CN109867643B - Polysubstituted furan derivative and synthesis thereof - Google Patents
Polysubstituted furan derivative and synthesis thereof Download PDFInfo
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- CN109867643B CN109867643B CN201711250718.6A CN201711250718A CN109867643B CN 109867643 B CN109867643 B CN 109867643B CN 201711250718 A CN201711250718 A CN 201711250718A CN 109867643 B CN109867643 B CN 109867643B
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Abstract
The invention discloses a polysubstituted furan derivative and a synthesis method thereof. alpha-carbonyl-N, S-ketene acetal and ylide are used as initial raw materials, salt is used as an accelerant, under the heating condition, a furan ring is constructed in one step, a polysubstituted furan derivative is generated, and the obtained furan derivative has certain potential pharmaceutical activity. The method has the advantages of easily obtained raw materials, simple and convenient operation, mild synthesis reaction conditions, high reaction efficiency and diversity of functional groups.
Description
Technical Field
The invention relates to an unsaturated oxygen-containing heterocyclic compound polysubstituted furan derivative and a synthesis method thereof. alpha-carbonyl-N, S-ketene acetal is used as initial raw material and salt is used as promoter, and the multi-substituted furan derivative is generated in one step through cyclization reaction.
Compared with the reported synthetic method of the furan derivative, the method has the advantages of easily obtained raw materials, simple and convenient operation, high synthesis reaction efficiency, 68-91% of yield, and good stereoselectivity and functional group diversity of the product. The polysubstituted furan skeleton structure synthesized by the method can be used as an intermediate of structures of medicines and chemical products.
Background
The furan derivative is not only a structural unit of a natural product and an important drug, but also an important intermediate for organic synthesis, and is widely applied to the fields of medicines, pesticides, chemical engineering and the like. Drugs containing furan-like backbones, such as the novel analgesic Bicifadine (org. Lett.2006,8,3885), the antibiotic indomycin Indolozomycin (J.Am. chem. Soc.1993,115,30), the HCV protease inhibitor bocepredyverine (org. Process Res.Dev. arms ASAP, DOI:10.1021/op500065 t).
At present, there are two main methods for synthesizing furan derivatives: transition metal catalyzed coupling reactions and cyclization reactions of unsaturated ketones or alcohols. The invention synthesizes a series of polysubstituted furan derivatives with different structures by using alpha-carbonyl-N, S-ketene acetal 2 which is easy to prepare, has structural diversity and multiple reaction centers as a raw material and through one-step cyclization reaction under the promotion of salt.
Disclosure of Invention
The invention aims to realize the construction of furan rings by one step by taking alpha-carbonyl-N, S-ketene acetal 2 which is easy to prepare, has structural diversity and multiple reaction centers as a raw material to synthesize the polysubstituted furan derivative with potential pharmaceutical activity.
In order to achieve the purpose, the technical scheme of the invention is as follows:
the invention provides a synthesis method of a polysubstituted furan derivative 1, which specifically comprises the steps of taking alpha-carbonyl-N, S-ketene acetal 2 as an initial raw material and salt as an accelerant to perform cyclization reaction to generate the polysubstituted furan derivative 1 in one step;
the molecular structural formula of the alpha-carbonyl-N, S-ketene acetal 2 is as follows,
R1selected from the following groups: methyl, aryl, naphthalene, furan, thiophene or arylcyclopropane; r2Is methyl, aryl, naphthalene ring, furan ring, thiophene ring or aryl cyclopropane; r4Is methyl, aryl or arylcyclopropane; wherein aryl isPhenyl and aryl with substituent groups on the benzene ring, wherein the substituent groups on the benzene ring are 1-5 of methyl, methoxy, fluorine, chlorine, bromine, iodine, trifluoromethyl, nitro, cyano and carboxyl, and the number of the substituent groups is 1-5.
The molecular structural formula of the sulfur ylide 3 is as follows:
R3selected from the following groups: methyl or aryl; 2R5Is methyl or aryl; wherein the aryl is phenyl and aryl with substituent groups on the benzene ring, the substituent groups on the benzene ring are 1-5 of methyl, methoxy, fluorine, chlorine, bromine, iodine, trifluoromethyl, nitro, cyano and carboxyl, and the number of the substituent groups is 1-5.
The synthetic route is shown in the following reaction formula,
wherein: the salt promoter is zinc chloride (ZnCl)2) Zinc bromide (ZnBr)2) Lithium chloride (LiCl), lithium bromide (LiBr), copper bromide (CuBr)2) One or more than two of the alpha-carbonyl-N, S-ketene acetals 2 and the salt in a molar ratio of 1:0.1-1: 1.0;
the reaction solvent is one or a mixture of more than two of N, N-Dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N-methylpyrrolidone (NMP), toluene and 1, 4-dioxane; the molar concentration of the alpha-carbonyl-N, S-ketene acetal in the reaction solvent is 0.05-1.0M;
the reaction atmosphere is air, oxygen, nitrogen or argon; the reaction time is 0.1-48 hours; the reaction temperature is 0-130 ℃.
The salt in the reaction of alpha-carbonyl-N, S-ketene acetal 2 to form 1 is preferably ZnCl2Or CuBr2。
The reaction of the alpha-carbonyl-N, S-ketene acetal 2 to form 1 is preferably carried out in the aprotic nonpolar solvent toluene.
The reaction time for the formation of 1 from the alpha-carbonyl-N, S-ketene acetal 2 is preferably from 5 to 12 hours.
The optimal reaction temperature for the reaction of alpha-carbonyl-N, S-ketene acetal 2 to produce 1 is 100-120 ℃.
The preferred molar ratio of 2 to salt in the reaction of alpha-carbonyl-N, S-ketene 2 to 1 is from 1:0.1 to 1: 1.0.
The preferred molar ratio of 2 to 3 in the reaction of alpha-carbonyl-N, S-ketene 2 to 1 is from 1:1.0 to 1: 5.0.
The invention has the following advantages:
1) the synthon alpha-carbonyl-N, S-ketene acetal 2 has structural diversity and can be used for synthesizing polysubstituted furan derivatives 1 with different types and structures.
2) The synthon 2 is 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 polysubstituted furan derivative 1 uses ZnX which has lower price and is relatively nontoxic2As an accelerator.
4) The synthesis reaction of the polysubstituted furan derivative 1 builds furan rings in one step, and the yield of the product is high and can reach 91 percent at most.
5) The polysubstituted furan derivative 1 product has good stereoselectivity and functional group diversity and wide applicability.
In a word, the invention utilizes the structural diversity and multiple reaction centers of the alpha-carbonyl-N, S-ketene acetal 2 to efficiently synthesize the polysubstituted furan derivatives 1 with different types and structures, the raw materials are cheap and easy to obtain, the polysubstituted furan structure is obtained, the operation is simple and convenient, and the yield of the target product is high.
Detailed Description
In a toluene solvent at 110 ℃, the dithioketene derivative A and the arylamine B react to generate alpha-carbonyl-N, S-ketene acetal 2.
The specific process is as follows: dithioketene derivative A (10.0mmol) and arylamine B (10.0mmol) were dissolved in 20mL of toluene, and BF was added3.OEt2(10 mol%) in 110 ℃ oil bath stirring reaction, TLC detection, raw material two condensation ketene dithio reaction complete stop reaction. After cooling to room temperature, the volatile components were removed under reduced pressure and then separated by column chromatography on silica gel (eluent petroleum ether (60-90 ℃)/ethyl acetate, v/v 20:1) to give the desired product 2. The target product is confirmed by the measurement of nuclear magnetic resonance spectrum and high-resolution mass spectrum.
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-aniline-1-butene-3-one 2a (0.5mmol), thioylide 3(1.0mmol) and zinc chloride (0.05mmol) were weighed in sequence into a 25mL Schlenk reaction flask, and 5mL of toluene was added under nitrogen, and the flask was put in an oil bath at 110 ℃ for reaction for 12 hours. After completion of the reaction, the mixture was cooled to room temperature, the volatile components were removed under reduced pressure, and then the residue was subjected to silica gel column chromatography (petroleum ether (60-90 ℃ C.)/ethyl acetate, v/v ═ 50:1 as an eluent) to give the desired product 1a (74mg, yield 71%) as a yellow solid. 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-benzylamine-1-butene-3-p-methoxybenzene-3-one 2b (0.5mmol), thioylide 3(1.0mmol) and zinc chloride (0.05mmol) were weighed in sequence in a 25mL Schlenk reaction flask, and 5mL of toluene was added under nitrogen, and the flask was put in an oil bath at 110 ℃ for reaction for 12 hours. After completion of the reaction, the mixture was cooled to room temperature, the volatile components were removed under reduced pressure, and then the residue was subjected to silica gel column chromatography (petroleum ether (60-90 ℃ C.)/ethyl acetate, v/v ═ 50:1 as an eluent) to give the desired product 1b (165mg, yield 86%) as a yellow solid. The target product is confirmed by the measurement of nuclear magnetic resonance spectrum and high-resolution mass spectrum.
Typical compound characterization data
2-Phenylacetyl-3-benzylamino-5-p-methoxyphenyl furan derivative (1b) as a yellow solid, mp 111-.1H NMR(400MHz,CDCl3)δ8.21(dd,J＝2.9Hz,2H,aromatic CH),7.91(dd,J＝7.6Hz,1H,NH),7.69(d,J＝8.8Hz,2H,aromatic CH),7.52(dd,J＝23Hz,3H,aromatic CH),7.36(m,4H,aromatic CH),6.97(d,J＝8.8Hz,2H,aromatic CH),6.36(s,1H,furan),4.63(m,2H,CH2),3.87(s,3H,OCH3).13C{H}NMR(100MHz,CDCl3)δ178.2,160.8,158.2,151.9,138.4,138.1,135.0,130.9,128.7,128.6,128.1,127.3,126.9,126.8,121.9,114.2,94.9,55.3,48.5.C25H21NO3HRMS theoretical value of ([ M + H ]]+) 384.1626; measured value 384.1628.
The method has the advantages of easily obtained raw materials, simple and convenient operation, mild synthesis reaction conditions, high reaction efficiency and diversity of functional groups.
Claims (6)
1. A method for synthesizing polysubstituted furan derivative 1 is characterized by comprising the following steps: the molecular structural formula of the polysubstituted furan derivative 1 is as follows:
R1selected from methyl, R2And R3Is phenyl or phenyl with substituent, the substituent in the phenyl with substituent is 1-5 of methyl, methoxy, fluorine, chlorine, bromine, iodine, trifluoromethyl, nitro, cyano and carboxyl, and the number of the substituent is 1-5;
the synthesis method of the polysubstituted furan derivative 1 comprises the following steps: taking alpha-carbonyl-N, S-ketene acetal 2 as a starting material and salt as an accelerant, and carrying out cyclization reaction with sulfur ylide 3 under the heating condition to generate a polysubstituted furan derivative 1 in one step;
the molecular structural formula of the alpha-carbonyl-N, S-ketene acetal 2 is as follows:
R1 、R2as defined for derivative 1; r4Is methyl;
the molecular structural formula of the sulfur ylide 3 is as follows:
R3as defined for derivative 1; 2R in the formula5Is methyl;
the synthetic route is shown in the following reaction formula,
wherein: the salt promoter is zinc chloride (ZnCl)2) Or zinc bromide (ZnBr)2) One or two of them;
the reaction solvent is toluene; the reaction atmosphere is one or two of nitrogen or argon.
2. The method for synthesizing polysubstituted furan derivative 1 according to claim 1, wherein:
the molar ratio of the alpha-carbonyl-N, S-ketene acetal 2 to the salt is 1:0.1-1: 1.0;
the molar concentration of the alpha-carbonyl-N, S-ketene acetal in the reaction solvent is 0.05-1.0M;
the reaction time is 0.1-48 hours; the reaction temperature is 0-130 ℃.
3. The method for synthesizing polysubstituted furan derivative 1 according to claim 1, wherein:
the reaction time for the production of 1 from the alpha-carbonyl-N, S-ketene acetal 2 is 5 to 12 hours.
4. The method for synthesizing polysubstituted furan derivative 1 according to claim 1, wherein:
the reaction temperature for generating 1 from the alpha-carbonyl-N, S-ketene acetal 2 is 100 ℃ and 120 ℃.
5. The method for synthesizing polysubstituted furan derivative 1 according to claim 1, wherein:
the molar ratio of the 2 to the salt promoter in the reaction of generating 1 from the alpha-carbonyl-N, S-ketene acetal 2 is 1:0.1-1: 1.0.
6. The method for synthesizing polysubstituted furan derivative 1 according to claim 1, wherein:
the molar ratio of 2 to 3 in the reaction of producing 1 from alpha-carbonyl-N, S-ketene acetal 2 is 1:1.0-1: 5.0.
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| CN112920111B (en) * | 2019-12-06 | 2022-05-17 | 中国科学院大连化学物理研究所 | Polysubstituted pyridine derivative and synthetic method thereof |
| CN112174880B (en) * | 2020-10-15 | 2022-07-29 | 华侨大学 | Preparation method of 1,3,4, 6-tetra-substituted pyridone derivative |
| CN112142642B (en) * | 2020-10-15 | 2022-03-04 | 华侨大学 | Preparation method of 1,2, 3-trisubstituted-5-trifluoromethyl pyrrole derivative |
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| Bo Sung Kim等.Reactions of Thioaroylketene S,N-Acetals with 1,3-Dicarbonyl Compounds in the Presence of Mercury(II) Acetate: A General Route to 2-Acyl- and 2-Aroyl-3-(alkylamino)-5-arylthiophenes and 2-(Ethoxycarbonyl)-3-(methylamino)-5-arylthiophenes.《J. Org. Chem.》.1998,第63卷(第18期),6086-6087. * |
| DAVID M. MCKINNO等.The reactions of isothiazolium salts with selected nucleophilic reagents. The preparation of thieno[2,3-c]isothiazolium salts.《Can. J. Chem.》.1977,第55卷1123-1128. * |
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| Reactions of Thioaroylketene S,N-Acetals with 1,3-Dicarbonyl Compounds in the Presence of Mercury(II) Acetate: A General Route to 2-Acyl- and 2-Aroyl-3-(alkylamino)-5-arylthiophenes and 2-(Ethoxycarbonyl)-3-(methylamino)-5-arylthiophenes;Bo Sung Kim等;《J. Org. Chem.》;19980819;第63卷(第18期);6086-6087 * |
| Rhodium(II)-mediated reactions of thiobenzoylketene S,N-acetals with -diazo carbonyl compounds: synthesis of 2-substituted 3-alkylamino-5-phenylthiophenes;Hyun Min Song等;《J. Chem. Soc., Perkin Trans. 1》;20021014;2414-2417 * |
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| The reactions of isothiazolium salts with selected nucleophilic reagents. The preparation of thieno[2,3-c]isothiazolium salts;DAVID M. MCKINNO等;《Can. J. Chem.》;19771231;第55卷;1123-1128 * |
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