CN104250236A - Synthetic method of gamma-alkyl oxyacyl methyl-gamma-butyrolactone and delta- alkyl oxyacyl methyl-delta-valerolactone - Google Patents
Synthetic method of gamma-alkyl oxyacyl methyl-gamma-butyrolactone and delta- alkyl oxyacyl methyl-delta-valerolactone Download PDFInfo
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- CN104250236A CN104250236A CN201410332641.7A CN201410332641A CN104250236A CN 104250236 A CN104250236 A CN 104250236A CN 201410332641 A CN201410332641 A CN 201410332641A CN 104250236 A CN104250236 A CN 104250236A
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- sulfonylmethyl
- unsaturated carboxylic
- beta
- alkyl
- carboxylic acid
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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
- C07D307/26—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
- C07D307/32—Oxygen atoms
- C07D307/33—Oxygen atoms in position 2, the oxygen atom being in its keto or unsubstituted enol form
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/16—Heterocyclic compounds containing six-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
- C07D309/28—Heterocyclic compounds containing six-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
- C07D309/30—Oxygen atoms, e.g. delta-lactones
Abstract
The invention belongs to the field of chemical technology, and in particular to a synthetic method of gamma-alkyl oxyacyl methyl-gamma-butyrolactone and delta- alkyl oxyacyl methyl-delta-valerolactone. CuH compound as a reducing agent reacts with keto ester, alpha, beta-unsaturated carboxylic ester; keto ester, alpha,beta-unsaturated carboxylic ester, a silicon hydride or boron hydride react with each other with CuH compound as the catalyst; and other copper compound, phosphine ligand, silicon hydride or boron hydride react with each other to generate a catalyst, which directly catalyses silicon hydride or boron hydrogen to react with keto ester, alpha,beta-unsaturated carboxylic ester. The synthesis reaction is carried out through the above three methods. reaction of this three method of The method of the invention uses cascade reaction for synthesis, three steps of reaction are carried out continuously in the same reaction vessel; separation of intermediates is not required, so as to avoid the separation process and the resulting loss; and the method has simple operation, improved reaction efficiency, and good application value.
Description
Technical field
The invention belongs to chemical technology field, be specifically related to one
γ-hydrocarbon oxygen sulfonylmethyl
-the synthetic method of gamma-butyrolactone, δ-hydrocarbon oxygen sulfonylmethyl-δ-valerolactone.
Background technology
Gamma-butyrolactone and δ-valerolactone compound are important organic synthesis intermediate and biologically active substance.From endophyte of plant
pestalotiopsis photiniaemiddle separation obtains gamma-butyrolactone material
1with
2, to breast carcinoma cell strain MDA-MB-231 strain inhibited (Ding, G.; Zheng, Z. H.; Liu, S. C.; Zhang, H.; Guo, L. D.; Che, Y. S.
j. Nat. Prod.,
2009,
72, 942).From lichens
punctelia microsticta (Muell. Arg.) Krogthe Paraconic acid of middle separation
3and derivative
4there is anti-inflammatory, anti-tumor activity (Maier, M. S.; Marimon, D. I. G..; Stortz, C. A.; Adler, M. T.
j. Nat. Prod.
1999,
62, 1565; Park, B. K.; Nakagawa, M.; Hirota, A.; Nakayama, M.
j. Antibiot.
1988,
41, 751.).Ester compound
5can Antifungi cell Mitochondria respiratory chain transfer transport, disturb mitochondrial aerobic repiration (van Tamelen, E. E.; Dickie, J. P.; Loomans, M. E.; Dewey, R. S.; Strong, F. M.
j. Am. Chem. Soc. 1961,
83, 1639).The compound that carboxyl and lactone are connected by saturated carbon atom is same has biological activity.From mushroom
lycoperdon perlatumthe lactone compound Lycoperdic acid of middle separation
6a kind of potential non-NMDA type glutamate receptor agonists (Kaname, M.; Yoshifuji, S.
tetrahedron Lett. 1992,
33, 8103).
The gamma-butyrolactone of anamorphic zone β-carboxyl or β--oxyl acyl group, the method for δ-valerolactone compound comprise chemical synthesis and biocatalysis, fermentation method.Chemical synthesis comprises replaced succinate ester deprotonation-to the addition of carbonyl compound-cyclization (Pohmakotr, M.; Issaree, A.; Sampaongoen, L.; Tuchinda, P.; Reutrakul, V.
tetrahedron Lett. 2003,
44, 7937; Pohmakotr, M.; Soorukram, D.; Tuchinda, P.; Prabpai, S.; Kongsaeree, P.; Reutrakul, V.
tetrahedron Lett.,
2004,
45, 4315; Barros, M. T.; Maycock, C. D.; Ventura, M. R.
org. Lett. 2003,
5, 4097), to aldol addition cyclization (Lam, H. W. in the reduction-molecule of esters of unsaturated carboxylic acids; Joensuu, P. M.
org. Lett. 2005,
7, 4225), addition (Muniz Machado Rodrigues, the S. of the Reformatsky of halo dicarboxylic ester reaction-to carbonyl; Da Silva, G. V. J.; Gomes Constantino, M.
planta Medica 2012,
78, 1285), the method such as substituted epoxy ethane and propanedioic acid condensation all can be used to prepare δ-valerolactone, gamma-butyrolactone skeleton.But adopt saturated carboxylic acid ester deprotonation method synthesis cyclic lactone to need to carry out, and generate a large amount of aldol adduct at low temperatures, need further cyclisation just can obtain cyclic lactone.Reformatsky reaction need use pre-synthesis bromo dicarboxylic ester and a large amount of organometallic reagent.The people such as Blanc synthesize keto ester with caproyl chloride, after seven steps such as Ru-SYNPHOS catalytic reduction ketone carbonyl, allylation, cyclisation, Ester hydrolysis, generate compound
4(-)-methylenolactocin, reaction needed uses precious metal Ru, low temperature and condition of high voltage, and complex steps (Blanc, D.; Madec, J.; Popowyck, F.; Ayad, T.; Phanavath, P.; Ratovelomanana-Vidal, V.; Gen ê t, J.-P.
adv. Synth. Catal. 2007,
349, 943).Lam etc. adopt aldol addition cyclization in copper catalysis silane reduction esters of unsaturated carboxylic acids-molecule; obtain cyclic lactone; reaction conditions is gentle but to require in reactant, containing ester group with in position containing carbonyl, only to give in molecule and introduce hydrogen atom (Lam, H. W.; Joensuu, P. M.
org. Lett. 2005,
7, 4225).Lam etc. utilize Co (acac)
2 .2H
2o-catalysis Et
2zn, α, gamma-butyrolactone (Lumby, the R. J. R. of the Reactive Synthesis between β-unsaturated monoamide monoesters, carbonyl compound; Joensuu, P. M.; Lam, H. W.
org. Lett. 2007,
9, 4367).We are recently reported copper catalysis silane reduction unsaturated dicarboxylic acid ester-to aldol addition between molecule of carbonyl compound-lactonize cascade reaction, and high productivity obtains cyclic lactone (Li, Z. C.; Zhang, Z. L.; Yuan, L.; Jiang, L.; Li, Z. S.; Li, Z. N.
synlett.
2004,
25, 724).The lactone of these methods synthesis, with β-ester base, is β-hydrocarbon oxygen acyl group-gamma-butyrolactone.
Band
β-carboxymethyl-gamma-butyrolactone (δ-valerolactone) and precursor thereof
βthe structure of-hydrocarbon oxygen sulfonylmethyl-gamma-butyrolactone (δ-valerolactone) with
β-carboxy-y-butyrolactone (δ-valerolactone) closely, has important biological activity, is also to synthesize other
β-carboxy-y-butyrolactone,
βthe intermediate of-carboxyl-δ-valerolactone.But not yet have so far by one pot reaction anamorphic zone easily
βthe method of-hydrocarbon oxygen sulfonylmethyl-gamma-butyrolactone, the method for bibliographical information need be synthesized by multistep stepwise reaction, wherein relates to the process of complicated separation and purification intermediate compound.The method studying convenient, fast this compounds of synthesis is significant.
summary of the invention
For the problems referred to above, the present invention will provide one in a mild condition, the method for synthesis γ succinct, efficient, easy and simple to handle, with low cost-hydrocarbon oxygen sulfonylmethyl-gamma-butyrolactone, δ-hydrocarbon oxygen sulfonylmethyl-δ-valerolactone.
γ-hydrocarbon oxygen sulfonylmethyl-the gamma-butyrolactone of the present invention's synthesis, the structure of δ-hydrocarbon oxygen sulfonylmethyl-δ-valerolactone are respectively shown in following structure A, B:
The present invention includes three kinds of methods:
Method 1:
With stable, pure CuH compound as [CuHPPh
3]
6for reductive agent, with keto ester and α, beta-unsaturated carboxylic acid ester Reactive Synthesis γ-hydrocarbon oxygen sulfonylmethyl-gamma-butyrolactone, δ-hydrocarbon oxygen sulfonylmethyl-δ-valerolactone;
Method 2:
With stable, pure CuH compound for catalyzer, keto ester, α, beta-unsaturated carboxylic acid ester and silicon hydride or hydroborates Reactive Synthesis γ-hydrocarbon oxygen sulfonylmethyl-gamma-butyrolactone, δ-hydrocarbon oxygen sulfonylmethyl-δ-valerolactone.
Method 3:
Reacted by other copper compound, Phosphine ligands, silicon hydride or hydroborates in reaction process and generate catalyzer; do not need separation and purification; direct catalyzed hydrosilation compound or hydroborates and keto ester, α, the reaction of beta-unsaturated carboxylic acid ester, synthesis γ-hydrocarbon oxygen sulfonylmethyl-gamma-butyrolactone, δ-hydrocarbon oxygen sulfonylmethyl-δ-valerolactone.
Synthesis γ-hydrocarbon oxygen sulfonylmethyl-gamma-butyrolactone, δ-hydrocarbon oxygen sulfonylmethyl-δ-valerolactone reaction formula are respectively such as formula shown in (1), (2).
Keto ester in the present invention refers to the δ-one acid esters in the middle γ-one acid esters of formula (1) or formula (2), wherein difference 2,3, interval carbon atom between ketone carbonyl and ester group.
R wherein
1for aryl or substituted aryl or not with the aliphatic alkyl of carbonyl conjugation.Aryl comprises phenyl, naphthyl, anthryl, furyl, thienyl, pyrryl, pyridyl etc.; Substituted aryl refers to the aryl that in aryl, is replaced to all H atom by other substituting group, and other substituting group can be independently C
1-C
8alkyl, C
3-C
8cycloalkyl, halogen, alkane (C
1-C
8) oxygen base ,-OPh ,-O-substituted-phenyl (substituting group C
1-C
4) ,-OCO-alkyl (C
1-C
8), containing the acyl group ,-NO of 1-8 carbon atom
2,-NH
2, containing single hydrocarbylamino of 1-8 carbon atom or Dialkylamino, ester group ,-CONH containing 1-8 carbon atom
2,-CONH-alkyl (C
1-C
8) ,-CON-dialkyl (C
1-C
8) etc. group; Aliphatic alkyl refers to the saturated or unsaturated alkyl of the straight or branched containing 1-18 carbon atom;
R
2, R
3, R
5, R
6, R
7can be independently H, F, Cl, Br, I, C
1-C
10alkyl, phenyl, halo alkyl or 1-4 carbon atom the group such as-oxyl;
R
4, R
8for C
1-C
10alkyl or substituted hydrocarbon radical.
Described CuH compound refers to the compound containing Cu-H key, and the Phosphine ligands wherein usually also containing coordination, has [CuHPL]
acomposition (a=1,2,3 ..., 10).L wherein can be Phosphine ligands L1-L12.R in L
9, R
10, R
11can be independently C
1-C
10the group such as alkyl, phenyl, halo alkyl; R
9, R
10also (CH can be had
2)
cshown structure, c=1,2,3 ..., 10.
Other described copper compound refers to the copper compound not containing Cu-H key, comprises CuF (PPh
3)
3 .2MeOH, CuL
dx, CuL
dx
2, containing the C of 0-3 crystal water
2-C
18copper (II) salt of carboxylic acid or halogenated carboxylic acid or (I) salt, C
1-C
18alcohol or replacement C
1-C
18cu (I) compound etc. of alcohol, L is wherein Phosphine ligands, and halogen is F, Cl, Br, I, and substituting group is halogen or alkoxyl group, d=0,1,2,3, X=F, Cl, Br, I,-oxyl containing 1-18 carbon atom.
Described silicon hydride be in molecule at least containing a Si-H key compound, can be the single silicon hydride of structure, also can be the mixture of silicon hydride.Corresponding silicon hydride has following general formula: R
12 dh
esiX
4-d-e(X represents halogen; E=1,2,3 arbitrary integers; And d and e Zhi He≤4).Or R
12r
13r
14si (OSiHR
15)
foSiR
12r
13r
14or R
12(OSiHR
13)
foR
12(f=1,2,3 ..., the integer of 1000); Or H
gr
12 3-gsiOSi R
12 3-gh
g(g=1,2,3).
Described hydroborates contains at least one B-H key, has BH
2r
12or BHR
12r
13structure composition or their mixture.
Above-mentioned R
12, R
13, R
14, R
15for aryl or substituted aryl or aliphatic alkyl.Wherein aryl comprises phenyl, naphthyl, anthryl, furyl, thienyl, pyrryl, pyridyl etc.; Above-mentioned substituted aryl refers to the aryl that in aryl, is substituted with a substituent to all H atom.Substituting group can be independently C
1-C
8alkyl, C
1-C
8cycloalkyl, halogen, alkoxyl group (C
1-C
8) ,-OPh, C
1-C
4the phenoxy group ,-OCO alkyl (C that replace
1-C
8), containing the acyl group ,-NO of 1-8 carbon atom
2,-NH
2, containing a hydrocarbylamino of 1-8 carbon atom or Dialkylamino, ester group ,-CONH containing 1-8 carbon atom
2,-CONH-alkyl (C
1-C
8) ,-CON-dialkyl (C
1-C
8) etc. group; Aliphatic alkyl refers to the saturated or unsaturated alkyl of the straight or branched of 1-8 carbon atom.
Reactions steps of the present invention is as follows:
Reaction solvent can be ethers or aromatic hydrocarbons, comprise methyl ether, ether, butyl ether, tetrahydrofuran (THF), 1,4-dioxane, glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, benzene,toluene,xylene etc. also can be water or alcohols, nitrile, halogenated alkyl solvent etc.Described solvent can be single solvent, also can be the mixture of above-mentioned solvent.The 1-1000 that the volumetric usage (mL) of solvent is the weight (g) of substrate keto ester doubly.
Method 1: adopt stable, pure CuH compound as [CuHPPh
3]
6for reductive agent
(1a). at rare gas element as under argon gas, nitrogen atmosphere ,-78 DEG C of-70 DEG C of temperature ranges, add pure CuH compound and reaction solvent, stir 1-60 min.
With molar amount, the consumption of CuH is α, and the 1-5 of beta-unsaturated carboxylic acid ester doubly.
(1b). by keto ester and α, beta-unsaturated carboxylic acid ester mixes with the solution of (1a) and stirs ,-78 DEG C of-70 DEG C of temperature ranges reactions.
With molar amount, α, the consumption of beta-unsaturated carboxylic acid ester is 1-50 times of keto ester.
(1c). monitor reaction process by TLC or GC or HPLC; as keto ester or α; when the relative quantity of beta-unsaturated carboxylic acid ester no longer obviously reduces; to adding ammonium fluoride solution or dilute hydrochloric acid termination reaction in reaction system; after stirring reaction liquid 1-60 min, through conventional aftertreatment, column chromatography or the ordinary method such as underpressure distillation or recrystallization isolation andpurification is adopted to obtain target product γ-hydrocarbon oxygen sulfonylmethyl-gamma-butyrolactone, δ-hydrocarbon oxygen sulfonylmethyl-δ-valerolactone.
The volumetric molar concentration of ammonium fluoride solution is 0.001 mol/L – saturated solution, and solvent is methyl alcohol or ethanol or methanol-water or alcohol-water, and the volume ratio of alcohol and water is 0:100 to 100:0.With molar amount, the consumption of Neutral ammonium fluoride is the 1-20 times of CuH.The concentration of dilute hydrochloric acid is 0.01 mol/L – 6 mol/L, and with molar amount, the consumption of hydrochloric acid is 0.01-50 times of CuH in (1a).
Method 2: adopt stable, pure CuH compound as [CuHPPh
3]
6for catalyzer, silicon hydride or hydroborates are reductive agent
(2a). at rare gas element as under argon gas, nitrogen atmosphere, add CuH and reaction solvent, stir 1-60 min.
With molar amount, the consumption of CuH is α, 0.0001-1 times of beta-unsaturated carboxylic acid ester.
(2b) .-78 DEG C of-70 DEG C of temperature ranges, by keto ester, α, beta-unsaturated carboxylic acid ester, silicon hydride or hydroborates to add in any order in the solution of (2a) and stir, or by other order by keto ester, α, the solution mixing of beta-unsaturated carboxylic acid ester, silicon hydride or hydroborates, (2a), stirring reaction, monitors reaction process by TLC or GC or HPLC.
With molar amount, α, the consumption of beta-unsaturated carboxylic acid ester is 1-50 times of keto ester; Silicon hydride or hydroborates are α, 1 – 5 times of beta-unsaturated carboxylic acid ester.
(2c). as keto ester or α; beta-unsaturated carboxylic acid ester relative quantity when no longer obviously reducing; ammonium fluoride solution or dilute hydrochloric acid are added in the reaction mixture of step (2b); after stirring 1-60 min, obtain target product γ-hydrocarbon oxygen sulfonylmethyl-gamma-butyrolactone, δ-hydrocarbon oxygen sulfonylmethyl-δ-valerolactone through conventional aftertreatment, column chromatography or the ordinary method such as underpressure distillation or recrystallization isolation andpurification.
Identical with (1c) of the composition of ammonium fluoride solution, concentration, with molar amount, the consumption of Neutral ammonium fluoride be silicon hydride or hydroborates 1-20 times.Identical also with step (1c) of the concentration of dilute hydrochloric acid, with molar amount, the consumption of dilute hydrochloric acid be the 0.01-50 of silicon hydride or hydroborates doubly.
It is reductive agent that method 3 adopts the CuH generated in reaction system to be catalyzer, silicon hydride or hydroborates
(3a). at rare gas element as under argon gas, nitrogen atmosphere ,-78 DEG C of-70 DEG C of temperature ranges, add other copper compound, Phosphine ligands, reaction solvent, stir 1-60 min; Add silicon hydride or hydroborates again, stir 1-60 min, preparation CuH catalyzer.Also by other any order of addition(of ingredients), above-mentioned several material is mixed to form CuH catalyzer.
(3b) .-78 DEG C of-70 DEG C of temperature ranges, by keto ester, α, beta-unsaturated carboxylic acid ester mixes with the solution of step (3a), and stirring reaction no longer obviously reduces to the relative quantity of keto ester or esters of unsaturated carboxylic acids.
With molar amount, the consumption of other copper compound is α, the 0.0001-of beta-unsaturated carboxylic acid ester 1 times, the consumption of Phosphine ligands is α, 0.0001 – 1 times of beta-unsaturated carboxylic acid ester, the consumption of silicon hydride or hydroborates is α, and the 1-5 of beta-unsaturated carboxylic acid ester doubly.
With molar amount, α, the consumption of beta-unsaturated carboxylic acid ester is 1 to 50 times of keto ester.
(3c). by the reaction mixture of ammonium fluoride solution or dilute hydrochloric acid and step (3b); after stirring 1-60 min, obtain target product γ-hydrocarbon oxygen sulfonylmethyl-gamma-butyrolactone, δ-hydrocarbon oxygen sulfonylmethyl-δ-valerolactone through conventional aftertreatment, column chromatography or the ordinary method such as underpressure distillation or recrystallization isolation andpurification.
Identical with (2c) of the composition of ammonium fluoride solution, concentration, consumption.Identical also with step (2c) of the concentration of dilute hydrochloric acid, consumption.
The inventive method is by cascade reaction synthetic gamma butyrolactone, δ-valerolactone, three-step reaction is carried out continuously, the loss not needing isolation of intermediate products, avoid middle sepn process and cause thus in same reaction vessel, easy and simple to handle, improve reaction efficiency, there is good using value.
Embodiment
Now in conjunction with specific experiment, the present invention is further detailed.
Embodiment 1
Reacted as follows by method 1, obtain product.
Reacted as follows by method 1, obtain product.
[CuHPPh is added in the reaction flask of the drying of crossing to nitrogen replacement
3]
6(4.890 g, 15 mmol CuH), toluene (30 mL), stirring and dissolving, is chilled to-30 DEG C, and maintains this temperature in follow-up reaction.To instilling 4-oxo-4-phenylbutyrate methyl esters (2.300 g in above-mentioned solution, 12.0 mmol) and 2-butylene acid methyl esters (1.6 mL, 15.1 mmol) at the solution of toluene (10 mL), about 20 min drip off, and continue stirring reaction and react 0.5 h.Be warming up to room temperature, stir 0.5 h, then add the saturated NH of 20 mL
4the Cl aqueous solution, and continue stirring 0.5 h.Leave standstill phase-splitting.With toluene aqueous phase extracted (3 × 10 mL); organic phase after merging is through saturated common salt water washing; anhydrous sodium sulfate drying, concentrated after; γ-phenyl-γ-(1-methoxyl group acyl group) propyl group-gamma-butyrolactone (3.02 g, productive rate 96%) is obtained again through column chromatography for separation.Also target product is obtained by underpressure distillation.
Embodiment 2
Reacted as follows by method 2, obtain product.
Dried reaction flask is vacuumized, nitrogen injection, three times repeatedly, add [CuHPPh
3]
6(16 mg, 0.049 mmol CuH) and toluene (1 mL), stir 2 min and make [CuHPPh at 25 DEG C
3]
6quan Rong.To adding poly-(methyl hydrogen siloxane) (120 mL in above-mentioned solution, 2.00 mmol SiH), 4-oxo-4-phenylbutyrate methyl esters (0.193 g, 1.00 mmol), the toluene solution (2 mL) of methyl acrylate (137 mL, 0.152 mmol) is added after stirring 2 min.The NH of 2 mL 1.5 mol/L is added after stirring reaction 2.0 h
4the methanol-water solution (methyl alcohol: water=3:1) of F; phase-splitting is left standstill after stirring 0.5 h; aqueous phase filtrate is with dichloromethane extraction (3 × 10 mL); organic phase after merging is through saturated common salt water washing; anhydrous sodium sulfate drying, concentrated after; product γ-phenyl-γ-(1-methoxyl group acyl group) ethyl-gamma-butyrolactone (0.203 g, productive rate 82%) is obtained again through column chromatography for separation.
Carry out embodiment 3 to embodiment 7 by method 3, obtain product.
Embodiment 3
Under nitrogen atmosphere, in the reaction flask of drying, add CuF (5.0 mg, 0.060 mmol), two (two-phenyl phosphino-) ferrocene of 1,1'-, (33.2 mg, 0.060 mmol), ethyl acetate (3mL), stirs 30 min at 40 DEG C.To adding diphenyl silane (2.22 mL in above-mentioned solution, 24.0 mmol SiH), stir 30 min, and then add 4-oxo-4-phenylbutyrate methyl esters (2.30 g, 12 mmol), the ethyl acetate solution (10 mL) of instillation methyl acrylate (2.20 mL, 24 mmol), about 10 min drip off, and stir 5 h.To the NH adding 30 mL 1.5 mol/L in reaction mixture
4the methanol-water solution (methyl alcohol: water=3:1) of F, leaves standstill phase-splitting after stirring 0.5 h.Aqueous phase is extracted with ethyl acetate (3 × 30 mL).Organic phase after merging is through saturated common salt water washing, anhydrous sodium sulfate drying, concentrated, and column chromatography for separation obtains product γ-phenyl-γ-(1-methoxyl group acyl group) ethyl-gamma-butyrolactone (1.63 g, productive rate 55%).
Embodiment 4
Under nitrogen atmosphere, in the reaction flask of drying, add CuF (PPh
3)
32MeOH (28 mg, 0.032 mmol), two (2-diphenylphosphine phenyl) ether (16 mg, 0.030 mmol), toluene (1 mL), stirred at ambient temperature 15 min, then adds poly-(methyl hydrogen siloxane) (0.36 mL, 6.0 mmol), and stir 30 min.Then give in above-mentioned reaction mixture and instill 4-oxo-4-phenylbutyrate methyl esters (0.576 g, 3.00 mmol) and methyl acrylate (0.40 mL, the 4.4 mmol) solution in toluene (5 mL).The NH of 5 mL 1.5 mol/L is added after continuing stirring 4.0 h
4the aqueous solution of F, then leave standstill phase-splitting after stirring 0.5 h.With toluene aqueous phase extracted (3 × 10 mL); organic phase after merging is through saturated common salt water washing, anhydrous sodium sulfate drying, concentrated; column chromatography for separation obtains product γ-phenyl-γ-(1-methoxyl group acyl group) ethyl-gamma-butyrolactone (0.700 g, productive rate 94%).
Embodiment 5
Under nitrogen atmosphere, in dry reaction bottle, add CuF (PPh
3)
32MeOH (4.7 mg, 0.0054 mmol), 4,5-two (diphenylphosphine)-9,9-dimethyl xanthene (2.9 mg, 0.0050 mmol), toluene (1mL).Stirred at ambient temperature 15 min, adds diphenyl silane (0.20 mL, 4.9 mmol H), stirs 30 min.Slowly add 4-oxo-4-(4-bromophenyl) methyl-butyrate (0.678 g, 2.50 mmol) and tert-butyl acrylate (0.43 ml, 3.0 mmol) toluene solution (2 mL), add 5 mL NH after stirring 6.0 h
4methanol-water solution (1.5 mol/L of F; solvent methanol: water=3:1); phase-splitting is left standstill after stirring 1 h again; with toluene aqueous phase extracted (3 × 10 mL); organic phase after merging is through saturated common salt water washing, anhydrous magnesium sulfate drying, concentrated; column chromatography for separation obtains product γ-to bromophenyl-γ-(1-tert.-butoxy acyl group) ethyl-gamma-butyrolactone (0.783 g, productive rate 85%).
Embodiment 6
25 DEG C, under nitrogen atmosphere, in the reaction flask of drying, add CuF (PPh
3)
32MeOH (4.7 mg, 0.0054 mmol), Isosorbide-5-Nitrae-bis-(diphenylphosphine) butane (2.1 mg, 0.0050 mmol), benzene (0.5 mL), stirs 15 min; Add poly-(methyl hydrogen siloxane) (45 mL, 0.75 mmol SiH), stir 30 min.To adding the benzole soln (1 mL) of 4-oxo-4-(2-p-methoxy-phenyl) methyl-butyrate (56 mg, 0.25 mmol) with 2-methyl methacrylate (42 mL, 0.39 mmol) in reaction mixture.2 mL NH are added after stirring 16 h
4the methanol-water solution (methyl alcohol: water=3:1) (1.5 mol/L) of F; phase-splitting is left standstill after stirring 0.5 h again; with benzene aqueous phase extracted (3 × 3 mL); organic phase after merging is through saturated common salt water washing, anhydrous magnesium sulfate drying, concentrated; column chromatography for separation obtains product γ-o-methoxyphenyl-γ-(1-methyl isophthalic acid-methoxyl group acyl group) ethyl-gamma-butyrolactone (43 mg, productive rate 59%).
Embodiment 7
Under nitrogen atmosphere, in the reaction flask of drying, add Cu (O
2cCH
3)
2.H
2o (5 mg, 0.025 mmol), 4, two (diphenylphosphine)-9 of 5-, 9-dimethyl xanthene (14 mg, 0.024 mmol), methyl tertiary butyl ether (3 mL), 1 is added after stirring 15 min at 0 DEG C, 1,3,3-tetramethyl-two silicon ether (90 mL, 1.02 mmol SiH), then stir 2 h.Give in the reaction system stirred and add 5-oxo-5-(3-p-methoxy-phenyl) methyl valerate (0.139 g, 0.589 mmol) and tert-butyl acrylate (100 mL, 0.690 mmol) t-butyl methyl ether solution (1 mL), stir after 6.0h and add 5 mL NH
4the methanol-water solution (1.5 mol/L, solvent methanol: water=3:1) of F, then stir 1 h.Leave standstill, filter, filtrate phase-splitting, aqueous phase methyl tertiary butyl ether washing (3 × 5 mL), merges organic phase.Saturated common salt water washing organic phase, anhydrous sodium sulfate drying.Concentrated by rotary evaporation, column chromatography for separation obtains product δ-m-methoxyphenyl-δ-(1-tert.-butoxy acyl group) ethyl-δ-valerolactone (0.122 g, productive rate 74%).
。
Claims (5)
1.
γ-hydrocarbon oxygen sulfonylmethyl
-the synthetic method of gamma-butyrolactone, δ-hydrocarbon oxygen sulfonylmethyl-δ-valerolactone, it is characterized in that, structure is:
。
2. according to claim 1
γ-hydrocarbon oxygen sulfonylmethyl
-the synthetic method of gamma-butyrolactone, δ-hydrocarbon oxygen sulfonylmethyl-δ-valerolactone, it is characterized in that, synthetic method is:
Method 1: with CuH compound be reductive agent, with keto ester, α, beta-unsaturated carboxylic acid ester Reactive Synthesis γ-hydrocarbon oxygen sulfonylmethyl-gamma-butyrolactone, δ-hydrocarbon oxygen sulfonylmethyl-δ-valerolactone;
Method 2: with CuH compound for catalyzer, keto ester, α, Reactive Synthesis γ-hydrocarbon oxygen sulfonylmethyl-gamma-butyrolactone, δ-hydrocarbon oxygen sulfonylmethyl-δ-valerolactone between beta-unsaturated carboxylic acid ester, silicon hydride or hydroborates;
Method 3: reacted by other copper compound, Phosphine ligands, silicon hydride or hydroborates in reaction process and generate catalyzer, direct catalyzed hydrosilation compound or hydroborates and keto ester, α, the reaction of beta-unsaturated carboxylic acid ester, synthesis γ-hydrocarbon oxygen sulfonylmethyl-gamma-butyrolactone, δ-hydrocarbon oxygen sulfonylmethyl-δ-valerolactone; Synthesis γ-hydrocarbon oxygen sulfonylmethyl-gamma-butyrolactone, δ-hydrocarbon oxygen sulfonylmethyl-δ-valerolactone reaction formula are respectively such as formula shown in (1), (2):
；
Wherein, R
1for aryl or substituted aryl or not with the aliphatic alkyl of carbonyl conjugation, aryl comprises phenyl, naphthyl, anthryl, furyl, thienyl, pyrryl or pyridyl; Substituted aryl refers to the aryl that in aryl, is replaced to all H atom by other substituting group, and other substituting group is C
1-C
8alkyl, C
3-C
8cycloalkyl, halogen, C
1-C
8alkoxyl group ,-OPh, substituting group be C
1-C
4-O-substituted-phenyl, C
1-C
8-OCO-alkyl, acyl group ,-NO containing 1-8 carbon atom
2,-NH
2, containing single hydrocarbylamino of 1-8 carbon atom or Dialkylamino, ester group ,-CONH containing 1-8 carbon atom
2, C
1-C
8-CONH-alkyl or C
1-C
8-CON-dialkyl; Aliphatic alkyl refers to the saturated or unsaturated alkyl of the straight or branched containing 1-18 carbon atom;
R
2, R
3, R
5, R
6, R
7for H, F, Cl, Br, I, C
1-C
10alkyl, phenyl, halo alkyl or 1-4 carbon atom-oxyl; R
4, R
8for C
1-C
10alkyl or substituted hydrocarbon radical.
3. according to claim 2
γ-hydrocarbon oxygen sulfonylmethyl
-the synthetic method of gamma-butyrolactone, δ-hydrocarbon oxygen sulfonylmethyl-δ-valerolactone, is characterized in that, described CuH compound refers to the compound containing Cu-H key, and the Phosphine ligands containing coordination, has [CuHPL]
acomposition a=1,2,3 ..., 10, L is wherein Phosphine ligands L1-L12:
，
R in L
9, R
10, R
11for C
1-C
10alkyl, phenyl or halo alkyl; R
9, R
10there is (CH
2)
cstructure, c=1,2,3 ..., 10;
Other described copper compound refers to the copper compound not containing Cu-H key, comprises CuF (PPh
3)
3 .2MeOH, CuL
dx, CuL
dx
2, d=0,1,2,3; X=F, Cl, Br, I, containing the-oxyl of 1-18 carbon atom, the C containing 0-3 crystal water
2-C
18copper (II) salt of carboxylic acid or halogenated carboxylic acid or (I) salt, C
1-C
18alcohol or replacement C
1-C
18cu (I) compound of alcohol, halogen is wherein F, Cl, Br, I, and substituting group is halogen or alkoxyl group;
Described silicon hydride is the compound at least containing a Si-H key in molecule, and the mixture of the single silicon hydride of structure or silicon hydride, corresponding silicon hydride has following general formula: R
12 dh
esiX
4-d-e, X represents halogen, e=1,2,3 arbitrary integers, and d and e Zhi He≤4; Or R
12r
13r
14si (OSiHR
15)
foSiR
12r
13r
14or R
12(OSiHR
13)
foR
12, f=1,2,3 ..., the integer of 1000, or H
gr
12 3-gsiOSi R
12 3-gh
g, g=1,2,3;
Described hydroborates contains at least one B-H key, has BH
2r
12or BHR
12r
13structure composition or their mixture; R
12, R
13, R
14, R
15for aryl or substituted aryl or aliphatic alkyl, wherein aryl comprises phenyl, naphthyl, anthryl, furyl, thienyl, pyrryl or pyridyl; Above-mentioned substituted aryl refers to the aryl that in aryl, is substituted with a substituent to all H atom, and substituting group is C
1-C
8alkyl, C
1-C
8cycloalkyl, halogen, C
1-C
8alkoxyl group ,-OPh, C
1-C
4the phenoxy group, the C that replace
1-C
8-OCO alkyl, acyl group ,-NO containing 1-8 carbon atom
2,-NH
2, containing a hydrocarbylamino of 1-8 carbon atom or Dialkylamino, ester group ,-CONH containing 1-8 carbon atom
2, C
1-C
8-CONH-alkyl or C
1-C
8-CON-dialkyl; Aliphatic alkyl refers to the saturated or unsaturated alkyl of the straight or branched of 1-8 carbon atom.
4. according to claim 2
γ-hydrocarbon oxygen sulfonylmethyl
-the synthetic method of gamma-butyrolactone, δ-hydrocarbon oxygen sulfonylmethyl-δ-valerolactone, is characterized in that, the step of synthetic method is:
Method 1: adopt CuH compound to be reductive agent
(1a). under inert gas atmosphere ,-78 DEG C of-70 DEG C of temperature ranges, add CuH compound and reaction solvent, stir
1-60 min, with molar amount, the consumption of CuH is α, the 1-5 of beta-unsaturated carboxylic acid ester doubly,
(1b). by keto ester and α, beta-unsaturated carboxylic acid ester mixes with the solution of (1a) and stirs ,-78 DEG C of-70 DEG C of temperature ranges reactions, with molar amount, α, the consumption of beta-unsaturated carboxylic acid ester is 1-50 times of keto ester,
(1c). monitor reaction process by TLC or GC or HPLC; when the relative quantity of keto ester or esters of unsaturated carboxylic acids no longer obviously reduces; ammonium fluoride solution is added in reaction system; or dilute hydrochloric acid termination reaction; after stirring reaction liquid 1-60 min; through conventional aftertreatment, column chromatography or underpressure distillation or recrystallization method isolation andpurification is adopted to obtain target product γ-hydrocarbon oxygen sulfonylmethyl-gamma-butyrolactone, δ-hydrocarbon oxygen sulfonylmethyl-δ-valerolactone
The volumetric molar concentration of ammonium fluoride solution is 0.001 mol/L – saturated solution, solvent is methyl alcohol or ethanol or methanol-water or alcohol-water, the volume ratio of alcohol and water is 0:100 to 100:0, with molar amount, the consumption of Neutral ammonium fluoride is the 1-20 times of CuH, the concentration of dilute hydrochloric acid is 0.01 mol/L – 6 mol/L, and with molar amount, the consumption of hydrochloric acid is 0.01-50 times of CuH in (1a);
Method 2: adopting CuH compound to be catalyzer, silicon hydride or hydroborates is reductive agent
(2a). under inert gas atmosphere, add CuH and reaction solvent, stir 1-60 min, with molar amount, the consumption of CuH is α, 0.0001-1 times of beta-unsaturated carboxylic acid ester,
(2b) .-78 DEG C of-70 DEG C of temperature ranges, by keto ester, α, beta-unsaturated carboxylic acid ester, silicon hydride or hydroborates to add in any order in the solution of (2a) and stir, or by other order by keto ester, α, the solution mixing of beta-unsaturated carboxylic acid ester, silicon hydride or hydroborates, (2a), stirring reaction, reaction process is monitored by TLC or GC or HPLC, with molar amount, α, the consumption of beta-unsaturated carboxylic acid ester is 1-50 times of keto ester; Silicon hydride or hydroborates are α, 1 – 5 times of beta-unsaturated carboxylic acid ester,
(2c). when keto ester or esters of unsaturated carboxylic acids relative quantity no longer obviously reduce time; ammonium fluoride solution or dilute hydrochloric acid are added in the reaction mixture of step (2b); after stirring 1-60 min; target product γ-hydrocarbon oxygen sulfonylmethyl-gamma-butyrolactone, δ-hydrocarbon oxygen sulfonylmethyl-δ-valerolactone is obtained through conventional aftertreatment, column chromatography or underpressure distillation or recrystallization method isolation andpurification
The volumetric molar concentration of ammonium fluoride solution is 0.001 mol/L – saturated solution, solvent is methyl alcohol or ethanol or methanol-water or alcohol-water, the volume ratio of alcohol and water is 0:100 to 100:0, with molar amount, the consumption of Neutral ammonium fluoride be silicon hydrogen or hydroborates 1-20 times, the concentration of dilute hydrochloric acid is 0.01 mol/L – 6 mol/L, and with molar amount, the consumption of dilute hydrochloric acid is 0.01-50 times of silicon hydride or hydroborates;
Method 3: adopting the CuH generated in reaction system to be catalyzer, silicon hydride or hydroborates is reductive agent
(3a). under inert gas atmosphere ,-78 DEG C of-70 DEG C of temperature ranges, add other copper compound, Phosphine ligands, reaction solvent, stir 1-60 min; Add silicon hydride or hydroborates again, stir 1-60 min, preparation CuH catalyzer, or by other any order of addition(of ingredients), above-mentioned several material is mixed to form CuH catalyzer, with molar amount, the consumption of other copper compound is α, the 0.0001-of beta-unsaturated carboxylic acid ester 1 times, and the consumption of Phosphine ligands is α, 0.0001 – 1 times of beta-unsaturated carboxylic acid ester, the consumption of silicon hydride or hydroborates is α, and the 1-5 of beta-unsaturated carboxylic acid ester doubly
(3b) .-78 DEG C of-70 DEG C of temperature ranges, by keto ester, α, beta-unsaturated carboxylic acid ester mixes with the solution of step (3a), and stirring reaction is to keto ester or α, and the relative quantity of beta-unsaturated carboxylic acid ester no longer reduces, with molar amount, α, the consumption of beta-unsaturated carboxylic acid ester is 1 to 50 times of keto ester, and the consumption of silicon hydride or hydroborates is α, beta-unsaturated carboxylic acid ester 1-5 doubly
(3c). by the reaction mixture of ammonium fluoride solution or dilute hydrochloric acid and step (3b); after stirring 1-60 min; target product γ-hydrocarbon oxygen sulfonylmethyl-gamma-butyrolactone, δ-hydrocarbon oxygen sulfonylmethyl-δ-valerolactone is obtained through conventional aftertreatment, column chromatography or underpressure distillation or recrystallization method isolation andpurification
The volumetric molar concentration of ammonium fluoride solution is 0.001 mol/L – saturated solution, solvent is methyl alcohol or ethanol or methanol-water or alcohol-water, the volume ratio of alcohol and water is 0:100 to 100:0, with molar amount, the consumption of Neutral ammonium fluoride is the 1-20 times of silicon hydride or hydroborates, the concentration of dilute hydrochloric acid is 0.01 mol/L – 6 mol/L, and with molar amount, the consumption of hydrochloric acid is 0.01-50 times of silicon hydride or hydroborates.
5. according to claim 4
γ-hydrocarbon oxygen sulfonylmethyl
-the synthetic method of gamma-butyrolactone, δ-hydrocarbon oxygen sulfonylmethyl-δ-valerolactone; it is characterized in that; described reaction solvent is ethers or aromatic hydrocarbons; comprise methyl ether, ether, butyl ether, tetrahydrofuran (THF), 1; 4-dioxane, glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, benzene,toluene,xylene etc.; the mixture of one or more in water or alcohols, nitrile or halogenated alkyl solvent, the volumetric usage of solvent be the 1-1000 of the weight of substrate keto ester doubly.
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| CN104693162A (en) * | 2015-03-26 | 2015-06-10 | 大连大学 | Method for synthesizing beta-ester group-gamma-butyrolactone |
| CN104961714A (en) * | 2015-05-20 | 2015-10-07 | 苏州大学 | Synthetic method of alpha,beta-unsaturated butyrolactone |
| CN106831665A (en) * | 2016-12-14 | 2017-06-13 | 大连大学 | Enantioselective synthesis γ replaces the method that gamma butyrolactone and δ replace δ valerolactones |
| CN112457276A (en) * | 2020-12-03 | 2021-03-09 | 大连大学 | Method for synthesizing butylphthalide |
| CN114349725A (en) * | 2022-02-24 | 2022-04-15 | 大连大学 | Method for synthesizing 3, 3-disubstituted phthalide |
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| CN114349725A (en) * | 2022-02-24 | 2022-04-15 | 大连大学 | Method for synthesizing 3, 3-disubstituted phthalide |
| CN114524789A (en) * | 2022-02-24 | 2022-05-24 | 大连大学 | Method for enantioselectively synthesizing 3, 3-disubstituted isobenzofuran-1 (3H) -ketone |
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