CN108148021B - 2-imine (3H) polysubstituted furan or thiophene derivative and synthesis thereof - Google Patents
2-imine (3H) polysubstituted furan or thiophene derivative and synthesis thereof Download PDFInfo
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Abstract
The invention discloses a 2-imine (3H) polysubstituted furan (or thiophene) derivative and a synthetic method thereof. 1-alkylthio-1-amino-1-alkene-3-ketone (or thione) and p-toluenesulfonylhydrazone are used as initial raw materials, copper salt is used as a catalyst, under the condition of alkaline heating, 2-imine (3H) polysubstituted furan (or thiophene) derivatives are generated through cyclization and carbene insertion reaction in one step, and the obtained 2-imine furan derivatives can be further converted to generate butyrolactone derivatives or open-loop to form ketone ester structure products. The method has the advantages of easily obtained raw materials, simple and convenient operation, mild synthesis reaction conditions, high reaction efficiency, good product stereoselectivity and diversity of functional groups.
Description
Technical Field
The invention relates to an unsaturated oxygen (or sulfur) containing heterocyclic compound 2-imine (3H) polysubstituted furan (or thiophene) derivative and a synthetic method thereof. 1-alkylthio-1-amino-1-alkene-3-ketone 3 (or thioketone 4) and p-toluenesulfonylhydrazone 5 are taken as initial raw materials, and CuBr2Under the condition of heating and serving as a catalyst, the 2-imine (3H) polysubstituted furan (or thiophene) derivative is generated in one step through cyclization and carbene insertion reaction.
P-toluenesulfonylhydrazone (N-Tosylhydrazone, Angew. chem. int. Ed.2011,50, 7486-containing 7500; Acc. chem. Res.2016,49, 115-containing 127) is a very important intermediate in organic synthesis, and has been widely researched and applied since the discovery in the middle of the last century. The p-toluenesulfonylhydrazone can be used as a novel coupling component to be applied to cross-coupling reaction catalyzed by transition metal, carbon-carbon bonds and carbon heteroatom bonds are efficiently constructed to synthesize a multifunctional organic compound, and synthesis and conversion which are difficult to realize in other reactions are realized.
The p-toluenesulfonylhydrazone is used as a starting material and undergoes a carbene catalysis process, including cyclopropanation reaction, ylide forming reaction, insertion reaction and the like. For the carbene insertion reaction, the carbene insertion into C-H (chem. Commun.2015,51, 7986-. The study on the C-C reaction (chem.Soc.Rev.2016,45, 506-516; J.Am.chem.Soc.2014,136,3013-3015) of carbene insertion mainly focuses on the cleavage of the alpha-C bond of the cyclic ketone (or alcohol) compound and the ring expansion reaction to obtain the (n +1) -membered cyclic ketone (or alcohol) compound. The Bchner reaction (chem.Ber.1885,18,2371; Angew.chem.int.Ed.2015,54, 3056-3060; Synlett 2015,26, 59-62) is a reaction of benzene ring and diazo compound under the catalysis of transition metal catalyst to undergo ring expansion reaction of metal carbene inserted into carbon-carbon bond of benzene ring to obtain seven-membered cyclic compound, and has wide application in the fields of medicine synthesis and materials.
The use of p-toluenesulfonylhydrazone as a metal carbene precursor for the insertion of the olefin C ═ C has not been reported in the literature. We successfully achieved carbene insertion into olefin C ═ C using thionoketene as the polarized internal olefin, reacted with p-toluenesulfonylhydrazone, using cupric bromide as the catalyst, to give the iminofuran product.
Background
The compound of imine furan and furanone is widely existed in natural products and synthetic compounds, has a plurality of biological and pharmaceutical activities, and is widely applied to the fields of medicine, pesticide, spice, food and the like. The 2-imine furan derivative can be easily hydrolyzed to generate the 2-furanone derivative under the acidic condition. For example, gossypic iminolactone (GIL, structure: J.Med.Chem.1991,34, 3301-3305; biochem.Pharmacol.2001,62,81-89) containing an iminofuran structure, which is extracted from gossypol, a natural product, has anti-HIV activity. Cyclic imine derivatives (ACS Symposium Series 584; American Chemical Society: Washington DC, 1995; Chapter 6, pp 60-69) have herbicidal activity. A natural product Spirostribbnin A (structure shown below) isolated from coral tree has many biological activities (Tetrahedron Lett.2001,42,1081). Other polysubstituted 2-furanone derivatives such as spirofuranones (structure below) have antibacterial and antifungal activity (bioorg. med. chem.2003,11,407).
The invention realizes that the metal carbene is inserted into the C ═ C bond of the olefin to synthesize the polysubstituted imine furan derivative. A new organic synthesis methodology for carbene insertion alkenyl C ═ C bonds was developed. The invention has the advantages of easily obtained raw materials, simple and convenient operation, mild synthesis reaction conditions, high efficiency, high yield of 44-82 percent, and good stereoselectivity and functional group diversity of the product.
Disclosure of Invention
The invention aims to synthesize the polysubstituted furan (or thiophene) derivative with potential pharmaceutical activity by taking 1-alkylthio-1-amino-1-alkene-3-ketone 3 (or thioketone 4) which is easy to prepare and has structural diversity and multiple reaction centers and p-toluenesulfonylhydrazone 5 as raw materials and realizing the generation of C-O bonds (or C-S bonds) and 2C-C bonds in one step through intramolecular cyclization and carbene insertion reaction.
In order to achieve the purpose, the technical scheme of the invention is as follows:
at 80 ℃, dithioketene A and primary amine B react in an ethanol solvent to generate 1-alkylthio-1-amino-1-alkene-3-ketone 3 (reaction formula 1). 1-alkylthio-1-amino-1-alkene-3-ketone 3 and Lawson reagent are subjected to toluene reflux to obtain 1-alkylthio-1-amino-1-alkene-3-thioketone 4 (reaction formula 2). The ketone and p-toluenesulfonylhydrazide are prepared into p-toluenesulfonylhydrazone 5 (reaction formula 3) in a methanol solution at 65 ℃.
Then under argon, CuBr2In the presence of a catalyst, 1-alkylthio-1-amino-1-alkene-3-ketone 3 (or thioketone 4) and p-toluenesulfonylhydrazone 5 are used as raw materials to perform intramolecular cyclization and carbene insertion reaction in an organic solvent under alkaline conditions (reaction formulas 4 and 5). And after the reaction is finished, performing product separation and characterization according to a conventional separation and purification method to obtain the 2-imine (3H) polysubstituted furan 1 (or thiophene 2) derivative.
The technical scheme is characterized in that:
1-alkylthio-1-amino-1-alkene-3-ketone 3 (or thioketone 4) and p-toluenesulfonylhydrazone 5 are reactants, A and B are raw materials of 3, and the substituent groups are as follows:
R1selected from the following groups: methyl, phenyl ring containing different substituents (such as hydrogen, methyl, methoxy, fluorine, chlorine, bromine, trifluoromethyl, etc.), naphthyl, furyl or thienyl;
R2is selected from the following groups: alkyl, allyl, benzyl or heterocyclic methylene with 1-18 carbon atoms;
r is selected from the following groups: methyl, ethyl or benzyl;
R3selected from the following groups: methyl, phenyl ring containing different substituents (e.g. hydrogen, methyl, methoxy, fluoro, chloro, bromo, iodo, trifluoromethyl, etc.), naphthyl, furyl or thienyl.
R4Selected from the following groups: methyl, ethyl or a benzene ring containing various substituents (e.g., hydrogen, methyl, methoxy, fluoro, chloro, bromo, iodo, trifluoromethyl, etc.).
2. The metal catalyst is Pd2(dba)3、Pd(OAc)2、Pd(PPh3)2Cl2、RuCl2(PPh3)3、[RuCl2(p-cymene)]2、[Rh(COD)Cl]2、[Cp*RhCl2]2、CuBr、CuI、CuCl2、CuBr2(ii) a Wherein, CuI and CuBr2The effect is better.
3. The alkali is one of lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, potassium tert-butoxide or lithium tert-butoxide; among them, the tert-butoxide has a good effect.
4. The reaction solvent is one of toluene, 1,4-dioxane, 1, 2-Dichloroethane (DCE), Dichloromethane (DCM), ethanol, N-Dimethylformamide (DMF) or dimethyl sulfoxide (DMSO); among them, the reaction is most effective in an aprotic solvent, toluene.
5. The molar concentration of the starting material 3 (or 4) is 0.05-1.0M, preferably 0.1M.
6. The reaction time is 0.5-48 hours. Wherein the optimal reaction time is 16-30 hours.
7. The reaction temperature is 40-140 ℃. Wherein the optimal reaction temperature is 100-120 ℃.
The invention has the following advantages:
1) the raw material 1-alkylthio-1-amino-1-alkene-3-ketone 3 (or thioketone 4) and p-toluenesulfonylhydrazone 5 have structural diversity, and can be used for synthesizing 2-imine (3H) polysubstituted furan 1 (or thiophene 2) derivatives with different types and structures.
2) The raw materials 3 (or 4) and 5 are easy to prepare, the preparation raw materials are cheap and easy to obtain, the cost is low, and the industrial production is easy to realize.
3) The synthesis reaction of the 2-imine (3H) polysubstituted furan 1 (or thiophene 2) derivative is performed by one-step cyclization and carbene is inserted into a C ═ C bond, the conditions are mild, the product yield is high, and the highest product yield can reach 82%.
4) The 2-imine (3H) polysubstituted furan 1 (or thiophene 2) derivative product has good stereoselectivity and functional group diversity and wide applicability.
In conclusion, the invention utilizes the structural diversity and multiple reaction centers of 1-alkylthio-1-amino-1-alkene-3-ketone 3 (or thioketone 4) to efficiently synthesize the 2-imine (3H) polysubstituted furan 1 (or thiophene 2) derivatives with different types and structures, the raw materials are cheap and easy to obtain, the synthesis reaction is further cyclized, and carbene is inserted into a C ═ C bond, the operation is simple and convenient, the yield of the target product is high, and the functionalization can be further realized.
Detailed Description
The following examples are provided to aid in the further understanding of the present invention, but the invention is not limited thereto.
Example 1
In a glove box, 1-methylthio-1-benzylamino-1-en-3-one 3a (0.5mmol), p-toluenesulfonylhydrazone 5a (1.5mmol), cuprous iodide (0.1mmol), and potassium tert-butoxide (1.5mmol) were weighed in sequence, and in a 25mL Schlenk reaction flask, 5mL of toluene solvent was added under nitrogen, stirred at room temperature for 2 minutes, and placed in an oil bath at 100 ℃ for reaction for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, filtered through celite, extracted with ethyl acetate and 10% by mass aqueous ammonia, the organic phase was collected, dried over anhydrous magnesium sulfate, filtered, and the volatile components were removed under reduced pressure, followed by separation by silica gel column chromatography (the eluent was petroleum ether (60-90 ℃)/ethyl acetate, v/v ═ 20:1) to obtain the desired product 1a (128mg, yield 75%) as a colorless liquid. The target product is confirmed by the measurement of nuclear magnetic resonance spectrum and high-resolution mass spectrum.
Example 2
In a glove box, 1-methylthio-1-benzylamino-1-en-3-one 3b (0.5mmol), p-toluenesulfonylhydrazone 5a (1.5mmol), copper bromide (0.05mmol) and lithium tert-butoxide (1.5mmol) were weighed in sequence into a 25mL Schlenk reaction flask, and 5mL of toluene solvent was added under nitrogen, stirred at room temperature for 2 minutes and placed in an oil bath at 110 ℃ for reaction for 24 hours. After the reaction was completed, the mixture was cooled to room temperature, filtered through celite, extracted with ethyl acetate and 10% by mass aqueous ammonia, the organic phase was collected, dried over anhydrous magnesium sulfate, filtered, and the volatile components were removed under reduced pressure, followed by separation by silica gel column chromatography (the eluent was petroleum ether (60-90 ℃)/ethyl acetate, v/v ═ 20:1) to obtain the objective product 1b (145mg, yield 82%) as a colorless liquid. The target product is confirmed by the measurement of nuclear magnetic resonance spectrum and high-resolution mass spectrum.
Example 3
In a glove box, sequentially weighing 1-methylthio-1-benzylamino-1-en-3-one 3d (0.5mmol), p-toluenesulfonylhydrazone 5a (0.5mmol) and Pd2(dba)3(0.025mmol), lithium carbonate (0)5mmol) was placed in a 25mL Schlenk reaction flask, and 5mL of 1,4-dioxane solvent was added under argon, stirred at room temperature for 2 minutes, and placed in an oil bath at 100 ℃ for reaction for 48 hours. After the reaction was completed, the mixture was cooled to room temperature, filtered through celite, extracted with ethyl acetate and 10% by mass aqueous ammonia, the organic phase was collected, dried over anhydrous magnesium sulfate, filtered, and the volatile components were removed under reduced pressure, followed by separation by silica gel column chromatography (the eluent was petroleum ether (60-90 ℃)/ethyl acetate, v/v ═ 20:1) to obtain the objective product 1d (129mg, yield 69%) as a colorless liquid. The target product is confirmed by the measurement of nuclear magnetic resonance spectrum and high-resolution mass spectrum.
Example 4
In a glove box, 1-methylthio-1-benzylamino-1-en-3-one 3e (0.5mmol), p-toluenesulfonylhydrazone 5a (2.0mmol) and RuCl are weighed in sequence2(PPh3)3(0.15mmol), lithium tert-butoxide (1.5mmol) was placed in a 25mL Schlenk reaction flask, 10mL of an ethanol solvent was added under nitrogen, stirred at room temperature for 2 minutes, and placed in an 80 ℃ oil bath for reaction for 40 hours. After the reaction was completed, the mixture was cooled to room temperature, filtered through celite, extracted with ethyl acetate and 10% by mass aqueous ammonia, the organic phase was collected, dried over anhydrous magnesium sulfate, filtered, and the volatile components were removed under reduced pressure, followed by separation by silica gel column chromatography (the eluent was petroleum ether (60-90 ℃)/ethyl acetate, v/v ═ 20:1) to obtain the objective product 1e (109mg, yield 66%) as a colorless liquid. The target product is confirmed by the measurement of nuclear magnetic resonance spectrum and high-resolution mass spectrum.
Example 5
In a glove box, 3g (0.5mmol) of 1-methylthio-1-methylamino-1-en-3-one, 5a (1.5mmol) of p-toluenesulfonylhydrazone, 0.05mmol of cuprous iodide and 1.5mmol of potassium tert-butoxide are weighed in sequence in a 25mL Schlenk reaction flask, 20mL of DCM solvent is added under nitrogen, the mixture is stirred at room temperature for 2 minutes and placed in an oil bath at 40 ℃ for reaction for 16 hours. After the reaction was completed, the mixture was cooled to room temperature, filtered through celite, extracted with ethyl acetate and 10% by mass aqueous ammonia, the organic phase was collected, dried over anhydrous magnesium sulfate, filtered, and the volatile components were removed under reduced pressure, followed by separation by silica gel column chromatography (the eluent was petroleum ether (60-90 ℃)/ethyl acetate, v/v ═ 20:1), to obtain 1g (100mg, yield 76%) of the objective product as a colorless liquid. The target product is confirmed by the measurement of nuclear magnetic resonance spectrum and high-resolution mass spectrum.
Example 6
In a glove box, 1-methylthio-1-octadecylamino-1-en-3-one was weighed in order for 3h (0.5mmol), p-toluenesulfonylhydrazone 5a (2.0mmol), cuprous bromide (0.1mmol), and lithium tert-butoxide (2.0mmol) in a 25mL Schlenk reaction flask, and 5mL of a toluene solvent was added under nitrogen, stirred at room temperature for 2 minutes, and placed in an oil bath at 60 ℃ for reaction for 6 hours. After the reaction was completed, the mixture was cooled to room temperature, filtered through celite, extracted with ethyl acetate and 10% by mass aqueous ammonia, the organic phase was collected, dried over anhydrous magnesium sulfate, filtered, and the volatile components were removed under reduced pressure, followed by separation by silica gel column chromatography (eluent petroleum ether (60-90 ℃)/ethyl acetate, v/v ═ 20:1) to obtain the objective product as a colorless liquid for 1h (148mg, yield 59%). The target product is confirmed by the measurement of nuclear magnetic resonance spectrum and high-resolution mass spectrum.
Example 7
In a glove box, 1-methylthio-1-furamethyleneamino-1-en-3-one 3j (0.5mmol), p-toluenesulfonylhydrazone 5a (1.5mmol), cuprous iodide (0.1mmol), and potassium tert-butoxide (1.5mmol) were weighed in sequence in a 25mL Schlenk reaction flask, and 5mL of an ethanol solvent was added under nitrogen, stirred at room temperature for 2 minutes, and placed in an oil bath at 70 ℃ for reaction for 48 hours. After the reaction was completed, the mixture was cooled to room temperature, filtered through celite, extracted with ethyl acetate and 10% by mass aqueous ammonia, the organic phase was collected, dried over anhydrous magnesium sulfate, filtered, and the volatile components were removed under reduced pressure, followed by separation by silica gel column chromatography (the eluent was petroleum ether (60-90 ℃)/ethyl acetate, v/v ═ 20:1) to obtain the objective product 1j (130mg, yield 79%) as a colorless liquid. The target product is confirmed by the measurement of nuclear magnetic resonance spectrum and high-resolution mass spectrum.
Example 8
In a glove box, 1-methylthio-1-benzylamino-1-en-3-one 3a (0.5mmol), p-toluenesulfonylhydrazone 5c (1.5mmol), cuprous iodide (0.1mmol), and potassium phosphate (1.5mmol) were weighed in sequence into a 25mL Schlenk reaction flask, and 5mL of DMF solvent was added under nitrogen, stirred at room temperature for 2 minutes, and placed in an oil bath at 100 ℃ for reaction for 2 hours. After the reaction was completed, the mixture was cooled to room temperature, filtered through celite, extracted with ethyl acetate and 10% by mass aqueous ammonia, the organic phase was collected, dried over anhydrous magnesium sulfate, filtered, and the volatile components were removed under reduced pressure, followed by separation by silica gel column chromatography (the eluent was petroleum ether (60-90 ℃)/ethyl acetate, v/v ═ 20:1) to obtain 1l (118mg, yield 68%) of the objective product as a colorless liquid. The target product is confirmed by the measurement of nuclear magnetic resonance spectrum and high-resolution mass spectrum.
Example 9
In a glove box, 1-methylthio-1-benzylamino-1-ene-3-thione 4a (0.5mmol), p-toluenesulfonylhydrazone 5a (1.5mmol), cuprous iodide (0.05mmol) and potassium tert-butoxide (1.5mmol) were weighed in sequence into a 25mL Schlenk reaction flask, and 5mL of toluene as a solvent was added under nitrogen, stirred at room temperature for 2 minutes and placed in an oil bath at 100 ℃ for reaction for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, filtered through celite, extracted with ethyl acetate and 10% by mass aqueous ammonia, the organic phase was collected, dried over anhydrous magnesium sulfate, filtered, and the volatile components were removed under reduced pressure, followed by separation by silica gel column chromatography (the eluent was petroleum ether (60-90 ℃)/ethyl acetate, v/v ═ 20:1) to obtain the objective product 2a (119mg, yield 67%) as a colorless liquid. The target product is confirmed by the measurement of nuclear magnetic resonance spectrum and high-resolution mass spectrum.
Claims (5)
1. 2-imine (3)H) Process for the synthesis of polysubstituted furan or thiophene derivatives, 2-imines (3)H) Polysubstituted furan derivative 1, or 2-imine (3)H) The molecular structural formula of the polysubstituted thiophene derivative 2 is as follows:
the 2-imine (3)H) The synthesis method of the polysubstituted furan or thiophene derivative comprises the following steps: 1-alkylthio-1-amino-1-alkene-3-ketone 3 or thioketone 4 and p-toluenesulfonylhydrazone 5 are used as initial raw materials, transition metal is used as a catalyst, cyclization and carbene insertion reaction are carried out in a solvent under the condition of alkaline heating, and 2-imine (3) is generated in one stepH) Polysubstituted furan derivative 1, or 2-imine (3)H) A polysubstituted thiophene derivative 2;
the synthetic route is shown in the following reaction formula,
R1selected from the following groups: methyl, benzene ring containing one or more than two substituents of hydrogen, methyl, methoxy, fluorine, chlorine, bromine and trifluoromethyl, naphthyl, furyl or thienyl;
R2is selected from the following groups: alkyl with 1-18 carbon atoms, allyl, benzyl, furan methylene or tetrahydrofuran methylene;
r is selected from the following groups: methyl, ethyl or benzyl;
R3selected from the following groups: first of allPhenyl, naphthyl, furyl or thienyl containing one or more substituents of hydrogen, methyl, methoxyl, fluorine, chlorine, bromine, iodine and trifluoromethyl;
R4selected from the following groups: methyl, ethyl or benzene ring containing one or more substituents of hydrogen, methyl, methoxy, fluorine, chlorine, bromine, iodine and trifluoromethyl;
the metal catalyst is Pd2(dba)3、Pd(OAc)2、Pd(PPh3)2Cl2、RuCl2(PPh3)3、[RuCl2(p-cymene)]2、[Rh(COD)Cl]2、[Cp*RhCl2]2、CuBr、CuI、CuCl2、CuBr2One or more than two of them;
the alkali is one or more of lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, potassium tert-butoxide or lithium tert-butoxide.
2. A method of synthesis according to claim 1, characterized in that:
wherein: the mol ratio of 1-alkylthio-1-amino-1-alkene-3-ketone 3 or thioketone 4 to p-toluenesulfonylhydrazone 5 is 1:1-1: 4;
the mol ratio of the 1-alkylthio-1-amino-1-alkene-3-ketone 3 or the thioketone 4 to the metal catalyst is 1:0.05-1: 0.3;
the molar ratio of 1-alkylthio-1-amino-1-en-3-one 3 or thioketone 4 to the base is 1:1-1: 4;
the reaction solvent is one or more of toluene, 1,4-dioxane, 1, 2-Dichloroethane (DCE), Dichloromethane (DCM), ethanol, N-Dimethylformamide (DMF) or dimethyl sulfoxide (DMSO); the molar concentration of the 1-alkylthio-1-amino-1-alkene-3-ketone 3 or the thioketone 4 in the reaction solvent is 0.05-1.0M;
the reaction atmosphere is nitrogen and/or argon; the reaction time is 0.5 to 48 hours; the reaction temperature is 40-140 ℃.
3. A synthesis method according to claim 1 or 2, characterized in that: in the reaction of generating 1 from 1-alkylthio-1-amino-1-alkene-3-ketone 3, the molar ratio of 1-alkylthio-1-amino-1-alkene-3-ketone 3 to the metal catalyst is 1: 0.2; in the reaction of producing 2 from thione 4, the molar ratio of thione 4 to the metal catalyst was 1: 0.2.
4. A synthesis method according to claim 1 or 2, characterized in that: in the reaction of generating 1 from 1-alkylthio-1-amino-1-alkene-3-ketone 3, the molar ratio of 1-alkylthio-1-amino-1-alkene-3-ketone 3 to alkali is 1: 3; in the reaction of forming 2 of thione 4, the molar ratio of thione 4 to base is 1: 3.
5. A synthesis method according to claim 1 or 2, characterized in that: the reaction of 1-alkylthio-1-amino-1-alkene-3-ketone 3 to generate 1 is carried out in an aprotic solvent; the reaction of thione 4 to form 2 is carried out in an aprotic solvent.
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