CN110683943B - Fluoro 1, 3-eneyne compound and preparation method thereof - Google Patents
Fluoro 1, 3-eneyne compound and preparation method thereof Download PDFInfo
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Abstract
The invention relates to a fluoro 1, 3-eneyne compound and a preparation method thereof, which comprises the steps of mixing an alpha, alpha-iodine difluoroacetone compound, substituted terminal alkyne, a catalyst and alkali according to the molar ratio of (1-1.5) to (1.5-2.5) to (0.01-0.1) to (1-2) under the protection of inert gas, adding the mixture into a solvent, and carrying out reaction separation and purification to obtain the target fluoro 1, 3-eneyne compound. Compared with the prior art, the preparation method for synthesizing the 1, 3-eneyne compound is a one-pot method, has the advantages of high yield, mild reaction conditions, high selectivity, wide functional group compatibility, simple preparation method, easy operation and the like, and has better industrial production prospect.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and relates to a fluoro 1, 3-eneyne compound and a preparation method thereof.
Background
After the fluorine atom or the fluorine-containing group is introduced into the organic compound molecule, the physical property, the chemical property and the physiological property (such as lipophilicity, metabolic stability, binding capacity with target protein, cell membrane penetrability and bioavailability) of the organic compound are obviously improved compared with the parent molecule. With the wide application of fluorine-containing organic compounds in the fields of medicines, pesticides, materials and the like, the method is particularly important for developing a new synthetic method of the fluorine-containing organic compounds.
1, 3-eneyne compounds (1, 3-enyne) are important unsaturated compounds, which are important structural units and synthetic building blocks of a plurality of natural products and drug intermediates, such as terbinafine and the like. 1,3-enyne compounds are also multifunctional building blocks in material science. At present, the synthesis of 1, 3-eneynes has been reported in the literature, for example: (1) laurean.i, takumi.y, eiichi.n.syn.lett.2014,25,0527; (2) fateh.v.s, mineia.w, rafel.c.g.syn.lett.2008,12,1889; (3) Chao, feng, daming, yang, luo, org, lett, 2014,16,5956, (4) carlo.b, lucia.c, valria.v.syn, lett, 2016,03,2079; (5) Xin xin.q, x.f.wu.et al.eur.j.org.chem.2017,2940-2943. The synthetic methods reported in the above documents include a coupling reaction from an alkenyl halide to obtain a 1,3-enyne compound and a reaction of a substrate with a special structure under the action of a catalyst to produce the 1,3-enyne compound, and the two methods have the disadvantages of narrow application range, complicated steps and the like.
Chinese patent CN101492340A discloses a preparation method of a 1, 3-eneyne compound, which is characterized in that under the protection of nitrogen at room temperature, an alkenyl iodine compound, substituted terminal alkyne, a catalyst, cesium carbonate and a ligand are mixed according to the molar ratio of (1-1.5) to (1-3) to (0.1-0.15) to (0.1-0.3), then the mixture is put into a solvent of toluene and xylene, heated to 110 ℃, reacted for 36-72 hours, and separated and purified to obtain the compound. The synthesis of 1, 3-eneyne compounds in the above patent uses Sonigoshira coupling, which uses aryl or alkenyl iodine as a substrate, to obtain 1, 3-eneyne compounds, wherein the alkenyl iodine still needs to be prepared in steps, the reaction conditions are harsh, and the reaction time is long.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a fluoro 1, 3-eneyne compound and a preparation method thereof. The invention starts from alpha, alpha-iodine difluoroacetone compounds, synthesizes 1, 3-eneyne compounds by a one-pot method, generates alkenyl iodide through addition in the reaction process, and then carries out Sonigoshira coupling, and has the advantages of one-pot method, high selectivity, high yield and the like
The purpose of the invention can be realized by the following technical scheme:
a fluoro 1, 3-eneyne compound has a structural formula shown as follows:
wherein R is 1 、R 2 Respectively one of phenyl, phenyl containing substituent, alkyl or heterocyclic group.
Further, when R is 1 When it is a substituted phenyl group, saidThe substituent comprises one or more of a fluorine substituent, a bromine substituent, a chlorine substituent, trifluoromethoxy, methoxy, trifluoromethyl, methyl or phenyl;
when R is 2 When the phenyl group contains a substituent, the substituent comprises one or more of a fluorine substituent, a bromine substituent, a chlorine substituent, a trifluoromethyl group, a methoxy group, a methyl group, a phenyl group, an ethyl group, a propyl group, a tert-butyl group or a methyl group.
The preparation method of the fluoro 1, 3-eneyne compound comprises the following steps: under the protection of nitrogen, mixing alpha, alpha-iododifluoroketone compound shown as a formula I, substituted terminal alkyne shown as a formula II, a catalyst and alkali according to a molar ratio of (1-1.5) to (1.5-2.5) to (0.01-0.1) to (1-2), adding the mixture into a solvent toluene, reacting for 4-10h at 40-90 ℃, and separating and purifying to obtain the fluoro 1, 3-eneyne compound shown as a formula III.
Preferably, the equivalent ratio of the alpha, alpha-iododifluoroketone compound to the substituted terminal alkyne is 1.5-2.0, when the equivalent ratio of the substituted terminal alkyne is 0.5.eq-1.0eq, the addition of the by-product and the alkenyl iodide are more, the catalyst has better catalytic effect when the amount of the catalyst is 5mol%, the yield of the target product is reduced when the amount of the catalyst is 1mol%, the reaction has better reaction effect when the amount of the preferred base is 2.0eq, the reaction temperature is between 40 ℃ and 90 ℃, the reaction time is long when the temperature is too low, and the yield of the target compound III is reduced.
The alpha, alpha-iododifluoroketone compound shown in the formula I can be prepared by the following preparation method:
1) Mixing the methyl-containing acetone compound shown as a formula IV with ethyl trifluoroacetate, adding the mixture into anhydrous diethyl ether or anhydrous tetrahydrofuran (30 ml), and adding an initiator NaH, wherein the molar ratio of the methyl-containing acetone compound shown as the formula IV to the ethyl trifluoroacetate to the initiator is 1.25:2.5, reacting at room temperature for 2 hours, quenching the reaction product, adjusting the pH value, extracting, drying and concentrating to obtain a compound shown as a formula V;
2) Mixing the compound shown as the formula V with a selective fluorination reagent (N-fluorine-N' - (fluoromethyl) triethylenediamine bistetrafluoroborate) (according to a molar ratio of 1: 2.2), adding the mixture into 30ml of acetonitrile, reacting for 4-8h at 50 ℃, and extracting, drying and concentrating the reaction product to obtain the compound shown as the formula VI;
3) Adding a compound shown as a formula VI into anhydrous tetrahydrofuran, and adding LiBr and I 2 、Et 3 N, wherein, the compound shown as the formula VI, liBr and I 2 And Et 3 And (2) reacting at room temperature for 0.5h, wherein the molar ratio of N is 1.
The preparation of α, α -iododifluoroketones can also be referred to the following references: j.p.john, d.a.colby, j.org.chem.76 (2011) 9163-9168
Further, the catalyst used was palladium tetrakistriphenylphosphine. Because the price of the tetrakistriphenylphosphine palladium is cheaper than that of other palladium catalysts, and the fluorine substituted 1, 3-eneyne product obtained by taking the tetrakistriphenylphosphine palladium as the catalyst has higher yield.
Further, the base used includes one of potassium carbonate, potassium phosphate, triethylamine or cesium carbonate. The base acts as a dehalogenation. Further, the base used is potassium phosphate. Potassium phosphate is used as alkali, and the yield of the target product is better than that of other target products.
Furthermore, the reaction temperature is 75-85 ℃, and the reaction time is 4-8h.
The reaction product is low in conversion rate and the yield of the target compound III is reduced due to the excessively low temperature, and the reaction time is too short, so that the product is added as a byproduct.
Furthermore, the mol ratio of the alpha, alpha-iodine difluoroacetone compound to the substituted terminal alkyne is 1 (1). The equivalent ratio of the alpha, alpha-iododifluoroketone compound to the substituted terminal alkyne should be 1.5-2.0, and when the amount of the substituted terminal alkyne is less, the addition amount of the byproduct alkenyl iodide is more and the atom economy of the alpha, alpha-iododifluoroketone compound is low.
Further, the separation and purification process comprises the steps of extracting the mixture after reaction, and then carrying out column chromatography separation.
Further, the extractant used in the extraction process is ethyl acetate;
the eluent used in the column chromatography separation process is a mixture of petroleum ether and ethyl acetate in a volume ratio of (300-50): 1. The petroleum ether and ethyl acetate system is commonly used for separation and purification, when the volume ratio of petroleum ether to ethyl acetate is smaller, the polarity of the eluent is higher, the product is easy to elute with impurities, the purity is reduced, when the volume ratio of petroleum ether to ethyl acetate is larger, the polarity of the eluent is lower, the column separation time is longer, and the efficiency is lower.
Compared with the prior art, the preparation method for synthesizing the 1, 3-eneyne compound is a one-pot method, has the advantages of high yield, mild reaction conditions, high selectivity, wide functional group compatibility, simple preparation method, easy operation and the like, and has better industrial production prospect.
Detailed Description
The present invention will be described in detail with reference to specific examples. The present embodiment is implemented on the premise of the technical solution of the present invention, and a detailed implementation manner and a specific operation process are given, but the scope of the present invention is not limited to the following embodiments.
The iododifluoroketones such as α, α -iododifluoroacetophenone used in examples 1 to 7 are known compounds and prepared by themselves, and reference may be made to the following methods:
(1).J.P.John,D.A.Colby,J.Org.Chem.76(2011)9163-9168；
(2).H.Chen,J.X.Wang,J.J.Wu,Y.J.W.Huang,F.H.Wu,J.Fluorine.Chem 200(2017)41–46；
(3)P.Peng,J.J.Wu,J.Q.Liang,T.Y.Zhang,J.W.Huang,F.H.Wu,RSC Adv.,7(2017)56034–56037；
(4).J.X.Wang,J.J.Wu,H.Chen,S.W.Zhang,F.H.Wu,Chin Chem Lett.26(2015)1381–1384.
(5).D.F.Wang,J.J.Wu,J.W.Huang,J.Q.Liang,P.Peng,H.Chen,F.H.Wu,Tetrahedron 73(2017)3478-3484；
(6).P.Peng,G.Z.Huang,Y.X.Sun,X.Wang,J.J.Wu,F.H.Wu,Org.Biomol.Chem.17(2019)6426–6431。
example 1:
(E) -2, 2-difluoro-1, 4, 6-triphenyl-3-en-5-yn-1-one
Potassium phosphate (0.212g, 1mmol) was placed in a 10mL pressure-resistant reaction tube, tetratriphenylphosphine palladium (0.057g, 0.05mmol) was added and nitrogen was substituted three times, α -iododifluoroacetophenone (0.282g, 1mmol), phenylacetylene (204mg, 2mmol) were dissolved in 3mL toluene and added to the pressure-resistant reaction tube, and reacted at 80 ℃ for 4 to 10 hours, and completion of the reaction was monitored by Thin Layer Chromatography (TLC). Quenching the reaction by water, extracting the mixed solution obtained after the reaction for 4 times by using ethyl acetate, collecting an organic phase, concentrating, performing column chromatography separation by using a mixture of petroleum ether and ethyl acetate with the volume ratio of 200 as an eluent, and finally obtaining a yellow oily liquid (yield is 85%), namely the target product (E) -2, 2-difluoro-1, 4, 6-triphenyl-3-en-5-alkyne-1-ketone). Performing nuclear magnetic resonance hydrogen spectrum, nuclear magnetic resonance carbon spectrum, nuclear magnetic resonance fluorine spectrum characterization and high-resolution mass spectrum on the oily liquid, wherein the characterization results are as follows:
1 H NMR(500MHz,CDCl 3 ):δ7.78(d,J＝7.8Hz,2H),7.56(t,J＝7.4Hz,1H),7.43(dd,J＝7.6,1.7Hz,2H),7.37(t,J＝7.9Hz,2H),7.32(m,4H),7.25(m,4H),6.57(t,J＝12.8Hz,1H)；
13 C NMR(125MHz,CDCl 3 ):δ187.19(t, 2 ’J C-F ＝29.38Hz),135.58,134.07,133.96(t, 3 J C-F ＝9.375Hz),131.84,129.75,129.73,129.71,129.12,128.79,128.43,128.09,127.59(t, 2 J C-F ＝26.875Hz),126.69,122.19,114.73(t, 1 J C-F ＝246.25Hz),93.66,89.32；
19 F NMR(376Hz,CDCl 3 ):δ-88.25(d,J＝11.28Hz,2F)；
HRMS(EI-TOF)calculated[M]+for C 24 H 16 F 2 O:358.1169,found:358.1165.
example 2:
(E) -2, 2-difluoro-1- (4-fluorophenyl) -4, 6-diphenyl-3-en-5-yn-1-one
Potassium phosphate (0.212g, 1mmol) was placed in a 10mL pressure-resistant reaction tube, tetratriphenylphosphine palladium (0.057g, 0.05mmol) was added, nitrogen gas was replaced three times, 2-difluoro-2-iodo-1-phenylethane-1-one (0.3g, 1mmol), phenylacetylene (204mg, 2mmol) were dissolved in 3mL toluene and added to the pressure-resistant reaction tube, and the reaction was allowed to react at 80 ℃ for 4 to 10 hours, and the completion of the reaction was monitored by TLC. The reaction was quenched with water, and the mixture after the reaction was extracted 4 times with ethyl acetate, the organic phase was collected, concentrated, and column chromatography was performed using a mixture of petroleum ether and ethyl acetate at a volume ratio of 200 as an eluent to obtain a yellow oily liquid (yield 75%) which was the target product (E) -2, 2-difluoro-1- (4-fluorophenyl) -4, 6-diphenyl-3-en-5-yn-1-one (please confirm).
Performing nuclear magnetic resonance hydrogen spectrum, nuclear magnetic resonance carbon spectrum and nuclear magnetic resonance fluorine spectrum characterization on the oily liquid, wherein the characterization results are as follows:
1 H NMR(500MHz,CDCl 3 ):δ7.80(dd,J＝8.5,5.5Hz,2H),7.43(d,J＝7.8Hz,2H),7.31(d,J＝7.6Hz,4H),7.24(d,J＝5Hz,4H)；7.04(t,J＝7.5Hz,2H),6.56(t,J＝12.75Hz,1H)；
13 C NMR(125MHz,CDCl 3 ):δ185.6(t, 2 ’J C-F ＝29.375Hz),166.20(d, 1 ”J C-F ＝256.25Hz),135.52,134.16(t, 3 ’J C-F ＝9.375Hz),132.55(d, 3 ”J C-F ＝10Hz),131.85,129.21,129.18,128.80,128.45,128.21,128.12,127.37(t, 2 J C-F ＝26.875),122.12,115.72(d, 2 ”J C-F ＝21.25Hz),114.68(t, 1 J C-F ＝246.25),93.88,89.19；
19 F NMR(376MHz,CDCl 3 ):δ-88.15(d,J＝11.28Hz,2F),δ-102.54(m,1F)；
HRMS(ESI-TOF)calculated[M+H] + for C 24 H 15 F 3 O:376.1153，found:377.1154
example 3:
(E) -2, 2-difluoro-4, 6-bis (4-fluorophenyl) -1-phenylhex-3-en-5-yn-1-one
Potassium phosphate (0.212g, 1mmol) was placed in a 10mL pressure-resistant reaction tube, tetratriphenylphosphine palladium (0.057g, 0.05mmol) was added and nitrogen was substituted three times, α, α, α -iododifluoroacetophenone (0.282g, 1mmol), 4-fluoroacetylene (240mg, 2mmol) were dissolved with 3mL of toluene and added to the pressure-resistant reaction tube, and reacted at 80 ℃ for 4 to 10 hours, and the completion of the reaction was monitored by TLC. Quenching the reaction by using water, extracting the mixed solution after the reaction by using ethyl acetate for 4 times, collecting an organic phase, concentrating, and performing column chromatography separation by using a mixture of petroleum ether and ethyl acetate with the volume ratio of 200 as an eluent to obtain a yellow oily liquid (yield is 80%), wherein the yellow oily liquid is the target product (E) -2, 2-difluoro-4, 6-bis (4-fluorophenyl) -1-phenylhex-3-en-5-alkyne-1-ketone.
Performing nuclear magnetic resonance hydrogen spectrum, nuclear magnetic resonance carbon spectrum and nuclear magnetic resonance fluorine spectrum characterization on the oily liquid, wherein the characterization results are as follows:
1 H NMR(500MHz,CDCl 3 ):δ7.75(d,J＝7.8Hz,2H),7.51(t,J＝7.4Hz,1H),7.34(t,J＝7.0Hz,4H),7.18-7.15(m,2H),6.95(t,J＝7.5Hz,2H),6.87(t,J＝10Hz,2H),6.49(t,J＝12.8Hz,1H)；
13 C NMR(125MHz,CDCl 3 ):δ187.11(t, 2 ’JC-F＝30Hz),163.12(d, 1 ”J C-F ＝248.75Hz),163.03(d, 1 ”’J C-F ＝250Hz),134.20,133.85,133.79,132.72(t, 3 J C-F ＝9.375Hz),131.68,130.75,130.68,128.50,127.72(t, 2 J C-F ＝26.875Hz),115.58(d, 2 ”J C-F ＝85Hz),115.2(d, 2 ”’J C-F ＝85Hz),114.66(t, 1 J C-F ＝246.875Hz),92.69,88.83；
19 F NMR(376MHz,CDCl3):δ-89.42(d,J＝12.5Hz,2F),-109.95(s,1F),-112.41(s,1F)；
HRMS(ESI-TOF)calculated[M+H]+for C 24 H 14 F 4 O:395.1059,found:395.1055
example 4:
(E) -4, 4-difluoro-1, 6, 8-triphenyl-5-en-7-yn-3-one
Potassium phosphate (0.212g, 1mmol) was placed in a 10mL pressure-resistant reaction tube, tetrakistriphenylphosphine palladium (0.057g, 0.05mmol) was added and nitrogen was substituted three times, 1-difluoro-1-iodo-4-phenylbutan-2-one (0.310g, 1mmol), phenylacetylene (204mg, 2mmol) were dissolved in 3mL toluene and added to the pressure-resistant reaction tube, and the reaction was carried out at 80 ℃ for 4 to 10 hours, and the completion of the reaction was monitored by TLC. Quenching the reaction by water, extracting the mixed solution after the reaction by ethyl acetate for 4 times, collecting an organic phase, concentrating, and performing column chromatography separation by using a mixture of petroleum ether and ethyl acetate with a volume ratio of 200 as an eluent to obtain a yellow oily liquid (yield is 75%), namely the target product (E) -4, 4-difluoro-1, 6, 8-triphenyl-5-en-7-yn-3-one).
Performing nuclear magnetic resonance hydrogen spectrum, nuclear magnetic resonance carbon spectrum and nuclear magnetic resonance fluorine spectrum characterization on the oily liquid, wherein the characterization results are as follows:
1 H NMR(500MHz,CDCl3):δ7.43(d,J＝10Hz,2H),7.41-7.38(m,2H),7.36(d,J＝5Hz,3H),7.32(t,J＝5Hz,3H),7.24(t,J＝7.4Hz,2H),7.18(t,J＝7.5Hz,1H),7.08(d,J＝5Hz,2H),6.33(t,J＝15Hz,1H)；
13 C NMR(125MHz,CDCl3):198.26(t, 2 J C-F ＝30.62Hz),140.13,135.97,134.29(t, 3 J C-F ＝9.375Hz),131.84,129.18,129.14,128.72,128.58,128.44,128.32,128.28,126.62(t, 2 J C-F ＝26.875Hz),126.36,122.19,113.97(t, 1 J C-F ＝246.87Hz),93.91,89.17,38.51,28.69；
19 F NMR(376MHz,CDCl 3 ):δ-95.14(d,J＝12.7Hz,2F)；
HRMS(ESI-TOF)calculated[M+H] + for C 26 H 20 F 2 o:387.1560, found:386.1559 example 5:
(E) -2, 2-difluoro-1-phenyl-4, 6-bis (4-propylphenyl) hex-3-en-5-yn-1-one
Potassium phosphate (0.212g, 1mmol) was placed in a 10mL pressure-resistant reaction tube, tetratriphenylphosphine palladium (0.057g, 0.05mmol) was added, nitrogen gas was replaced three times, α -iododifluoroacetophenone (0.282g, 1mmol), 4-propyl-phenylacetylene (288mg, 2mmol) were dissolved in 3mL toluene and added to the pressure-resistant reaction tube, and reacted at 80 ℃ for 4 to 10 hours, and the completion of the reaction was monitored by TLC. Quenching the reaction by water, extracting the mixed solution after the reaction by ethyl acetate for 4 times, collecting an organic phase, concentrating, and performing column chromatography separation by using a mixture of petroleum ether and ethyl acetate with a volume ratio of 200 as an eluent to obtain a yellow oily liquid (yield 76%), wherein the yellow oily liquid is the target product (E) -2, 2-difluoro-1-phenyl-4, 6-di (4-propylphenyl) hex-3-en-5-alkyne-1-ketone.
Performing nuclear magnetic resonance hydrogen spectrum, nuclear magnetic resonance carbon spectrum and nuclear magnetic resonance fluorine spectrum characterization on the oily liquid, wherein the characterization results are as follows:
1 H NMR(500MHz,CDCl 3 ):δ7.74(d,J＝5Hz,2H),7.52(t,J＝7.5Hz,1H),7.36-7.33(m,4H),7.12(dd,J＝11.9,8.2Hz,4H),7.02(d,J＝8.2Hz,2H),6.53(t,J＝12.6Hz,1H),2.57-2.54(m,4H),1.65-1.57(m,4H),0.93(dt,J＝21.8,7.3Hz,6H)；
13 C NMR(125MHz,CDCl 3 ):187.18(t, 2 ’J C-F ＝29.375Hz),144.41,143.97,134.17(t, 3 J C-F ＝10Hz),133.90,132.98,131.93,131,76,129.61,128.81,128.60,128.31,128.13,126.90(t, 2 J C-F ＝27.5Hz),119.45,114.75(t, 1 J C-F ＝245.62Hz),93.72,89.00,38.00,37.84,24.44,24.29,13.83,13.73；
19 F NMR(376MHz,CDCl 3 ):δ-87.72(d,J＝11.28Hz,2F)；
HRMS(ESI-TOF)calculated[M]+for C 30 H 28 F 2 O:443.2186，found：443.2180
example 6:
(E) -2, 2-difluoro-4, 6-diphenyl-1- (p-tolyl) hex-3-en-5-yn-1-one
Potassium phosphate (0.212g, 1mmol) was placed in a 10mL pressure-resistant reaction tube, tetratriphenylphosphine palladium (0.057g, 0.05mmol) was added and nitrogen was substituted three times, 4-methyl-. Alpha.,. Alpha. -iododifluoroacetophenone (0.372g, 1mmol), phenylacetylene (204mg, 2mmol) were dissolved with 3mL of toluene and added to the pressure-resistant reaction tube, and reacted at 80 ℃ for 4 to 10 hours, and the completion of the reaction was monitored by TLC. And (2) quenching the reaction by using water, extracting the mixed solution after the reaction for 4 times by using ethyl acetate, collecting an organic phase, concentrating, and performing column chromatography separation by using a mixture of petroleum ether and ethyl acetate with the volume ratio of 200 as an eluent to obtain a yellow oily liquid (yield 76%), wherein the yellow oily liquid is the target product (E) -2, 2-difluoro-4, 6-diphenyl-1- (p-tolyl) hex-3-en-5-yn-1-one.
Performing nuclear magnetic resonance hydrogen spectrum, nuclear magnetic resonance carbon spectrum and nuclear magnetic resonance fluorine spectrum characterization on the oily liquid, wherein the characterization results are as follows:
1 H NMR(500MHz,CDCl 3 ):δ7.81(d,J＝5Hz,2H),7.72(dd,J＝13.3,7.4Hz,1H),7.43(d,J＝5Hz,3H),7.30-7.23(m,6H),6.85(d,J＝10Hz,2H),6.56(t,J＝13.0Hz,1H),2.37(s,3H)；
13 C NMR(125MHz,CDCl 3 ):δ186.81(t, 2 ’J C-F ＝28.75Hz),145.24,135.64,133.80(t, 3 J C-F ＝9.375Hz),131.83,129.94,129.18,129.08,129.05,128.78,128.42,128.05,127.71(t, 2 J C-F ＝26.875Hz),122.24,122.19,114.82(t, 1 J C-F ＝246.25Hz),93.53,89.43,21.81；
19 F NMR(376Hz,CDCl 3 ):δ-89.30(d,J＝12.06Hz,2F)；
HRMS(ESI-TOF)calculated[M+H]+for C 25 H 18 F 2 O:373.1404,found:373.1399
example 7:
(E) -4, 6-bis (4-ethylphenyl) -2, 2-difluoro-1-phenylhex-3-en-5-yn-1-one
Potassium phosphate (0.212g, 1mmol) was placed in a 10mL pressure-resistant reaction tube, tetratriphenylphosphine palladium (0.057g, 0.05mmol) was added, nitrogen gas was replaced three times, α, α, α -iododifluoroacetophenone (0.282g, 1mmol), 4-ethylphenylacetylene (260mg, 2mmol) were dissolved with 3mL of toluene and added to the pressure-resistant reaction tube, and reacted at 80 ℃ for 4 to 10 hours, and the completion of the reaction was monitored by TLC. Quenching the reaction with water, extracting the mixed solution after the reaction with ethyl acetate for 4 times, collecting an organic phase, concentrating, performing column chromatography separation by using a mixture of petroleum ether and ethyl acetate with a volume ratio of 200 as an eluent, and finally obtaining a yellow oily liquid (yield 76%), namely the target product (E) -4, 6-bis (4-ethylphenyl) -2, 2-difluoro-1-phenylhex-3-en-5-yn-1-one).
Performing nuclear magnetic resonance hydrogen spectrum, nuclear magnetic resonance carbon spectrum and nuclear magnetic resonance fluorine spectrum characterization on the oily liquid, wherein the characterization results are as follows:
1 H NMR(500MHz,CDCl 3 ):δ7.75(d,J＝8Hz,2H),7.52(t,J＝7.5Hz,1H),7.36-7.33(m,4H),7.14(dd,J＝10.6,8.2Hz,4H),7.05(d,J＝8Hz,2H),6.52(t,J＝12.75Hz,1H),2.64-2.59(m,4H),1.24-1.89(m,6H)；
13 C NMR(125MHz,CDCl 3 ):187.28(t, 2 ’J C-F ＝28.75Hz),145.63,145.48,134.15(t, 3 J C-F ＝9.375Hz),133.90,133.03,131.96,131,85,129.61,128.87,128.32,127.98,127.53,126.81(t, 2 J C-F ＝26.875Hz),119.44,114.79(t, 1 J C-F ＝245.625Hz),93.71,88.99,28.88,28.70,15.45,15.27；
19 F NMR(376MHz,CDCl3):δ-88.91(d,J＝11.50Hz,2F)；
HRMS(ESI-TOF)calculated[M+H]+for C 28 H 24 F 2 O:415.1873，found：415.1874
example 8:
potassium carbonate (0.276g, 2mmol) was placed in a 10mL pressure-resistant reaction tube, tetrakistriphenylphosphine palladium (0.012g, 0.01mmol) was added thereto and nitrogen was substituted three times, α -iododifluoroacetophenone (0.423g, 1.5mmol), phenylacetylene (255mg, 2.5mmol) were dissolved in 3mL toluene and added to the pressure-resistant reaction tube, and the reaction was carried out at 40 ℃ for 10 hours with monitoring of completion of the reaction by Thin Layer Chromatography (TLC). Quenching the reaction by water, extracting the mixed solution obtained after the reaction for 4 times by using ethyl acetate, collecting an organic phase, concentrating, and performing column chromatography separation by using a mixture of petroleum ether and ethyl acetate with a volume ratio of 300 as an eluent to obtain the product (E) -2, 2-difluoro-1, 4, 6-triphenyl-3-en-5-yn-1-one.
Example 9:
triethylamine (0.152g, 1.5 mmol) was placed in a 10mL pressure-resistant reaction tube, tetratriphenylphosphine palladium (0.115g, 0.1mmol) was added for nitrogen substitution three times, α -iododifluoroacetophenone (0.423g, 1.5 mmol), phenylacetylene (153mg, 1.5 mmol) were dissolved with 3mL of toluene and added to the pressure-resistant reaction tube, reacted at 90 ℃ for 4 hours, and the completion of the reaction was monitored by Thin Layer Chromatography (TLC). Quenching the reaction with water, extracting the mixed solution obtained after the reaction with ethyl acetate for 4 times, collecting an organic phase, concentrating, and performing column chromatography separation by using a mixture of petroleum ether and ethyl acetate with a volume ratio of 50 as an eluent to obtain the product (E) -2, 2-difluoro-1, 4, 6-triphenyl-3-en-5-yn-1-one.
Example 10:
cesium carbonate (0.326g, 1mmol) was placed in a 10mL pressure resistant reaction tube, tetratriphenylphosphine palladium (0.057g, 0.05mmol) was added to replace with nitrogen three times, 4-trifluoromethoxy- α, α -iododifluoroacetophenone (1 mmol), 4-trifluoromethylphenylacetylene (2 mmol) were dissolved in 3mL of toluene and added to the pressure resistant reaction tube, and reacted at 75 ℃ for 8 hours, and completion of the reaction was monitored by Thin Layer Chromatography (TLC). Quenching the reaction with water, extracting the mixed solution obtained after the reaction with ethyl acetate for 4 times, collecting an organic phase, concentrating, and performing column chromatography separation by using a mixture of petroleum ether and ethyl acetate with a volume ratio of 200.
Example 11:
potassium phosphate (0.212g, 1mmol) was placed in a 10mL pressure-resistant reaction tube, tetratriphenylphosphine palladium (0.057g, 0.05mmol) was added and nitrogen was substituted three times, 4-trifluoromethoxy- α, α -iododifluoroacetophenone (1 mmol), 4-trifluoromethylphenylacetylene (2 mmol) were dissolved with 3mL of toluene and added to the pressure-resistant reaction tube, reacted at 85 ℃ for 6 hours, and completion of the reaction was monitored by Thin Layer Chromatography (TLC). Quenching the reaction with water, extracting the mixed solution obtained after the reaction for 4 times by using ethyl acetate, collecting an organic phase, concentrating, and performing column chromatography separation by using a mixture of petroleum ether and ethyl acetate with a volume ratio of 200 as an eluent to finally obtain a product.
Example 12:
potassium phosphate (0.212g, 1mmol) was placed in a 10mL pressure-resistant reaction tube, tetratriphenylphosphine palladium (0.057g, 0.05mmol) was added and nitrogen was substituted three times, and α, α -iododifluoroacetone (1 mmol), 5-methyl-1-hexyne (2 mmol) were dissolved in 3mL of toluene and added to the pressure-resistant reaction tube, reacted at 85 ℃ for 6 hours, and completion of the reaction was monitored by Thin Layer Chromatography (TLC). Quenching the reaction with water, extracting the mixed solution obtained after the reaction with ethyl acetate for 4 times, collecting an organic phase, concentrating, and performing column chromatography separation by using a mixture of petroleum ether and ethyl acetate with a volume ratio of 200.
Example 13:
potassium phosphate (0.212g, 1mmol) was placed in a 10mL pressure-resistant reaction tube, tetratriphenylphosphine palladium (0.057g, 0.05mmol) was added and nitrogen was replaced three times, 4-trifluoromethyl-. Alpha.,. Alpha. -iododifluoroacetophenone (1 mmol), 4-methoxyphenylacetylene (264 mg, 2mmol) were dissolved with 3mL of toluene and added to the pressure-resistant reaction tube, reacted at 85 ℃ for 6 hours, and completion of the reaction was monitored by Thin Layer Chromatography (TLC). Quenching the reaction with water, extracting the mixed solution obtained after the reaction for 4 times by using ethyl acetate, collecting an organic phase, concentrating, and performing column chromatography separation by using a mixture of petroleum ether and ethyl acetate with a volume ratio of 200 as an eluent to finally obtain a product.
Example 14:
potassium phosphate (0.212g, 1mmol) was placed in a 10mL pressure-resistant reaction tube, tetratriphenylphosphine palladium (0.057g, 0.05mmol) was added for nitrogen substitution three times, 4-bromo-. Alpha.,. Alpha. -iododifluoroacetophenone (1 mmol), 4-chloroacetylacetylene (2 mmol) were dissolved with 3mL of toluene and added to the pressure-resistant reaction tube, reacted at 85 ℃ for 6 hours, and the completion of the reaction was monitored by Thin Layer Chromatography (TLC). Quenching the reaction with water, extracting the mixed solution obtained after the reaction for 4 times by using ethyl acetate, collecting an organic phase, concentrating, and performing column chromatography separation by using a mixture of petroleum ether and ethyl acetate with a volume ratio of 200 as an eluent to finally obtain a product.
Example 15:
potassium phosphate (0.212g, 1mmol) was placed in a 10mL pressure resistant reaction tube, tetrakistriphenylphosphine palladium (0.057g, 0.05mmol) was added and nitrogen was substituted three times, 4-methoxy- α, α -iododifluoroacetophenone (1 mmol), 4-tert-butylacetylene (2 mmol) were dissolved in 3mL toluene and added to the pressure resistant reaction tube, and reacted at 85 ℃ for 6 hours, and completion of the reaction was monitored by Thin Layer Chromatography (TLC). Quenching the reaction with water, extracting the mixed solution obtained after the reaction for 4 times by using ethyl acetate, collecting an organic phase, concentrating, and performing column chromatography separation by using a mixture of petroleum ether and ethyl acetate with a volume ratio of 200 as an eluent to finally obtain a product.
Example 16:
potassium phosphate (0.212g, 1mmol) was placed in a 10mL pressure-resistant reaction tube, tetratriphenylphosphine palladium (0.057g, 0.05mmol) was added for nitrogen substitution three times, 4-chloro-. Alpha.,. Alpha. -iododifluoroacetophenone (1 mmol), 4-bromophenylacetylene (2 mmol) were dissolved with 3mL of toluene and added to the pressure-resistant reaction tube, reacted at 85 ℃ for 6 hours, and completion of the reaction was monitored by Thin Layer Chromatography (TLC). Quenching the reaction with water, extracting the mixed solution obtained after the reaction for 4 times by using ethyl acetate, collecting an organic phase, concentrating, and performing column chromatography separation by using a mixture of petroleum ether and ethyl acetate with a volume ratio of 200 as an eluent to finally obtain a product.
Example 17:
potassium phosphate (0.212g, 1mmol) was placed in a 10mL pressure-resistant reaction tube, tetratriphenylphosphine palladium (0.057g, 0.05mmol) was added and nitrogen was replaced three times, 2-chloro-4-phenyl-6-methyl- α, α -iododifluoroacetophenone (1 mmol), 6-fluoro-4-phenyl-2-methylphenylacetylene (2 mmol) were dissolved with 3mL of toluene and added to the pressure-resistant reaction tube, reacted at 85 ℃ for 6 hours, and the completion of the reaction was monitored by Thin Layer Chromatography (TLC). Quenching the reaction with water, extracting the mixed solution obtained after the reaction for 4 times by using ethyl acetate, collecting an organic phase, concentrating, and performing column chromatography separation by using a mixture of petroleum ether and ethyl acetate with a volume ratio of 200 as an eluent to finally obtain a product.
Example 18:
potassium phosphate (0.212g, 1mmol) was placed in a 10mL pressure-resistant reaction tube, tetratriphenylphosphine palladium (0.057g, 0.05mmol) was added and nitrogen gas was substituted three times, 1- (4-pyridyl) -2, 2-difluoro-2-iodoethane-1-one (1 mmol), propyne (2 mmol) were dissolved with 3mL of toluene and added to the pressure-resistant reaction tube, reacted at 85 ℃ for 6 hours, and completion of the reaction was monitored by Thin Layer Chromatography (TLC). Quenching the reaction with water, extracting the mixed solution obtained after the reaction for 4 times by using ethyl acetate, collecting an organic phase, concentrating, and performing column chromatography separation by using a mixture of petroleum ether and ethyl acetate with a volume ratio of 200 as an eluent to finally obtain a product.
Example 19:
potassium phosphate (0.212g, 1mmol) was placed in a 10mL pressure-resistant reaction tube, tetratriphenylphosphine palladium (0.057g, 0.05mmol) was added and nitrogen was substituted three times, α -iododifluoroacetophenone (1 mmol), 4-ethynylpyridine (2 mmol) were dissolved in 3mL toluene and added to the pressure-resistant reaction tube, and reacted at 85 ℃ for 6 hours, and completion of the reaction was monitored by Thin Layer Chromatography (TLC). Quenching the reaction with water, extracting the mixed solution obtained after the reaction for 4 times by using ethyl acetate, collecting an organic phase, concentrating, and performing column chromatography separation by using a mixture of petroleum ether and ethyl acetate with a volume ratio of 200 as an eluent to finally obtain a product.
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 modifications and alterations without departing from the scope of the present invention.
Claims (4)
1. A preparation method of a fluoro 1, 3-eneyne compound is characterized in that the compound has the following structural formula:
wherein R is 1 、R 2 Respectively is one of phenyl, phenyl containing substituent, alkyl or heterocyclic group;
when R is 1 When the phenyl group contains a substituent, the substituent comprises one or more of a fluorine substituent, a bromine substituent, a chlorine substituent, trifluoromethyl, methoxy, phenyl, methyl, ethyl or trifluoromethoxy;
when R is 2 When the phenyl group contains a substituent, the substituent comprises one or more of a fluorine substituent, a bromine substituent, a chlorine substituent, a trifluoromethyl group, a methoxy group, a phenyl group, a methyl group, an ethyl group, a propyl group or a tert-butyl group;
the preparation method specifically comprises the following steps:
under the protection of inert gas, mixing alpha, alpha-iododifluoroketone compound, substituted terminal alkyne, catalyst and alkali according to the molar ratio of (1-1.5) to (1.5-2.5) to (0.01-0.1) to (1-2), adding into solvent, reacting, separating and purifying to obtain the target product fluoro 1, 3-eneyne compound;
the structural formula of the alpha, alpha-iododifluoroketone compound is as follows:
the structural general formula of the substituted terminal alkyne is as follows:
the catalyst is palladium tetratriphenylphosphine;
the base is one of potassium carbonate, potassium phosphate, triethylamine or cesium carbonate;
the reaction temperature is 40-90 ℃, and the reaction time is 4-10h;
the mol ratio of the alpha, alpha-iododifluoroketone compound to the substituted terminal alkyne is 1 (1-2).
2. The method for preparing a fluorinated 1,3-enyne compound according to claim 1, wherein the base used is potassium phosphate.
3. The preparation method of the fluoro-1, 3-eneyne compound according to claim 1, wherein the separation and purification process comprises: and extracting the reacted mixture, and then performing column chromatography separation.
4. The method for preparing fluoro-1, 3-eneyne compounds according to claim 3, wherein the extractant used in the extraction process is ethyl acetate;
the eluent used in the column chromatography separation process is a mixture of petroleum ether and ethyl acetate in a volume ratio of (300-50): 1.
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