CN116283815B - Preparation method of 1, 3-benzoxazine compound - Google Patents

Preparation method of 1, 3-benzoxazine compound Download PDF

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CN116283815B
CN116283815B CN202310531547.3A CN202310531547A CN116283815B CN 116283815 B CN116283815 B CN 116283815B CN 202310531547 A CN202310531547 A CN 202310531547A CN 116283815 B CN116283815 B CN 116283815B
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姜东方
章泽恒
潘静
文思妙妙
齐振杰
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Harvest Pharmaceutical Co ltd
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Abstract

The invention provides a preparation method of a 1, 3-benzoxazine compound, which takes a compound shown in a formula I and a formula II as a raw material, and the compound reacts to generate the 1, 3-benzoxazine compound under the catalysis of a catalyst, bronsted acid and visible light. The reaction substrate has wide application range, can obtain different substituted 1, 3-benzoxazines with good to moderate yield, has the advantages of simple and mild condition and the like for green synthesis, and has wide application prospect in the aspects of synthesizing the medical intermediates and fine chemical raw materials.

Description

Preparation method of 1, 3-benzoxazine compound
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of a 1, 3-benzoxazine compound.
Background
Benzoxazines are an important class of nitrogen-oxygen heterocycles that are frequently found in natural products, agrochemicals and pharmaceuticals. In the pharmaceutical industry, benzoxazine compounds have been used as anxiolytic, anti-angina pectoris drug, antineoplastic, active antihypertensive, anticonvulsant and pancreatic lipase inhibitor for treating obesity, and have wide application prospects. Zheng-Hai Wang, dong-Hui Wang, org. Lett.2022, 24, 2, 782-785 discloses a method for copper-catalyzed synthesis of benzoxazoles from phenols and cyclic oxime esters, which yields benzoxazoles in moderate to good yields. S, ohashi, H, ishida, ISBN 9780128041703, 2017 and Pages 3-8 disclose various synthesis methods of 1, 3-benzoxazine compounds, such as condensation reaction of o-amino benzyl alcohol and ketone, reaction of formaldehyde and phenol with primary amine, and the like, and the two synthesis methods are Mannich condensation reactions, and have the defects of long condensation time, high temperature, low product yield and the like. Chun-Ying Wang, jia-Bin Han, long Wang, and Xiang-Ying Tang J. Org. Chem. 2019, 84, 14258-14269 disclose a formal [4+2] cycloaddition of N-p-toluenehydrazone with o-benzoquinone methyl ether, which yields a variety of 1, 3-benzoxazinone derivatives under Lewis acid catalysis, with only 38% yield when the benzo aldoxime is selected as the reaction substrate. Therefore, the research of a method for efficiently synthesizing the 1, 3-benzoxazine compound has important significance.
Disclosure of Invention
The invention aims to provide a preparation method of a 1, 3-benzoxazine compound, which is characterized in that a compound shown in a formula II is used as a raw material, and the raw material reacts with a compound shown in a formula I under the catalysis of a catalyst, bronsted acid and visible light to generate the 1, 3-benzoxazine compound shown in the formula III:
。
said R is 1 Is hydrogen or any one of C1-C10 unsubstituted alkyl, C1-C10 oxygen substituted alkyl, phenyl substituted monoalkenyl, phenyl substituted monoalkynyl, oxygen-containing heterocyclic group, nitrogen-containing heterocyclic group, sulfur-containing heterocyclic group, unsubstituted aromatic hydrocarbon group, methyl substituted, methoxy substituted, halogen substituted and nitro substituted phenyl; said R is 2 Is hydrogen or any one of phenyl, methyl substituted phenyl, methoxy substituted phenyl, halogen substituted phenyl, naphthyl, anthryl, furyl, thienyl, methyl, tertiary butyl and benzyl; said R is 3 Is any one of hydrogen, halogen, methyl and methoxy.
Preferably, the preparation method comprises the following steps: adding a compound shown in a formula I, a compound shown in a formula II and a catalyst into a proton solvent, adding Bronsted acid, reacting under the condition of visible light illumination at the temperature of 30-32 ℃ for 10-24 hours, monitoring the reaction progress by TLC, quenching the reaction by using a saturated ammonium chloride solution after the reaction is finished, and separating by using column chromatography with dichloromethane as an extraction solvent to obtain the 1, 3-benzoxazine compound.
Preferably, the molar ratio of the compound of formula I to the compound of formula II to the Bronsted acid to the catalyst is 1: 1-5: 0.1 to 0.5:0.01 to 0.05.
Preferably, the catalyst is selected from any one of the following structures:
。
preferably, the protic solvent is Dichloromethane (DCM), acetonitrile (MeCN), thionyl chloride (DMSO), toluene (PhMe), ethanol (EtOH), methanol (MeOH), chloroform (CHCl) 3 ) Ethyl Acetate (EA), 1,4-dioxane (1, 4-dioxane), 1, 2-Dichloroethane (DCE) as a single solvent or as a mixture.
Preferably, the Bronsted acid is any one of trifluoromethanesulfonic acid (TfOH), trifluoroacetic acid (TFA), p-toluenesulfonic acid (TsOH), formic acid (HCOOH) and acetic acid (AcOH).
Preferably, the preparation method comprises the following steps: adding a compound shown in a formula I, a compound shown in a formula II and a catalyst cat-1 into dichloromethane, adding p-toluenesulfonic acid, reacting under the illumination of blue LEDs and nitrogen atmosphere at the reaction temperature of 30-32 ℃ for 24 h, monitoring the reaction progress by TLC, adding a saturated ammonium chloride solution after the reaction is finished, extracting with dichloromethane, washing, merging and concentrating organic phases, and separating by column chromatography to obtain the 1, 3-benzoxazine compound.
Preferably, the 1, 3-benzoxazine compound is a compound shown in the formula III-1-37 shown in figures 1-5.
The invention provides a novel synthesis method of 1, 3-benzoxazine compounds, wherein 2- (hydroxymethyl) phenol compounds are cyclized with oxime compounds to obtain target compounds through [4+2] under the catalysis of a catalyst, bronsted acid and visible light. The application range of the reaction substrate is wide, different substituted 1, 3-benzoxazine compounds can be obtained with good to moderate yield, and the method has the advantages of simple and mild conditions and the like of green synthesis. In addition, gram-scale reaction and synthesis application show that the reaction has wide application prospect in the aspects of synthesizing the pharmaceutical intermediates and fine chemical raw materials.
Drawings
FIG. 1 is a diagram of the structure of a compound of formula III-1 to 9;
FIG. 2 is a diagram of the structure of a compound of formula III-10-18;
FIG. 3 is a diagram of the structure of compounds of formulas III-19-26;
FIG. 4 is a diagram of the structure of compounds of formulas III-27-32;
FIG. 5 is a diagram showing the structure of the compounds of formulas III-33 to 37.
Detailed Description
In order to better understand the technical scheme and advantages of the present invention, the present invention will be further described below through the specific embodiments.
The catalyst numbers and corresponding chemical structures are shown below.
Example 1:2, 4-diphenyl-2HBenzo [e][1,3]Oxazine-3 (4)H) Process for the synthesis of alcohols
The method comprises the steps of sequentially adding benzaldehyde oxime (0.1 mmol, 12 mg), 2- (hydroxy (phenyl) methyl) phenol (0.11 mmol, 20 mg), bronsted acid (0.01 mmol), catalyst (0.002 mmol) and proton type solvent (2 mL) into a reaction bottle, carrying out blue light LED irradiation reaction at 30-32 ℃ in a nitrogen atmosphere for 24 h, adding saturated ammonium chloride solution after the reaction is finished, extracting with dichloromethane, washing, combining and concentrating organic phases, and separating by column chromatography to obtain a target product III-1. By taking mesitylene as an internal standard, through 1 H NMR calculated yield. The corresponding III-1 yields under the conditions of different catalysts, bronsted acid and solvents are as follows:
(1) And (3) a photocatalyst: cat-1; bransted acid: acOH; solvent: DCM; III-1 yield: 36%;
(2) And (3) a photocatalyst: cat-2; bransted acid: acOH; solvent: DCM; III-1 yield: 23%;
(3) And (3) a photocatalyst: cat-3; bransted acid: acOH; solvent: DCM; III-1 yield: trace;
(4) And (3) a photocatalyst: cat-4; bransted acid: acOH; solvent: DCM; III-1 yield: trace;
(5) And (3) a photocatalyst: cat-1; bransted acid: tfOH; solvent: DCM; III-1 yield: 42%;
(6) And (3) a photocatalyst: cat-1; bransted acid: TFA; solvent: DCM; III-1 yield: 56% of a glass fiber;
(7) And (3) a photocatalyst: cat-1; bransted acid: tsOH; solvent: DCM; III-1 yield: 74%;
(8) And (3) a photocatalyst: cat-1; bransted acid: HCOOH; solvent: DCM; III-1 yield: 46%;
(9) And (3) a photocatalyst: cat-1; bransted acid: tsOH; solvent: meCN; III-1 yield: 27%;
(10) And (3) a photocatalyst: cat-1; bransted acid: tsOH; solvent: DMSO; III-1 yield: 11%;
(11) And (3) a photocatalyst: cat-1; bransted acid: tsOH; solvent: phMe; III-1 yield: 39%;
(12) And (3) a photocatalyst: cat-1; bransted acid: tsOH; solvent: 1,4-dioxane; III-1 yield: 32%;
(13) And (3) a photocatalyst: cat-1; bransted acid: tsOH; solvent: etOH; III-1 yield: 18%;
(14) And (3) a photocatalyst: the method is free; bransted acid: tsOH; solvent: DCM; III-1 yield: 37%;
(15) And (3) a photocatalyst: cat-1 (protected from light); bransted acid: tsOH; solvent: DCM; III-1 yield: 14%.
Example 2: the synthetic route is the same as that of example 1, benzaldoxime (10 mmol), 2- (hydroxy (phenyl) methyl) phenol (11 mmol), p-toluenesulfonic acid TsOH (1 mmol), cat-1 (0.4 mmol) and methylene dichloride (100 mL) are sequentially added into a reaction bottle, a blue light LED is irradiated at 30-32 ℃ for reaction 24 h in a nitrogen atmosphere, saturated ammonium chloride solution is added after the reaction is finished, methylene dichloride is used for extraction, washing, organic phases are combined and concentrated, and the target product III-1 can be obtained through column chromatography separation, and the yield is 71%.
Example 3: synthesis of 1, 3-benzoxazine compound by taking 2- (hydroxy (phenyl) methyl) phenol as raw material
Sequentially adding the phenol (0.2 mmol) in a formula I, the 2- (hydroxy (phenyl) methyl) phenol (0.22 mmol), the p-toluenesulfonic acid TsOH (0.02 mmol), the cat-1 (0.004 mmol) and the methylene dichloride (2 mL) into a reaction bottle, carrying out a blue light LED irradiation reaction for 12 h in a nitrogen atmosphere at 30 ℃, adding a saturated ammonium chloride solution after the reaction is finished, extracting and washing the methylene dichloride, merging and concentrating the organic phases, and separating by column chromatography to obtain the target product in a formula III-a. The structures and yields corresponding to formula I and formula III-a are shown below:
(1) Formula I is 4-methylbenzaldehyde oxime, then formula III-a is 4-phenyl-2- (p-tolyl) -2H-benzo [ e ] [1,3] oxazin-3 (4H) -ol, i.e. III-2, yield: 76%;
(2) Formula I is 4-methoxybenzaldehyde oxime, then formula III-a is 2- (4-methoxyphenyl) -4-phenyl-2H-benzo [ e ] [1,3] oxazin-3 (4H) -ol, i.e. III-3, yield: 81% of a glass fiber;
(3) Formula I is 4-chlorobenzaldehyde oxime, then formula III-a is 2- (4-chlorophenyl) -4-phenyl-2H-benzo [ e ] [1,3] oxazin-3 (4H) -ol, i.e. III-4, yield: 70% of the total weight of the steel sheet;
(4) Formula I is 4-bromobenzaldehyde oxime, then formula III-a is 2- (4-bromophenyl) -4-phenyl-2H-benzo [ e ] [1,3] oxazin-3 (4H) -ol, i.e. III-6, yield: 58%;
(5) Formula I is 4-nitrobenzaldehyde oxime, then formula III-a is 2- (4-nitrophenyl) -4-phenyl-2H-benzo [ e ] [1,3] oxazin-3 (4H) -ol, i.e. III-5, yield: 43%.
(6) Formula I is benzo [ d ] [1,3] dioxazole-4-formaldoxime, then formula III-a is 2- (benzo [ d ] [1,3] dioxol-5-yl) -4-phenyl-2H-benzo [ e ] [1,3] oxazin-3 (4H) -ol, i.e. III-25, yield: 79%;
(7) Formula I is 1-naphthaldehyde oxime, then formula III-a is 2- (naphthalen-2-yl) -4-phenyl-2H-benzo [ e ] [1,3] oxazin-3 (4H) -ol, i.e. III-7, yield: 71%;
(8) Formula I is furan-2-carbaldehyde oxime, then formula III-a is 2- (furan-2-yl) -4-phenyl-2H-benzo [ e ] [1,3] oxazin-3 (4H) -ol, i.e. III-8, yield: 66%;
(9) Formula I is thiophene-2-carbaldehyde oxime, then formula III-a is 4-phenyl-2- (thiophen-2-yl) -2H-benzo [ e ] [1,3] oxazin-3 (4H) -ol, i.e. III-9, yield: 54%;
(10) Formula I is quinoline-4-formaldoxime, then formula III-a is 4-phenyl-2- (quinolin-3-yl) -2H-benzo [ e ] [1,3] oxazin-3 (4H) -ol, i.e. III-20, yield: 39%;
(11) Formula I is aldoxime, then formula III-a is 2-methyl-4-phenyl-2H-benzo [ e ] [1,3] oxazin-3 (4H) -ol, i.e. III-11, yield: 75%;
(12) Formula I is a pivalaldoxime, then formula III-a is 2- (tert-butyl) -4-phenyl-2H-benzo [ e ] [1,3] oxazin-3 (4H) -ol, i.e. III-14, yield: 70% of the total weight of the steel sheet;
(13) Formula I is cyclopentylaldoxime, formula III-a is 2-cyclopentyl-4-phenyl-2H-benzo [ e ] [1,3] oxazin-3 (4H) -ol, i.e. III-17, yield: 71%;
(14) Formula I is (2E) -cinnamaldehyde oxime, then formula III-a is (E) -4-phenyl-2-styryl-2H-benzo [ E ] [1,3] oxazin-3 (4H) -ol, i.e. III-10, yield: 68%;
(15) Formula I is 5-phenylpent-4-yn aldoxime, then formula III-a is 4-phenyl-2- (4-phenyl-3-yn-1-yl) -2H-benzo [ e ] [1,3] oxazin-3 (4H) -ol, i.e. III-12, yield: 70% of the total weight of the steel sheet;
(16) Formula I is 2-phenoxyaldoxime, then formula III-a is 2- (phenoxymethyl) -4-phenyl-2H-benzo [ e ] [1,3] oxazin-3 (4H) -ol, i.e. III-13, yield: 65%;
(17) Formula I is propan-2-one oxime, then formula III-a is 2, 2-dimethyl-4-phenyl-2H-benzo [ e ] [1,3] oxazin-3 (4H) -ol, i.e. III-15, yield: 77%.
(18) The formula I is pent-3-one oxime, and the formula III-a is 2, 2-diethyl-4-phenyl-2H-benzo [ e ] [1,3] oxazin-3 (4H) -ol, namely III-19, and the yield is: 73%;
(19) Formula I is 1-cyclopropylethanol-1-ketoxime, then formula III-a is 2-cyclopropyl-2-methyl-4-phenyl-2H-benzo [ e ] [1,3] oxazin-3 (4H) -ol, i.e. III-16, yield: 69%;
(20) Formula I is 1-phenethan-1-one oxime, then formula III-a is 2-methyl-2, 4-diphenyl-2H-benzo [ e ] [1,3] oxazin-3 (4H) -ol, i.e. III-23, yield: 62%;
(21) Formula I is cyclohexanone oxime, then formula III-a is 4-phenylspiro [ benzo [ e ] [1,3] oxazin-2, 1' -cyclohexane ] -3 (4H) -ol, i.e. III-21, yield: 70% of the total weight of the steel sheet;
(22) Formula I is tetrahydro-4H-pyran-4-one oxime, then formula III-a is 4-phenyl-2 ',3',5',6' -tetrahydrospiro [ benzo [ e ] [1,3] oxazin-2, 4' -pyran ] -3 (4H) -ol, i.e. III-22, yield: 64%.
Example 4: synthesis of 1, 3-benzoxazine compound by using benzaldehyde oxime as raw material
The method comprises the steps of sequentially adding benzaldehyde oxime (0.2 mmol), p-toluenesulfonic acid TsOH (0.22 mmol), cat-1 (0.004 mmol) and dichloromethane (2 mL) into a reaction bottle, carrying out blue light LED irradiation reaction at 30 ℃ in a nitrogen atmosphere for 24 h, adding saturated ammonium chloride solution after the reaction is finished, extracting with dichloromethane, washing, merging and concentrating organic phases, and separating by column chromatography to obtain a target product of formula III-b. The corresponding structures and yields of formulas II, III-b are shown below:
(1) Formula II is 2- (hydroxy (p-tolyl) methyl) phenol, then formula III-b is 2-phenyl-4- (p-tolyl) -2H-benzo [ e ] [1,3] oxazin-3 (4H) -ol, i.e. III-30, yield: 72%;
(2) Formula II is 2- (hydroxy (4-methoxyphenyl) methyl) phenol, then formula III-b is 4- (4-methoxyphenyl) -2-phenyl-2H-benzo [ e ] [1,3] oxazin-3 (4H) -ol, i.e. III-27, yield: 61%;
(3) Formula II is 2- ([ 1,1 '-biphenyl ] -4-yl (hydroxy) methyl) phenol, then formula III-b is 4- ([ 1,1' -biphenyl ] -4-yl) -2-phenyl-2H-benzo [ e ] [1,3] oxazin-3 (4H) -ol, i.e. III-31, yield: 60 percent;
(4) Formula II is 1- (4- (hydroxy (2-hydroxyphenyl) methyl) phenyl) ethan-1-one, then formula III-b is 1- (4- (3-hydroxy-2-phenyl-3, 4-dihydro-2H-benzo [ e ] [1,3] oxazin-4-yl) phenyl) ethan-1-one, i.e. III-28, yield: 70% of the total weight of the steel sheet;
(5) Formula II is 2- (hydroxy (naphthalen-1-yl) methyl) phenol, then formula III-b is 4- (naphthalen-1-yl) -2-phenyl-2H-benzo [ e ] [1,3] oxazin-3 (4H) -ol, i.e. III-29, yield: 66%;
(6) Formula II is 2- (hydroxy (thiophen-3-yl) methyl) phenol, then formula III-b is 2-phenyl-4- (thiophen-3-yl) -2H-benzo [ e ] [1,3] oxazin-3 (4H) -ol, i.e. III-32, yield: 57%;
(7) Formula II is 2- (1-hydroxy-2, 2-dimethylpropyl) phenol, then formula III-b is 4- (tert-butyl) -2-phenyl-2H-benzo [ e ] [1,3] oxazin-3 (4H) -ol, i.e. III-33, yield: 68%;
(8) Formula II is 2- (hydroxy (phenyl) methyl) -4-methylphenol, then formula III-b is 6-methyl-2, 4-diphenyl-2H-benzo [ e ] [1,3] oxazin-3 (4H) -ol, i.e. III-37, yield: 73%;
(9) Formula II is 2- (hydroxy (phenyl) methyl) -4-methoxyphenol, then formula III-b is 6-methoxy-2, 4-diphenyl-2H-benzo [ e ] [1,3] oxazin-3 (4H) -ol, i.e., III-36, yield: 68%;
(10) Formula II is 4-chloro-2- (hydroxy (phenyl) methyl) phenol, then formula III-b is 6-chloro-2, 4-diphenyl-2H-benzo [ e ] [1,3] oxazin-3 (4H) -ol, i.e. III-35, yield: 55%.
It should be noted that the above embodiments are only for illustrating the technical solution of the present invention, and are not limiting; although the invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical scheme described in the foregoing embodiments can be modified or some or all of the technical features thereof can be replaced by equivalents; such modifications and substitutions do not depart from the spirit of the invention.

Claims (3)

1. The preparation method of the 1, 3-benzoxazine compound is characterized in that the compound of the formula I and the compound of the formula II are used as raw materials, dichloromethane is used as a solvent, and the 1, 3-benzoxazine compound shown in the formula III is generated by the reaction at 30-32 ℃ under the catalysis of catalysts cat-1, bronsted acid and blue LED illumination:
；
wherein R1 is hydrogen or any one of C1-C10 unsubstituted alkyl, phenyl substituted monoalkenyl, phenyl substituted monoalkynyl, oxygen-containing heterocyclic group, nitrogen-containing heterocyclic group, sulfur-containing heterocyclic group, unsubstituted aromatic hydrocarbon group, methyl substituted, methoxy substituted, halogen substituted and nitro substituted phenyl;
r2 is any one of hydrogen or phenyl, methyl substituted phenyl, methoxy substituted phenyl, halogen substituted phenyl, naphthyl, anthryl, furyl, thienyl, methyl, tertiary butyl and benzyl;
r3 is any one of hydrogen, halogen or methyl and methoxy;
the structure of the catalyst cat-1 is shown as follows:
；
the Bronsted acid is any one of trifluoromethanesulfonic acid, trifluoroacetic acid, p-toluenesulfonic acid and formic acid.
2. The preparation method of the 1, 3-benzoxazine compound according to claim 1, which is characterized in that the compound of the formula I, the compound of the formula II and a catalyst cat-1 are put into methylene dichloride, the Bronsted acid is added for reaction under the illumination condition of blue LEDs, the temperature is 30-32 ℃ and the time is 10-24 hours, the reaction progress is monitored by TLC, after the reaction is finished, the saturated ammonium chloride solution is used for quenching the reaction, and the methylene dichloride is used as an extraction solvent, and the 1, 3-benzoxazine compound is obtained by column chromatography separation.
3. A preparation method of a 1, 3-benzoxazine compound according to claim 2, wherein the molar ratio of the compound of formula I, the compound of formula II, the bronsted acid and the catalyst cat-1 is 1: 1-5: 0.1 to 0.5:0.01 to 0.05.
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