CN111635312A - Synthesis method of (E) -2-fluoroalkyl-3-butenoate compound - Google Patents
Synthesis method of (E) -2-fluoroalkyl-3-butenoate compound Download PDFInfo
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Abstract
The invention belongs to the technical field of chemical organic synthesis, and discloses a copper-catalyzed alkyne, diazo compound and 2-fluoro malonic acid dialkyl ester derivative through alkyne 1, 1-bifunctional reaction, and one-step synthesis of (E) -2-fluoroalkyl-3-butenoate compound: (ii) a dialkyl 2-fluoromalonate derivative is used as a monofluoroalkyl reagent, and a monofluoroalkyl group is introduced into an alkyne at the end to form a compound containing a quaternary C-F centerE) -2-fluoroalkyl-3-butenoate compound. The one-step synthesis method is direct and efficient, has simple reaction steps, good selectivity and productsThe purity is higher; the used reaction substrates are all easily obtained from industry, are environment-friendly, low in price and wide in range, and can be used for synthesizing various products (A), (B), (C), (E) The (E) -2-fluoroalkyl-3-butenoate compound is high in economical efficiency and environment-friendly, and is suitable for industrial mass production.
Description
Technical Field
The invention relates to the technical field of chemical organic synthesis, in particular to a method for synthesizing an (E) -2-fluoroalkyl-3-butenoate compound.
Background
In chemical organic synthesis, crotonate compounds are important organic synthesis intermediates, and derivatives thereof are widely found in natural products. The introduction of fluorine atoms or fluorine-containing functional groups into organic molecules can obviously improve the lipophilicity and metabolic stability of the organic molecules and improve the drug effect of biological medicines. Therefore, the development of a practical and effective method for synthesizing fluorine-containing butenoate compounds is of great significance to the development of medicines, agrochemicals and organic materials. However, due to the few and difficult research methods, fluorocrotonate-containing compounds, especially fluorocrotonate-containing drug molecules containing quaternary C-F centers, currently account for a very low proportion of fluorine-containing drugs in the market and clinical development.
Due to the unique properties of fluorine-containing compounds, methods of introducing fluorine or fluorine-containing groups into organic molecules have attracted extensive attention in drug design. Despite the significant advances currently made in fluorination, trifluoromethylation and difluoroalkylation, the mono-fluoroalkyl reagents remain quite scarce, and few are available, especially in the synthesis of trifluoride compounds. Thus, there remains a need to develop efficient methods for synthesizing fluorides that utilize existing monofluoroalkylation reagents.
Alkynes have a wide range of functionalities and are readily available, and thus, bifunctional of alkynes has become a powerful new method for synthesizing a large number of chemicals, particularly multi-substituted alkenes. In this context, the 1, 2-bifunctional reaction of alkynes always predominates, whether transition metal-catalyzed or metal-free. In contrast, 1-difunctionalization of alkynes is much less than 1, 2-difunctionalization. In recent years, the study of 1, 1-difunctionalization of alkynes has been of interest, especially for reactions with diazo compounds. However, three-component selective 1, 1-difunctionalization of alkynes has been less explored due to competition for 1, 2-difunctionalization and coupling reactions of any two of the three components. Therefore, studies on 1, 1-bifunctional alkynes are very necessary.
Disclosure of Invention
The invention aims to provide a method for directly synthesizing (E) -2-fluoroalkyl-3-butenoate compounds in one step by alkyne 1, 1-bifunctional reaction of three components of alkyne, diazo compounds and 2-fluoro-malonic acid dialkyl ester derivatives under the catalysis of CuI, which comprises the following steps: taking a 2-fluoro dialkyl malonate derivative as a monofluoroalkyl reagent, introducing monofluoroalkyl into terminal alkyne, and generating the (E) -2-fluoroalkyl-3-butenoate compound containing a quaternary C-F center.
The technical scheme of the invention is as follows:
a synthetic method of (E) -2-fluoroalkyl-3-butenoate compound comprises the following synthetic route:
the compound 1 is a phenylacetylene compound with various substituents on an aromatic ring, 2-ethynyl pyridine, 2-ethynyl thiophene, 3-ethynyl thiophene, propargyl methyl ether, cyclopropyl acetylene or 1-hexyne.
The compound 2 is a diazo compound, including but not limited to the following compounds: ethyl diazoacetate and ethyl diazophenylacetate.
The compound 3 is a dialkyl 2-fluoro malonate derivative, including but not limited to the following compounds: dimethyl-2-fluoromalonate and diethyl-2-fluoromalonate.
The synthesis method of the (E) -2-fluoroalkyl-3-butenoate compound comprises the following synthesis steps: adding a solvent into a sealed tube provided with a stirrer, adding a diazo compound, alkyne and 2-fluoro-malonic acid dialkyl ester derivatives, and uniformly mixing; adding cuprous iodide and alkali into a sealing tube, filling nitrogen into a glass conduit connected with the nitrogen, and sealing the tube opening by using a cock after air is sufficiently expelled; stirring and reacting for 2.0 hours at the temperature of 80-100 ℃; cooling the reacted system to room temperature, adding distilled water into the system, extracting and combining organic phases; distilling under reduced pressure to remove the solvent of the organic phase, and performing silica gel column chromatography to obtain the product.
Further, the molar ratio of the alkyne, the diazo compound and the 2-fluoro-malonic acid dialkyl ester derivative is 1.0: 1.2-1.5: 1.5-2.0.
Further, the amount of the cuprous iodide is 10 mol%.
Further, the base is K2CO3、Na2CO3、K3PO4Or Et3N, preferably K2CO3(ii) a The amount of the base used was 1.5 equiv.
Further, the solvent is acetone or tetrahydrofuran.
Compared with the prior art, the invention has the following advantages:
(1) the invention fills the blank of the method for directly and effectively synthesizing the (E) -2-fluoroalkyl-3-butenoate compound by taking the diazo compound and the 2-fluoro malonic acid dialkyl ester derivative as coupling components and carrying out alkyne 1, 1-bifunctional reaction. The one-step synthesis method is direct and efficient, and the reaction steps are simple.
(2) The reaction substrates used in the invention are all easily obtained from industry, are environment-friendly, low in price and wide in range, and can be used for synthesizing various (E) -2-fluoroalkyl-3-butenoate compounds. Therefore, the synthesis method is high in economy and environment-friendly, and is suitable for industrial mass production.
(3) The selectivity is excellent. The interference of 1, 2-double-group functionalization and coupling reaction between two substrates is avoided as much as possible, and the obtained 1, 1-double-functionalization reaction product has higher purity.
Drawings
FIG. 1 is a scheme showing that (E) -2-fluoroalkyl-3-butenoate compound 4a1H NMR spectrum.
FIG. 2 is a diagram of (E) -2-fluoroalkyl-3-butenoate compound 4a13C NMR spectrum.
FIG. 3 is a diagram of (E) -2-fluoroalkyl-3-butenoate compound 4a19F NMR spectrum.
FIG. 4 is a diagram of (E) -2-fluoroalkyl-3-butenoate compound 4c1H NMR spectrum.
FIG. 5 is a diagram of (E) -2-fluoroalkyl-3-butenoate compound 4c13C NMR spectrum.
FIG. 6 is a diagram of (E) -2-fluoroalkyl-3-butenoate compound 4c19F NMR spectrum.
FIG. 7 is a diagram of (E) -2-fluoroalkyl-3-butenoate compound 4f1H NMR spectrum.
FIG. 8 is a drawing showing a scheme for preparing (E) -2-fluoroalkyl-3-butenoate compound 4f13C NMR spectrum.
FIG. 9 is a drawing showing a scheme for preparing (E) -2-fluoroalkyl-3-butenoate compound 4f19F NMR spectrum.
Detailed Description
To further illustrate the technical means and effects of the present invention, the following detailed description is given with reference to the accompanying drawings and specific embodiments.
Example 1
First, ethyl diazoacetate (66. mu.L, 0.6mmol), phenylacetylene (57. mu.L, 0.50mmol), and dimethyl 2-fluoromalonate (117.3mg,0.75mmol) were added to a sealed tube containing a stirrer and an acetone (1.0mL) solvent, and mixed well. Then, CuI (9.5mg,0.05mmol) and K were added2CO3(103.6mg,0.75mmol), purged with nitrogen for about 3 minutes using a nitrogen-connected glass tube, sufficiently purged of air, sealed with a cock and reacted at 80 ℃ for 2.0 hours with stirring. After the reaction, the system was cooled to room temperature, 3.0ml of distilled water was added to the reaction system, extraction was performed with ethyl acetate, the organic phases were combined, the solvent of the organic phase was removed by distillation under reduced pressure, and 146.0mg of the product 4a was obtained by silica gel column chromatography, with a yield of 86%. The reaction is shown in the following formula:
spectrogram analysis data:
Yellow oil.1H NMR(400MHz,CDCl3):＝1.24(t,J＝7.2Hz,3H),3.46(d,J＝2.0Hz,2H),3.87(s,6H),4.13(q,J＝7.2Hz,2H),7.11(s,1H),7.27-7.36(m,5H)；13C NMR(100MHz,CDCl3):＝13.9,33.7(d,J＝5.0Hz),53.5,60.9,94.8(d,J＝201.0Hz),127.1(d,J＝20.0Hz),127.9,128.3,128.4,133.6(d,J＝11.0Hz),135.1,165.5(d,J＝26.0Hz),170.5；19F NMR(376MHz,CDCl3):＝-159.9.HRMS(ESI-TOF).Calcd for C17H20FO6,[M+H]+m/z 339.1244,Found 339.1246.
example 2
First, ethyl diazoacetate (66. mu.L, 0.6mmol), 4-chlorophenylacetylene (60. mu.L, 0.50mmol), and dimethyl 2-fluoromalonate (117.3mg,0.75mmol) were added to a sealed tube containing a stirrer and an acetone (1.0mL) solvent, and mixed well. Then, CuI (9.5mg,0.05mmol) and K were added2CO3(103.6mg,0.75mmol), purged with nitrogen for about 3 minutes using a nitrogen-connected glass tube, sufficiently purged of air, sealed with a cock and reacted at 80 ℃ for 2.0 hours with stirring. After the reaction, the system was cooled to room temperature, 3.0ml of distilled water was added to the reaction system, extraction was performed with ethyl acetate, the organic phases were combined, the solvent of the organic phase was removed by distillation under reduced pressure, and 150.7mg of the product 4b was obtained by silica gel column chromatography, with a yield of 81%. The reaction is shown in the following formula:
spectrogram analysis data:
Yellow oil.1H NMR(400MHz,CDCl3):＝1.25(t,J＝7.2Hz,3H),3.43(d,J＝1.6Hz,2H),3.88(s,6H),4.14(q,J＝7.2Hz,2H),7.06(s,1H),7.23(d,J＝8.4Hz,2H),7.33(d,J＝8.4Hz,2H)；13C NMR(100MHz,CDCl3):＝14.0,33.7(d,J＝5.0Hz),53.6,61.0,94.7(d,J＝201.0Hz),127.8(d,J＝20.0Hz),128.6,129.8,132.5(d,J＝11.0Hz),133.6,133.9,165.4(d,J＝26.0Hz),170.4；19F NMR(376MHz,CDCl3):＝-160.1.HRMS(ESI-TOF).Calcdfor C17H19ClFO6,[M+H]+m/z 373.0854,Found 373.0847.
example 3
First, the flask was charged with a stirrer and acetone (1.0mL)Ethyl diazoacetate (66. mu.L, 0.6mmol), 3-ethynylthiophene (50. mu.L, 0.50mmol), dimethyl 2-fluoropropanedioate (117.3mg,0.75mmol) were added to a sealed tube of solvent and mixed well. Then, CuI (9.5mg,0.05mmol) and K were added2CO3(103.6mg,0.75mmol), purged with nitrogen for about 3 minutes using a nitrogen-connected glass tube, sufficiently purged of air, sealed with a cock and reacted at 80 ℃ for 2.0 hours with stirring. After the reaction, the system was cooled to room temperature, 3.0ml of distilled water was added to the reaction system, extraction was performed with ethyl acetate, the organic phases were combined, the solvent of the organic phase was removed by distillation under reduced pressure, and 132.4mg of the product 4c was obtained by silica gel column chromatography, with a yield of 77%. The reaction is shown in the following formula:
spectrogram analysis data:
Yellow oil.1H NMR(400MHz,CDCl3):＝1.25(t,J＝7.2Hz,3H),3.54(d,J＝1.6Hz,2H),3.86(s,6H),4.16(q,J＝7.2Hz,2H),7.01(s,1H),7.08-7.09(m,1H),7.30-7.32(m,1H),7.35(s,1H)；13C NMR(100MHz,CDCl3):＝13.9,34.1(d,J＝5.0Hz),53.4,60.9,94.9(d,J＝201.0Hz),125.0,125.5,125.7,127.6(d,J＝12.0Hz),128.2,135.8,165.4(d,J＝26.0Hz),170.3；19F NMR(376MHz,CDCl3):＝-159.4.HRMS(ESI-TOF).Calcd forC15H17FNaO6S,[M+Na]+m/z367.0628,Found 367.0622.
example 4
First, ethyl diazoacetate (66. mu.L, 0.6mmol), cyclopropylacetylene (45. mu.L, 0.50mmol), and dimethyl 2-fluoromalonate (117.3mg,0.75mmol) were added to a sealed tube containing a stirrer and acetone (1.0mL) solvent and mixed well. Then, CuI (9.5mg,0.05mmol) and K were added2CO3(103.6mg,0.75mmol), purged with nitrogen for about 3 minutes using a nitrogen-connected glass tube, sufficiently purged of air, sealed with a cock and reacted at 80 ℃ for 2.0 hours with stirring. After the reaction was completed, the system was cooled to room temperature, 3.0ml of distilled water was added to the reaction system, followed by extraction with ethyl acetate and combination ofThe organic phase was distilled off under reduced pressure to remove the solvent from the organic phase, and the resulting extract was separated by silica gel column chromatography to obtain 52.9mg of product 4d with a yield of 35%. The reaction is shown in the following formula:
spectrogram analysis data:
Yellow oil.1H NMR(400MHz,CDCl3):＝0.49-0.52(m,2H),0.83-0.88(m,2H),1.24(t,J＝7.2Hz,3H),1.46-1.54(m,1H),3.40(s,2H),3.82(s,6H),4.13(q,J＝7.2Hz,2H),5.34(d,J＝10.0Hz,1H)；13C NMR(100MHz,CDCl3):＝7.6,10.8,14.1,33.1(d,J＝4.0Hz),53.4,60.8,94.9(d,J＝199.0Hz),122.6(d,J＝20.0Hz),139.5(d,J＝11.0Hz),165.8(d,J＝26.0Hz),170.5；19F NMR(376MHz,CDCl3):＝-159.0.HRMS(ESI-TOF).Calcdfor C14H19FNaO6,[M+Na]+m/z325.1063,Found 325.1066.
example 5
First, ethyl diazophenylacetate 2b (114mg,0.6mmol), phenylacetylene (57. mu.L, 0.50mmol), and dimethyl 2-fluoromalonate (117.3mg,0.75mmol) were added to a sealed tube containing a stirrer and a tetrahydrofuran (1.0mL) solvent and mixed well. Then, CuI (9.5mg,0.05mmol) and K were added2CO3(103.6mg,0.75mmol), purged with nitrogen for about 3 minutes using a nitrogen-connected glass tube, sufficiently purged of air, sealed with a cock and reacted at 80 ℃ for 2.0 hours with stirring. After the reaction, the system was cooled to room temperature, 3.0ml of distilled water was added to the reaction system, extraction was performed with ethyl acetate, the organic phases were combined, the solvent of the organic phase was removed by distillation under reduced pressure, and 156.0mg of the product 4e was obtained by silica gel column chromatography, with a yield of 39%. The reaction is shown in the following formula:
spectrogram analysis data:
Yellow oil.1H NMR(400MHz,CDCl3):＝3.52(s,3H),3.69(s,3H),3.88(s,3H),5.14(s,1H),7.11(s,1H),7.18-7.24(m,6H),7.29-7.35(m,4H)；13C NMR(100MHz,CDCl3):＝50.3(d,J＝2.0Hz),52.2,53.3,53.7,95.5(d,J＝200.0Hz),127.2,128.0,128.5(d,J＝3.0Hz),129.7(d,J＝2.0Hz),132.1,132.3,134.5,134.5,135.3,135.6,165.6(d,J＝26.0Hz),165.9(d,J＝25.0Hz),171.3；19F NMR(376MHz,CDCl3):＝-160.4.HRMS(ESI-TOF).Calcd for C22H21FNaO6,[M+Na]+m/z 423.1220,Found 423.1212.
example 6
First, ethyl diazoacetate (66. mu.L, 0.6mmol), phenylacetylene (57. mu.L, 0.50mmol), and 2-fluoroacetylacetylmorphine 3b (142.0mg,0.75mmol) were added to a sealed tube containing a stirrer and an acetone (1.0mL) solvent, and mixed well. Then, CuI (9.5mg,0.05mmol) and K were added2CO3(103.6mg,0.75mmol), purged with nitrogen for about 3 minutes using a nitrogen-connected glass tube, sufficiently purged of air, sealed with a cock and reacted at 80 ℃ for 2.0 hours with stirring. After the reaction, the system was cooled to room temperature, 3.0ml of distilled water was added to the reaction system, extraction was performed with ethyl acetate, the organic phases were combined, the solvent of the organic phase was removed by distillation under reduced pressure, and 132.0mg of the product 4f was obtained by silica gel column chromatography, with a yield of 70%. The reaction is shown in the following formula:
spectrogram analysis data:
Yellow oil.1H NMR(400MHz,CDCl3):＝1.24(t,J＝7.2Hz,3H),2.36(d,J＝3.6Hz,3H),3.03(dd,J1＝1.6Hz,J2＝16.8Hz,1H),3.44(d,J＝17.2Hz,1H),3.52-3.80(m,8H),4.11-4.17(m,1H),6.86(s,1H),7.30-7.38(m,5H)；13C NMR(100MHz,CDCl3):＝14.0,26.1,34.0(d,J＝5.0Hz),43.0,46.8(d,J＝9.0Hz),61.1,66.4,66.6,102.3(d,J＝196.0Hz),127.8(d,J＝21.0Hz),128.2,128.4,128.6,134.5(d,J＝8.0Hz),134.9,164.5(d,J＝21.0Hz),171.1,198.9(d,J＝30.0Hz)；19F NMR(376MHz,CDCl3):＝-157.7.HRMS(ESI-TOF).Calcd for C20H24FNNaO5,[M+Na]+m/z 400.1536,Found 400.1528.
the above description is only for the specific embodiment of the present invention, but the protection scope of the present invention is not limited thereto, and other modifications or equivalent substitutions made by the technical solution of the present invention by the ordinary skilled in the art should be covered within the scope of the claims of the present invention without departing from the spirit and scope of the technical solution of the present invention.
Claims (9)
1. A method for synthesizing (E) -2-fluoroalkyl-3-butenoate is characterized in that the synthetic route is as follows:
2. the method for synthesizing (E) -2-fluoroalkyl-3-butenoate according to claim 1, wherein the compound 1 is a phenylacetylene compound having various substituents on the aromatic ring, 2-ethynyl pyridine, 2-ethynyl thiophene, 3-ethynyl thiophene, propargyl methyl ether, cyclopropylacetylene or 1-hexyne.
3. The process for the synthesis of (E) -2-fluoroalkyl-3-butenoate according to claim 1, wherein said compound 2 is a diazo compound, including but not limited to the following compounds: ethyl diazoacetate and ethyl diazophenylacetate.
4. The method for the synthesis of (E) -2-fluoroalkyl-3-butenoate according to claim 1, wherein said compound 3 is a dialkyl 2-fluoro malonate derivative, including but not limited to the following compounds: dimethyl-2-fluoromalonate and diethyl-2-fluoromalonate.
5. Process for the synthesis of (E) -2-fluoroalkyl-3-butenoate according to any one of claims 1 to 4, characterized by comprising the following steps: adding a solvent into a sealed tube provided with a stirrer, adding a diazo compound, alkyne and 2-fluoro-malonic acid dialkyl ester derivatives, and uniformly mixing; adding cuprous iodide and alkali into a sealing tube, filling nitrogen into a glass conduit connected with the nitrogen, and sealing the tube opening by using a cock after air is sufficiently expelled; stirring and reacting for 2.0 hours at the temperature of 80-100 ℃, and cooling a system after the reaction to room temperature; adding distilled water into the system, extracting, and combining organic phases; distilling under reduced pressure to remove the solvent of the organic phase, and performing silica gel column chromatography to obtain the product.
6. The method for synthesizing (E) -2-fluoroalkyl-3-butenoate according to claim 5, wherein the molar ratio of the diazo compound to the alkyne to the dialkyl 2-fluoromalonate derivative is 1.0:1.2 to 1.5:1.5 to 2.0.
7. The method for synthesizing (E) -2-fluoroalkyl-3-butenoic acid ester according to claim 5, wherein the amount of cuprous iodide used is 10 mol%.
8. The method for synthesizing (E) -2-fluoroalkyl-3-butenoate according to claim 5, wherein said base is K2CO3、Na2CO3、K3PO4Or Et3N, preferably K2CO3(ii) a The amount of the base used was 1.5 equiv.
9. The method for synthesizing (E) -2-fluoroalkyl-3-butenoate according to claim 5, wherein the solvent is acetone or tetrahydrofuran.
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| YUNHE LV等: "Copper-Catalyzed 1,1-Alkylmonofl uoroalkylation of Terminal Alkynes with Diazo Compounds and 2 ‑Fluoro-1,3-dicarbonyl Compounds: Access toward ( E )‑ β-Mono fl uoroalkyl-β, γ-unsaturated Esters or Ketones", 《J. ORG. CHEM. 》 * |
| YUNHE LV等: "Copper-catalyzed 1,1-arylalalkynes with diazo esters and organoboronic akylation of terminal acids", 《CHEM COMM》 * |
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