CN102924511A - Beta-Ketophosphonate compound preparation method - Google Patents
Beta-Ketophosphonate compound preparation method Download PDFInfo
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- CN102924511A CN102924511A CN2012102026454A CN201210202645A CN102924511A CN 102924511 A CN102924511 A CN 102924511A CN 2012102026454 A CN2012102026454 A CN 2012102026454A CN 201210202645 A CN201210202645 A CN 201210202645A CN 102924511 A CN102924511 A CN 102924511A
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- 0 *1C2*(*CC3)C3C12 Chemical compound *1C2*(*CC3)C3C12 0.000 description 2
- PPBRXRYQALVLMV-UHFFFAOYSA-N C=Cc1ccccc1 Chemical compound C=Cc1ccccc1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 description 1
- UAJRSHJHFRVGMG-UHFFFAOYSA-N COc1ccc(C=C)cc1 Chemical compound COc1ccc(C=C)cc1 UAJRSHJHFRVGMG-UHFFFAOYSA-N 0.000 description 1
Abstract
The present invention discloses a preparation method for preparing beta-Ketophosphonates represented by a formula (III). The beta-Ketophosphonate is an oxygen-containing compound having a value, and is especially adopted as an important synthesis intermediate to be widely used in the famous HWE reaction to synthesize alpha,beta-unsaturated carbonyl compounds. According to the present invention, simple and commercialized olefin and hydrogen-phosphorite are adopted as raw materials to directly utilize oxygen as an oxidizing agent and an oxygen source under transition metal catalysis to prepare the beta-Ketophosphonates; the preparation method has advantages of cheap and easily available raw materials, mild reaction conditions, environmental-friendliness, high atom economy, wide substrate adaptability range, and no requirement of harsh reaction conditions such as equivalent organic metal reagent use, low temperature, no water, no oxygen and the like; and the method further has advantages of short preparation period, easy product purification, stable process conditions, convenient operation and safety, and is suitable for large-scale production.
Description
Technical field
The invention belongs to the synthetic chemistry field, relate to the preparation method of a kind of β-carbonylic phosphonic acid ester cpds, directly utilize alkene, hydrogen-phosphorous acid ester and the oxygen that relate to particularly a kind of catalysis synthesize the method for β-carbonylic phosphonic acid ester cpds.
Background technology
(β-Ketophosphonates) is extremely valuable oxygenatedchemicals to β-carbonylic phosphonic acid ester, especially be widely used in famous HWE(Horner-Wadsworth-Emmons as important synthetic intermediate) react and synthesize α, beta-unsaturated carbonyl compound.Further, they can be used as useful precursor and synthesize beta-amino phosphonic acids and the beta-hydroxy phosphonic acids with chirality.Beta-amino phosphonic acids and beta-hydroxy phosphonic acids all show very interesting biologically active chemical, such as: anti-tumor activity, Antiphytoviral, sterilization, inhibitory enzyme activity, the important biological activity such as anti-oxidant.In addition, β-carbonylic phosphonic acid ester self also show very widely biological activity such as: resisting hyperosteogeny, suppress osteoporosis, inhibition tumor cell growth and opposing or treatment cancer, suppress lactamase etc. and outstanding metal complex ability.Its structural formula is as follows:
At present report β-carbonylic phosphonic acid ester synthesis method mainly comprises following several:
1.Arbuzov reaction:
Arbuzov reaction generally is at high temperature to obtain β-carbonylic phosphonic acid ester with ketone and the phosphite reactions of highly active alpha-halogen.But often be accompanied by the generation of other side reaction (Perkow reaction) in this reaction, make it be restricted in actual applications (Arbuzov, B.A.Pure Appl.Chem.1964,9,307.).
2. the acylation reaction of dialkyl phosphonate negative ion:
(1) acylation reaction of phosphonic acid ester alkyl negative ion and aldehyde:
α-chloromethyl phosphonic acid ester obtains alcoxyl lithium salts intermediate with aldehyde generation addition reaction after generating α-lithium chloromethyl phosphonic acid ester salt under the normal-butyl Role of lithium, alcoxyl lithium salts intermediate is eliminated hydrogenchloride under alkaline condition subsequently, and then hydrolysis obtains product β-carbonylic phosphonic acid ester (Savignac under the process acidic conditions, P.Synth Commun.1978,682.);
(2) acylation reaction of phosphonic acid ester alkyl negative ion and acyl chlorides:
Use dialkyl methyl phosphonate after generating lithium salts under the butyl Role of lithium, further generate the organic copper intermediate with the cuprous halide reaction, the organic copper intermediate of generation obtains β-carbonylic phosphonic acid ester cpds (Savignac, P. with acyl chloride reaction again; Mathey, F.Tetrahedron Lett 1976,33,2829);
(3) acylation reaction of phosphonic acid ester alkyl negative ion and carbonic ether:
This reaction generally be the phosphonic acid ester that replaces of carbonic ether and alkyl under-78 ° of C normal-butyl Role of lithiums nucleophilic addition occurs after, then (Corey, the E.J. that a part alcohol obtains β-carbonylic phosphonic acid ester cpds taken off in hydrolysis under acidic conditions; Kwiatkowski, G. T.J. Am.Chem.Soc.1996,88,5654.);
(4) acylation reaction of phosphonic acid ester alkyl negative ion and nitrile compound:
Use diethyl phosphonate under the normal-butyl Role of lithium, to obtain intermediate 1, intermediate 1 and multiple electrophilic reagent such as PhSSPh, PhSCl, MeSSMe, PhSeBr, PhSO with the nitrile compound reaction as raw material
2The Cl reaction obtains the intermediate 2 that heteroatoms replaces, at last at 6N-H
2SO
4Effect under, intermediate 2 changes into β-carbonylic phosphonic acid ester (Lee, K.; Oh, S.Y.Synth Commun.1991,21,279.).
3. the reaction of the synthetic β of other type-carbonylic phosphonic acid ester:
(1) alpha-brominated ketone compound can be at LiN (TMS)
2With obtain corresponding β-carbonylic phosphonic acid ester (Sampson, P. with phosphoryl chloride dialkyl reaction under the tertiary butyl Role of lithium; Hammond, G.B.; Wiemer, D.F.J.Org.Chem.1986,51,4342.);
(2) reaction of α-nitro epoxy alkane and dialkyl phosphate negative ion can obtain ring-type β-carbonylic phosphonic acid ester cpds (Kim, D.Y.; Kong, M.S.J.Chem.SOC.Perkin Trans.11994,3359.);
(3) triethyl phosphonic acids acetic ester is at Mg (OEt)
2With the carbonate chloride reaction, then, hydrolysis obtains corresponding β-carbonylic phosphonic acid ester (Kim, D.Y. under acidic conditions under the effect of (1 equivalent); Kong, M.S.; Rhie, D.Y.Synth Commun.1995,25,2865.);
(4) Co compound or the metal M g with equivalent can obtain β-carbonylic phosphonic acid ester (Orsini, F. at phosphonic acid ester and the various carbonate reaction of mediation alpha-halogen; Teodoro, E.D.; Ferrari, M.Synthesis 2002,1683.).
In sum, because the β-importance of carbonylic phosphonic acid ester cpds in organic chemistry and biological chemistry, in recent years, its Study of synthesis method has been subject to people's extensive concern.Multiple synthetic method grows up, but these methods mostly exist obvious defective, for example: loaded down with trivial details operation steps, relatively harsh reaction conditions, extra step go to prepare complicated raw material, the organometallic reagent that needs equivalent, anhydrous solvent and lower temperature of reaction etc., make troubles to industrial production.So the method for inventing the especially eco-friendly synthetic β of a kind of gentleness, facility, Atom economy-carbonylic phosphonic acid ester in the synthetic chemical industry field always in the urgent need to.
Summary of the invention
Technical problem to be solved by this invention is to overcome the weak point in the above-mentioned currently known methods, the research and design utilization be simple and easy to commercialized raw materials by the novel method gentle, convenient, that the especially eco-friendly catalyzed oxidation approach of Atom economy synthesize β-carbonylic phosphonic acid ester cpds, the some of them product is to synthesize the key intermediate with bioactive natural product.
Method of the present invention obtains compound (III) take commercial alkene, hydrogen-phosphorous acid ester and oxygen as starting raw material under the effect of metal catalyst and alkali.The method effectively obtains β-carbonylic phosphonic acid ester cpds through single step reaction under simple operation, avoided using the harsh reaction conditions such as organometallic reagent, anhydrous and oxygen-free and low temperature of equivalent, is fit to scale operation.Reaction formula is as follows:
R wherein
1Be aryl, aralkyl, alkyl, cycloalkyl, virtue amino, alkylamino, alkoxyl group; R
2Be hydrogen atom, aryl, aralkyl, alkyl, cycloalkyl; R
3Be aryl, aralkyl, alkyl, cycloalkyl;
Work as R
1During for aryl, R
1Can be and replace or unsubstituted aryl, aryl comprises monokaryon aromatic hydrocarbon group such as phenyl or multinuclear aromatic yl group such as naphthyl, green onion base, phenanthryl etc., and monokaryon and multinuclear aryl can replace in one or more positions; Work as R
1During for the monokaryon aryl that replaces, preferred substituting group is lower paraffin hydrocarbons, halogen, lower alkoxy, nitro, cyano group, ethanoyl, ester group, the carbalkoxy that contains 1-6 carbon atom;
Described aryl can contain heteroatoms, and wherein heteroatoms is selected from nitrogen, oxygen or sulphur, and these heteroaryls can be unsubstituted or be replaced by above-mentioned substituting group;
Work as R
1During for the monokaryon heteroaryl, R
1Be pyridyl, furyl, pyrryl, imidazolyl, thiazolyl, thiotolene base etc.;
Preferred multinuclear aryl comprises xenyl, naphthyl, pyrryl, benzothienyl, benzofuryl, indyl, quinolyl, pyrazinyl, methylpyrrole base, imidazolyl, pyrazolyl, pyridyl etc.;
Work as R
1During for aralkyl, aralkyl represents aromatic yl elementary alkyl, wherein aryl as defined above, and low alkyl group contains 1-6 carbon atom; Described aryl can be unsubstituted or replacement, and preferred unsubstituted aralkyl is benzyl; The aralkyl that replaces comprises methoxy-benzyl, methyl-benzyl, fluoro benzyl, chloro benzyl, nitrobenzyl, styroyl, picolyl etc.;
Work as R
1During for alkyl, R
1For having the straight or branched alkyl of 1-22 carbon atom, preferred alkyl is to contain the low alkyl group of 1-8 carbon atom such as ethyl, propyl group, sec.-propyl, butyl, n-pentyl, hexyl, heptyl, octyl group etc.;
Work as R
1During for cycloalkyl, R
1Be cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or the diamantane etc. with 3-12 carbon atom;
Work as R
1During for virtue amino, aryl definition wherein is the same;
Work as R
1Be alkylamino, alkyl definition wherein is the same;
Work as R
1Be alkoxyl group, alkyl definition wherein is the same;
R
2In aryl, aralkyl, alkyl, the same R of definition of cycloalkyl
1
R
3The same R of the definition of middle aryl, aralkyl, alkyl, cycloalkyl
1
The present invention is take simple olefins (I), hydrogen-phosphorous acid ester (II) and the oxygen of commercial product as starting raw material,
R wherein
1, R
2And R
3Definition with above-mentioned.
The used metal catalyst of the present invention comprises cupric bromide, cupric chloride, cuprous bromide, cuprous chloride, cuprous iodide, four cyano phosphofluoric acid ketone, copper trifluoromethanesulfcomposite, ferric bromide, iron trichloride, ferrous bromide, iron protochloride, tribromide ruthenium, palladium, Palladous chloride, gold tribromide, platinum dichloride, indium tribromide etc.; Also above-mentioned two or more mixing metal catalyst altogether, preferred cupric bromide and ferric bromide or cupric chloride and iron trichloride make up.
The used alkali of the present invention can be divided into organic bases and mineral alkali.Organic bases comprises triethylamine, Trimethylamine 99, pyridine, diethylamine, diisopropyl ethyl amine, N, N, N, N-Tetramethyl Ethylene Diamine, 1.8-diazabicylo (5.4.0) hendecene-7(DBU), 1,5-diaza-bicyclo [5.3.0]-5-nonene (DBN), Isosorbide-5-Nitrae-diaza-bicyclo [2.2.2] octane (DABCO) etc.; Mineral alkali comprises yellow soda ash, salt of wormwood, cesium carbonate, sodium bicarbonate, potassiumphosphate etc., and preferred bases is: triethylamine.
The used solvent of the present invention can be non-protonic solvent and protic solvent, non-protonic solvent comprises methylene dichloride, chloroform, 1,2-ethylene dichloride, 1,2-glycol dimethyl ether, tetrahydrofuran (THF), 1,4-dioxane, acetonitrile, ethyl acetate, toluene, benzene, methyl-sulphoxide, DMF etc.; Protic solvent comprises methyl alcohol, ethanol, propyl alcohol, Virahol, water etc.; Also can carry out in above-mentioned two or more mixed solvent, the preferred reaction solvent is: dimethyl sulfoxide (DMSO).
Temperature of reaction of the present invention is generally 0 ℃～100 ℃, preferred 25 ℃～60 ℃; The mol ratio of alkene and hydrogen-phosphorous acid ester is 1:1～1:8, and preferred 1:1～1:2; Reaction can be reacted in purity oxygen, also can react in air, preferably reacts in purity oxygen.
The invention provides the synthetic method of β-carbonylic phosphonic acid ester cpds, compare the reaction conditions of the harshnesses such as the method raw material cheaply is easy to get, reaction conditions gentleness, environmental friendliness, Atom economy are high, substrate wide accommodation, the organometallic reagent that does not need to use equivalent, low temperature and anhydrous and oxygen-free with in the past traditional method; Present method also has that preparation cycle is short, easy purification of products, stable process conditions, advantage easy to operate and safe, can carry out scale operation.
Utilize the synthetic β of the inventive method-carbonylic phosphonic acid ester to can be used as synthetic multiple key intermediate with bioactive natural product.For example product 2-carbonyl-2-phenylethyl phosphinic acid ethyl ester can be for the synthesis of the natural product (-) with significant osteoporosis disease-diospongin B(G.Sabitha, P.Padmaja, J.S.Yadav, Helv.Chim.Acta 2008,91,2235.).
Embodiment
Further specify the present invention below by specific embodiment, it should be understood that the preparation method of the embodiment of the invention is only used for illustrating the present invention, rather than limitation of the present invention; Under the prerequisite of the present invention design, preparation method's of the present invention simple modifications is all belonged to the protection domain that the present invention requires.
Embodiment 1:
Under the room temperature, in the 250mL round-bottomed flask, add successively FeBr
3(2.2g, 7.5mmol, 5.0mol%), CuBr
2(0.83g, 3.8mmol, 2.5mol%), vinylbenzene (15.6g, 0.15mol), hydrogen-diethyl phosphite (41.4g, 0.3mol), Et
3N (21mL, 0.15mol) and DMSO (50mL).Then, cover stop,threeway, put balloon.After the displaced air, pour oxygen, repeatable operation three times.Reaction mixture is heated to 55 ° of C and stirs 48 hours (TLC detection reaction).Then, stopped reaction adds 100mL water in reaction mixture, with 200mL dichloromethane extraction reaction mixture, organic phase is used 0.1N/L hydrochloric acid (100mL * 1) successively, water (100mL * 3) and saturated sodium-chloride water solution (100mL * 1) washing.Tell organic layer, spend the night with anhydrous sodium sulfate drying.Filter, concentrating under reduced pressure obtains the oily crude product.With the mixtures of eluents flushing of sherwood oil and ethyl acetate, rapid column chromatography (silicagel column) obtains corresponding product β-carbonylic phosphonic acid ester (faint yellow oily thing 26g, productive rate 68%) at last.
1H?NMR(CDCl
3,600MHz,ppm):δ8.01(d,J=8.1Hz,2H),7.58(t,J=7.4Hz,1H),7.48(t,J=7.7Hz,2H),4.17-4.11(m,4H),3.63(d,J=22.7Hz,2H),1.28(t,J=7.1Hz,6H);
13C?NMR(CDCl
3,150MHz,ppm):δ191.9(d,J
CP=6.8Hz),136.6,133.6,129.0,128.6,62.6(d,J
CP=5.7Hz),38.5(d,J
CP=128.9Hz),16.2(d,J
CP=5.7Hz);
31P?NMR(CDCl
3,121MHz):δ20.46;HRMS?calc.for?C
12H
18O
4P(M+H)
+,257.0943;found,257.0947.
Embodiment 2:
Under the room temperature, in the 50mL round-bottomed flask, add successively FeBr
3(0.74g, 2.5mmol, 5.0mol%), CuBr
2(0.28g, 1.3mmol, 2.5mol%), vinylbenzene (5.2g, 50mmol), hydrogen-diisopropyl phosphite (16.6g, 100mmol), Et
3N (7mL, 50mmol) and DMSO (10mL).Then, cover stop,threeway, put balloon.After the displaced air, pour oxygen, repeatable operation three times.Reaction mixture is heated to 55 ° of C and stirred 48 hours.Then, stopped reaction adds 50mL water in reaction mixture, with 100mL dichloromethane extraction reaction mixture, organic phase is used 0.1N/L hydrochloric acid (50mL * 1) successively, water (50mL * 3) and saturated sodium-chloride water solution (50mL * 1) washing.Tell organic layer, spend the night with anhydrous sodium sulfate drying.Filter, concentrating under reduced pressure obtains the oily crude product.With the mixtures of eluents flushing of sherwood oil and ethyl acetate, rapid column chromatography (silicagel column) obtains corresponding product β-carbonylic phosphonic acid ester (faint yellow oily thing 10.5g, productive rate 74%) at last.
1H?NMR(CDCl
3,600MHz,ppm):δ8.01(d,J=7.7Hz,2H),7.57(t,J=7.3Hz,1H),7.47(t,J=7.7Hz,2H),4.75-4.70(m,2H),3.59(d,J=23.1Hz,2H),1.27(t,J=5.1Hz,12H);
13C?NMR(CDCl
3,150MHz,ppm):δ192.1,136.8,133.5,129.1,128.5,71.5(d,J
CP=6.8Hz),39.8(d,J
CP=130.0Hz),23.9,23.7;
31P?NMR(CDCl
3,121MHz):δ18.26;HRMS?calc.for?C
14H
21O
4NaP(M+Na)
+,307.1075;found,307.1068.
Embodiment 3:
Under the room temperature, in the 50mL round-bottomed flask, add successively FeBr
3(0.74g, 2.5mmol, 5.0mol%), CuBr
2(0.28g, 1.3mmol, 2.5mol%), 4-vinyl toluene (5.9g, 50mmol), hydrogen-diisopropyl phosphite (16.6g, 100mmol), Et
3N (7mL, 50mmol) and DMSO (10mL).Then, cover stop,threeway, put balloon.After the displaced air, pour oxygen, repeatable operation three times.Reaction mixture is heated to 55 ° of C and stirred 48 hours.Then, stopped reaction adds 50mL water in reaction mixture, with 100mL dichloromethane extraction reaction mixture, organic phase is used 0.1N/L hydrochloric acid (50mL * 1) successively, water (50mL * 3) and saturated sodium-chloride water solution (50mL * 1) washing.Tell organic layer, spend the night with anhydrous sodium sulfate drying.Filter, concentrating under reduced pressure obtains the oily crude product.With the mixtures of eluents flushing of sherwood oil and ethyl acetate, rapid column chromatography (silicagel column) obtains corresponding product β-carbonylic phosphonic acid ester (faint yellow oily thing 10.3g, productive rate 69%) at last.
1H?NMR(CDCl
3,600MHz,ppm):δ7.92(d,J=8.0Hz,2H),7.26(d,J=8.0Hz,2H),4.75-4.69(m,2H),3.56(d,J=22.7Hz,2H),2.41(s,3H),1.28(t,J=5.9Hz,12H);
13C?NMR(CDCl
3,150MHz,ppm):δ191.6,144.4,134.3,129.3,129.2,71.4(d,J
CP=6.8Hz),39.7(d,J
CP=128.9Hz),23.9(d,J
CP=3.4Hz),23.7(d,J
CP=5.7Hz),21.7;
31P?NMR(CDCl
3,121MHz):δ18.55.HRMS?calc.for?C
15H
23O
4NaP(M+Na)
+,321.1232;found,321.1242.
Embodiment 4:
Under the room temperature, in the 50mL round-bottomed flask, add successively FeBr
3(0.74g, 2.5mmol, 5.0mol%), CuBr
2(0.28g, 1.3mmol, 2.5mol%), 3-vinyl toluene (5.9g, 50mmol), hydrogen-diisopropyl phosphite (16.6g, 100mmol), Et
3N (7mL, 50mmol) and DMSO (10mL).Then, cover stop,threeway, put balloon.After the displaced air, pour oxygen, repeatable operation three times.Reaction mixture is heated to 55 ° of C and stirred 48 hours.Then, stopped reaction adds 50mL water in reaction mixture, with 100mL dichloromethane extraction reaction mixture, organic phase is used 0.1N/L hydrochloric acid (50mL * 1) successively, water (50mL * 3) and saturated sodium-chloride water solution (50mL * 1) washing.Tell organic layer, spend the night with anhydrous sodium sulfate drying.Filter, concentrating under reduced pressure obtains the oily crude product.With the mixtures of eluents flushing of sherwood oil and ethyl acetate, rapid column chromatography (silicagel column) obtains corresponding product β-carbonylic phosphonic acid ester (faint yellow oily thing 9.5g, productive rate 64%) at last.
1H?NMR(CDCl
3,600MHz,ppm):δ7.82(d,J=8.0Hz,2H),7.39(d,J=7.7Hz,1H),7.36(t,J=7.5Hz,1H),4.76-4.71(m,2H),3.58(d,J=22.7Hz,2H),2.42(s,3H),1.29(d,J=2.9Hz,6H,overlap),1.28(d,J=2.9Hz,6H,overlap);
13C?NMR(CDCl
3,150MHz,ppm):δ192.2(d,J
CP=6.8Hz),138.2,136.8,134.2,129.6,128.4,126.4,71.4(d,J
CP=6.8Hz),39.7(d,J
CP=130.0Hz),23.9(d,J
CP=3.4Hz),23.7(d,J
CP=4.6Hz),21.3;
31P?NMR(CDCl
3,121MHz):δ18.40;HRMS?calc.for?C
15H
23O
4NaP(M+Na)
+,321.1232;found,321.1231.
Embodiment 5:
Under the room temperature, in the 50mL round-bottomed flask, add successively FeBr
3(0.74g, 2.5mmol, 5.0mol%), CuBr
2(0.28g, 1.3mmol, 2.5mol%), 2-methyl styrene (5.9g, 50mmol), hydrogen-diisopropyl phosphite (16.6g, 100mmol), Et
3N (7mL, 50mmol) and DMSO (10mL).Then, cover stop,threeway, put balloon.After the displaced air, pour oxygen, repeatable operation three times.Reaction mixture is heated to 55 ° of C and stirred 48 hours.Then, stopped reaction adds 50mL water in reaction mixture, with 100mL dichloromethane extraction reaction mixture, organic phase is used 0.1N/L hydrochloric acid (50mL * 1) successively, water (50mL * 3) and saturated sodium-chloride water solution (50mL * 1) washing.Tell organic layer, spend the night with anhydrous sodium sulfate drying.Filter, concentrating under reduced pressure obtains the oily crude product.With the mixtures of eluents flushing of sherwood oil and ethyl acetate, rapid column chromatography (silicagel column) obtains corresponding product β-carbonylic phosphonic acid ester (faint yellow oily thing 8.9g, productive rate 60%) at last.
1H?NMR(CDCl
3,600MHz,ppm):δ7.73(d,J=7.7Hz,1H),7.37(t,J=7.5Hz,1H),7.28-7.23(m,2H),4.73-7.68(m,2H),3.54(d,J=22.7Hz,2H),2.51(s,3H),1.26(d,J=6.2Hz,6H,overlap),1.24(d,J=6.2Hz,6H,overlap);
13C?NMR(CDCl
3,150MHz,ppm):δ195.3(d,J
CP=6.9Hz),138.7,137.7,131.8,131.6,129.6,125.5,71.3(d,J
CP=6.8Hz),42.5(d,J
CP=128.9Hz),23.9(d,J
CP=3.4Hz),23.7(d,J
CP=5.7Hz),21.2;
31P?NMR(CDCl
3,121MHz):δ18.52;HRMS?calc.for?C
15H
23O
4NaP(M+Na)
+,321.1232;found,321.1230.
Embodiment 6:
Under the room temperature, in the 50mL round-bottomed flask, add successively FeBr
3(0.74g, 2.5mmol, 5.0mol%), CuBr
2(0.28g, 1.3mmol, 2.5mol%), 4-methoxy styrene (6.7g, 50mmol), hydrogen-diisopropyl phosphite (16.6g, 100mmol), Et
3N (7mL, 50mmol) and DMSO (10mL).Then, cover stop,threeway, put balloon.After the displaced air, pour oxygen, repeatable operation three times.Reaction mixture is heated to 55 ° of C and stirred 48 hours.Then, stopped reaction adds 50mL water in reaction mixture, with 100mL dichloromethane extraction reaction mixture, organic phase is used 0.1N/L hydrochloric acid (50mL * 1) successively, water (50mL * 3) and saturated sodium-chloride water solution (50mL * 1) washing.Tell organic layer, spend the night with anhydrous sodium sulfate drying.Filter, concentrating under reduced pressure obtains the oily crude product.With the mixtures of eluents flushing of sherwood oil and ethyl acetate, rapid column chromatography (silicagel column) obtains corresponding product β-carbonylic phosphonic acid ester (faint yellow oily thing 11g, productive rate 70%) at last.
1H?NMR(CDCl
3,600MHz,ppm):δ7.96(d,J=8.8Hz,2H),6.89(d,J=8.8Hz,2H),4.70-4.65(m,2H),3.83(s,3H),3.49(d,J=23.2Hz,2H),1.24(t,J=6.1Hz,12H);
13C?NMR(CDCl
3,150MHz,ppm):δ190.4(d,J
CP=6.9Hz),163.8,131.5,129.8,113.6,71.3(d,J
CP=6.8Hz),55.5,39.6(d,J
CP=130.0Hz),23.9(d,J
CP=3.4Hz),23.7(d,J
CP=4.6Hz);
31P?NMR(CDCl
3,121MHz):δ18.76;HRMS?calc.for?C
15H
24O
5P(M+H)
+,315.1361;found,315.1365.
Embodiment 7:
Under the room temperature, in the 50mL round-bottomed flask, add successively FeBr
3(0.74g, 2.5mmol, 5.0mol%), CuBr
2(0.28g, 1.3mmol, 2.5mol%), 4-bromstyrol (9.1g, 50mmol), hydrogen-diisopropyl phosphite (16.6g, 100mmol), Et
3N (7mL, 50mmol) and DMSO (10mL).Then, cover stop,threeway, put balloon.After the displaced air, pour oxygen, repeatable operation three times.Reaction mixture is heated to 55 ° of C and stirred 48 hours.Then, stopped reaction adds 50mL water in reaction mixture, with 100mL dichloromethane extraction reaction mixture, organic phase is used 0.1N/L hydrochloric acid (50mL * 1) successively, water (50mL * 3) and saturated sodium-chloride water solution (50mL * 1) washing.Tell organic layer, spend the night with anhydrous sodium sulfate drying.Filter, concentrating under reduced pressure obtains the oily crude product.With the mixtures of eluents flushing of sherwood oil and ethyl acetate, rapid column chromatography (silicagel column) obtains corresponding product β-carbonylic phosphonic acid ester (faint yellow oily thing 10.3g, productive rate 57%) at last.
1H?NMR(CDCl
3,600MHz,ppm):δ7.89(d,J=8.5Hz,2H),7.61(b?r.t,J=8.4Hz,2H),4.75-4.69(m,2H),3.55(d,J=22.7Hz,2H),1.29(d,J=3.3Hz,6H,overlap),1.28(d,J=3.3Hz,6H,overlap);
13C?NMR(CDCl
3,150MHz,ppm):δ191.1(d,J
CP=6.8Hz),135.4,131.8,130.7,128.8,71.6(d,J
CP=6.8Hz),39.9(d,J
CP=128.9Hz),23.9(d,J
CP=3.4Hz),23.8(d,J
CP=4.6Hz);
31P?NMR(CDCl
3,121MHz):δ17.76;HRMS?calc.for?C
14H
20O
4NaPBr(M+Na)
+,385.0180;found,385.0188.
Embodiment 8:
Under the room temperature, in the 50mL round-bottomed flask, add successively FeBr
3(0.74g, 2.5mmol, 5.0mol%), CuBr
2(0.28g, 1.3mmol, 2.5mol%), 4-chloro-styrene (6.9g, 50mmol), hydrogen-diisopropyl phosphite (16.6g, 100mmol), Et
3N (7mL, 50mmol) and DMSO (10mL).Then, cover stop,threeway, put balloon.After the displaced air, pour oxygen, repeatable operation three times.Reaction mixture is heated to 55 ° of C and stirred 48 hours.Then, stopped reaction adds 50mL water in reaction mixture, with 100mL dichloromethane extraction reaction mixture, organic phase is used 0.1N/L hydrochloric acid (50mL * 1) successively, water (50mL * 3) and saturated sodium-chloride water solution (50mL * 1) washing.Tell organic layer, spend the night with anhydrous sodium sulfate drying.Filter, concentrating under reduced pressure obtains the oily crude product.With the mixtures of eluents flushing of sherwood oil and ethyl acetate, rapid column chromatography (silicagel column) obtains corresponding product β-carbonylic phosphonic acid ester (faint yellow oily thing 10g, productive rate 63%) at last.
1H?NMR(CDCl
3,600MHz,ppm):δ7.98-7.96(m,2H),7.45-7.43(m,2H),4.75-4.69(m,2H),3.55(d,J=22.7Hz,2H),1.29(d,J=3.3Hz,6H,overlap),1.28(d,J=3.3Hz,6H,overlap);
13C?NMR(CDCl
3,150MHz,ppm):δ190.8(d,J
CP=5.7Hz),140.0,135.0,130.6,128.8,71.6(d,J
CP=6.8Hz),39.9(d,J
CP=128.9Hz),23.9(d,J
CP=3.4Hz),23.7(d,J
CP=5.7Hz);
31P?NMR(CDCl
3,121MHz):δ17.79;HRMS?calc.for?C
14H
21O
4PCl(M+H)
+,319.0866;found,319.0866.
Embodiment 9:
Under the room temperature, in the 50mL round-bottomed flask, add successively FeBr
3(0.74g, 2.5mmol, 5.0mol%), CuBr
2(0.28g, 1.3mmol, 2.5mol%), 4-fluorobenzene ethene (6.1g, 50mmol), hydrogen-diisopropyl phosphite (16.6g, 100mmol), Et
3N (7mL, 50mmol) and DMSO (10mL).Then, cover stop,threeway, put balloon.After the displaced air, pour oxygen, repeatable operation three times.Reaction mixture is heated to 55 ° of C and stirred 48 hours.Then, stopped reaction adds 50mL water in reaction mixture, with 100mL dichloromethane extraction reaction mixture, organic phase is used 0.1N/L hydrochloric acid (50mL * 1) successively, water (50mL * 3) and saturated sodium-chloride water solution (50mL * 1) washing.Tell organic layer, spend the night with anhydrous sodium sulfate drying.Filter, concentrating under reduced pressure obtains the oily crude product.With the mixtures of eluents flushing of sherwood oil and ethyl acetate, rapid column chromatography (silicagel column) obtains corresponding product β-carbonylic phosphonic acid ester (faint yellow oily thing 10.4g, productive rate 69%) at last.
1H?NMR(CDCl
3,600MHz,ppm):δ8.09-8.07(m,2H),7.17-7.13(m,2H),4.76-4.71(m,2H),3.57(d,J=23.1Hz,2H),1.30(d,J=3.7Hz,6H,overlap),1.29(d,J=3.7Hz,6H,overlap);
13C?NMR(CDCl
3,150MHz,ppm):δ190.4(d,J
CP=6.8Hz),166.9,165.2,133.2,132.0,131.9,115.7,115.5,71.5(d,J
CP=6.8Hz),39.9(d,J
CP=128.9Hz),23.9(d,J
CP=3.4Hz),23.7(d,J
CP=4.6Hz);
31PNMR(CDCl
3,121MHz):δ17.96;HRMS?calc.for?C
14H
20O
4NaPF(M+Na)
+,325.0981;found,325.0978.
Embodiment 10:
Under the room temperature, in the 50mL round-bottomed flask, add successively FeBr
3(0.74g, 2.5mmol, 5.0mol%), CuBr
2(0.28g, 1.3mmol, 2.5mol%), 4-vinyl benzene yl acetate (8.1g, 50mmol), hydrogen-diisopropyl phosphite (16.6g, 100mmol), Et
3N (7mL, 50mmol) and DMSO (10mL).Then, cover stop,threeway, put balloon.After the displaced air, pour oxygen, repeatable operation three times.Reaction mixture is heated to 55 ° of C and stirred 48 hours.Then, stopped reaction adds 50mL water in reaction mixture, with 100mL dichloromethane extraction reaction mixture, organic phase is used 0.1N/L hydrochloric acid (50mL * 1) successively, water (50mL * 3) and saturated sodium-chloride water solution (50mL * 1) washing.Tell organic layer, spend the night with anhydrous sodium sulfate drying.Filter, concentrating under reduced pressure obtains the oily crude product.With the mixtures of eluents flushing of sherwood oil and ethyl acetate, rapid column chromatography (silicagel column) obtains corresponding product β-carbonylic phosphonic acid ester (faint yellow oily thing 10.9g, productive rate 64%) at last.
1H?NMR(CDCl
3,600MHz,ppm):δ8.06(d,J=8.5Hz,2H),7.21(d,J=8.4Hz,2H),4.75-4.70(m,2H),3.57(d,J=22.7Hz,2H),2.32(s,3H),1.29(d,J=2.9Hz,6H,overlap),1.28(d,J=2.6Hz,6H,overlap);
13C?NMR(CDCl
3,150MHz,ppm):δ190.8(d,J
CP=6.8Hz),168.7,154.7,134.3,130.8,121.7,71.6(d,J
CP=6.8Hz),39.9(d,J
CP=128.9Hz),23.9(d,J
CP=4.6Hz),23.7(d,J
CP=4.6Hz),21.1;
31PNMR(CDCl
3,121MHz):δ18.05;HRMS?calc.for?C
16H
23O
6NaP(M+Na)
+,365.1130;found,365.1133.
Embodiment 11:
Under the room temperature, in the 50mL round-bottomed flask, add successively FeBr
3(0.74g, 2.5mmol, 5.0mol%), CuBr
2(0.28g, 1.3mmol, 2.5mol%), 4-cyano-styrene (6.45g, 50mmol), hydrogen-diisopropyl phosphite (16.6g, 100mmol), Et
3N (7mL, 50mmol) and DMSO (10mL).Then, cover stop,threeway, put balloon.After the displaced air, pour oxygen, repeatable operation three times.Reaction mixture is heated to 55 ° of C and stirred 48 hours.Then, stopped reaction adds 50mL water in reaction mixture, with 100mL dichloromethane extraction reaction mixture, organic phase is used 0.1N/L hydrochloric acid (50mL * 1) successively, water (50mL * 3) and saturated sodium-chloride water solution (50mL * 1) washing.Tell organic layer, spend the night with anhydrous sodium sulfate drying.Filter, concentrating under reduced pressure obtains the oily crude product.With the mixtures of eluents flushing of sherwood oil and ethyl acetate, rapid column chromatography (silicagel column) obtains corresponding product β-carbonylic phosphonic acid ester (faint yellow oily thing 10.5g, productive rate 68%) at last.
1H?NMR(CDCl
3,600MHz,ppm):δ8.13(d,J=8.1Hz,2H),7.78(d,J=8.1Hz,2H),4.75-4.69(m,2H),3.59(d,J=23.1Hz,2H),1.28(d,J=6.2Hz,12H);
13CNMR(CDCl
3,150MHz,ppm):δ190.9(d,J
CP=6.8Hz),139.6,132.3,129.5,117.8,116.7,71.8(d,J
CP=6.8Hz),40.3(d,J
CP=128.9Hz),23.9(d,J
CP=3.4Hz),23.7(d,J
CP=4.6Hz);
31P?NMR(CDCl
3,121MHz):δ16.94;HRMS?calc.forC
15H
20NO
4NaP(M+Na)
+,332.1028;found,332.1033.
Embodiment 12:
Under the room temperature, in the 50mL round-bottomed flask, add successively FeBr
3(0.74g, 2.5mmol, 5.0mol%), CuBr
2(0.28g, 1.3mmol, 2.5mol%), 2-naphthalene alkene (7.7g, 50mmol), hydrogen-diisopropyl phosphite (16.6g, 100mmol), Et
3N (7mL, 50mmol) and DMSO (10mL).Then, cover stop,threeway, put balloon.After the displaced air, pour oxygen, repeatable operation three times.Reaction mixture is heated to 55 ° of C and stirs 48 hours (TLC detection reaction).Then, stopped reaction adds 50mL water in reaction mixture, with 100mL dichloromethane extraction reaction mixture, organic phase is used 0.1N/L hydrochloric acid (50mL * 1) successively, water (50mL * 3) and saturated sodium-chloride water solution (50mL * 1) washing.Tell organic layer, spend the night with anhydrous sodium sulfate drying.Filter, concentrating under reduced pressure obtains the oily crude product.With the mixtures of eluents flushing of sherwood oil and ethyl acetate, rapid column chromatography (silicagel column) obtains corresponding product β-carbonylic phosphonic acid ester (faint yellow oily thing 8.8g, productive rate 53%) at last.
1H?NMR(CDCl
3,600MHz,ppm):δ8.57(s,1H),8.07-8.06(m,1H),7.98(d,J=8.0Hz,1H),7.88(t,J=9.0Hz,2H),7.61(t,J=7.5Hz,1H),7.55(t,J=7.5Hz,1H),4.77-4.72(m,2H),3.72(d,J=22.7Hz,2H),1.28(d,J=2.2Hz,6H,overlap),1.27(d,J=1.8Hz,6H,overlap);
13C?NMR(CDCl
3,150MHz,ppm):δ191.9(d,J
CP=5.7Hz),135.7,134.1,132.4,131.5,129.8,128.7,128.3,127.7,126.8,124.3,71.5(d,J
CP=5.7Hz),39.9(d,J
CP=130.0Hz),23.9(d,J
CP=3.4Hz),23.8(d,J
CP=4.6Hz);
31P?NMR(CDCl
3,121MHz):δ18.43;HRMS?calc.for?C
18H
24O
4P(M+H)
+,335.1412;found,335.1420.
Embodiment 13:
Under the room temperature, in the 50mL round-bottomed flask, add successively FeBr
3(0.74g, 2.5mmol, 5.0mol%), CuBr
2(0.28g, 1.3mmol, 2.5mol%), 2-thiazolinyl pyridine (5.25g, 50mmol), hydrogen-diisopropyl phosphite (16.6g, 100mmol), Et
3N (7mL, 50mmol) and DMSO (10mL).Then, cover stop,threeway, put balloon.After the displaced air, pour oxygen, repeatable operation three times.Reaction mixture is heated to 55 ° of C and stirred 48 hours.Then, stopped reaction adds 50mL water in reaction mixture, with 100mL dichloromethane extraction reaction mixture, organic phase is used 0.1N/L hydrochloric acid (50mL * 1) successively, water (50mL * 3) and saturated sodium-chloride water solution (50mL * 1) washing.Tell organic layer, spend the night with anhydrous sodium sulfate drying.Filter, concentrating under reduced pressure obtains the oily crude product.With the mixtures of eluents flushing of sherwood oil and ethyl acetate, rapid column chromatography (silicagel column) obtains corresponding product β-carbonylic phosphonic acid ester (faint yellow oily thing 8.0g, productive rate 56%) at last.
1H?NMR(CDCl
3,600MHz,ppm):δ8.70(d,J=4.4Hz,1H),8.06(d,J=7.7Hz,1H),7.83(t,J=7.7Hz,1H),7.49-7.47(m,1H),4.77-4.71(m,2H),3.98(d,J=22.7Hz,2H),1.28(d,J=5.8Hz,6H,overlap),1.24(d,J=6.2Hz,6H,overlap);
13C?NMR(CDCl
3,150MHz,ppm):δ194.0,153.0,148.9,136.9,127.3,122.2,71.1(d,J
CP=5.7Hz),37.0(d,J
CP=130.0Hz),24.1(d,J
CP=3.4Hz),23.7(d,J
CP=5.7Hz);
31P?NMR(CDCl
3,121MHz):δ19.07;HRMS?calc.for?C
13H
21NO
4P(M+H)
+,286.1208;found,286.1219.
Embodiment 14:
Under the room temperature, in the 50mL round-bottomed flask, add successively FeBr
3(0.74g, 2.5mmol, 5.0mol%), CuBr
2(0.28g, 1.3mmol, 2.5mol%), (E)-1-phenyl propylene (5.9g, 50mmol), hydrogen-diisopropyl phosphite (16.6g, 100mmol), Et
3N (7mL, 50mmol) and DMSO (10mL).Then, cover stop,threeway, put balloon.After the displaced air, pour oxygen, repeatable operation three times.Reaction mixture is heated to 55 ° of C and stirred 48 hours.Then, stopped reaction adds 50mL water in reaction mixture, with 100mL dichloromethane extraction reaction mixture, organic phase is used 0.1N/L hydrochloric acid (50mL * 1) successively, water (50mL * 3) and saturated sodium-chloride water solution (50mL * 1) washing.Tell organic layer, spend the night with anhydrous sodium sulfate drying.Filter, concentrating under reduced pressure obtains the oily crude product.With the mixtures of eluents flushing of sherwood oil and ethyl acetate, rapid column chromatography (silicagel column) obtains corresponding product β-carbonylic phosphonic acid ester (faint yellow oily thing 9.2g, productive rate 62%) at last.
1H?NMR(DMSO-d
6,600MHz,ppm):7.91(d,J=7.7Hz,2H),7.54(t,J=7.3Hz,1H),7.43(t,J=7.5Hz,2H),4.48-4.38(m,2H),4.34-4.27(m,1H),1.25(dd,J
1=17.6Hz,J
2=7.0Hz,3H),1.10(d,J=6.2Hz,3H),1.07(d,J=6.2Hz,3H,overlap),1.04(d,J=6.2Hz,3H,overlap),1.01(d,J=6.2Hz,3H);
13C?NMR(DMSO-d
6,150MHz,ppm):δ197.1,137.4,133.7,129.3,128.9,70.9(t,J
CP=5.7Hz),41.5(d,J
CP=126.6Hz),24.1(d,J
CP=6.8Hz),23.8(d,J
CP=6.8Hz),12.4(d,J
CP=6.8Hz);
31P?NMR(CDCl
3,121MHz):δ22.07.HRMS?calc.forC
15H
23O
4NaP(M+Na)
+,321.1232;found,321.1234.
Embodiment 15:
Under the room temperature, in the 50mL round-bottomed flask, add successively FeBr
3(0.74g, 2.5mmol, 5.0mol%), CuBr
2(0.28g, 1.3mmol, 2.5mol%), 1,2-dihydronaphthalene (6.5g, 50mmol), hydrogen-diisopropyl phosphite (16.6g, 100mmol), Et
3N (7mL, 50mmol) and DMSO (10mL).Then, cover stop,threeway, put balloon.After the displaced air, pour oxygen, repeatable operation three times.Reaction mixture is heated to 55 ° of C and stirred 48 hours.Then, stopped reaction adds 50mL water in reaction mixture, with 100mL dichloromethane extraction reaction mixture, organic phase is used 0.1N/L hydrochloric acid (50mL * 1) successively, water (50mL * 3) and saturated sodium-chloride water solution (50mL * 1) washing.Tell organic layer, spend the night with anhydrous sodium sulfate drying.Filter, concentrating under reduced pressure obtains the oily crude product.With the mixtures of eluents flushing of sherwood oil and ethyl acetate, rapid column chromatography (silicagel column) obtains corresponding product β-carbonylic phosphonic acid ester (faint yellow oily thing 8.06g, productive rate 52%) at last.
1H?NMR(DMSO-d
6,600MHz,ppm):8.04(d,J=7.9Hz,1H),7.46(t,J=7.5Hz,1H),7.29(t,J=7.5Hz,1H),7.23(d,J=7.6Hz,1H),4.81-4.70(m,2H),3.34-3.29(m,1H),3.16(dt,J
1=25.9Hz,J
2=5.4Hz,1H),2.90(dt,J
1=16.8Hz,J
2=5.3Hz,1H),2.54-2.39(m,2H),1.35(d,J=6.2Hz,3H),1.32(d,J=6.1Hz,3H),1.20(t,J=6.5Hz,6H);
13C?NMR(DMSO-d
6,150MHz,ppm):δ192.6,143.9,133.6,132.4,128.6,127.6,126.6,71.3(d,J
CP=6.8Hz),71.1(d,J
CP=6.8Hz),48.0(d,J
CP=132.3Hz),27.3(d,J
CP=6.8Hz),24.6,24.1,24.0,23.8;
31P?NMR(CDCl
3,121MHz):δ21.38.HRMS?calc.for?C
16H
24O
4P(M+H)
+,311.1412;found,311.1407.
Embodiment 17:
Under the room temperature, in the 50mL round-bottomed flask, add successively FeBr
3(0.74g, 2.5mmol, 5.0mol%), CuBr
2(0.28g, 1.3mmol, 2.5mol%), 1-octene (5.6g, 50mmol), hydrogen-diisopropyl phosphite (16.6g, 100mmol), Et
3N (7mL, 50mmol) and DMSO (10mL).Then, cover stop,threeway, put balloon.After the displaced air, pour oxygen, repeatable operation three times.Reaction mixture is heated to 55 ° of C and stirred 48 hours.Then, stopped reaction adds 50mL water in reaction vessel, and with 100mL dichloromethane extraction reaction mixture, organic phase is used 0.1N/L hydrochloric acid (50mL * 1) successively, water (50mL * 3) and saturated sodium-chloride water solution (50mL * 1) washing.Tell organic layer, spend the night with anhydrous sodium sulfate drying.Filter, concentrating under reduced pressure obtains the oily crude product.With the mixtures of eluents flushing of sherwood oil and ethyl acetate, rapid column chromatography (silicagel column) obtains corresponding product β-carbonylic phosphonic acid ester (faint yellow oily thing 3.8g, productive rate 26%) at last.
1H?NMR(CDCl
3,600MHz,ppm):4.75-4.70(m,2H),3.02(d,J=22.7Hz,2H),2.61(t,J=7.3Hz,2H),1.58-1.55(m,2H),1.34(d,J=2.9Hz,6H,overlap),1.33(d,J=2.9Hz,6H,overlap),1.31-1.28(m,6H),0.87(t,J=6.8Hz,3H);
13C?NMR(CDCl
3,150MHz,ppm):δ202.3(d,J
CP=5.7Hz),71.3(d,J
CP=6.8Hz),43.9,43.7(d,J
CP=126.6Hz),31.6,28.7,23.9(d,J
CP=3.4Hz),23.8(d,J
CP=4.6Hz),23.4,22.5,14.0;
31P?NMR(CDCl
3,121MHz):δ18.57.HRMS?calc.forC
14H
29O
4NaP(M+Na)
+,315.1701;found,315.1703.
Embodiment 18:
Under the room temperature, in the 50mL round-bottomed flask, add successively FeBr
3(0.74g, 2.5mmol, 5.0mol%), CuBr
2(0.28g, 1.3mmol, 2.5mol%), 9-thiazolinyl carbazole (9.65g, 50mmol), hydrogen-diisopropyl phosphite (16.6g, 100mmol), Et
3N (7mL, 50mmol) and DMSO (10mL).Then, cover stop,threeway, put balloon.After the displaced air, pour oxygen, repeatable operation three times.Reaction mixture is heated to 55 ° of C and stirred 48 hours.Then, stopped reaction adds 50mL water in reaction mixture, with 100mL dichloromethane extraction reaction mixture, organic phase is used 0.1N/L hydrochloric acid (50mL * 1) successively, water (50mL * 3) and saturated sodium-chloride water solution (50mL * 1) washing.Tell organic layer, spend the night with anhydrous sodium sulfate drying.Filter, concentrating under reduced pressure obtains the oily crude product.With the mixtures of eluents flushing of sherwood oil and ethyl acetate, rapid column chromatography (silicagel column) obtains corresponding product β-carbonylic phosphonic acid ester (faint yellow oily thing 9.51g), productive rate 51% at last.
1H?NMR(CDCl
3,600MHz,ppm):8.25(d,J=8.5Hz,2H),7.98(d,J=7.7Hz,2H),7.48(t,J=7.9Hz,2H),7.39(t,J=7.5Hz,2H),4.90-4.85(m,2H),3.80(d,J=21.3Hz,2H),1.32(t,J=6.8Hz,12H);
13C?NMR(CDCl
3,150MHz,ppm):δ165.1(d,J
CP=6.8Hz),138.6,127.4,126.5,124.0,119.8,116.3,71.9(d,J
CP=6.8Hz),38.8(d,J
CP=138.0Hz),24.1(d,J
CP=2.3Hz),23.8(d,J
CP=5.7Hz);
31PNMR(CDCl
3,121MHz):δ17.56.HRMS?calc.for?C
20H
25NO
4P(M+H)
+,374.1521;found,374.1523.
Embodiment 19:
Under the room temperature, in the 50mL round-bottomed flask, add successively FeBr
3(0.74g, 2.5mmol, 5.0mol%), CuBr
2(0.28g, 1.3mmol, 2.5mol%), vinylbenzene (5.2g, 50mmol), hydrogen-di-n-butyl phosphite (19.4g, 100mmol), Et
3N (7mL, 50mmol) and DMSO (10mL).Then, cover stop,threeway, put balloon.After the displaced air, pour oxygen, repeatable operation three times.Reaction mixture is heated to 55 ° of C and stirred 48 hours.Then, stopped reaction adds 50mL water in reaction vessel, and with 100mL dichloromethane extraction reaction mixture, organic phase is used 0.1N/L hydrochloric acid (50mL * 1) successively, water (50mL * 3) and saturated sodium-chloride water solution (50mL * 1) washing.Tell organic layer, spend the night with anhydrous sodium sulfate drying.Filter, concentrating under reduced pressure obtains oily matter.With the mixtures of eluents flushing of sherwood oil and ethyl acetate, rapid column chromatography (silicagel column) obtains corresponding product β-carbonylic phosphonic acid ester (faint yellow oily thing 11.2g, productive rate 72%) at last.
1H?NMR(CDCl
3,600MHz,ppm):δ8.01(d,J=7.7Hz,2H),7.58(t,J=7.5Hz,1H),7.47(t,J=7.7Hz,2H),4.10-4.02(m,4H),3.63(d,J=22.7Hz,2H),1.62-1.56(m,4H),1.36-1.29(m,4H),0.88(t,J=7.5Hz,6H);
13C?NMR(CDCl
3,150MHz,ppm):δ191.9,136.6,133.6,129.0,128.6,66.3(d,J
CP=6.8Hz),38.4(d,J
CP=128.9Hz),32.3(d,J
CP=5.7Hz),18.6,13.5;
31P?NMR(CDCl
3,121MHz):δ20.42;HRMS?calc.for?C
16H
26O
4P(M+H)
+,313.1569;found,313.1573.
Embodiment 20:
Under the room temperature, in the 50mL round-bottomed flask, add successively FeCl
3(0.41g, 2.5mmol, 5.0mol%), CuCl
2(0.18g, 1.3mmol, 2.5mol%), vinylbenzene (5.2g, 50mmol), hydrogen-diisopropyl phosphite (16.6g, 100mmol), Et
3N (7mL, 50mmol) and DMSO (10mL).Then, cover stop,threeway, put balloon.After the displaced air, pour oxygen, repeatable operation three times.Reaction mixture is heated to 55 ° of C and stirred 48 hours.Then, stopped reaction adds 50mL water in reaction mixture, with 100mL dichloromethane extraction reaction mixture, organic phase is used 0.1N/L hydrochloric acid (50mL * 1) successively, water (50mL * 3) and saturated sodium-chloride water solution (50mL * 1) washing.Tell organic layer, spend the night with anhydrous sodium sulfate drying.Filter, concentrating under reduced pressure obtains the oily crude product.With the mixtures of eluents flushing of sherwood oil and ethyl acetate, rapid column chromatography (silicagel column) obtains corresponding product β-carbonylic phosphonic acid ester (faint yellow oily thing 9.9g, productive rate 70%) at last.
1H?NMR(CDCl
3,600MHz,ppm):δ8.01(d,J=7.7Hz,2H),7.57(t,J=7.3Hz,1H),7.47(t,J=7.7Hz,2H),4.75-4.70(m,2H),3.59(d,J=23.1Hz,2H),1.27(t,J=5.1Hz,12H);
13C?NMR(CDCl
3,150MHz,ppm):δ192.1,136.8,133.5,129.1,128.5,71.5(d,J
CP=6.8Hz),39.8(d,J
CP=130.0Hz),23.9,23.7;
31P?NMR(CDCl
3,121MHz):δ18.26;HRMS?calc.for?C
14H
21O
4NaP(M+Na)
+,307.1075;found,307.1068.
Embodiment 21
Do not use FeBr
3And CuBr
2, only use CuCl
2(0.18g, 1.3mmol, 2.5mol%) as catalyzer, all the other are all identical with embodiment 20, carry out operation, obtain the product identical with embodiment 20, and yield is 43%.
Embodiment 22
Use ZnBr
2Replace FeBr
3, all the other are all identical with embodiment 2, carry out operation, obtain the product identical with embodiment 2, and yield is 41%.
Embodiment 23
Use AlBr
3Replace FeBr
3, all the other are all identical with embodiment 2, carry out operation, obtain the product identical with embodiment 2, and yield is 50%.
Embodiment 24
Use BiBr
3Replace FeBr
3, all the other are all identical with embodiment 2, carry out operation, obtain the product identical with embodiment 2, and yield is 60%.
Embodiment 25
Do not use FeBr
3, only use CuBr
2(0.28g, 1.3mmol, 2.5mol%) as catalyzer, all the other are all identical with embodiment 2, carry out operation, obtain the product identical with embodiment 2, and yield is 44%.
Embodiment 26
Do not use FeBr
3, only use CuBr
2(2.24g, 10.4mmol, 20mol%) as catalyzer, all the other are all identical with embodiment 2, carry out operation, obtain the product identical with embodiment 2, and yield is 32%.
Embodiment 27
Do not use alkali Et
3N, all the other are all identical with embodiment 2, carry out operation, and the result has not detected product and has generated.
Claims (17)
1. β-carbonylic phosphonic acid ester cpds shown in the general formula (III)
R wherein
1Be aryl, aralkyl, alkyl, cycloalkyl, virtue amino, alkylamino, alkoxyl group; R
2Be hydrogen atom, aryl, aralkyl, alkyl, cycloalkyl; R
3Be aryl, aralkyl, alkyl, cycloalkyl.
According to claim 1 described in the preparation method of β-carbonylic phosphonic acid ester, it is characterized in that, described preparation method is as follows:
Take simple commercial alkene, hydrogen-phosphorous acid ester and oxygen as starting raw material, step is as follows:
Hydrogen-phosphorous acid ester of the alkene of general formula I and general formula I I carries out the phosphine oxide reaction under metal catalyst, alkali and oxygen, obtain the β of general formula III-carbonylic phosphonic acid ester cpds; R wherein
1Be aryl, aralkyl, alkyl, cycloalkyl, virtue amino, alkylamino, alkoxyl group; R
2Be hydrogen atom, aryl, aralkyl, alkyl, cycloalkyl; R
3Be aryl, aralkyl, alkyl, cycloalkyl;
Work as R
1During for aryl, R
1Can be and replace or unsubstituted aryl, aryl comprises monokaryon aromatic hydrocarbon group such as phenyl, or multinuclear aromatic yl group such as naphthyl, green onion base, phenanthryl etc., and monokaryon and multinuclear aryl can replace in one or more positions; Work as R
1During for the monokaryon aryl that replaces, preferred substituting group is lower paraffin hydrocarbons, halogen, lower alkoxy, nitro, cyano group, ethanoyl, ester group, the carbalkoxy that contains 1-6 carbon atom;
Described aryl can contain heteroatoms, and wherein heteroatoms is selected from nitrogen, oxygen or sulphur, and these heteroaryls can be unsubstituted or be replaced by above-mentioned substituting group;
Work as R
1During for the monokaryon heteroaryl, R
1Be pyridyl, furyl, pyrryl, imidazolyl, thiazolyl, thiotolene base etc.;
Preferred multinuclear aryl comprises xenyl, naphthyl, pyrryl, benzothienyl, benzofuryl, indyl, quinolyl, pyrazinyl, methylpyrrole base, imidazolyl, pyrazolyl, pyridyl etc.;
Work as R
1During for aralkyl, aralkyl represents aromatic yl elementary alkyl, wherein aryl as defined above, and low alkyl group contains 1-6 carbon atom; Described aryl can be unsubstituted or replacement, and preferred unsubstituted aralkyl is benzyl; The aralkyl that replaces comprises methoxy-benzyl, methyl-benzyl, fluoro benzyl, chloro benzyl, nitrobenzyl, styroyl, picolyl etc.;
Work as R
1During for alkyl, R
1For having the straight or branched alkyl of 1-22 carbon atom, preferred alkyl is to contain the low alkyl group of 1-8 carbon atom such as ethyl, propyl group, sec.-propyl, butyl, n-pentyl, isopentyl, hexyl, heptyl, octyl group etc.;
Work as R
1During for cycloalkyl, R
1Be cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or the diamantane etc. with 3-12 carbon atom;
Work as R
1During for virtue amino, aryl definition wherein is the same;
Work as R
1Be alkylamino, alkyl definition wherein is the same;
Work as R
1Be alkoxyl group, alkyl definition wherein is the same;
R
2In aryl, aralkyl, alkyl, the same R of definition of cycloalkyl
1
R
3In aryl, aralkyl, alkyl, the same R of definition of cycloalkyl
1
3. the preparation method of described β-carbonylic phosphonic acid ester cpds according to claim 2, it is characterized in that, in aforesaid method: the phosphine oxide reaction of synthetic β-carbonylic phosphonic acid ester can be at methylene dichloride, chloroform, 1, the 2-ethylene dichloride, tetrahydrofuran (THF), 1, the 4-dioxane, 1, the 2-glycol dimethyl ether, acetonitrile, ethyl acetate, toluene, benzene, methyl-sulphoxide, N, carry out in the non-protonic solvents such as dinethylformamide, also can methyl alcohol, ethanol, propyl alcohol, Virahol, carry out in the protic solvents such as water, also can carry out in above-mentioned two or more mixed solvent, the preferred reaction solvent is: methyl-sulphoxide.
4. the preparation method of described β-carbonylic phosphonic acid ester cpds according to claim 2, it is characterized in that, described metal catalyst can be cupric bromide, cupric chloride, cuprous bromide, cuprous chloride, cuprous iodide, four cyano phosphofluoric acid ketone, copper trifluoromethanesulfcomposite, ferric bromide, iron trichloride, ferrous bromide, iron protochloride, tribromide ruthenium, palladium, Palladous chloride, gold tribromide, platinum dichloride, indium tribromide etc.; Also above-mentioned two or more mixed metal catalyst, preferred catalyst is cupric bromide and ferric bromide or cupric chloride and iron trichloride combination.
5. the preparation method of described β-carbonylic phosphonic acid ester cpds according to claim 2, it is characterized in that, the used alkali of this phosphine oxide reaction is triethylamine, Trimethylamine 99, pyridine, diethylamine, diisopropyl ethyl amine, N, N, N, N-Tetramethyl Ethylene Diamine, 1.8-diazabicylo (5.4.0) hendecene-7(DBU), 1, the organic basess such as 5-diaza-bicyclo [5.3.0]-5-nonene (DBN), Isosorbide-5-Nitrae-diaza-bicyclo [2.2.2] octane (DABCO); Also can be the mineral alkalis such as yellow soda ash, salt of wormwood, cesium carbonate, sodium bicarbonate, potassiumphosphate, preferred bases is triethylamine.
6. the preparation method of described β-carbonylic phosphonic acid ester cpds according to claim 2 is characterized in that, temperature of reaction is generally 0 ℃～100 ℃, preferred 25 ℃～60 ℃; The mol ratio of alkene and hydrogen-phosphorous acid ester is 1:1～1:8, and preferred 1:1～1:2.
7. the preparation method of described β-carbonylic phosphonic acid ester cpds according to claim 2 is characterized in that, reaction can be reacted in purity oxygen, also can react in air, preferably reacts in purity oxygen.
8. the preparation method of described β-carbonylic phosphonic acid ester cpds according to claim 2 is characterized in that, take alkene, hydrogen-phosphorous acid ester and oxygen or air as starting raw material, in the presence of metal catalyst and alkali, carries out following reaction:
Wherein, work as R
1During for aryl, R
1Can be and replace or unsubstituted aryl, aryl comprises monokaryon aromatic hydrocarbon group such as phenyl, or multinuclear aromatic yl group such as naphthyl, green onion base, phenanthryl etc., and monokaryon and multinuclear aryl can replace in one or more positions; Work as R
1During for the monokaryon aryl that replaces, preferred substituting group is lower paraffin hydrocarbons, halogen, lower alkoxy, nitro, cyano group, acetoxyl group, ester group, the carbalkoxy that contains 1-6 carbon atom;
Described aryl can contain heteroatoms, and wherein heteroatoms is selected from nitrogen, oxygen or sulphur, and these heteroaryls can be unsubstituted or be replaced by above-mentioned substituting group;
Work as R
1During for the monokaryon heteroaryl, R
1Be pyridyl, furyl, pyrryl, imidazolyl, thiazolyl, thiotolene base etc.;
Preferred multinuclear aryl comprises xenyl, naphthyl, pyrryl, benzothienyl, benzofuryl, indyl, quinolyl, pyrazinyl, methylpyrrole base, imidazolyl, pyrazolyl, pyridyl etc.;
Work as R
1During for aralkyl, aralkyl represents aromatic yl elementary alkyl, wherein aryl as defined above, and low alkyl group contains 1-6 carbon atom; Described aryl can be unsubstituted or replacement, and preferred unsubstituted aralkyl is benzyl; The aralkyl that replaces comprises methoxy-benzyl, methyl-benzyl, fluoro benzyl, chloro benzyl, nitrobenzyl, styroyl, picolyl etc.;
Work as R
1During for alkyl, R
1For having the straight or branched alkyl of 1-22 carbon atom, preferred alkyl is to contain the low alkyl group of 1-8 carbon atom such as ethyl, propyl group, sec.-propyl, butyl, n-pentyl, isopentyl, hexyl, heptyl, octyl group etc.;
Work as R
1During for cycloalkyl, R
1Be cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or the diamantane etc. with 3-12 carbon atom;
Work as R
1During for virtue amino, aryl definition wherein is the same;
Work as R
1Be alkylamino, alkyl definition wherein is the same;
Work as R
1Be alkoxyl group, alkyl definition wherein is the same;
R
2In aryl, aralkyl, alkyl, the same R of definition of cycloalkyl
1
R
3In aryl, aralkyl, alkyl, the same R of definition of cycloalkyl
1;
Described metal catalyst is one or both or the two or more combination that is selected from the following substances group: cupric bromide, cupric chloride, cuprous bromide, cuprous chloride, cuprous iodide, four cyano phosphofluoric acid ketone, copper trifluoromethanesulfcomposite, ferric bromide, iron trichloride, ferrous bromide, iron protochloride, tribromide ruthenium, palladium, Palladous chloride, gold tribromide, platinum dichloride, indium tribromide; Described catalyzer is preferably the combination of cupric bromide and ferric bromide or the combination of cupric chloride and iron trichloride;
Described alkali is organic bases or mineral alkali.
9. the preparation method of described β-carbonylic phosphonic acid ester cpds according to claim 8 is characterized in that, temperature of reaction is generally 0 ℃～100 ℃, preferred 25 ℃～60 ℃; The mol ratio of alkene and hydrogen-phosphorous acid ester is 1:1～1:8, and preferred 1:1～1:2.
10. according to claim 8 or the preparation method of 9 described β-carbonylic phosphonic acid ester cpds; it is characterized in that, in aforesaid method: the phosphine oxide acylation reaction of synthetic β-carbonylic phosphonic acid ester is carried out in non-protonic solvent or protic solvent or two or more non-protonic solvent and/or protic solvent.
11. the preparation method of each described β-carbonylic phosphonic acid ester cpds according to claim 8-10, it is characterized in that, in aforesaid method: the phosphine oxide acylation reaction of synthetic β-carbonylic phosphonic acid ester is being selected from methylene dichloride, chloroform, 1,2-ethylene dichloride, tetrahydrofuran (THF), 1,4-dioxane, 1, carry out in the non-protonic solvent of 2-glycol dimethyl ether, acetonitrile, ethyl acetate, toluene, benzene, methyl-sulphoxide, DMF; Perhaps in the protic solvent that is selected from methyl alcohol, ethanol, propyl alcohol, Virahol, water, carry out; Perhaps be selected from two or more the mixed solvent of above-mentioned non-protonic solvent and protic solvent and carry out.
12. the preparation method of each described β-carbonylic phosphonic acid ester cpds is characterized in that R according to claim 8-11
1For replacing or unsubstituted following radicals: monokaryon aryl, multinuclear aryl or heteroaryl or virtue amino, alkyl, cycloalkyl, work as R
1During for the above-mentioned group that replaces, substituting group is lower paraffin hydrocarbons, halogen, lower alkoxy, cyano group, acetoxyl group, the ester group that contains 1-6 carbon atom;
R
2Be hydrogen atom, aryl, aralkyl, alkyl, cycloalkyl;
R
3For having the straight or branched alkyl of 1-22 carbon atom, preferred alkyl is the low alkyl group that contains 1-8 carbon atom, preferred ethyl, propyl group, sec.-propyl, butyl, n-pentyl, isopentyl, hexyl, heptyl, octyl group.
13. the preparation method of each described β-carbonylic phosphonic acid ester cpds according to claim 8-12, it is characterized in that, described alkali is selected from triethylamine, Trimethylamine 99, pyridine, diethylamine, diisopropyl ethyl amine, N, N, N, N-Tetramethyl Ethylene Diamine, 1.8-diazabicylo (5.4.0) hendecene-7(DBU), 1,5-diaza-bicyclo [5.3.0]-5-nonene (DBN), 1, the organic bases of 4-diaza-bicyclo [2.2.2] octane (DABCO) perhaps is selected from the mineral alkali of yellow soda ash, salt of wormwood, cesium carbonate, sodium bicarbonate, potassiumphosphate; Described alkali is preferably triethylamine.
14. the preparation method of each described β-carbonylic phosphonic acid ester cpds is characterized in that R according to claim 8-13
1Be to replace or unsubstituted following radicals: the straight or branched alkyl (preferably alkyl is the low alkyl group that contains 1-8 carbon atom, more preferably ethyl, propyl group, sec.-propyl, butyl, n-pentyl, isopentyl, hexyl, heptyl, octyl group) that phenyl, naphthyl or pyridyl or virtue be amino, have 1-22 carbon atom, have the cycloalkyl of 3-12 carbon atom; Work as R
1During for the above-mentioned group that replaces, substituting group is lower paraffin hydrocarbons, halogen, lower alkoxy, cyano group, acetoxyl group, the ester group that contains 1-6 carbon atom;
R
2Be hydrogen atom, alkyl or aralkyl;
R
3For having the straight or branched alkyl of 1-22 carbon atom, preferred alkyl is the low alkyl group that contains 1-8 carbon atom, preferred ethyl, propyl group, sec.-propyl, butyl, n-pentyl, isopentyl, hexyl, heptyl, octyl group.
15. the preparation method of described β-carbonylic phosphonic acid ester cpds is characterized in that R according to claim 14
1For replacing or unsubstituted following radicals: phenyl, naphthyl or pyridyl or virtue are amino, R
2Be hydrogen atom, alkyl (being preferably alkyl, more preferably hydrogen atom), R
3Be ethyl, propyl group, sec.-propyl or butyl.
16. the preparation method of described β-carbonylic phosphonic acid ester cpds is characterized in that according to claim 15, described catalyzer is the combination of cupric bromide and ferric bromide or the combination of cupric chloride and iron trichloride; Described alkali is triethylamine.
17. the preparation method of described β-carbonylic phosphonic acid ester cpds according to claim 16, described solvent is methyl-sulphoxide.
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| CN104341449A (en) * | 2014-09-30 | 2015-02-11 | 苏州大学 | Method for preparing beta-carbonyl phosphonate derivatives |
| CN104370960A (en) * | 2014-09-30 | 2015-02-25 | 苏州大学 | Preparation method of beta-hydroxyphosphonate derivatives |
| CN104497044A (en) * | 2014-12-11 | 2015-04-08 | 华侨大学 | Method for efficiently preparing beta-carboxyl phosphate |
| CN105330690A (en) * | 2015-10-19 | 2016-02-17 | 赵丽娜 | Synthetic method of drug intermediate aryl ketone phosphate ester compound |
| CN106279274A (en) * | 2016-08-01 | 2017-01-04 | 河南省科学院化学研究所有限公司 | A kind of preparation method by alkene synthesis β carbonylic phosphonic acid ester derivant |
| CN107522741A (en) * | 2017-09-04 | 2017-12-29 | 信阳师范学院 | A kind of new synthetic method of phosphate compounds |
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| CN104341449A (en) * | 2014-09-30 | 2015-02-11 | 苏州大学 | Method for preparing beta-carbonyl phosphonate derivatives |
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| CN104497044A (en) * | 2014-12-11 | 2015-04-08 | 华侨大学 | Method for efficiently preparing beta-carboxyl phosphate |
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| CN107522741A (en) * | 2017-09-04 | 2017-12-29 | 信阳师范学院 | A kind of new synthetic method of phosphate compounds |
| CN107522741B (en) * | 2017-09-04 | 2019-05-24 | 信阳师范学院 | A kind of synthetic method of phosphate compounds |
| CN112375099A (en) * | 2020-12-07 | 2021-02-19 | 西南大学 | Quaternary carbon phosphonate and preparation method thereof |
| CN113773345A (en) * | 2021-10-07 | 2021-12-10 | 湖南科技学院 | Method for preparing beta-carbonyl phosphonate compound |
| CN113773345B (en) * | 2021-10-07 | 2024-05-03 | 湖南科技学院 | Method for preparing beta-carbonyl phosphonate compound |
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