CN109776488B - Synthesis method of alpha-ketoamide compound with ortho-aldehyde group - Google Patents
Synthesis method of alpha-ketoamide compound with ortho-aldehyde group Download PDFInfo
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Abstract
The invention discloses a method for synthesizing an ortho aldehyde group alpha-ketoamide compound, which comprises the step of reacting benzo [ c ] shown in a formula I]Dissolving isoxazole and benzoylformic acid shown as a formula II in an organic solvent, reacting in an inert atmosphere under the action of a catalyst, and purifying the obtained reaction solution to obtain the alpha-ketoamide compound with ortho aldehyde group shown as a formula III. The invention has the advantages of low price of the used raw materials, environmental protection, small dosage of the catalyst, high catalytic efficiency, wide application range of the substrate,
Description
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to a synthesis method of an o-aldehyde alpha-ketoamide compound.
Technical Field
The alpha-ketoamide of ortho aldehyde group is the core skeleton structure of bioactive substances, synthetic drugs and natural drugs, and has wide application in biological and pharmacological research. In addition, the alpha-ketoamide part with the ortho aldehyde group is widely present in bactericides, bactericide precursors and various inhibitors, and is also a key intermediate for synthesizing some important compounds.
The only existing method for synthesizing alpha-ketoamide compounds with ortho-aldehyde groups (Z. Naturforsch B,1995,50,326-332) is to synthesize the alpha-ketoamide compounds by using benzoyl chloride and anthranilic aldehyde. The method uses raw materials with halogen atoms, has large pollution, is not beneficial to green environmental protection, and the anthranilic aldehyde is expensive, thereby greatly increasing the synthesis cost. Therefore, cheap and easily available raw materials are adopted, high-efficiency catalysts participate in the reaction and the development of environment-friendly and high-efficiency green synthesis paths are of great significance, and a method for synthesizing the o-aldehyde alpha-ketoamide is urgently needed.
Disclosure of Invention
Aiming at the defects in the prior art, the invention aims to provide a synthesis method of an o-aldehyde alpha-ketoamide compound, which has the advantages of low raw material price, environmental protection, small catalyst consumption, high catalytic efficiency and wide applicable substrate range.
In order to achieve the purpose, the invention adopts the following technical scheme:
a method for synthesizing alpha-ketoamide compounds with ortho-aldehyde groups comprises the following steps: dissolving benzo [ c ] isoxazole shown in formula I and aryl/heteroaryl formylic acid shown in formula II in an organic solvent, reacting under the action of a catalyst, purifying the obtained reaction solution to obtain the o-aldehyde alpha-ketoamide compound shown in formula III, wherein the reaction is carried out in an inert atmosphere,
in formula I, formula II or formula III:
R1is H, OMe, F, Cl, Br or CF3；
R2Is composed of
In the reaction process of the invention, firstly, the phosphorus ligand reduces the bivalent copper catalyst to one valence, and then the copper catalyst is inserted in the I to obtain an intermediate 1
Followed by coordination with formula II to give another intermediate 2
Then reduced to eliminate to obtain intermediate 3, followed by oxidation of intermediate 3 with divalent copper
To obtain the alpha-ketoamide compound with ortho aldehyde group in the formula III.
Preferably, the catalyst is a copper catalyst and simultaneously comprises a phosphorus ligand; or the catalyst is a complex of a copper catalyst and a phosphorus ligand.
Preferably, the copper catalyst is copper bromide, the phosphorus ligand is triphenylphosphine, and the complex of the copper catalyst and the phosphorus ligand is CuBr (PPh)3)3。
Preferably, the organic solvent is toluene, dioxane, acetonitrile or 1, 2-dichloroethane.
Preferably, the reaction temperature is 90-130 ℃, and the reaction time is 10-14 h.
Preferably, the ratio of the amounts of benzo [ c ] isoxazole of formula I and aryl/heteroarylformylcarboxylic acid of formula II is 1:1.5 to 2.5.
Preferably, the ratio of the benzo [ c ] isoxazole shown in formula I to the copper catalyst and the phosphorus ligand is 1: 0.03-0.07: 0.1-0.3.
Preferably, the amount ratio of the benzo [ c ] isoxazole represented by formula i to the copper catalyst and phosphorus ligand complex is 1: 0.03-0.07.
Preferably, the amount of the organic solvent added is 6-14 mL/mmol based on the amount of the benzo [ c ] isoxazole represented by formula I.
Preferably, the purification method comprises the following steps: adding column chromatography silica gel into the obtained reaction liquid, distilling under reduced pressure to remove the solvent, drying until the silica gel adsorbs the product powder, loading the product on a column, eluting with mixed liquid of petroleum ether and ethyl acetate, collecting the product by TLC spot plate, and evaporating and concentrating to obtain the o-aldehyde alpha-ketoamide compound shown in formula III.
The purification method can use 100-200 mesh column chromatography silica gel; the volume ratio of the petroleum ether to the ethyl acetate can be 20:1, and the volume ratio can also be adjusted as required.
The inert gas used in the present invention may be N2He or Ar, etc.
Compared with the prior art, the invention has the following beneficial effects: the prior art is prepared by condensing benzoyl chloride and anthranilic aldehyde, the method uses raw materials with halogen atoms, the pollution is large, the green and environment-friendly effects are not facilitated, the anthranilic aldehyde is high in price, and the synthesis cost is greatly increased. The method for synthesizing the alpha-ketoamide also reserves ortho-aldehyde group while synthesizing the alpha-ketoamide, the ortho-aldehyde group can be modified, and other molecules with biological activity are further synthesized, the used raw materials are low in price and environment-friendly, the catalyst is low in price and dosage, the copper catalyst only needs 0.05 equivalent, the catalysis efficiency is high, the substrate application range is wide, and the yield of various electron-withdrawing and electron-donating groups is high.
Detailed Description
The technical solution of the present invention will be further described in detail with reference to the following specific examples.
The benzo [ c ] isoxazole starting material used according to the invention can be prepared on its own according to the existing literature, for example from Wang, f.; xu, p.; wang, s.y.; ji, S.J.org.Lett.2018,20, 2204-. The invention provides a synthesis method which comprises the following steps:
adding o-nitrobenzaldehyde (3mmol) and anhydrous stannous chloride (9mmol) into a reaction flask with magnetic stirring, preparing a solution of methanol and ethyl acetate (1:1,20ml), adding into the reaction flask, and stirring at room temperature for 24 hours. At the end of the reaction, the reaction was quenched with saturated sodium bicarbonate solution (20ml), extracted with ethyl acetate (3 × 10ml), the organic phase was washed with water (20ml), with saturated brine (20ml), the organic phase was dried over anhydrous sodium sulfate, left to stand, filtered and concentrated by evaporation, purified by column chromatography petroleum ether: purification of ethyl acetate 30:1 afforded the product.
The synthetic route is as follows:
the substituted aryl/heteroaryl formylcarboxylic acids used in the present invention can be prepared by themselves according to the existing methods, and the present invention provides the following synthetic methods:
a50 ml round bottom flask was taken and added the corresponding methyl ketone (5mmol), selenium dioxide (6mmol), 10ml pyridine and the reaction mixture was stirred at 110 ℃ for 1 hour, then the temperature was lowered to 90 ℃ and stirred for 21 hours. The reaction was checked by TLC. Separating by column chromatography to obtain the raw material.
The synthetic route is as follows:
example 1
The formula for preparing the o-aldehyde α -ketoamide compound in this example is as follows:
the preparation method comprises the following steps: 0.3mmol of 5-methoxybenzo [ c ] isoxazole (44.7mg), 0.6mmol of benzoylcarboxylic acid (90.1mg), 0.015mmol of copper bromide (3.3mg) and 0.06mmol of triphenylphosphine (15.7mg) were added to a 25ml schlenk tube, and the reaction tube was replaced with argon three times under reduced pressure. 1, 2-dichloroethane (3ml) was added thereto, and the mixture was stirred at 110 ℃ for 12 hours. And after the reaction is finished, adding 100-mesh and 200-mesh column chromatography silica gel, distilling under reduced pressure to remove the solvent, carrying out silica gel column chromatography separation on the crude product, eluting by using mixed liquid of petroleum ether and ethyl acetate (petroleum ether: ethyl acetate: 6:1), carrying out TLC (thin layer chromatography) elution tracking detection, collecting eluent containing the target product, merging the target product eluent, and carrying out evaporation concentration to obtain the alpha-ketoamide compound with the ortho-position aldehyde group shown in the formula III. The material was a yellow solid in 72% yield.
Characterization data: m.p.112-114 ℃;1H NMR(400MHz,CDCl3)δ12.23(s,1H),9.98(s,1H),8.81(d,J＝8.9Hz,1H),8.42-8.38(m,2H),7.66(t,J＝7.4Hz,1H),7.52(t,J＝7.8Hz,2H),7.27-7.22(m,2H),3.90(s,3H)；13C NMR(101MHz,CDCl3)δ194.6,187.0,160.2,156.0,134.4,133.1,132.6,131.2,128.5,123.8,121.8,121.5,120.1,55.7；ATR-FTIR(cm-1):3236,2049,1666,1592,1520,1464,1331,1278,1166,1129,1033,923,883,763,679；HRMS(ESI-TOF)m/z(M+H)+Calcd for C16H13NO4 284.0917；Found 284.0913.
example 2
The formula for preparing the o-aldehyde α -ketoamide compound in this example is as follows:
the preparation method comprises the following steps: 0.3mmol of 5-fluorobenzo [ c ]]Isoxazole (41.1mg), 0.6mmol benzoylcarboxylic acid (90.1mg), 0.015mmol CuBr (PPh)3)3(13.9mg) was put into a 25ml schlenk tube, and the reaction tube was purged with argon three times under reduced pressure. 1, 2-dichloroethane (3ml) was added thereto, and the mixture was stirred at 110 ℃ for 12 hours. And after the reaction is finished, adding 100-mesh and 200-mesh column chromatography silica gel, distilling under reduced pressure to remove the solvent, carrying out silica gel column chromatography separation on the crude product, eluting by using mixed liquid of petroleum ether and ethyl acetate (petroleum ether: ethyl acetate: 20:1), carrying out TLC (thin layer chromatography) elution tracking detection, collecting eluent containing the target product, merging the target product eluent, and carrying out evaporation concentration to obtain the alpha-ketoamide compound with the ortho-position aldehyde group shown in the formula III. The material was a yellow solid in 70% yield.
Characterization data: m.p.133-135 ℃;1H NMR(400MHz,CDCl3)δ12.33(s,1H),9.97(s,1H),8.89(dd,J＝9.2,4.7Hz,1H),8.44-8.35(m,2H),7.70-7.63(m,1H),7.56-7.45(m,3H),7.41(m,1H)；13C NMR(101MHz,CDCl3)δ193.6(d,J＝1.8Hz),186.6,160.1(d,J＝59.8Hz),157.3,135.5(d,J＝2.9Hz),134.6,133.0,131.3,128.6,123.9(d,J＝5.3Hz),122.9(d,J＝22.0Hz),122.2(d,J＝6.9Hz),121.5(d,J＝22.6Hz)；19F NMR(376MHz,CDCl3)δ-116.62；ATR-FTIR(cm-1):3224,2866,1664,1513,1445,1389,1275,1144,1110,948,880,784,683；HRMS(ESI-TOF)m/z(M+H)+Calcd for C15H10FNO3 272.0717；Found 272.0715.
example 3
The formula for preparing the o-aldehyde α -ketoamide compound in this example is as follows:
the preparation method comprises the following steps:
0.3mmol of 5-chlorobenzo [ c ] isoxazole (46mg), 0.6mmol of benzoylcarboxylic acid (90.1mg), 0.015mmol of copper bromide (3.3mg) and 0.06mmol of triphenylphosphine (15.7mg) were added to a 25ml schlenk tube, and the reaction tube was replaced with argon three times under reduced pressure. 1, 2-dichloroethane (3ml) was added thereto, and the mixture was stirred at 110 ℃ for 12 hours. And after the reaction is finished, adding 100-mesh and 200-mesh column chromatography silica gel, distilling under reduced pressure to remove the solvent, carrying out silica gel column chromatography separation on the crude product, eluting by using mixed liquid of petroleum ether and ethyl acetate (petroleum ether: ethyl acetate: 20:1), carrying out TLC (thin layer chromatography) elution tracking detection, collecting eluent containing the target product, merging the target product eluent, and carrying out evaporation concentration to obtain the alpha-ketoamide compound with the ortho-position aldehyde group shown in the formula III. The material was a yellow solid in 75% yield.
Characterization data: m.p.135-136 ℃;1H NMR(400MHz,CDCl3)δ12.39(s,1H),9.96(s,1H),8.84(d,J＝8.9Hz,1H),8.39-8.37(m,2H),7.73(d,J＝2.5Hz,1H),7.69-7.62(m,2H),7.54-7.50(m,2H)；13C NMR(101MHz,CDCl3)δ193.7,186.4,160.5,137.6,135.7,135.3,134.6,132.9,131.3,129.4,128.6,123.9,121.7；ATR-FTIR(cm-1):3222,2857,2752,2162,1686,1662,1572,1499,1444,1383,1274,1187,1152,892,728,676；HRMS(ESI-TOF)m/z(M+H)+Calcd for C15H10ClNO3288.0422；Found 288.0431.
example 4
The formula for preparing the o-aldehyde α -ketoamide compound in this example is as follows:
the preparation method comprises the following steps: 0.3mmol of 6-bromobenzo [ c ]]Isoxazole (59.4mg), 0.6mmol benzoylcarboxylic acid (90.1mg), 0.015mmol CuBr (PPh)3)3(13.9mg) was put into a 25ml schlenk tube, and the reaction tube was purged with argon three times under reduced pressure. 1, 2-dichloroethane (3ml) was added thereto, and the mixture was stirred at 110 ℃ for 12 hours. And after the reaction is finished, adding 100-mesh and 200-mesh column chromatography silica gel, distilling under reduced pressure to remove the solvent, carrying out silica gel column chromatography separation on the crude product, eluting by using mixed liquid of petroleum ether and ethyl acetate (petroleum ether: ethyl acetate: 25:1), carrying out TLC (thin layer chromatography) elution tracking detection, collecting eluent containing the target product, merging the target product eluent, and carrying out evaporation concentration to obtain the alpha-ketoamide compound with the ortho-position aldehyde group shown in the formula III. The material was a yellow solid in 80% yield.
Characterization data: m.p.153-159 ℃;1H NMR(400MHz,CDCl3)δ12.52(s,1H),9.97(s,1H),9.11(d,J＝1.3Hz,1H),8.40-8.38(m,2H),7.69-7.60(m,2H),7.55-7.48(m,3H)；13C NMR(101MHz,CDCl3)δ194.0,186.2,160.5,139.8,136.9,134.7,132.8,131.5,131.3,128.6,127.5,123.2,121.5；ATR-FTIR(cm-1):3220,2867,2162,1979,1665,1590,1573,1446,1278,1146,949,880,785,678；HRMS(ESI-TOF)m/z(M+H)+Calcd for C15H10BrNO3 331.9917；Found 331.9913.
example 5
The formula for preparing the o-aldehyde α -ketoamide compound in this example is as follows:
the preparation method comprises the following steps: 0.3mmol of 6-fluorobenzo [ c ] isoxazole (41.1mg), 0.6mmol of benzoylcarboxylic acid (90.1mg), 0.015mmol of copper bromide (3.3mg) and 0.06mmol of triphenylphosphine (15.7mg) were added to a 25ml schlenk tube, and the reaction tube was replaced with argon three times under reduced pressure. Dioxane (3ml) was added and stirred at 110 ℃ for 12 hours. And after the reaction is finished, adding 100-mesh and 200-mesh column chromatography silica gel, distilling under reduced pressure to remove the solvent, carrying out silica gel column chromatography separation on the crude product, eluting by using mixed liquid of petroleum ether and ethyl acetate (petroleum ether: ethyl acetate: 20:1), carrying out TLC (thin layer chromatography) elution tracking detection, collecting eluent containing the target product, merging the target product eluent, and carrying out evaporation concentration to obtain the alpha-ketoamide compound with the ortho-position aldehyde group shown in the formula III. The material was a yellow solid in 71% yield.
Characterization data: m.p.156-158 ℃;1H NMR(400MHz,CDCl3)δ12.65(s,1H),9.96(s,1H),8.64(dd,J＝11.5,2.3Hz,1H),8.39(dd,J＝8.3,1.1Hz,2H),7.77(dd,J＝8.5,6.2Hz,1H),7.70-7.64(m,1H),7.53(t,J＝7.8Hz,2H),7.02(m,1H)；13C NMR(101MHz,CDCl3)δ193.5,186.2,167.0(d,J＝257.2Hz),160.7,141.5(d,J＝13.6Hz),138.5(d,J＝11.7Hz),134.7,132.8,131.3,128.6,119.7,111.5(d,J＝22.9Hz),107.8(d,J＝28.6Hz)；19F NMR(376MHz,CDCl3)δ-97.48；ATR-FTIR(cm-1):3220,2161,1677,1590,1514,1446,1280,1199,1170,1107,1004,869,782,678；HRMS(ESI-TOF)m/z(M+H)+Calcd for C15H10FNO3 272.0718；Found 272.0716.
example 6
The formula for preparing the o-aldehyde α -ketoamide compound in this example is as follows:
the preparation method comprises the following steps: 0.3mmol of benzo [ c ]]Isoxazole (35.7mg), 0.6mmol of p-methylbenzoylcarboxylic acid (98.4mg), 0.015mmol of CuBr (PPh)3)3(13.9mg) was put into a 25ml schlenk tube, and the reaction tube was purged with argon three times under reduced pressure. 1, 2-dichloroethane (3ml) was added thereto, and the mixture was stirred at 110 ℃ for 12 hours. After the reaction is finished, the reaction solution is added,adding 100-mesh 200-mesh column chromatography silica gel, distilling under reduced pressure to remove the solvent, carrying out silica gel column chromatography separation on the crude product, eluting with a mixed solution of petroleum ether and ethyl acetate (petroleum ether: ethyl acetate: 20:1), carrying out TLC elution tracking detection, collecting eluent containing a target product, merging the target product eluent, and carrying out evaporation concentration to obtain the alpha-ketoamide compound with ortho-position aldehyde group shown in the formula III. The material was a yellow solid in 83% yield.
Characterization data: m.p.121-125 ℃;1H NMR(400MHz,CDCl3)δ12.45(s,1H),10.01(s,1H),8.85(d,J＝8.4Hz,1H),8.31(d,J＝8.3Hz,2H),7.76(dd,J＝7.6,1.5Hz,1H),7.71-7.66(m,1H),7.36-7.30(m,3H),2.44(s,3H)；13C NMR(101MHz,CDCl3)δ194.9,186.2,160.9,145.8,139.2,136.1,135.9,131.4,130.5,129.3,124.1,122.9,120.1,21.9；ATR-FTIR(cm-1):3218,3105,2833,2749,1670,1583,1521,1452,1414,1287,1261,1195,1158,1118,998,869,789,672；HRMS(ESI-TOF)m/z(M+H)+Calcd for C16H13NO3 268.0968；Found 268.0968.
example 7
The formula for preparing the o-aldehyde α -ketoamide compound in this example is as follows:
the preparation method comprises the following steps: 0.3mmol of benzo [ c ] isoxazole (35.7mg), 0.6mmol of p-methoxybenzoylcarboxylic acid (108mg), 0.015mmol of copper bromide (3.3mg) and 0.06mmol of triphenylphosphine (15.7mg) were added to a 25ml schlenk tube, and the reaction tube was replaced with argon three times under reduced pressure. 1, 2-dichloroethane (3ml) was added thereto, and the mixture was stirred at 110 ℃ for 12 hours. And after the reaction is finished, adding 100-mesh and 200-mesh column chromatography silica gel, distilling under reduced pressure to remove the solvent, carrying out silica gel column chromatography separation on the crude product, eluting by using a mixed solution of petroleum ether and ethyl acetate (petroleum ether: ethyl acetate: 15:1), carrying out TLC (thin layer chromatography) elution tracking detection, collecting eluent containing the target product, merging the target product eluent, and carrying out evaporation concentration to obtain the alpha-ketoamide compound with the ortho-position aldehyde group shown in the formula III. The material was a pink solid in 80% yield.
Characterization data: m.p.170-172 ℃;1H NMR(400MHz,CDCl3)δ12.46(s,1H),10.01(s,1H),8.85(d,J＝8.4Hz,1H),8.46(d,J＝8.9Hz,2H),7.76(dd,J＝7.6,1.1Hz,1H),7.68(t,J＝7.9Hz,1H),7.33(t,J＝7.5Hz,1H),6.98(d,J＝8.9Hz,2H),3.90(s,3H)；13C NMR(101MHz,CDCl3)δ194.9,184.7,164.8,161.3,139.3,136.1,135.9,134.0,126.1,124.1,122.9,120.1,113.9,55.6；ATR-FTIR(cm-1):3217,2845,2161,2050,1675,1582,1518,1453,1287,1257,1158,1029,868,761,654；HRMS(ESI-TOF)m/z(M+H)+Calcd for C16H13NO4 284.0917；Found 284.0916.
example 8
The formula for preparing the o-aldehyde α -ketoamide compound in this example is as follows:
the preparation method comprises the following steps: 0.3mmol of benzo [ c ] isoxazole (35.7mg), 0.6mmol of 2-naphthoyl carboxylic acid (120.1mg), 0.015mmol of copper bromide (3.3mg) and 0.06mmol of triphenylphosphine (15.7mg) were added to a 25ml schlenk tube, and the reaction tube was replaced with argon three times under reduced pressure. Acetonitrile (3ml) was added and stirred at 110 ℃ for 12 hours. And after the reaction is finished, adding 100-mesh and 200-mesh column chromatography silica gel, distilling under reduced pressure to remove the solvent, carrying out silica gel column chromatography separation on the crude product, eluting by using a mixed solution of petroleum ether and ethyl acetate (petroleum ether: ethyl acetate: 15:1), carrying out TLC (thin layer chromatography) elution tracking detection, collecting eluent containing the target product, merging the target product eluent, and carrying out evaporation concentration to obtain the alpha-ketoamide compound with the ortho-position aldehyde group shown in the formula III. The material was a yellow solid in 81% yield.
Characterization data: m.p.156-158 ℃;1H NMR(400MHz,CDCl3)δ12.55(s,1H),10.03(s,1H),9.21(s,1H),8.91(d,J＝8.4Hz,1H),8.27(dd,J＝8.7,1.7Hz,1H),8.03(d,J＝8.1Hz,1H),7.91(dd,J＝17.8,8.4Hz,2H),7.78(dd,J＝7.6,1.5Hz,1H),7.74-7.69(m,1H),7.67-7.63(m,1H),7.59-7.55(m,1H),7.36(td,J＝7.5,0.9Hz,1H)；13C NMR(101MHz,CDCl3)δ195.0,186.4,160.9,139.2,136.2,136.1,135.9,134.8,132.3,130.3,130.3,129.4,128.5,127.8,126.9,125.4,124.2,122.9,120.1；ATR-FTIR(cm-1):3215,1673,1582,1519,1450,1288,1198,1151,1113,840,804,756,735,661；HRMS(ESI-TOF)m/z(M+H)+Calcd for C19H13NO3 304.0968；Found 304.0975.
example 9
The formula for preparing the o-aldehyde α -ketoamide compound in this example is as follows:
the preparation method comprises the following steps: 0.3mmol of benzo [ c ] isoxazole (35.7mg), 0.6mmol of 2, 4-difluorobenzoylcarboxylic acid (111.6mg), 0.015mmol of copper bromide (3.3mg) and 0.06mmol of triphenylphosphine (15.7mg) were added to a 25ml schlenk tube, and the reaction tube was replaced with argon three times under reduced pressure. Dioxane (3ml) was added and stirred at 110 ℃ for 12 hours. And after the reaction is finished, adding 100-mesh and 200-mesh column chromatography silica gel, distilling under reduced pressure to remove the solvent, carrying out silica gel column chromatography separation on the crude product, eluting by using a mixed solution of petroleum ether and ethyl acetate (petroleum ether: ethyl acetate: 15:1), carrying out TLC (thin layer chromatography) elution tracking detection, collecting eluent containing the target product, merging the target product eluent, and carrying out evaporation concentration to obtain the alpha-ketoamide compound with the ortho-position aldehyde group shown in the formula III. The material was a white solid in 72% yield.
Characterization data: m.p.165-166 ℃;1H NMR(400MHz,CDCl3)δ12.36(s,1H),10.01(s,1H),8.80(d,J＝8.4Hz,1H),8.05-8.00(m,1H),7.78(dd,J＝7.6,1.5Hz,1H),7.71-7.66(m,1H),7.36(td,J＝7.5,0.9Hz,1H),7.05-7.00(m,1H),6.96-6.91(m,1H)；13C NMR(101MHz,CDCl3)δ195.1,185.6(d,J＝1.8Hz),167.7(d,J＝12.3Hz),164.7(dd,J＝76.5,12.5Hz),161.7(d,J＝12.9Hz),160.0,138.9,136.1(d,J＝12.8Hz),134.0(dd,J＝10.8,3.1Hz),124.4,122.8,120.2,119.1(dd,J＝11.4,3.5Hz),112.0(dd,J＝21.7,3.7Hz),105.1(t,J＝25.4Hz)；19F NMR(376MHz,CDCl3)δ-99.25(d,J＝13.0Hz),-104.26(d,J＝13.0Hz)；ATR-FTIR(cm-1):3062,1682,1586,1531,1453,1425,1286,1202,1152,1107,996,864,818,752,634；HRMS(ESI-TOF)m/z(M+H)+Calcd for C15H9F2NO3 290.0623；Found 290.0619.
example 10
The formula for preparing the o-aldehyde α -ketoamide compound in this example is as follows:
the preparation method comprises the following steps: 0.3mmol of benzo [ c ] isoxazole (35.7mg), 0.6mmol of 2, 4-dichlorobenzoyl carboxylic acid (131.4mg), 0.015mmol of copper bromide (3.3mg) and 0.06mmol of triphenylphosphine (15.7mg) were added to a 25ml schlenk tube, and the reaction tube was replaced with argon three times under reduced pressure. 1, 2-dichloroethane (3ml) was added thereto, and the mixture was stirred at 110 ℃ for 12 hours. And after the reaction is finished, adding 100-mesh and 200-mesh column chromatography silica gel, distilling under reduced pressure to remove the solvent, carrying out silica gel column chromatography separation on the crude product, eluting by using a mixed solution of petroleum ether and ethyl acetate (petroleum ether: ethyl acetate: 15:1), carrying out TLC (thin layer chromatography) elution tracking detection, collecting eluent containing the target product, merging the target product eluent, and carrying out evaporation concentration to obtain the alpha-ketoamide compound with the ortho-position aldehyde group shown in the formula III. The material was a yellow solid in 70% yield.
Characterization data: m.p.182-183 ℃;1H NMR(400MHz,CDCl3)δ12.45(s,1H),10.03(s,1H),8.78(d,J＝8.4Hz,1H),7.79(dd,J＝7.6,1.6Hz,1H),7.71-7.66(m,2H),7.51(d,J＝1.9Hz,1H),7.37(m,2H)；13C NMR(101MHz,CDCl3)δ195.1,188.3,159.3,139.1,138.9,136.2,136.0,134.3,132.3,132.1,130.5,127.1,124.5,122.9,120.1；ATR-FTIR(cm-1):3182,2161,1670,1588,1530,1451,1374,1280,1208,1153,1066,989,866,812,753,666；HRMS(ESI-TOF)m/z(M+H)+Calcd for C15H9Cl2NO3 322.0032；Found 322.0031.
example 11
The formula for preparing the o-aldehyde α -ketoamide compound in this example is as follows:
the preparation method comprises the following steps: 0.3mmol of benzo [ c ]]Isoxazole (35.7mg), 0.6mmol 2-thenoylcarboxylic acid (93.6mg), 0.015mmol CuBr (PPh)3)3(13.9mg) was put into a 25ml schlenk tube, and the reaction tube was purged with argon three times under reduced pressure. Toluene (3ml) was added and stirred at 110 ℃ for 12 hours. And after the reaction is finished, adding 100-mesh and 200-mesh column chromatography silica gel, distilling under reduced pressure to remove the solvent, carrying out silica gel column chromatography separation on the crude product, eluting by using mixed liquid of petroleum ether and ethyl acetate (petroleum ether: ethyl acetate: 20:1), carrying out TLC (thin layer chromatography) elution tracking detection, collecting eluent containing the target product, merging the target product eluent, and carrying out evaporation concentration to obtain the alpha-ketoamide compound with the ortho-position aldehyde group shown in the formula III. The material was a yellow solid in 70% yield.
Characterization data: m.p.171-173 ℃;1H NMR(400MHz,CDCl3)δ12.64(s,1H),10.02(s,1H),8.84(d,J＝8.4Hz,1H),8.46(d,J＝3.8Hz,1H),7.87(d,J＝4.8Hz,1H),7.77(d,J＝7.6Hz,1H),7.69(t,J＝7.9Hz,1H),7.35(t,J＝7.5Hz,1H),7.23(t,J＝4.3Hz,1H)；13C NMR(101MHz,CDCl3)δ194.9,177.7,159.9,138.8,138.7,138.2,136.3,136.1,135.9,128.3,124.4,123.1,120.2；ATR-FTIR(cm-1):3182,3103,2922,1670,1645,1584,1526,1497,1406,1276,1202,1053,857,758,730；HRMS(ESI-TOF)m/z(M+H)+Calcd for C13H9NO3S 260.0376；Found 260.0375.
finally, the above embodiments are only for illustrating the technical solutions of the present invention and not for limiting, although the present invention has been described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions may be made to the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention, and all of them should be covered in the claims of the present invention.
Claims (8)
1. A method for synthesizing an o-aldehyde group alpha-ketoamide compound is characterized in that benzo [ c ] isoxazole shown in formula I and aryl/heteroaryl formylic acid shown in formula II are dissolved in an organic solvent, reaction is carried out under the action of a catalyst, the obtained reaction solution is purified to obtain the o-aldehyde group alpha-ketoamide compound shown in formula III, the reaction is carried out in an inert atmosphere,
Ι Ⅱ Ⅲ，
in formula I, formula II or formula III:
R1is H, OMe, F, Cl, Br or CF3；
R2Is prepared from,
、
、
、
、
、
、
、
、
Or
；
The catalyst is copper bromide and also comprises triphenylphosphine; or the catalyst is CuBr (PPh)3)3。
2. The method for synthesizing α -ketoamide compounds with ortho aldehyde group according to claim 1, wherein the organic solvent is toluene, dioxane, acetonitrile or 1, 2-dichloroethane.
3. The method for synthesizing the o-aldehyde α -ketoamide compounds according to claim 1, wherein the reaction temperature is 90-130 ℃ and the reaction time is 10-14 h.
4. The method for synthesizing o-aldehyde α -ketoamide compounds according to claim 1, wherein the ratio of the amounts of benzo [ c ] isoxazole represented by formula I and aryl/heteroaryl formylic acid represented by formula II is 1: 1.5-2.5.
5. The method for synthesizing o-aldehyde α -ketoamide compounds according to claim 1, wherein the amount ratio of benzo [ c ] isoxazole represented by formula I to the copper bromide and triphenylphosphine is 1: 0.03-0.07: 0.1-0.3.
6. The method of claim 1, wherein the compound is selected from the group consisting of alpha-ketoamides having ortho-aldehyde groupsBenzo [ c ] shown in formula I]Isoxazole with CuBr (PPh)3)3The amount ratio of the substances (A) is 1: 0.03-0.07.
7. The method for synthesizing the o-aldehyde α -ketoamide compounds according to claim 1, wherein the amount of the organic solvent added is 6 to 14mL/mmol based on the amount of the benzo [ c ] isoxazole represented by formula i.
8. The method for synthesizing the o-aldehyde α -ketoamide compounds according to claim 1, wherein the purification method comprises: adding column chromatography silica gel into the obtained reaction liquid, distilling under reduced pressure to remove the solvent, carrying out silica gel column chromatography separation on the crude product, eluting with mixed liquid of petroleum ether and ethyl acetate, carrying out TLC elution tracking detection, collecting eluent containing a target product, merging the target product eluent, and carrying out evaporation concentration to obtain the o-aldehyde alpha-ketoamide compound shown in the formula III.
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| CN104892547A (en) * | 2015-05-14 | 2015-09-09 | 南京师范大学 | Catalytic carbonylation method for synthesis of alpha-keto amide |
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