CN108558944B - Preparation method of 4-phosphoryl-1, 4, 5-trisubstituted 1,2, 3-triazole - Google Patents

Preparation method of 4-phosphoryl-1, 4, 5-trisubstituted 1,2, 3-triazole Download PDF

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CN108558944B
CN108558944B CN201810440062.2A CN201810440062A CN108558944B CN 108558944 B CN108558944 B CN 108558944B CN 201810440062 A CN201810440062 A CN 201810440062A CN 108558944 B CN108558944 B CN 108558944B
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宋汪泽
郑楠
郑玉斌
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Dalian University of Technology
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Abstract

The invention belongs to the technical field of organic synthesis, and provides a preparation method of 4-phosphoryl-1, 4, 5-trisubstituted 1,2, 3-triazole. In an organic solvent, in the presence of rhodium tetracarbonyldichloride dimer [ Rh (CO)2Cl]2Catalyzing alkynyl phosphate ester under the action of catalystThe compound and azide are used for preparing 4-phosphoryl-1, 4, 5-trisubstituted 1,2, 3-triazole. The preparation method of the 4-phosphoryl-1, 4, 5-trisubstituted 1,2, 3-triazole product has mild reaction conditions and the product yield is not lower than 67%. The preparation method has mild and green reaction conditions and high reaction efficiency, is more suitable for large-scale production requirements, and the prepared 4-phosphoryl-1, 4, 5-trisubstituted 1,2, 3-triazole compound has potential physiological activity.

Description

Preparation method of 4-phosphoryl-1, 4, 5-trisubstituted 1,2, 3-triazole
Technical Field
The invention belongs to the technical field of organic synthesis, and relates to a preparation method of 4-phosphoryl-1, 4, 5-trisubstituted 1,2, 3-triazole.
Background
Alkyne-azide cycloaddition reaction is one of the most important methods for preparing 1,2, 3-triazole. In recent years, a series of documents and patents have reported a method for producing a 1,2, 3-triazole compound.
Since the copper-catalyzed terminal alkyne-azide cycloaddition reaction was reported in 2001 by the Medal project group and Sharpless project group, respectively (j.org.chem.,2002,67,3057 and angew.chem.int.ed.,2002,41,2596), the reaction was widely studied and focused. However, for copper-catalyzed alkyne-azide cycloaddition reactions, mixtures of 4-phosphoryl-1, 4, 5-trisubstituted 1,2, 3-triazole and 5-phosphoryl-1, 4, 5-trisubstituted 1,2, 3-triazole are frequently formed (ARKIVOC,2012,252). How to change the regioselectivity of the internal alkyne-azide cycloaddition reaction is the focus of our attention. Although some methods for changing the regioselectivity of the internal alkyne-azide cycloaddition reaction have been reported at present, the preparation technology of 4-phosphoryl-1, 4, 5-trisubstituted 1,2, 3-triazole has not been reported in a public way at present. 4-phosphoryl-1, 4, 5-trisubstituted 1,2, 3-triazole compounds are important compounds for researching protein phosphorylation, so that the research on the preparation method of the compounds is of great significance.
The invention adopts various alkynyl phosphate and organic azide compounds as raw materials and uses 2.5mol percent of [ Rh (CO ]2Cl]2The 4-phosphoryl-1, 4, 5-trisubstituted 1,2, 3-triazole compound is obtained as a catalyst at the temperature of 40 ℃ with the yield of 67-94%.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a method for synthesizing 4-phosphoryl-1, 4, 5-trisubstituted 1,2, 3-triazole compounds.
The technical scheme of the invention is as follows:
a preparation method of 4-phosphoryl-1, 4, 5-trisubstituted 1,2, 3-triazole comprises the following steps:
in an organic solvent, in the presence of dicarbonyl rhodium dichloride dimer ([ Rh (CO))2Cl]2) Under the action of a catalyst, the alkynyl phosphate compound and azide are catalyzed to prepare 4-phosphoryl-1, 4, 5-trisubstituted 1,2, 3-triazole, and the reaction formula is as follows:
Figure GDA0002333776190000021
wherein R is1And R2Is a hydrogen atom, an alkyl group, an alkoxy group or an aryl group, R1And R2The same or different;
R3is alkyl, alkoxy or aryl;
R4is alkyl or aryl;
i is alkynyl phosphate compound;
the reaction temperature is 25-65 ℃, the reaction time is 8-24 h, and the 4-phosphoryl-1, 4, 5-trisubstituted 1,2, 3-triazole with the yield not less than 67 percent is prepared.
The molar ratio of the alkynylamine compounds to the azide is 1:1, and the concentration of the alkynyl phosphate compounds is 0.01-0.1 mmol/ml.
The [ Rh (CO) ]2Cl]2The amount of the alkynyl phosphate compound is 0.5-50 mol%.
The organic solvent is one or more of benzene, toluene, diethyl ether, methyl tert-butyl ether, dichloromethane, tetrahydrofuran, trifluorotoluene, cyclohexane and petroleum ether, and preferably the solvent is dichloromethane, toluene or chloroform.
The invention has the beneficial effects that: the preparation method of the 4-phosphoryl-1, 4, 5-trisubstituted 1,2, 3-triazole product has mild reaction conditions and the product yield is not lower than 67%. The preparation method has mild and green reaction conditions and high reaction efficiency, is more suitable for large-scale production requirements, and the prepared 4-phosphoryl-1, 4, 5-trisubstituted 1,2, 3-triazole compound has potential physiological activity.
Detailed Description
The following further describes the specific embodiments of the present invention in combination with the technical solutions.
Example 1: preparation of 4-phosphodiester- (1-benzyl) -5-phenyl-1H-1, 2, 3-triazole
Diethyl phenylethynyl phosphate (0.2mmol, 47.6mg) was dissolved in dichloromethane (2mL) under air, and benzyl azide (0.3mmol, 40.2mg) and [ Rh (CO) ] were added2Cl]2(0.005mmol, 1.9mg), stirring the reaction mixture at 40 deg.C, reacting for 12h, and after completion of the reaction, separating by column chromatography to obtain 66mg of a yellow oily product, yield 89%.
Figure GDA0002333776190000031
1H NMR(500MHz,CDCl3,TMS):δ7.48-7.47(m,1H),7.44-7.41(m,2H),7.28-7.25(m,5H),7.03-7.01(m,2H),5.44(s,2H),4.16-4.08(m,4H),1.21(t,J＝7.5Hz,6H).13C NMR(125MHz,CDCl3):δ143.0(d,JC-P＝32.5Hz),136.0(d,JC-P＝240.0Hz),134.7,130.0,129.9,128.8,128.6,128.4,127.6,125.7,62.8(d,JC-P＝5.0Hz),52.0,16.1(d,JC-P＝6.3Hz).31PNMR(200MHz,CDCl3):δ7.3.HRMS(ESI)m/z calcd for C19H22N3O3P(M+Na)+394.1291,found394.1297.
Example 2: preparation of 4-phosphodiester- (1-p-methylbenzyl) -5-phenyl-1H-1, 2, 3-triazole
Diethyl phenylethynyl phosphate (0.2mmol, 47.6mg) was dissolved in dichloromethane (2mL) under air, and p-methylbenzyl azide (0.3mmol, 44.1mg) and [ Rh (CO) ] were added2Cl]2(0.005mmol, 1.9mg) and the reaction mixture was stirred at 40 ℃ for 12 hours, and after completion of the reaction, the product was isolated by column chromatography to give 78mg as a yellow oil in 92% yield.
Figure GDA0002333776190000032
1H NMR(500MHz,CDCl3,TMS):δ7.49-7.42(m,3H),7.29-7.27(m,2H),7.07(d,J＝5.0Hz,2H),6.92(d,J＝10.0Hz,2H),5.39(s,2H),4.13-4.06(m,4H),2.30(s,3H),1.20(t,J＝5.0Hz,6H).13C NMR(125MHz,CDCl3):δ142.9(d,JC-P＝33.8Hz),138.2,135.9(d,JC-P＝240.0Hz),131.7,130.1,130.0,129.5,128.6,127.6,125.8,62.8(d,JC-P＝5.0Hz),51.8,21.1,16.1(d,JC-P＝6.3Hz).31P NMR(200MHz,CDCl3):δ7.4.HRMS(ESI)m/z calcd forC20H24N3O3P(M+Na)+408.1447,found 408.1454.
Example 3: preparation of 4-phosphodiethyl ester- (1-p-chlorobenzyl) -5-phenyl-1H-1, 2, 3-triazole
Diethyl phenylethynyl phosphate (0.2mmol, 47.6mg) was dissolved in dichloromethane (2mL) under air, and p-chlorobenzyl azide (0.3mmol, 50.1mg) and [ Rh (CO) ] were added2Cl]2(0.005mmol, 1.9mg), stirring the reaction mixture at 40 deg.C, reacting for 12h, and after completion of the reaction, separating by column chromatography to obtain 65.6mg of a yellow oily product, yield 81%.
Figure GDA0002333776190000041
1H NMR(400MHz,CDCl3,TMS):δ7.51-7.44(m,3H),7.28-7.24(m,4H),6.97(d,J＝8.0Hz,2H),5.42(s,2H),4.15-4.08(m,4H),1.22(t,J＝8.0Hz,6H).13C NMR(125MHz,CDCl3):δ143.0(d,JC-P＝32.5Hz),136.1(d,JC-P＝240.0Hz),134.5,133.1,130.3,129.8,129.1,128.7,125.5,115.4,63.0(d,JC-P＝6.3Hz),51.3,16.1(d,JC-P＝6.3Hz).31P NMR(200MHz,CDCl3):δ7.1.HRMS(ESI)m/z calcd for C19H21ClN3O3P(M+Na)+408.1447,found408.1454.
Example 4: preparation of 4-phosphodiester- (1-phenylethyl) -5-phenyl-1H-1, 2, 3-triazole
Diethyl phenylethynyl phosphate (0.2mmol, 47.6mg) was dissolved in dichloromethane (2mL) under air, and phenethyl azide (0.3mmol, 44.1mg) and [ Rh (CO) ] were added2Cl]2(0.005mmol, 1.9mg), stirring the reaction mixture at 40 deg.C, reacting for 12h, and after completion of the reaction, separating by column chromatography to obtain 65.6mg of a yellow oily product, 84% yield.
Figure GDA0002333776190000051
1H NMR(400MHz,CDCl3,TMS):δ7.47-7.38(m,3H),7.28-7.22(m,2H),7.05(d,J＝4.0Hz,2H),6.91-6.81(m,3H),4.44(t,J＝8.0Hz,2H),4.14-4.04(m,4H),3.17(t,J＝8.0Hz,2H),1.22(t,J＝8.0Hz,6H).13C NMR(125MHz,CDCl3):δ143.5(d,JC-P＝32.5Hz),136.7,135.2(d,JC-P＝238.8Hz),130.0,129.7,129.3,128.7,128.6,127.1,125.6,62.8(d,JC-P＝5.0Hz),49.5,36.4,16.1(d,JC-P＝7.5Hz).31P NMR(200MHz,CDCl3):δ7.3.HRMS(ESI)m/z calcd for C20H24N3O3P(M+Na)+408.1447,found 408.1453.
Example 5: preparation of 4-phosphate- (1-benzyl) -5-p-methoxyphenyl-1H-1, 2, 3-triazole
P-methoxyphenyl ethynyl phosphate (0.2mmol, 42.4mg) was dissolved in dichloromethane (2mL) under air, and benzyl azide (0.3mmol, 40.2mg) and [ Rh (CO) ] were added2Cl]2(0.005mmol, 1.9mg), stirring the reaction mixture at 40 deg.C, reacting for 12h, and after completion of the reaction, separating by column chromatography to give 46.2mg of a colorless oily product, yield 67%.
Figure GDA0002333776190000052
1H NMR(400MHz,CDCl3,TMS):δ10.25(br s,2H),7.42(d,J＝8.0Hz,2H),7.26-7.24(m,3H),7.04-7.01(m,2H),6.87(d,J＝8.0Hz,2H),5.53(s,2H),3.75(s,3H).13C NMR(100MHz,CDCl3):δ161.8,144.8(d,JC-P＝22.0Hz),134.0(d,JC-P＝209.0Hz),132.2,132.0,129.1,129.0,128.2,114.7,113.6,55.5,54.8.31P NMR(160MHz,CDCl3):δ-5.8.HRMS(ESI)m/z calcd for C16H16N3O4P(M+Na)+368.0771,found 368.0778.
Example 6: preparation of 4-phosphodiester- (1-benzyl) -5-p-methoxyphenyl-1H-1, 2, 3-triazole
p-Methoxyphenylethynyl phosphate diethoxy (0.2mmol, 53.6mg) was dissolved in dichloromethane (2mL) under air, and benzyl azide (0.3mmol, 40.2mg) and [ Rh (CO) ] were added2Cl]2(0.005mmol, 1.9mg) and the reaction mixture was stirred at 40 ℃ for 12 hours, after completion of the reaction, the product was isolated by column chromatography to give 75.4mg as a yellow oily product in 94% yield.
Figure GDA0002333776190000061
1H NMR(500MHz,CDCl3,TMS):δ7.29-7.27(m,3H),7.21(d,J＝10.0Hz,2H),7.08-7.04(m,2H),6.94(d,J＝10.0Hz,2H),5.43(s,2H),4.14-4.10(m,4H),3.85(s,3H),1.23(t,J＝7.5Hz,6H).13C NMR(125MHz,CDCl3):δ161.0,143.1(d,JC-P＝33.8Hz),135.0(d,JC-P＝238.8Hz),134.9,131.3,128.8,128.3,127.5,117.4,114.1,62.8(d,JC-P＝5.0Hz),55.4,51.8,16.1(d,JC-P＝6.3Hz).31P NMR(200MHz,CDCl3):δ7.6.HRMS(ESI)m/z calcd forC20H24N3O4P(M+Na)+424.1397,found 424.1402.

Claims (8)

1. A preparation method of 4-phosphoryl-1, 4, 5-trisubstituted 1,2, 3-triazole is characterized by comprising the following steps:
in an organic solvent, in the presence of rhodium tetracarbonyldichloride dimer [ Rh (CO)2Cl]2Under the action of catalyst, alkynyl phosphate compound and azide are catalyzed to prepare 4-Phosphoryl-1, 4, 5-trisubstituted 1,2, 3-triazole, the reaction formula is as follows:
Figure FDA0002333776180000011
wherein R is1And R2Is a hydrogen atom, an alkyl group, an alkoxy group or an aryl group, R1And R2The same or different;
R3is alkyl, alkoxy or aryl;
R4is alkyl or aryl;
i is alkynyl phosphate compound;
the reaction temperature is 25-65 ℃, the reaction time is 8-24 h, and the 4-phosphoryl-1, 4, 5-trisubstituted 1,2, 3-triazole with the yield not less than 67 percent is prepared.
2. The preparation method of 4-phosphoryl-1, 4, 5-trisubstituted 1,2, 3-triazole according to claim 1, wherein the molar ratio of alkynyl phosphate compounds to azide is 1:1, and the concentration of alkynyl phosphate compounds is 0.01-0.1 mmol/ml.
3. The method for preparing 4-phosphoryl-1, 4, 5-trisubstituted 1,2, 3-triazole according to claim 1 or 2, characterized in that [ Rh (CO) ]2Cl]2The amount of the alkynyl phosphate compound is 0.5-50 mol%.
4. The preparation method of 4-phosphoryl-1, 4, 5-trisubstituted 1,2, 3-triazole according to claim 1 or 2, characterized in that the organic solvent is one or a mixture of more than two of benzene, toluene, diethyl ether, methyl tert-butyl ether, dichloromethane, tetrahydrofuran, trifluorotoluene, cyclohexane and petroleum ether.
5. The preparation method of 4-phosphoryl-1, 4, 5-trisubstituted 1,2, 3-triazole according to claim 3, wherein the organic solvent is one or more of benzene, toluene, diethyl ether, methyl tert-butyl ether, dichloromethane, tetrahydrofuran, trifluorotoluene, cyclohexane and petroleum ether.
6. The method for preparing 4-phosphoryl-1, 4, 5-trisubstituted 1,2, 3-triazole according to claim 1,2 or 5, wherein the organic solvent is dichloromethane, toluene or chloroform.
7. The method for preparing 4-phosphoryl-1, 4, 5-trisubstituted 1,2, 3-triazole according to claim 3, wherein the organic solvent is dichloromethane, toluene or chloroform.
8. The preparation method of 4-phosphoryl-1, 4, 5-trisubstituted 1,2, 3-triazole according to claim 4, wherein the organic solvent is dichloromethane, toluene or chloroform.
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