CN102659755A - Preparation method of base-catalyzed multisubstituted thiophene - Google Patents
Preparation method of base-catalyzed multisubstituted thiophene Download PDFInfo
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- CN102659755A CN102659755A CN2012100953164A CN201210095316A CN102659755A CN 102659755 A CN102659755 A CN 102659755A CN 2012100953164 A CN2012100953164 A CN 2012100953164A CN 201210095316 A CN201210095316 A CN 201210095316A CN 102659755 A CN102659755 A CN 102659755A
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Abstract
The invention relates to a preparation method of a base-catalyzed multisubstituted thiophene. The preparation method realizes base-catalyzed intramolecular one-step synthesis. The preparation method is characterized in that bis(alkylthio)enyne is rearranged in the presence of an alkali as a catalyst, wherein based on a bis(alkylthio)dialkenyl intermediate, sulphur of alkylthio groups attacks middle carbon of dialkenyl and alkyl of the alkylthio groups moves to a dialkenyl end; and after a series of cascade reactions, one-step synthesis of the base-catalyzed multisubstituted thiophene having a high functionalization degree is realized, wherein R1 represents aryl or heteroaryl; R2 represents aryl; R' represents alkyl; and EWG represents acyl or acylamino. The preparation method can efficiently prepare high-purity thiophene derivatives.
Description
Technical field
[0001] the invention belongs to the Synthetic Organic Chemistry technical field, be specifically related to a kind of preparation method of polysubstituted thiophene of base catalysis.
Background technology
[0002] thiophene is one type of important heterogeneous ring compound; Be not only the key structure unit of many biologically active native products, medicine and organic conductive material etc.; But also be multiduty organic synthesis, so the compound method of development thiphene ring be always one of important subject of Synthetic Organic Chemistry (
J. Org. Chem.,
2010,
75, 6998-7001.;
Tetrahedron,
2004,
60, 6085-6089.;
Org. Lett.,
2006,
8, 1625-1628.).Up to the present the method that has developed comprises: Hinsberg building-up reactions, Gewald building-up reactions, intramolecularly building-up reactions, polycomponent coupling method and other multistep operant response etc.Wherein, the substituted alkynes alkene of alkylthio prepares the existing bibliographical information of molecule inner ring condensation reaction of the thiophenes method of highly functionalization, but its its shortcoming is to use precious metals such as Pd, Au, Ag, and environment is had pollution, the shortage practical value (
J. Org. Chem.,
2010,
75, 6998-7001.;
Angew. Chem. Int. Ed.,
2006,
45, 4473 – 4475.;
Org. Lett.,
2009,
11, 5710-5713).In addition, these disclosed catalystsystem also have some defectives, for example: the substrate narrow range, long reaction time, reactions step is complicated, and the product productive rate is low etc.
In recent years, the organic chemical reactions of base catalysis becomes one of focus direction of current organic chemistry research, and the chemical reaction of multiple base catalysis is in the news, such as carbon-to-carbon linked reaction, carbon-heteroatoms linked reaction, intramolecular reaction, multi-component reaction etc. (
Eur. J. Org. Chem.,
2005,
24, 5277-5288).Rapid deterioration along with global ecological environment; How to realize that Sustainable development has become the significant problem of face of mankind, with decontamination from the source, save resource be the Green Chemistry research of the core strong means that become the increasingly serious ecological environment problem of solution (
Energy Environ. Sci. 2009,
2, 1038-1049.).
Up to the present, bibliographical information is not also seen in the reaction that under base catalysis, prepares the thiophenes of highly functionalization by the substituted alkynes alkene of 1,1-bialkyl sulphide.
Summary of the invention
The preparation method who the purpose of this invention is to provide a kind of intramolecularly one-step synthesis polysubstituted thiophene of base catalysis.The substituted alkynes alkene of 1,1-bialkyl sulphide is at first reset under the catalysis of alkali; Join the alkene midbody through the substituted thiazolinyl of 1,1-bialkyl sulphide, sulphur is to joining the attack of alkene middle carbon in the alkylthio, and the alkyl in the alkylthio is to joining the migration of alkene end position; Through a series of cascade reactions, the thiophene of one-step synthesis highly functionalization.
Reaction equation involved in the present invention is following:
Comprise that the substituted alkynes alkene of 1,1-bialkyl sulphide is at first reset under the catalysis of alkali, joins the alkene midbody through the substituted thiazolinyl of 1,1-bialkyl sulphide with a kind of molecule inner ring condensation reaction that the substituted alkynes alkene of 1,1-bialkyl sulphide prepares the thiophenes method of highly functionalization under the catalysis of alkali; Sulphur is to joining the attack of alkene middle carbon in the alkylthio; Alkyl in the alkylthio is to joining the migration of alkene end position, a series of cascade reactions of process, the thiophene of one-step synthesis highly functionalization; Wherein, R
1Be aryl, heteroaryl, R
2Be aryl, R
'Be alkyl, EWG is acyl group, carboxamido-group.Can obtain highly purified thiophene derivant efficiently with the inventive method.
Detailed process can be represented as follows:
(1)From functionalized dithio keteal and alkynol is the synthetic substituted alkynes ene compound of 1,1-bialkyl sulphide of raw material
1
Its consumption is: the mol ratio of functionalized dithio keteal and propynol and trivalent iron salt is 1:1.1:0.3.Solvent is a polar solvent, for example
N, N-N (DMF), 1,4-dioxane, ethanol, acetonitrile.
(2)In certain reaction temperature and solvent, by the substituted alkynes alkene of 1,1-bialkyl sulphide
1The thiophenes of preparation highly functionalization under base catalysis
2
With respect to the substituted alkynes alkene of 1,1-bialkyl sulphide
1, the amount of alkali is
11.0 times of consumption.Temperature of reaction is 15-40 ° of C, is the best with 25 ° of C.Alkali can be selected DBU, triethylamine.Solvent can be selected toluene, 1, and 4-dioxane, methyl alcohol, DMSO 99.8MIN. are best with high boiling point, nonpolar DMSO 99.8MIN..
The present invention has simple to operate; Raw material and reagent are easy to get, mild condition, reaction system environmental protection; The product easy separation and easy purification; Be applicable to the thiophenes of synthetic various highly functionalizations, be specially adapted to large-scale industrial production, can make highly purified thiophenes efficiently, with high yield.
Description of drawings
Fig. 1 is the preparing method's of the polysubstituted thiophene of base catalysis reaction expression;
Fig. 2 is a thiophene
2b 1The nuclear magnetic resonance spectrum of H-NMR;
Fig. 3 is a thiophene
2b 13The nuclear magnetic resonance spectrum of C-NMR;
Fig. 4 is a thiophene
2e 1The nuclear magnetic resonance spectrum of H-NMR;
Fig. 5 is a thiophene
2e 13The nuclear magnetic resonance spectrum of C-NMR.
Embodiment
Following embodiment will help to explain the present invention, but not limit to its scope.
Embodiment 1
1) the substituted alkynes alkene of 1,1-bialkyl sulphide
1aPreparation
In the 25 mL round-bottomed flasks that have magnetic stirring apparatus, add acetonitrile (CH
3CN) (4 mL), α-ethanoyl dithio keteal (0.190g, 2.0 mmol) and 1,3-phenylbenzene propynol (0.499g, 12 mmol), under 25 ° of C of room temperature, whipped state, TLC detects substrate and disappears, and reaction finishes.In reaction solution impouring saturated sodium-chloride water solution (10 mL),, merge organic phase with methylene dichloride (3 * 10 mL) extraction; Calcium Chloride Powder Anhydrous is dry, filter; Organic solvent is removed in underpressure distillation then, obtains solid mixture, and (elutriant is V through silica gel column chromatography
Sherwood oil: V
ETHYLE ACETATE=10: 1) obtain yellow liquid 0.57g, the structure of product turns out to be the substituted alkynes alkene of 1,1-bialkyl sulphide through NMR, MS
1a, yield is 75%.
2) thiophene derivant
2aPreparation
In the 25 mL round-bottomed flasks that have magnetic stirring apparatus, add DMSO 99.8MIN. (2 mL), the substituted alkynes alkene of 1,1-bialkyl sulphide
1a(0.38g, 1.0 mmol) and DBU (0.152ml, 1.0 mmol) after stirring, put it into and continue in 25 ° of C oil baths to stir.TLC detects substrate and disappears, and reaction finishes.With (10 mL) in the reaction solution impouring saturated sodium-chloride water solution; Extract with methylene dichloride (3 * 10 mL); Merge organic phase; Water (3 * 10 mL) backwash organic phase then, dry through Calcium Chloride Powder Anhydrous, filter, step such as underpressure distillation obtains the heavy-gravity solid, (elutriant is V to pass through silica gel column chromatography at last
Sherwood oil: V
ETHYLE ACETATE=9: 1) obtain yellow liquid 0.32g, turn out to be pyrrole derivative through NMR, MS
2a, the substituted alkynes alkene of its yield 1,1-bialkyl sulphide
1aFor the basis is 85%.
The spectrum elucidation data
2a:
1 H-NMR?(500?MHz,?CDCl
3)?δ?7.41-7.37?(m,?3H),?7.27-7.22?(m,?2H),?7.19-7.14?(m,?3H),?7.10-7.07?(m,?2H),?3.82?(t,?
J?=?7.5?Hz,?1H),?3.03-2.97?(m,?2H),?2.01-1.92?(m,?2H),?1.79?(s,?3H),?1.39?(t,?
J?=?7.5?Hz,?3H),?0.82?(t,?
J?=?7.5?Hz,?3H);?
13 C-NMR?(CDCl
3,?125?MHz)?δ?195.9,?144.0,?143.8,?138.7,?136.5,?129.9,?129.7,?128.6,?128.5,?128.4,?127.8,?127.4,?126.4,?46.5,?30.7,?30.5,?30.2,?13.8,?12.5;
?HRMS?(ESI)?m/z?calculated?for?C
23H
25OS
2?[M+H]
+:?381.1347,?found?381.1345.
Embodiment 2
Use carboxamido-group
1bReplace in " instance 1 "
1a, triethylamine is an alkali, and other conditions are with " instance 1 ", and experimental result is seen table 1.
The spectrum elucidation data
2b:
1 H-NMR?(500?MHz,?CDCl
3)?δ?7.43-7.35?(m,?3H),?7.24?(t,?
J?=?7.5?Hz,?2H),?7.21-7.14?(m,?3H),?7.07?(d,?
J?=?7.5?Hz,?2H),?5.60?(s,?1H),?5.29?(s,?1H),?3.79?(t,?
J?=?7.5Hz,?1H),?2.98?(dd,?
J?=?7.0,?7.5?Hz,?2H),?2.01-1.91?(m,?2H),?1.37?(t,?
J?=?7.5?Hz,?3H),?0.81?(t,?
J?=?7.5?Hz,?3H);?
13 C-NMR?(CDCl
3,?125?MHz)?δ?165.9,?145.0,?143.7,?140.2,?138.0,?135.6,?133.1,?129.8,?128.6,?128.3,?128.0,?127.3,?126.3,?46.6,?30.7,?30.6,?14.0,?12.5;?
HRMS?(ESI)?m/z?calculated?for?C
22H
24NOS
2?[M+H]
+:?382.1299,?found?382.1319.
Embodiment 3
Use the methyl cinnamoyl
1cReplace in " instance 1 "
1a, temperature is 15 ℃, and other conditions are with " instance 1 ", and experimental result is seen table 1.
The spectrum elucidation data
2c:
1 H-NMR?(500?MHz,?CDCl
3)?δ?7.42-7.33?(m,?4H),?7.26?(t,?
J?=?7.5?Hz,?2H),?7.23-7.19?(m,?2H),?7.19-7.13?(m,?3H),?7.04?(d,?
J?=?7.5?Hz,?2H),?7.00?(d,?
J?=?8.0?Hz,?2H),?6.38?(d,?
J?=?15.5?Hz,?1H),?3.96?(t,?
J?=?7.5?Hz,?1H),?3.00?(dd,?
J?=?7.5?,?7.0?Hz,?2H),?2.29?(s,?1H),?1.99?(dd,?
J?=?7.5,?7.5?Hz,?2H),?1.36?(t,?
J?=?7.5?Hz,?3H),?0.84?(t,?
J?=?7.5?Hz,?3H);?
13 C-NMR?(CDCl
3,?125?MHz)?δ?188.1,?144.6,?143.8,?143.0,?142.8,?140.3,?139.9,?138.7,?136.2,?132.1,?130.0,?129.2,?128.5,?128.4,?128.1,?127.6,?127.4,?126.3,?125.1,?46.5,?30.9,?30.7,?21.3,?13.9,?12.5;
?HRMS?(ESI)?m/z?calculated?for?C
32H
33OS
2?[M+H]
+:?497.1973,?found?497.1973.
Use rubigan
1dReplace in the instance 1
1a, toluene is solvent, and other conditions are with instance 1, and experimental result is seen table 1.
The spectrum elucidation data
2d:
1 H-NMR?(500?MHz,?CDCl
3)?δ?13.7?(d,?
J?=?7.5?Hz,?2H),?7.25?(t,?
J?=?7.5?Hz,?2H),?7.18?(t,?
J?=?7.5?Hz,?1H),?7.07?(d,?
J?=?7.0?Hz,?4H),?3.75?(t,?
J?=?7.5?Hz,?1H),?3.00?(dd,?
J?=?7.5,?7.5?Hz,?2H),?2.01-1.93?(m,?2H),?1.85?(s,?3H),?1.39?(t,?
J?=?7.5?Hz,?3H),?0.82?(t,?
J?=?7.5?Hz,?3H);?
13 C-NMR?(CDCl
3,?125?MHz)?δ?195.6,?144.7,?144.4,?143.6,?138.5,?137.3,?134.9,?133.9,?131.2,?128.7,?128.5,?127.3,?126.5,?46.6,?30.81,?30.8,?30.3,?13.7,?12.6;
?HRMS?(ESI)?m/z?calculated?for?C
23H
24ClOS
2?[M+H]
+:?415.0957,?found?415.0913.
Embodiment 5
Use normal-butyl
1fReplace in the instance 1
1a, temperature is 40 ℃, and other conditions are with instance 1, and experimental result is seen table 1.
The spectrum elucidation data
2f:
1 H-NMR?(500?MHz,?CDCl
3)?δ?7.3-7.37?(m,?3H),?7.25?(t,?
J?=?7.5?Hz,?2H),?7.17?(t,?
J?=?7.5?Hz,?3H),?7.10?(d,?
J?=?7.5?Hz,?2H),?3.90?(t,?
J?=?7.5?Hz,?3H),?2.99?(t,?
J?=?7.5?Hz,?2H),?1.96-1.90?(m,?2H),?1.77?(s,?3H),?1.72?(dd,?
J?=?8.0,?8.0?Hz,?2H),?1.49?(dd,?
J?=?7.5,?7.5?Hz,?2H),?1.27-1.16?(m,?3H),?1.16-1.05?(m,?1H),?0.95?(t,?
J?=?7.5?Hz,?3H),?0.81?(t,?
J?=?7.5?Hz,?3H);?
13 C-NMR?(CDCl
3,?125?MHz)?δ?195.7,?145.6,?144.0,?143.8,?138.6,?137.9,?136.5,?129.9,?128.5,?128.4,?127.8,?127.3,?126.3,?44.6,?37.4,?35.6,?30.5,?30.4,?29.8,?22.3,?22.0,?13.8,?13.6;?
HRMS?(ESI)?m/z?calculated?for?C
27H
33OS
2?[M+H]
+:?437.1973,?found?437.1971.
Embodiment 6
Use fluorophenyl
4gReplace in the instance 1
1a, methyl alcohol is solvent, and other conditions are with instance 1, and experimental result is seen table 1.
The spectrum elucidation data
2g:
1 H-NMR?(500?MHz,?CDCl
3)?δ?1.37?(t,?
J?=?7.5?Hz,?3H),?2.97?(q,?
J?=?7.5?Hz,?2H),?3.97?(s,?2H),?6.36?(d,?
J?=?15.5?Hz,?1H),?6.94-7.01?(m,?4H),?7.06?(t,?
J?=?7.0?Hz,?2H),?7.21?(d,?
J?=?8.5?Hz,?2H),?7.27?(t,?
J?=?7.0?Hz,?2H),?7.36-7.42?(m,?4H);?
13 C-NMR?(CDCl
3,?125?MHz)?δ?13.78,?30.37,?33.36,?115.25,?115.42,?126.23,?127.87,?128.70,?128.80,?129.17,?129.79,?129.86,?133.39,?135.36,?135.38,?135.70,?135.91,?138.49,?138.83,?138.99,?140.89,?145.75,?160.57,?162.52,?186.99;
?HRMS?(ESI)?m/z?calculated?for?C
28H
23ClFOS
2[M+H]
+:?493.0863,?found?493.1011.
Table 1
Claims (3)
1. the preparation method of the polysubstituted thiophene of base catalysis is characterized in that related reaction equation is following:
Wherein, R
1Be aryl, heteroaryl, R
2Be aryl, R
'Be alkyl, EWG is acyl group, carboxamido-group,
Detailed process is following:
From functionalized dithio keteal and alkynol is the synthetic substituted alkynes ene compound of 1,1-bialkyl sulphide of raw material
1:
Its consumption is: the mol ratio of functionalized dithio keteal and propynol and trivalent iron salt is 1:1.1:0.3, and solvent is a polar solvent;
In certain reaction temperature and solvent, by the substituted alkynes alkene of 1,1-bialkyl sulphide
1The thiophenes of preparation highly functionalization under base catalysis
2:
With respect to the substituted alkynes alkene of 1,1-bialkyl sulphide
1, the amount of alkali is
11.0 times of consumption, temperature of reaction is 15-40 ° of C, alkali is selected DBU, triethylamine, solvent is selected toluene, 1,4-dioxane, methyl alcohol, DMSO 99.8MIN..
2. press the preparation method of the polysubstituted thiophene of the described base catalysis of claim 1, it is characterized in that the solvent in (1) does
N, N-N (DMF), 1,4-dioxane, ethanol, acetonitrile, the temperature of reaction in (2) is 25 ° of C.
3. press the polysubstituted thiophene of the base catalysis of the described method preparation of claim 1.
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Application publication date: 20120912 |