CN103204833A - Preparation method of fully-substituted tetrahydrofuran derivative - Google Patents
Preparation method of fully-substituted tetrahydrofuran derivative Download PDFInfo
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- CN103204833A CN103204833A CN201310098499XA CN201310098499A CN103204833A CN 103204833 A CN103204833 A CN 103204833A CN 201310098499X A CN201310098499X A CN 201310098499XA CN 201310098499 A CN201310098499 A CN 201310098499A CN 103204833 A CN103204833 A CN 103204833A
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D307/18—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
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Abstract
The invention relates to a preparation method of fully-substituted tetrahydrofuran derivative. The fully-substituted tetrahydrofuran derivative is synthetized by the action of aryldiazoacetate, aldehyde and dipolarophile under the catalysis of rhodium acetate. The materials for the preparation method are easy to obtain. Four chiral carbons are simultaneously established by one-pot process. A preparation route is short. The operation is simple. Reaction conditions are mild. The preparation method has the advantages of high atomic economy, high yield, and no environment pollution, is convenient for the preparation of the fully-substituted tetrahydrofuran derivative to provide diversified compound frameworks, and is of great significance to screening of new drugs and pharmaceutical preparation techniques.
Description
Technical field
The invention belongs to medicine synthesising chemical technology field, relate to a kind of preparation method of full substituted tetrahydrofuran derivative.
Background technology
Tetrahydrofuran derivatives is the important skeleton structure that a class has special medicinal compound, also often is found to be present in the synthetic of bioactive natural product.Hybocarpone (J.Am.Chem.Soc.2004,126,607) for example, Monensin A (Chem.Rev.2003,103,2921), Phyllanthocin (J.Am.Chem.Soc.2005,127,11958) etc.Therefore, the new synthetic method of development has great importance for the substituted tetrahydrofuran derivative.
1 of carbonyl ylide participation, the 3-Dipolar Cycloaddition is widely used in the structure of tetrahydrofuran (THF).2004, professor Nair found diester malonate diazonium, and the carbonyl ylide that aromatic aldehyde forms under the catalysis of acetic acid rhodium can be caught by trans nitro alkene, thus the tetrahydrofuran (THF) that is replaced entirely.(J.Org.Chem.2004，69，1413.)。2009, professor Fox proved that too alpha-alkyl ester diazonium equally above-mentioned similar reaction can take place and obtain good stereoselectivity (J.Am.Chem.Soc.2009,131,1101.).
The shortcoming of prior art is that the diazonium compound instrument that reacts is limited to diester malonate diazonium or alpha-alkyl ester diazonium, and simultaneously aldehyde and dipole body also have certain limitation, and this is for the diversity of compound and further to derive be disadvantageous.
Summary of the invention
The present invention overcomes the above-mentioned deficiency of prior art, has proposed a kind of preparation method of full substituted tetrahydrofuran derivative.The present invention can form the carbonyl ylide by aryl acetate diazonium and phenylacrolein or aromatic aldehyde under the catalysis of acetic acid rhodium, take place 1 with dipolarophile body such as trans nitro alkene again, the 3-Dipolar Cycloaddition, form new full substituted tetrahydrofuran derivative preparation method, thereby multifarious compound skeleton is provided, new medicament screen and pharmaceutical technology are had very important significance.
The present invention proposes a kind of preparation method suc as formula the full substituted tetrahydrofuran derivative shown in (I), it is characterized in that, aryl acetate diazonium, aldehyde and dipolarophile body react synthetic described full substituted tetrahydrofuran derivative under the catalysis of acetic acid rhodium;
In the formula (I), Ar
1For phenyl or have the phenyl of substituted radical; R
1Be phenyl, the phenyl that has substituted radical, phenylacrolein, replacement phenylacrolein; R
2For phenyl or have phenyl, hydrogen, the ester group of substituted radical; R
3Be nitro, ester group;
Described preparation method's reaction formula is:
In the formula (II), Ar
1For phenyl or have the phenyl of substituted radical; R
1Be phenyl, the phenyl that has substituted radical, phenylacrolein, replacement phenylacrolein; R
2For phenyl or have phenyl, hydrogen, the ester group of substituted radical; R
3Be nitro, ester group.
Wherein, the mol ratio of described aryl acetate diazonium, aldehyde, dipolarophile body, acetic acid rhodium is (1.0-2.0): (1.0-2.0): 1.0: (0.01-0.02).
Preferably, the mol ratio of described aryl acetate diazonium, aldehyde, dipolarophile body, acetic acid rhodium is 1.5: 1.3: 1.0: 0.01.
Wherein, described aryl acetate diazonium is the benzene diazonium methyl acetate, a bromophenyl diazoacetic acid methyl esters, and to bromophenyl diazoacetic acid methyl esters, rubigan diazoacetic acid methyl esters, p-methoxyphenyl diazoacetic acid methyl esters, p-methylphenyl diazoacetic acid methyl esters.
Wherein, described aldehyde is phenyl aldehyde, p-bromobenzaldehyde, phenylacrolein, p-methoxyphenyl phenylacrolein, 2-furyl phenylacrolein.
Wherein, described dipolarophile body is trans phenyl nitro alkene, trans o-methoxyphenyl nitro alkene, trans bromophenyl nitro alkene, trans o-bromophenyl nitro alkene, trans bromophenyl nitro alkene, trans p-nitrophenyl nitro alkene, trans 2-furyl base nitro alkene, methyl acrylate, ethyl propenoate, trans dimethyl fumarate, dimethyl butyn.
Preparation method of the present invention comprises: add aldehyde, dipolarophile body, acetic acid rhodium, water-retaining agent, organic solvent in reaction flask, wherein, the add-on of organic solvent is 25-30ml/mmol dipolarophile body; The nitranilide ester is dissolved in obtains diazonium solution in the organic solvent, wherein, the amount that is used for the organic solvent of dissolving diazonium is 25-30ml/mmol; By peristaltic pump the diazonium drips of solution is added in the reaction flask under-40 ℃, stirring is spent the night, and revolves to boil off to desolventize to obtain thick product, through column chromatography, obtains suc as formula the full substituted tetrahydrofuran derivative shown in (I).
Among the present invention, described organic solvent is chloroparaffin, toluene or dimethylbenzene.
The invention provides the preparation synthetic method that a kind of raw material is cheap and easy to get, prepare short, simple to operate, the free of contamination full substituted tetrahydrofuran derivative of route.In order to achieve the above object, the inventive method is to use diazonium compound, and aldehyde and dipolarophile body realize that three component reaction synthesize full substituted tetrahydrofuran derivative under the catalysis of acetic acid rhodium.The present invention forms carbonyl ylide with the aldehyde effect by the nitranilide ester earlier under the catalysis of Rh (II), pass through this active intermediate of seizure of dipolarophile body again, thereby constructs the target product substituted tetrahydrofuran derivative compound suc as formula (I).The present invention makes up four synthetic full substituted tetrahydrofuran derivatives of chiral carbon preparation one step simultaneously.
Raw material aromatic aldehyde and the Nitromethane 99Min. of the organic solvent that the present invention is used and preparation nitro alkene (see also J.Am.Chem.Soc.2008,130,2438-2439), diazonium raw material Arylacetic acids methyl esters, triazo-compound, ethyl acetate, ethanol, methyl acrylate, ethyl propenoate, trans dimethyl fumarate; But dimethyl butyn is all buied in market.Toluene is before use through the hydrolith processed, and other organic solvents all make purifying in advance before reaction and during column chromatography or distillation is handled.
The present invention has advantage and beneficial effect comprises: the raw materials used aryl acetate diazonium of the present invention, aldehyde, dipolarophile body and organic solvent are cheap and easy to get, and be synthetic with low cost.Synthetic route of the present invention is simple, a step establishing target product.The present invention has Atom economy, highly selective, and high yields etc. meet the requirement of Green Chemistry.The present invention is synthetic full substituted tetrahydrofuran derivative quickly and easily, is conducive to further derive, thereby multifarious compound skeleton is provided, and new medicament screen and pharmaceutical technology are had extremely important meaning.
Embodiment
In conjunction with following specific embodiments and the drawings, the present invention is described in further detail, and protection content of the present invention is not limited to following examples.Under the spirit and scope that do not deviate from inventive concept, variation and advantage that those skilled in the art can expect all are included in the present invention, and are protection domain with the appending claims.Implement process of the present invention, condition, reagent, experimental technique etc., except the following content of mentioning specially, be universal knowledege and the common practise of this area, the present invention is not particularly limited content.
Preparation method's of the present invention reaction scheme specifically comprises: take by weighing earlier aldehyde in molar ratio: the dipolarophile body: acetic acid rhodium=1.3: 1.0: 0.01, with aldehyde, dipolarophile body, acetic acid rhodium and organic solvent add in the reaction flask, water-retaining agent
Molecular sieve 2-5g/mmol.Wherein, the add-on of organic solvent is 25-30ml/mmol dipolarophile body; Then, aryl acetate diazonium is dissolved in the organic solvent, aryl acetate diazonium add-on is 1.5mmol/mmo dipolarophile body, obtains diazonium solution.Wherein, the amount for the organic solvent that dissolves diazonium is 25-30ml/mmol aryl acetate diazonium.Under-40 ℃, by peristaltic pump the diazonium drips of solution is added in the reaction flask then, dropwised in 1 hour, continue to stir and to spend the night, again temperature of reaction is returned to room temperature gradually, 40 ℃-50 ℃ revolve to boil off and desolventize, and obtain thick product; Be ethyl acetate with thick product volume ratio: sherwood oil=1: 50～solution carried out column chromatography in 1: 10, obtained the pure product of full substituted tetrahydrofuran derivative.
Embodiment 1
Take by weighing trans phenyl nitro alkene (0.20mmol), and the acetic acid rhodium (1.00mg, 0.002mmol), phenylacrolein (0.30mmol),
Molecular sieve (100mg) is put into the small test tube reactor with them, is cooled to-40 ℃ in low-temp reaction is bathed, and adds the 2.0ml methylene dichloride that heavily steams.Take by weighing phenyl diazoacetic acid methyl esters (0.30mmol) and be dissolved in the methylene dichloride that 1.0ml heavily steams, and injected reaction system in 1 hour by peristaltic pump, inject the back that finishes and continue to stir and spend the night, be warming up to room temperature gradually.Filter, filtrate is revolved to boil off in 40 ℃ and is desolventized, again by column chromatography (eluent: sherwood oil: ethyl acetate=1: 50～1: 20) isolate and obtain full substituted tetrahydrofuran derivative A.Yield 75%, dr are 90: 10.
Embodiment 2
Take by weighing trans phenyl nitro alkene (0.20mmol), and the acetic acid rhodium (1.00mg, 0.002mmol), phenylacrolein (0.30mmol),
Molecular sieve (100mg) is put into the small test tube reactor with them, is cooled to-40 ℃ in low-temp reaction is bathed, and adds the 2.0ml methylene dichloride that heavily steams.Take by weighing p-methylphenyl diazoacetic acid methyl esters (0.30mmol) and be dissolved in the methylene dichloride that 1.0ml heavily steams, and injected reaction system in 1 hour by peristaltic pump, inject the back that finishes and continue to stir and spend the night, be warming up to room temperature gradually.Filter, filtrate is revolved to boil off in 40 ℃ and is desolventized, again by column chromatography (eluent: sherwood oil: ethyl acetate=1: 50～1: 20) isolate and obtain full substituted tetrahydrofuran derivative B.Yield 90%, dr was greater than 95: 5.
Embodiment 3
Take by weighing trans phenyl nitro alkene (0.20mmol), and the acetic acid rhodium (1.00mg, 0.002mmol), phenylacrolein (0.30mmol),
Molecular sieve (100mg) is put into the small test tube reactor with them, is cooled to-40 ℃ in low-temp reaction is bathed, and adds the 2.0ml methylene dichloride that heavily steams.Take by weighing bromophenyl diazoacetic acid methyl esters (0.30 mmol) is dissolved in the methylene dichloride that 1.0ml heavily steams, and injected reaction system in 1 hour by peristaltic pump, inject the back that finishes and continue to stir and spend the night, be warming up to room temperature gradually.Filter, filtrate is revolved to boil off in 40 ℃ and is desolventized, again by column chromatography (eluent: sherwood oil: ethyl acetate=1: 50～1: 20) isolate and obtain full substituted tetrahydrofuran derivative C.Yield 71%dr is 93: 7.
Embodiment 4
Take by weighing trans phenyl nitro alkene (0.20mmol), and the acetic acid rhodium (1.00mg, 0.002mmol), phenylacrolein (0.30mmol),
Molecular sieve (100mg) is put into the small test tube reactor with them, is cooled to-40 ℃ in low-temp reaction is bathed, and adds the 2.0ml methylene dichloride that heavily steams.Take by weighing fluorophenyl diazoacetic acid methyl esters (0.30mmol) is dissolved in the methylene dichloride that 1.0ml heavily steams, and injected reaction system in 1 hour by peristaltic pump, inject the back that finishes and continue to stir and spend the night, be warming up to room temperature gradually.Filter, filtrate is revolved to boil off in 40 ℃ and is desolventized, again by column chromatography (eluent: sherwood oil: ethyl acetate=1: 50～1: 20) isolate and obtain full substituted tetrahydrofuran derivative D.Yield 65%, dr was greater than 95: 5.
Embodiment 5
Take by weighing trans phenyl nitro alkene (0.20mmol), and the acetic acid rhodium (1.00mg, 0.002mmol), phenylacrolein (0.30mmol),
Molecular sieve (100mg) is put into the small test tube reactor with them, is cooled to-40 ℃ in low-temp reaction is bathed, and adds the 2.0ml methylene dichloride that heavily steams.Take by weighing rubigan diazoacetic acid methyl esters (0.30mmol) and be dissolved in the methylene dichloride that 1.0ml heavily steams, and injected reaction system in 1 hour by peristaltic pump, inject the back that finishes and continue to stir and spend the night, be warming up to room temperature gradually.Filter, filtrate is revolved to boil off in 40 ℃ and is desolventized, again by column chromatography (eluent: sherwood oil: ethyl acetate=1: 50～1: 20) isolate and obtain full substituted tetrahydrofuran derivative E.Yield 76%, dr was greater than 95: 5.
Embodiment 6
Take by weighing trans o-methoxyphenyl nitro alkene (0.20mmol), and the acetic acid rhodium (1.00mg, 0.002mmol), phenylacrolein (0.30mmol),
Molecular sieve (100mg) is put into the small test tube reactor with them, is cooled to-40 ℃ in low-temp reaction is bathed, and adds the 2.0ml methylene dichloride that heavily steams.Take by weighing phenyl diazoacetic acid methyl esters (0.30mmol) and be dissolved in the methylene dichloride that 1.0ml heavily steams, and injected reaction system in 1 hour by peristaltic pump, inject the back that finishes and continue to stir and spend the night, be warming up to room temperature gradually.Filter, filtrate is revolved to boil off in 40 ℃ and is desolventized, again by column chromatography (eluent: sherwood oil: ethyl acetate=1: 50～1: 20) isolate and obtain full substituted tetrahydrofuran derivative F.Yield 48%, dr was greater than 95: 5.
Embodiment 7
Take by weighing trans chloro nitro alkene (0.20mmol), and the acetic acid rhodium (1.00mg, 0.002mmol), phenylacrolein (0.30mmol),
Molecular sieve (100mg) is put into the small test tube reactor with them, is cooled to-40 ℃ in low-temp reaction is bathed, and adds the 2.0ml methylene dichloride that heavily steams.Take by weighing phenyl diazoacetic acid methyl esters (0.30mmol) and be dissolved in the methylene dichloride that 1.0ml heavily steams, and injected reaction system in 1 hour by peristaltic pump, inject the back that finishes and continue to stir and spend the night, be warming up to room temperature gradually.Filter, filtrate is revolved to boil off in 40 ℃ and is desolventized, again by column chromatography (eluent: sherwood oil: ethyl acetate=1: 50～1: 20) isolate and obtain full substituted tetrahydrofuran derivative G.Yield 70%, dr was greater than 95: 5.。
Embodiment 8
Take by weighing trans o-bromophenyl nitro alkene (0.20mmol), and the acetic acid rhodium (1.00mg, 0.002mmol), phenylacrolein (0.30mmol),
Molecular sieve (100mg) is put into the small test tube reactor with them, is cooled to-40 ℃ in low-temp reaction is bathed, and adds the 2.0ml methylene dichloride that heavily steams.Take by weighing phenyl diazoacetic acid methyl esters (0.30mmol) and be dissolved in the methylene dichloride that 1.0ml heavily steams, and injected reaction system in 1 hour by peristaltic pump, inject the back that finishes and continue to stir and spend the night, be warming up to room temperature gradually.Filter, filtrate is revolved to boil off in 40 ℃ and is desolventized, again by column chromatography (eluent: sherwood oil: ethyl acetate=1: 50～1: 20) isolate and obtain full substituted tetrahydrofuran derivative H.Yield 43%, dr are 83: 17.。
Embodiment 9
Take by weighing trans to bromophenyl nitro alkene (0.20mmol), the acetic acid rhodium (1.00mg, 0.002mmol), phenylacrolein (0.30mmol),
Molecular sieve (100mg) is put into the small test tube reactor with them, is cooled to-40 ℃ in low-temp reaction is bathed, and adds the 2.0ml methylene dichloride that heavily steams.Take by weighing phenyl diazoacetic acid methyl esters (0.30mmol) and be dissolved in the methylene dichloride that 1.0ml heavily steams, and injected reaction system in 1 hour by peristaltic pump, inject the back that finishes and continue to stir and spend the night, be warming up to room temperature gradually.Filter, filtrate is revolved to boil off in 40 ℃ and is desolventized, again by column chromatography (eluent: sherwood oil: ethyl acetate=1: 50～1: 20) isolate and obtain full substituted tetrahydrofuran derivative I.Yield 58%, dr are 88: 12.
Embodiment 10
Take by weighing trans p-nitrophenyl nitro alkene (0.20mmol), and the acetic acid rhodium (1.00mg, 0.002mmol), p-methoxyphenyl phenylacrolein (0.30mmol),
Molecular sieve (100mg) is put into the small test tube reactor with them, is cooled to-40 ℃ in low-temp reaction is bathed, and adds the 2.0ml methylene dichloride that heavily steams.Take by weighing phenyl diazoacetic acid methyl esters (0.30mmol) and be dissolved in the methylene dichloride that 1.0ml heavily steams, and injected reaction system in 1 hour by peristaltic pump, inject the back that finishes and continue to stir and spend the night, be warming up to room temperature gradually.Filter, filtrate is revolved to boil off in 40 ℃ and is desolventized, again by column chromatography (eluent: sherwood oil: ethyl acetate=1: 50～1: 20) isolate and obtain full substituted tetrahydrofuran derivative J.Yield 45%, dr was greater than 95: 5.
Embodiment 11
Take by weighing trans 2-furans nitro alkene (0.20mmol), and the acetic acid rhodium (1.00mg, 0.002mmol), phenylacrolein (0.30mmol),
Molecular sieve (100mg) is put into the small test tube reactor with them, is cooled to-40 ℃ in low-temp reaction is bathed, and adds the 2.0ml methylene dichloride that heavily steams.Take by weighing phenyl diazoacetic acid methyl esters (0.30mmol) and be dissolved in the methylene dichloride that 1.0ml heavily steams, and injected reaction system in 1 hour by peristaltic pump, inject the back that finishes and continue to stir and spend the night, be warming up to room temperature gradually.Filter, filtrate is revolved to boil off in 40 ℃ and is desolventized, again by column chromatography (eluent: sherwood oil: ethyl acetate=1: 50～1: 20) isolate and obtain full substituted tetrahydrofuran derivative K.Yield 71%, dr are 92: 8.
Embodiment 12
Take by weighing trans phenyl nitro alkene (0.20mmol), and the acetic acid rhodium (1.00mg, 0.002mmol), 2-furyl phenylacrolein (0.30mmol),
Molecular sieve (100mg) is put into the small test tube reactor with them, is cooled to-40 ℃ in low-temp reaction is bathed, and adds the 2.0ml methylene dichloride that heavily steams.Take by weighing phenyl diazoacetic acid methyl esters (0.30mmol) and be dissolved in the methylene dichloride that 1.0ml heavily steams, and injected reaction system in 1 hour by peristaltic pump, inject the back that finishes and continue to stir and spend the night, be warming up to room temperature gradually.Filter, filtrate is revolved to boil off in 40 ℃ and is desolventized, again by column chromatography (eluent: sherwood oil: ethyl acetate=1: 50～1: 20) isolate and obtain full substituted tetrahydrofuran derivative L.Yield 40%, dr are 93: 7.
Embodiment 13
Take by weighing trans phenyl nitro alkene (0.20mmol), and the acetic acid rhodium (1.00mg, 0.002mmol), p-methoxyphenyl phenylacrolein (0.30mmol),
Molecular sieve (100mg) is put into the small test tube reactor with them, is cooled to-40 ℃ in low-temp reaction is bathed, and adds the 2.0ml methylene dichloride that heavily steams.Take by weighing phenyl diazoacetic acid methyl esters (0.30mmol) and be dissolved in the methylene dichloride that 1.0ml heavily steams, and injected reaction system in 1 hour by peristaltic pump, inject the back that finishes and continue to stir and spend the night, be warming up to room temperature gradually.Filter, filtrate is revolved to boil off in 40 ℃ and is desolventized, again by column chromatography (eluent: sherwood oil: ethyl acetate=1: 50～1: 20) isolate and obtain full substituted tetrahydrofuran derivative M.Yield 45%, dr was greater than 95: 5.
Embodiment 14
Take by weighing trans phenyl nitro alkene (0.20mmol), and the acetic acid rhodium (1.00mg, 0.002mmol), p-bromobenzaldehyde (0.30mmol),
Molecular sieve (100mg) is put into the small test tube reactor with them, is cooled to-40 ℃ in low-temp reaction is bathed, and adds the 2.0ml methylene dichloride that heavily steams.Take by weighing phenyl diazoacetic acid methyl esters (0.30mmol) and be dissolved in the methylene dichloride that 1.0ml heavily steams, and injected reaction system in 1 hour by peristaltic pump, inject the back that finishes and continue to stir and spend the night, be warming up to room temperature gradually.Filter, filtrate is revolved to boil off in 40 ℃ and is desolventized, again by column chromatography (eluent: sherwood oil: ethyl acetate=1: 50～1: 20) isolate and obtain full substituted tetrahydrofuran derivative N.Yield 65%, dr was greater than 95: 5.
Embodiment 15
Take by weighing methyl acrylate (0.20mmol), and the acetic acid rhodium (1.00mg, 0.002mmol), phenylacrolein (0.30mmol),
Molecular sieve (100mg) is put into the small test tube reactor with them, is cooled to-40 ℃ in low-temp reaction is bathed, and adds the 2.0ml methylene dichloride that heavily steams.Take by weighing phenyl diazoacetic acid methyl esters (0.30mmol) and be dissolved in the methylene dichloride that 1.0ml heavily steams, and injected reaction system in 1 hour by peristaltic pump, inject the back that finishes and continue to stir and spend the night, be warming up to room temperature gradually.Filter, filtrate is revolved to boil off in 40 ℃ and is desolventized, again by column chromatography (eluent: sherwood oil: ethyl acetate=1: 50～1: 20) isolate and obtain full substituted tetrahydrofuran derivative O.Yield 70%, dr are 90: 10.
Embodiment 16
Take by weighing trans dimethyl fumarate (0.20mmol), and the acetic acid rhodium (1.00mg, 0.002mmol), phenylacrolein (0.30mmol),
Molecular sieve (100mg) is put into the small test tube reactor with them, is cooled to-40 ℃ in low-temp reaction is bathed, and adds the 2.0ml methylene dichloride that heavily steams.Take by weighing phenyl diazoacetic acid methyl esters (0.30mmol) and be dissolved in the methylene dichloride that 1.0ml heavily steams, and injected reaction system in 1 hour by peristaltic pump, inject the back that finishes and continue to stir and spend the night, be warming up to room temperature gradually.Filter, filtrate is revolved to boil off in 40 ℃ and is desolventized, again by column chromatography (eluent: sherwood oil: ethyl acetate=1: 50～1: 20) isolate and obtain full substituted tetrahydrofuran derivative P.Yield 92%, dr are 50: 50.
Embodiment 17
Take by weighing dimethyl butyn (0.20mmol), and the acetic acid rhodium (1.00mg, 0.002mmol), phenylacrolein (0.30mmol),
Molecular sieve (100mg) is put into the small test tube reactor with them, is cooled to-40 ℃ in low-temp reaction is bathed, and adds the 2.0ml methylene dichloride that heavily steams.Take by weighing phenyl diazoacetic acid methyl esters (0.30mmol) and be dissolved in the methylene dichloride that 1.0ml heavily steams, and injected reaction system in 1 hour by peristaltic pump, inject the back that finishes and continue to stir and spend the night, be warming up to room temperature gradually.Filter, filtrate is revolved to boil off in 40 ℃ and is desolventized, again by column chromatography (eluent: sherwood oil: ethyl acetate=1: 50～1: 20) isolate and obtain full substituted tetrahydrofuran derivative Q.Yield 81%, dr was greater than 95: 5.
。
Claims (7)
1. the preparation method suc as formula the full substituted tetrahydrofuran derivative shown in (I) is characterized in that, aryl acetate diazonium, aldehyde and dipolarophile body react synthetic described full substituted tetrahydrofuran derivative under the catalysis of acetic acid rhodium;
In the formula (I), Ar
1For phenyl or have the phenyl of substituted radical; R
1Be phenyl, the phenyl that has substituted radical, phenylacrolein, replacement phenylacrolein; R
2For phenyl or have phenyl, hydrogen, the ester group of substituted radical; R
3Be nitro, ester group; Described preparation method's reaction formula is:
In the formula (II), Ar
1For phenyl or have the phenyl of substituted radical; R
1Be phenyl, the phenyl that has substituted radical, phenylacrolein, replacement phenylacrolein; R
2For phenyl or have phenyl, hydrogen, the ester group of substituted radical; R
3Be nitro, ester group.
2. preparation method as claimed in claim 1 is characterized in that, the mol ratio of described aryl acetate diazonium, aldehyde, dipolarophile body, acetic acid rhodium is (1.0-2.0): (1.0-2.0): 1.0: (0.01-0.02).
3. preparation method as claimed in claim 1, it is characterized in that, described aryl acetate diazonium is the benzene diazonium methyl acetate, between bromophenyl diazoacetic acid methyl esters, to bromophenyl diazoacetic acid methyl esters, rubigan diazoacetic acid methyl esters, p-methoxyphenyl diazoacetic acid methyl esters, p-methylphenyl diazoacetic acid methyl esters.
4. preparation method as claimed in claim 1 is characterized in that, described aldehyde is phenyl aldehyde, p-bromobenzaldehyde, phenylacrolein, p-methoxyphenyl phenylacrolein, 2-furyl phenylacrolein.
5. preparation method as claimed in claim 1 is characterized in that, described dipolarophile body is trans phenyl nitro alkene, trans o-methoxyphenyl nitro alkene, trans bromophenyl nitro alkene, trans o-bromophenyl nitro alkene, trans bromophenyl nitro alkene, trans p-nitrophenyl nitro alkene, trans 2-furyl base nitro alkene, methyl acrylate, ethyl propenoate, trans dimethyl fumarate, dimethyl butyn.
6. preparation method as claimed in claim 1 is characterized in that, step comprises: add aldehyde, dipolarophile body, acetic acid rhodium, water-retaining agent, organic solvent in reaction flask, wherein, the add-on of organic solvent is 25-30ml/mmol dipolarophile body; Aryl acetate diazonium is dissolved in obtains diazonium solution in the organic solvent, wherein, the amount that is used for the organic solvent of dissolving aryl acetate diazonium is 25-30ml/mmol; By peristaltic pump the diazonium drips of solution is added in the reaction flask under-40 ℃, stirring is spent the night, and revolves to boil off to desolventize to obtain thick product, through column chromatography, obtains suc as formula the full substituted tetrahydrofuran derivative shown in (I).
7. preparation method as claimed in claim 6 is characterized in that, described organic solvent is chloroparaffin, toluene or dimethylbenzene.
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