CN113582978A - 3-thio-benzofuran derivative and synthesis method thereof - Google Patents
3-thio-benzofuran derivative and synthesis method thereof Download PDFInfo
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Abstract
The invention provides a 3-thio-benzofuran derivative and a synthesis method thereof. The isatin derived propargyl alcohol compound and thiophenol are subjected to Meyer-Schuster rearrangement/nucleophilic addition/intramolecular cyclization reaction in an organic solvent under the action of an acidic reagent to obtain the 3-thio-benzofuran derivative. The method has the advantages of cheap and easily obtained raw materials, simple steps, easily realized reaction conditions, high yield of target products and good diversity of functional groups of the products, and can prepare the 3-sulfo-and 2-substituted benzofuran derivatives by a one-pot method, thereby being beneficial to subsequent application.
Description
Technical Field
The invention relates to a 3-thio-benzofuran derivative and a synthetic method thereof, belonging to the field of research and development of new drugs.
Background
Benzofuran structures are a class of compound backbones that are widely found in natural products and drug molecules. Natural products containing benzofuran skeletons exhibit good biological activities such as antitumor, antifungal, antioxidant, anti-inflammatory and the like, and therefore, the synthesis of such compounds is of great significance (see a.h. banskota, y.tezuka, k.microdorkawa, k.matsushige, s.kadota, j.nat. prod.2000,63, 1277-. Among them, 3-thio-benzofuran changes the electronegativity and physicochemical properties of the whole molecule due to the incorporation of sulfur heteroatom (see X.ZHao, L.ZHang, X.Lu, T.Li, K.Lu, J.org.chem.2015,80, 2918-2924), and has wider application prospect.
The prior synthesis of 3-thiobenzofuran has been achieved mainly by transition metal-catalyzed electrophilic addition reactions (scheme 1) (see the literature "p.franzmann, s.b.beil, p.m. winterscheid, d.schollmeyer, s.r.waldvogel, Synlett2017,28, 957-. However, expensive noble metals such as palladium, gold and the like are needed to be used as catalysts for synthesis under severe conditions such as high temperature and high pressure, the used raw materials are high in cost and not easy to obtain, the reaction conditions are not easy to realize, the preparation method is complicated, and the yield of the target product is low.
Chinese patent document CN105732552A discloses a method for preparing 2-or 3-thio-benzofuran compounds; directly applying benzofuran derivatives to react with sulfonyl chloride under the action of potassium iodide and triphenylphosphine to synthesize 2-or 3-thio benzofuran derivatives. However, the reaction needs to be carried out under severe conditions such as high temperature, and the tolerance to some sensitive functional groups is not high, which is not favorable for the application in the subsequent drug derivation. Chinese patent document CN104592179A discloses a method for preparing 3-thio-benzofuran compounds; directly applying benzofuran derivatives to react with sulfonyl hydrazide under the catalysis of iodine to synthesize 3-sulfo benzofuran derivatives. However, the substitution at the 2-position in the structure of the obtained product is limited to alkyl or aryl, and there is no description on a heterocycle, particularly a nitrogen-containing heterocycle, which is commonly used in the synthesis of a drug.
Disclosure of Invention
Aiming at the defects in the prior art, the invention provides a 3-thio-benzofuran derivative and a synthesis method thereof. The method has the advantages of cheap and easily obtained raw materials, simple steps, easily realized reaction conditions, high yield of target products and good diversity of functional groups of the products, and can prepare the 3-sulfo-and 2-substituted benzofuran derivatives by a one-pot method, thereby being beneficial to subsequent application.
The technical scheme of the invention is as follows:
a3-thio-benzofuran derivative has a structure shown in the following formula I:
wherein in the structural formula I, R1Is alkyl with 1-18 carbon atoms, acetyl, phenyl, benzyl or benzoyl; r2Is one or more than two of methyl, methoxy, hydrogen atom, fluorine, chlorine, bromine, trifluoromethyl or oxygen trifluoromethyl, the number of the substituent groups is 1,2 or 3, and different substituent groups are the same or different; r3Is hydrogen atom, methyl, chlorine, tertiary butyl or phenyl; r4Is one or more than two of hydrogen atom, methyl, methoxy, fluorine, chlorine or bromine, the number of the substituent groups is 1,2 or 3, and different substituent groups are the same or different.
Preferred according to the invention are those in the formula I in which R1Is methyl or benzyl; r2Is hydrogen atom or bromine, and the number of the substituent groups is 1; r3Is a hydrogen atom; r4Is a hydrogen atom or a methyl group.
Preferably, according to the present invention, the 3-thio-benzofuran derivative has a structure represented by formula Ia, formula Ib, formula Ic or formula Id below:
according to the invention, the substituent R2Can be substituted at any substitutable position on the benzene ring, and the substituent R2May be one or more, and the substituents may be the same or different; substituent R4Can be substituted at any substitutable position on the benzene ring, and the substituent R4May be one or more, and the substituents may be the same or different.
The synthesis method of the 3-thio-benzofuran derivative comprises the following steps:
reacting a compound shown in a formula II with a compound shown in a formula III in an organic solvent under the action of an acidic reagent to obtain a 3-thio-benzofuran derivative (I);
wherein, the compound of formula II and the substituent R in the structural formula of the compound of formula III1、R2、R3、R4And a substituent R in the structural formula of the compound of the formula I1、R2、R3、R4Have the same meaning.
According to the invention, the compound of formula II is prepared by the existing method by taking isatin as a starting material; synthetic methods are described in the literature "org.biomol.chem., 2018,16, 6133".
According to the invention, the organic solvent is preferably one or a mixture of more than two of acetonitrile, 1, 4-dioxane, 2,2, 2-trifluoroethanol, hexafluoroisopropanol, toluene, N, N-Dimethylformamide (DMF), dichloromethane or 1, 2-dichloroethane; preferably, the organic solvent is dichloromethane; the volume ratio of the molar weight of the compound shown in the formula II to the organic solvent is 0.01-1 mol/L.
According to the invention, the acidic reagent is preferably one or a mixture of more than two of p-toluenesulfonic acid, trifluoroacetic acid, boron trifluoride diethyl etherate, copper trifluoromethanesulfonate or ferric trichloride; preferably boron trifluoride diethyl etherate; the molar ratio of the acidic reagent to the compound of formula II is 0.8-5:1, preferably 1.2: 1.
According to the invention, the molar ratio of the compound of formula II to the compound of formula III is preferably 1:0.8 to 3, preferably 1: 1.2.
Preferably, according to the invention, the reaction atmosphere is one or two of air, nitrogen, oxygen or argon.
According to the present invention, the reaction temperature is preferably 10 to 50 ℃, more preferably 20 to 30 ℃, and still more preferably 25 ℃. The reaction time is from 1 to 24 hours, preferably from 10 to 12 hours.
The preferred method for separating and purifying the 3-thio-benzofuran derivative is silica gel column chromatography, and the eluent is a mixture of petroleum ether/ethyl acetate at 60-90 ℃; preferably, the volume ratio of petroleum ether to ethyl acetate is 8: 1.
The reaction route of the invention is as follows:
wherein R is1Is alkyl with 1-18 carbon atoms, acetyl, phenyl, benzyl or benzoyl; r2Is one or more than two of methyl, methoxy, hydrogen atom, fluorine, chlorine, bromine, trifluoromethyl or oxygen trifluoromethyl, the number of the substituent groups is 1,2 or 3, and different substituent groups are the same or different; r3Is hydrogen atom, methyl, chlorine, tertiary butyl or phenyl; r4Is one or more than two of hydrogen atom, methyl, methoxy, fluorine, chlorine or bromine, the number of the substituent groups is 1,2 or 3, and different substituent groups are the same or different.
The invention has the following technical characteristics and beneficial effects:
1. the method does not need metal catalyst, and under the action of acidic reagents such as boron trifluoride ether and the like, the isatin-derived propargyl alcohol compound and thiophenol are subjected to Meyer-Schuster rearrangement/nucleophilic addition/intramolecular cyclization reaction by utilizing a series reaction strategy to obtain the 3-thio-benzofuran derivative.
2. The invention does not use expensive noble metal catalysts such as palladium, gold and the like, and the used raw materials are cheap and easy to obtain; the reaction does not need harsh conditions, and the reaction conditions are mild and easy to realize; the preparation method and the operation are simple, and the 3-sulfo and 2-substituted benzofuran derivatives can be prepared by one step through a one-pot method; the yield of the target product is high and can reach 87%; and the product has good functional group diversity. The 3-thio-benzofuran compound obtained by the invention can provide a candidate compound for new drug discovery, and also can provide a new more green, efficient and concise method for synthesis of 3-thio-benzofuran derivatives.
3. The method effectively reduces the generation of rearrangement byproducts and improves the molar yield of the target product by selecting proper solvent and acid reagent.
Drawings
FIG. 1 is an H-NMR spectrum of the compound of formula Ia prepared in example 1.
Detailed Description
The present invention is described in detail below with reference to examples, but the present invention is not limited thereto.
The methods described in the examples are conventional methods unless otherwise specified; the reagents used are commercially available without further indication.
The yields in the examples are all molar yields.
Example 1
A method for synthesizing 3-thio-benzofuran derivatives comprises the following steps:
for the synthesis of 3-hydroxy-3- ((2-hydroxyphenyl) ethynyl) -1-methylindol-2-one (IIa), see the literature "org.biomol.chem., 2018,16, 6133".
The preparation steps of the compound Ia are as follows: a10 mL round-bottomed flask was charged with Compound IIa (27.9mg, 0.1mmol), dichloromethane (2 mL), thiophenol IIIa (13.2mg, 0.12mmol), boron trifluoride ether (17mg, 0.12mmol) under nitrogen, and reacted at 25 ℃ for 12 hours under nitrogen. Chromatography on silica gel (eluent: petroleum ether (60-90 ℃)/ethyl acetate 8:1, V: V) afforded Ia (32.3mg, molar yield 87%) as a pale yellow solid with a purity of greater than 95%. The target product is confirmed by the measurement of nuclear magnetic resonance spectrum and high-resolution mass spectrum.
Characterization data of the compound Ia, light yellow solid, melting point 197-198 ℃;
the nuclear magnetic spectrum is shown in FIG. 1, and the nuclear magnetic data is as follows:
1H NMR(CDCl3,400MHz):δ7.47–7.42(m,1H),7.37(d,J＝8.2Hz,1H),7.31(dd,J＝8.0,3.2Hz,1H),7.29–7.19(m,6H),7.14(d,J＝7.2Hz,1H),7.01–6.95(m,2H),6.89(d,J＝7.6Hz,1H),5.33(s,1H),3.29(s,3H)；13C NMR(CDCl3,100MHz)δ13C NMR(100MHz,CDCl3)δ172.7,156.3,154.7,144.4,135.9,129.0,128.9,128.8,127.2,126.0,125.8,125.2,124.4,123.5,122.8,120.2,111.6,109.6,108.5,45.0,26.7；IR(neat):3145,2929,1715,1610,1254,965,846cm-1；HRMS-ESI(m/z):calcd for C23H17NO2S[M+H]+:372.1053；found 372.1055.
example 2
A method for synthesizing 3-thio-benzofuran derivatives comprises the following steps:
the synthesis of compound IIb is described in the literature "org.biomol.chem., 2018,16, 6133".
The preparation steps of the compound Ib are as follows: a10 mL round-bottomed flask was charged with Compound IIb (35.7mg, 0.1mmol), dichloromethane (2 mL), thiophenol IIIa (13.2mg, 0.12mmol), boron trifluoride ether (17mg, 0.12mmol) under nitrogen, and reacted at 25 ℃ for 12 hours under nitrogen. Chromatography on silica gel (eluent: petroleum ether (60-90 ℃)/ethyl acetate 8:1, V: V) afforded Ib (38.2mg, 85% molar yield) as a pale yellow solid with a purity of greater than 95%. The target product is confirmed by the measurement of nuclear magnetic resonance spectrum and high-resolution mass spectrum.
Characterization data of the compound Ib comprise light yellow solid, melting point 220-221 ℃;
the nuclear magnetic data are as follows:
1H NMR(400MHz,CDCl3)δ7.47(d,J＝7.7Hz,1H),7.44–7.36(m,2H),7.30(d,J＝7.3Hz,1H),7.26–7.20(m,5H),7.15(dd,J＝5.8,2.7Hz,1H),7.04(s,1H),6.74(d,J＝8.3Hz,1H),5.31(s,1H),3.25(d,J＝5.3Hz,3H).13C NMR(101MHz,CDCl3)δ172.13,155.46,154.76,143.48,135.78,131.81,129.10,128.82,127.86,127.68,127.31,126.12,125.45,123.68,120.31,115.44,111.71,110.16,109.90,44.88,26.82.HRMS-ESI(m/z):calcd for C23H16BrNO2S[M+H]+:449.0085；found 449.0088.
example 3
A method for synthesizing 3-thio-benzofuran derivatives comprises the following steps:
methods for the synthesis of compound IIc are described in the literature "org.biomol.chem., 2018,16, 6133"
The preparation steps of the compound Ic are as follows: a10 mL round-bottomed flask was charged with Compound IIc (35.5mg, 0.1mmol), dichloromethane (2 mL), thiophenol IIIa (13.2mg, 0.12mmol), boron trifluoride ether (17mg, 0.12mmol) under nitrogen, and reacted at 25 ℃ for 12 hours under nitrogen. Chromatography on silica gel (eluent: petroleum ether (60-90 ℃)/ethyl acetate 8:1, V: V) afforded Ib (40.2mg, 90% molar yield) as a pale yellow solid with a purity of greater than 95%. The target product is confirmed by the measurement of nuclear magnetic resonance spectrum and high-resolution mass spectrum.
Characterization data for compound Ic light yellow solid, melting point 242-243 ℃;
1H NMR(400MHz,CDCl3)δ7.45(d,J＝7.3Hz,1H),7.42–7.35(m,3H),7.30(dt,J＝13.6,5.6Hz,6H),7.26–7.18(m,4H),7.18–7.14(m,1H),7.00(d,J＝7.3Hz,1H),6.94(t,J＝7.3Hz,1H),6.78(d,J＝7.9Hz,1H),5.43(s,1H),5.00(q,J＝15.7Hz,2H).13C NMR(100MHz,CDCl3)δ172.89,156.35,154.76,143.50,135.81,135.44,129.00,128.83,128.76,127.67,127.32,127.22,126.07,125.87,125.20,124.50,123.49,122.84,120.25,111.65,109.53,45.04,44.20.
example 4
A method for synthesizing 3-thio-benzofuran derivatives comprises the following steps:
the preparation steps of the compound Id are as follows: a10 mL round-bottomed flask was charged with Compound IIa (27.9mg, 0.1mmol), dichloromethane (2 mL), thiophenol IIIb (14.9mg, 0.12mmol), boron trifluoride ether (17mg, 0.12mmol) under nitrogen, and reacted at 25 ℃ for 12 hours under nitrogen. Chromatography on silica gel (eluent: petroleum ether (60-90 ℃)/ethyl acetate 8:1, V: V) afforded Id (33.9mg, 88% molar yield) as a pale yellow solid with a purity of greater than 95%. The target product is confirmed by the measurement of nuclear magnetic resonance spectrum and high-resolution mass spectrum.
Characterization data of the compound Id comprise light yellow solid, melting point 201-202 ℃;
the nuclear magnetic data are as follows:
1H NMR(400MHz,CDCl3)δ7.44(d,J＝7.6Hz,1H),7.38–7.30(m,2H),7.29–7.16(m,5H),7.07–6.98(m,4H),6.91(d,J＝7.8Hz,1H),5.35(s,1H),3.31(s,3H),2.28(s,3H).13CNMR(101MHz,CDCl3)δ172.77,155.92,154.69,144.42,135.87,132.10,129.76,128.90,128.84,127.68,126.09,125.08,124.45,123.38,122.80,120.23,111.59,110.24,108.48,44.96,26.69,20.94.
comparative example 1
A method for synthesizing 3-thio-benzofuran derivatives comprises the following steps:
a10 mL round-bottom flask was charged with Compound IIa (27.9mg, 0.1mmol), dichloromethane (2 mL), thiophenol IIIa (13.2mg, 0.12mmol), and lanthanum triflate (70.3mg, 0.12mmol) was added under nitrogen and reacted at 25 ℃ for 12 hours under nitrogen. Chromatography on silica gel (eluent: petroleum ether (60-90 ℃)/ethyl acetate 8:1, V: V) afforded Ia (24.9mg, 67% molar yield) as a pale yellow solid with a purity of greater than 95%. The target product is confirmed by the measurement of nuclear magnetic resonance spectrum and high-resolution mass spectrum.
From this comparative example, it is clear that the choice of the type of acidic reagent has a significant influence on the yield of the desired product.
Comparative example 2
A method for synthesizing 3-thio-benzofuran derivatives comprises the following steps:
a10 mL round-bottomed flask was charged with Compound IIa (27.9mg, 0.1mmol), tetrahydrofuran 2mL, thiophenol IIIa (13.2mg, 0.12mmol), boron trifluoride diethyl etherate (17mg, 0.12mmol) under nitrogen, and reacted at 25 ℃ for 12 hours under nitrogen. Chromatography on silica gel (eluent: petroleum ether (60-90 ℃)/ethyl acetate 8:1, V: V) afforded Ia (27.1mg, 73% molar yield) as a pale yellow solid with a purity of greater than 95%. The target product is confirmed by the measurement of nuclear magnetic resonance spectrum and high-resolution mass spectrum.
As can be seen from this comparative example, the choice of the solvent type has a certain influence on the yield of the desired product.
Claims (10)
1. A 3-thio-benzofuran derivative having the structure shown in formula I below:
wherein in the structural formula I, R1Is alkyl with 1-18 carbon atoms, acetyl, phenyl, benzyl or benzoyl; r2Is one or more than two of methyl, methoxy, hydrogen atom, fluorine, chlorine, bromine, trifluoromethyl or oxygen trifluoromethyl, the number of the substituent groups is 1,2 or 3, and different substituent groups are the same or different; r3Is hydrogen atom, methyl, chlorine, tertiary butyl or phenyl; r4Is one or more than two of hydrogen atom, methyl, methoxy, fluorine, chlorine or bromine, the number of the substituent groups is 1,2 or 3, and different substituent groups are the same or different.
2. The 3-thio-benzofuran derivative of claim 1, wherein R in formula I1Is methyl or benzyl; r2Is hydrogen atom or bromine, and the number of the substituent groups is 1; r3Is a hydrogen atom; r4Is a hydrogen atom or a methyl group.
3. The 3-thioxobenzofuran derivative of claim 1 wherein the 3-thioxobenzofuran derivative has a structure represented by formula Ia, formula Ib, formula Ic or formula Id below:
4. a process for the synthesis of 3-thio-benzofuran derivatives as claimed in any one of claims 1 to 3, comprising the steps of:
reacting a compound shown in a formula II with a compound shown in a formula III in an organic solvent under the action of an acidic reagent to obtain a 3-thio-benzofuran derivative (I);
wherein, the compound of formula II and the substituent R in the structural formula of the compound of formula III1、R2、R3、R4And a substituent R in the structural formula of the compound of the formula I1、R2、R3、R4Have the same meaning.
5. The method for synthesizing a 3-thio-benzofuran derivative according to claim 4, wherein the organic solvent is one or a mixture of two or more of acetonitrile, 1, 4-dioxane, 2,2, 2-trifluoroethanol, hexafluoroisopropanol, toluene, N, N-Dimethylformamide (DMF), dichloromethane, or 1, 2-dichloroethane; preferably, the organic solvent is dichloromethane; the volume ratio of the molar weight of the compound shown in the formula II to the organic solvent is 0.01-1 mol/L.
6. The method for synthesizing a 3-thio-benzofuran derivative according to claim 4, wherein the acidic reagent is one or a mixture of two or more of p-toluenesulfonic acid, trifluoroacetic acid, boron trifluoride diethyl etherate, copper trifluoromethanesulfonate, and ferric trichloride; preferably boron trifluoride diethyl etherate; the molar ratio of the acidic reagent to the compound of formula II is 0.8-5:1, preferably 1.2: 1.
7. The method of claim 4, wherein the molar ratio of the compound of formula II to the compound of formula III is 1:0.8-3, preferably 1: 1.2.
8. The method of claim 4, wherein the reaction atmosphere is one or two of air, nitrogen, oxygen, and argon.
9. The process for the synthesis of 3-thio-benzofuran derivatives according to claim 4, wherein the reaction temperature is 10-50 ℃, preferably 20-30 ℃, and more preferably 25 ℃.
10. The method for synthesizing 3-thio-benzofuran derivative according to claim 4, wherein the separation and purification method of the 3-thio-benzofuran derivative is silica gel column chromatography, and the eluent is a mixture of petroleum ether/ethyl acetate at 60-90 ℃; preferably, the volume ratio of petroleum ether to ethyl acetate is 8: 1.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20100292190A1 (en) * | 2005-02-14 | 2010-11-18 | Bionomics Limited | Novel tubulin polymerisation inhibitors |
| CN105732552A (en) * | 2016-04-12 | 2016-07-06 | 天津师范大学 | Preparation method of 2-bit or 3-bit thiobenzofuran compound |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20100292190A1 (en) * | 2005-02-14 | 2010-11-18 | Bionomics Limited | Novel tubulin polymerisation inhibitors |
| CN105732552A (en) * | 2016-04-12 | 2016-07-06 | 天津师范大学 | Preparation method of 2-bit or 3-bit thiobenzofuran compound |
Non-Patent Citations (1)
| Title |
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| JIANXIAO LI等: "Assembly of 3-Sulfenylbenzofurans and 3-Sulfenylindoles by Palladium-Catalyzed Cascade Annulation/Arylthiolation Reaction" * |
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