CN107235886B - Synthesis method of 2, 3-dihydropyrrole ring - Google Patents

Synthesis method of 2, 3-dihydropyrrole ring Download PDF

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CN107235886B
CN107235886B CN201710536483.0A CN201710536483A CN107235886B CN 107235886 B CN107235886 B CN 107235886B CN 201710536483 A CN201710536483 A CN 201710536483A CN 107235886 B CN107235886 B CN 107235886B
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肖华
孔祥文
刘丽华
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Hefei University of Technology
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    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/46—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with hetero atoms directly attached to the ring nitrogen atom
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Abstract

The invention discloses a method for synthesizing a 2, 3-pyrroline ring compound by adopting p-toluenesulfonyl imine and disubstituted allene under the condition of a phosphine catalyst. The invention is a convenient way for synthesizing the 2, 3-pyrroline cyclic compound without participation of metal reagents, and the obtained hydrogenated pyrrole product is a common basic structure in some bioactive molecules and has potential pharmaceutical chemistry research value. The method for synthesizing the 2, 3-dihydropyrrole has mild conditions, simple and easily obtained raw materials and can conveniently prepare 2-substituted 2, 3-dihydropyrrole compounds with different positions.

Description

Synthesis method of 2, 3-dihydropyrrole ring
Technical Field
The invention relates to the field of chemical synthesis of medicines, in particular to a method for synthesizing 2, 3-dihydropyrrole rings and derivatives thereof by utilizing sulfimide and α gamma disubstituted allenoic acid ester.
Background
2, 3-pyrroline and derivatives thereof are basic structural units of a plurality of medicinal molecules and natural products with medicinal values, and are important medical intermediate structures, for example, spirotriptostatin B is a cell cycle inhibitor separated from marine fungus Aspergillus, β lactam antibiotics of penems with wide clinical application, and active ingredients of african brown ant venom gland secretion, myrmecillin 430A and the like all contain structural fragments of 2, 3-pyrroline rings.
Figure BDA0001340731900000011
The derivatives are also widely applied to the fields of high molecular materials, new materials, foods and the like, and because 2, 3-dihydropyrrole ring structures generally exist in a plurality of bioactive molecules, the synthesis method attracts attention of people, and most methods reported in the literature are metal-catalyzed cycloaddition reaction of aziridine and alkyne, cyclization reaction of strained cyclopropane and amine compounds, intramolecular series cyclization reaction under metal catalysis and the like. The method for rapidly and efficiently synthesizing the 2, 3-dihydropyrrole ring at normal temperature without using a metal catalyst is less, particularly the operation is simple, and a method for synthesizing the 2, 3-dihydropyrrole ring and the derivative thereof in one step is reported to be developed.
Disclosure of Invention
The invention aims to provide a method for efficiently and quickly preparing pyrrole rings at normal temperature by utilizing imine and disubstituted allene under mild reaction conditions without using a metal catalyst.
The synthesis method of the 2, 3-dihydropyrrole ring adopts p-toluenesulfonimide and disubstituted allene to synthesize the 2, 3-dihydropyrrole ring compound under the condition of a phosphine catalyst.
In the above method for synthesizing 2, 3-dihydropyrrole ring, preferably, the p-toluenesulfonimide is aryl or alkyl substituted p-toluenesulfonimide, as shown in formula i, R is aryl or alkyl, and the aryl substituted p-toluenesulfonimide includes (E) -N-benzylidene-4-methylbenzenesulfonamide, (E) -N-halobenzylidene-4-methylbenzenesulfonamide, (E) -N-methoxybenzylidene-4-methylbenzenesulfonamide, formula iii and derivatives thereof; the alkyl-substituted p-toluenesulfonimide comprises a compound shown as a formula IV and a derivative taking the compound shown as the formula IV as a parent nucleus structure.
Figure BDA0001340731900000021
In the above method for synthesizing 2, 3-dihydropyrrole ring, preferably, the disubstituted allene is α, and the γ disubstituted allenic acid ester is shown as formula ii.
In the above method for synthesizing a 2, 3-dihydropyrrole ring, the phosphine catalyst is preferably at least one of triphenylphosphine, tributylphosphine, tricyclohexylphosphine, tri-p-methoxytriphenylphosphine, and tri-p-fluorotriphenylphosphine.
In the above method for synthesizing a 2, 3-dihydropyrrole ring, preferably, the molar ratio of the p-toluenesulfonylimide to the disubstituted allene is 1:1.5-3, and the molar ratio of the phosphine catalyst to the p-toluenesulfonylimide is 0.5-1.5: 1.
In the above-mentioned method for synthesizing 2, 3-dihydropyrrole ring, preferably, the disubstituted allene can be synthesized by the following general method (simple Xu, Lili Zhou, Renqin Ma, Haibin Song and Zhengjie He. "phospine-media Stereoselective recycling reaction of α -substisted Allenoates with Aromatic Aldehydes (J)," org. Lett.,2010,12(3), pp 544-547) by synthesizing an intermediate in a polar solvent such as ethyl acetate, ethyl bromide in dichloromethane, removing hydrogen bromide in an aqueous KOH solution (10g of potassium hydroxide +120ml of distilled water) to form a phosphophyllode, and then combining the phosphophyllode with ethyl bromide in chloroform under heating and refluxing, and then adding propionyl chloride and triethylamine under the conditions of α.
Among the above-mentioned synthetic methods of 2, 3-dihydropyrrole rings, it is preferable that the p-toluenesulfonylimide (Ts-imine) can be prepared by a commonly used laboratory maturation method such as a two-step method (Bing Zhou, Yaxi Yang, Sui Lin, Yuancao Li., "Rhodium-Catalyzed Direct Addition of industries to N-sulfoaldilides 2013) or a method of preparing various aryl, alkyl substituted sulfonylimides by dehydrating titanium tetrachloride (W.Brian Jennings. authors. P.the organic working page. Carl J.Lovel." Anefficient method for the preparation of N-phospho and N-phospho intermediates obtained from metals of metals 3725, moisture of 3784).
The preparation method of Ts imine is as follows:
the method comprises the following steps: the two-step synthesis method has the following reaction formula 1:
Figure 7
reaction scheme 1
A250 ml round-bottom flask was taken, and p-toluenesulfonamide (30mmol), sodium benzenesulfonate (30mmol), formic acid (45ml), and H were added in this order2O (45ml) and benzaldehyde (30mmol), and stirred at room temperature for 3 daysFiltering, washing the solid with water, washing with petroleum ether, dissolving the solid in mixed solution of dichloromethane and sodium bicarbonate, stirring at room temperature, filtering, washing the organic layer with saturated saline solution, drying with anhydrous sodium sulfate, removing solvent by rotary evaporation to obtain the target compound, and further recrystallizing. The yield was about 80%. When the benzaldehyde is benzaldehyde, the obtained target compound is (E) -N-benzylidene-4-methylbenzenesulfonamide; when the benzaldehyde is 2-chlorobenzaldehyde, the obtained target compound is (E) -N- (2-chlorobenzylidene) -4-methylbenzenesulfonamide; when the benzaldehyde is 2-methoxybenzaldehyde, the obtained target compound is (E) -N- (2-methoxybenzylidene) -4-methylbenzenesulfonamide.
The second method comprises the following steps: the titanium tetrachloride dehydration one-step method has the following reaction formula 2:
Figure 9
reaction formula 2
20mmol of (aromatic) aldehydes are dissolved in 1, 2-dichloromethane (160ml), Ts amine (20mmol) is added, 24mmol of titanium tetrachloride and 80mmol of triethylamine are slowly added dropwise under reflux, the mixture is returned to room temperature after continuous reflux for 10 minutes, and the mixture is subjected to aftertreatment. When the (aromatic) aldehyde is benzaldehyde, the obtained target compound is (E) -N-benzylidene-4-methylbenzenesulfonamide; when the (aromatic) aldehyde is 2-chlorobenzaldehyde, the obtained target compound is (E) -N- (2-chlorobenzylidene) -4-methylbenzenesulfonamide; when the (aromatic) aldehyde is 2-methoxybenzaldehyde, the obtained target compound is (E) -N- (2-methoxybenzylidene) -4-methylbenzenesulfonamide; when the (aromatic) aldehyde is furfural, the resulting target compound is formula iii. And when isobutyraldehyde is used as the (aromatic) aldehyde, the target compound is represented by formula IV.
And (3) post-treatment: the mixture was diluted with 200ml of dichloromethane, and the organic layer was washed with 1M HCl, saturated sodium bicarbonate, brine and then rotary evaporated.
The synthesis method comprises the steps of adding p-toluenesulfonimide, disubstituted allene and a reaction solvent into a reaction vessel, uniformly mixing, adding a phosphine catalyst, stirring for reaction for 10-20h, and carrying out aftertreatment to obtain a product.
The above synthesis method, the reaction progress was monitored by TLC, and the reaction was monitored by petroleum ether: ethyl acetate 2-4: and 1, taking a lower point of p-toluenesulfonyl imide on a TLC plate as a product, and waiting for the reaction to be completed.
In the synthesis method, the post-treatment is that after the reaction is finished, thin-layer chromatography separation is adopted, and the used mobile phase is petroleum ether: and (3) eluting with ethyl acetate at a ratio of 4-10:1, collecting a mobile phase, and performing rotary evaporation to obtain the product.
The reaction mechanism of the technical scheme of the invention is as follows: firstly, an intermediate product (formula V) is formed by the action of an electron-deficient allene and triphenylphosphine, then a methyl group with negative electrons and an imine double bond are subjected to nucleophilic addition, and double bond migration is carried out to form a final product, wherein the reaction formula is as shown in the following reaction formula 3:
Figure 5
reaction formula 3
The specific operation steps are as follows: firstly, preparing raw material p-toluenesulfonyl imine, then adding the prepared p-toluenesulfonyl imine, disubstituted allenic acid ester and organic solvent into a reaction bottle, finally adding phosphine catalyst, stirring for reaction for 10-20h, monitoring the reaction progress by TLC, taking the lower point of the p-toluenesulfonyl imine on a TLC platelet (petroleum ether: ethyl acetate ═ 2-4: 1, v/v) as a product, and separating by thin layer chromatography after the reaction is finished, wherein the mobile phase is petroleum ether: and (3) eluting with ethyl acetate 4-10:1(v/v), collecting a mobile phase, and performing rotary evaporation to obtain the product.
In the above method for synthesizing 2, 3-dihydropyrrole ring, the organic solvent may be one of dichloromethane, chloroform, toluene, tetrahydrofuran, anhydrous ether, acetone, ethyl acetate, acetonitrile, DMF, n-hexane, and 1, 2-dichloroethane.
The invention has the beneficial effects that the invention provides a new method for synthesizing 2, 3-dihydropyrrole ring by using Ts imine and α gamma disubstituted allene, which is a convenient way for synthesizing 2, 3-dihydropyrrole ring compound without metal reagent, the obtained hydrogenated pyrrole product is a common basic structure in some bioactive molecules, and the research has high pharmaceutical chemistry research value.
Detailed Description
The following examples are further illustrative of the present invention as to the technical content of the present invention, but the essence of the present invention is not limited to the following examples, and one of ordinary skill in the art can and should understand that any simple changes or substitutions based on the essence of the present invention should fall within the protection scope of the present invention.
Example 1(α, Synthesis of gamma-disubstituted allenic acid ester)
Adding 47.2g of triphenylphosphine and 200ml of ethyl acetate into a 500ml three-neck flask, stirring for 10min, dissolving 20ml of ethyl bromoacetate into 60ml of ethyl acetate, adding the ethyl bromoacetate into the reaction solution to generate white precipitate, and continuing stirring for 12h for aftertreatment: after filtration, washing with ether and drying over anhydrous sodium sulfate, dissolution with 200 dichloromethane, addition of aqueous KOH (10g KOH +120ml water), 2 extractions of the aqueous phase with dichloromethane, drying over anhydrous sodium sulfate in combination with the organic phase, removal of the solvent dichloromethane by rotary evaporation to give the crude phosphorus ylide product of the first step. The reaction formula 4 is as follows:
Figure 11
reaction formula 4
Dissolving the phosphorus ylide product in 25ml of trichloromethane, heating and refluxing for 18h, recovering the room temperature, performing rotary evaporation to remove the solvent, dissolving 7.7ml of triethylamine in 100ml of dichloromethane, adding the dichloromethane into the reaction system, stirring for 2h, adding 1.95ml of propionyl chloride into the reaction system in an ice-water bath, and reacting for 10h at the room temperature. And (2) performing aftertreatment, namely performing rotary evaporation to remove dichloromethane, adding diethyl ether to dissolve the dichloromethane, filtering crude diatomite to obtain a solution, performing rotary evaporation to obtain a light yellow liquid, and separating a product (petroleum ether: ethyl acetate: 50:1) by using a thin layer chromatography method to obtain a product, namely the allenoic acid ester (formula II). Yield (58%). The reaction formula 5 is as follows:
Figure 13
reaction formula 5
Example 2 (Synthesis of p-toluenesulfonylimide)
A250 ml round-bottom flask was taken, and p-toluenesulfonamide (30mmol), sodium benzenesulfonate (30mmol), formic acid (45ml), and H were added in this order2O (45ml) and benzaldehyde (30mmol), stirring at room temperature for 3 days, filtering, washing the solid with water, washing with petroleum ether, dissolving the solid in a mixed solution of dichloromethane and sodium bicarbonate, stirring at room temperature, filtering, washing the organic layer with saturated saline solution, drying with anhydrous sodium sulfate, removing the solvent by rotary evaporation to obtain the target compound (E) -N-benzylidene-4-methylbenzenesulfonamide, and further carrying out recrystallization treatment. The yield was about 80%. The reaction formula 6 is as follows:
Figure 15
reaction formula 6
Example 3
To a reaction flask, 1mL of toluene was added, 26mg (0.1mmol) of (E) -N-benzylidene-4-methylbenzenesulfonamide from example 2 and 48.8mg (0.2mmol) of the dienoic acid ester (formula II) from example 1 were added, and the mixture was stirred for 10 minutes, then 31.4mg (0.12mmol) of triphenylphosphine was added and the mixture was stirred at room temperature for 12 to 15 hours, monitored by TLC (petroleum ether: ethyl acetate ═ 3: 1), and the lower point of p-toluenesulfonylimide on the platelet was taken as the product, and after the reaction was completed, the product was isolated by thin layer chromatography (petroleum ether: ethyl acetate ═ 10:1) to give the corresponding product (formula VI) at 36.6mg with a yield of 77.7%. Its nuclear magnetic resonance hydrogen spectrum:1H NMR(600MHz,CDCl3)δ7.82(d,J＝8.0 Hz,1H),7.75(d,J＝8.2Hz,1H),7.35-7.27(m,7H),5.25-5.05(m,2H),4.51(m,1H), 4.18-4.10(m,4H),3.08(m,1H),2.83(m,1H),2.66(m,1H),2.47(m,1H),2.46-2.43 (s,3H),2.25(m,1H),1.29-1.23(m,6H)。
Figure BDA0001340731900000063
Figure BDA0001340731900000071
example 4
Ts imine was reacted with (0.1mmol,29.3mg) of (E) -N- (2-chlorobenzylidene) -4-methylbenzenesulfonamide, which was represented by the following reaction scheme 7, otherwise similar to example 3, to give the corresponding product 31.2mg in 61.7% yield.
Figure 17
Reaction formula 7
Example 5
Ts imine was taken (0.1mmol,29.3mg) of (E) -N- (3-chlorobenzylidene) -4-methylbenzenesulfonamide, otherwise as in example 3, to give 29.3mg of the corresponding product in 58% yield.
Example 6
Ts imine was taken (0.1mmol,29.3mg) of (E) -N- (4-chlorobenzylidene) -4-methylbenzenesulfonamide, otherwise as in example 3, to give the corresponding product 29.4mg in 58.1% yield. Its nuclear magnetic resonance hydrogen spectrum:1H NMR(600 MHz,CDCl3)δ7.81(d,J＝6.0Hz,1H),7.73(d,J＝6.0Hz,1H),7.32(d,J＝12.0Hz, 2H),7.28(d,J＝12.0Hz,2H),7.21(d,J＝12.0Hz,2H),5.19-4.99(m,2H),4.53(m,1H),4.23(m, 1H),4.17-4.10(m,3H),2.80(m,1H),2.42(s,3H),2.25(m,1H),1.31(m,2H),1.29-1.23 (m,6H)。
example 7
Ts imine was substituted with (0.1mmol,27.7mg) of (E) -N- (4-fluorobenzylidene) -4-methylbenzenesulfonamide, otherwise prepared in example 3, to give 23.7mg of the corresponding product in 48.5% yield.
Example 8
Ts imine was substituted with (0.1mmol,27.7mg) of (E) -N- (3-fluorobenzylidene) -4-methylbenzenesulfonamide, otherwise prepared in example 3, to give the corresponding product 26.1mg in 53.4% yield. Its nuclear magnetic resonance hydrogen spectrum:1H NMR(600 MHz,CDCl3)δ7.81(d,J＝9.8Hz,1H),7.73(d,J＝8Hz,1H),7.30(d,J＝8.3,4H),7.21(m, 2H),5.28-4.99(m,2H),4.53(m,1H),4.25-4.21(m,4H),2.81-2.73(m,1H),2.43(m,4H), 1.32(m,2H),1.26-1.21(m,6H)。
example 9
Ts imine was substituted with (0.1mmol,28.9mg) of (E) -N- (3-methoxybenzylidene) -4-methylbenzenesulfonamide, otherwise as in example 3, to give 28.6mg of the corresponding product in 57.1% yield.1H NMR(600MHz,CDCl3)δ 7.84(d,J＝6.00Hz,1H),7.77(d,J＝6.00Hz,1H),7.45(d,J＝14.6Hz,1H),7.34(d,J＝5.99Hz,1H),7. 30(d,J＝0Hz,1H),7.23(d,J＝12.00Hz,1H),6.95(d,J＝10.4Hz,1H),6.83(d,J＝18.00Hz,1H),5.41- 5.31(m,1H),5.16-4.97(m,1H),4.26-4.13(m,4H),3.79(s,3H),3.30-3.03(m,1H),2.93-2.76(m, 1H),2.67-2.49(m,1H),2.44(s,3H),2.04-1.96(m,1H),1.66-1.62(m,1H),1.33-1.25(m,6H)。
Example 10
Ts imine was substituted with (0.1mmol,28.9mg) of (E) -N- (2-methoxybenzylidene) -4-methylbenzenesulfonamide, otherwise as in example 3, to give 35.8mg of the corresponding product in 71.5% yield.
Example 11
Ts imine was treated with (0.1mmol,28.9mg) of (E) -N- (4-methoxybenzylidene) -4-methylbenzenesulfonamide and the same procedure as in example 3 gave 29.6mg of the corresponding product in 59%.
Example 12
Adding 1mL of toluene into a reaction bottle, adding (0.1mmol,24.9mg) of a compound shown as a formula III (the synthesis method is a titanium tetrachloride dehydration method, namely 20mmol of furfural is dissolved in 1, 2-dichloromethane (160mL), adding Ts amine (20mmol), heating and refluxing, slowly dripping 24mmol of titanium tetrachloride, adding 80mmol of triethylamine, continuing heating and refluxing for 10 minutes, then returning to the room temperature, performing post-treatment, diluting with 200mL of dichloromethane, washing an organic layer with 1M HCl, washing with saturated sodium bicarbonate, washing with salt water, performing rotary evaporation, passing through a column, obtaining about 71 percent of yield), 48.8mg (0.2mmol) of allene diester, stirring for a few minutes, then weighing 31.4mg (0.12mmol) of triphenylphosphine, stirring at the room temperature, monitoring by TLC, separating a product by thin layer chromatography after the reaction is completed (petroleum ether: ethyl acetate is 4:1), 16.8mg of the corresponding product (formula VII) are obtained in a yield of 36%. Its nuclear magnetic resonance hydrogen spectrum:1H NMR(600MHz,CDCl3)δ7.82(d,J＝7.8Hz,1H),7.78(d,J＝8.4Hz,1H), 7.33(d,J＝6.0Hz,2H),7.29(m,1H),6.32-6.27(m,2H),5.31-5.12(m,2H),4.60-4.56(m,2H),4,45 (m,1H),4.23(m,1H),4.38(m,2H),4.12(m,3H),3.06-2.92(m,1H),2.43(m,3H),1.32-1.16(m,6H) .
Figure BDA0001340731900000081
Figure BDA0001340731900000091
Example 13
Ts is a compound represented by formula IV (0.1mmol,22.5mg) synthesized by heating dehydration of titanium tetrachloride by dissolving 20mmol of iso-butyraldehyde in 1, 2-dichloromethane (160ml), adding Ts amine (20mmol), heating reflux and slowly dropping 24mmol of titanium tetrachloride, adding 80mmol of triethylamine, heating reflux for 10min, returning to room temperature, and post-treating by diluting with 200ml of dichloromethane, washing the organic layer with 1M HCl, saturated sodium bicarbonate, brine, and rotary evaporating to obtain a product (VIII) in a yield of about 80%. Example 12 is otherwise identical to example 12, 11.6mg of the corresponding product (VIII) is obtained in a yield of 26.5%. Its nuclear magnetic resonance hydrogen spectrum:1H NMR (600MHz,CDCl3)δ7.74(d,J＝30.0Hz,2H),7.28(d,J＝12.0Hz,2H),5.12(m,1H), 4.46(m,1H),4.22-4.13(m,4H),3.73(m,1H),3.30(m,1H),2.72(m,1H),2.42(m,3H),1.81(m,3H), 1.30(m,2H),1.27-1.24(m,4H),0.91(m,3H),0.84(m,3H).
Figure BDA0001340731900000092

Claims (4)

  1. the synthesis method of the 2, 3-dihydropyrrole ring is characterized in that substituted p-toluenesulfonyl imine and disubstituted allene are adopted to synthesize a 2, 3-dihydropyrrole ring compound under the condition of a phosphine catalyst; the substituted p-toluenesulfonyl imide is (E) -N-benzylidene-4-methylbenzenesulfonamide, (E) -N-halogenated benzylidene-4-methylbenzenesulfonamide, (E) -N-methoxyl benzylidene-4-methylbenzenesulfonamide, a compound shown in a formula III or a compound shown in a formula IV; the disubstituted allene is a compound shown as a formula II, and the phosphine catalyst is triphenylphosphine; the molar ratio of the substituted p-toluenesulfonyl imine to the disubstituted allene is 1:1.5-3, the molar ratio of the phosphine catalyst to the substituted p-toluenesulfonyl imine is 0.5-1.5:1,
    Figure DEST_PATH_IMAGE001
    Figure 595638DEST_PATH_IMAGE002
    。
  2. 2. the synthesis method of claim 1, wherein the substituted p-toluenesulfonimide, the disubstituted allene and the reaction solvent are added into a reaction vessel, mixed uniformly, added with the phosphine catalyst, stirred and reacted for 10-20h, and subjected to post-treatment to obtain the product.
  3. 3. The synthetic method of claim 2 wherein the progress of the reaction is monitored by TLC, in the presence of petroleum ether: ethyl acetate = 2-4: and 1, taking the lower point of the TLC plate substituted for the p-toluenesulfonyl imide as a product, and waiting for the reaction to be completed.
  4. 4. The synthesis method according to claim 2, characterized in that the post-treatment is a thin layer chromatography separation after the reaction is completed, and the mobile phase is petroleum ether: ethyl acetate =4-10:1, the mobile phase was collected and rotary evaporated to give the product.
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