CN117567387A - Method for preparing benzoxazine-4-ketone series compounds by using nitroaromatic hydrocarbon - Google Patents

Method for preparing benzoxazine-4-ketone series compounds by using nitroaromatic hydrocarbon Download PDF

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CN117567387A
CN117567387A CN202311576806.0A CN202311576806A CN117567387A CN 117567387 A CN117567387 A CN 117567387A CN 202311576806 A CN202311576806 A CN 202311576806A CN 117567387 A CN117567387 A CN 117567387A
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尹志平
安通顺
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Nanjing Dechuan Pharmaceutical Technology Co ltd
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Nanjing Dechuan Pharmaceutical Technology Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/04—1,3-Oxazines; Hydrogenated 1,3-oxazines
    • C07D265/12—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems
    • C07D265/14—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D265/20—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with hetero atoms directly attached in position 4
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Abstract

The invention discloses a method for preparing benzoxazine-4-ketone series compounds by using nitroaromatic hydrocarbon, which comprises the following steps: adding nitroarene solid raw materials and Mo (CO) into a sealed tube 6 、Pd(OAc) 2 Xanthophos, covering a rubber plug and vacuumizing; adding liquid aryl halogenated raw material, diPEA and solvent 1, 4-dioxane, and replacing a rubber plug with a Teflon screw cap; placing the sealed tube into an aluminum ingot heating module for reaction; after the reaction is completed, the reaction mixture is cooled to room temperature, quenched by saturated brine, extracted by ethyl acetate, and concentrated by rotary evaporation under reduced pressure, and finally the target product is obtained by column chromatography separation. The method uses the corresponding nitroarene as the raw material directly, uses molybdenum hexacarbonyl as the core reducing agent and carbon monoxide source, can efficiently synthesize the benzoxazine-4-ketone series compound with various types in one step in the presence of transition metal palladium, has advantages in atomic economy and step economy, and can further reduce the preparation cost.

Description

Method for preparing benzoxazine-4-ketone series compounds by using nitroaromatic hydrocarbon
Technical Field
The invention relates to a method for preparing benzoxazine-4-ketone series compounds by using nitroaromatic hydrocarbon.
Background
Benzoxazine-4-one is used as a very important heterocyclic skeleton structure and has wide application in medicine, material and pesticide chemistry. For example, the new weight-reducing agent cetiristat, UV-3638, and some plant pest-resistant agents all contain a core backbone structure of benzoxazin-4-one.
Traditionally, the classical synthesis mode of the heterocyclic skeleton mainly relies on the serial cyclization reaction of 2-aminobenzoic acid and acyl chloride for synthesis, the substrate source is limited, acyl chloride and strong base reagents are needed to be utilized, and the research on the structure-activity relationship of polyfunctional groups of pharmaceutical chemistry and the large-scale preparation are not facilitated.
Disclosure of Invention
The invention aims to provide a method for preparing benzoxazine-4-ketone series compounds by using nitroaromatic hydrocarbon, and provides a novel efficient palladium-catalyzed reduction dicarbonylation reaction of nitroaromatic hydrocarbon and aryl halide, which is used for synthesizing different types of benzoxazine-4-ketone products, so as to solve the problems that the substrate sources are limited, acyl chloride and strong base reagents are needed, and the research on the structure-activity relationship of polyfunctional groups of pharmaceutical chemistry and the large-scale preparation are unfavorable.
In order to achieve the above purpose, the present invention provides the following technical solutions: a method for preparing benzoxazine-4-one series compounds by using nitroaromatic hydrocarbon, which comprises the following steps:
step (A), adding nitroarene solid raw materials (1 equivalent) and Mo (CO) into a preheated vacuum-dried pressure-resistant sealed tube 6 、Pd(OAc) 2 The weight ratio of the xanthos to the xanthos is 75-85:100-110:4-5:11-12, covering a rubber plug of the sealing tube;
step (B), connecting double calandria through needle, vacuumizing and replacing argon for at least three times;
step (C), adding liquid aryl halogenated raw material (2 equivalent), diPEA (5 equivalent) and solvent 1, 4-dioxane (2 ml) through a syringe, and rapidly replacing a rubber plug by using a Teflon screw cap;
step (D), placing the pressure-resistant sealing tube into an aluminum ingot heating module, and heating and stirring for 24 hours at 120 ℃;
and (E) after the reaction is finished, cooling the reaction mixture to 25 ℃, quenching the reaction mixture with saturated salt water, extracting the reaction mixture with ethyl acetate for at least three times, merging all organic phases, concentrating the organic phases by rotary evaporation under reduced pressure, and finally separating the organic phases by column chromatography to obtain a target product.
Preferably, the nitroaromatic solid raw material in the step (a) is selected from one or more of the following: 1-bromo-2-nitrobenzene, 1-bromo-4, 5-difluoronitrobenzene, methyl 4-bromo-3-nitrobenzoate, 4-bromo-3-nitrotoluene.
Preferably, the liquid raw material in the step (C) comprises iodobenzene, 3-iodopyridine, 2-iodofuran, 1-iodonaphthalene, 4-iodobenzoic acid methyl ester, bromobenzotrifluoride, 2-iodothiophene and phenyl trifluoro methane sulfonate.
Preferably, in the step (A), nitroaromatic solid raw materials (0.4 mmol,80.4 mg) and Mo (CO) 6 (105.2mg,0.4mmol)、Pd(OAc) 2 (5mol％，4.5mg)、xantphos(5mol％，11.6mg)。
Preferably, in the step (C), the liquid aryl halide is selected from iodobenzene (0.4 mmol,80.4 mg), diPEA (2.0 mmol,323 μl) and solvent 1, 4-dioxane (2 mL).
Compared with the prior art, the invention has the advantages that:
1. the substrate of the invention has wide sources, the o-bromonitrobenzene and the iodobenzene are common commercially available products, the types are various, the cost is low, the benzoxazine-4-one product containing different functional group substitutions can be produced in batch, and a potential method is provided for the subsequent research on the activity of the related pharmaceutical chemical structure-activity relationship based on the heterocyclic parent nucleus structure;
2. the method utilizes the commercially available molybdenum hexacarbonyl with stable properties as a reducing agent and a solid carbonyl source, is simple and convenient to operate, successfully avoids the use of carbon monoxide gas and a high-pressure reaction kettle device, and is safer and more reliable;
3. the invention has high reaction yield and selectivity, good substrate universality and functional group compatibility, different iodo-aromatic hydrocarbon, bromo-aromatic hydrocarbon and trifluoromethane sulfonate aromatic hydrocarbon can be used as reaction starting materials to synthesize a target product with good yield, and in addition, the substrate derived from steroid hormone estrone can be well adapted to the reaction conditions, so that the application value of the method is more highlighted;
4. the method uses the corresponding nitroarene as the raw material directly, uses molybdenum hexacarbonyl as the core reducing agent and carbon monoxide source, can efficiently synthesize the benzoxazine-4-ketone series compound with various types in one step in the presence of transition metal palladium, has more advantages in atomic economy and step economy, and can further reduce the preparation cost.
Drawings
FIG. 1 is a template reaction diagram of a conditional screen of the present invention;
FIG. 2 is a diagram of phosphine ligands used in the condition screening of the present invention;
FIG. 3 is a diagram showing the synthesis of the compound of example 1 of the present invention;
FIG. 4 is a diagram showing the synthesis of the compound of example 2 of the present invention;
FIG. 5 is a diagram showing the synthesis of the compound of example 3 of the present invention;
FIG. 6 is a diagram showing the synthesis of the compound of example 4 of the present invention;
FIG. 7 is a diagram showing the synthesis of the compound of example 5 of the present invention;
FIG. 8 is a diagram showing the synthesis of the compound of example 6 of the present invention;
FIG. 9 is a diagram showing the synthesis of the compound of example 7 of the present invention;
FIG. 10 is a diagram showing the synthesis of the compound of example 8 of the present invention;
FIG. 11 is a diagram showing the synthesis of the compound of example 9 of the present invention;
FIG. 12 is a diagram showing the synthesis of the compound of example 10 of the present invention.
Detailed Description
The following description of the embodiments of the present invention will be made clearly and completely with reference to the accompanying drawings, in which it is apparent that the embodiments described are only some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
In order to successfully find the optimal reaction conditions for the preparation process of the present application, we first used commercially available 1-bromo-2-nitrobenzene and iodobenzene as model substrates, for imagingA number of prior growths and screening operations have been performed in response to various factors such as the different metal palladium salts, phosphine ligands, bases, solvents, and temperatures of the reaction yields. The best reaction conditions were finally found to be the use of 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene ligand (ligand 1) as phosphine ligand, pd (OAc) 2 N, N-Diisopropylethylamine (DiPEA) acts as an organic base, mo (CO), as a metal catalyst 6 As a reducing agent and a carbonyl source, the target product 3a can be obtained in 82% isolation yield by reacting for 24 hours at 120℃in a 1, 4-dioxane solvent.
Referring to fig. 1-12, the present invention provides a technical solution: a method for preparing benzoxazine-4-ketone series compounds by using nitroaromatic hydrocarbon; the method comprises the following steps:
step (A), adding nitroarene solid raw materials (1 equivalent) and Mo (CO) into a preheated vacuum-dried pressure-resistant sealed tube 6 、Pd(OAc) 2 The weight ratio of the xanthos to the xanthos is 75-85:100-110:4-5:11-12, covering a rubber plug of the sealing tube;
step (B), connecting double calandria through needle, vacuumizing and replacing argon for at least three times;
step (C), adding liquid aryl halogenated raw material (2 equivalent), diPEA (5 equivalent) and solvent 1, 4-dioxane (2 ml) through a syringe, and rapidly replacing a rubber plug by using a Teflon screw cap;
step (D), placing the pressure-resistant sealing tube into an aluminum ingot heating module, and heating and stirring for 24 hours at 120 ℃;
and (E) after the reaction is finished, cooling the reaction mixture to 25 ℃, quenching the reaction mixture with saturated salt water, extracting the reaction mixture with ethyl acetate for at least three times, merging all organic phases, concentrating the organic phases by rotary evaporation under reduced pressure, and finally separating the organic phases by column chromatography to obtain a target product.
Further, the nitroaromatic solid raw material in the step (A) is selected from one or more of the following: 1-bromo-2-nitrobenzene, 1-bromo-4, 5-difluoronitrobenzene, methyl 4-bromo-3-nitrobenzoate, 4-bromo-3-nitrotoluene.
Further, the liquid raw material in the step (C) comprises iodobenzene, 3-iodopyridine, 2-iodofuran, 1-iodonaphthalene, 4-iodobenzoic acid methyl ester, p-bromobenzotrifluoride, 2-iodothiophene and phenyl trifluoro methane sulfonate.
Further, in the step (A), nitroaromatic solid raw materials (0.4 mmol,80.4 mg), mo (CO) 6 (105.2mg,0.4mmol)、Pd(OAc) 2 (5mol％，4.5mg)、xantphos(5mol％，11.6mg)。
Further, in the step (C), iodobenzene (0.4 mmol,80.4 mg), diPEA (2.0 mmol, 323. Mu.L) and 1, 4-dioxane (2 mL) as solvents were used as the liquid aryl halide starting material.
Example 1
As shown in fig. 3, the synthesis method is as follows: into a pressure-resistant sealed tube (10 mL) which had been previously dried by heating under vacuum, 1-bromo-4, 5-difluoronitrobenzene (0.4 mmol,94.8 mg) as a solid material and Mo (CO) were introduced 6 (105.2mg,0.4mmol)、Pd(OAc) 2 (5 mol%,4.5 mg), xantphos (5 mol%,11.6 mg), and then a rubber stopper was plugged, and a double row of tubes were connected through a needle, and vacuum was pulled and argon was replaced three times. Subsequently, liquid raw material iodobenzene (0.8 mmol, 93. Mu.L), diPEA (2.0 mmol, 323. Mu.L), solvent 1, 4-dioxane (2 mL) was added via syringe and the rubber stopper was quickly replaced with a Teflon screw cap. The pressure-resistant sealed tube is put into an aluminum ingot heating module and heated and stirred for 24 hours at 120 ℃. After the reaction was completed, the reaction mixture was cooled to room temperature, quenched with saturated brine (3 mL), extracted three times with ethyl acetate (3 x5 mL), and all the organic phases were combined, concentrated by rotary evaporation under reduced pressure, and finally purified by column chromatography with ethyl acetate: petroleum ether (30:1) is eluted and separated to obtain the target product, white solid, and the yield is 85%. The results of the nuclear magnetic characterization of the product are: 1 H NMR(400MHz,CDCl 3 )δ8.31-8.20(m,2H),7.98(dd,J＝9.3,8.2Hz,1H),7.64-7.55(m,1H),7.55-7.41(m,3H). 13 C NMR(101MHz,CDCl 3 )δ157.84,157.82,157.80,157.42,157.28,154.83,154.69,151.35,151.21,148.83,148.69,145.07,145.04,144.96,144.93,133.03,129.50,128.79,128.31,116.42,116.40,116.23,116.20,115.65,115.46,113.77,113.74,113.70,113.67。
example 2
As shown in fig. 4, the synthesis method is as follows: into a pressure-resistant sealed tube (10 mL) which had been previously dried by vacuum heating was charged methyl 4-bromo-3-nitrobenzoate as a solid material(0.4mmol,103.2mg)、Mo(CO) 6 (105.2mg,0.4mmol)、Pd(OAc) 2 (5 mol%,4.5 mg), xantphos (5 mol%,11.6 mg), and then a rubber stopper was plugged, and a double row of tubes were connected through a needle, and vacuum was pulled and argon was replaced three times. Subsequently, liquid raw material iodobenzene (0.8 mmol, 90. Mu.L), diPEA (2.0 mmol, 323. Mu.L), solvent 1, 4-dioxane (2 mL) was added via syringe and the rubber stopper was quickly replaced with a Teflon screw cap. The pressure-resistant sealed tube is put into an aluminum ingot heating module and heated and stirred for 24 hours at 120 ℃. After the reaction was completed, the reaction mixture was cooled to room temperature, quenched with saturated brine (3 mL), extracted three times with ethyl acetate (3 x5 mL), and all the organic phases were combined, concentrated by rotary evaporation under reduced pressure, and finally purified by column chromatography with ethyl acetate: petroleum ether (10:1) is eluted and separated to obtain the target product, which is white solid with the yield of 65 percent. The results of the nuclear magnetic characterization of the product are: 1 H NMR(400MHz,CDCl 3 )δ8.41-8.24(m,4H),8.14(dd,J＝8.2,1.6Hz,1H),7.65-7.57(m,1H),7.54(t,J＝7.5Hz,2H),4.01(s,3H). 13 C NMR(101MHz,CDCl 3 )δ165.51,158.92,157.68,147.02,137.41,132.97,129.83,128.83(2C),128.69,128.44,128.39,120.02,52.85。
example 3
As shown in fig. 5, the synthesis method is as follows: 1-bromo-2-nitrobenzene (0.4 mmol,80.4 mg) as a solid material and Mo (CO) were added to a pressure-tight tube (10 mL) which had been previously dried by heating under vacuum 6 (105.2mg,0.4mmol)、Pd(OAc) 2 (5 mol%,4.5 mg), xantphos (5 mol%,11.6 mg), and then a rubber stopper was plugged, and a double row of tubes were connected through a needle, and vacuum was pulled and argon was replaced three times. Subsequently, 3-iodopyridine (0.8 mmol, 83. Mu.L), diPEA (2.0 mmol, 323. Mu.L), solvent 1, 4-dioxane (2 mL) was added via syringe and the rubber stopper was quickly replaced with a Teflon screw cap. The pressure-resistant sealed tube is put into an aluminum ingot heating module and heated and stirred for 24 hours at 120 ℃. After the reaction was completed, the reaction mixture was cooled to room temperature, quenched with saturated brine (3 mL), extracted three times with ethyl acetate (3 x5 mL), and all the organic phases were combined, concentrated by rotary evaporation under reduced pressure, and finally purified by column chromatography with ethyl acetate: petroleum ether (8:1) is eluted and separated to obtain the target product, which is white solid with the yield of 49 percent. The results of the nuclear magnetic characterization of the product are: 1H NMR(400MHz,CDCl3)δ9.51(dd,J＝2.3,0.9Hz,1H),8.79(dd,J＝4.9,1.7Hz,1H),8.55(dt,J＝8.0,2.0Hz,1H),8.26(dd,J＝7.9,1.5Hz,1H),7.86(ddd,J＝8.1,7.3,1.5Hz,1H),7.72(dd,J＝8.2,1.2Hz,1H),7.56(td,J＝7.6,1.2Hz,1H),7.46(ddd,J＝8.1,4.9,0.9Hz,1H).13C NMR(101MHz,CDCl3)δ158.93,155.32,152.93,149.65,146.43,136.77,135.45,128.82,128.72,127.36,126.34,123.45,117.12。
Example 4
As shown in fig. 6, the synthesis method is as follows: 1-bromo-2-nitrobenzene (0.4 mmol,80.4 mg) as a solid material and Mo (CO) were added to a pressure-tight tube (10 mL) which had been previously dried by heating under vacuum 6 (105.2mg,0.4mmol)、Pd(OAc) 2 (5 mol%,4.5 mg), xantphos (5 mol%,11.6 mg), and then a rubber stopper was plugged, and a double row of tubes were connected through a needle, and vacuum was pulled and argon was replaced three times. Subsequently, 2-iodofuran (0.8 mmol, 77. Mu.L), diPEA (2.0 mmol, 323. Mu.L), solvent 1, 4-dioxane (2 mL) was added via syringe and the rubber stopper was quickly replaced with a Teflon screw cap. The pressure-resistant sealed tube is put into an aluminum ingot heating module and heated and stirred for 24 hours at 120 ℃. After the reaction was completed, the reaction mixture was cooled to room temperature, quenched with saturated brine (3 mL), extracted three times with ethyl acetate (3×5 mL), and all the organic phases were combined and concentrated by rotary evaporation under reduced pressure, and finally purified by column chromatography with ethyl acetate: petroleum ether (20:1) is eluted and separated to obtain the target product, which is white solid with the yield of 69 percent. The results of the nuclear magnetic characterization of the product are: 1 H NMR(300MHz,CDCl 3 )δ8.22(ddd,J＝7.9,1.5,0.6Hz,1H),7.82(ddd,J＝8.1,7.3,1.6Hz,1H),7.74-7.68(m,2H),7.51(ddd,J＝7.9,7.3,1.2Hz,1H),7.37(dd,J＝3.5,0.8Hz,1H),6.62(dd,J＝3.5,1.7Hz,1H). 13 C NMR(75MHz,CDCl 3 )δ158.59,149.76,147.06,146.66,144.38,136.78,128.75,128.26,127.13,117.20,116.89,112.55。
example 5
As shown in fig. 7, the synthesis method is as follows: 1-bromo-2-nitrobenzene (0.4 mmol,80.4 mg) as a solid material and Mo (CO) were added to a pressure-tight tube (10 mL) which had been previously dried by heating under vacuum 6 (105.2mg,0.4mmol)、Pd(OAc) 2 (5 mol%,4.5 mg), xantphos (5 mol%,11.6 mg), and then a rubber stopper is attached by a needleAnd (3) connecting double discharge pipes, vacuumizing and replacing argon three times. Subsequently, liquid 1-iodonaphthalene (0.8 mmol, 117. Mu.L), diPEA (2.0 mmol, 323. Mu.L), solvent 1, 4-dioxane (2 mL) was added via syringe and the rubber stopper was quickly replaced with a Teflon screw cap. The pressure-resistant sealed tube is put into an aluminum ingot heating module and heated and stirred for 24 hours at 120 ℃. After the reaction was completed, the reaction mixture was cooled to room temperature, quenched with saturated brine (3 mL), extracted three times with ethyl acetate (3×5 mL), and all the organic phases were combined and concentrated by rotary evaporation under reduced pressure, and finally purified by column chromatography with ethyl acetate: petroleum ether (30:1) is eluted and separated to obtain the target product, white solid, and the yield is 85%. The results of the nuclear magnetic characterization of the product are: 1 H NMR(400MHz,CDCl 3 )δ9.15(d,J＝8.2Hz,1H),8.31(ddd,J＝11.0,7.6,1.4Hz,2H),8.04(d,J＝8.2Hz,1H),7.93(d,J＝8.1Hz,1H),7.86(ddd,J＝8.6,7.2,1.5Hz,1H),7.79(dd,J＝8.1,1.2Hz,1H),7.66(ddd,J＝8.5,6.8,1.5Hz,1H),7.62-7.52(m,3H). 13 C NMR(101MHz,CDCl 3 )δ159.69,157.53,146.70,136.55,133.98,133.14,130.66,129.98,128.78,128.54,128.46,127.82,127.34,126.86,126.34,125.71,124.74,116.89。
example 6
As shown in fig. 8, the synthesis method is as follows: 1-bromo-2-nitrobenzene (0.4 mmol,80.4 mg) as a solid material and Mo (CO) were added to a pressure-tight tube (10 mL) which had been previously dried by heating under vacuum 6 (105.2mg,0.4mmol)、Pd(OAc) 2 (5 mol%,4.5 mg), xantphos (5 mol%,11.6 mg), and then a rubber stopper was plugged, and a double row of tubes were connected through a needle, and vacuum was pulled and argon was replaced three times. Subsequently, methyl 4-iodobenzoate (0.8 mmol, 104. Mu.L), diPEA (2.0 mmol, 323. Mu.L), solvent 1, 4-dioxane (2 mL) was added via syringe and the rubber stopper was quickly replaced with a Teflon screw cap. The pressure-resistant sealed tube is put into an aluminum ingot heating module and heated and stirred for 24 hours at 120 ℃. After the reaction was completed, the reaction mixture was cooled to room temperature, quenched with saturated brine (3 mL), extracted three times with ethyl acetate (3×5 mL), and all the organic phases were combined and concentrated by rotary evaporation under reduced pressure, and finally purified by column chromatography with ethyl acetate: petroleum ether (30:1) is eluted and separated to obtain the target product, which is white solid with the yield of 60 percent. The results of the nuclear magnetic characterization of the product are: 1 H NMR(400MHz,CDCl 3 )δ8.41-8.32(m,2H),8.27-8.21(m,1H),8.19-8.11(m,2H),7.84(ddd,J＝8.0,7.3,1.6Hz,1H),7.71(d,J＝7.5Hz,1H),7.55(ddd,J＝7.8,7.3,1.2Hz,1H),3.96(s,3H). 13 C NMR(101MHz,CDCl 3 )δ166.22,159.13,156.06,146.56,136.68,134.07,133.43,129.81,128.76,128.65,128.19,127.41,117.04,52.44。
example 7
As shown in fig. 9, the synthesis method is as follows: 1-bromo-2-nitrobenzene (0.4 mmol,80.4 mg) as a solid material and Mo (CO) were added to a pressure-tight tube (10 mL) which had been previously dried by heating under vacuum 6 (105.2mg,0.4mmol)、Pd(OAc) 2 (5 mol%,4.5 mg), xantphos (5 mol%,11.6 mg), and then a rubber stopper was plugged, and a double row of tubes were connected through a needle, and vacuum was pulled and argon was replaced three times. Liquid raw material p-bromobenzotrifluoride (0.8 mmol, 112. Mu.L), diPEA (2.0 mmol, 323. Mu.L), solvent 1, 4-dioxane (2 mL) was then added via syringe and the rubber stopper was quickly replaced with a Teflon screw cap. The pressure-resistant sealed tube is put into an aluminum ingot heating module and heated and stirred for 24 hours at 120 ℃. After the reaction was completed, the reaction mixture was cooled to room temperature, quenched with saturated brine (3 mL), extracted three times with ethyl acetate (3×5 mL), and all the organic phases were combined and concentrated by rotary evaporation under reduced pressure, and finally purified by column chromatography with ethyl acetate: petroleum ether (30:1) is eluted and separated to obtain the target product, which is white solid with the yield of 65 percent. The results of the nuclear magnetic characterization of the product are: 1 H NMR(300MHz,CDCl 3 )δ8.46-8.35(m,2H),8.24(ddd,J＝7.9,1.6,0.5Hz,1H),7.84(ddd,J＝8.2,7.3,1.6Hz,1H),7.79-7.66(m,3H),7.55(ddd,J＝7.9,7.3,1.2Hz,1H). 13 C NMR(75MHz,CDCl 3 )δ158.94,155.63,146.46,136.69,134.0(q,J＝32.0Hz),133.52,128.84,128.68,128.57,127.43,125.7(q,J＝3.7Hz),123.7(q,J＝272Hz),117.10。
example 8
As shown in fig. 10, the synthesis method is as follows: 1-bromo-2-nitrobenzene (0.4 mmol,80.4 mg) as a solid material and Mo (CO) were added to a pressure-tight tube (10 mL) which had been previously dried by heating under vacuum 6 (105.2mg,0.4mmol)、Pd(OAc) 2 (5 mol%,4.5 mg), xantphos (5 mol%,11.6 mg), then a rubber plug is plugged, a double row of pipes are connected through a needle,vacuum was applied and argon was replaced three times. Subsequently, liquid starting material 2-iodothiophene (0.8 mmol, 88. Mu.L), diPEA (2.0 mmol, 323. Mu.L), solvent 1, 4-dioxane (2 mL) was added via syringe and the rubber stopper was quickly replaced with a Teflon screw cap. The pressure-resistant sealed tube is put into an aluminum ingot heating module and heated and stirred for 24 hours at 120 ℃. After the reaction was completed, the reaction mixture was cooled to room temperature, quenched with saturated brine (3 mL), extracted three times with ethyl acetate (3×5 mL), and all the organic phases were combined and concentrated by rotary evaporation under reduced pressure, and finally purified by column chromatography with ethyl acetate: petroleum ether (20:1) is eluted and separated to obtain the target product, white solid, and the yield is 78%. The results of the nuclear magnetic characterization of the product are: 1 H NMR(400MHz,CDCl 3 )δ8.21(dd,J＝7.9,1.5Hz,1H),7.96(dd,J＝3.8,1.2Hz,1H),7.86-7.75(m,1H),7.68-7.56(m,2H),7.48(td,J＝7.6,1.1Hz,1H),7.17(dd,J＝5.0,3.8Hz,1H). 13 C NMR(101MHz,CDCl 3 )δ159.02,153.64,147.01,136.61,134.14,132.36,131.72,128.69,128.31,127.92,126.81,116.65。
example 9
As shown in fig. 11, the synthesis method is as follows: into a pressure-resistant sealed tube (10 mL) which had been previously dried by vacuum heating, 4-bromo-3-nitrotoluene (0.4 mmol,86.4 mg) as a solid material and Mo (CO) were introduced 6 (105.2mg,0.4mmol)、Pd(OAc) 2 (5 mol%,4.5 mg), xantphos (5 mol%,11.6 mg), and then a rubber stopper was plugged, and a double row of tubes were connected through a needle, and vacuum was pulled and argon was replaced three times. Subsequently, phenyl trifluoromethane sulfonate (0.8 mmol, 130. Mu.L), diPEA (2.0 mmol, 323. Mu.L), solvent 1, 4-dioxane (2 mL) was added via syringe and the rubber stopper was quickly replaced with a Teflon screw cap. The pressure-resistant sealed tube is put into an aluminum ingot heating module and heated and stirred for 24 hours at 120 ℃. After the reaction was completed, the reaction mixture was cooled to room temperature, quenched with saturated brine (3 mL), extracted three times with ethyl acetate (3×5 mL), and all the organic phases were combined and concentrated by rotary evaporation under reduced pressure, and finally purified by column chromatography with ethyl acetate: petroleum ether (10:1) is eluted and separated to obtain the target product, which is white solid with the yield of 65 percent. The results of the nuclear magnetic characterization of the product are: 1 H NMR(400MHz,CDCl 3 )δ8.35-8.24(m,2H),8.11(d,J＝8.0Hz,1H),7.60-7.54(m,1H),7.53-7.47(m,3H),7.32(ddd,J＝8.0,1.6,0.7Hz,1H),2.51(s,3H). 13 C NMR(101MHz,CDCl 3 )δ159.58,157.16,148.06,146.97,132.48,130.29,129.58,128.67,128.38,128.21,127.15,114.34,22.07。
example 10
As shown in fig. 12, the synthesis method is as follows: into a pressure-resistant sealed tube (10 mL) which had been previously dried by vacuum heating, was charged 1-bromo-2-nitrobenzene (0.4 mmol,80.4 mg) as a solid material, mo (CO) 6 (105.2mg,0.4mmol)、Pd(OAc) 2 (5 mol%,4.5 mg), xantphos (5 mol%,11.6 mg), trifluoromethane sulfonate substrate (0.8 mmol,322 mg), and then a rubber stopper was plugged, and a double drain tube was connected through a needle, and vacuum was pulled and argon was replaced three times. DiPEA (2.0 mmol, 323. Mu.L) was then added via syringe, solvent 1, 4-dioxane (2 mL) and the rubber stopper was replaced quickly with a Teflon screw cap. The pressure-resistant sealed tube is put into an aluminum ingot heating module and heated and stirred for 24 hours at 120 ℃. After the reaction was completed, the reaction mixture was cooled to room temperature, quenched with saturated brine (3 mL), extracted three times with ethyl acetate (3×5 mL), and all the organic phases were combined and concentrated by rotary evaporation under reduced pressure, and finally purified by column chromatography with ethyl acetate: petroleum ether (3:1) is eluted and separated to obtain the target product, which is white solid with the yield of 37 percent. The results of the nuclear magnetic characterization of the product are: 1 H NMR(400MHz,CDCl 3 )δ8.22(dd,J＝7.9,1.5Hz,1H),8.06(dd,J＝8.2,2.0Hz,1H),8.03(s,1H),7.81(ddd,J＝8.7,7.3,1.6Hz,1H),7.67(dd,J＝8.2,1.1Hz,1H),7.50(td,J＝7.6,1.2Hz,1H),7.42(d,J＝8.2Hz,1H),3.12-2.91(m,2H),2.59-2.42(m,2H),2.36(td,J＝10.8,4.3Hz,1H),2.23-1.96(m,4H),1.69-1.46(m,6H),0.93(s,3H). 13 C NMR(101MHz,CDCl 3 )δ220.39,159.72,157.21,147.09,145.00,137.14,136.51,128.74,128.53,128.01,127.55,127.05,125.81,125.66,116.89,50.49,47.87,44.67,37.77,35.78,31.49,29.25,26.25,25.52,21.55,13.79。
although embodiments of the present invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made therein without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.

Claims (5)

1. A method for preparing benzoxazine-4-ketone series compounds by using nitroaromatic hydrocarbon is characterized in that: the method comprises the following steps:
step (A), adding nitroarene solid raw materials (1 equivalent) and Mo (CO) into a preheated vacuum-dried pressure-resistant sealed tube 6 、Pd(OAc) 2 The weight ratio of the xanthos to the xanthos is 75-85:100-110:4-5:11-12, covering a rubber plug of the sealing tube;
step (B), connecting double calandria through needle, vacuumizing and replacing argon for at least three times;
step (C), adding liquid aryl halogenated raw material (2 equivalent), diPEA (5 equivalent) and solvent 1, 4-dioxane (2 ml) through a syringe, and rapidly replacing a rubber plug by using a Teflon screw cap;
step (D), placing the pressure-resistant sealing tube into an aluminum ingot heating module, and heating and stirring for 24 hours at 120 ℃;
and (E) after the reaction is finished, cooling the reaction mixture to 25 ℃, quenching the reaction mixture with saturated salt water, extracting the reaction mixture with ethyl acetate for at least three times, merging all organic phases, concentrating the organic phases by rotary evaporation under reduced pressure, and finally separating the organic phases by column chromatography to obtain a target product.
2. A process for the preparation of benzoxazin-4-ones by means of nitroaromatics according to claim 1, characterized in that: the nitroaromatic solid raw material in the step (A) is selected from one or more of the following: 1-bromo-2-nitrobenzene, 1-bromo-4, 5-difluoronitrobenzene, methyl 4-bromo-3-nitrobenzoate, 4-bromo-3-nitrotoluene.
3. A process for the preparation of benzoxazin-4-ones by means of nitroaromatics according to claim 1, characterized in that: the liquid raw materials in the step (C) comprise iodobenzene, 3-iodopyridine, 2-iodofuran, 1-iodonaphthalene, 4-iodobenzoic acid methyl ester, p-bromobenzotrifluoride, 2-iodothiophene and phenyl trifluoro methane sulfonate.
4. According to the weightsThe method for preparing benzoxazine-4-one series compounds by using nitroaromatic hydrocarbon as claimed in claim 1, wherein the method comprises the following steps: in the step (A), nitroaromatic solid raw materials (0.4 mmol,80.4 mg) and Mo (CO) 6 (105.2mg,0.4mmol)、Pd(OAc) 2 (5mol％，4.5mg)、xantphos(5mol％，11.6mg)。
5. A process for the preparation of benzoxazin-4-ones by means of nitroaromatics according to claim 1, characterized in that: the liquid aryl halide in step (C) was selected from iodobenzene (0.4 mmol,80.4 mg), diPEA (2.0 mmol, 323. Mu.L), and solvent 1, 4-dioxane (2 mL).
CN202311576806.0A 2023-11-24 2023-11-24 Method for preparing benzoxazine-4-ketone series compounds by using nitroaromatic hydrocarbon Pending CN117567387A (en)

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