CN108948077B - Alpha-phosphorylated alpha-amino acid ester compound and synthesis method thereof - Google Patents
Alpha-phosphorylated alpha-amino acid ester compound and synthesis method thereof Download PDFInfo
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- -1 alpha-amino acid ester compound Chemical class 0.000 title claims abstract description 37
- 235000008206 alpha-amino acids Nutrition 0.000 title claims abstract description 18
- 238000001308 synthesis method Methods 0.000 title abstract description 8
- 238000006243 chemical reaction Methods 0.000 claims abstract description 45
- 150000001875 compounds Chemical class 0.000 claims abstract description 17
- 238000000034 method Methods 0.000 claims abstract description 11
- 239000003054 catalyst Substances 0.000 claims abstract description 9
- 239000000758 substrate Substances 0.000 claims abstract description 6
- 239000003960 organic solvent Substances 0.000 claims abstract description 5
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Natural products NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims abstract description 4
- 239000004471 Glycine Substances 0.000 claims abstract description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 36
- 238000004440 column chromatography Methods 0.000 claims description 11
- 238000003756 stirring Methods 0.000 claims description 11
- 238000006366 phosphorylation reaction Methods 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- 238000010189 synthetic method Methods 0.000 claims description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- 238000000926 separation method Methods 0.000 claims description 3
- 230000002194 synthesizing effect Effects 0.000 claims description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- 238000001514 detection method Methods 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 238000002390 rotary evaporation Methods 0.000 claims description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 abstract description 10
- 238000005160 1H NMR spectroscopy Methods 0.000 abstract description 10
- 238000003786 synthesis reaction Methods 0.000 abstract description 9
- 229910052723 transition metal Inorganic materials 0.000 abstract description 6
- 230000015572 biosynthetic process Effects 0.000 abstract description 5
- 230000007613 environmental effect Effects 0.000 abstract description 4
- 150000003624 transition metals Chemical class 0.000 abstract description 4
- 239000007800 oxidant agent Substances 0.000 abstract description 3
- 230000001590 oxidative effect Effects 0.000 abstract description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 abstract 1
- 238000010438 heat treatment Methods 0.000 abstract 1
- 238000004896 high resolution mass spectrometry Methods 0.000 abstract 1
- 229910052760 oxygen Inorganic materials 0.000 abstract 1
- 239000001301 oxygen Substances 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 36
- 239000012298 atmosphere Substances 0.000 description 18
- 239000002904 solvent Substances 0.000 description 18
- 239000007787 solid Substances 0.000 description 10
- 238000012512 characterization method Methods 0.000 description 9
- KPOBHNYTWJSVKF-UHFFFAOYSA-L cobalt(2+);diperchlorate;hexahydrate Chemical compound O.O.O.O.O.O.[Co+2].[O-]Cl(=O)(=O)=O.[O-]Cl(=O)(=O)=O KPOBHNYTWJSVKF-UHFFFAOYSA-L 0.000 description 9
- 238000006356 dehydrogenation reaction Methods 0.000 description 9
- 238000004821 distillation Methods 0.000 description 9
- 238000001816 cooling Methods 0.000 description 8
- 125000000217 alkyl group Chemical group 0.000 description 5
- 238000005859 coupling reaction Methods 0.000 description 5
- 238000006880 cross-coupling reaction Methods 0.000 description 5
- LXCYSACZTOKNNS-UHFFFAOYSA-N diethoxy(oxo)phosphanium Chemical compound CCO[P+](=O)OCC LXCYSACZTOKNNS-UHFFFAOYSA-N 0.000 description 5
- 150000001370 alpha-amino acid derivatives Chemical class 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 230000008878 coupling Effects 0.000 description 3
- 238000010168 coupling process Methods 0.000 description 3
- JJIXGUZFWHQSNF-UHFFFAOYSA-N 2-(n-ethyl-4-methylanilino)acetic acid Chemical compound OC(=O)CN(CC)C1=CC=C(C)C=C1 JJIXGUZFWHQSNF-UHFFFAOYSA-N 0.000 description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 2
- 230000000975 bioactive effect Effects 0.000 description 2
- 239000010949 copper Substances 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- 125000006575 electron-withdrawing group Chemical group 0.000 description 2
- RFCHXXFHULMCDW-UHFFFAOYSA-N ethyl 2-(4-methylanilino)acetate Chemical compound CCOC(=O)CNC1=CC=C(C)C=C1 RFCHXXFHULMCDW-UHFFFAOYSA-N 0.000 description 2
- 239000011574 phosphorus Substances 0.000 description 2
- 229910052698 phosphorus Inorganic materials 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- BEGRMYIDFCYOLT-UHFFFAOYSA-N 2-(N-benzyl-4-methylanilino)acetic acid Chemical compound C1=CC(C)=CC=C1N(CC(O)=O)CC1=CC=CC=C1 BEGRMYIDFCYOLT-UHFFFAOYSA-N 0.000 description 1
- COWDMMGPCXCPAS-UHFFFAOYSA-N 2-(n,4-dimethylanilino)acetic acid Chemical compound OC(=O)CN(C)C1=CC=C(C)C=C1 COWDMMGPCXCPAS-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- FQEUOBAVARCOSV-UHFFFAOYSA-N 4-hydroxy-1,3,2,4lambda5-dioxazaphosphetidine 4-oxide Chemical compound N1OP(=O)(O1)O FQEUOBAVARCOSV-UHFFFAOYSA-N 0.000 description 1
- 229910021580 Cobalt(II) chloride Inorganic materials 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 229910021592 Copper(II) chloride Inorganic materials 0.000 description 1
- JXBAVRIYDKLCOE-UHFFFAOYSA-N [C].[P] Chemical compound [C].[P] JXBAVRIYDKLCOE-UHFFFAOYSA-N 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229910001914 chlorine tetroxide Inorganic materials 0.000 description 1
- 150000001868 cobalt Chemical class 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- BVXOPEOQUQWRHQ-UHFFFAOYSA-N dibutyl phosphite Chemical compound CCCCOP([O-])OCCCC BVXOPEOQUQWRHQ-UHFFFAOYSA-N 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- CZHYKKAKFWLGJO-UHFFFAOYSA-N dimethyl phosphite Chemical compound COP([O-])OC CZHYKKAKFWLGJO-UHFFFAOYSA-N 0.000 description 1
- NFORZJQPTUSMRL-UHFFFAOYSA-N dipropan-2-yl hydrogen phosphite Chemical compound CC(C)OP(O)OC(C)C NFORZJQPTUSMRL-UHFFFAOYSA-N 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- NTNZTEQNFHNYBC-UHFFFAOYSA-N ethyl 2-aminoacetate Chemical compound CCOC(=O)CN NTNZTEQNFHNYBC-UHFFFAOYSA-N 0.000 description 1
- 239000003063 flame retardant Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 238000005691 oxidative coupling reaction Methods 0.000 description 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Chemical compound [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 description 1
- 230000000361 pesticidal effect Effects 0.000 description 1
- 150000008301 phosphite esters Chemical class 0.000 description 1
- KRQGUSROPNJSPG-UHFFFAOYSA-N propan-2-yl 2-(4-methylanilino)acetate Chemical compound CC(C)OC(=O)CNC1=CC=C(C)C=C1 KRQGUSROPNJSPG-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000002356 single layer Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/40—Esters thereof
- C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
- C07F9/4006—Esters of acyclic acids which can have further substituents on alkyl
- C07F9/4009—Esters containing the structure (RX)2P(=X)-alk-N...P (X = O, S, Se)
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/40—Esters thereof
- C07F9/4071—Esters thereof the ester moiety containing a substituent or a structure which is considered as characteristic
- C07F9/4075—Esters with hydroxyalkyl compounds
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Crystallography & Structural Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Catalysts (AREA)
Abstract
The invention discloses an α -phosphorylated α -amino acid ester compound and a synthesis method thereof, and the method comprises the steps of in the presence of a transition metal catalyst and in an organic solvent,Nheating aryl glycine ester and phosphite ester compound to react to obtain α -phosphorylated α -amino acid ester compound, wherein the structure of the compound is shown in the specification1H NMR、13C NMR and HR-MS, etc. The method of the invention does not need to functionalize the reaction substrates in advance, adopts oxygen in the air as a green oxidant, and directly passes through the two reaction substratesNThe synthesis method has the advantages of high atom utilization rate, short synthesis route, environmental friendliness, mild synthesis reaction conditions, simple operation steps, high atom economy, suitability for large-scale synthesis and good application prospect.
Description
Technical Field
The invention belongs to the field of organic synthesis, relates to synthesis of alpha-substituted alpha-amino acid compounds, and particularly relates to a synthetic method of alpha-phosphorylation of alpha-amino acid derivatives.
Background
Dehydrogenation Cross-Coupling (dehydrogenation Cross-Coupling) reaction is favored by chemists as a novel organic synthesis reaction which directly utilizes two carbon-hydrogen bonds in a reaction substrate to perform dehydrogenation Coupling to form a new carbon-carbon bond or a new carbon-hybrid bond under an oxidation condition. Compared with the traditional organic synthesis method, the reaction does not need to functionalize the reaction substrate in advance, so that the synthesis route is simpler and more convenient, the atom utilization rate is higher, and the reaction efficiency is improved. Transition metal catalyzed dehydrogenation cross-coupling reactions have evolved dramatically in modern organic synthetic chemistry in recent years. Phosphorus-containing organic matters generally exist in bioactive molecules, flame retardants, extracting agents and phosphorus-containing ligands, and the cross-coupling of dehydrogenation by using transition metal catalysis is undoubtedly the most convenient and effective synthetic method for constructing carbon-phosphorus.
α -amino acid is widely existed in natural products and bioactive molecules in nature, wherein, α -phosphoramidate compound has very important application value for obtaining α -phosphoramidate compound by constructing carbon-phosphorus bond due to important bioactivity, pesticide activity and the like, however, the report of constructing carbon-phosphorus bond by cross dehydrogenation coupling reaction of α -phosphorylation catalyzed by transition metal α -amino acid ester compound is rare so far, in 2013, Yangtong et al report that imino phosphate is synthesized by oxidative coupling reaction of α -amino ketone and diphenyl phosphorus oxide compound catalyzed by copper, in 2016, the group of Li dynasty army subjects reportsN-dehydrogenizing cross-coupling reaction of arylglycine amides with phosphorous acid diesters. However, it is possible to use a single-layer,Nthe aryl glycine ester can not effectively carry out the cross-dehydrogenation coupling in the reaction system, and the cross-dehydrogenation coupling reaction for catalyzing the α -phosphorylation of α -amino acid ester compound is not reported in any patent and literature at present.
Disclosure of Invention
The invention aims to solve the technical problem of providing a green synthesis method for preparing alpha-phosphorylated alpha-amino acid ester compounds by catalyzing alpha-amino acid derivatives to perform alpha-imidization by transition metals. It is an important method for synthesizing novel alpha-substituted alpha-amino acid derivatives. The method takes the transition metal salt which is easy to obtain in commerce as a catalyst and air as a terminal oxidant, and synthesizes the alpha-phosphorylation product of the alpha-amino acid ester by one step through the direct cross dehydrogenation coupling of the alpha-amino acid ester and the phosphite ester.
In order to solve the technical problems, the invention provides a synthetic method of alpha-phosphorylation of alpha-amino acid ester compounds, which has good chemical selectivity, high atom economy and environmental friendliness. The synthesis method has the advantages of mild reaction conditions, simple and convenient operation, environmental protection, high product purity, convenient separation and purification, and suitability for large-scale synthesis application.
The invention adopts the following technical scheme: an alpha-phosphorylated alpha-amino acid ester compound, the structural formula of which is shown in formula (I):
wherein R is1May be an electron donating group or an electron withdrawing group. Preferably, the electron donating group may be an alkyl group; the electron withdrawing group may be phenyl. R2Are various alkyl or allyl groups. When R is2When alkyl, it may be methyl, ethyl, isopropyl, tert-butyl or benzyl.
R3And may be various alkyl groups or benzyl groups. Preferably, the alkyl group can be, but is not limited to, methyl, ethyl, isopropyl, tert-butyl.
The invention relates to a synthesis method of α -amino acid ester compound α -phosphorylation, which comprises the following steps of adopting in organic solvent in the presence of catalystNTaking aryl glycine ester (II) and phosphorous diester compound (III) as reaction substrates, stirring for reaction for 12 hours until TLC detection reaction is complete, performing rotary evaporation and concentration, and performingThe product α -phosphorylated α -amino acid ester compound (I) can be efficiently prepared by column chromatography separation, and the reaction general formula is as follows:
(II) (III) (I)
in the preparation method of the invention, the catalyst is CoO or CoCl2、Co(OAc)2、Co(ClO4)2•6H2O、CuO、CuCl2Or Cu (OTf)2Preferably Co (ClO)4)2•6H2O; the amount of the catalyst is 10 mol% based on the compound represented by the formula (III).
Preferably, the organic solvent in said step is acetonitrile or 1, 2-dichloroethane, most preferably acetonitrile.
Preferably, the temperature in said step is from room temperature to 100 ℃, most preferably 80 ℃.
In the production method of the present invention, the molar ratio of the compound represented by the formula (II) to the compound represented by the formula (III) is preferably 1: 1-10, most preferably 1: 8.
compared with the prior art, the invention has the following advantages and beneficial effects: the synthesis method of alpha-phosphorylation of the alpha-amino acid ester compound is a process flow with the advantages of simple and convenient operation, mild reaction conditions, high atom economy, environmental friendliness and the like. The invention adopts the cobalt salt which is easy to obtain commercially as the catalyst, the air as the terminal oxidant, the reaction operation is simple and convenient, the condition is mild, the environment is protected, the product is easy to separate and purify, the method is suitable for large-scale preparation, and the method has good application prospect.
Detailed Description
The present invention will be described in further detail below with reference to specific examples, but the embodiments of the present invention are not limited thereto.
Example 1
In the air atmosphereN-4-tolylglycine ethyl ester (0.2mmol), diethyl phosphiteThe ester (1.6mmol) and cobalt perchlorate hexahydrate (0.02 mmol) were added to a dry reaction tube with stirring magnetons. Acetonitrile solvent (2 mL) was then added to the tube and the reaction tube was placed in an air atmosphere 80oAnd C, reacting for 12 hours under an oil bath. After the reaction is finished, cooling to room temperature, removing the solvent by reduced pressure distillation through a rotary evaporator, and separating and purifying the residue by column chromatography to obtain pure light yellow solid 3a with the yield of 83%. The structural characterization data for the compound of 3a is as follows:
light yellow solid; mp 75.2-76.4 °C;1H NMR (400 MHz, CDCl3):7.00(d,J= 6.4 Hz, 2H), 6.61 (dd,J= 5.4 Hz,J= 1.4 Hz, 2H), 4.47 (d,J= 18.4Hz, 1H), 4.27-4.17 (m, 6H), 2.24 (s, 3H), 1.36-1.31 (m, 6H), 1.27 (t,J= 5.6Hz, 3H);13C NMR (100 MHz, CDCl3):168.5 (d,J= 2.4 Hz), 143.8 (d,J= 9.0Hz), 129.8, 128.8, 114.2, 64.2 (d,J= 4.5 Hz), 63.6 (d,J= 4.7 Hz), 62.2,56.8 (d,J= 118.0 Hz), 20.5, 16.5 (d,J= 4.8 Hz), 16.4 (d,J= 5.4 Hz),14.1; HRMS (ESI) calcd for C15H25NO5P (M+H)+330.1465, found 330.1467.
example 2
In the air atmosphereNEthyl-4-tolylglycine (0.2mmol), dimethyl phosphite (1.6mmol) and cobalt perchlorate hexahydrate (0.02 mmol) were added to a dry reaction tube with stirring magnetons. Acetonitrile solvent (2 mL) was then added to the tube and the reaction tube was placed in an air atmosphere 80oAnd C, reacting for 12 hours under an oil bath. After the reaction is finished, cooling to room temperature, removing the solvent by reduced pressure distillation through a rotary evaporator, and separating and purifying the residue by column chromatography to obtain pure light yellow solid 3b with the yield of 95%. The structural characterization data for the 3b compound is as follows:
light yellow solid; mp 69.2-70.1 °C;1H NMR (400 MHz, CDCl3):7.01(d,J= 6.4 Hz, 2H), 6.61 (dd,J= 6.8 Hz, 2H), 4.52 (d,J= 19.2 Hz, 1H),4.30-4.23 (m, 2H), 3.86 (s, 3H), 3.84 (s, 3H), 2.24 (s, 3H), 1.28 (t,J= 6.4Hz, 3H);13C NMR (100 MHz, CDCl3):168.3 (d,J= 2.6 Hz), 143.7 (d,J= 9.4Hz), 129.9, 129.0, 114.3, 62.4,56.5 (d,J= 119.4 Hz), 54.5 (d,J= 4.6 Hz),53.9 (d,J= 5.3 Hz), 20.5, 14.1; HRMS (ESI) calcd for C13H19NO5P (M-H)-300.1006, found 300.1003.
example 3
In the air atmosphereNEthyl-4-tolylglycine (0.2mmol), diisopropyl phosphite (1.6mmol) and cobalt perchlorate hexahydrate (0.02 mmol) were added to a dry reaction tube with stirring magnetons. Acetonitrile solvent (2 mL) was then added to the tube and the reaction tube was placed in an air atmosphere 80oAnd C, reacting for 12 hours under an oil bath. After the reaction is finished, cooling to room temperature, removing the solvent by reduced pressure distillation through a rotary evaporator, and separating and purifying the residue by column chromatography to obtain pure light yellow solid 3c with the yield of 76%. The structural characterization data for the 3c compound is as follows:
light yellow solid; mp 67.9-68.6 °C;1H NMR (400 MHz, CDCl3):6.99(d,J= 6.4 Hz, 2H), 6.59 (dd,J= 8.8 Hz,J= 2.0 Hz, 2H), 4.85-4.76 (m,2H), 4.41 (d,J= 19.2 Hz, 1H), 4.22 (q,J= 6.4 Hz, 2H), 2.23 (s, 3H), 1.36-1.31 (m, 6H), 1.37-1.29 (m, 12H), 1.26 (t,J= 6.4 Hz, 3H);13C NMR (100 MHz,CDCl3):168.8 (d,J= 1.6 Hz), 144.1 (d,J= 10.6 Hz), 129.8, 128.6, 114.2,72.9 (d,J= 6.3 Hz), 72.4 (d,J= 5.8 Hz), 61.9, 57.8 (d,J= 119.6 Hz),24.3 (d,J= 3.3 Hz), 24.0 (d,J= 2.9 Hz), 23.8 (d,J= 4.3 Hz), 23.7 (d,J= 3.5 Hz), 20.5, 14.1; HRMS (ESI) calcd for C17H29NO5P (M+H)+358.1778, found358.1776.
example 4
In the air atmosphereN-4-tolylglycine ethyl ester (0.2mmol), dibutyl phosphite (1.6mmol) and cobalt perchlorate hexahydrate (0.02 mmol) were added to a dry reaction tube with stirring magnetons. Acetonitrile solvent (2 mL) was then added to the tube and the reaction tube was placed in an air atmosphere 80oAnd C, reacting for 12 hours under an oil bath. After the reaction is finished, cooling to room temperature, removing the solvent by reduced pressure distillation through a rotary evaporator, and separating and purifying the residue by column chromatography to obtain pure light yellow oily liquid 3d with the yield of 62%. The structural characterization data for the 3d compound is as follows:
light yellow oil;1H NMR (400 MHz, CDCl3):6.99 (d,J= 6.4 Hz, 2H),6.60 (dd,J= 8.8 Hz,J= 2.0 Hz, 2H), 4.48 (d,J= 18.8 Hz, 1H), 4.23 (d,J= 6.4 Hz, 2H), 4.19-4.05 (m, 4H), 2.23 (s, 3H), 1.71-1.61 (m, 4H), 1.46-1.28(m, 4H), 1.26 (t,J= 5.6 Hz, 3H), 0.96-0.89 (m, 6H);13C NMR (100 MHz,CDCl3):168.6 (d,J= 1.8 Hz), 143.9 (d,J= 10.1 Hz), 129.8, 128.7, 114.2,67.7 (d,J= 6.1 Hz), 67.1 (d,J= 5.8 Hz), 65.5 (d,J= 5.1 Hz), 62.1, 56.7(d,J= 118.7 Hz), 32.5 (d,J= 5.6 Hz), 32.4 (d,J= 5.0 Hz), 20.4, 18.7,18.6 (d,J= 1.4 Hz), 14.1, 13.5; HRMS (ESI) calcd for C19H31NO5P (M-H)-384.1945, found 384.1942.
example 5
In the air atmosphereNMethyl-4-tolylglycine (0.2mmol), diethyl phosphite (1.6mmol) and cobalt perchlorate hexahydrate (0.02 mmol) were addedDry reaction tube with stirring magnetons. Acetonitrile solvent (2 mL) was then added to the tube and the reaction tube was placed in an air atmosphere 80oAnd C, reacting for 12 hours under an oil bath. After the reaction is finished, cooling to room temperature, removing the solvent by reduced pressure distillation through a rotary evaporator, and separating and purifying the residue by column chromatography to obtain pure light yellow solid 3e with the yield of 78%. The structural characterization data for the 3e compound is as follows:
light yellow solid; mp 73.5-74.8 °C;1H NMR (400 MHz, CDCl3):7.00(d,J= 6.8 Hz, 2H), 6.60 (d,J= 6.8 Hz, 2H), 4.50 (d,J= 18.8 Hz, 1H),4.27-4.17 (m, 4H), 3.78 (s, 3H), 2.24 (s, 3H), 1.35 (t,J= 5.2 Hz, 3H), 1.32(t,J= 5.2 Hz, 3H);13C NMR (100 MHz, CDCl3):169.5 (d,J= 2.4 Hz), 143.8(d,J= 9.6 Hz), 129.9, 128.9, 114.2, 64.1 (d,J= 4.7 Hz), 63.7 (d,J= 5.4Hz), 56.6 (d,J= 119.0 Hz), 53.0, 20.4, 16.4 (d,J= 6.4 Hz), 16.3; HRMS(ESI) calcd for C14H23NO5P (M+H)+316.1308, found 316.1311.
example 6
In the air atmosphereN-4-tolylglycine isopropyl ester (0.2mmol), diethyl phosphite (1.6mmol) and cobalt perchlorate hexahydrate (0.02 mmol) were added to a dry reaction tube with stirring magnetons. Acetonitrile solvent (2 mL) was then added to the tube and the reaction tube was placed in an air atmosphere 80oAnd C, reacting for 12 hours under an oil bath. After the reaction is finished, cooling to room temperature, removing the solvent by reduced pressure distillation through a rotary evaporator, and separating and purifying the residue by column chromatography to obtain pure light yellow solid 3f with the yield of 69%. The structural characterization data for the 3f compound is as follows:
light yellow solid; mp 76.0-77.5 °C;1H NMR (400 MHz, CDCl3):7.00 (d,J= 6.4 Hz, 2H), 6.60 (d,J= 6.0 Hz, 2H), 5.11-5.07 (m, 1H), 4.44 (d,J=18.4 Hz, 1H), 4.25-4.20 (m, 4H), 2.24 (s, 3H), 1.35 (t,J= 5.4 Hz, 3H), 1.32(t,J= 5.6 Hz, 3H), 1.27 (d,J= 5.2 Hz, 3H), 1.27 (d,J= 4.8 Hz, 3H);13CNMR (100 MHz, CDCl3):168.0 (d,J= 2.0 Hz), 143.9 (d,J= 9.0 Hz), 129.8,128.7, 114.3, 70.0, 64.0 (d,J= 6.2 Hz), 63.4 (d,J= 5.7 Hz), 56.9 (d,J=118.1 Hz), 21.8, 21.6, 20.5, 16.5 (d,J= 4.1 Hz), 16.4 (d,J= 5.2 Hz); HRMS(ESI) calcd for C16H27NO5P (M+H)+344.1621, found 344.1619.
example 7
In the air atmosphereN-tert-butyl 4-tolylglycinate (0.2mmol), diethyl phosphite (0.2mmol) and cobalt perchlorate hexahydrate (0.02 mmol) were added to a dry reaction tube with stirring magnetons. Acetonitrile solvent (2 mL) was then added to the tube and the reaction tube was placed in an air atmosphere 80oAnd C, reacting for 12 hours under an oil bath. After the reaction is finished, the reaction product is cooled to room temperature, the solvent is removed by reduced pressure distillation through a rotary evaporator, and the residue is separated and purified through column chromatography to obtain pure light yellow oily liquid 3g, wherein the yield is 67%. The structural characterization data for 3g of compound is as follows:
light yellow oil;1H NMR (400 MHz, CDCl3):7.00 (d,J= 6.4 Hz, 2H),6.61 (d,J= 6.0 Hz, 2H), 4.37 (d,J= 18.0 Hz, 1H), 4.26-4.12 (m, 4H), 2.24(s, 3H), 1.46 (s, 9H), 1.36 (t,J= 5.8 Hz, 3H), 1.31 (t,J= 5.6 Hz, 3H);13CNMR (100 MHz, CDCl3):167.4 (d,J= 1.3 Hz), 144.2 (d,J= 8.2 Hz), 129.8,128.5, 114.2, 83.1, 63.9 (d,J= 5.9 Hz), 63.3 (d,J= 6.0 Hz), 57.5 (d,J=119.2 Hz), 27.9, 20.5, 16.5 (d,J= 4.4 Hz), 16.4 (d,J= 5.4 Hz); HRMS (ESI)calcd for C17H29NO5P (M+H)+358.1778, found 358.1776.
example 8
In the air atmosphereNBenzyl-4-tolylglycine (0.2mmol), diethyl phosphite (0.2mmol) and cobalt perchlorate hexahydrate (0.02 mmol) were added to a dry reaction tube with stirring magnetons. Acetonitrile solvent (2 mL) was then added to the tube and the reaction tube was placed in an air atmosphere 80oAnd C, reacting for 12 hours under an oil bath. After the reaction is finished, cooling to room temperature, removing the solvent by reduced pressure distillation through a rotary evaporator, and separating and purifying the residue by column chromatography to obtain pure light yellow oily liquid for 3 hours, wherein the yield is 80%. The structural characterization data for the 3h compound is as follows:
light yellow oil;1H NMR (400 MHz, CDCl3):7.33-7.30 (m, 5H), 6.98 (d,J= 6.8 Hz, 2H), 6.59 (d,J= 6.8 Hz, 2H), 5.24-5.16 (m, 2H), 4.54 (d,J=18.8 Hz, 1H), 4.23-4.06 (m, 4H), 2.23 (s, 3H), 1.36-1.31 (m, 6H), 1.26 (t,J= 5.6 Hz, 3H), 1.25 (t,J= 5.6 Hz, 3H);13C NMR (100 MHz, CDCl3):168.5 (d,J= 2.5 Hz), 143.8 (d,J= 10.0 Hz), 135.1, 129.9, 128.9, 128.5, 128.4,114.3, 67.8, 64.3 (d,J= 6.1 Hz), 63.7 (d,J= 5.8 Hz), 62.2, 56.8 (d,J=118.4 Hz), 20.5, 16.4 (d,J= 4.0 Hz), 16.3 (d,J= 3.9 Hz); HRMS (ESI) calcdfor C20H27NO5P (M+H)+392.1621, found 392.1621.
example 9
In the air atmosphereN-4- (1,1' -biphenyl) glycine ethyl ester (0.2mmol), diethyl phosphite (0.2mmol) and cobalt perchlorate hexahydrate (0.02 mmol) were added to a dry reaction tube with stirring magnetons. Acetonitrile solvent (2 mL) was then added to the tube and the reaction was allowed to proceedThe test tube is placed in an air atmosphere 80oAnd C, reacting for 12 hours under an oil bath. After the reaction is finished, cooling to room temperature, removing the solvent by reduced pressure distillation through a rotary evaporator, and separating and purifying the residue by column chromatography to obtain pure light yellow oily liquid 3i with the yield of 65%. The structural characterization data for the 3i compound is as follows:
light yellow oil;1H NMR (400 MHz, CDCl3):7.52 (dd,J= 6.8 Hz,J=0.8 Hz, 2H), 7.45 (dd,J= 5.2 Hz,J= 1.6 Hz, 2H), 7.39 (t,J= 6.2 Hz, 2H),7.29-7.26 (m, 1H),6.76 (dd,J= 5.2 Hz,J= 1.6 Hz, 2H), 4.68 (brs, 1H), 4.56(d,J= 18.4 Hz, 1H), 4.31-4.18 (m, 6H), 2.24 (s, 3H), 1.36-1.31 (m, 6H),1.36 (t,J= 5.6 Hz, 3H), 1.33 (t,J= 5.6 Hz, 3H), 1.29 (t,J= 5.6 Hz, 3H);13C NMR (100 MHz, CDCl3):168.4 (d,J= 1.6 Hz), 145.6 (d,J= 8.3 Hz),140.9, 132.4, 128.7, 128.0, 126.5, 114.3, 64.2 (d,J= 4.7 Hz), 63.7 (d,J=6.1 Hz), 62.4, 56.8 (d,J= 117.3 Hz), 20.5, 16.5 (d,J= 5.3 Hz), 16.4,14.2; HRMS (ESI) calcd for C20H27NO5P (M+H)+392.1621, found 392.1627.
Claims (3)
1. a synthetic method of alpha-phosphorylation of alpha-amino acid ester compounds is disclosed, wherein the structural formula of the compounds is shown as the formula (I):
wherein R is1Is methyl or phenyl; r2Is methyl, ethyl, isopropyl, tert-butyl or benzyl; r3Is methyl, ethyl, isopropyl, tert-butyl or benzyl;
the method is characterized by comprising the following steps:
in the presence of a catalyst in an organic solventNAryl glycine ester (II) and phosphite ester compound (III) are used as reaction substrates, stirring is carried out for 12 hours until TLC detection reaction is completed, and the product α -phosphorylated α -amino acid ester compound (I) can be prepared by rotary evaporation concentration and column chromatography separation, and the reaction general formula is as follows:
the catalyst is Co (ClO)4)2•6H2O; the amount of the catalyst is 10 mol percent of the compound shown in the formula (III);
the organic solvent is acetonitrile or 1, 2-dichloroethane.
2. The method for synthesizing alpha-aminoacylation according to claim 1, wherein the temperature in the step (a) is from room temperature to 100 ℃.
3. The method for synthesizing alpha-aminoacylation according to claim 1, wherein the molar ratio of the compound represented by formula (II) to the compound represented by formula (III) is 1: 1-10.
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