CN1166657C - Dihydrofuran heterocyclic compounds and synthesis process thereof - Google Patents
Dihydrofuran heterocyclic compounds and synthesis process thereof Download PDFInfo
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- CN1166657C CN1166657C CNB021371237A CN02137123A CN1166657C CN 1166657 C CN1166657 C CN 1166657C CN B021371237 A CNB021371237 A CN B021371237A CN 02137123 A CN02137123 A CN 02137123A CN 1166657 C CN1166657 C CN 1166657C
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Abstract
The present invention relates to a dihydrofuran compound and a synthesis method thereof. The dihydrofuran compound has a structural general formula disclosed on the right. A ring formation part of the dihydrofuran compound can be a single ring or a combined ring, R<2> which is a substituent group is hydrogen and alkyl, R<1> is hydrogen and alkyl, R<5> is alkanoyl and carbalkoxy, or R<1> and R<5> are connected to form C3 to C4 sub-alkanoyl. E is an electron withdrawing group which contains ester groups and acyl groups. The synthesis method is characterized in that electron deficiency diene and alkyne react with a nucleophilic reagent with dual nucleophilic sites. The synthesis method has the advantages of simplicity, convenience, moderate conditions and high yield rate. The compound is applied to an intermediate body of synthetic medicine.
Description
Technical field
The present invention relates to a kind of heterogeneous ring compound and synthetic method thereof, particularly relate to a kind of dihydrofuran compound and synthetic method thereof.
Background technology
Dihydrofuran class organic heterocyclic molecule is widely used in organic synthesis, agricultural chemicals, medicine and other fields, is the structural unit of important chemical product in these fields.In many molecules with physiologically active, these structural units have also been comprised.For example, compound 1 is a kind of enzyme inhibitors (Lee, D.-S.; Lee, S.-H.; Nah, J.-G.; Hong, S.-D.Biosci.Biotechnol.Biochem.1999,63,2236), compound 2 is a kind of ion channel blocking agent (Butensch n, I that relate to immunologic function; M ller K; H nsel, W.J.Med.Chem.2001,44,1249).Compound 3 is to isolate material (Jong, the T.T. with anti-platelet aggregation effect from natural product; Wu, T.S.Phytochemistry (s) 1989,28,245).Compound 4 is natural product (Kato, the S. with anthelmintic action; Shibayama, M.; Munakata, K.J. Chem..Soc.Perkin Trans.I 1973,712).The method of synthesizing dihydro furans heterogeneous ring compound is many, and common has: utilize the reaction of ionic type of acid-base catalysis, free radical reaction, (Newkome, G.R. such as the reaction of metal catalytic; Paudler, W.W.Contemporary Heterocyclic Chemistry:Syntheses, Reactionsand Application, Wiley:New York 1982).Simultaneously, a lot of synthesizing dihydro furans heterocyclic reaction conditionss need be comparatively violent with heavy metal catalysis or reaction conditions, and this has limited its range of application undoubtedly.
Summary of the invention
The problem to be solved in the present invention provides a kind of dihydrofuran heterocyclic compounds, and easy, efficient, the universal method of synthetic this heterocyclic compounds of mild condition.
Dihydrofuran compound provided by the present invention has following general structure
Wherein, become loop section be monocycle or and ring,
Substituent R
2Be hydrogen, alkyl, be recommended as hydrogen, C
1～C
5Alkyl;
R
1Be hydrogen, alkyl, be recommended as hydrogen, C
1～C
5Alkyl; R
5For alkyloyl, carbalkoxy, be recommended as C
1～C
5Alkyloyl, C
1～C
5Carbalkoxy, for example formyl radical, ethanoyl, propionyl, methoxycarbonyl, ethoxycarbonyl etc. are especially recommended R
5Be COMe, COOEt.
Perhaps R
1, R
5Be connected to C
3～C
4The alkylene acyl group;
Described E is the electron-withdrawing group that comprises ester group and acyl group, recommends C
1～C
10Ester group or acyl group, for example COOEt, COOMe, COOBn, COCH
3, COPh, COCy etc.
In institute's synthetic dihydrofuran compound for example:
R
3Be OEt, OMe, OBn, CH
3, Ph, Cy R
4Be Me, OEt
Method of the present invention is to be raw material with electron-deficient alkynes or electron-deficient connection alkene with having the nucleophilic reagent that parents examine the center, in organic solvent, is R ' with the molecular formula
3The organic phosphine of P is that catalyzer reacts and makes, and the aryl of R '=alkyl, cycloalkyl, aryl or replacement is recommended R '=C
1-12Straight or branched alkane, C
5-6The aryl of cycloalkyl, aryl or replacement, especially recommending R ' is phenyl; Wherein electron-deficient alkynes or the connection alkene, nucleophilic reagent, the mol ratio of organic phosphine is 0.2-2: 1: 0.01-0.5, under 0 ℃ to 150 ℃ temperature, reacted 0.5-96 hour.Recommend electron-deficient alkynes or connection alkene, nucleophilic reagent, the mol ratio of organic phosphine is 0.8-1.2: 1: 0.1-0.3, the recommendation response temperature is reaction between the room temperature to 150 ℃, especially is recommended in reaction between 70～130 ℃.
Described electron-deficient alkynes refers to the alkynes that contains electron-withdrawing group E, and wherein alkynes partly contains 2 to 3 carbon atoms; Described electron-deficient connection alkene refers to the connection alkene that contains electron-withdrawing group E, wherein joins alkene and partly contains 3 carbon atoms, and E as previously mentioned; Described electron-deficient alkynes or electron-deficient connection alkene are recommended the 2-butyne ketone of replacement, 2-butyne acid esters, 2,2 of 3-divinyl acid esters or replacement, 3-divinyl ketone etc.The structural formula that the described parents of having examine the nucleophilic reagent at center is
R in the formula
1, R
2, R
5As previously mentioned,
Reaction process for example following formula is represented:
R in the formula
1, R
2, R
5, R ', E as previously mentioned.
Recommend electron-deficient alkynes, the electron-deficient connection alkene of use as follows:
R＝OEt，CH
3，Ph、OCH
3，OBn，Cy，Ph、
nPr
Recommend two centers nucleophilic reagent of use as follows:
In the inventive method, described organic solvent can be polar solvent or non-polar solvent, preferably uses the solvent of drying.As benzene, tetracol phenixin, sherwood oil, tetrahydrofuran (THF), dimethyl formamide, ether, trichloromethane, toluene, methylene dichloride, dimethylbenzene, hexanaphthene, normal hexane, normal heptane, dioxane, acetonitrile etc.
Adopt the prepared product of present method can use recrystallization, methods such as column chromatography are separated.As the method with recrystallization, recommending solvent is the mixed solvent of polar solvent and non-polar solvent.For example, Virahol-sherwood oil, methylene dichloride-sherwood oil, ethyl acetate-sherwood oil, ethyl acetate-normal hexane, acetone-sherwood oil, Virahol-ethyl acetate-mixed solvents such as sherwood oil.Use column chromatography, can be with the stationary phase of silica gel or aluminum oxide, used developping agent is the mixed solvent of polar solvent and non-polar solvent.The recommendation solvent is Virahol-sherwood oil, methylene dichloride-sherwood oil, ethyl acetate-sherwood oil, ethyl acetate-normal hexane, acetone-sherwood oil, Virahol-ethyl acetate-mixed solvents such as sherwood oil, its volume ratio can be respectively a polar solvent: non-polar solvent=1-0.1: 1.For example: ethyl acetate: sherwood oil=1: 10, Virahol: sherwood oil=1: 10.
Because dihydrofuran class organic heterocyclic molecule is widely used in organic synthesis, agricultural chemicals, medicine and other fields, is the structural unit of important chemical product in these fields.In many molecules with physiologically active, these structural units have also been comprised, so utilize the inventive method institute synthetic heterogeneous ring compound to be expected to be converted into important pharmaceutical intermediate.
The invention provides a kind of easy, method of synthesizing dihydro furans heterogeneous ring compound efficiently, this method is simple, mild condition, can be under neutrallty condition synthetic product successfully, reaction yield is better, generally reaches 61-98%.
Embodiment
To help to understand the present invention by following embodiment, but not limit content of the present invention.
Embodiment 1: electron-deficient connection alkene in the presence of triphenylphosphine with the reaction of carbon-oxygen type pair centers nucleophilic reagent.
In toluene, add the two center nucleophilic reagents (1mmol) of triphenylphosphine (0.2mmol) and corresponding carbon-oxygen type, be warming up to 70～80 ℃ of dissolvings, the toluene solution that adds electron-deficient connection alkene (1mmol) subsequently is (at Compound P 2, P3, P4, in the building-up reactions of P5, the toluene solution of electron-deficient connection alkene slowly drops in the reaction system with syringe pump), continue reaction and show that until thin-layer chromatography raw material disappears, removal of solvent under reduced pressure, column chromatography get accordingly and encircle dihydrofuran derivative.
The P1:(reactant: 2,3-divinyl acetoacetic ester, cyclohexanedione)
IR (neat) ν 2947,1736,1635,1404,1181 cm
-1.
1H NMR (300MHz, CDCl
3) δ 5.14 (m, 1H), 4.14 (q, J=7.1Hz, 2H), 2.98 (dd, J=14.6,10.1Hz, 1H), 2.74 (dd, J=16,7.7Hz, 1H), 2.57 (dd, J=16,5.7Hz, 1H), 2.45 (dd, J=14.6,5.7Hz, 1H), 2.37 (t, J=6.5Hz, 2H), 2.30 (t, J=6.5Hz, 2H), 1.99 (m, 2H), 1.23 (t, J=7.1Hz, 3H) .MS (m/z) 224 (M
+), 179,178,150,137 (100), 108,81,48,41. ultimate analysis C
12H
16O
4: calculated value C, 64.27; H, 7.19. measured value C, 64.18; H, 7.32.
Embodiment 2: in acetonitrile or benzene, add the two center nucleophilic reagents (1mmol) of triphenylphosphine (0.2mmol) and corresponding carbon-oxygen type, be warming up to 110～120 ℃ of dissolvings, the toluene solution that adds electron-deficient connection alkene (1mmol) subsequently is (in Compound P 2, in the building-up reactions of P3, the toluene solution of electron-deficient connection alkene slowly drops in the reaction system with syringe pump), continue reaction and show that until thin-layer chromatography raw material disappears, removal of solvent under reduced pressure, column chromatography get accordingly and encircle dihydrofuran derivative.
The P2:(reactant: 3,4-pentadiene-2-ketone, cyclohexanedione)
IR (neat) ν 2948,1715,1628,1406,1233,1181cm
-1.
1H NMR (300MHz, CDCl
3) δ 5.21 (m, 1H), 3.06 (dd, J=10.5,14.7Hz, 1H), 2.98 (dd, J=17.4,7.2Hz, 1H), 2.75 (dd, J=17.4,4.8Hz, 1H), 2.46 (dd, J=14.7,7.2Hz, 1H), 2.42 (t, J=6.2Hz, 2H), 2.35 (t, J=6.5Hz, 2H), 2.22 (s, 3H), 2.03 (m, 2H) .MS (m/z) 194 (M
+), 137 (100), 108.96,95,81,55,43,41. ultimate analysis C
11H
14O
3: calculated value C, 68.02; H, 7.27. measured value C, 64.04; H, 7.54.
P3:(reactant: 1-phenyl-2,3-divinyl ketone, cyclohexanedione)
Mp 101-102.IR (KBr) ν 2952,1679,1648,1629,1412,1212,1182,758,688cm
-1.
1H NMR (300MHz, CDCl
3) δ 7.96 (d, J=7.2Hz, 2H), 7.60 (t, J=7.2Hz, 1H), 7.48 (t, J=7.2Hz), 5.43 (m, 1H), 3.55 (dd, J=17.2,7.1Hz), 3.25 (dd, J=17.2,6.8Hz, 1H), 3.13 (dd, J=14.6,7.2Hz, 1H), 2.56 (dd, J=14.6,7.2Hz, 1H), 2.40 (t, J=6.4Hz, 2H), 2.35 (t, J=6.4Hz, 2H), 2.04 (m, 2H) .MS (m/z) 259 (M
++ 1,100), 258 (M
+), 137,120,108,105,77,51. ultimate analysis C
16H
16O
3: calculated value C, 74.98; H, 6.29. measured value C, 74.99; H, 6.31.
Embodiment 3: electron-deficient connection alkene in the presence of tributylphosphine with the reaction of carbon-oxygen type pair centers nucleophilic reagent.
Reaction process and aftertreatment are with embodiment 1, and the toluene solution of electron-deficient connection alkene slowly drops in the reaction system with syringe pump, and catalyzer changes tributylphosphine into.
The P4:(reactant: 3,4-pentadiene-2-ketone, methyl ethyl diketone)
IR (neat) ν 2926,1716,1670,1618,1602,1324,1228cm
-1.
1H NMR (300MHz, CDCl
3) δ 5.02 (m, 1H), 3.17 (dd, J=11.5,14.3Hz, 1H), 2.96 (dd, J=17.0,7.1Hz, 1H), 2.71 (dd, J=17.0,6.2Hz, 1H), 2.57 (dd, J=14.3,7.5Hz, 1H), 2.21 (s, 3H), 2.19 (s, 3H), 2.17 (s, 3H) .MS (m/z) 182 (M
+), 125,109,97,43 (100), 41. ultimate analysis C
10H
14O
3: calculated value C, 68.02; H, 7.27. measured value C, 64.04; H, 7.54.
The P5:(reactant: 3,4-pentadiene-2-ketone, methyl aceto acetate)
Mp?43-44℃.IR(KBr)ν2982，1716，1698，1648，1602，1375，1227，1068cm
-1.
1H?NMR(300MHz，CDCl
3)δ5.04(m，1H)，4.18(q，J＝7.2Hz，2H)，3.12(dd，J＝10.2，14.4Hz.1H)，2.96(dd，J＝17.1，7.0Hz，1H)，2.71(dd，J＝17.1，6.0Hz，1H)，2.51(dd，J＝14.4，7.5Hz，1H)，2.25(s，3H)，2.18(s，3H)，1.29(t，J＝7.2Hz，3H)。
MS (m/z) 212 (M
+), 167,155,154,126,125,109,102,43 (100). ultimate analysis C
11H
16O
4: calculated value C, 62.25; H, 7.60. measured value C, 62.48; H, 7.74.
Embodiment 4: electron-deficient alkynes in the presence of triphenylphosphine with the reaction of the two centers of carbon-oxygen type nucleophilic reagent.
In toluene, add the two center nucleophilic reagents (1mmol) of triphenylphosphine (0.2mmol) and corresponding carbon-oxygen type, be warming up to 80 ℃ of dissolvings, the solution that adds the toluene of electron-deficient alkynes (1mmol) subsequently, continue reaction and show that until thin-layer chromatography raw material disappears, removal of solvent under reduced pressure, column chromatography get corresponding dihydrofuran derivative.
P6:(reactant: tetrolic acid methyl esters, cyclohexanedione)
IR (neat) ν 2953,1740,1635,1405,1223,1181cm
-1.
1H NMR (300MHz, CDCl
3) δ 5.20 (m, 1H), 3.73 (s, 3H), 3.03 (dd, J=10.1,14.6Hz, 1H), 2.79 (dd, J=16.1,7.9Hz, 1H), 2.65 (dd, J=16.1,5.6Hz, 1H), 2.55 (dd, J=14.6,7.3Hz, 1H), 2.42 (t, J=6.4Hz, 2H), 2.35 (t, J=6.4Hz, 2H), 2.05 (m, 2H) .MS (m/z) 210 (M
+), 178,150,137 (100), 108,43,41. ultimate analysis C
11H
14O
4: C, calculated value 62.85; H, 6.71. measured value C, 62.90; H, 6.84
Embodiment 5: electron-deficient alkynes in the presence of tributylphosphine with the reaction of the two centers of carbon-oxygen type nucleophilic reagent.
Reaction process and aftertreatment are with embodiment 4, and catalyzer changes tributylphosphine into.
P7:(reactant: 2-butyne acid benzyl ester, cyclohexanedione)
IR(neat)ν2948，1737，1635，1404，1181，752，699cm
-1.
1H?NMR(300MHz，CDCl
3)δ7.26-7.38(m，5H)，5.21(m，1H)，5.16(S，2H)，3.02(dd，J＝10.2，14.7Hz，1H)，2.82(dd，J＝16.2，7.8Hz，1H)，2.69(dd，J＝16.2，5.7Hz，1H)，2.51(dd，J＝14.7，7.2Hz，1H)，2.39(t，J＝6.3Hz，2H)，2.33(t，J＝6.3Hz，2H)，2.02(m，2H)。
MS (m/z) 210 (M
+), 178,150,137 (100), 108,43,41. ultimate analysis C
17H
18O
4: calculated value C, 71.31; H, 6.34. measured value C, 71.60; H, 6.73.
P8:(reactant: 1-cyclohexyl-2-butyne ketone, cyclohexanedione)
IR (pure) ν 2932,2856,1707,1648,1633,1404,1231,1182cm
-1.
1H NMR (300MHz, CDCl
3) δ 5.22 (m, 1H), 2.96-3.08 (m, 2H), 2.74 (dd, J=17.1,5.8Hz, 1H), 2.32-2.45 (m, 5H), 2.03 (m, 2H), 1.67-1.88 (m, 5H), 1.18-1.40 (m, 6H) .MS (m/z) 264 (M
++ 2,100), 153,137,83,81,55,41. ultimate analysis C
16H
22O
3: calculated value C, 73.25; H, 8.45. measured value C, 72.96; H, 8.05.
Claims (8)
1. dihydrofuran compound is characterized in that having following general structure:
Wherein,
Substituent R
2Be hydrogen or C
1～C
5Alkyl;
R
1Be hydrogen or C
1～C
5Alkyl, R
5Be C
1～C
5Alkyloyl or C
1～C
5Carbalkoxy;
Perhaps R
1, R
5Be connected to C
3～C
4The alkylene acyl group;
Described E is C
1～C
10Ester group or acyl group.
2. dihydrofuran compound as claimed in claim 1 is characterized in that described E is COOEt, COOMe, COOBn, COCH
3, COPh or COCy.
3. dihydrofuran compound as claimed in claim 1 is characterized in that having following structural formula:
R
3Be OEt, OMe, OBn, CH
3, Ph, Cy R
4Be Me, OEt
4. the synthetic method of dihydrofuran compound as claimed in claim 1 is characterized in that be raw material with electron-deficient alkynes or electron-deficient connection alkene with having the nucleophilic reagent that parents examine the center, in organic solvent, is R ' with the molecular formula
3The organic phosphine of P is that catalyzer reacts and makes, and R ' is C
1-4Straight or branched alkyl or phenyl, wherein electron-deficient alkynes or the connection alkene, nucleophilic reagent, the mol ratio of organic phosphine is 0.2-2: 1: 0.01-0.5, under 0 ℃ to 150 ℃ temperature, reacted 0.5-96 hour, described electron-deficient alkynes refers to
Or
Described electron-deficient connection alkene refers to
E according to claim 1; The general structure that the described parents of having examine the nucleophilic reagent at center is
R in the formula
1, R
2, R
5According to claim 1.
5. the method for synthesizing dihydro furan compound as claimed in claim 4 is characterized in that products therefrom is again through recrystallization, column chromatography purification.
6. the method for synthesizing dihydro furan compound as claimed in claim 4 is characterized in that reactant adopts the mode sample introduction that drips slowly.
7. the method for synthesizing dihydro furan compound as claimed in claim 4, it is characterized in that reacting employed solvent is polarity or non-polar solvent.
8. the method for synthesizing dihydro furan compound as claimed in claim 4, it is characterized in that reacting the solvent that uses in described recrystallization, the column chromatography purification method is the mixed solvent of polarity or non-polar solvent.
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