CN107311963B - Method for synthesizing tetra-substituted furan compound by using tetracarbonyl compound as raw material - Google Patents

Method for synthesizing tetra-substituted furan compound by using tetracarbonyl compound as raw material Download PDF

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CN107311963B
CN107311963B CN201710472280.XA CN201710472280A CN107311963B CN 107311963 B CN107311963 B CN 107311963B CN 201710472280 A CN201710472280 A CN 201710472280A CN 107311963 B CN107311963 B CN 107311963B
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CN107311963A (en
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唐强
罗娟
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Chongqing Medical University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/40—Radicals substituted by oxygen atoms
    • C07D307/46—Doubly bound oxygen atoms, or two oxygen atoms singly bound to the same carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Furan Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

The invention provides a method for synthesizing tetra-substituted furan by using a tetracarbonyl compound as a raw material, which is characterized in that the tetracarbonyl compound and titanium tetrachloride react under stirring by using dichloromethane or toluene as a solvent under the protection of inert gas, and the tetra-substituted furan compound is obtained after the reaction is finished and separated. The synthesis method has the advantages of easily available raw materials, low cost, mild reaction conditions, simple and easily-controlled operation, less side reactions, simple post-treatment, high product yield, great saving of production cost, good economic benefit and suitability for industrial mass production.

Description

Method for synthesizing tetra-substituted furan compound by using tetracarbonyl compound as raw material
Technical Field
The invention relates to a preparation method of a polysubstituted furan compound, in particular to a method for efficiently synthesizing the tetrasubstituted furan compound by taking a tetracarbonyl compound as a raw material and titanium tetrachloride as a condensing agent through a Paal-Knorr reaction.
Background
Furan is an important five-membered heterocyclic compound, and particularly, tetrasubstituted furan derivatives are core structural units of many natural products, medicines and functional materials. Tetra-substituted furans generally have certain biological activities, such as antibacterial, insecticidal, anticancer, anti-inflammatory, antiallergic, hair growth promoting, immunosuppressive, etc.
Many reports are reported about the synthesis of tetra-substituted furan compounds, for example, the tetra-substituted furan compound is prepared by using simple furan as a substrate to carry out structural modification; olefin and alkyne are taken as substrates, and tetra-substituted furan compounds and the like are prepared through a transition metal catalytic cyclization reaction. One of the most classical methods is the Paal-Knorr furan synthesis reaction, which uses 1, 4-dicarbonyl compound as raw material and can prepare polysubstituted furan compound by condensation reaction. Typical conditions for this reaction include: a) bronsted acids (e.g., concentrated sulfuric acid, concentrated hydrochloric acid, trifluoroacetic acid, p-toluenesulfonic acid, and the like); b) lewis acids (e.g. Bi (NO)3)3·5H2O，InCl3，SnCl2·2H2O); c) ionic liquids or eutectic solvents; d) microwave or ultrasonic assisted condensation reaction. Although there are many methods available for this reaction, these methods have certain limitations and are effective only on a portion of the substrate. Therefore, new high-efficiency furan synthesis methods are urgently needed to be developed.
Titanium tetrachloride is a typical lewis acid, has a strong affinity for oxygen-containing compounds, and is widely used in various functional group conversion reactions in organic chemistry. In addition, titanium tetrachloride is a very water-absorbing agent and is often used as a dehydration reagent in the preparation and synthesis of imine or enamine. However, no document is reported at present when titanium tetrachloride is used as a dehydration reagent for the Paal-Knorr furan synthesis reaction.
Disclosure of Invention
The invention aims to provide a method for efficiently synthesizing tetra-substituted furan compound by using tetracarbonyl compound as raw material and titanium tetrachloride as condensing agent to carry out Paal-Knorr reaction.
In order to achieve the purpose, the technical scheme provided by the invention is as follows:
the invention relates to a method for synthesizing tetra-substituted furan compound by using tetracarbonyl compound as raw material: in the presence of titanium tetrachloride, a tetracarbonyl compound shown in a general formula (I) is subjected to condensation reaction in a solvent to obtain a tetra-substituted furan compound shown in a general formula (II), wherein the chemical reaction formula (A) is shown as follows:
Figure GSB0000166038830000021
wherein R is1And R3Same, selected from phenyl, C1-C6Alkyl or alkoxy of (a); r2And R4Same, selected from phenyl, C1-C6Alkyl or alkoxy of, and R1、R2、R3And R4Not simultaneously alkoxy.
Preferably, R1And R3Same, selected from phenyl, C1-C4Alkyl or alkoxy of (a); r2And R4Same, selected from phenyl, C1-C4Alkyl or alkoxy of, and R1、R2、R3And R4Not simultaneously alkoxy.
Wherein the solvent is selected from dichloromethane or toluene.
Wherein the reaction temperature is 0-140 ℃, and the reaction time is 0.1-100 hours.
Preferably, the reaction temperature is 20-80 ℃ and the reaction time is 0.1-24 hours.
Wherein the molar ratio of the tetracarbonyl compound to the titanium tetrachloride is 1 to (1-5).
The method for synthesizing the tetra-substituted furan compound by taking the tetracarbonyl compound as the raw material comprises the following operation steps: under the protection of inert gas, the tetracarbonyl compound and titanium tetrachloride react with dichloromethane or toluene as solvent under stirring, and the tetra-substituted furan compound is obtained after the reaction is finished and separated.
Wherein the progress of the reaction was followed by TLC.
In the method for synthesizing the tetra-substituted furan compound by using the tetracarbonyl compound as the raw material, the separation method comprises the following steps: adding saturated ammonium chloride aqueous solution into the reaction solution for quenching to obtain two-phase solution, separating out an organic phase, extracting a water phase with dichloromethane, combining the organic phase and drying with anhydrous sodium sulfate, performing reduced pressure rotary evaporation and concentration, and then separating by adopting column chromatography.
Preferably, the solvent is toluene, the reaction temperature is 80 ℃, the reaction time is 0.5-2 hours, and the molar ratio of the tetracarbonyl compound to the titanium tetrachloride is 1: 2-3.
Compared with the existing polysubstituted furan synthesis method, the method has the following advantages:
(1) the method for preparing tetra-substituted furan compound by using the tetracarbonyl compound as the substrate through the Paal-Knorr furan synthesis reaction uses titanium tetrachloride as the dehydration reagent for the first time, expands the substrate range of the Paal-Knorr furan synthesis method, and has practical application value.
(2) The tetra-substituted furan compound is difficult to obtain by using the above tetra-carbonyl compound as a raw material through a conventional method, and the method can efficiently synthesize a plurality of tetra-substituted furan compounds, has mild reaction conditions, one-pot reaction and simple operation, and reduces the production cost.
(3) The synthesis method has the advantages of good regioselectivity, less side reactions, easy product separation, simple post-treatment and good yield (about 80%).
In conclusion, the synthesis method (one-pot reaction) disclosed by the invention has the advantages of readily available raw materials, low cost, mild reaction conditions, simplicity and easiness in operation and control, fewer side reactions, simplicity in post-treatment, higher product yield, great saving in production cost, better economic benefit and suitability for industrial mass production.
Detailed Description
The present invention is illustrated in detail by the following examples, but the present invention is not limited to the examples.
Example 1: condensation reaction of Tetracarbonyl Compound Ia
Figure GSB0000166038830000031
In a 50mL two-necked flask equipped with a reflux condenser and under nitrogen atmosphere, freshly distilled toluene (20mL), the tetracarbonyl compound Ia (5mmol) and titanium tetrachloride (10mmol) were added in this order. The reaction was heated to 80 ℃ with stirring for 0.5-2 hours, monitored by TLC and quenched by addition of saturated aqueous ammonium chloride (10mL) to give a biphasic solution. The upper toluene solution was separated by a separatory funnel, and the lower aqueous solution was extracted with dichloromethane (3X 10 mL). The resulting toluene and methylene chloride solution were mixed, dried over anhydrous sodium sulfate, concentrated by rotary evaporation under reduced pressure, and directly subjected to silica gel column chromatography to obtain furan IIa as a yellow oil in 68% yield.
1H NMR(400MHz，CDCl3)δ2.41(s，6H)，2.39(s，6H)；13C NMR(101MHz，CDCl3)δ195.72，153.87，123.26，30.57，13.62；MS(ESI)calcd for C10H13O3(M+H)+：181.1，Found：181.2.
Example 2: condensation reaction of Tetracarbonyl Compound Ib
Figure GSB0000166038830000032
In a 50mL two-necked flask equipped with a reflux condenser and under nitrogen atmosphere, freshly distilled toluene (20mL), a tetracarbonyl compound Ib (5mmol) and titanium tetrachloride (10mmol) were added in this order. The reaction was heated to 80 ℃ with stirring for 0.5-2 hours, monitored by TLC and quenched by addition of saturated aqueous ammonium chloride (10mL) to give a biphasic solution. The upper toluene solution was separated by a separatory funnel, and the lower aqueous solution was extracted with dichloromethane (3X 10 mL). The resulting toluene and methylene chloride solution were mixed, dried over anhydrous sodium sulfate, concentrated by rotary evaporation under reduced pressure, and directly subjected to silica gel column chromatography to give furan IIb as a brown oil in 77% yield.
1H NMR(400MHz，CDCl3)δ7.74-7.65(m，8H)，7.44(t，J＝7.5Hz，3H)，7.36-7.31(m，6H)，7.26(dd，J＝8.9，6.6Hz，3H)；13C NMR(101MHz，CDCl3)δ191.44，152.91，137.49，133.29，129.44，129.34，128.86，128.61，128.38，127.22，123.25；HRMS(ESI)calcd forC19H25O2(M+H)+：429.1491，Found：429.1483.
Example 3: condensation reaction of Tetracarbonyl Compound Ic
Figure GSB0000166038830000041
In a 50mL two-necked flask equipped with a reflux condenser and under a nitrogen blanket, freshly distilled toluene (20mL), the tetracarbonyl compound Ic (5mmol) and titanium tetrachloride (10mmol) were added in this order. The reaction was heated to 80 ℃ with stirring for 0.5-2 hours, monitored by TLC and quenched by addition of saturated aqueous ammonium chloride (10mL) to give a biphasic solution. The upper toluene solution was separated by a separatory funnel, and the lower aqueous solution was extracted with dichloromethane (3X 10 mL). The resulting toluene was mixed with a dichloromethane solution, dried over anhydrous sodium sulfate, concentrated by rotary evaporation under reduced pressure, and directly subjected to silica gel column chromatography to give furan IIc as a colorless oil in a yield of 57%.
1H NMR(400MHz，CDCl3)δ4.28(q，J＝7.1Hz，4H)，2.42(s，6H)，1.32(t，J＝7.1Hz，6H)；13C NMR(101MHz，CDCl3)δ163.64，155.47，113.71，60.60，14.21，13.08；MS(ESI)calcdfor C10H13O3(M+H)+：241.1，Found：241.0.
Example 4: condensation reaction of Tetracarbonyl Compound Id
Figure GSB0000166038830000042
In a 50mL two-necked flask equipped with a reflux condenser and under nitrogen atmosphere, methylene chloride (20mL), a tetracarbonyl compound Id (5mmol) and titanium tetrachloride (20mmol) were added in this order. The reaction was heated to 40 ℃ with stirring for 0.5-2 hours, monitored by TLC and quenched by addition of saturated aqueous ammonium chloride (10mL) to give a biphasic solution. The lower dichloromethane solution was separated by a separatory funnel, and the upper aqueous solution was extracted with dichloromethane (3X 10 mL). The resulting dichloromethane solutions were mixed, dried over anhydrous sodium sulfate, concentrated by rotary evaporation under reduced pressure, and directly subjected to silica gel column chromatography to give furan IId as a colorless oil in 55% yield.
Example 5: condensation reaction of Tetracarbonyl Compound Ie
Figure GSB0000166038830000051
In a 50mL flask under nitrogen atmosphere, methylene chloride (20mL), a tetracarbonyl compound Ie (5mmol) and titanium tetrachloride (25mmol) were added in this order. The reaction was stirred at 20 ℃ for 12 hours, monitored by TLC and quenched by addition of saturated aqueous ammonium chloride (10mL) to give a biphasic solution. The lower dichloromethane solution was separated by a separatory funnel, and the upper aqueous solution was extracted with dichloromethane (3X 10 mL). The resulting dichloromethane solutions were mixed, dried over anhydrous sodium sulfate, concentrated by rotary evaporation under reduced pressure, and directly subjected to silica gel column chromatography to give furan IIe as an oil in 60% yield.

Claims (2)

1. A method for synthesizing tetra-substituted furan compound by using tetracarbonyl compound as raw material is characterized in that: in the presence of titanium tetrachloride, a tetracarbonyl compound shown in a general formula (I) is subjected to condensation reaction in a solvent to obtain a tetra-substituted furan compound shown in a general formula (II), wherein the chemical reaction formula (A) is shown as follows:
Figure FSB0000185831250000011
wherein R is1、R2、R3And R4Same, selected from phenyl;
the operation steps are as follows: under the protection of inert gas, reacting the tetracarbonyl compound and titanium tetrachloride by taking toluene as a solvent under stirring at 80 ℃, adding a saturated ammonium chloride aqueous solution into a reaction solution after the reaction is finished, quenching to obtain a two-phase solution, separating an organic phase, extracting a water phase by using dichloromethane, combining the organic phase, drying by using anhydrous sodium sulfate, carrying out reduced pressure rotary evaporation concentration, then separating by using column chromatography, and separating to obtain the tetra-substituted furan compound;
wherein the molar ratio of the tetracarbonyl compound to the titanium tetrachloride is 1 to (2-3); the reaction time is 0.5-2 hours.
2. The method for synthesizing tetra-substituted furan compounds starting from tetra-carbonyl compounds according to claim 1, wherein the progress of the reaction is followed by TLC.
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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101580498A (en) * 2009-05-26 2009-11-18 西南大学 Green synthesis method of furane derivative

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101580498A (en) * 2009-05-26 2009-11-18 西南大学 Green synthesis method of furane derivative

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* Cited by examiner, † Cited by third party
Title
Ruthenium-Catalyzed Diyne Hydrative Cyclization: Synthesis of Substituted 1,3-Diene Synthons;Barry M. Trost et al.;《Organic Letters》;20050506;第7卷(第11期);第2097-2099页 *
Sterically-crowded pyrroles;H. Snith Broadbent et al.;《Journal of Heterocyclic Chemistry》;19681231;第5卷(第6期);第757-767页 *

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