CN109810069B - Preparation method of polysubstituted 1,3, 5-triazine - Google Patents
Preparation method of polysubstituted 1,3, 5-triazine Download PDFInfo
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Abstract
The invention discloses a preparation method of polysubstituted 1,3, 5-triazine, which specifically comprises the steps of taking substituted formamidine hydrochloride as a reaction substrate, taking sodium difluorochloroacetate as a carbon synthon, and obtaining symmetrical or asymmetrical polysubstituted 1,3, 5-triazine by breaking carbon-chlorine, carbon-carbon and carbon-fluorine bonds under the action of equivalent inorganic base; the chemical structural general formula of the substituted formamidine hydrochloride is as follows:
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of polysubstituted 1,3, 5-triazine.
Background
1,3, 5-triazine is a very important class of nitrogen-containing heterocyclic compounds, which not only show very excellent biological activity, but also can be used as ligands of metal catalysis and organometallic materials. The conventional process generally synthesizes 2, 4-diphenyl-1, 3, 5-triazine (Angew. chem.1960,72,956; chem. Ber.1963,96,3265; Monatsh. chem.1995,126, 99; Zhurnal organic coskoi Khimii,1987,23,2443) by high temperature condensation of two molecules of benzamidine hydrochloride and some formylating agents, however the substrate range is narrow, the yield is generally low and the reaction conditions are severe. In recent years, some subjects synthesize multi-substituted 1,3, 5-triazine (org.Lett.2014,16,3082; org.Lett.2015,17,2894; org.Lett.2017,19,6228; org.Biomol.Chem.2018,16,2629; adv.Synth.Catal.2019,361,1166.) under copper or iodine catalysis by using substituted formamidine hydrochloride as a substrate and N, N-dimethylformamide, dimethyl sulfoxide, fatty ether, tertiary amine, dichloromethane and other reagents as novel carbon synthons. Although the substrates are wide ranging, catalysts and oxidants are used in the reaction and a large number of environmentally unfriendly by-products are produced.
Disclosure of Invention
Aiming at the technical problems, the invention provides a preparation method of polysubstituted 1,3, 5-triazine, which is green, environment-friendly, economical and practical.
In order to solve the technical problems, the invention adopts the following technical scheme:
a preparation method of polysubstituted 1,3, 5-triazine comprises the steps of firstly adding substituted formamidine hydrochloride, sodium difluorochloroacetate and inorganic base into a reaction container, then adding a reaction solvent, reacting for 24 hours at 80-120 ℃, quenching with water after the reaction is finished, extracting with ethyl acetate, combining organic phases, drying with anhydrous sodium sulfate, concentrating, and carrying out column chromatography with a mixed solvent of petroleum ether and ethyl acetate to obtain polysubstituted 1,3, 5-triazine.
The chemical structural general formula of the substituted formamidine hydrochloride is as follows:
wherein R is phenyl, 4-tolyl, 4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-trifluoromethylphenyl, 4-bromophenyl, 4-nitrophenyl, 3-tolyl, 3-methoxyphenyl, 3-bromophenyl, 2-tolyl, 2-ethoxyphenyl, 2-fluorophenyl, 3-pyridyl or cyclopropyl, and the substituted formamidine hydrochloride is selected from one or two of the compounds corresponding to the structural general formula.
The inorganic base is selected from one of sodium carbonate, potassium carbonate and cesium carbonate.
The reaction solvent is selected from one of acetonitrile, ethanol, dimethyl sulfoxide and N, N-dimethylformamide.
The molar ratio of the substituted formamidine hydrochloride to the sodium difluorochloroacetate to the inorganic base is (4-10) to 4: 8.
Structural general formula of substituted formamidine hydrochloride
When only one corresponding compound is used, namely R is selected from one substituent group, the molar ratio of the substituted formamidine hydrochloride, the sodium difluorochloroacetate and the inorganic base is 4:4: 8.
Structural general formula of substituted formamidine hydrochloride
When the corresponding compounds are two compounds, namely R is selected from two of the substituent groups, the molar ratio of the substituted formamidine hydrochloride, the sodium difluorochloroacetate and the inorganic base is 10:4:8, wherein the molar ratio of the two substituted formamidine hydrochlorides is 8:2 or 2: 8.
The substituent is phenyl, 4-tolyl, 4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-trifluoromethylphenyl, 4-bromophenyl, 4-nitrophenyl, 3-tolyl, 3-methoxyphenyl, 3-bromophenyl, 2-tolyl, 2-ethoxyphenyl, 2-fluorophenyl, 3-pyridyl, cyclopropyl.
Compared with the prior art, the invention has the following advantages:
1. the invention does not need any catalyst or oxidant, reduces the production cost and improves the safety;
2. the method does not need anhydrous and anaerobic operation, is simple and practical to operate, and is easy to realize large-scale production;
3. compared with the prior art, the product yield is obviously improved, the method is suitable for different substituted formamidine hydrochlorides, and the substrate range is wider;
4. the reaction byproducts in the invention are inorganic salt, carbon dioxide and water, and are greener compared with the prior method.
Detailed Description
The present invention will be described in further detail with reference to specific examples. Reagents, equipment and methods employed in the present invention are reagents, equipment and methods conventionally commercially available in the art and conventionally used unless otherwise specified.
The first embodiment is as follows:
to a reaction flask were added 1a (4mmol), sodium difluorochloroacetate (4mmol), cesium carbonate (8mmol) and acetonitrile (10mL), followed by heating at 120 ℃ for 24 hours. After the reaction is finished, water is firstly used for quenching, then ethyl acetate is used for extraction, organic phases are combined and dried by anhydrous sodium sulfate, the mixture is concentrated and then is subjected to column chromatography by using a mixed solvent of petroleum ether and ethyl acetate, and the product 3a can be obtained, wherein the yield is 96%. Light yellow solid, Mp is 74-75 deg.C;1H NMR(600MHz,CDCl3):9.26(s,1H),8.66-8.63(m,4H),7.63-7.59(m,2H),7.57-7.54(m,4H)；13C NMR(150MHz,CDCl3):171.3,166.7,135.5,132.8,128.9,128.7.
example two:
to the reaction flask were added 1a (4mmol), sodium difluorochloroacetate (4mmol), sodium carbonate (8mmol) and acetonitrile (10mL), followed by heating at 120 ℃ for 24 hours. After the reaction is finished, water is firstly used for quenching, then ethyl acetate is used for extraction, organic phases are combined and dried by anhydrous sodium sulfate, the mixture is concentrated and then is subjected to column chromatography by using a mixed solvent of petroleum ether and ethyl acetate, and the product 3a can be obtained, wherein the yield is 83%. Light yellow solid, Mp is 74-75 deg.C;1H NMR(600MHz,CDCl3):9.26(s,1H),8.66-8.63(m,4H),7.63-7.59(m,2H),7.57-7.54(m,4H)；13C NMR(150MHz,CDCl3):171.3,166.7,135.5,132.8,128.9,128.7.
example three:
to the reaction flask were added 1a (4mmol), sodium difluorochloroacetate (4mmol), potassium carbonate (8mmol) and acetonitrile (10mL), followed by heating at 120 ℃ for 24 hours. After the reaction is finished, water is firstly used for quenching, then ethyl acetate is used for extraction, organic phases are combined and dried by anhydrous sodium sulfate, and after concentration, petroleum ether and ethyl acetate mixed solvent is used for carrying out column chromatography to obtain the product 3a, wherein the yield is 78%. Light yellow solid, Mp is 74-75 deg.C;1H NMR(600MHz,CDCl3):9.26(s,1H),8.66-8.63(m,4H),7.63-7.59(m,2H),7.57-7.54(m,4H)；13C NMR(150MHz,CDCl3):171.3,166.7,135.5,132.8,128.9,128.7.
example four:
to the reaction flask were added 1a (4mmol), sodium difluorochloroacetate (4mmol), cesium carbonate (8mmol) and ethanol (10mL), followed by heating at 120 ℃ for 24 hours. After the reaction is finished, water is firstly used for quenching, then ethyl acetate is used for extraction, organic phases are combined and dried by anhydrous sodium sulfate, and after concentration, the product 3a can be obtained by performing column chromatography by using a mixed solvent of petroleum ether and ethyl acetate, and the yield is 20%. Light yellow solid, Mp is 74-75 deg.C;1H NMR(600MHz,CDCl3):9.26(s,1H),8.66-8.63(m,4H),7.63-7.59(m,2H),7.57-7.54(m,4H)；13C NMR(150MHz,CDCl3):171.3,166.7,135.5,132.8,128.9,128.7.
example five:
to the reaction flask were added 1a (4mmol), sodium difluorochloroacetate (4mmol), cesium carbonate (8mmol) and DMSO (10mL), followed by heating at 120 ℃ for 24 hours. After the reaction is finished, water is firstly used for quenching, then ethyl acetate is used for extraction, organic phases are combined and dried by anhydrous sodium sulfate, the mixture is concentrated and then is subjected to column chromatography by using a mixed solvent of petroleum ether and ethyl acetate, and the product 3a can be obtained, wherein the yield is 68%. Light yellow solid, Mp is 74-75 deg.C;1H NMR(600MHz,CDCl3):9.26(s,1H),8.66-8.63(m,4H),7.63-7.59(m,2H),7.57-7.54(m,4H)；13C NMR(150MHz,CDCl3):171.3,166.7,135.5,132.8,128.9,128.7.
example six:
1a (4mmol) and difluorochloroethyl were added to a reaction flaskSodium (4mmol), cesium carbonate (8mmol) and DMF (10mL) were then heated at 120 ℃ for 24 hours. After the reaction is finished, water is firstly used for quenching, then ethyl acetate is used for extraction, the organic phases are combined and dried by anhydrous sodium sulfate, and after concentration, the product 3a can be obtained by performing column chromatography by using the mixed solvent of petroleum ether and ethyl acetate, and the yield is 72%. Light yellow solid, Mp is 74-75 deg.C;1H NMR(600MHz,CDCl3):9.26(s,1H),8.66-8.63(m,4H),7.63-7.59(m,2H),7.57-7.54(m,4H)；13C NMR(150MHz,CDCl3):171.3,166.7,135.5,132.8,128.9,128.7.
example seven:
to a reaction flask were added 1a (4mmol), sodium difluorochloroacetate (4mmol), cesium carbonate (8mmol) and acetonitrile (10mL), followed by heating at 100 ℃ for 24 hours. After the reaction is finished, water is firstly used for quenching, then ethyl acetate is used for extraction, organic phases are combined and dried by anhydrous sodium sulfate, and after concentration, petroleum ether and ethyl acetate mixed solvent is used for carrying out column chromatography to obtain the product 3a, wherein the yield is 93%. Light yellow solid, Mp is 74-75 deg.C;1H NMR(600MHz,CDCl3):9.26(s,1H),8.66-8.63(m,4H),7.63-7.59(m,2H),7.57-7.54(m,4H)；13C NMR(150MHz,CDCl3):171.3,166.7,135.5,132.8,128.9,128.7.
example eight:
to a reaction flask were added 1a (4mmol), sodium difluorochloroacetate (4mmol), cesium carbonate (8mmol) and acetonitrile (10mL), followed by heating at 80 ℃ for 24 hours. After the reaction is finished, water is firstly used for quenching, then ethyl acetate is used for extraction, organic phases are combined and dried by anhydrous sodium sulfate, the mixture is concentrated and then is subjected to column chromatography by using a mixed solvent of petroleum ether and ethyl acetate, and the product 3a can be obtained, wherein the yield is 92%. Light yellow solid, Mp is 74-75 deg.C;1H NMR(600MHz,CDCl3):9.26(s,1H),8.66-8.63(m,4H),7.63-7.59(m,2H),7.57-7.54(m,4H)；13C NMR(150MHz,CDCl3):171.3,166.7,135.5,132.8,128.9,128.7.
example nine:
1b (4mmol), sodium difluorochloroacetate (4mmol), cesium carbonate (8mmol) and acetonitrile (10mL) were added to a reaction flask, followed by heating at 120 ℃ for 24 hours. After the reaction is finished, water is firstly used for quenching, then ethyl acetate is used for extraction, organic phases are combined and dried by anhydrous sodium sulfate, and after concentration, the product 3b can be obtained by performing column chromatography by using a mixed solvent of petroleum ether and ethyl acetate, and the yield is 76%. White solid, Mp: 159-;1H NMR(600MHz,CDCl3):9.19(s,1H),8.52(d,J＝8.2Hz,4H),7.34(d,J＝8.0Hz,4H),2.46(s,6H)；13C NMR(150MHz,CDCl3):171.1,166.3,143.5,1328,129.5,128.9,21.7.
example ten:
to the reaction flask were added 1c (4mmol), sodium difluorochloroacetate (4mmol), cesium carbonate (8mmol) and acetonitrile (10mL), followed by heating at 120 ℃ for 24 hours. After the reaction is finished, water is firstly used for quenching, then ethyl acetate is used for extraction, organic phases are combined and dried by anhydrous sodium sulfate, the mixture is concentrated and then is subjected to column chromatography by using a mixed solvent of petroleum ether and ethyl acetate, and the product 3c can be obtained, wherein the yield is 62%. White solid, Mp: 158-;1H NMR(600MHz,CDCl3):9.11(s,1H),8.59-8.57(m,4H),7.04-7.02(m,4H),3.91(s,6H)；13C NMR(150MHz,CDCl3):170.5,166.3,163.4,130.7,128.1,114.0,55.4.
example eleven:
1d (4mmol), sodium difluorochloroacetate (4mmol), cesium carbonate (8mmol) and acetonitrile (10mL) were added to a reaction flask, followed by 120 deg.CThe reaction was heated for 24 hours. After the reaction is finished, water is firstly used for quenching, then ethyl acetate is used for extraction, organic phases are combined and dried by anhydrous sodium sulfate, the mixture is concentrated and then is subjected to column chromatography by using a mixed solvent of petroleum ether and ethyl acetate, and the product 3d can be obtained, wherein the yield is 87%. White solid, Mp: 154-;1H NMR(600MHz,CDCl3):9.18(s,1H),8.64-8.61(m,4H),7.23-7.19(m,4H)；13C NMR(150MHz,CDCl3):170.3,166.6,165.9(d,J＝252.6Hz),131.5(d,J＝2.7Hz),131.2(d,J＝9.2Hz),115.9(d,J＝21.8Hz).
example twelve:
1e (4mmol), sodium difluorochloroacetate (4mmol), cesium carbonate (8mmol) and acetonitrile (10mL) were added to a reaction flask, followed by heating at 120 ℃ for 24 hours. After the reaction is finished, water is firstly used for quenching, then ethyl acetate is used for extraction, organic phases are combined and dried by anhydrous sodium sulfate, and after concentration, the product 3e can be obtained by performing column chromatography by using a mixed solvent of petroleum ether and ethyl acetate, wherein the yield is 93%. White solid, Mp:189-191 deg.C;1H NMR(600MHz,CDCl3):9.23(s,1H),8.56(d,J＝8.1Hz,4H),7.51(d,J＝8.1Hz,4H)；13C NMR(150MHz,CDCl3):170.5,166.8,139.3,133.8,130.2,129.1.
example thirteen:
1f (4mmol), sodium difluorochloroacetate (4mmol), cesium carbonate (8mmol) and acetonitrile (10mL) were added to a reaction flask, followed by heating at 120 ℃ for 24 hours. After the reaction is finished, water is firstly used for quenching, then ethyl acetate is used for extraction, organic phases are combined and dried by anhydrous sodium sulfate, the mixture is concentrated and then is subjected to column chromatography by using a mixed solvent of petroleum ether and ethyl acetate, and the product 3f can be obtained, wherein the yield is 86%. White solid, Mp: 151-;1H NMR(600MHz,CDCl3):9.34(s,1H),8.75(d,J＝8.2Hz,4H),7.82(d,J＝8.2Hz,4H)；13C NMR(150MHz,CDCl3):170.4,167.1,138.4,134.4(q,J＝32.6Hz),129.3,125.8(q,J＝3.5Hz),123.8(q,J＝270.9Hz).
example fourteen:
a reaction flask was charged with 1g (4mmol), sodium difluorochloroacetate (4mmol), cesium carbonate (8mmol) and acetonitrile (10mL), and then heated at 120 ℃ for reaction for 24 hours. After the reaction is finished, water is firstly used for quenching, then ethyl acetate is used for extraction, organic phases are combined and dried by anhydrous sodium sulfate, and after concentration, the product 3g can be obtained by performing column chromatography by using a mixed solvent of petroleum ether and ethyl acetate, and the yield is 77%. White solid, Mp:195-197 deg.C;1H NMR(600MHz,CDCl3):9.23(s,1H),8.48(d,J＝8.5Hz,4H),7.68(d,J＝8.5Hz,4H)；13C NMR(150MHz,CDCl3):170.6,166.8,134.3,132.1,130.4,128.1.
example fifteen:
to the reaction flask were added 1h (4mmol), sodium difluorochloroacetate (4mmol), cesium carbonate (8mmol) and acetonitrile (10mL), followed by heating at 120 ℃ for 24 hours. After the reaction is finished, water is firstly used for quenching, then ethyl acetate is used for extraction, organic phases are combined and dried by anhydrous sodium sulfate, the mixture is concentrated and then subjected to column chromatography by using a mixed solvent of petroleum ether and ethyl acetate to obtain a product for 3 hours, and the yield is 90%. White solid, Mp:87-89 deg.C;1H NMR(600MHz,CDCl3):9.23(s,1H),8.45-8.43(m,4H),7.46-7.40(m,4H),2.49(s,6H)；13C NMR(150MHz,CDCl3):171.4,166.5,138.5,135.4,133.6,129.3,128.7,126.1,21.5.
example sixteen:
1i (4mmol), sodium difluorochloroacetate (4mmol), cesium carbonate (8mmol) and ethyl acetate were added to a reaction flaskNitrile (10mL) was added and the reaction was heated at 120 ℃ for 24 hours. After the reaction is finished, water is firstly used for quenching, then ethyl acetate is used for extraction, organic phases are combined and dried by anhydrous sodium sulfate, the mixture is concentrated and then subjected to column chromatography by using a mixed solvent of petroleum ether and ethyl acetate to obtain a product 3i, and the yield is 75%. White solid, Mp: 109-;1H NMR(600MHz,CDCl3):9.25(s,1H),8.24(d,J＝7.8Hz,2H),8.16(s,2H),7.46(t,J＝7.8Hz,2H),7.15(dd,J1＝8.0Hz,J2＝1.9Hz,2H),3.94(s,6H)；13C NMR(150MHz,CDCl3):171.1,166.6,159.9,136.9,129.8,121.4,119.2,113.3,55.4.
example seventeen:
1j (4mmol), sodium difluorochloroacetate (4mmol), cesium carbonate (8mmol) and acetonitrile (10mL) were added to a reaction flask, followed by heating at 120 ℃ for 24 hours. After the reaction is finished, water is firstly used for quenching, then ethyl acetate is used for extraction, organic phases are combined and dried by anhydrous sodium sulfate, the mixture is concentrated and then is subjected to column chromatography by using a mixed solvent of petroleum ether and ethyl acetate to obtain a product 3j, and the yield is 50%. White solid, Mp 182-;1H NMR(600MHz,CDCl3):9.27(s,1H),8.76(t,J＝1.5Hz,2H),8.56(d,J＝7.8Hz,2H),7.74(dd,J1＝7.9Hz,J2＝1.0Hz,2H),7.44(t,J＝7.9Hz,2H)；13C NMR(150MHz,CDCl3):170.3,166.9,137.3,135.9,131.8,130.3,127.5,123.1.
example eighteen:
1k (4mmol), sodium difluorochloroacetate (4mmol), cesium carbonate (8mmol) and acetonitrile (10mL) were added to a reaction flask, followed by heating at 120 ℃ for 24 hours. After the reaction is finished, water is firstly used for quenching, then ethyl acetate is used for extraction, organic phases are combined and dried by anhydrous sodium sulfate, and after concentration, the product 3k can be obtained by performing column chromatography by using a mixed solvent of petroleum ether and ethyl acetate, and the yield is 75%.A light-yellow liquid, wherein the light-yellow liquid,1H NMR(600MHz,CDCl3):9.32(s,1H),8.15(dd,J1＝7.7Hz,J2＝0.7Hz,2H),7.43(td,J1＝7.4Hz,J2＝1.1Hz,2H),7.36-7.31(m,4H),2.72(s,6H)；13C NMR(150MHz,CDCl3):173.8,165.6,138.9,135.4,131.8,131.2,131.1,126.1,22.0.
example nineteenth:
1l (4mmol), sodium difluorochloroacetate (4mmol), cesium carbonate (8mmol) and acetonitrile (10mL) were added to a reaction flask, followed by heating at 120 ℃ for 24 hours. After the reaction is finished, water is firstly used for quenching, then ethyl acetate is used for extraction, organic phases are combined and dried by anhydrous sodium sulfate, and after concentration, the product 3l can be obtained by performing column chromatography by using a mixed solvent of petroleum ether and ethyl acetate, and the yield is 84%. A colorless liquid, and a non-coloring liquid,1H NMR(600MHz,CDCl3):9.32(s,1H),7.99(dd,J1＝7.7Hz,J2＝1.8Hz,2H),7.48-7.44(m,2H),7.07(td,J1＝7.5Hz,J2＝0.8Hz,2H),7.04(d,J＝8.4Hz,2H),4.16(q,J＝7.0Hz,4H),1.44(t,J＝7.0Hz,6H)；13C NMR(150MHz,CDCl3):172.6,165.4,158.0,132.5,132.2,126.2,120.5,113.4,64.5,14.7.
example twenty:
1m (4mmol), sodium difluorochloroacetate (4mmol), cesium carbonate (8mmol) and acetonitrile (10mL) were added to a reaction flask, followed by heating at 120 ℃ for 24 hours. After the reaction is finished, water is firstly used for quenching, then ethyl acetate is used for extraction, organic phases are combined and dried by anhydrous sodium sulfate, the mixture is concentrated and then is subjected to column chromatography by using a mixed solvent of petroleum ether and ethyl acetate, and the product 3m can be obtained, wherein the yield is 73%. White solid, Mp 63-65 deg.C;1H NMR(600MHz,CDCl3):9.39(s,1H),8.36(td,J1＝7.7Hz,J2＝1.7Hz,2H),7.58-7.54(m,2H),7.34-7.30(m,2H),7.27-7.23(m,2H)；13C NMR(150MHz,CDCl3):170.4(d,J＝5.1Hz),166.5,162.2(d,J＝258.3Hz),134.0(d,J＝9.3Hz),132.2,124.4(d,J＝3.8Hz),124.0(d,J＝7.8Hz),117.3(d,J＝22.4Hz).
example twenty one:
1n (4mmol), sodium difluorochloroacetate (4mmol), cesium carbonate (8mmol) and acetonitrile (10mL) were added to a reaction flask, followed by heating at 120 ℃ for 24 hours. After the reaction is finished, water is firstly used for quenching, then ethyl acetate is used for extraction, organic phases are combined and dried by anhydrous sodium sulfate, and after concentration, the product 3n can be obtained by performing column chromatography by using a mixed solvent of petroleum ether and ethyl acetate, and the yield is 21%. Light yellow solid, Mp:181-183 ℃;1H NMR(600MHz,CDCl3):9.83(s,2H),9.34(s,1H),8.89(d,J＝7.8Hz,2H),8.87(d,J＝3.3Hz,2H),7.54-7.51(dd,J1＝7.4Hz,J2＝4.9Hz,2H)；13C NMR(150MHz,CDCl3):170.0,167.0,153.1,150.1,136.5,131.0,123.8.
example twenty two:
to the reaction flask were added 1o (4mmol), sodium difluorochloroacetate (4mmol), cesium carbonate (8mmol) and acetonitrile (10mL), followed by heating at 120 ℃ for 24 hours. After the reaction is finished, water is firstly used for quenching, then ethyl acetate is used for extraction, organic phases are combined and dried by anhydrous sodium sulfate, the mixture is concentrated and then is subjected to column chromatography by using a mixed solvent of petroleum ether and ethyl acetate, and the product 3o can be obtained, wherein the yield is 52%. A light-yellow liquid, wherein the light-yellow liquid,1H NMR(600MHz,CDCl3):8.71(s,1H),2.12-2.07(m,2H),1.23-1.19(m,4H),1.15-1.11(m,4H)；13C NMR(150MHz,CDCl3):179.6,164.6,17.7,12.0.
example twenty three:
to a reaction flask were added 1a (8mmol), 1c (2mmol), sodium difluorochloroacetate (4mmol), cesium carbonate (8mmol) and acetonitrile (10mL), followed by heating at 120 ℃ for 24 hours. After the reaction is finished, water is firstly used for quenching, then ethyl acetate is used for extraction, organic phases are combined and dried by anhydrous sodium sulfate, and after concentration, the product 3p can be obtained by performing column chromatography by using a mixed solvent of petroleum ether and ethyl acetate, and the yield is 60%. White solid, Mp: 107-;1H NMR(600MHz,CDCl3):9.18(s,1H),8.63-8.59(m,4H),7.61-7.58(m,1H),7.56-7.53(m,2H),7.05-7.02(m,2H),3.91(s,3H)；13C NMR(150MHz,CDCl3):171.0,170.8,166.5,163.6,135.7,132.7,130.8,128.8,128.7,127.9,114.1,55.5.
example twenty-four:
to the reaction flask were added 1h (8mmol), 1c (2mmol), sodium difluorochloroacetate (4mmol), cesium carbonate (8mmol), and acetonitrile (10mL), followed by heating at 120 ℃ for 24 hours. After the reaction is finished, water is firstly used for quenching, then ethyl acetate is used for extraction, organic phases are combined and dried by anhydrous sodium sulfate, the mixture is concentrated and then is subjected to column chromatography by using a mixed solvent of petroleum ether and ethyl acetate, and the product 3q can be obtained, wherein the yield is 58%. White solid, Mp 111-;1H NMR(600MHz,CDCl3):9.17(s,1H),8.62-8.58(m,2H),8.43-8.41(m,2H),7.45-7.39(m,2H),7.06-7.02(m,2H),3.91(s,3H),2.48(s,3H)；13C NMR(150MHz,CDCl3):171.1,170.7,166.3,163.5,138.4,135.5,133.5,130.9,129.3,128.6,127.9,126.0,114.1,55.4,21.5.
example twenty-five:
to the reaction flask were added 1d (8mmol), 1c (2mmol), sodium difluorochloroacetate (4mmol), cesium carbonate (8mmol) and acetonitrile (10mL), followed by heating at 120 ℃ for 24 hours. After the reaction is finished, quenching the mixture by water and then using ethyl acetateExtracting ester, combining organic phases, drying with anhydrous sodium sulfate, concentrating, and performing column chromatography with mixed solvent of petroleum ether and ethyl acetate to obtain product 3r with yield of 61%. White solid, Mp: 152-;1H NMR(600MHz,CDCl3):9.15(s,1H),8.65-8.62(m,2H),8.59-8.57(m,2H),7.23-7.19(m,2H),7.05-7.02(m,2H),3.91(s,3H)；13C NMR(150MHz,CDCl3):170.8,170.0,166.4,165.8(d,J＝252.3Hz),163.6,131.9(d,J＝2.9Hz),131.2(d,J＝9.2Hz),130.8,127.8,115.8(d,J＝21.7Hz),114.1,55.5.
example twenty-six:
1e (8mmol), 1c (2mmol), sodium difluorochloroacetate (4mmol), cesium carbonate (8mmol) and acetonitrile (10mL) were added to a reaction flask, followed by heating at 120 ℃ for 24 hours. After the reaction is finished, water is firstly used for quenching, then ethyl acetate is used for extraction, organic phases are combined and dried by anhydrous sodium sulfate, the mixture is concentrated and then is subjected to column chromatography by using a mixed solvent of petroleum ether and ethyl acetate, and the product can be obtained in a yield of 74 percent for 3 s. Yellow solid, Mp: 128-;1H NMR(600MHz,CDCl3):9.16(s,1H),8.59-8.54(m,4H),7.52-7.49(m,2H),7.05-7.02(m,2H),3.91(s,3H)；13C NMR(150MHz,CDCl3):170.9,170.1,166.5,163.7,139.0,134.2,130.9,130.1,129.0,127.8,114.1,55.5.
example twenty-seven:
a reaction flask was charged with 1g (8mmol), 1c (2mmol), sodium difluorochloroacetate (4mmol), cesium carbonate (8mmol) and acetonitrile (10mL), and then heated at 120 ℃ for 24 hours. After the reaction is finished, water is firstly used for quenching, then ethyl acetate is used for extraction, organic phases are combined and dried by anhydrous sodium sulfate, and after concentration, the product is obtained by performing column chromatography by using a mixed solvent of petroleum ether and ethyl acetate, wherein the yield is 45%. White solid, Mp:170-172 deg.C;1H NMR(600MHz,CDCl3):9.17(s,1H),8.60-8.55(m,4H),7.52-7.49(m,2H),7.05-7.02(m,2H),3.92(s,3H)；13C NMR(150MHz,CDCl3):170.9,170.1,166.5,163.7,139.0,134.2,130.9,130.1,129.0,127.7,114.1,55.5.
example twenty-eight:
to a reaction flask were added 1a (8mmol), 1i (2mmol), sodium difluorochloroacetate (4mmol), cesium carbonate (8mmol) and acetonitrile (10mL), followed by heating at 120 ℃ for 24 hours. After the reaction is finished, water is firstly used for quenching, then ethyl acetate is used for extraction, organic phases are combined and dried by anhydrous sodium sulfate, and after concentration, the product 3u can be obtained by performing column chromatography by using a mixed solvent of petroleum ether and ethyl acetate, and the yield is 47%. White solid, Mp 85-87 deg.C;1H NMR(600MHz,CDCl3):9.24(s,1H),8.65-8.61(m,2H),8.24(d,J＝7.7Hz,1H),8.17-8.16(m,1H),7.60(t,J＝7.3Hz,1H),7.54(t,J＝7.5Hz,2H),7.45(t,J＝7.9Hz,1H),7.16-7.13(m,1H),3.93(s,3H)；13C NMR(150MHz,CDCl3):171.2,171.1,166.6,159.9,136.9,135.4,132.8,129.7,128.9,128.7,121.4,119.1,113.3,55.4.
example twenty-nine:
to a reaction flask were added 1a (8mmol), 1p (2mmol), sodium difluorochloroacetate (4mmol), cesium carbonate (8mmol) and acetonitrile (10mL), followed by heating at 120 ℃ for 24 hours. After the reaction is finished, water is firstly used for quenching, then ethyl acetate is used for extraction, organic phases are combined and dried by anhydrous sodium sulfate, the mixture is concentrated and then is subjected to column chromatography by using a mixed solvent of petroleum ether and ethyl acetate, and the product 3v can be obtained, wherein the yield is 33%. White solid, Mp: 171-;1H NMR(600MHz,CDCl3):9.31(s,1H),8.81-8.78(m,2H),8.64-8.62(m,2H),8.39-8.36(m,2H),7.66-7.62(m,1H),7.59-7.55(m,2H)；13CNMR(150MHz,CDCl3):171.8,169.4,167.0,150.4,141.2,134.9,133.3,129.8,129.0,128.9,123.8.
example thirty:
to a reaction flask were added 1a (8mmol), 1o (2mmol), sodium difluorochloroacetate (4mmol), cesium carbonate (8mmol) and acetonitrile (10mL), followed by heating at 120 ℃ for 24 hours. After the reaction is finished, water is firstly used for quenching, then ethyl acetate is used for extraction, organic phases are combined and dried by anhydrous sodium sulfate, and after concentration, the product 3w can be obtained by performing column chromatography by using a mixed solvent of petroleum ether and ethyl acetate, and the yield is 40%. White solid, Mp 53-55 deg.C;1H NMR(600MHz,CDCl3):8.99(s,1H),8.49(d,J＝7.7Hz,2H),7.57(t,J＝7.2Hz,1H),7.50(t,J＝7.6Hz,2H),2.29-2.24(m,1H),1.37-1.33(m,2H),1.24-1.20(m,2H)；13C NMR(150MHz,CDCl3):180.6,170.4,165.4,135.3,132.7,128.8,128.6,18.1,12.4.
the foregoing shows and describes the general principles and features of the present invention, together with the advantages thereof. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, which are described in the specification and illustrated only to illustrate the principle of the present invention, but that various changes and modifications may be made therein without departing from the spirit and scope of the present invention, which fall within the scope of the invention as claimed. The scope of the invention is defined by the appended claims and equivalents thereof.
Claims (5)
1. A preparation method of polysubstituted 1,3, 5-triazine is characterized by comprising the following steps: firstly, adding substituted formamidine hydrochloride, sodium difluorochloroacetate and inorganic base into a reaction container, then adding a reaction solvent, then reacting for 24 hours at the temperature of 80-120 ℃, quenching with water after the reaction is finished, extracting with ethyl acetate, combining organic phases, drying with anhydrous sodium sulfate, concentrating, and carrying out column chromatography with a mixed solvent of petroleum ether and ethyl acetate to obtain polysubstituted 1,3, 5-triazine;
the chemical structural general formula of the substituted formamidine hydrochloride is as follows:
wherein R is phenyl, 4-tolyl, 4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-trifluoromethylphenyl, 4-bromophenyl, 4-nitrophenyl, 3-tolyl, 3-methoxyphenyl, 3-bromophenyl, 2-tolyl, 2-ethoxyphenyl, 2-fluorophenyl, 3-pyridyl or cyclopropyl, and the substituted formamidine hydrochloride is selected from one or two of the compounds corresponding to the structural general formula;
the inorganic base is selected from one of sodium carbonate, potassium carbonate and cesium carbonate;
the organic solvent is selected from one of acetonitrile, ethanol, dimethyl sulfoxide (DMSO) and N, N-Dimethylformamide (DMF).
2. The process for the preparation of polysubstituted 1,3, 5-triazines according to claim 1, characterized in that: the molar ratio of the substituted formamidine hydrochloride to the sodium difluorochloroacetate to the inorganic base is (4-10) to 4: 8.
3. The process for the preparation of polysubstituted 1,3, 5-triazines according to claim 2, characterized in that: when substituted formamidine hydrochloride
When R is selected from one of the substituent groups, the molar ratio of the substituted formamidine hydrochloride, the sodium difluorochloroacetate and the inorganic base is 4:4: 8.
4. The process for the preparation of polysubstituted 1,3, 5-triazines according to claim 2, characterized in that: when substituted formamidine hydrochloride
When R is selected from two substituents, the molar ratio of the substituted formamidine hydrochloride, the sodium difluorochloroacetate and the inorganic base is 10:4:8, wherein the molar ratio of the two substituted formamidine hydrochlorides is 8:2 or 2: 8.
5. The process for the preparation of polysubstituted 1,3, 5-triazines according to claim 3 or 4, characterized in that: the substituent is phenyl, 4-tolyl, 4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-trifluoromethylphenyl, 4-bromophenyl, 4-nitrophenyl, 3-tolyl, 3-methoxyphenyl, 3-bromophenyl, 2-tolyl, 2-ethoxyphenyl, 2-fluorophenyl, 3-pyridyl, cyclopropyl.
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| CN104262273A (en) * | 2014-09-10 | 2015-01-07 | 安徽师范大学 | Synthesis method of 1,3,5-triazine derivatives |
| CN106866563A (en) * | 2015-12-11 | 2017-06-20 | 中国科学院大连化学物理研究所 | A kind of method for preparing the pyrrolotriazine derivatives of bis- substitutions of 2,4- -1,3,5 |
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| CN104262273A (en) * | 2014-09-10 | 2015-01-07 | 安徽师范大学 | Synthesis method of 1,3,5-triazine derivatives |
| CN106866563A (en) * | 2015-12-11 | 2017-06-20 | 中国科学院大连化学物理研究所 | A kind of method for preparing the pyrrolotriazine derivatives of bis- substitutions of 2,4- -1,3,5 |
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| Title |
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| Alkyl Ether as a One-Carbon Synthon: Route to 2,4-Disubstituted 1,3,5-Triazines via C−H Amination/C−O Cleavage under Transition-Metal-Free Conditions;Yizhe Yan,et al.;《Org. Lett.》;20171102;6228-6231 * |
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