CN110256492B - Phosphonic-containing carboxylic acid compound and preparation method thereof - Google Patents
Phosphonic-containing carboxylic acid compound and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a phosphonic-containing carboxylic acid compound and a preparation method thereof. The preparation method comprises the following steps: mixing and dissolving a reaction substrate, a phosphine oxide compound and alkali, adding a photocatalyst in a carbon dioxide atmosphere, and then carrying out an illumination reaction at 10-60 ℃ for 2-24 hours at 1-100W. The method has the advantages of mild reaction conditions, wide selectivity of reaction substrates, amplification to gram-scale and basically unaffected yield.
Description
Technical Field
The invention belongs to the field of synthesis for converting a dioxy compound into a carboxylic acid, and particularly relates to a phosphine-containing carboxylic acid compound and a preparation method thereof.
Background
It is known that carboxylic acid compounds are widely present in drug molecules and natural products, and have not only a wide range of applications in organic synthesis but also a wide range of physiological activities. The introduction of phosphine-containing groups into carboxylic acid compounds can utilize the special property of phosphorus atoms to regulate and control the functions of the carboxylic acid compounds, and particularly has wide application in the research fields of biochemistry, pharmaceutical chemistry, organic chemistry and the like. The traditional method for synthesizing the phosphine-containing amino acid has the defects of long synthesis route, harsh reaction conditions, difficult obtainment of raw materials and the like, thereby limiting the wide application of the methods.
Thus, there is a need in the art for a method of developing a phosphine-containing carboxylic acid, and in particular a phosphine-containing α -amino acid, that overcomes the above-mentioned disadvantages.
Disclosure of Invention
Aiming at the defects in the prior art, the invention provides a phosphonic acid compound and a preparation method thereof, which can effectively solve the problems of long synthetic route and harsh reaction conditions of the conventional phosphonic acid compound.
In order to achieve the purpose, the technical scheme adopted by the invention for solving the technical problems is as follows:
a phosphine-containing carboxylic acid compound having the general chemical structure:
wherein, X is any one of an aryl group, a substituted aryl group, an alkyl group or an alkoxy group; a is any one of hydrogen, alkyl, amino, protected amino, aryl, heteroaryl, substituted aryl or substituted heteroaryl, ester group or hydroxyl; b is any one of hydrogen, alkyl, amino, protected amino, aryl, heteroaryl, substituted aryl or substituted heteroaryl, ester group or hydroxyl; c is hydrogen or alkyl.
Further, the chemical structural formula is
Wherein X is an aryl group, a substituted aryl group, an alkyl group or an alkoxy group;
R1is aryl, substituted aryl or substituted heteroaryl; r2Is any one of aryl, substituted heteroaryl and alkyl; r3Is any one of hydrogen, alkyl or branched alkyl;
R4is any one of an aryl group, a substituted aryl group or a substituted heteroaryl group; r5Is any one of hydrogen, alkyl or substituted alkyl; r6Is any one of hydrogen, alkyl or branched alkyl;
R7is any one of an aryl group, a substituted aryl group or a substituted heteroaryl group; r8Is any one of hydrogen, alkyl or substituted alkyl;
R9is any one of hydrogen, alkyl, branched alkyl or heteroatom-substituted alkyl; r10Is any one of aryl, heteroaryl or substituted aryl, heteroaryl and alkyl.
Further, the chemical structural formula of the phosphine-containing carboxylic acid compound is as follows:
the method for preparing the phosphine-containing carboxylic acid compound comprises the following steps:
mixing and dissolving a reaction substrate, a phosphine oxide compound and alkali, adding a photocatalyst in a carbon dioxide atmosphere, and then carrying out an illumination reaction at 10-60 ℃ for 2-24 hours at 1-100W;
wherein the addition amount of the phosphine-oxygen compound is 1-3 times of the amount of the reaction substrate substance; the addition amount of the alkali is 1-20 times of the amount of the reaction substrate substance; the addition amount of the photocatalyst is 0.1-5% of the amount of the reaction substrate substance;
the reaction substrate is an enamide compound, an olefin compound, an alkenyl silyl ether compound or an acrylate compound.
Further, the enamide compound has the structural formula:
wherein R is1Is aryl, substituted aryl or heteroaryl; r2Is any one of aryl, substituted heteroaryl and alkyl; r3Is any one of hydrogen, alkyl or branched alkyl.
Further, the olefin compound has the structural formula:
wherein R is4Is any one of aryl, substituted aryl or heteroaryl; r5Is any one of hydrogen, alkyl or substituted alkyl; r6Is any one of hydrogen, alkyl or branched alkyl.
Further, the structural formula of the alkenyl silyl ether compound is as follows:
wherein R is7Is any one of aryl, substituted aryl or heteroaryl; r8Is any one of hydrogen, alkyl or substituted alkyl.
Further, acrylate compounds
Wherein R is9Is any one of hydrogen, alkyl, branched alkyl or heteroatom-substituted alkyl; r10Is aryl, heteroaryl or substitutedAny of aryl, heteroaryl or alkyl of (a).
Further, the phosphine oxide compound is an aryl phosphine oxide compound, a phosphonate ester compound or an alkyl phosphine oxide compound.
Further, the phosphine oxide compound is diarylphosphine oxide, dialkoxy phosphite or dialkylphosphine oxide.
Further, the base is lithium carbonate, sodium carbonate or cesium carbonate.
Further, the photocatalyst is 4CzIPN, Ir [ (ppy)2(dtbppy)]PF6、Ir[(ppy)2(dtbppy)]PF6Ir[dF(CF3)ppy]2(dtbbpy)PF6Or Ir [ dF (Me) ppy]2(dtbbpy)PF6。
Further, the reaction conditions were: in a carbon dioxide atmosphere, the reaction is carried out for 10-12 h at 20-25 ℃ under 30-35W illumination.
Further, the light source used in the light reaction is blue light.
Further, still include: after the reaction is finished, quenching the reaction product by acid, extracting the reaction product for at least 5 times by ethyl acetate, combining and concentrating organic phases extracted each time, and purifying the concentrated product by column chromatography.
Further, the acid is hydrochloric acid.
Furthermore, an eluant used in column chromatography is a dichloromethane-methanol mixed solution with a volume ratio of 100: 1-20: 1 or a petroleum ether-ethyl acetate mixed solution with a volume ratio of 2: 1-1: 1, and glacial acetic acid accounting for 0.1-0.6% of the total volume of the dichloromethane-methanol mixed solution and the petroleum ether-ethyl acetate mixed solution is added into the dichloromethane-methanol mixed solution and the petroleum ether-ethyl acetate mixed solution.
The invention has the beneficial effects that:
1. the invention can efficiently synthesize the carboxylic acid compound containing phosphine under the condition of light induction and the existence of photocatalyst, and simultaneously, the invention also comprises a method for efficiently synthesizing alpha-amino acid containing phosphine and alpha-hydroxy acid containing phosphine.
2. The method has mild reaction conditions and wide selectivity of reaction substrates, and the yield is basically not influenced when the reaction substrate is amplified to gram-scale; meanwhile, the defects of long reaction route and harsh reaction conditions in the prior art are overcome, and the method has a good industrial application prospect.
Detailed Description
The following description of the embodiments of the present invention is provided to facilitate the understanding of the present invention by those skilled in the art, but it should be understood that the present invention is not limited to the scope of the embodiments, and it will be apparent to those skilled in the art that various changes may be made without departing from the spirit and scope of the invention as defined and defined in the appended claims, and all matters produced by the invention using the inventive concept are protected.
Example 1
A phosphine-containing carboxylic acid compound having the chemical formula:
the reaction equation is as follows:
the preparation method of the compound comprises the following steps:
(1) to a dry 10mL Schlenk tube was added 45mg, 0.2mmol of enamide (1a), then the reaction tube was transferred to a glove box and 49mg, 0.24mmol of diphenylphosphine oxide (2a) and 41mg, 0.3mmol of potassium carbonate were added;
(2) taking out the reaction tube, connecting the reaction tube with a double-row tube connected with a carbon dioxide steel cylinder, pumping carbon dioxide on the double-row tube for 3 times, removing nitrogen in the tube to fill the tube with carbon dioxide gas, and then adding 2mL of DMF and a photosensitizer 4CzIPN (32 muL, 0.1mol percent, 5mg dissolved in 1mL of DMF) in a carbon dioxide atmosphere;
(3) finally, the reaction solution was placed 2 to 3cm from a 30W blue LED lamp, stirred at room temperature (25 ℃) for 12 hours, then the mixture was quenched with 4.5mL of water and 0.5mL of 2N hydrochloric acid, the reaction mixture was extracted with ethyl acetate at least 5 times, and the organic phases obtained from each extraction were combined and concentrated directlyAnd (5) shrinkage and spin drying. The residue was purified by flash column chromatography (eluent CH)2Cl2/MeOH 100/1-20/1: containing 0.2% AcOH) gave the pure desired product in 89% yield.
The product was a white solid with nuclear magnetic data:1H NMR(400MHz,DMSO-d6)13.36(s,1H),8.48(s,1H),7.90–7.79(m,2H),7.68–7.59(m,2H),7.58–7.43(m,8H),7.42–7.35(m,2H),7.29–7.13(m,6H),4.16(dd,J＝15.0,6.6Hz,1H),3.68–3.58(m,1H).13C NMR(101MHz,DMSO-d6)172.85(d,J＝5.6Hz),164.94,140.16(d,J＝9.1Hz),135.72(d,J＝98.9Hz),133.90,133.17(d,J＝99.0Hz),132.04(d,J＝2.6Hz),131.88,131.29(d,J＝2.9Hz),130.78(d,J＝9.5Hz),130.40(d,J＝9.3Hz),129.13(d,J＝11.5Hz),128.65,128.36(d,J＝11.8Hz),128.34,127.70,127.01,126.44,62.58(d,J＝5.0Hz),34.10(d,J＝70.9Hz).31P NMR(162MHz,DMSO-d6)26.92.HRMS(ESI+):calculated m/z[M+H]+for[C28H24NO4PH]+:470.1516,found:470.1513.
example 2
A phosphine-containing carboxylic acid compound having the chemical formula:
the reaction equation is as follows:
the preparation method of the compound comprises the following steps:
(1) to a 10mL dry Schlenk tube were added 45mg, 0.2mmol of enamide (1a) and 4CzIPN (4mg, 2 mol%), then the reaction tube was transferred to a glove box and 98mg, 0.3mmol of cesium carbonate was added;
(2) taking out the reaction tube, connecting the reaction tube with a double-row tube connected with a carbon dioxide steel cylinder, pumping carbon dioxide on the double-row tube for 3 times, removing nitrogen in the tube to fill the tube with carbon dioxide gas, and then adding 2mL of DMF and 31 mu L of 0.24mmol of diethyl phosphite (2g) in the carbon dioxide atmosphere;
(3) and finally, placing the reaction solution at a distance of 2-3cm from a 30W blue LED lamp, stirring for 12 hours at room temperature (25 ℃), then adding 5mL of water, extracting for at least 3 times by using ethyl acetate to remove impurities, then adding 0.5mL of 2N hydrochloric acid, extracting for at least 4 times by using an organic solvent ethyl acetate, and directly concentrating after combining the organic phases obtained by extraction to obtain a pure target product, wherein the yield is 78%.
The compound is a white solid, and the nuclear magnetic data of the compound are as follows:1H NMR(400MHz,DMSO-d6)13.59(s,1H),8.24(s,1H),7.86–7.77(m,2H),7.61–7.56(m,1H),7.56–7.45(m,4H),7.38–7.31(m,2H),7.32–7.26(m,1H),4.00–3.89(m,2H),3.86–3.70(m,2H),3.44–3.33(m,2H),3.15(dd,J＝18.7,15.2Hz,1H),1.13(t,J＝7.0Hz,3H),0.97(t,J＝7.0Hz,3H).13C NMR(101MHz,DMSO-d6)172.82(d,J＝6.0Hz),165.38,140.40(d,J＝13.7Hz),134.65,132.09,129.07,128.63,127.89,127.33,126.23(d,J＝1.4Hz),61.85(d,J＝4.6Hz),61.65(d,J＝6.1Hz),61.51(d,J＝6.7Hz),30.12(d,J＝139.8Hz),16.47(d,J＝6.1Hz),16.26(d,J＝6.2Hz).31P NMR(162MHz,DMSO-d6)26.28.HRMS(ESI+):calculated m/z[M+H]+for[C20H24NO6PH]+:406.1414,found:406.1413.
example 3
A phosphine-containing carboxylic acid compound having the chemical formula:
the reaction equation is as follows:
the preparation method of the compound comprises the following steps:
(1) 1mg, 0.5 mol% 4CzIPN was added to a 10mL dry Schlenk tube, then the reaction tube was transferred to a glove box and 49mg, 0.24mmol diphenylphosphine oxide (2a) and 98mg, 0.3mmol cesium carbonate were added;
(2) taking out the reaction tube, connecting the reaction tube with a double-row tube connected with a carbon dioxide steel cylinder, pumping carbon dioxide on the double-row tube for 3 times, removing nitrogen in the tube to fill the tube with carbon dioxide gas, and then adding 2mL of DMF and 23 mu L of 0.2mmol of styrene (8a) in the atmosphere of carbon dioxide;
(3) finally, the reaction solution was placed 2 to 3cm from a 30W blue LED lamp, stirred at room temperature (25 ℃) for 12 hours, then the mixture was quenched with 4.5mL of water and 0.5mL of 2N hydrochloric acid, the reaction mixture was extracted with ethyl acetate at least 3 times, and the organic phases obtained by the extraction were combined and directly concentrated and dried by spin-drying. The residue was purified by flash column chromatography (eluent PE/EA 2/1-1/1: containing 0.2-0.6% AcOH) to afford the pure desired product in 81% yield.
The compound is a white solid, and the nuclear magnetic data of the compound are as follows:1H NMR(400MHz,DMSO-d6)12.50(s,1H),7.87–7.77(m,2H),7.77–7.66(m,2H),7.59–7.45(m,4H),7.45–7.37(m,2H),7.29–7.12(m,5H),3.90–3.74(m,1H),3.29–3.14(m,1H),2.97–2.79(m,1H).13C NMR(101MHz,DMSO-d6)173.90(d,J＝6.7Hz),139.68(d,J＝9.3Hz),134.53(d,J＝97.7Hz),133.80(d,J＝97.0Hz),132.04(d,J＝2.7Hz),131.82(d,J＝2.7Hz),130.90(d,J＝9.0Hz),130.82(d,J＝9.1Hz),129.00(d,J＝11.5Hz),128.87(d,J＝11.4Hz),128.84,128.19,127.58,45.10(d,J＝2.1Hz),32.74(d,J＝70.1Hz).31P NMR(162MHz,DMSO-d6)27.89.HRMS(ESI-):calculated m/z[M-H]-for[C21H18O3P]-:349.0999,found:349.0999.
example 4
A phosphine-containing carboxylic acid compound having the chemical formula:
the reaction equation is as follows:
the preparation method of the compound comprises the following steps:
(1) 2mg, 2 mol% 4CzIPN was added to a 10mL dry Schlenk tube, then the reaction tube was transferred to a glove box and 49mg, 0.24mmol diphenyl phosphine oxide (2a) and 98mg, 0.3mmol cesium carbonate were added;
(2) taking out the reaction tube, connecting the reaction tube with a double-row tube connected with a carbon dioxide steel cylinder, pumping carbon dioxide on the double-row tube for 3 times, removing nitrogen in the tube to fill the tube with carbon dioxide gas, and then adding 2mL of DMF and 21 mu L of 0.2mmol of methyl methacrylate (10a) in the atmosphere of carbon dioxide;
(3) finally, the reaction solution was placed 2 to 3cm from a 30W blue LED lamp, stirred at room temperature (25 ℃) for 12 hours, then the mixture was quenched with 4.5mL of water and 0.5mL of 2N hydrochloric acid, the reaction mixture was extracted with ethyl acetate at least 3 times, and the organic phases obtained by the extraction were combined and directly concentrated and dried by spin-drying. The residue was purified by flash column chromatography (eluent PE/EA 2/1-1/1: containing 0.2-0.6% AcOH) to afford the pure desired product in 85% yield.
The compound is a white solid, and the nuclear magnetic data of the compound are as follows:1H NMR(400MHz,DMSO-d6)13.15(s,1H),7.89–7.77(m,4H),7.60–7.45(m,6H),3.44(s,3H),3.16–2.93(m,2H),1.35(s,3H).13C NMR(101MHz,DMSO-d6)172.79(d,J＝12.6Hz),171.34(d,J＝6.3Hz),135.32(d,J＝98.0Hz),134.91(d,J＝98.1Hz),132.02(d,J＝2.6Hz),131.97(d,J＝2.6Hz),130.71(d,J＝9.4Hz),130.65(d,J＝9.3Hz),52.61,51.29(d,J＝2.5Hz),34.95(d,J＝71.1Hz),21.09(d,J＝2.7Hz).31P NMR(162MHz,DMSO-d6)25.18.HRMS(ESI+):calculated m/z[M+H]+for[C18H19O5PH]+:347.1043,found:347.1042.
comparative example 1
Compared with the example 1, potassium carbonate is absent in the step (1), and the rest processes are the same as the example 1; the yield of the prepared compound was then checked to be 21%.
Comparative example 2
Compared with the example 1, the photocatalyst is lacked in the reaction process, and the rest processes are the same as the example 1; the yield of the prepared compound was then checked to be 0%.
Comparative example 3
Compared with the example 1, the reaction process lacks illumination, and the rest processes are the same as the example 1; the yield of the prepared compound was then checked to be 0%.
Comparative example 4
Compared with the example 1, the reaction process lacks carbon dioxide, and the rest processes are the same as the example 1; the yield of the prepared compound was then determined to be less than 5%.
This demonstrates that the phosphine-containing carboxylic acid compound can be efficiently synthesized only by combining the reaction conditions of the present invention.
Claims (5)
1. A method for producing a phosphine-containing carboxylic acid compound, comprising the steps of:
mixing and dissolving a reaction substrate, a phosphine oxide compound and alkali, adding a photocatalyst in a carbon dioxide atmosphere, and performing illumination reaction at 10-60 ℃ for 2-24 hours at 1-100W to obtain the phosphine carboxylic acid compound;
wherein the addition amount of the phosphine-oxygen compound is 1-3 times of the amount of the reaction substrate substance; the addition amount of the alkali is 1-20 times of the amount of the reaction substrate substance; the addition amount of the photocatalyst is 0.1-5% of the amount of the reaction substrate substance;
the photocatalyst is 4 CzIPN;
the phosphine oxide compound is diaryl phosphine oxide, dialkoxy phosphite or dialkyl phosphine oxide;
the reaction substrate is an enamide compound, an olefin compound or an acrylate compound;
the structural formula of the enamide compound is as follows:
(ii) a Wherein R is1Is aryl, substituted aryl or heteroaryl; r2Is an aromatic radical, substitutedAny one of heteroaryl and alkyl; r3Is any one of hydrogen, alkyl or branched alkyl;
the olefin compound has a structural formula:
(ii) a Wherein R is4Is any one of aryl, substituted aryl or heteroaryl; r5Is any one of hydrogen, alkyl or substituted alkyl; r6Is any one of hydrogen, alkyl or branched alkyl;
the acrylic ester compound
(ii) a Wherein R is9Is any one of hydrogen, alkyl, branched alkyl or heteroatom-substituted alkyl; r10Is any one of aryl, heteroaryl or substituted aryl, heteroaryl or alkyl;
the chemical structural general formula of the phosphine-containing carboxylic acid compound is as follows:
Wherein, X is any one of aryl, alkyl or alkoxy;
R1is aryl, substituted aryl or substituted heteroaryl; r2Is any one of aryl, substituted heteroaryl and alkyl; r3Is any one of hydrogen, alkyl or branched alkyl;
R4is any one of an aryl group, a substituted aryl group or a substituted heteroaryl group; r5Is hydrogen,Any one of alkyl or substituted alkyl; r6Is any one of hydrogen, alkyl or branched alkyl;
R8is hydrogen; r9Is any one of hydrogen, alkyl, branched alkyl or heteroatom-substituted alkyl; r10Is any one of aryl, heteroaryl or substituted aryl, heteroaryl or alkyl.
2. The method of claim 1, wherein the reaction conditions are: in a carbon dioxide atmosphere, the reaction is carried out for 10-12 h at 20-25 ℃ under 30-35W illumination.
3. The production method according to claim 1 or 2, wherein a light source used in the light reaction is blue light.
4. The method of claim 1, further comprising: after the reaction is finished, quenching the reaction product by acid, extracting the reaction product for at least 5 times by ethyl acetate, combining and concentrating organic phases extracted each time, and purifying the concentrated product by column chromatography.
5. The preparation method according to claim 4, wherein the eluent used in the column chromatography is a dichloromethane-methanol mixture at a volume ratio of 100:1 to 20:1, or a petroleum ether-ethyl acetate mixture at a volume ratio of 2:1 to 1:1, and glacial acetic acid accounting for 0.1 to 0.6% of the total volume of the dichloromethane-methanol mixture and the petroleum ether-ethyl acetate mixture is added to the dichloromethane-methanol mixture and the petroleum ether-ethyl acetate mixture.
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| JP2001253891A (en) * | 2000-03-13 | 2001-09-18 | Natl Inst Of Advanced Industrial Science & Technology Meti | Phosphinyl group-containing n-substituted amino acid derivative and method for producing the same |
| CN108752232A (en) * | 2018-05-14 | 2018-11-06 | 四川大学 | A kind of synthetic method of α-quaternary carbon amino acid |
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| JP2001253891A (en) * | 2000-03-13 | 2001-09-18 | Natl Inst Of Advanced Industrial Science & Technology Meti | Phosphinyl group-containing n-substituted amino acid derivative and method for producing the same |
| CN108752232A (en) * | 2018-05-14 | 2018-11-06 | 四川大学 | A kind of synthetic method of α-quaternary carbon amino acid |
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