CN101440076A - Process for synthesizing optical activity 2-(1'(Z) alkenyl iodo-alkyl) tetrahydrofuran - Google Patents

Process for synthesizing optical activity 2-(1'(Z) alkenyl iodo-alkyl) tetrahydrofuran Download PDF

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CN101440076A
CN101440076A CNA2008101626869A CN200810162686A CN101440076A CN 101440076 A CN101440076 A CN 101440076A CN A2008101626869 A CNA2008101626869 A CN A2008101626869A CN 200810162686 A CN200810162686 A CN 200810162686A CN 101440076 A CN101440076 A CN 101440076A
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tetrahydrofuran
iodo
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麻生明
吕博
傅春玲
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Zhejiang University ZJU
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Abstract

The invention discloses a method for synthesizing optically active (S)-2-(1'(Z)alkenyl iodoalkyl)tetrahydrofuran. An optically active (R)-4, 5-allenol is taken as a reaction substrate and is subjected to iodocyclization reaction with an electrophilic reagent, namely N-iodosuccinimide to generate the optically active (S)-2-(1'(Z)alkenyl iodoalkyl)tetrahydrofuran (large amount) and (R)-2-(1'(E)alkenyl iodoalkyl)tetrahydrofuran (small amount); and the optically active (S)-2-(1'(Z) alkenyl iodoalkyl)tetrahydrofuran with Z configuration is obtained by utilizing the speed difference that a Z/E isomer is subjected to Sonogashira coupling reaction with propiolic alcohol under the co-catalysis of dichlorobis(triphenylphosphine)palladium and cuprous iodide. The method has simple operation, is easy to obtain the raw material and the reagent, has the reaction with high region and stereoselectivity, can synchronously introduce a plurality of substitional groups, is easy to separate and purify a product, and is suitable to synthesize various substituted optically active tetrahydrofuran compounds.

Description

The synthetic method of optical activity 2-(1 ' (Z) alkenyl iodo-alkyl) tetrahydrofuran (THF)
Technical field
The present invention relates to the method for the tetrahydrofuran (THF) compounds of a kind of efficient synthesis of optically active (S)-2-alkyl replacement.
Background technology
The tetrahydrofuran (THF) compounds is one of a kind of very important intermediate in the organic synthesis, also is one of structural unit common in the natural product.Many compounds that contain this skeleton have been proved and have had many potential physiologically actives at present, and at biological technical field, there is huge value of exploiting and utilizing aspects such as medicine and agricultural chemicals.And optically active tetrahydrofuran (THF) compounds has in this compounds and occupies very important ratio, the tetrahydrofuran (THF) compounds of (S)-2-alkyl of bibliographical information replacement in the past mainly is by there is second line of a couplet enol or alkynes ether self ring closure reaction (Angew.Chem.Int.Ed.2007 at chiral ligand, 46,283; J.Org.Chem.2004,69,8387.) or directly utilize chirality connection enol self ring closure reaction methods such as (J.Am.Chem.Soc.2006,128,9066) to realize.But these methods are often by introducing costliness and disagreeableness heavy metal catalyst of environment and expensive chiral ligand being carried out.And self ring closure reaction limits to substituent introducing very much, therefore develops under a kind of room temperature need not catalyzer, and (S)-2-alkyl substituted tetrahydro furfuran compound of the three-dimensional monistic synthetic replacement of high yield will be to the very quantum jump of synthetic method in the past.
Summary of the invention
The synthetic method that the purpose of this invention is to provide a kind of optical activity 2-(1 ' (Z) alkenyl iodo-alkyl) tetrahydrofuran (THF), utilization contains 4 of a chirality, the iodine cyclization takes place in 5-connection enol and electrophilic reagent N-iodo succimide (NIS), by Sonogashira coupling kinetic resolution method, (the S)-2-of synthesis of optically active (1 ' (Z) alkenyl iodo-alkyl) tetrahydrofuran (THF).
The invention provides the synthetic method of optical activity 2-(1 ' (Z) alkenyl iodo-alkyl) tetrahydrofuran (THF), with (R)-4,5-connection enol is reaction substrate and electrophilic reagent N-iodo succimide generation iodine cyclization, high regioselectivity ground generate optical activity (S)-2-(1 ' (Z) alkenyl iodo-alkyl) tetrahydrofuran (THF) with (R)-2-(1 ' (E) alkenyl iodo-alkyl) tetrahydrofuran (THF); Utilize Z/E isomer speed with propiolic alcohol generation Sonogashira linked reaction under two (triphenylphosphine) palladium chlorides and the common catalysis of cuprous iodide different, obtain optically active (S)-2-(1 ' (Z) alkenyl iodo-alkyl) tetrahydrofuran (THF).
Reaction formula is as follows:
Figure A200810162686D00041
R is an alkyl, and wherein alkyl is C nH 2n+1(n=1-6), " (S) ", " (R) " refer to the absolute configuration of chiral centre, and " (E) ", " (Z) " refer to the cis-trans configurations of carbon-carbon double bond in the molecule, and " N-" refers to the substituting group above the nitrogen-atoms.
The steps include:
1, iodine cyclization: add reaction substrate (R)-4 in reactor, 5-joins enol, organic solvent dichloromethane and electrophilic reagent N-iodo succimide (NIS), and stirring reaction is 45～55 minutes under the room temperature;
2, after step 1 is finished, add saturated sodium thiosulfate solution, be stirred to colourless back extracted with diethyl ether, anhydrous sodium sulfate drying, filter, concentrate, rapid column chromatography obtains (S)-2-(1 ' (Z) alkenyl iodo-alkyl) tetrahydrofuran (THF) (in a large number) and (R)-2-(1 ' (E) alkenyl iodo-alkyl) tetrahydrofuran (THF) (on a small quantity) mixture;
3, kinetic resolution reaction: the mixture that step 2 obtains is transferred in the reaction flask, added two (triphenylphosphine) palladium chloride then successively, cuprous iodide, propiolic alcohol, diethylamide and anhydrous acetonitrile react in anhydrous acetonitrile, stirring at room reaction 20 minutes;
4, after step 3 is finished, add ether cancellation reaction, concentrate, silica gel column chromatography obtains (S)-2-(1 ' (Z) alkenyl iodo-alkyl) tetrahydrofuran (THF) fast.
Reaction substrate of the present invention (R)-4,5-connection enol concentration in organic solvent dichloromethane is 0.05～0.2mol/L.
Optical activity among the present invention (R)-4, the mol ratio of 5-connection enol and N-iodo succimide is 1: 1.0～2.0.
The Sonogashira linked reaction takes place with propiolic alcohol under the catalysis at two (triphenylphosphine) palladium chlorides and cuprous iodide in step 2 product of the present invention altogether, and this step reaction solvent of kinetic resolution is an acetonitrile, and the concentration of product in acetonitrile is 0.05～0.15mol/L.
In the step 3 kinetic resolution reaction of the present invention, the mol ratio of mixture and propargyl alcohol is 1: 0.15～0.35, the mol ratio of mixture and diethylamide is 1: 0.15～0.35, the mol ratio of mixture and two (triphenylphosphine) palladium chloride is 1: 0.015～0.055, and the mol ratio of mixture and cuprous iodide is 1: 0.015～0.055.
The present invention has overcome the drawback of traditional method, has the following advantages: (1) reaction times is short, and mild condition is suitable for polysubstituted 4, and 5-joins enol; (2) reaction has the zone and the stereoselectivity of height; (3) can synthesize 2-(1 ' (Z) alkenyl iodo-alkyl) the tetrahydrofuran (THF) compounds of high-optical-purity; (4) the easily separated purifying of product.
Innovative point of the present invention has been to develop the novel method of the tetrahydrofuran (THF) compounds of a kind of high zone and the synthetic high-optical-purity of stereoselectivity.
Utilizing the productive rate of optical activity 2-(1 ' (Z) alkenyl iodo-alkyl) the tetrahydrofuran (THF) compounds of present method preparation is 68-75%.Optical purity (ee%) is 95-97%.
Embodiment
Following examples help to understand the present invention, but are not limited to content of the present invention.
Embodiment 1
In reaction tubes, add (R)-4,5-diene undecyl alcohol (33.4mg, 0.20mmol, 95% ee), methylene dichloride, (54.4mg 0.24mmol), opens under the room temperature and stirs, reaction 55min NIS.Add saturated Na 2S 2O 3Solution is stirred to colourless back use extracted with diethyl ether, anhydrous sodium sulfate drying, filter, concentrate, rapid column chromatography obtain (S)-2-(1-iodo-1 (Z)-heptenyl) tetrahydrofuran (THF) with (R)-2-(1-iodo-1 (E)-heptenyl) tetrahydrofuran (THF) liquid, be total to 54.3mg, productive rate 93%, Z/E=90/10.
1H?NMR(300MHz，CDCl 3)δ[6.31，(t，J＝7.8Hz，E-isomer，0.1H)，5.90(t，J＝6.8Hz，Z-isomer，0.9H)]，4.18(t，J＝6.5Hz，1H)，4.08-3.95(m，1H)，3.92-3.80(m，1H)，2.21-2.10(m，2H)，2.10-1.80(m，4H)，1.46-1.22(m，6H)，0.88(t，J＝6.8Hz，3H).
Under nitrogen protection with the above-mentioned mixture that obtains [(S)-2-(1-iodo-1 (Z)-heptenyl) tetrahydrofuran (THF) with (R)-2-(1-iodo-1 (E)-heptenyl) tetrahydrofuran (THF)] (54.3mg; 0.18mmol; Z/E=90/10); propiolic alcohol (3.2mg; 0.057mmol); diethylamide (4.4mg, 0.06mmol), two (triphenylphosphine) palladium chloride (4.9mg; 0.007mmol) and cuprous iodide (1.6mg; 0.008mmol) in anhydrous acetonitrile, react, add ether cancellation reaction under the room temperature behind the 20min, concentrate; rapid column chromatography obtains (S)-2-(1-iodo-1 (Z)-heptenyl) tetrahydrofuran (THF) 44.1mg; the rate of recovery 81%, Z/E〉99/1, ee=95%.
[α] 20 D＝+14.0(c＝0.89，CHCl 3).
1H?NMR(300MHz，CDCl 3)δ?5.90(t，J＝6.6Hz，1H)，4.18(t，J＝6.3Hz，1H)，4.05-3.95(m，1H)，3.92-3.81(m，1H)，2.21-2.10(m，2H)，2.10-1.80(m，4H)，1.46-1.22(m，6H)，0.88(t，J＝6.2Hz，3H)；
13C?NMR(75MHz，CDCl 3)δ?135.6，112.4，84.7，69.2，35.5，32.8，31.3，27.9，25.7，22.5，14.0；IR(neat)v(cm -1)：2956，2926，2857，1641，1459，1361，1305，1259，1181，1062；
MS(70eV，EI)m/z(％)：294(M +，10.76)，97(100)；
HRMS?calcd?for?C 11H 19OI(M +)：294.0481.Found：294.0482.
Embodiment 2
(R)-4,5-diene lauryl alcohol (34.9mg, 0.19mmol, 98%ee), methylene dichloride, NIS (54.7mg, 0.24mmol) at room temperature react 45min, obtain product (S)-2-(1-iodo-1 (Z)-octenyl) tetrahydrofuran (THF) with (R)-2-(1-iodo-1 (E)-octenyl) tetrahydrofuran (THF) 51.7mg altogether, liquid, productive rate 88%, Z/E=90/10.
1H?NMR(300MHz，CDCl 3)δ[6.31(t，J＝7.7Hz，E-isomer，0.1H)，5.91(t，J＝6.8Hz，Z-isomer，0.9H)]，4.19(t，J＝6.2Hz，1H)，4.06-3.95(m，1H)，3.92-3.80(m，1H)，2.21-2.10(m，2H)，2.10-1.80(m，4H)，1.46-1.22(m，8H)，0.87(m，3H).
Under nitrogen protection with the above-mentioned product that obtains [(S)-2-(1-iodo-1 (Z)-octenyl) tetrahydrofuran (THF) with (R)-2-(1-iodo-1 (E)-octenyl) tetrahydrofuran (THF)] (51.7mg; 0.17mmol; Z/E=90/10); propiolic alcohol (2.7mg; 0.048mmol), diethylamide (3.2mg, 0.04mmol); two (triphenylphosphine) palladium chloride (4.3mg; 0.006mmol) (1.5mg 0.008mmol) reacts in anhydrous acetonitrile, adds ether cancellation reaction under the room temperature behind the 20min with cuprous iodide; concentrate; rapid column chromatography obtains (S)-2-(1-iodo-1 (Z)-octenyl) tetrahydrofuran (THF) 39.6mg, liquid, the rate of recovery 77%; Z/E〉99/1, ee=97%.[α] 20 D＝+12.7(c＝0.88，CHCl 3).
1H?NMR(300MHz，CDCl 3)δ?5.90(t，J＝6.6Hz，1H)，4.18(t，J＝6.3Hz，1H)，4.06-3.95(m，1H)，3.96-3.81(m，1H)，2.21-2.10(m，2H)，2.10-1.80(m，4H)，1.46-1.22(m，8H)，0.88(t，J＝6.6Hz，3H).
13C?NMR(75MHz，CDCl 3)δ?135.6，112.4，84.7，69.2，35.6，32.8，31.7，28.8，28.2，25.7，22.6，14.1；
IR(neat)v(cm -1)：2961，2926，2856，1642，1459，1360，1260，1181，1061；
MS(70eV，EI)m/z(％)：308(M +，7.14)，97(100)；
HRMS?calcd?for?C 12H 21OI(M +)：308.0637.Found：308.0639.
Embodiment 3
1) filling (R)-4, (stirring reaction is 45～55 minutes under the room temperature for 0.20mmol, adding N-iodo succimide (0.24mmol) methylene dichloride (1mL) 95%ee) and in the reaction flask of methylene dichloride (1mL) for 5-connection enol;
2) after step (1) is finished, add entry (10mL) and saturated sodium thiosulfate (10mL), with ether (20mL * 3) extraction, anhydrous sodium sulfate drying.Concentrating under reduced pressure after the elimination anhydrous sodium sulphate obtains product behind silica gel column chromatography;
3) transfer in the reaction flask in the product that (2) are obtained, add two (triphenylphosphine) palladium chloride (0.007mmol) then successively, cuprous iodide (0.007mmol), propiolic alcohol (0.057mmol), diethylamide (0.06mmol) and anhydrous acetonitrile (2mL) were stirring at room reaction 20 minutes;
4) after step (3) was finished, directly quick silica gel column chromatography obtained (S)-2-(1 ' (Z) alkenyl iodo-alkyl) tetrahydrofuran (THF).

Claims (8)

1, the synthetic method of a kind of optically active (S)-2-(1 ' (Z) alkenyl iodo-alkyl) tetrahydrofuran (THF), with optical activity (R)-4,5-connection enol is reaction substrate and electrophilic reagent N-iodo succimide generation iodine cyclization, high regioselectivity ground generate optical activity (S)-2-(1 ' (Z) alkenyl iodo-alkyl) tetrahydrofuran (THF) with (R)-2-(1 ' (E) alkenyl iodo-alkyl) tetrahydrofuran (THF); Utilize Z/E isomer speed with propiolic alcohol generation Sonogashira linked reaction under two (triphenylphosphine) palladium chlorides and the common catalysis of cuprous iodide different, obtain optically active (S)-2-(1 ' (Z) alkenyl iodo-alkyl) tetrahydrofuran (THF); Reaction formula is as follows:
Figure A200810162686C00021
R is an alkyl, and wherein alkyl is C nH 2n+1, n=1-6 in the formula the steps include:
1) iodine cyclization: add reaction substrate (R)-4 in reactor, 5-joins enol, organic solvent dichloromethane and electrophilic reagent N-iodo succimide (NIS), and stirring reaction is 45～55 minutes under the room temperature;
2) after step 1 is finished, add saturated sodium thiosulfate solution, be stirred to colourless back extracted with diethyl ether, anhydrous sodium sulfate drying, filter, concentrate, rapid column chromatography, obtain (S)-2-(1 '-iodo-1 ' (Z)-heptenyl) tetrahydrofuran (THF) with (R)-2-(1 '-iodo-1 ' (E)-heptenyl) tetrahydrofuran compound;
3) kinetic resolution reaction: the mixture that step 2 obtains is transferred in the reaction flask, under nitrogen protection, added two (triphenylphosphine) palladium chloride then successively, cuprous iodide, propiolic alcohol, diethylamide and anhydrous acetonitrile react in anhydrous acetonitrile, stirring at room reaction 20 minutes;
4) after step 3 is finished, add ether cancellation reaction, concentrate, silica gel column chromatography obtains (S)-2-(1 ' (Z) alkenyl iodo-alkyl) tetrahydrofuran (THF) fast.
2, synthetic method according to claim 1 is characterized in that: reaction substrate optical activity (R)-4, the mol ratio of 5-connection enol and electrophilic reagent N-iodo succimide is 1: 1.0～2.0.
3, synthetic method according to claim 1 is characterized in that: the concentration of mixture in acetonitrile is 0.05～0.15mol/L.
4, synthetic method according to claim 1 is characterized in that: the mol ratio of mixture and two (triphenylphosphine) palladium chloride is 1: 0.015～0.055.
5, synthetic method according to claim 1 is characterized in that: the mol ratio of mixture and cuprous iodide is 1: 0.015～0.055.
6, synthetic method according to claim 1 is characterized in that: the mol ratio of mixture and propiolic alcohol is 1: 0.15～0.35.
7, synthetic method according to claim 1 is characterized in that: the mol ratio of mixture and diethylamide is 1: 0.15～0.35.
8, synthetic method according to claim 1 is characterized in that: (R)-4,5-connection enol concentration in methylene dichloride is 0.05～0.2mol/L.
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103254029A (en) * 2013-03-29 2013-08-21 浙江大学 Synthesis method of 2-iodoallyfluoride compound
CN103694204A (en) * 2013-12-25 2014-04-02 河南理工大学 1,2,4-trisubstituent furan compound and preparation method thereof
CN116143134A (en) * 2023-02-17 2023-05-23 江苏海格新材料有限公司 Preparation method of silicon micropowder for integrated circuit packaging

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103254029A (en) * 2013-03-29 2013-08-21 浙江大学 Synthesis method of 2-iodoallyfluoride compound
CN103694204A (en) * 2013-12-25 2014-04-02 河南理工大学 1,2,4-trisubstituent furan compound and preparation method thereof
CN103694204B (en) * 2013-12-25 2015-05-13 河南理工大学 1,2,4-trisubstituent furan compound and preparation method thereof
CN116143134A (en) * 2023-02-17 2023-05-23 江苏海格新材料有限公司 Preparation method of silicon micropowder for integrated circuit packaging
CN116143134B (en) * 2023-02-17 2023-10-20 江苏海格新材料有限公司 Preparation method of silicon micropowder for integrated circuit packaging

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