CN110483429B - Preparation method of 3, 5-disubstituted-4, 5-dihydroisoxazole - Google Patents
Preparation method of 3, 5-disubstituted-4, 5-dihydroisoxazole Download PDFInfo
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- C07—ORGANIC CHEMISTRY
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- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
- C07D261/04—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
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- 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
- C07D409/04—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 directly linked by a ring-member-to-ring-member bond
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6527—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having nitrogen and oxygen atoms as the only ring hetero atoms
- C07F9/653—Five-membered rings
Abstract
The invention relates to a preparation method of 3, 5-disubstituted-4, 5-dihydroisoxazole, which comprises the following steps: (1) Mixing an aryl-substituted propiolic alcohol compound, a nucleophilic reagent containing nitrogen, oxygen, sulfur or phosphorus heteroatoms, N-halogenated succinimide, acid and a solvent, heating and reacting under the reflux condition; (2) Adding hydroxylamine hydrochloride into a reaction system after the reaction is finished, and reacting under the reflux condition to obtain the 3, 5-disubstituted-4, 5-dihydroisoxazole. Compared with the prior art, the preparation method has the advantages of high yield up to 85%, simple operation, mild conditions, high conversion rate, few byproducts and the like.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a preparation method of 3, 5-disubstituted-4, 5-dihydroisoxazole.
Background
Isoxazoles have heterocyclic structures, are very important compounds and are widely used for organic synthesis. The compound has a plurality of biological activities and good pharmacological properties, and has great help effect on human in the aspects of reducing blood sugar of human, eliminating pain of human, resisting inflammation of human, killing harmful bacteria, controlling and reducing harm of AIDS virus, and the like. In addition, some isoxazole derivatives exhibit agricultural chemical effects and have the effect of inhibiting the growth of weeds and soil bacteria, so that they are also widely used in the fields of agricultural chemicals and insecticides. Aiming at the market demand, the high-efficiency synthesis of isoxazole compounds is continuously explored in scientific research work. Vinay Kumar, koravangala s. topic group reports a synthetic method in RSC Advances in 2015, as shown in fig. 1, which proceeds through four steps to obtain the final product, wherein the i step is the reaction of allyl bromide, TBAB, naOH and toluene-distilled water (1), the reaction temperature is 55 ℃, and the reaction time is 5 hours; step ii is with the reactant at NH 2 OH、HCl、CH 3 COONa、CH 3 Reacting in OH at room temperature for 3 hours; step iii is performed in NCS, et 3 N、CHCl 3 Reacting at room temperature for 3 hours; step iv is in Et 3 N、CHCl 3 In the reaction, the reaction is carried out for 6 hours under the condition of 0 ℃ to room temperature, and the reaction conditions are changed three times during the whole reaction process. Such reactions are clearly economically and environmentally less advantageous. Therefore, the simple and high-efficiency construction of the 3, 5-disubstituted-4, 5-dihydroisoxazole is a problem to be solved urgently.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a brand-new preparation method of 3, 5-disubstituted-4, 5-dihydroisoxazole, which is simple and convenient to operate.
The purpose of the invention can be realized by the following technical scheme:
a preparation method of 3, 5-disubstituted-4, 5-dihydroisoxazole comprises the following steps:
(1) Mixing aryl-substituted propiolic alcohol compound, nucleophilic reagent, N-halogenated succinimide, acid and solvent, heating and reacting under reflux conditions;
(2) Adding hydroxylamine hydrochloride into a reaction system after the reaction is finished, and reacting under the reflux condition to obtain the 3, 5-disubstituted-4, 5-dihydroisoxazole.
The reaction equation of the invention is as follows:
the invention relates to a preparation method of 3, 5-disubstituted-4, 5-dihydroisoxazole, which takes 3-aryl prop-2-alkyne-1-alcohol and derivatives thereof, nucleophilic reagent containing heteroatoms such as nitrogen, oxygen, sulfur or phosphorus, N-halogenated succinimide and hydroxylamine hydrochloride as raw materials, and realizes the one-pot synthesis of the 3, 5-disubstituted-4, 5-dihydroisoxazole by tandem Meyer-Schuster rearrangement reaction/conjugate addition/halogenation reaction/cyclization reaction under the catalysis of Lewis acid. Compared with the prior art, in the preparation process, the preparation method has the advantages that reaction conditions such as reaction temperature, reaction pressure, solvent and the like are inconvenient, the preparation method can be synthesized by adopting a one-pot method, the reaction conditions are mild, the intermediate treatment step is omitted, few byproducts are generated, the operation is more convenient, and the preparation method has practical application value.
The invention optimizes the type and the input amount of Lewis acid catalyst, the type and the input amount of nucleophilic reagent, the type and the input amount of N-halogenated succinimide, the input amount of hydroxylamine hydrochloride, the type and the amount of solvent, the input sequence and the input time of the N-halogenated succinimide and the input amount of the hydroxylamine hydrochloride, so that four different types of reactions, namely Meyer-Schuster rearrangement reaction/conjugate addition reaction/halogenation reaction/cyclization reaction can be smoothly carried out under one reaction condition, the reaction rates are matched, the amount of by-products such as intermediate products and the like is reduced, the yield of target products is greatly improved, and the highest yield of the preparation method can reach 85 percent.
Wherein the aryl-substituted propargyl alcohol compound has the molecular formula:
in particular to 3-aryl propyl-2-alkyne-1-alcohol and derivatives thereof; wherein Ar is selected from phenyl, substituted phenyl, pyridyl, naphthyl or thienyl, preferably phenyl, 4-fluoro-phenyl, 4-chloro-phenyl, 4-bromo-phenyl, 4-methyl-phenyl, 4-phenyl, 4-methoxy-phenyl, 2-naphthyl or 2-thienyl.
The nucleophilic reagent is a nucleophilic reagent containing hetero atoms, and the specific molecular formula is R 1 -Z, wherein Z is a nitrogen, oxygen, sulfur or phosphorus heteroatom; the R is 1 Selected from the group consisting of alkyl and derivatives thereof, aryl and derivatives thereof, sulfonyl and derivatives thereof, benzenesulfonyl and derivatives thereof, formyl and derivatives thereof, benzoyl and derivatives thereof, phosphine-containing groups and derivatives thereof, or phosphite and derivatives thereof.
More preferably, the nucleophile is selected from methanol, ethanol, benzyl alcohol, propanethiol, benzylthiol, 4-methylbenzylthiol, 4-methoxybenzylthiol, acetamide, benzamide, p-methylbenzamide, benzenesulfonamide, p-methylbenzenesulfonamide, phenylphosphine, phenyl (phenyl) phosphine, dimethyl phosphite or diethyl phosphite.
The halogen element in the N-halogenated succinimide is chlorine, bromine or iodine.
In the invention, the acid is a catalyst, specifically is Lewis acid, and is preferably one or more of trifluoromethanesulfonic acid, ferric trifluoromethanesulfonate, copper trifluoromethanesulfonate, bismuth trifluoromethanesulfonate, silver trifluoromethanesulfonate and scandium trifluoromethanesulfonate.
The solvent is selected from one or more of dioxane, dichloroethane, toluene, benzene or tetrahydrofuran.
The molar ratio of aryl-substituted propiolic alcohol compound, nucleophilic reagent, N-halogenated succinimide, hydroxylamine hydrochloride and acid is 1: (1-2.0): (1-1.5): (2.0-2.5): (0.05-0.2); the molar concentration of the aryl-substituted propiolic compound in the solvent is 1:5 to 1:30mol/L.
In the whole reaction process, the reaction is carried out under the reflux condition, the reaction temperature is the reflux temperature, the reflux temperature is the boiling point of the used solvent, and the reaction temperature is 40-110 ℃.
The feeding sequence of each raw material can influence the synthesis of the product, and if the feeding sequence is not correct, the target product cannot be obtained completely; and the feed ratio of each raw material and TLC detection are incorrect, the yield of the product is low, and the purification is difficult.
The reaction time control is completed by detecting the content of reactants, specifically, the aryl-substituted propiolic alcohol compound is monitored by TLC to be completely reacted, and the step (1) is completed; and (3) adding water into the reaction solution to quench the reaction after the reaction in the step (2) is finished.
Compared with the prior art, the invention has the following advantages:
(1) The method has the advantages of easily obtained raw materials, simple one-pot operation, mild conditions, no intermediate treatment step, convenient production and easy expanded production;
(2) By optimizing the reaction conditions, the reaction yield is high, and the maximum yield of the target product can be 85 percent.
Drawings
FIG. 1 is a diagram showing a reaction path in the prior art.
Detailed Description
The present invention will be described in detail with reference to specific examples. The following examples will aid those skilled in the art in further understanding the present invention, but are not intended to limit the invention in any manner. It should be noted that variations and modifications can be made by persons skilled in the art without departing from the spirit of the invention. All falling within the scope of the invention.
A preparation method of 3, 5-disubstituted-4, 5-dihydroisoxazole has the following reaction equation:
the method specifically comprises the following steps:
sequentially adding aryl-substituted propiolic alcohol compound (2 mmol), nucleophilic reagent (2-4 mmol), N-halogenated succinimide (2-3 mmol), solvent (10-60 mL) and acid (0.1-0.4 mmol) into a sealed tube, heating, and reacting under the reflux condition; after monitoring that the aryl substituted propiolic alcohol compound completely disappears through TLC, adding hydroxylamine hydrochloride (4-5 mmol) into the reaction liquid; and (3) continuing TLC monitoring reaction, adding water for quenching after the reaction is completed, adding ethyl acetate (3X 15 mL) for extracting an organic phase, washing the obtained organic phase with a saturated sodium chloride solution, drying the organic phase with anhydrous sodium sulfate, concentrating the organic phase on a rotary evaporator, and purifying the obtained concentrated solution by column chromatography to obtain the 3, 5-disubstituted-4, 5-dihydroisoxazole.
Wherein, the aryl-substituted propiolic alcohol compound is-arylpropyl-2-alkyne-1-alcohol and derivatives thereof; ar is selected from phenyl, substituted phenyl, pyridyl, naphthyl or thienyl, preferably phenyl, 4-fluoro-phenyl, 4-chloro-phenyl, 4-bromo-phenyl, 4-methyl-phenyl, 4-phenyl, 4-methoxy-phenyl, 2-naphthyl or 2-thienyl.
Z in the nucleophilic reagent is nitrogen, oxygen, sulfur or phosphorus heteroatom; the R is 1 Selected from alkyl and its derivatives, aryl and its derivatives, sulfonyl and its derivatives, benzenesulfonyl and its derivatives, and formylAnd derivatives thereof, benzoyl and derivatives thereof, phosphine-containing groups and derivatives thereof, or phosphites and derivatives thereof.
In the examples of the present invention, the phosphorus nucleophile is preferably selected from methanol, ethanol, benzyl alcohol, propanethiol, benzylthiol, 4-methylbenzylthiol, 4-methoxybenzylthiol, acetamide, benzamide, p-methylbenzamide, benzenesulfonamide, p-methylbenzenesulfonamide, phenylphosphine, phenyl (phenyl) phosphine, dimethyl phosphite or diethyl phosphite.
The halogen element in the N-halogenated succinimide is chlorine, bromine or iodine.
In the present invention, the acid is a catalyst, specifically a lewis acid, and examples of the acid include trifluoromethanesulfonic acid, iron trifluoromethanesulfonate, copper trifluoromethanesulfonate, bismuth trifluoromethanesulfonate, silver trifluoromethanesulfonate, and scandium trifluoromethanesulfonate.
The solvent can be selected from dioxane, dichloroethane, toluene, benzene or tetrahydrofuran.
The following are specific embodiments of the present invention.
The raw materials used in the examples are commercially available products, and therefore, no other contents need to be provided.
The acid, N-halogenated succinimide, dioxane, dichloroethane, benzotrifluoride, toluene, benzene or tetrahydrofuran, ethyl acetate, petroleum ether and anhydrous sodium sulfate used in the embodiments of the present invention are all Chinese medicine reagents.
The information of the equipment and the manufacturer used in the embodiments of the present invention is as follows:
the stirrer is as follows: a Shanghai plum Yimpu MYPII-2 constant-temperature magnetic stirrer;
the circulating water pump is as follows: shanghai Yukang circulation multipurpose vacuum pump SHB-IIIA;
the rotary evaporator comprises: shanghai Yukang rotary evaporator W.S 206B;
the oil pump is as follows: shanghai Yukang 2XZ-2 rotary-vane vacuum pump.
Example 1
The preparation method of 4-methyl-N- (3-phenyl-4, 5-dihydroisoxazol-5-yl) benzenesulfonamide comprises the following steps:
the procedure of the preparation method is described above with reference to the specific 3-phenylprop-2-yn-1-ol, p-toluenesulfonamide, N-bromosuccinimide, hydroxylamine hydrochloride, solvent and acid loading 3-phenylprop-2-yn-1-ol (2 mmol), p-toluenesulfonamide (4 mmol), NBS (3 mmol), hydroxylamine hydrochloride (4 mmol), dioxane (10 mL) and bismuth triflate (0.2 mmol).
The synthesized product is characterized, and nuclear magnetic data are obtained 1 H NMR(500MHz,CDCl 3 )δ:9.14-9.12(d,J＝9.0,1H),7.74-7.72(d,J＝8.0,2H),7.64-7.63(t,J＝4.0,2H),7.46-7.45(d,J＝4.0,3H),7.42-7.41(d,J＝8.0,2H),5.96-5.92(m,1H),3.73-3.67(q,J＝9.0,1H),3.22-3.17(m,1H),2.41(s,3H)； 13 C NMR(CDCl 3 ,125MHz)δ:156.19,143.98,137.82,130.75,129.80(2),128.92(2),128.51(2),127.24(2),85.37,41.09,29.68,21.61。
The yield of the target product was calculated to be 85%.
Example 2
The molecular formula of the target product is as follows:
the procedure of the preparation method is described above with reference to the specific 3-phenylprop-2-yn-1-ol, p-toluenesulfonamide, N-bromosuccinimide, hydroxylamine hydrochloride, solvent and acid loading 3-phenylprop-2-yn-1-ol (2 mmol), p-toluenesulfonamide (4 mmol), NBS (3 mmol), hydroxylamine hydrochloride (4 mmol), dioxane (10 mL) and bismuth triflate (0.2 mmol).
The synthesized product is characterized, and the obtained nuclear magnetic data is 3- (4-bromophenyl) prop-2-alkyne-1-alcohol, p-methylbenzenesulfonamide, N-iodosuccinimide, hydroxylamine hydrochloride, solvent and acid sample adding conditions are that3- (4-bromophenyl) prop-2-yn-1-ol (2 mmol), p-methylbenzenesulfonamide (2 mmol), NIS (32 mmol), hydroxylamine hydrochloride (5 mmol), dichloroethane (10 mL) and copper trifluoromethanesulfonate (0.15 mmol); HRMS Calcd for C 16 H 16 BrN 2 O 3 S[M+H] + :395.0065，found：395.0068。
The yield of the desired product was calculated to be 60%.
Example 3
The preparation method of 4-methyl-N- (3- (naphthalene-2-yl) -4, 5-dihydroisoxazol-5-yl) benzene sulfonamide comprises the following steps:
processes for the preparation methods As referred to above, specific 3- (naphthalen-2-yl) propan-2-yn-1-ol, p-methylbenzenesulfonamide, N-iodosuccinimide, hydroxylamine hydrochloride, solvent and acid loading were 3- (naphthalen-2-yl) propan-2-yn-1-ol (2 mmol), p-methylbenzenesulfonamide (3.6 mmol), NIS (3 mmol), hydroxylamine hydrochloride (4.4 mmol), dichloroethane (10 mL) and ferric triflate (0.18 mmol).
Characterizing the synthesized product, and obtaining nuclear magnetic data of HRMS Calcd for C 20 H 19 N 2 O 3 S[M+H] + :367.1116，found：367.1113。
The yield of the desired product was calculated to be 60%.
Example 4
The molecular formula of the target product is as follows:
processes for the preparation methods As referred to above, specific 3- (4-fluorophenyl) propan-2-yn-1-ol, p-methoxybenzenesulfonamide, N-bromosuccinimide, hydroxylamine hydrochloride, solvent and acid loading were 3- (4-fluorophenyl) propan-2-yn-1-ol (2 mmol), p-methoxybenzenesulfonamide (4 mmol), NBS (3 mmol), hydroxylamine hydrochloride (4.2 mmol), toluene (10 mL) and trifluoromethanesulfonic acid (0.2 mmol).
The synthesized product is characterized, and the obtained nuclear magnetic data is HRMS Calcd for C 16 H 16 FN 2 O 4 S[M+H] + :351..0815，found：351.0817。
The yield of the desired product was calculated to be 70%.
Example 5
The preparation method of 4-methyl-N- (3-phenyl-4, 5-dihydroisoxazol-5-yl) benzamide comprises the following steps:
processes for the preparation methods were as described above, with reference to 3-phenylprop-2-yn-1-ol, p-methylbenzamide, N-iodosuccinimide, hydroxylamine hydrochloride, solvent and acid loading 3-phenylprop-2-yn-1-ol (2 mmol), p-methylbenzamide (4.2 mmol), NIS (2.6 mmol), hydroxylamine hydrochloride (4.4 mmol), dioxane (10 mL) and bismuth triflate (0.17 mmol).
The synthesized product is characterized, and the obtained nuclear magnetic data is HRMS Calcd for C 17 H 17 N 2 O 2 [M+H] + :281.1290，found：281.1287。
The yield of the target product was calculated to be 76%.
Example 6
The preparation method of 4-methyl-N- (3- (thiophene-2-yl) -4, 5-dihydroisoxazole-5-yl) benzamide comprises the following steps:
the procedure of the preparation method is as described above, with reference to the specific 3- (thien-2-yl) prop-2-yn-1-ol, p-methylbenzamide, N-bromosuccinimide, hydroxylamine hydrochloride, solvent and acid loading 3- (thien-2-yl) prop-2-yn-1-ol (2 mmol), p-methylbenzamide (4.2 mmol), NBS (3 mmol), hydroxylamine hydrochloride (4 mmol), dioxane (10 mL) and bismuth triflate (0.2 mmol).
The synthesized product is characterized, and the obtained nuclear magnetic data is HRMS Calcd for C 15 H 15 N 2 O 2 S[M+H] + :287.0854，found：287.0852。
The yield of the desired product was calculated to be 65%.
Example 7
The molecular formula of the target product is as follows:
the procedure of the preparation method is as described above, with reference to the specific 3-phenylprop-2-yn-1-ol, ethanol, N-iodosuccinimide, hydroxylamine hydrochloride, solvent and acid loading 3-phenylprop-2-yn-1-ol (2 mmol), ethanol (3 mmol), NIS (2.8 mmol), hydroxylamine hydrochloride (4.2 mmol), benzene (10 mL) and bismuth triflate (0.16 mmol).
Characterizing the synthesized product, and obtaining nuclear magnetic data of HRMS Calcd for C 11 H 14 NO 2 [M+H] + :192.1025，found：192.1027。
The yield of the target product was calculated to be 75%.
Example 8
The molecular formula of the target product is as follows:
the procedure of the preparation method was as described above, with reference to the specific 3-phenylprop-2-yn-1-ol, benzyl alcohol, N-bromosuccinimide, hydroxylamine hydrochloride, solvent and acid loading conditions 3-phenylprop-2-yn-1-ol (2 mmol), benzyl alcohol (3.6 mmol), NBS (2.8 mmol), hydroxylamine hydrochloride (4.2 mmol), benzene (10 mL) and iron triflate (0.2 mmol).
Characterizing the synthesized product, and obtaining nuclear magnetic data of HRMS Calcd for C 16 H 16 NO 2 [M+H] + :254.1181，found：254.1179。
The yield of the desired product was calculated to be 82%.
Example 9
The molecular formula of the target product is as follows:
the procedure for the preparation method was as described above, with reference to the details of 3- (4-nitrophenyl) propan-2-yn-1-ol, benzyl alcohol, N-bromosuccinimide, hydroxylamine hydrochloride, solvent and acid loading 3- (4-nitrophenyl) propan-2-yn-1-ol (2 mmol), benzyl alcohol (3.6 mmol), NBS (2.8 mmol), hydroxylamine hydrochloride (4.2 mmol), benzene (10 mL) and ferric triflate (0.2 mmol).
The synthesized product is characterized, and the obtained nuclear magnetic data is HRMS Calcd for C16H15N2O4[ M + H ]] + :299.1032，found：299.1035。
The yield of the desired product was calculated to be 77%.
Example 10
The molecular formula of the target product is as follows:
processes for the preparation methods were as described above, with reference to 3- (p-tolyl) propan-2-yn-1-ol, ethanol, N-bromosuccinimide, hydroxylamine hydrochloride, solvent and acid loading 3- (p-tolyl) propan-2-yn-1-ol (2 mmol), ethanol (3 mmol), NBS (3.0 mmol), hydroxylamine hydrochloride (4.0 mmol), toluene (10 mL) and bismuth triflate (0.14 mmol).
The synthesized product is characterized, and the obtained nuclear magnetic data is HRMS Calcd for C 12 H 16 NO 2 [M+H] + :206.1181，found：206.1183。
The yield of the desired product was calculated to be 73%.
Example 11
The molecular formula of the target product is as follows:
the procedure of the preparation method is as described above, with reference to the specific 3- (naphthalen-2-yl) propan-2-yn-1-ol, ethanol, N-bromosuccinimide, hydroxylamine hydrochloride, solvent and acid loading 3- (naphthalen-2-yl) propan-2-yn-1-ol (2 mmol), ethanol (3 mmol), NBS (3.0 mmol), hydroxylamine hydrochloride (4.0 mmol), toluene (10 mL) and bismuth triflate (0.2 mmol).
The synthesized product is characterized, and the obtained nuclear magnetic data is HRMS Calcd for C 14 H 14 NO 2 [M+H] + :228.1025，found：228.1027。
The yield of the desired product was calculated to be 80%.
Example 12
The molecular formula of the target product is as follows:
processes for the preparation methods reference is made to the above, specific 3-phenylprop-2-yn-1-ol, propane-1-thiol, N-bromosuccinimide, hydroxylamine hydrochloride, solvent and acid loading 3-phenylprop-2-yn-1-ol (2 mmol), propane-1-thiol (3.4 mmol), NBS (2.8 mmol), hydroxylamine hydrochloride (4.0 mmol), 1, 4-dioxane (10 mL) and copper triflate (0.2 mmol).
Characterizing the synthesized product, and obtaining nuclear magnetic data of HRMS Calcd for C 12 H 16 NOS[M+H] + :222.0953，found：222.0955。
The yield of the desired product was calculated to be 77%.
Example 13
The molecular formula of the target product is as follows:
processes for the preparation methods As referred to above, specific 3- (thien-2-yl) prop-2-yn-1-ol, propane-1-thiol, N-iodosuccinimide, hydroxylamine hydrochloride, solvent and acid loading were 3- (thien-2-yl) prop-2-yn-1-ol (2 mmol), propane-1-thiol (3.4 mmol), NIS (2.8 mmol), hydroxylamine hydrochloride (4.0 mmol), 1, 4-dioxane (10 mL) and bismuth triflate (0.2 mmol).
Characterizing the synthesized product, and obtaining nuclear magnetic data of HRMS Calcd for C 12 H 16 NOS[M+H] + :228.0517，found：228.0514。
The yield of the desired product was calculated to be 78%.
Example 14
The molecular formula of the target product is as follows:
preparation procedures described above for specific 3-phenylprop-2-yn-1-ol, benzyl thiol, N-bromosuccinimide, hydroxylamine hydrochloride, solvent and acid loading 3-phenylprop-2-yn-1-ol (2 mmol), benzyl thiol (3.0 mmol), NBS (2.6 mmol), hydroxylamine hydrochloride (4.0 mmol), tetrahydrofuran (10 mL) and bismuth triflate (0.2 mmol).
Characterizing the synthesized product, and obtaining nuclear magnetic data of HRMS Calcd for C 16 H 16 NOS[M+H] + :270.3700，found：270.3702。
The yield of the target product was calculated to be 72%.
Example 15
The molecular formula of the target product is as follows:
processes for the preparation methods were as described above, with reference to 3-phenylprop-2-yn-1-ol, methyl (phenyl) phosphine, N-iodosuccinimide, hydroxylamine hydrochloride, solvent and acid loading 3-phenylprop-2-yn-1-ol (2 mmol), methyl (phenyl) phosphine (3.0 mmol), NIS (2.6 mmol), hydroxylamine hydrochloride (4.0 mmol), toluene (10 mL) and bismuth triflate (0.2 mmol).
The synthesized product is characterized, and the obtained nuclear magnetic data is HRMS Calcd for C 16 H 17 NOP[M+H] + :270.1408，found：270.1411。
The yield of the target product was calculated to be 62%.
Example 16
A preparation method of diethyl (3- (naphthalene-2-yl) -4, 5-dihydroisoxazol-5-yl) phosphonate ester comprises the following steps:
processes for the preparation methods were as described above, with reference to specific 3- (naphthalen-2-yl) propan-2-yn-1-ol, diethyl phosphite, N-bromosuccinimide, hydroxylamine hydrochloride, solvent and acid loading 3- (naphthalen-2-yl) propan-2-yn-1-ol (2 mmol), diethyl phosphite (3.0 mmol), NBS (2.6 mmol), hydroxylamine hydrochloride (4.0 mmol), tetrahydrofuran (10 mL) and bismuth triflate (0.2 mmol).
Characterizing the synthesized product, and obtaining nuclear magnetic data of HRMS Calcd for C 17 H 21 NO 4 P[M+H] + :334.1208，found：334.1210。
The yield of the desired product was calculated to be 50%.
Example 17
A preparation method of dimethyl (3- (p-tolyl) -4, 5-dihydroisoxazol-5-yl) phosphonate ester comprises the following steps:
processes for the preparation methods were as described above, with reference to specific 3- (p-tolyl) propan-2-yn-1-ol, dimethyl phosphite, N-iodosuccinimide, hydroxylamine hydrochloride, solvent and acid loading being 3- (p-tolyl) propan-2-yn-1-ol (2 mmol), dimethyl phosphite (3.0 mmol), NIS (2.6 mmol), hydroxylamine hydrochloride (4.6 mmol), dichloroethane (10 mL) and ferric triflate (0.2 mmol).
Characterizing the synthesized product, and obtaining nuclear magnetic data of HRMS Calcd for C 12 H 17 NO 4 P[M+H] + :270.0895，found：270.0893。
The yield of the desired product was calculated to be 52%.
Example 18
The preparation method of 4-methyl-N- (3-phenyl-4, 5-dihydroisoxazol-5-yl) benzenesulfonamide comprises the following steps:
the procedure for the preparation is as described above for the specific 3-phenylpropan-2-yn-1-ol, p-toluenesulfonamide, N-bromosuccinimide, hydroxylamine hydrochloride, solvent and acid loading 3-phenylpropan-2-yn-1-ol (2 mmol), p-toluenesulfonamide (4 mmol), NBS (2 mmol), hydroxylamine hydrochloride (5 mmol), dioxane (60 mL) and bismuth trifluoromethanesulfonate 0.4 mmol.
The synthesized product is characterized, and nuclear magnetic data are obtained 1 H NMR(500MHz,CDCl 3 )δ:9.14-9.12(d,J＝9.0,1H),7.74-7.72(d,J＝8.0,2H),7.64-7.63(t,J＝4.0,2H),7.46-7.45(d,J＝4.0,3H),7.42-7.41(d,J＝8.0,2H),5.96-5.92(m,1H),3.73-3.67(q,J＝9.0,1H),3.22-3.17(m,1H),2.41(s,3H)； 13 C NMR(CDCl 3 ,125MHz)δ:156.19,143.98,137.82,130.75,129.80(2),128.92(2),128.51(2),127.24(2),85.37,41.09,29.68,21.61。
The yield of the desired product was calculated to be 75%.
Example 19
The preparation method of 4-methyl-N- (3-phenyl-4, 5-dihydroisoxazol-5-yl) benzenesulfonamide comprises the following steps:
the procedure of the preparation method is described above with reference to the specific 3-phenylprop-2-yn-1-ol, p-toluenesulfonamide, N-bromosuccinimide, hydroxylamine hydrochloride, solvent and acid loading 3-phenylprop-2-yn-1-ol (2 mmol), p-toluenesulfonamide (4 mmol), NBS (3 mmol), hydroxylamine hydrochloride (5 mmol), dioxane (10 mL) and bismuth triflate 0.1 mmol.
The synthesized product is characterized, and nuclear magnetic data is obtained 1 H NMR(500MHz,CDCl 3 )δ:9.14-9.12(d,J＝9.0,1H),7.74-7.72(d,J＝8.0,2H),7.64-7.63(t,J＝4.0,2H),7.46-7.45(d,J＝4.0,3H),7.42-7.41(d,J＝8.0,2H),5.96-5.92(m,1H),3.73-3.67(q,J＝9.0,1H),3.22-3.17(m,1H),2.41(s,3H)； 13 C NMR(CDCl 3 ,125MHz)δ:156.19,143.98,137.82,130.75,129.80(2),128.92(2),128.51(2),127.24(2),85.37,41.09,29.68,21.61。
The yield of the target product was calculated to be 72%.
The preparation method in the embodiment takes 3-aryl-prop-2-yne-1-ol and derivatives thereof, nucleophilic reagents containing nitrogen, oxygen, sulfur and phosphorus, N-halogenated succinimide and hydroxylamine hydrochloride as raw materials, and tandem Meyer-Schuster rearrangement reaction/conjugate addition/halogenation reaction/cyclization reaction is carried out under the action of Lewis acid, so that the one-pot synthesis of 3, 5-disubstituted-4, 5-dihydroisoxazole is realized. The preparation method has the highest yield of 85 percent, has the advantages of simple operation, mild conditions, high conversion rate, few byproducts and the like, and provides a brand-new synthesis method for constructing the 4, 5-dihydro isoxazole compound.
The foregoing description of specific embodiments of the present invention has been presented. It is to be understood that the present invention is not limited to the specific embodiments described above, and that various changes and modifications may be made by one skilled in the art within the scope of the appended claims without departing from the spirit of the invention.
Claims (7)
1. A preparation method of 3, 5-disubstituted-4, 5-dihydroisoxazole is characterized by comprising the following steps:
(1) Mixing aryl-substituted propiolic alcohol compound, nucleophilic reagent, N-halogenated succinimide, acid and solvent, heating and reacting under reflux conditions; the nucleophile is selected from methanol, ethanol, benzyl alcohol, propanethiol, benzylthiol, 4-methylbenzylthiol, 4-methoxybenzylthiol, acetamide, benzamide, p-methylbenzamide, benzenesulfonamide, p-methylbenzenesulfonamide, phenylphosphine, phenyl (phenyl) phosphine, dimethyl phosphite or diethyl phosphite; the aryl-substituted propargyl alcohol compound has the molecular formula:
wherein Ar is selected from phenyl, pyridyl, naphthyl or thienyl, 4-fluoro-phenyl, 4-chloro-phenyl, 4-bromo-phenyl, 4-methyl-phenyl, 4-phenyl, 4-methoxy-phenyl, 2-naphthyl or 2-thienyl;
(2) Adding hydroxylamine hydrochloride into a reaction system after the reaction is finished, and reacting under the reflux condition to obtain the 3, 5-disubstituted-4, 5-dihydroisoxazole.
2. The method for preparing 3, 5-disubstituted-4, 5-dihydroisoxazole according to claim 1, characterized in that Ar is phenyl.
3. The method for preparing 3, 5-disubstituted-4, 5-dihydroisoxazole according to claim 1, wherein the halogen element in the N-halogenated succinimide is chlorine, bromine or iodine.
4. A process for preparing a 3, 5-disubstituted-4, 5-dihydroisoxazole as claimed in claim 1 wherein the acid is selected from one or more of trifluoromethanesulfonic acid, ferric trifluoromethanesulfonate, copper trifluoromethanesulfonate, bismuth trifluoromethanesulfonate, silver trifluoromethanesulfonate and scandium trifluoromethanesulfonate.
5. The method for preparing 3, 5-disubstituted-4, 5-dihydroisoxazole according to claim 1, characterized in that the solvent is one or more selected from dioxane, dichloroethane, toluene, benzene or tetrahydrofuran.
6. The method for preparing 3, 5-disubstituted-4, 5-dihydroisoxazole according to claim 1, wherein the molar ratio of the aryl-substituted propiolic compound, the nucleophilic reagent, the N-halosuccinimide, the hydroxylamine hydrochloride and the acid is 1: (1-2.0): (1-1.5): (2.0-2.5): (0.05-0.2); the molar concentration of the aryl-substituted propiolic compound in the solvent is 1:5 to 1:30mol/L.
7. The process for preparing 3, 5-disubstituted-4, 5-dihydroisoxazoles according to claim 1, characterized in that the completion of the reaction of the aryl-substituted propargyl alcohols is monitored by TLC and the reaction of step (1) is completed; monitoring the reaction completion of the product generated in the step (1) by TLC, and completing the step (2) reaction; and (3) adding water into the reaction solution to quench the reaction after the reaction in the step (2) is finished.
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