CN110483429A - The preparation method of one kind 3,5- bis- substitution -4,5- dihydro-isoxazole - Google Patents
The preparation method of one kind 3,5- bis- substitution -4,5- dihydro-isoxazole Download PDFInfo
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- CN110483429A CN110483429A CN201910791322.5A CN201910791322A CN110483429A CN 110483429 A CN110483429 A CN 110483429A CN 201910791322 A CN201910791322 A CN 201910791322A CN 110483429 A CN110483429 A CN 110483429A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—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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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- 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 present invention relates to one kind 3,5- bis- replaces -4, the preparation method of 5- dihydro-isoxazole, the following steps are included: the propiolic alcohol compound, nitrogenous that (1) replaces aryl, oxygen, the nucleopilic reagent of sulphur or phosphorus heteroatoms, N- halosuccinimides, acid and solvent mixing, heat, react under counterflow condition；(2) hydroxylamine hydrochloride is added in the reaction system completed to reaction, is reacted under counterflow condition, obtain described kind of 3,5- bis- and replace -4,5- dihydro-isoxazole.Compared with prior art, preparation method maximum output of the invention has many advantages, such as that easy to operate, mild condition and high conversion rate by-product are few up to 85%.
Description
Technical field
The present invention relates to technical field of organic synthesis, replace -4,5- dihydro-isoxazole more particularly, to one kind 3,5- bis-
Preparation method.
Background technique
Isoxazole possesses heterocycle structure, is a kind of very important compound, is widely used in organic synthesis.This compound
With many bioactivity, and also have good pharmacological characteristics, it reduce mankind's blood glucose, eliminate the mankind pain,
Resist the inflammation of the mankind, kill harmful bacteria and control and reduce the harm of AIDS virus etc. has biggish help to the mankind
Effect.In addition, some Isoxazole derivatives show agriculture chemistry effectiveness, there is the effect for inhibiting weeds and soil bacteria growth
Can, so it is also widely used in pesticide and field of pesticides.For this market demand, the height of isoxazole class compound
Effect synthesis is constantly explored in research work always.Vinay Kumar, Koravangala S. seminar in 2015
A kind of synthetic method is reported on RSC Advances magazine, as shown in Figure 1, this method obtains final product by four steps,
In, the i-th step is allyl bromide, bromoallylene, TBAB, NaOH and toluene-distilled water (1:1) reaction, and reaction temperature is 55 DEG C, the reaction time
It is 5 hours；I-th i step is reactant in NH2OH、HCl、CH3COONa、CH3In OH, react at room temperature 3 hours；I-th ii step is
In NCS, Et3N、CHCl3In, it reacts at room temperature 3 hours；I-th v step is in Et3N、CHCl3In, 0 DEG C, under room temperature, is reacted
6 hours, change reaction condition three times during entire reaction process.On the obvious economically and environmentally close friend of such reaction more
It is unfavorable.Therefore simply and efficiently constructing 3,5- bis- replaces -4,5- dihydro-isoxazole to be a problem to be solved.
Summary of the invention
It is an object of the present invention to overcome the above-mentioned drawbacks of the prior art and provide a kind of completely new, operation letters
Just 3,5- bis- replaces the preparation method of -4,5- dihydro-isoxazole.
The purpose of the present invention can be achieved through the following technical solutions:
The preparation method of one kind 3,5- bis- substitution -4,5- dihydro-isoxazole, comprising the following steps:
(1) propiolic alcohol compound, nucleopilic reagent, N- halosuccinimides, acid and the solvent mixing replaced aryl,
It heats, is reacted under counterflow condition；
(2) hydroxylamine hydrochloride is added in the reaction system completed to reaction, is reacted under counterflow condition, obtains described kind of 3,5- bis-
Substitution -4,5- dihydro-isoxazole.
Reaction equation of the invention are as follows:
One kind 3,5- bis- of the invention replaces the preparation method of -4,5- dihydro-isoxazole, i.e., with 3- aryl propyl- 2- alkynes -1-
Alcohol and its derivative, nitrogenous, oxygen, the heteroatomic nucleopilic reagent such as sulphur or phosphorus, N- halosuccinimides and hydroxylamine hydrochloride are original
Material, under lewis acidic catalytic action by concatenated Meyer-Schuster rearrangement reaction/conjugate addition/halogenation/
Cyclization reaction realizes that 3,5- bis- replaces the one pot process of -4,5- dihydro-isoxazole.Compared with the prior art, system of the invention
During standby, the reaction conditions such as reaction temperature, reaction pressure and solvent are inconvenient, can synthesize to obtain using one kettle way, react
Mild condition, omit intermediate process step and by-product it is few, operation it is more convenient, have more practical application value.
The present invention is halogenated by optimization lewis acid catalyst type and inventory, nucleopilic reagent type and inventory, N-
The inventory of succinimide type and inventory and hydroxylamine hydrochloride, the type and amount of solvent and their feeding sequence and
Charging time, so that Meyer-Schuster rearrangement reaction/conjugate addition/halogenation/cyclization is anti-under a kind of reaction condition
Answer these four different types of reactions that can go on smoothly, and reaction rate matches, and reduces the by-products such as intermediate product
Amount, substantially increases the yield of target product, preparation method maximum output of the invention is up to 85%.
Wherein, the molecular formula for the propiolic alcohol compound that the aryl replaces are as follows:
Specially 3- aryl propyl- 2- alkynes -1- alcohol and its derivative；Wherein, the Ar is selected from phenyl, substituted-phenyl, pyridine
Base, naphthalene or thienyl, preferably phenyl, 4- fluoro-phenyl, the bromo- phenyl of the chloro- phenyl 4- of 4-, 4- methylphenyl, 4- phenyl-benzene
Base, 4- methoxyl group-phenyl, 2- naphthalene or 2- thienyl.
The nucleopilic reagent is containing heteroatomic nucleopilic reagent, and specific molecular formula is R1- Z, wherein Z is nitrogen, oxygen, sulphur or phosphorus
Hetero atom；The R1Selected from alkyl and its derivative, aryl and its derivative, sulfonyl and its derivative, benzenesulfonyl and its
Derivative, formoxyl and its derivative, benzoyl and its derivative containing phosphine groups and its derivative or phosphite ester and its spread out
Biology.
It is highly preferred that the nucleopilic reagent is selected from methanol, ethyl alcohol, benzylalcohol, propanethiol, benzyl mercaptan, 4- methyl benzyl mercaptan, 4-
Methoxybenzyl mercaptan, acetamide, benzamide, to methyl benzamide, benzsulfamide, p-methylphenyl sulphonylamine, Phenylphosphine, benzene
Base (phenyl) phosphine, dimethylphosphite or diethyl phosphite.
Halogen element is chlorine, bromine or iodine in the N- halosuccinimides.
In the present invention, acid is catalyst, specially lewis acid, preferably trifluoromethanesulfonic acid, trifluoromethanesulfonic acid iron, trifluoro
One or more of copper methane sulfonate, Bismuth triflate, silver trifluoromethanesulfonate or trifluoromethanesulfonic acid scandium.
The solvent is selected from one or more of dioxane, dichloroethanes, toluene, benzene or tetrahydrofuran.
The propiolic alcohol compound that aryl is replaced, nucleopilic reagent, N- halosuccinimides, hydroxylamine hydrochloride and acid
Molar ratio be 1:(1~2.0): (1~1.5): (2.0~2.5): (0.05~0.2)；The propiolic alcohol that the aryl replaces
Closing molar concentration of the object in the solvent is 1:5~1:30mol/L.
In entire reaction process, reacted under reflux conditions, reaction temperature is reflux temperature, and reflux temperature is used
The boiling point of solvent, the present invention in reaction temperature be 40-110 DEG C.
The feeding sequence of each raw material will affect the synthesis of product in the present invention, if feeding sequence is not right, completely no
To target product；And the feed ratio and TLC of each raw material detect incorrect, the low yield of product, and purification difficult.
Reaction time control of the invention is completed by the content of detection reactant, monitors the virtue specifically by TLC
The propiolic alcohol compound fully reacting that base replaces, step (1) reaction are completed；The step (2) is after the reaction was completed to anti-
Answer addition water quenching reaction in liquid.
Compared with prior art, the invention has the following advantages that
(1) method raw material of the invention is easy to get, and one kettle way is easy to operate, mild condition, omits intermediate process step, side
Just it produces, is easy expanding production；
(2) by optimization reaction condition, reaction yield is higher, and highest can obtain 85% target product yield.
Detailed description of the invention
Fig. 1 is reaction path diagram in the prior art.
Specific embodiment
The present invention is described in detail combined with specific embodiments below.Following embodiment will be helpful to the technology of this field
Personnel further understand the present invention, but the invention is not limited in any way.It should be pointed out that the ordinary skill of this field
For personnel, without departing from the inventive concept of the premise, various modifications and improvements can be made.These belong to the present invention
Protection scope.
One kind 3,5- bis- replaces the preparation method of -4,5- dihydro-isoxazole, reaction equation are as follows:
Specifically comprise the following steps:
Sequentially added in a tube sealing aryl substitution propiolic alcohol compound (2mmol), nucleopilic reagent (2~
4mmol), N- halosuccinimides (2~3mmol), solvent (10~60mL) and sour (0.1~0.4mmol), heating, reflux
Under the conditions of reacted；By TLC monitor aryl replace propiolic alcohol compound completely disappear after, be added into reaction solution
Hydroxylamine hydrochloride (4~5mmol)；Continue TLC monitoring reaction, water quenching is added after complete reaction and goes out, addition ethyl acetate (3 ×
Organic phase 15mL) is extracted, in Rotary Evaporators after resulting organic phase is washed with saturated sodium chloride solution, anhydrous sodium sulfate is dry
Upper concentration, obtained concentrate obtain 3,5- bis- by column chromatographic purifying and replace -4,5- dihydro-isoxazole.
Wherein, the propiolic alcohol compound that aryl replaces is specially-aryl propyl- 2- alkynes -1- alcohol and its derivative；Ar is selected from
Phenyl, substituted-phenyl, pyridyl group, naphthalene or thienyl, preferably phenyl, 4- fluoro-phenyl, the bromo- phenyl of the chloro- phenyl 4- of 4-, 4-
Methylphenyl, 4- phenyl-phenyl, 4- methoxyl group-phenyl, 2- naphthalene or 2- thienyl.
Z is nitrogen, oxygen, sulphur or phosphorus heteroatoms in nucleopilic reagent；The R1Selected from alkyl and its derivative, aryl and its derivative
Object, sulfonyl and its derivative, benzenesulfonyl and its derivative, formoxyl and its derivative, benzoyl and its derivative contain
Phosphine groups and its derivative or phosphite ester and its derivative.
In the embodiment of the present invention, methanol, ethyl alcohol, benzylalcohol, propanethiol, benzyl can be preferentially selected as using phosphorus nucleopilic reagent
Mercaptan, 4- methyl benzyl mercaptan, 4- methoxybenzyl mercaptan, acetamide, benzamide, to methyl benzamide, benzsulfamide, to first
Base benzsulfamide, Phenylphosphine, phenyl (phenyl) phosphine, dimethylphosphite or diethyl phosphite.
Halogen element is chlorine, bromine or iodine in N- halosuccinimides.
In the present invention, acid is used as catalyst, specially lewis acid, and selection can be enumerated as trifluoromethanesulfonic acid, trifluoro
Methanesulfonic acid iron, copper trifluoromethanesulfcomposite, Bismuth triflate, silver trifluoromethanesulfonate or trifluoromethanesulfonic acid scandium.
The selection of solvent can be enumerated as dioxane, dichloroethanes, toluene, benzene or tetrahydrofuran.
The following are a specific embodiment of the invention.
Used each raw material is commercial product in embodiment, therefore does not need to provide other content.
Acid used in various embodiments of the present invention, N- halosuccinimides, dioxane, dichloroethanes, benzotrifluoride,
Toluene, benzene or tetrahydrofuran, ethyl acetate, petroleum ether and anhydrous sodium sulfate are traditional Chinese medicines reagent.
Equipment used in various embodiments of the present invention and the information of manufacturer are as follows:
Blender are as follows: the Shanghai Pu Mei Ying MYPII-2 constant temperature blender with magnetic force；
Water circulating pump are as follows: Shanghai Yu Kang recycles multiplex vavuum pump SHB-IIIA；
Rotary Evaporators are as follows: Shanghai Yu Kang Rotary Evaporators W.S 206B；
Oil pump are as follows: Shanghai Yu Kang 2XZ-2 type rotary-vane vaccum pump.
Embodiment 1
The preparation method of 4- methyl-N- (3- phenyl -4,5- dihydro-isoxazole -5- base) benzsulfamide, the target product
Molecular formula are as follows:
The process of preparation method is referring to above, specific 3- phenyl propyl- 2- alkynes -1- alcohol, p-methylphenyl sulphonylamine, N- bromo
Succinimide, hydroxylamine hydrochloride, solvent and acid sample-adding situation are 3- phenyl propyl- 2- alkynes -1- alcohol (2mmol), to Methyl benzenesulfonyl
Amine (4mmol), NBS (3mmol), hydroxylamine hydrochloride (4mmol), dioxane (10mL) and Bismuth triflate (0.2mmol).
The product obtained to synthesis characterizes, and obtains nuclear magnetic data and is1H NMR(500MHz,CDCl3)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)；13C NMR(CDCl3,125MHz)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 for calculating target product is 85%.
Embodiment 2
The preparation method of N- (3- (4- bromophenyl) -4,5- dihydro-isoxazole -5- base) -4- methyl benzenesulfonamide, the target
The molecular formula of product are as follows:
The process of preparation method is referring to above, specific 3- phenyl propyl- 2- alkynes -1- alcohol, p-methylphenyl sulphonylamine, N- bromo
Succinimide, hydroxylamine hydrochloride, solvent and acid sample-adding situation are 3- phenyl propyl- 2- alkynes -1- alcohol (2mmol), to Methyl benzenesulfonyl
Amine (4mmol), NBS (3mmol), hydroxylamine hydrochloride (4mmol), dioxane (10mL) and Bismuth triflate (0.2mmol).
The product obtained to synthesis characterizes, and acquisition nuclear magnetic data is 3- (4- bromophenyl) propyl- 2- alkynes -1- alcohol, to first
Base benzsulfamide, N-iodosuccinimide, hydroxylamine hydrochloride, solvent and acid sample-adding situation are 3- (4- bromophenyl) propyl- 2- alkynes -1-
Alcohol (2mmol), p-methylphenyl sulphonylamine (2mmol), NIS (32mmol), hydroxylamine hydrochloride (5mmol), dichloroethanes (10mL) and
Copper triflate (0.15mmol)；HRMS Calcd for C16H16BrN2O3S[M+H]+: 395.0065, found:
395.0068。
The yield for calculating target product is 60%.
Embodiment 3
The preparation method of 4- methyl-N- (3- (naphthalene -2- base) -4,5- dihydro-isoxazole -5- base) benzsulfamide, the target produce
The molecular formula of object are as follows:
The process reference of preparation method is above, specific 3- (naphthalene -2- base) propyl- 2- alkynes -1- alcohol, p-methylphenyl sulphonylamine,
N-iodosuccinimide, hydroxylamine hydrochloride, solvent and acid sample-adding situation are 3- (naphthalene -2- base) propyl- 2- alkynes -1- alcohol (2mmol), right
Methyl benzenesulfonamide (3.6mmol), NIS (3mmol), hydroxylamine hydrochloride (4.4mmol), dichloroethanes (10mL) and trifluoromethanesulfonic acid
Iron (0.18mmol).
The product obtained to synthesis characterizes, and acquisition nuclear magnetic data is HRMS Calcd for C20H19N2O3S[M+H]+:
367.1116, found:367.1113.
The yield for calculating target product is 60%.
Embodiment 4
The preparation method of N- (3- (4- fluorophenyl) -4,5- dihydro-isoxazole -5- base) -4- methoxybenzenesulphoismide, the mesh
Mark the molecular formula of product are as follows:
The process of preparation method is referring to above, specific 3- (4- fluorophenyl) propyl- 2- alkynes -1- alcohol, to methoxybenzene sulphonyl
Amine, N-bromosuccinimide, hydroxylamine hydrochloride, solvent and acid sample-adding situation are 3- (4- fluorophenyl) propyl- 2- alkynes -1- alcohol
(2mmol), to methoxybenzenesulphoismide (4mmol), NBS (3mmol), hydroxylamine hydrochloride (4.2mmol), toluene (10mL) and trifluoro
Methanesulfonic acid (0.2mmol).
The product obtained to synthesis characterizes, and acquisition nuclear magnetic data is HRMS Calcd for C16H16FN2O4S[M+H]+:
351..0815, found:351.0817.
The yield for calculating target product is 70%.
Embodiment 5
The preparation method of 4- methyl-N- (3- phenyl -4,5- dihydro-isoxazole -5- base) benzamide, the target product
Molecular formula are as follows:
The process of preparation method is referring to above, specific 3- phenyl propyl- 2- alkynes -1- alcohol, to methyl benzamide, N- iodo
Succinimide, hydroxylamine hydrochloride, solvent and acid sample-adding situation are 3- phenyl propyl- 2- alkynes -1- alcohol (2mmol), to toluyl
Amine (4.2mmol), NIS (2.6mmol), hydroxylamine hydrochloride (4.4mmol), dioxane (10mL) and Bismuth triflate
(0.17mmol)。
The product obtained to synthesis characterizes, and acquisition nuclear magnetic data is HRMS Calcd for C17H17N2O2[M+H]+:
281.1290, found:281.1287.
The yield for calculating target product is 76%.
Embodiment 6
The preparation method of 4- methyl-N- (3- (thiophene -2- base) -4,5- dihydro-isoxazole -5- base) benzamide, the target
The molecular formula of product are as follows:
The process of preparation method is referring to above, specific 3- (thiophene -2- base) propyl- 2- alkynes -1- alcohol, to toluyl
Amine, N-bromosuccinimide, hydroxylamine hydrochloride, solvent and acid sample-adding situation are 3- (thiophene -2- base) propyl- 2- alkynes -1- alcohol
(2mmol), to methyl benzamide (4.2mmol), NBS (3mmol), hydroxylamine hydrochloride (4mmol), dioxane (10mL) and three
Fluorine methanesulfonic acid bismuth (0.2mmol).
The product obtained to synthesis characterizes, and acquisition nuclear magnetic data is HRMS Calcd for C15H15N2O2S[M+H]+:
287.0854, found:287.0852.
The yield for calculating target product is 65%.
Embodiment 7
The preparation method of 5- ethyoxyl -3- phenyl -4,5- dihydro-isoxazole, the molecular formula of the target product are as follows:
The process of preparation method is referring to above, specific 3- phenyl propyl- 2- alkynes -1- alcohol, ethyl alcohol, N- iodo succinyl Asia
Amine, hydroxylamine hydrochloride, solvent and acid sample-adding situation are 3- phenyl propyl- 2- alkynes -1- alcohol (2mmol), ethyl alcohol (3mmol), NIS
(2.8mmol), hydroxylamine hydrochloride (4.2mmol), benzene (10mL) and Bismuth triflate (0.16mmol).
The product obtained to synthesis characterizes, and acquisition nuclear magnetic data is HRMS Calcd for C11H14NO2[M+H]+:
192.1025, found:192.1027.
The yield for calculating target product is 75%.
Embodiment 8
The preparation method of 5- (benzyloxy) -3- phenyl -4,5- dihydro-isoxazole, the molecular formula of the target product are as follows:
The process of preparation method is referring to above, specific 3- phenyl propyl- 2- alkynes -1- alcohol, benzylalcohol, N- bromo succinyl Asia
Amine, hydroxylamine hydrochloride, solvent and acid sample-adding situation are 3- phenyl propyl- 2- alkynes -1- alcohol (2mmol), benzylalcohol (3.6mmol), NBS
(2.8mmol), hydroxylamine hydrochloride (4.2mmol), benzene (10mL) and trifluoromethane sulfonic acid iron (0.2mmol).
The product obtained to synthesis characterizes, and acquisition nuclear magnetic data is HRMS Calcd for C16H16NO2[M+H]+:
254.1181, found:254.1179.
The yield for calculating target product is 82%.
Embodiment 9
5- (benzyloxy) -3- (4- nitrobenzophenone) -4,5- dihydro-isoxazole preparation method, the molecular formula of the target product
Are as follows:
The process of preparation method is referring to above, specific 3- (4- nitrobenzophenone) propyl- 2- alkynes -1- alcohol, benzylalcohol, N- bromo amber
Amber acid imide, hydroxylamine hydrochloride, solvent and acid sample-adding situation are 3- (4- nitrobenzophenone) propyl- 2- alkynes -1- alcohol (2mmol), benzylalcohol
(3.6mmol), NBS (2.8mmol), hydroxylamine hydrochloride (4.2mmol), benzene (10mL) and trifluoromethane sulfonic acid iron (0.2mmol).
The product obtained to synthesis characterizes, and acquisition nuclear magnetic data is HRMS Calcd for C16H15N2O4 [M+H]+:
299.1032, found:299.1035.
The yield for calculating target product is 77%.
Embodiment 10
5- ethyoxyl -3- (p-methylphenyl) -4,5- dihydro-isoxazole preparation method, the molecular formula of the target product are as follows:
The process of preparation method is referring to above, specific 3- (p- tolyl) propyl- 2- alkynes -1- alcohol, ethyl alcohol, N- bromo amber
Amber acid imide, hydroxylamine hydrochloride, solvent and acid sample-adding situation are 3- (p- tolyl) propyl- 2- alkynes -1- alcohol (2mmol), ethyl alcohol
(3mmol), NBS (3.0mmol), hydroxylamine hydrochloride (4.0mmol), toluene (10mL) and Bismuth triflate (0.14mmol).
The product obtained to synthesis characterizes, and acquisition nuclear magnetic data is HRMS Calcd for C12H16NO2[M+H]+:
206.1181, found:206.1183.
The yield for calculating target product is 73%.
Embodiment 11
The preparation method of 5- methoxyl group -3- (naphthalene -2- base) -4,5- dihydro-isoxazole, the molecular formula of the target product are as follows:
The process of preparation method is referring to above, specific 3- (naphthalene -2- base) propyl- 2- alkynes -1- alcohol, ethyl alcohol, N- bromo amber
Acid imide, hydroxylamine hydrochloride, solvent and the sour situation that is loaded is 3- (naphthalene -2- base) propyl- 2- alkynes -1- alcohol (2mmol), ethyl alcohol (3mmol),
NBS (3.0mmol), hydroxylamine hydrochloride (4.0mmol), toluene (10mL) and Bismuth triflate (0.2mmol).
The product obtained to synthesis characterizes, and acquisition nuclear magnetic data is HRMS Calcd for C14H14NO2[M+H]+:
228.1025, found:228.1027.
The yield for calculating target product is 80%.
Embodiment 12
3- phenyl -5- (rosickyite base) -4,5- dihydro-isoxazole preparation method, the molecular formula of the target product are as follows:
The process of preparation method is referring to above, specific 3- phenyl propyl- 2- alkynes -1- alcohol, propane -1- mercaptan, N- bromo amber
Amber acid imide, hydroxylamine hydrochloride, solvent and acid sample-adding situation are 3- phenyl propyl- 2- alkynes -1- alcohol (2mmol), propane -1- mercaptan
(3.4mmol), NBS (2.8mmol), hydroxylamine hydrochloride (4.0mmol), Isosorbide-5-Nitrae-dioxane (10mL) and copper triflate
(0.2mmol)。
The product obtained to synthesis characterizes, and acquisition nuclear magnetic data is HRMS Calcd for C12H16NOS[M+H]+:
222.0953, found:222.0955.
The yield for calculating target product is 77%.
Embodiment 13
The preparation method of 5- (rosickyite base) -3- (thiophene -2- base) -4,5- dihydro-isoxazole, the molecular formula of the target product
Are as follows:
The process of preparation method is referring to above, specific 3- (thiophene -2- base) propyl- 2- alkynes -1- alcohol, propane -1- mercaptan, N-
Iodosuccinimide, hydroxylamine hydrochloride, solvent and the sour situation that is loaded is 3- (thiophene -2- base) propyl- 2- alkynes -1- alcohol (2mmol), and third
Alkane -1- mercaptan (3.4mmol), NIS (2.8mmol), hydroxylamine hydrochloride (4.0mmol), Isosorbide-5-Nitrae-dioxane (10mL) and fluoroform
Sulfonic acid bismuth (0.2mmol).
The product obtained to synthesis characterizes, and acquisition nuclear magnetic data is HRMS Calcd for C12H16NOS[M+H]+:
228.0517, found:228.0514.
The yield for calculating target product is 78%.
Embodiment 14
The preparation method of 5- (benzylthio) -3- phenyl -4,5- dihydro-isoxazole, the molecular formula of the target product are as follows:
The process of preparation method is referring to above, specific 3- phenyl propyl- 2- alkynes -1- alcohol, benzyl mercaptan, N- bromo succinyl Asia
Amine, hydroxylamine hydrochloride, solvent and acid sample-adding situation are 3- phenyl propyl- 2- alkynes -1- alcohol (2mmol), benzyl mercaptan (3.0mmol), NBS
(2.6mmol), hydroxylamine hydrochloride (4.0mmol), tetrahydrofuran (10mL) and Bismuth triflate (0.2mmol).
The product obtained to synthesis characterizes, and acquisition nuclear magnetic data is HRMS Calcd for C16H16NOS[M+H]+:
270.3700, found:270.3702.
The yield for calculating target product is 72%.
Embodiment 15
The preparation method of 5- (methyl (phenyl) phosphino-) -3- phenyl -4,5- dihydro-isoxazole, the molecular formula of the target product
Are as follows:
The process of preparation method is referring to above, specific 3- phenyl propyl- 2- alkynes -1- alcohol, methyl (phenyl) phosphine, N- iodo amber
Amber acid imide, hydroxylamine hydrochloride, solvent and acid sample-adding situation are 3- phenyl propyl- 2- alkynes -1- alcohol (2mmol), methyl (phenyl) phosphine
(3.0mmol), NIS (2.6mmol), hydroxylamine hydrochloride (4.0mmol), toluene (10mL) and Bismuth triflate (0.2mmol).
The product obtained to synthesis characterizes, and acquisition nuclear magnetic data is HRMS Calcd for C16H17NOP[M+H]+:
270.1408, found:270.1411.
The yield for calculating target product is 62%.
Embodiment 16
The preparation method of diethyl (3- (naphthalene -2- base) -4,5- dihydro-isoxazole -5- base) phosphonate ester, the target product
Molecular formula are as follows:
The process of preparation method is referring to above, specific 3- (naphthalene -2- base) propyl- 2- alkynes -1- alcohol, diethyl phosphite, N-
Bromosuccinimide, hydroxylamine hydrochloride, solvent and acid sample-adding situation are 3- (naphthalene -2- base) propyl- 2- alkynes -1- alcohol (2mmol), phosphorous
Diethyl phthalate (3.0mmol), NBS (2.6mmol), hydroxylamine hydrochloride (4.0mmol), tetrahydrofuran (10mL) and Bismuth triflate
(0.2mmol)。
The product obtained to synthesis characterizes, and acquisition nuclear magnetic data is HRMS Calcd for C17H21NO4P[M+H]+:
334.1208, found:334.1210.
The yield for calculating target product is 50%.
Embodiment 17
The preparation method of dimethyl (3- (p- tolyl) -4,5- dihydro-isoxazole -5- base) phosphonate ester, the target product
Molecular formula are as follows:
The process reference of preparation method is above, specific 3- (p- tolyl) propyl- 2- alkynes -1- alcohol, dimethylphosphite,
N-iodosuccinimide, hydroxylamine hydrochloride, solvent and acid sample-adding situation are 3- (p- tolyl) propyl- 2- alkynes -1- alcohol (2mmol),
Dimethylphosphite (3.0mmol), NIS (2.6mmol), hydroxylamine hydrochloride (4.6mmol), dichloroethanes (10mL) and trifluoro methylsulphur
Sour iron (0.2mmol).
The product obtained to synthesis characterizes, and acquisition nuclear magnetic data is HRMS Calcd for C12H17NO4P[M+H]+:
270.0895, found:270.0893.
The yield for calculating target product is 52%.
Embodiment 18
The preparation method of 4- methyl-N- (3- phenyl -4,5- dihydro-isoxazole -5- base) benzsulfamide, the target product
Molecular formula are as follows:
The process of preparation method is referring to above, specific 3- phenyl propyl- 2- alkynes -1- alcohol, p-methylphenyl sulphonylamine, N- bromo
Succinimide, hydroxylamine hydrochloride, solvent and acid sample-adding situation are 3- phenyl propyl- 2- alkynes -1- alcohol (2mmol), to Methyl benzenesulfonyl
Amine (4mmol), NBS (2mmol), hydroxylamine hydrochloride (5mmol), dioxane (60mL) and Bismuth triflate 0.4mmol).
The product obtained to synthesis characterizes, and obtains nuclear magnetic data and is1H NMR(500MHz,CDCl3)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)；13C NMR(CDCl3,125MHz)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 for calculating target product is 75%.
Embodiment 19
The preparation method of 4- methyl-N- (3- phenyl -4,5- dihydro-isoxazole -5- base) benzsulfamide, the target product
Molecular formula are as follows:
The process of preparation method is referring to above, specific 3- phenyl propyl- 2- alkynes -1- alcohol, p-methylphenyl sulphonylamine, N- bromo
Succinimide, hydroxylamine hydrochloride, solvent and acid sample-adding situation are 3- phenyl propyl- 2- alkynes -1- alcohol (2mmol), to Methyl benzenesulfonyl
Amine (4mmol), NBS (3mmol), hydroxylamine hydrochloride (5mmol), dioxane (10mL) and Bismuth triflate 0.1mmol).
The product obtained to synthesis characterizes, and obtains nuclear magnetic data and is1H NMR(500MHz,CDCl3)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)；13C NMR(CDCl3,125MHz)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 for calculating target product is 72%.
Preparation method in the present embodiment is with 3- aryl propyl- 2- alkynes -1- alcohol and its derivative, nitrogenous, oxygen, sulphur, the parent of phosphorus
Core reagent, N- N-halosuccinimides and hydroxylamine hydrochloride are raw material, carry out concatenated Meyer- under lewis acid effect
Schuster rearrangement reaction/conjugate addition/halogenation/cyclization reaction, to realize that 3,5- bis- replaces -4,5- dihydro-isoxazole
One pot process.Preparation method maximum output of the invention has easy to operate, mild condition and conversion ratio up to 85%
The advantages that high by-product is few provides a kind of completely new synthetic method for the building of 4,5- dihydro-isoxazole class compound.
Specific embodiments of the present invention are described above.It is to be appreciated that the invention is not limited to above-mentioned
Particular implementation, those skilled in the art can make various deformations or amendments within the scope of the claims, this not shadow
Ring substantive content of the invention.
Claims (9)
1. one kind 3,5- bis- replaces the preparation method of -4,5- dihydro-isoxazole, which comprises the following steps:
(1) propiolic alcohol compound, nucleopilic reagent, N- halosuccinimides, acid and the solvent mixing replaced aryl, adds
Heat is reacted under counterflow condition；
(2) hydroxylamine hydrochloride is added in the reaction system completed to reaction, is reacted under counterflow condition, obtains described kind of 3,5- bis- and take
Generation -4,5- dihydro-isoxazole.
2. the preparation method that a kind of 3,5- bis- according to claim 1 replaces -4,5- dihydro-isoxazole, which is characterized in that
The molecular formula for the propiolic alcohol compound that the aryl replaces are as follows:
Wherein, the Ar is selected from phenyl, substituted-phenyl, pyridyl group, naphthalene or thienyl, preferably phenyl, 4- fluoro-phenyl, 4-
The bromo- phenyl of chloro- phenyl 4-, 4- methylphenyl, 4- phenyl-phenyl, 4- methoxyl group-phenyl, 2- naphthalene or 2- thienyl.
3. the preparation method that a kind of 3,5- bis- according to claim 1 replaces -4,5- dihydro-isoxazole, which is characterized in that
The molecular formula of the nucleopilic reagent is R1- Z, wherein Z is nitrogen, oxygen, sulphur or phosphorus heteroatoms；The R1Selected from alkyl and its derivative,
Aryl and its derivative, sulfonyl and its derivative, benzenesulfonyl and its derivative, formoxyl and its derivative, benzoyl
And its derivative, containing phosphine groups and its derivative or phosphite ester and its derivative.
4. the preparation method that a kind of 3,5- bis- according to claim 3 replaces -4,5- dihydro-isoxazole, which is characterized in that
The nucleopilic reagent is selected from methanol, ethyl alcohol, benzylalcohol, propanethiol, benzyl mercaptan, 4- methyl benzyl mercaptan, 4- methoxybenzyl mercaptan, acetyl
Amine, benzamide, to methyl benzamide, benzsulfamide, p-methylphenyl sulphonylamine, Phenylphosphine, phenyl (phenyl) phosphine, phosphorous acid
Dimethyl ester or diethyl phosphite.
5. the preparation method that a kind of 3,5- bis- according to claim 1 replaces -4,5- dihydro-isoxazole, which is characterized in that
Halogen element is chlorine, bromine or iodine in the N- halosuccinimides.
6. the preparation method that a kind of 3,5- bis- according to claim 1 replaces -4,5- dihydro-isoxazole, which is characterized in that
The acid is selected from trifluoromethanesulfonic acid, trifluoromethanesulfonic acid iron, copper trifluoromethanesulfcomposite, Bismuth triflate, silver trifluoromethanesulfonate or three
One or more of fluorine methanesulfonic acid scandium.
7. the preparation method that a kind of 3,5- bis- according to claim 1 replaces -4,5- dihydro-isoxazole, which is characterized in that
The solvent is selected from one or more of dioxane, dichloroethanes, toluene, benzene or tetrahydrofuran.
8. the preparation method that a kind of 3,5- bis- according to claim 1 replaces -4,5- dihydro-isoxazole, which is characterized in that
The molar ratio of the propiolic alcohol compound that aryl is replaced, nucleopilic reagent, N- halosuccinimides, hydroxylamine hydrochloride and acid
For 1:(1~2.0): (1~1.5): (2.0~2.5): (0.05~0.2)；The propiolic alcohol compound that the aryl replaces is in institute
Stating the molar concentration in solvent is 1:5~1:30mol/L.
9. the preparation method that a kind of 3,5- bis- according to claim 1 replaces -4,5- dihydro-isoxazole, which is characterized in that
The propiolic alcohol compound fully reacting that the aryl replaces is monitored by TLC, step (1) reaction is completed；It is supervised by TLC
The product fully reacting that step (1) generates is surveyed, step (2) reaction is completed；The step (2) is after the reaction was completed to reaction solution
Middle addition water quenching reaction.
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| CN111484462A (en) * | 2020-05-22 | 2020-08-04 | 南京工业大学 | 4-isoxazoline compound and preparation method thereof |
| CN113200915A (en) * | 2021-04-21 | 2021-08-03 | 上海应用技术大学 | 3-aryl-4, 5-dihydro-1H-pyrazole-5 amine and preparation method thereof |
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| CN102285919A (en) * | 2011-07-12 | 2011-12-21 | 浙江工业大学 | Method for preparing 4-fluorinated pyrazole derivative |
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| CN102285919A (en) * | 2011-07-12 | 2011-12-21 | 浙江工业大学 | Method for preparing 4-fluorinated pyrazole derivative |
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| YUAN WANG ET AL.: "Bi(OTf)3 catalyzed synthesis of acyclic b-sulfanyl ketones via a tandem Meyer-Schuster rearrangement/conjugate addition reaction", 《TETRAHEDRON LETTERS》 * |
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| CN111484462A (en) * | 2020-05-22 | 2020-08-04 | 南京工业大学 | 4-isoxazoline compound and preparation method thereof |
| CN113200915A (en) * | 2021-04-21 | 2021-08-03 | 上海应用技术大学 | 3-aryl-4, 5-dihydro-1H-pyrazole-5 amine and preparation method thereof |
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