg, yield: 67%) by column chromatography.
Nuclear magnetism identification result ：1H NMR (400 MHz, CDCl3): δ 7.42 (s, 2H), 7.40 (s, 1H), 7.33 (d, J = 8.4 Hz, 2H), 7.24 (d, J = 8.0 Hz, 2H), 7.14 (d, J = 8.0 Hz, 2H), 3.69 (q, J = 7.2 Hz, 1H), 3.28 (dd, J = 4.8, 1.2 Hz, 2H), 2.46 (d, J = 7.2 Hz, 2H), 2.24 (s, 3H), 2.20 (s, 3H), 1.90-1.80 (m, 1H), 1.56 (d, J = 6.8 Hz, 3H), 0.90 (d, J = 6.8 Hz, 6H) ppm;13C NMR (100 MHz, CDCl3): δ198.1 (d, 4JCF = 0.7 Hz), 172.7, 157.0 (d, 3JCF = 2.1 Hz), 155.9 (d, 1JCF = 262.2 Hz), 141.0, 138.0, 137.8, 131.9, 129.8, 127.3, 119.2, 118.3, 110.4, 93.4 (d, 3JCF = 4.6 Hz), 80.7 (d, 3JCF = 3.0 Hz), 72.0 (d, 2JCF = 15.9 Hz), 47.6, 44.9, 30.1, 29.9, 28.0 (d, 4JCF = 1.3 Hz), 22.3, 18.5, 18.4 ppm; 19F NMR (376 MHz, CDCl3): δ -89.0 (s, 1F) ppm.
Example 13: synthesis of compound 3 ab: in a 15 mL reaction tube, (3- (trifluoromethyl) -3-en-1-yn-1-yl) benzene (19.6 mg,0.1 mmol), ethyl acetoacetate (19.0. Mu.L, 0.15 mmol), potassium phosphate (31.8 mg, 0.15 mmol), DMF (2 mL) were added and stirred at 50℃for 4 hours, after the reaction was completed, quenched, extracted, concentrated, and separated by column chromatography to give 3ab (22.9 mg, yield: 80%) as a white solid.
Nuclear magnetism identification result ：1H NMR (400 MHz, CDCl3): δ7.46-7.42 (m, 2H), 7.32-7.29 (m, 3H), 4.22 (q, J = 7.2 Hz, 2H), 3.23 (dd, J = 4.8, 1.2 Hz, 2H), 2.30 (t, J= 1.2 Hz, 3H), 1.31 (t, J = 7.2 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ166.3 (d, 4JCF = 1.7 Hz), 158.3 (d, 3JCF = 2.7 Hz), 156.1 (d, 1JCF = 262.2 Hz), 131.3, 128.3, 128.2, 123.0 (d, 5JCF = 0.4 Hz), 103.4 (d, 4JCF = 1.0 Hz), 93.4 (d, 3JCF= 4.6 Hz), 81.4 (d, 3JCF = 3.0 Hz), 72.1 (d, 2JCF = 15.4 Hz), 60.7, 27.0 (d, 4JCF = 1.6 Hz), 18.2, 14.2 ppm.
Example 14: synthesis of compound 3 bb: 1-methoxy-4- (3- (trifluoromethyl) -3-en-1-yn-1-yl) benzene (22.6 mg, 0.1 mmol), ethyl acetoacetate (19.0. Mu.L, 0.15 mmol), potassium phosphate (31.8 mg, 0.15 mmol), DMF (2 mL) were added to a 15 mL reaction tube and stirred at 50℃for 4 hours, after the reaction, quenched, extracted, concentrated, and separated by column chromatography to give 3bb (26.2 mg, yield: 83%) as a white solid.
Nuclear magnetism identification result ：1H NMR (400 MHz, CDCl3): δ 7.38 (d, J = 8.8 Hz, 2H), 6.84 (d, J = 8.8 Hz, 2H), 4.21 (q, J = 7.2 Hz, 2H), 3.81 (s, 3H), 3.22 (dd, J = 5.2, 2.0 Hz, 2H), 2.30 (s, 3H), 1.30 (t, J = 7.2 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ 166.4 (d, 4JCF = 1.8 Hz), 159.6, 158.4 (d, 3JCF = 2.7 Hz), 155.9 (d, 1JCF = 261.4 Hz), 132.8, 115.2, 113.9, 103.3, 93.4 (d, 3JCF = 4.6 Hz), 80.0 (d, 3JCF = 2.9 Hz), 72.3 (d, 2JCF = 15.5 Hz), 60.7, 55.3, 27.1 (d, 4JCF = 1.7 Hz), 18.2, 14.2 ppm; 19F NMR (376 MHz, CDCl3): δ -90.1 (s, 1F) ppm.
Example 15: synthesis of compound 3 cb: 1-methyl-3- (3- (trifluoromethyl) -3-en-1-yn-1-yl) benzene (21.0 mg, 0.1 mmol), ethyl acetoacetate (19.0. Mu.L, 0.15 mmol), potassium phosphate (31.8 mg, 0.15 mmol), DMF (2 mL) were added to a 15 mL reaction tube and stirred at 50℃for 4 hours, after the reaction, quenched, extracted, concentrated, and separated by column chromatography to give 3cb (24.0 mg, yield80%) as a white solid.
Nuclear magnetism identification result ：1H NMR (400 MHz, CDCl3): δ 7.27 (s, 1H), 7.24 (s, 1H), 7.20 (t, J = 7.2 Hz, 1H),7.12 (d, J = 7.2 Hz, 1H), 4.21 (q, J = 6.8 Hz, 2H),3.22 (dd, J = 4.8, 1.2 Hz, 2H), 2.33 (s, 3H), 2.30 (t, J = 1.2 Hz, 3H),1.31 (t, J = 7.2 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ166.3 (d, 4JCF = 1.6 Hz), 158.3 (d, 3JCF = 2.7 Hz), 156.1 (d, 1JCF = 262.0 Hz), 137.9, 131.9, 129.1, 128.4, 128.2, 122.8 (d, 4JCF = 0.9 Hz), 103.3 (d, 5JCF = 0.9 Hz), 93.6 (d, 3JCF= 4.5 Hz), 81.0 (d, 3JCF = 3.0Hz), 72.2 (d, 2JCF = 15.4 Hz), 60.7, 27.0 (d, 4JCF= 1.5 Hz), 21.2, 18.2, 14.2 ppm; 19F NMR (376 MHz, CDCl3): δ -89.5 (s, 1F) ppm.
Example 16: synthesis of Compound 3 db: 1-fluoro-4- (3- (trifluoromethyl) -3-en-1-yn-1-yl) benzene (21.4 mg, 0.1 mmol), ethyl acetoacetate (19.0. Mu.L, 0.15 mmol), potassium phosphate (31.8 mg, 0.15 mmol), DMF (2 mL) were added to a 15 mL reaction tube and stirred at 50℃for 4 hours, after completion of the reaction, quenched, extracted, concentrated, and separated by column chromatography to give 3db (24.6 mg, yield: 81%) as a white solid.
Nuclear magnetism identification result ：1H NMR (400 MHz, CDCl3): δ7.44-7.39 (m, 2H), 7.00 (tt, J= 8.4, 2.0 Hz, 2H), 4.21 (q, J = 7.2 Hz, 2H), 3.22 (dd, J = 4.8, 1.2 Hz, 2H), 2.30 (t, J = 1.2 Hz, 3H), 1.30 (t, J = 7.2 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ166.2 (d, 4JCF = 1.5 Hz), 162.4 (d, 1JCF = 248.1 Hz),158.3 (d, 3JCF = 1.8 Hz), 156.2 (d, 1JCF = 262.0 Hz), 133.2 (d, 3JCF = 8.3 Hz), 119.2 (d, 3JCF = 2.4 Hz), 115.6 (d, 2JCF = 22.0 Hz), 103.3 (d, 5JCF = 0.8 Hz), 92.3 (d, 3JCF = 4.5 Hz), 81.1 (d, 4JCF = 1.4 Hz), 72.0 (d, 2JCF = 15.5 Hz), 60.7 (d, 4JCF = 1.1 Hz), 26.9, 18.2 (d, 4JCF = 1.8 Hz), 14.2 ppm; 19F NMR (376 MHz, CDCl3): δ -89.2 (s, 1F), -110.0 (s, 1F) ppm.
Example 17: synthesis of compound 3 eb: 1-fluoro-3- (3- (trifluoromethyl) -3-en-1-yn-1-yl) benzene (21.4 mg, 0.1 mmol), ethyl acetoacetate (19.0. Mu.L, 0.15 mmol), potassium phosphate (31.8 mg, 0.15 mmol), DMF (2 mL) were added to a 15 mL reaction tube and stirred at 50℃for 4 hours, after the reaction, quenched, extracted, concentrated, and separated by column chromatography to give 3eb (24.0 mg, yield: 79%) as a white solid.
Nuclear magnetism identification result ：1H NMR (400 MHz, CDCl3): δ7.30-7.26 (m, 1H), 7.21 (dt, J= 8.0, 1.2 Hz, 1H), 7.13 (ddd, J = 9.6, 2.4, 1.6 Hz, 1H), 7.01 (tdd, J = 8.8, 2.8, 1.2 Hz, 1H), 4.22 (q, J = 7.2 Hz, 2H), 3.22 (dd, J = 4.8, 1.2 Hz, 2H), 2.30 (t, J = 1.2 Hz, 3H), 1.31 (t, J = 7.2 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ166.2 (d, 4JCF = 1.4 Hz), 162.3 (d, 1JCF = 245.0 Hz),158.3 (d, 4JCF = 1.9 Hz), 156.4 (d, 1JCF = 263.1 Hz), 129.8 (d, 3JCF = 8.6 Hz), 127.2 (d, 3JCF = 2.9 Hz), 124.9 (d, 3JCF = 9.7 Hz), 118.1 (d, 2JCF = 22.7 Hz), 115.5 (d, 2JCF = 21.1 Hz), 103.4, 92.2 (d, 3JCF = 4.0 Hz), 82.5 (d, 3JCF = 3.0 Hz), 71.9 (d, 2JCF= 15.5 Hz), 60.7, 26.9 (d, 4JCF = 1.1 Hz), 18.1, 14.2 ppm; 19F NMR (376 MHz, CDCl3): δ -88.5 (s, 1F), -113.0 (s, 1F) ppm.
Example 18: synthesis of compound 3 fb: 1-fluoro-2- (3- (trifluoromethyl) -3-en-1-yn-1-yl) benzene (21.4 mg, 0.1 mmol), ethyl acetoacetate (19.0. Mu.L, 0.15 mmol), potassium phosphate (31.8 mg, 0.15 mmol), DMF (2 mL) were added to a 15mL reaction tube and stirred at 50℃for 4 hours, after completion of the reaction, quenched, extracted, concentrated, and separated by column chromatography to give 3fb (24.3 mg, yield80%) as a white solid.
Nuclear magnetism identification result ：1H NMR (400 MHz, CDCl3): δ 7.42 (td, J = 7.2, 2.0 Hz, 1H), 7.31-7.25 (m, 1H),7.10-7.04 (m, 2H), 4.21 (q, J = 6.8 Hz, 2H) 3.24 (dd, J = 5.2, 1.2 Hz, 2H), 2.30 (t, J = 1.2 Hz, 3H), 1.30 (t, J = 7.2 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ166.1 (d, 4JCF = 1.9 Hz), 162.3 (d, 1JCF = 250.7 Hz),158.2 (d, 4JCF = 1.5 Hz), 156.3 (d, 1JCF = 262.3 Hz), 133.1, 129.8 (d, 3JCF = 8.4 Hz),123.9, 115.4 (d, 2JCF = 20.6 Hz), 111.7 (d, 2JCF = 15.1 Hz),103.4 (d, 3JCF = 4.3 Hz), 86.7 (d, 3JCF = 4.2 Hz), 86.4 (d, 3JCF = 3.4 Hz), 72.0 (d, 2JCF = 15.6 Hz), 60.7, 26.8 (d, 3JCF = 3.2 Hz), 18.0, 14.1 ppm; 19F NMR (376 MHz, CDCl3): δ -88.3 (s, 1F), -110.0 (s, 1F) ppm.
Example 19: synthesis of Compound 3 gb: 1-chloro-4- (3- (trifluoromethyl) -3-en-1-yn-1-yl) benzene (23.0 mg, 0.1 mmol), ethyl acetoacetate (19.0. Mu.L, 0.15 mmol), potassium phosphate (31.8 mg, 0.15 mmol), DMF (2 mL) were added to a 15 mL reaction tube and stirred at 50℃for 4 hours, after completion of the reaction, quenched, extracted, concentrated, and separated by column chromatography to give 3gb (27.2 mg, yield: 85%) as a white solid.
Nuclear magnetism identification result ：1H NMR (400 MHz, CDCl3): δ 7.36 (dt, J = 8.8, 2.0 Hz, 2H), 7.28 (dt, J = 8.8 2.0 Hz, 2H), 4.21 (q, J = 7.2 Hz, 2H), 3.22 (dd, J = 4.8, 1.2 Hz, 2H), 2.30 (t, J = 1.6 Hz, 3H),1.31 (t, J = 7.2 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ 166.2 (d, 4JCF = 1.5 Hz), 158.3 (d, 3JCF = 2.5 Hz), 156.3 (d, 1JCF = 262.5 Hz), 134.1, 132.5, 128.6, 121.5, 103.4, 92.3 (d, 3JCF = 4.5 Hz), 82.4 (d, 3JCF = 2.9 Hz), 71.9 (d, 2JCF = 15.3 Hz), 60.7, 26.9 (d, 4JCF= 1.0 Hz), 18.2, 14.2 ppm; 19F NMR (376 MHz, CDCl3): δ -88.8 (s, 1F) ppm.
Example 20: synthesis of compound 3 hb: 1-bromo-4- (3- (trifluoromethyl) -3-en-1-yn-1-yl) benzene (27.3 mg, 0.1 mmol), ethyl acetoacetate (19.0. Mu.L, 0.15 mmol), potassium phosphate (31.8 mg, 0.15 mmol), DMF (2 mL) were added to a 15 mL reaction tube and stirred at 50℃for 4 hours, after completion of the reaction, quenched, extracted, concentrated, and separated by column chromatography to give 3hb (29.8 mg, yield: 82%) as a white solid.
Nuclear magnetism identification result ：1H NMR (400 MHz, CDCl3): δ 7.44 (dt, J = 8.8, 2.0 Hz, 2H), 7.29 (dt, J = 8.4 2.0 Hz, 2H), 4.21 (q, J = 7.2 Hz, 2H), 3.22 (dd, J = 5.2, 1.2 Hz, 2H), 2.30 (t, J = 1.2 Hz, 3H),1.30 (t, J = 7.2 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ 166.2 (d, 4JCF = 1.6 Hz), 158.3 (d, 3JCF = 2.5 Hz), 156.3 (d, 1JCF = 262.5 Hz), 132.7, 131.5, 122.4, 122.0 (d, 5JCF = 0.5 Hz), 103.4 (d, 4JCF = 0.8 Hz), 92.4 (d, 3JCF = 4.6Hz), 82.6 (d, 3JCF = 3.1 Hz), 71.9 (d, 2JCF = 15.3 Hz), 60.7, 26.8 (d, 4JCF = 1.4 Hz), 18.2, 14.2 ppm; 19F NMR (376 MHz, CDCl3): δ -88.7 (s, 1F) ppm.
Example 21: synthesis of compound 3 ib: 4- (trifluoromethyl) -3-en-1-yn-1-yl) aniline (21.1 mg, 0.1 mmol), ethyl acetoacetate (19.0. Mu.L, 0.15 mmol), potassium phosphate (31.8 mg, 0.15 mmol), DMF (2 mL) were added to a 15 mL reaction tube and stirred at 50℃for 4 hours, after completion of the reaction, quenched, extracted, concentrated, and isolated as a white solid 3ib (21.7 mg, yield72%) by column chromatography.
Nuclear magnetism identification result ：1H NMR (400 MHz, CDCl3): δ 7.24 (d, J = 8.4 Hz, 2H), 6.59 (d, J = 8.4 Hz, 2H), 4.20 (q,J = 7.2 Hz, 2H), 3.81 (s, 2H), 3.20 (d, J = 4.0 Hz, 2H), 2.29 (s, 3H), 1. 30 (t, J = 7.2 Hz,3H) ppm; 13C NMR (100 MHz, CDCl3): δ 166.4 (d, 4JCF = 1.7 Hz), 158.3 (d, 3JCF = 2.7 Hz), 155.6 (d, 1JCF = 261.0 Hz), 146.6, 132.7, 114.6, 112.4, 103.3 (d, 4JCF = 0.9 Hz), 94.1 (d, 3JCF = 4.5 Hz), 79.1 (d, 3JCF = 3.0 Hz), 72.5 (d, 2JCF = 15.5 Hz), 27.2 (d, 3JCF = 1.6 Hz), 18.2, 14.2 ppm; 19F NMR (376 MHz, CDCl3): δ -90.7 (s, 1F) ppm.
Example 22: synthesis of compound 3 jb: 3- (3- (trifluoromethyl) -3-en-1-yn-1-yl) pyridine (19.7 mg, 0.1 mmol), ethyl acetoacetate (19.0. Mu.L, 0.15 mmol), potassium phosphate (31.8 mg, 0.15 mmol), DMF (2 mL) were added to a 15 mL reaction tube, stirred at 50℃for 4 hours, after the reaction, quenched, extracted, concentrated, and separated by column chromatography to give 3jb (19.2 mg, yield: 67%) as a white solid.
Nuclear magnetism identification result ：1H NMR (400 MHz, CDCl3): δ 8.67 (s, 1H), 8.51 (d, J = 1.6 Hz, 1H), 7.71 (d, J = 7.6 Hz, 1H), 7.26-7.23 (m, 1H), 4.21 (q, J = 7.2 Hz, 2H), 3.23 (d, J = 4.0 Hz, 2H), 2.30 (s, 3H), 1.31 (t, J = 7.2 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ 166.1 (d, 4JCF = 1.6 Hz), 158.3 (d, 3JCF = 2.6 Hz), 156.6 (d, 1JCF = 263.2 Hz), 151.9, 148.4, 138.1, 123.0, 120.3 (d, 4JCF = 1.2 Hz), 103.5, 90.0 (d, 3JCF = 4.4 Hz), 84.9 (d, 3JCF = 3.0 Hz), 71.7 (d, 2JCF = 15.3 Hz), 60.8, 26.8 (d, 4JCF = 1.2 Hz), 18.1, 14.2 ppm; 19F NMR (376 MHz, CDCl3): δ -87.9 (s, 1F) ppm.
Example 23: synthesis of Compound 3 mb: 4- (3- (trifluoromethyl) -3-en-1-yn-1-yl) benzonitrile (22.1 mg, 0.1 mmol), ethyl acetoacetate (19.0. Mu.L, 0.15 mmol), potassium phosphate (31.8 mg, 0.15 mmol), DMF (2 mL) were added to a 15mL reaction tube and stirred at 50℃for 4 hours, after the reaction, quenched, extracted, concentrated, and separated by column chromatography to give a white solid 3mb (15.2 mg, yield: 49%).
Nuclear magnetism identification result ：1H NMR (400 MHz, CDCl3): δ 7.60 (d, J = 8.4 Hz, 2H), 7.50 (d, J = 8.4 Hz, 2H), 4.22 (q, J = 7.2 Hz, 2H), 3.23 (dd, J = 4.8, 0.8 Hz, 2H), 2.31(s, 3H), 1.31 (t, J = 6.8 Hz, 3H)ppm; 13C NMR (100 MHz, CDCl3): δ 166.1 (d, 4JCF = 1.7 Hz), 158.3 (d, 3JCF = 2.5 Hz), 156.8 (d, 1JCF = 263.9 Hz), 132.0, 131.7, 128.0 (d, 5JCF = 0.6 Hz), 118.5, 111.3, 103.5 (d, 4JCF = 0.7 Hz), 91.9 (d, 3JCF = 4.6 Hz), 86.2 (d, 3JCF = 3.2 Hz), 71.6 (d, 2JCF = 15.2 Hz), 60.8, 26.7 (d, 4JCF = 1.3 Hz), 18.2, 14.2 ppm; 19F NMR (376 MHz, CDCl3): δ -87.0 (s, 1F) ppm.
Example 24: synthesis of Compound 3 ac: in a 15mL reaction tube, (3- (trifluoromethyl) -3-en-1-yn-1-yl) benzene (19.6 mg,0.1 mmol), 5-dimethyl-1, 3-cyclohexanedione (21.0 mg, 0.15 mmol), potassium phosphate (31.8 mg, 0.15 mmol), DMF (2 mL) were added and stirred at 50℃for 4 hours, after completion of the reaction, quenched, extracted, concentrated, and separated by column chromatography to give 3ac (24.1 mg, yield: 81%) as a white solid.
Nuclear magnetism identification result ：1H NMR (400 MHz, CDCl3): δ7.44-7.42 (m, 2H), 7.32-7.29 (m, 3H), 3.13 (dt, J = 5.2, 1.6 Hz, 2H), 2.36 (t, J = 1.6 Hz, 2H), 2.30 (s, 2H),1.11 (s, 6H) ppm; 13C NMR (100 MHz, CDCl3): δ197.2 (d, 4JCF = 0.7 Hz), 162.7 (d, 3JCF = 2.5 Hz), 156.2 (d, 1JCF = 263.3 Hz), 131.3, 128.3, 122.9, 110.1 (d, 4JCF = 1.0 Hz), 93.9 (d, 3JCF = 4.8 Hz), 81.2 (d, 3JCF = 2.7 Hz), 73.8 (d, 2JCF = 15.1 Hz), 50.4, 40.3, 32.3, 28.2, 23.5 (d, 4JCF = 1.4 Hz) ppm.
Example 25 synthesis of compound 3 bc: 1-methoxy-4- (3- (trifluoromethyl) -3-en-1-yn-1-yl) benzene (22.6 mg,0.1 mmol), 5-dimethyl-1, 3-cyclohexanedione (21.0 mg, 0.15 mmol), potassium phosphate (31.8 mg, 0.15 mmol), DMF (2 mL) were added to a 15 mL reaction tube, stirred at 50℃for 4 hours, after completion of the reaction, quenched, extracted, concentrated, and separated by column chromatography to give a white solid 3bc (27.6 mg, yield: 84%).
Nuclear magnetism identification result ：1H NMR (400 MHz, CDCl3): δ 7.39-7.35 (m, 2H), 6.86-6.82 (m, 2H), 3.81 (s, 3H), 3.12-3.10 (m, 2H), 2.36 (s, 2H), 2.30 (s, 2H), 1.11 (s, 6H) ppm; 13C NMR (100 MHz, CDCl3): δ 197.2, 162.7 (d, 3JCF = 2.5 Hz), 159.6, 155.9 (d, 1JCF = 262.7 Hz), 132.8, 115.0, 113.9, 110.1 (d, 4JCF = 0.9 Hz), 93.9 (d, 3JCF = 4.7 Hz), 79.8 (d, 3JCF = 2.6 Hz), 74.0 (d, 2JCF = 15.2 Hz), 55.3, 50.5, 40.4, 32.3, 28.2, 23.7 (d, 4JCF = 1.3 Hz) ppm; FTMS (ESI): Calculated for C20H19FNaO3 (M+Na)+: 349.12104; Found: 349.12049.
Example 26: synthesis of Compound 3 cc: 1-methyl-3- (3- (trifluoromethyl) -3-en-1-yn-1-yl) benzene (21.0 mg, 0.1 mmol), 5-dimethyl-1, 3-cyclohexanedione (21.0 mg, 0.15 mmol), potassium phosphate (31.8 mg, 0.15 mmol), DMF (2 mL) were added to a 15 mL reaction tube, stirred at 50℃for 4 hours, after completion of the reaction, quenched, extracted, concentrated, and separated by column chromatography to give 3cc (25.6 mg, yield82%) as a white solid.
Nuclear magnetism identification result ：1H NMR (400 MHz, CDCl3): δ7.26-7.23 (m, 2H), 7.20 (t, J = 7.2 Hz, 1H), 7.12 (d,J = 7.2 Hz, 1H), 3.12 (dt, J = 5.2, 1.6 Hz, 2H), 2.86 (t, J = 1.6 Hz, 2H), 2.33 (s, 3H),2.30 (s, 2H),1.11 (s, 6H) ppm; 13C NMR (100 MHz, CDCl3): δ197.2 (d, 4JCF = 0.7 Hz), 162.7 (d, 3JCF = 2.5 Hz), 156.2 (d, 1JCF= 263.1 Hz), 138.0, 131.9, 129.2, 128.4, 128.2, 122.7 (d, 5JCF = 0.7 Hz), 110.1 (d, 4JCF = 0.9 Hz), 94.1 (d, 3JCF = 4.8 Hz), 80.9 (d, 3JCF = 2.7 Hz), 73.9 (d, 2JCF = 15.1 Hz), 50.4, 40.3, 32.3, 28.2, 23.6 (d, 4JCF = 1.2 Hz) ppm; 19F NMR (376 MHz, CDCl3): δ -89.8 (s, 1F) ppm.
Example 27: synthesis of compound 3 dc: 1-fluoro-4- (3- (trifluoromethyl) -3-en-1-yn-1-yl) benzene (21.4 mg,0.1 mmol), 5-dimethyl-1, 3-cyclohexanedione (21.0 mg, 0.15 mmol), potassium phosphate (31.8 mg, 0.15 mmol), DMF (2 mL) were added to a 15 mL reaction tube, stirred at 50℃for 4 hours, after completion of the reaction, quenched, extracted, concentrated, and separated by column chromatography to give a white solid 3dc (25.9 mg, yield: 82%).
Nuclear magnetism identification result ：1H NMR (400 MHz, CDCl3): δ7.43-7.38 (m, 2H), 7.00 (tt, J= 8.8, 2.0 Hz, 2H), 3.11 (dt, J = 5.2, 1.6 Hz, 2H), 2.36 (t, J = 1.6 Hz, 2H), 2.30 (s, 2H),1.11 (s, 6H) ppm; 13C NMR (100 MHz, CDCl3): δ197.2 (d, 4JCF = 0.7 Hz), 162.7 (d, 3JCF = 2.5 Hz), 162.4 (d, 1JCF = 248.2 Hz), 156.2 (d, 1JCF = 263.2 Hz), 133.2 (d, 3JCF = 8.3 Hz), 119.0 (d, 4JCF = 3.3 Hz), 115.6 (d, 2JCF = 21.9 Hz), 110.0 (d, 4JCF = 1.0 Hz), 92.8 (d, 3JCF = 4.9 Hz), 80.9 (d, 3JCF = 2.6 Hz), 73.7 (d, 2JCF = 15.0 Hz), 50.4, 40.3, 32.3, 28.2, 23.5 (d, 4JCF = 1.2 Hz) ppm; 19F NMR (376 MHz, CDCl3): δ -89.5 (s, 1F), -110.8 (s, 1F) ppm.
Example 28: synthesis of compound 3 ec: 1-fluoro-3- (3- (trifluoromethyl) -3-en-1-yn-1-yl) benzene (21.4 mg,0.1 mmol), 5-dimethyl-1, 3-cyclohexanedione (21.0 mg, 0.15 mmol), potassium phosphate (31.8 mg, 0.15 mmol), DMF (2 mL) were added to a 15 mL reaction tube, stirred at 50℃for 4 hours, after completion of the reaction, quenched, extracted, concentrated, and separated by column chromatography to give a white solid 3ec (25.3 mg, yield: 80%).
Nuclear magnetism identification result ：1H NMR (400 MHz, CDCl3): δ7.30-7.24 (m, 1H), 7.20 (dt, J= 8.0, 1.2 Hz, 1H), 7.12 (ddd, J = 9.6, 2.4, 1.6 Hz, 1H), 7.01 (tdd, J = 8.4, 2.4, 1.2 Hz, 1H), 3.12 (dt, J = 5.2, 1.6 Hz, 2H), 2.36 (t, J = 1.6 Hz, 2H), 2.30 (s, 2H),1.11 (s, 6H) ppm; 13C NMR (100 MHz, CDCl3): δ197.1, 162.6 (d, 3JCF= 2.3 Hz), 162.3 (d, 1JCF = 245.0 Hz), 156.5 (d, 1JCF = 264.0 Hz), 129.8 (d, 3JCF = 8.5 Hz), 127.2 (d, 4JCF = 2.9 Hz), 124.7 (d, 3JCF = 9.5 Hz), 118.1 (d, 2JCF = 22.7 Hz), 115.6 (d, 2JCF = 21.0 Hz), 110.1, 92.6 (d, 3JCF = 4.2 Hz), 82.3 (d, 3JCF = 2.6 Hz), 73.5 (d, 2JCF = 15.0Hz), 50.4, 40.3, 32.3, 28.2, 23.4 ppm; 19F NMR (376 MHz, CDCl3): δ -88.7 (s, 1F), -112.9 (s, 1F) ppm.
Example 29: synthesis of compound 3 fc: 1-fluoro-2- (3- (trifluoromethyl) -3-en-1-yn-1-yl) benzene (21.4 mg,0.1 mmol), 5-dimethyl-1, 3-cyclohexanedione (21.0 mg, 0.15 mmol), potassium phosphate (31.8 mg, 0.15 mmol), DMF (2 mL) were added to a 15mL reaction tube, stirred at 50℃for 4 hours, after completion of the reaction, quenched, extracted, concentrated, and separated by column chromatography to give a white solid 3fc (25.6 mg, yield: 81%).
Nuclear magnetism identification result ：1H NMR (400 MHz, CDCl3): δ 7.41 (td, J = 7.2, 2.0 Hz, 1H), 7.31-7.26 (m, 1H), 7.11-7.04 (m, 2H), 3.14 (dt, J = 5.2, 1.6 Hz, 2H), 2.36 (t, J = 1.6 Hz, 2H), 2.30 (s, 2H),1.11 (s, 6H) ppm; 13C NMR (100 MHz, CDCl3): δ197.0, 162.6 (d, 3JCF = 1.4 Hz), 162.3 (d, 1JCF = 250.4 Hz), 156.4 (d, 1JCF = 264.9 Hz), 133.1, 130.0 (d, 3JCF = 7.8 Hz), 123.8 (d, 3JCF = 3.3 Hz), 115.4 (d, 2JCF = 20.6 Hz), 111.5 (d, 2JCF = 15.0 Hz), 110.0, 87.1 (d, 3JCF = 4.5 Hz), 86.3, 73.6 (d, 2JCF = 14.8 Hz), 50.4, 40.2, 32.2, 28.1, 23.4 ppm; 19F NMR (376 MHz, CDCl3): δ -88.6 (s, 1F), -109.9 (s, 1F) ppm.
Example 30: synthesis of Compound 3 gc: 1-chloro-4- (3- (trifluoromethyl) -3-en-1-yn-1-yl) benzene (23.0 mg, 0.1 mmol), 5-dimethyl-1, 3-cyclohexanedione (21.0 mg, 0.15 mmol), potassium phosphate (31.8 mg, 0.15 mmol), DMF (2 mL) were added to a 15 mL reaction tube, stirred at 50℃for 4 hours, after completion of the reaction, quenched, extracted, concentrated, and separated by column chromatography to give 3gc (28.6 mg, yield: 86%) as a white solid.
Nuclear magnetism identification result ：1H NMR (400 MHz, CDCl3): δ 7.35 (dt, J = 8.4, 2.0 Hz, 2H), 7.28 (dt, J = 8.4 2.0 Hz, 2H), 3.11 (dt, J = 5.2, 1.2 Hz, 2H), 2.36 (t, J = 1.6 Hz, 2H),2.30 (s, 2H),1.11 (s, 6H) ppm; 13C NMR (100 MHz, CDCl3): δ197.2 (d, 4JCF = 0.8 Hz), 162.6 (d, 3JCF = 2.4 Hz), 156.4 (d, 1JCF = 263.6 Hz), 134.3, 132.5, 128.6, 121.4 (d, 5JCF = 0.8 Hz), 110.0 (d, 4JCF = 1.0 Hz), 92.7 (d, 3JCF = 4.8 Hz), 82.3 (d, 3JCF = 2.7 Hz), 73.6 (d, 2JCF = 15.0 Hz), 50.4, 40.3, 32.3, 28.2, 23.4 (d, 4JCF = 1.3 Hz) ppm; 19F NMR (376 MHz, CDCl3): δ -89.0 (s, 1F) ppm.
Example 31: synthesis of compound 3 hc: 1-bromo-4- (3- (trifluoromethyl) -3-en-1-yn-1-yl) benzene (27.3 mg,0.1 mmol), 5-dimethyl-1, 3-cyclohexanedione (21.0 mg, 0.15 mmol), potassium phosphate (31.8 mg, 0.15 mmol), DMF (2 mL) were added to a 15mL reaction tube, stirred at 50℃for 4 hours, after completion of the reaction, quenched, extracted, concentrated, and separated by column chromatography to give a white solid 3hc (31.2 mg, yield: 83%).
Nuclear magnetism identification result ：1H NMR (400 MHz, CDCl3): δ 7.44 (dt, J = 8.4, 2.0 Hz, 2H), 7.28(dt, J = 8.8 2.0 Hz, 2H), 3.11 (dt, J = 4.8, 1.6 Hz, 2H), 2.36 (t, J= 1.6 Hz, 2H),2.30 (s, 2H),1.11 (s, 6H) ppm; 13C NMR (100 MHz, CDCl3): δ197.1 (d, 4JCF = 0.5 Hz), 162.6 (d, 3JCF = 2.4 Hz), 156.4 (d, 1JCF = 263.8 Hz), 132.7, 131.5, 122.5, 121.8 (d, 5JCF = 0.7 Hz), 110.0 (d, 4JCF = 1.0 Hz), 92.8 (d, 3JCF= 4.8 Hz), 82.5 (d, 3JCF = 2.7 Hz), 73.6 (d, 2JCF = 15.0 Hz), 50.4, 40.3, 32.3, 28.2, 23.4 (d, 4JCF = 1.2 Hz) ppm; 19F NMR (376 MHz, CDCl3): δ -88.9 (s, 1F) ppm.
Example 32: synthesis of Compound 3 ic: 4- (trifluoromethyl) -3-en-1-yn-1-yl) aniline (21.1 mg, 0.1 mmol), 5-dimethyl-1, 3-cyclohexanedione (21.0 mg, 0.15 mmol), potassium phosphate (31.8 mg, 0.15 mmol), DMF (2 mL) were added to a 15 mL reaction tube, stirred at 50℃for 4 hours, after completion of the reaction, quenched, extracted, concentrated, and separated by column chromatography to give 3ic (22.5 mg, yield: 72%) as a white solid.
Nuclear magnetism identification result ：1H NMR (400 MHz, CDCl3): δ 7.23 (d, J = 8.4 Hz, 2H), 6.59 (d, J = 8.4 Hz, 2H), 3.82 (s, 2H), 3.10 (d, J = 5.2 Hz, 2H), 2.35 (s, 3H), 2.29 (s, 2H) 1.10 (s, 6H) ppm; 13C NMR (100 MHz, CDCl3): δ197.3 (d, 4JCF = 0.7 Hz), 162.7 (d, 3JCF = 2.5 Hz), 155.7 (d, 1JCF = 262.1 Hz), 146.7, 132.7, 114.6, 112.2 (d, 5JCF = 0.6 Hz), 110.1 (d, 4JCF = 1.2 Hz), 94.6 (d, 3JCF = 4.8 Hz), 79.0 (d, 3JCF = 2.7 Hz), 74.2 (d, 2JCF = 15.2 Hz), 50.5, 40.4, 32.3, 28.2, 23.7 (d, 4JCF = 1.5 Hz) ppm; 19F NMR (376 MHz, CDCl3): δ -91.0 (d, J = 1.5 Hz, 1F) ppm.
Example 33: synthesis of compound 3 jc: 3- (3- (trifluoromethyl) -3-en-1-yn-1-yl) pyridine (19.7 mg, 0.1 mmol), 5-dimethyl-1, 3-cyclohexanedione (21.0 mg, 0.15 mmol), potassium phosphate (31.8 mg, 0.15 mmol), DMF (2 mL) were added to a 15 mL reaction tube, stirred at 50℃for 4 hours, after completion of the reaction, quenched, extracted, concentrated, and separated by column chromatography to give 3jc (20.6 mg, yield69%) as a white solid.
Nuclear magnetism identification result ：1H NMR (400 MHz, CDCl3): δ 8.67 (s, 1H), 8.52 (s, 1H), 7.70 (d, J = 7.6 Hz, 1H), 7.25-7.23 (m, 1H), 3.13 (d, J = 4.8 Hz, 2H), 2.36 (s, 2H), 2.30 (s, 2H), 1.11 (s, 6H) ppm; 13C NMR (100 MHz, CDCl3): δ 197.0 (d, 4JCF = 0.6 Hz), 162.6 (d, 3JCF = 2.3 Hz), 156.7 (d, 1JCF = 264.3 Hz), 151.9,148.5, 138.2, 123.0, 120.2, 110.1 (d, 4JCF = 0.9 Hz), 90.4 (d, 3JCF = 4.8 Hz), 84.7 (d, 3JCF = 2.8 Hz), 73.4 (d, 2JCF = 15.0 Hz), 50.4,40.3, 32.3, 28.2, 23.4 (d, 4JCF = 1.3 Hz) ppm; 19F NMR (376 MHz, CDCl3): δ -88.2 (s, 1F) ppm.
Example 34: synthesis of Compound 3 kc: 4, 4-dimethyl-6- (3- (trifluoromethyl) -3-en-1-yn-1-yl) chromium sulfate (29.6 mg, 0.1 mmol), 5-dimethyl-1, 3-cyclohexanedione (21.0 mg, 0.15 mmol), potassium phosphate (31.8 mg, 0.15 mmol), DMF (2 mL) were added to a reaction tube and stirred at 50℃for 4 hours, after completion of the reaction, quenched, extracted, concentrated and isolated by column chromatography to give a white solid 3kc (33.0 mg, yield: 83%).
Nuclear magnetism identification result ：1H NMR (400 MHz, CDCl3): δ 7.40 (d, J = 1.2 Hz, 1H), 7.07 (dd, J = 8.0, 1.6 Hz, 1H), 7.00 (d, J = 8.0 Hz, 1H), 3.11 (d, J = 4.8 Hz, 2H), 3.03-3.00 (m, 2H), 2.34 (t, J = 1.6 Hz, 2H), 2.28 (s, 2H),1.94-1.91 (m, 2H), 1.31 (s, 6H),1.10 (s, 6H) ppm; 13C NMR (100 MHz, CDCl3): δ197.1 (d, 4JCF = 0.7 Hz), 162.6 (d, 3JCF = 2.4 Hz), 155.9 (d, 1JCF = 262.8 Hz), 141.9, 133.0, 129.3, 128.6, 126.4, 118.1 (d, 5JCF = 0.6 Hz), 110.0 (d, 4JCF = 0.9 Hz), 94.2 (d, 3JCF = 4.8 Hz), 80.4 (d, 3JCF = 2.6 Hz), 73.9 (d, 2JCF = 15.1 Hz), 50.4, 40.2, 37.1, 32.8, 32.2, 29.8, 28.2, 23. 6 (d, 4JCF = 1.3 Hz), 23.1 ppm; 19F NMR (376 MHz, CDCl3): δ -90.0 (s, 1F) ppm.
Example 35: synthesis of compound 3 nc: 3- (3- (trifluoromethyl) -3-en-1-yn-1-yl) phenyl (S) -2- (4-isobutylphenyl) propionate (40.0 mg, 0.1 mmol), 5-dimethyl-1, 3-cyclohexanedione (21.0 mg, 0.15 mmol), potassium phosphate (31.8 mg, 0.15 mmol), DMF (2 mL), stirred at 50℃for 4 hours, quenched, extracted, concentrated, and separated by column chromatography to give 3nc (41.2 mg, yield: 82%) as a white solid.
Nuclear magnetism identification result ：1H NMR (400 MHz, CDCl3): δ 7.28-7.26 (m, 2H), 7.25-7.23 (m, 2H), 7.13 (dt, J = 8.0, 2.0 Hz, 1H), 7.07-7.06 (m, 1H), 6.96-6.91 (m, 1H), 3.91 (q, J = 7.2 Hz, 1H), 3.08 (dt, J = 5.2, 1.6 Hz, 2H), 2.45 (d, J = 7.2 Hz, 2H), 2.31 (t, J = 1.6 Hz, 2H), 2.27 (s, 2H),1.90-1.80 (m, 1H), 1.57 (d, J = 7.2 Hz, 3H), 1.07 (s, 6H), 0.89 (d, J = 6.4 Hz, 6H)ppm; 13C NMR (100 MHz, CDCl3): δ197.2, 172.8, 162.7 (d, 3JCF = 2.4 Hz), 156.3 (d, 1JCF = 263.7 Hz), 150.9, 140.7, 136.9, 129.4, 129.1, 128.6, 127.0, 124.1, 124.0, 121.6, 109.9 (d, 4JCF = 0.8 Hz), 92.8 (d, 3JCF = 4.8 Hz), 82.0 (d, 3JCF = 2.7 Hz), 73.6 (d, 2JCF = 15.0 Hz), 50.2, 45.0, 44.9, 40.1, 32.2, 30.0, 28.1, 23.3 (d, 4JCF = 0.8 Hz), 23.1, 22.3, 18.4 ppm; 19F NMR (376 MHz, CDCl3): δ -88.9 (s, 1F) ppm.
To further explore the practical applicability of the construction and synthesis method of the present invention, 3la and 82% 3nc with isolated yields of 67% and 82% respectively were obtained by reacting ibuprofen amidated substrate with acetylacetone and ibuprofen lipidated substrate with 5, 5-dimethyl-1, 3-cyclohexanedione, as shown in the following reactions (a) and (b). The target product well maintains the biological skeleton, has higher yield, and fully reflects the potential research significance of the reaction in the aspect of medicines.
Boron-containing compounds have long been favored synthetic blocks in organic chemistry because of their stable nature, low toxicity, and ease of conversion. In addition, the invention also makes the generated fluorine-containing pyran compound 3aa react with the bisboronic acid pinacol ester under the catalysis of copper to obtain a monoboronated product 4aba with 86% of separation yield, which lays a foundation for further derivative conversion and further shows the potential application value of the synthesized product. The specific reaction is shown in (c) in the following reaction.
。
In order to fully examine the reaction system of beta-trifluoromethyl-1, 3-eneyne and a methylene compound and enrich the diversity of products prepared by the invention. The invention utilizes the eneyne reagent 1a to react with cyanoacetone (2 e) and benzoyl acetonitrile (2 f) respectively to obtain target products 4ae and 4af containing cyano and fluorinated 4H-pyran active units in 82 percent and 47 percent yields. The specific reactions are shown in (a) and (b) below.
The comparison of the two can obtain better reaction effect when the two ends of the methylene are connected with functional groups with stronger absorptivity. When the eneyne reagent 1a was reacted with diethyl malonate (2 g), the gem-difluoro products 4ag-1 and 4ag-2 were obtained in isolation yields of 44% and 41%, respectively, as shown in the following (c). The formation of this product also validates the mechanism presumption of the present invention.
。
Finally, it should be noted that: the above embodiments are only for illustrating the technical solution of the present invention, and not for limiting the same; although the invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical scheme described in the foregoing embodiments can be modified or some or all of the technical features thereof can be replaced by equivalents; such modifications and substitutions do not depart from the spirit of the invention.

Claims (3)

1. A synthesis method of a monofluorinated 4H-pyran compound is characterized in that: beta-trifluoromethyl-1, 3-eneyne compound I reacts with acetylacetone II-a, ethyl acetoacetate II-b or 5, 5-dimethyl-1, 3-cyclohexanedione II-c respectively in alkali and solvent to synthesize a series of monofluorinated 4H-pyran compounds 3 under the same reaction conditions, wherein the reaction process is shown in the following reaction formula:；
Wherein: r 1 is any one of phenyl, 4-methoxyphenyl, 3-methylphenyl, 4-fluorophenyl, 3-fluorophenyl, 2-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-aminophenyl, 4-cyanophenyl, 3-pyridyl, 4-dimethylthiochroman, phenyl (S) -2- (4-isobutylphenyl) propionate or (R) -2- (4-isobutylphenyl) -N-amphetamine;
The alkali is potassium phosphate K 3PO4; the reaction solvent is N, N-dimethylformamide;
The molar ratio of the dosage of the beta-trifluoromethyl-1, 3-eneyne compound I to the dosage of the acetylacetone II-a, the acetoacetic acid ethyl ester II-b and the 5, 5-dimethyl-1, 3-cyclohexanedione II-c is 1:1.5;
the molar amount of the alkali is 100-200mol% of the beta-trifluoromethyl-1, 3-eneyne compound I;
The ratio of the beta-trifluoromethyl-1, 3-eneyne compound I to the solvent used is 1mmol (1-15) mL;
The reaction temperature is 50 ℃; the reaction time was 4h.
2. The method for synthesizing a monofluorinated 4H-pyran compound according to claim 1, characterized in that: the molar amount of the potassium phosphate is 150mol percent of the raw material beta-trifluoromethyl-1, 3-eneyne compound I.
3. The method for synthesizing a monofluorinated 4H-pyran compound according to claim 1, characterized in that: the ratio of beta-trifluoromethyl-1, 3-eneyne compound I to the solvent used was 1 mmol/2 mL.
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