CN110668991B - Method for cyanoalkylation reaction of 1,6-eneyne compound - Google Patents
Method for cyanoalkylation reaction of 1,6-eneyne compound Download PDFInfo
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Abstract
The invention relates to a method for the regioselective cyanoalkylation/cyclization reaction of 1,6-eneyne compounds and azoalkylnitriles in a catalyst-free and additive-free system. The method comprises the steps of adding 1,6-eneyne compounds, azoalkyl nitrile compounds and a solvent into a Schlenk reaction bottle, and stirring and reacting at a certain temperature under the air atmosphere condition to obtain the product 2-pyrrolidone compounds.
Description
Technical Field
The application belongs to the field of organic synthesis, and particularly relates to a method for carrying out regioselective cyanoalkylation/cyclization reaction on 1,6-enyne compounds and azoalkyl nitrile in a catalyst-free and additive-free system.
Background
In polymer chemistry, azoalkylnitriles are widely used as free radical initiators. Traditionally, they only initiate free radical processes and do not participate in chemical reactions. In recent years, azoalkylnitriles have been used as safe and low-toxic cyanating agents in systems in which copper catalysts and/or oxidizing agents are present. In addition, since the azoalkylnitrile is very easily decomposed during heating to generate a cyanoalkyl radical, it is widely used as a cyanoalkylating reagent in organic synthesis. In this context, chemists have developed cyanoalkylation of azoalkylnitriles with alkene and alkyne derivatives. However, the cyanoalkylation reaction of the azoalkylnitrile with the enyne derivative under a catalyst-free and additive-free system has not been reported.
The inventor carries out intensive research on the cyanoalkyl radical reaction in a system without a catalyst and an additive, and in the invention, the inventor provides a novel method for carrying out high-area selectivity cyanoalkylation/cyclization reaction on 1,6-eneyne compounds and azoalkyl nitrile which are used as reaction raw materials in a free radical process in a system without a catalyst and an additive.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a green, efficient, low-cost and high-selectivity cyanoalkylation/cyclization reaction method of 1,6-eneyne compounds and azoalkyl nitriles, which does not need any catalyst or additive and can prepare and obtain 2-pyrrolidone compounds at high yield in a high regioselectivity manner at a mild temperature.
The invention provides a cyanoalkylation/cyclization reaction method, which takes 1,6-eneyne compounds and azoalkylnitrile as raw materials and is prepared by the following steps:
adding 1,6-enyne compound shown in formula 1, azoalkyl nitrile shown in formula 2 and solvent into a Schlenk reaction bottle, placing the reaction bottle at a certain temperature under the air atmosphere condition, stirring for reaction, monitoring the reaction process by TLC or GC until the raw materials are completely reacted, and carrying out post-treatment to obtain the cyclized product 2-pyrrolidone compound (I).
The invention provides a 1,6-enyne and azoalkyl nitrile high-area selective free radical cyanoalkylation/cyclization reaction method, and the chemical reaction formula can be expressed as (see formula I):
in the reaction of the first formula, the reaction atmosphere may be an air atmosphere of 1atm, and a nitrogen atmosphere of 1atm or other inert gas atmosphere may be used instead.
The post-processing operation is as follows: extracting the reaction solution after the reaction is finished with ethyl acetate, drying an organic phase with anhydrous sodium sulfate, filtering, concentrating under reduced pressure to remove a solvent, and separating the residue by column chromatography, wherein the elution solvent is: ethyl acetate/n-hexane to obtain the target product 2-pyrrolidone compound (I).
In the compounds represented by formula 1, formula 2 and formula I, R 1 Selected from hydrogen, C 5 -C 14 Aryl radical, C 1 -C 10 Alkyl radical, C 1 -C 6 An acyl group;
R 2 selected from hydrogen, C 1 -C 6 Alkyl radical, C 5 -C 14 An aryl group;
R 3 is selected from C 1 -C 8 Alkyl radical, C 5 -C 14 An aryl group;
R 4 is selected from C 1 -C 6 Alkyl radical, C 5 -C 14 An aryl group;
R 5 is selected from C 1 -C 6 Alkyl radical, C 5 -C 14 An aryl group;
wherein each R is 1 -R 5 The aryl, alkyl and acyl groups having the number of carbon atoms in the substituents are optionally substituted by a substituent selected from the group consisting of halogen, C 1 -C 6 Alkyl radical, C 1 -C 6 Alkoxy radical, C 5 - C 14 Aryl, halogen substituted C 1 -C 6 Alkyl, -NO 2 、-CN、C 1 -C 6 alkyl-C (= O) -, C 1 -C 6 alkyl-OC (O =) -;
EWG = CN or COOMe.
Preferably, R 1 Is selected from C 1 -C 10 Alkyl radical, C 5 -C 14 An aryl group; wherein said C 1 -C 10 Alkyl radical, C 5 - C 14 Aryl is optionally substituted by a substituent selected from halogen, C 1 -C 6 Alkyl radical, C 1 -C 6 Alkoxy radical, C 5 -C 14 Aryl, halogen substituted C 1 -C 6 Alkyl, -NO 2 、-CN、C 1 -C 6 alkyl-C (= O) -, C 1 -C 6 alkyl-OC (O =) -;
R 2 selected from hydrogen;
R 3 is selected from C 1 -C 8 Alkyl radical, C 5 -C 14 Aryl, wherein said C 1 -C 6 Alkyl radical, C 5 -C 14 Aryl is optionally substituted by a substituent selected from halogen, C 1 -C 6 Alkyl radical, C 1 -C 6 Alkoxy radical, C 5 -C 14 Aryl, halogen substituted C 1 -C 6 Alkyl, -NO 2 、-CN、C 1 -C 6 alkyl-C (= O) -, C 1 -C 6 alkyl-OC (O =) -;
R 4 is selected from C 1 -C 6 An alkyl group;
R 5 is selected from C 1 -C 6 An alkyl group.
In the reaction of the invention, the solvent is selected from any one or a mixture of more of ethyl acetate, acetonitrile, toluene, N-dimethylformamide and water. Acetonitrile is preferred.
In the reaction of the present invention, the certain temperature is 40 to 80 ℃ and most preferably 60 ℃.
In the reaction of the present invention, the time required for complete conversion of the reaction starting material is 12 to 20 hours, preferably 16 hours.
In the reaction of the present invention, the molar ratio of 1,6-enyne compound of formula 1 to the azoalkylnitrile of formula 2 is 1: 1.2 to 1: 3. Preferably, the molar ratio of 1,6-enyne compound of formula 1 to the azoalkylnitrile of formula 2 is 1: 2.
The invention has the beneficial effects that: the method provides a 1,6-enyne compound and azo alkyl nitrile high-area selective free radical cyanoalkylation/cyclization reaction method under a catalyst-free and additive-free system, and a series of target products can be obtained in high yield without any catalyst or additive. The method has the advantages of wide application range of reaction substrates, simplicity, high efficiency, economy and greenness, and is particularly suitable for industrial production.
Detailed Description
The present invention will be described in further detail with reference to specific examples, but the present invention is not limited thereto.
The experimental methods described in the following examples are all conventional methods unless otherwise specified; the reagents and starting materials, if not otherwise specified, are commercially available and/or may be prepared according to known methods.
Examples 1-10 were experiments optimized for reaction conditions.
Example 1
To a Schlenk flask were added 1,6-enyne compound represented by formula 1a (39.8mg, 0.2mmol), azoalkylnitrile represented by formula 2a (65.6 mg,0.4 mmol), and ethyl acetate (2 mL), and the reaction was stirred under an air atmosphere at 60 ℃ and monitored by TLC for reverse reactionThe reaction was continued until the starting material disappeared (reaction time: 16 hours), after completion of the reaction, the reaction solution was concentrated under reduced pressure to remove the solvent, and the residue was separated by column chromatography (elution solvent: ethyl acetate/n-hexane) to obtain the objective product I-1 (71% yield); 1 H NMR (500MHz，CDCl 3 )δ：7.70(d，J＝8.0Hz，2H)，7.40(t，J＝8.0Hz，2H)，7.19(t，J＝7.5Hz，1H)， 5.43(t，J＝2.0Hz，1H)，5.34(t，J＝2.5Hz，1H)，4.71-4.6g(m，1H)，4.56-4.52(m，1H)，2.1g(d，J ＝14.5Hz，1H)，1.96(d，J＝14.5Hz，1H)，1.41(s，3H)，1.37(s，3H)，1.30(s，3H)； 13 C NMR(125 MHz，CDCl 3 )δ：176.0，142.7，138.8，129.1，125.1，124.5，120.2，111.1，52.2，48.5，47.7，30.9，30.5， 29.1，26.9；HRMSm/z(ESI)calcd for C 17 H 21 N 2 O([M+H] + )269.1648，found 269.1649。
example 2
The solvent was changed to ethyl acetate with acetonitrile (2 mL), and the same procedure as in example 1 was repeated, whereby the desired product I-1 was obtained in a yield of 80%.
Example 3
The solvent was changed to ethyl acetate with toluene (2 mL) under the same conditions as in example 1, to obtain the desired product I-1 in a yield of 32%.
Example 4
The solvent was changed to ethyl acetate with N, N-dimethylformamide (2 mL) under the same conditions as in example 1, whereby the desired product I-1 was obtained in a yield of 51%.
Example 5
The solvent was changed to ethyl acetate with water (2 mL) under the same conditions as in example 1 to obtain the desired product I-1 in a yield of 5%.
Example 6
The catalyst cuprous iodide (CuI, 7.6mg, 0.04mmol) was added under the same conditions as in example 2 to give the desired product I-1 in 81% yield.
Example 7
The amount of the azoalkylnitrile used was 1.2 equivalents (39.4 mg, 0.24mmol), and the other conditions were the same as in example 2, whereby the yield of the objective product I-1 was 53%.
Example 8
The amount of the azoalkylnitrile used was 3 equivalents (98.4 mg,0.6 mmol), and the other conditions were the same as in example 2, whereby the yield of the objective product I-1 was 81%.
Example 9
The reaction temperature was reduced to 40 ℃ and the other conditions were the same as in example 2, giving a yield of the target product I-1 of 23%.
Example 10
The reaction temperature was raised to 80 ℃ and the other conditions were the same as in example 2, giving the desired product I-1 in 71% yield.
As can be seen from the above-mentioned examples 1 to 10, the optimum reaction conditions are those of example 2, i.e., the amount of the azoalkylnitrile used is 2 equivalents (65.6 mg,0.4 mmol), the solvent is acetonitrile (2 mL), and the reaction temperature is 60 ℃. On the basis of obtaining the optimal reaction conditions, the inventor further selects 1,6-enyne compounds with different substituents and azoalkyl nitrile as raw materials under the optimal reaction conditions to develop a high-area selective free radical cyanoalkylation/cyclization reaction method.
Example 11
Adding 1,6-enyne compound (45.8mg, 0.2mmol) represented by formula 1b, an azoalkylnitrile (65.6 mg, 0.4mmol) represented by formula 2a, and ethyl acetate (2 mL) to a Schlenk flask, then stirring the reactor under an air atmosphere at 60 ℃ to react, monitoring the progress of the reaction by TLC until the raw material disappears (the reaction time is 16 hours), after completion of the reaction, concentrating the reaction solution under reduced pressure to remove the solvent, and separating the residue by column chromatography (the elution solvent is ethyl acetate/n-hexane) to obtain the target product I-2 (84 yield); 1 H NMR (500MHz，CDCl 3 )δ：7.59(d，J＝9.0Hz，2H)，6.93(d，J＝9.0Hz，2H)，5.41(t，J＝3.0Hz，1H)， 5.32(t，J＝2.0Hz，1H)，4.67-4.63(m，1H)，4.51-4.47(m，1H)，3.81(s，3H)，2.17(d，J＝14.5Hz， 1H)，1.94(d，J＝14.5Hz，1H)，1.40(s，3H)，1.36(s，3H)，1.30(s，3H)； 13 C NMR(125MHz，CDCl 3 )δ：175.5，157.0，143.0，132.0，124.6，122.0，114.3，110.9，55.5，52.6，48.2，47.8，30.9，30.5，29.1， 27.0；HRMS m/z(ESI)calcd for C 18 H 23 N 2 O 2 ([M+H] + )299.1754，found 299.1756。
example 12
Adding 1,6-enyne compound (42.6 mg, 0.2mmol) represented by formula 1c, an azoalkylnitrile (65.6 mg,0.4 mmol) represented by formula 2a, and ethyl acetate (2 mL) to a Schlenk flask, then stirring the reactor under an air atmosphere at 60 ℃ for reaction, monitoring the progress of the reaction by TLC until the raw materials disappear (the reaction time is 16 hours), after the reaction is completed, concentrating the reaction solution under reduced pressure to remove the solvent, and separating the residue by column chromatography (the elution solvent is ethyl acetate/n-hexane) to obtain the target product I-3 (82 yield); 1 H NMR (500MHz，CDCl 3 )δ：7.57(d，J＝8.5Hz，2H)，7.20(d，J＝8.0Hz，2H)，5.42(t，J＝2.0Hz，1H)， 5.33(t，J＝2.0Hz，1H)，4.69-4.65(m，1H)，4.52-4.49(m，1H)，2.34(s，3H)，2.16(d，J＝14.5Hz， 1H)，1.94(d，J＝14.5Hz，1H)，1.40(s，3H)，1.36(s，3H)，1.29(s，3H)； 13 CNMR(125MHz，CDCl 3 )δ：175.8，142.9，136.3，134.8，129.6，124.6，120.2，110.9，52.3，48.4，47.8，30.9，30.5，29.1，26.9， 20.9；HRMS m/z(ESI)calcd for C 18 H 23 N 2 O([M+H] + )283.1805，found 283.1806。
example 13
To a Schlenk flask were added 1,6-enyne compound of formula 1d (43.4 mg, 0.2mmol), an azoalkylnitrile of formula 2a (65.6 mg,0.4 mmol), ethyl acetate (2 mL), and the reactor was emptiedStirring the mixture under a gas atmosphere at 60 ℃ for reaction, monitoring the reaction progress by TLC until the raw materials disappear (the reaction time is 16 hours), concentrating the reaction solution under reduced pressure to remove the solvent after the reaction is finished, and performing column chromatography on the residue (the elution solvent is ethyl acetate/n-hexane) to obtain a target product I-4 (78 percent); 1 H NMR (500MHz，CDCl 3 )δ：7.68-7.65(m，2H)，7.10-7.06(m，2H)，5.43(t，J＝2.0Hz，1H)，5.33(t，J＝ 2.0Hz，1H)，4.68-4.65(m，1H)，4.53-4.50(m，1H)，2.18(d，J＝14.5Hz，1H)，1.94(d，J＝14.5Hz， 1H)，1.41(s，3H)，1.37(s，3H)，1.30(s，3H)； 13 C NMR(125MHz，CDCl 3 )δ：175.9，142.7，134.8， 129.3(d，J C-F ＝7.5Hz)，124.4，122.1(d，J C-F ＝7.5Hz)，115.7(d，J C-F ＝22.5Hz)，111.1，52.5，48.3，47.8，30.9，30.4，29.1，27.3； 19 F NMR(471MHz，CDCl 3 )δ：-116.9；HRMS m/z(ESI)calcd for C 17 H 20 FN 2 O([M+H] + )287.1554，found 287.1555。
example 14
Adding 1,6-enyne compound (46.6 mg, 0.2mmol) represented by formula 1e, azoalkylnitrile (65.6 mg,0.4 mmol) represented by formula 2a, and ethyl acetate (2 mL) to a Schlenk flask, stirring the reactor under an air atmosphere at 60 ℃ for reaction, monitoring the progress of the reaction by TLC until the raw material disappears (the reaction time is 16 hours), after the reaction is completed, concentrating the reaction solution under reduced pressure to remove the solvent, and separating the residue by column chromatography (the elution solvent is ethyl acetate/n-hexane) to obtain the target product I-5 (77 yield); 1 H NMR (500MHz，CDCl 3 )δ：7.67(d，J＝9.0Hz，2H)，7.35(d，J＝9.0Hz，2H)，5.43(t，J＝2.5Hz，1H)， 5.34(t，J＝2.0Hz，1H)，4.68-4.64(m，1H)，4.52-4.49(m，1H)，2.17(d，J＝14.5Hz，1H)，1.94(d， J＝14.5Hz，1H)，1.40(s，3H)，1.37(s，3H)，1.29(s，3H)； 13 C NMR(125MHz，CDCl 3 )δ：176.1， 142.5，137.3，130.2，129.1，124.4，121.3，111.2，52.2，48.5，47.8，30.8，30.4，29.1，27.3；HRMS m/z (ESI)calcd for C 17 H 20 ClN 2 O([M+H] + )303.1259，found 303.1260。
example 15
Adding 1,6-enyne compound (50.6 mg, 0.2mmol) represented by formula 1f, azoalkylnitrile (65.6 mg,0.4 mmol) represented by formula 2a, and ethyl acetate (2 mL) to a Schlenk flask, stirring the reactor under an air atmosphere at 60 ℃ for reaction, monitoring the progress of the reaction by TLC until the raw materials disappear (the reaction time is 16 hours), after the reaction is completed, concentrating the reaction solution under reduced pressure to remove the solvent, and separating the residue by column chromatography (the elution solvent is ethyl acetate/n-hexane) to obtain the target product I-6 (71 yield); 1 H NMR (500MHz，CDCl 3 )δ：7.88(d，J＝8.5Hz，2H)，7.65(d，J＝8.5Hz，2H)，5.46(t，J＝2.0Hz，1H)， 5.36(t，J＝2.0Hz，1H)，4.73-4.70(m，1H)，4.58-4.55(m，1H)，2.20(d，J＝14.5Hz，1H)，1.96(d， J＝14.5Hz，1H)，1.41(s，3H)，1.39(s，3H)，1.30(s，3H)； 13 C NMR(125MHz，CDCl 3 )δ：176.6， 142.2，141.7，126.8(q，J C-F ＝30.0Hz)，126.2(q，J C-F ＝2.7Hz)，124.3，119.6，119.3，111.4，52.0， 48.7，47.8，30.8，30.4，29.1，27.4； 19 F NMR(471MHz，CDCl 3 )δ：-62.2；HRMS m/z(ESI)calcd for C 18 H 20 F 3 N 2 O([M+H] + )337.1522，found 337.1524。
example 16
A Schlenk flask was charged with 1g of 1,6-enyne compound (44.8mg, 0.2mmol) represented by formula 2aAzoalkylnitrile (65.6 mg,0.4 mmol), ethyl acetate (2 mL), then the reactor was stirred under an air atmosphere at 60 ℃ for reaction, progress of the reaction was monitored by TLC until the starting material disappeared (reaction time 16 hours), after completion of the reaction, the reaction solution was concentrated under reduced pressure to remove the solvent, and the residue was separated by column chromatography (elution solvent: ethyl acetate/n-hexane) to obtain the objective product I-7 (62% yield); 1 H NMR (500MHz，CDCl 3 )δ：7.89(d，J＝8.5Hz，2H)，7.68(d，J＝9.0Hz，2H)，5.47(t，J＝1.5Hz，1H)， 5.36(t，J＝3.0Hz，1H)，4.72-4.68(m，1H)，4.57-4.54(m，1H)，2.20(d，J＝14.5Hz，1H)，1.95(d， J＝14.5Hz，1H)，1.41(s，3H)，1.38(s，3H)，1.29(s，3H)； 13 C NMR(125MHz，CDCl 3 )δ：176.9， 142.4，141.9，133.8，133.2，119.7，114.5，111.5，107.8，51.8，48.8，47.9，30.7，30.4，29.1，27.7； HRMS m/z(ESI)calcd for C 18 H 20 N 3 O([M+H] + )294.1601，found 294.1603。
example 17
Adding 1,6-enyne compound (55.0mg, 0.2mmol) represented by formula 1I, an azoalkylnitrile (65.6 mg, 0.4mmol) represented by formula 2a, and ethyl acetate (2 mL) to a Schlenk flask, then stirring the reactor under an air atmosphere at 60 ℃ for reaction, monitoring the progress of the reaction by TLC until the raw materials disappear (the reaction time is 16 hours), after the reaction is completed, concentrating the reaction solution under reduced pressure to remove the solvent, and separating the residue by column chromatography (the elution solvent is ethyl acetate/n-hexane) to obtain the target product I-8 (75 yield); 1 H NMR (500MHz，CDCl 3 )δ：7.34-7.30(m，4H)，7.17-7.13(m，6H)，5.53(t，J＝2.0Hz，1H)，5.44(t，J＝ 2.5Hz，1H)，4.30-4.27(m，1H)，3.50-3.47(m，1H)，3.19(d，J＝12.5Hz，1H)，2.67(d，J＝12.5Hz， 1H)，2.36(d，J＝14.5Hz，1H)，2.13(d，J＝14.5Hz，1H)，1.46(s，3H)，1.36(s，3H)； 13 C NMR(125 MHz，CDCl 3 )δ：174.4，140.2，138.3，135.1，130.5，128.9，127.9，127.0，125.4，124.8，121.2，112.2， 54.8，52.9，48.6，46.1，31.4，30.4，27.2；HRMS m/z(ESI)calcd for C 23 H 25 N 2 O([M+H] + )345.1961， found 345.1964。
example 18
Adding 1,6-enyne compound (52.2mg, 0.2mmol) represented by formula 1j, an azoalkylnitrile (65.6 mg, 0.4mmol) represented by formula 2a, and ethyl acetate (2 mL) to a Schlenk flask, then stirring the reactor under an air atmosphere at 60 ℃ for reaction, monitoring the progress of the reaction by TLC until the raw materials disappear (the reaction time is 16 hours), after the reaction is completed, concentrating the reaction solution under reduced pressure to remove the solvent, and separating the residue by column chromatography (the elution solvent is ethyl acetate/n-hexane) to obtain the target product I-9 (68 yield); 1 H NMR (500MHz，CDCl 3 )δ：7.34-7.30(m，4H)，7.17-7.13(m，6H)，5.53(t，J＝2.0Hz，1H)，5.44(t，J＝ 2.0Hz，1H)，4.29-4.26(m，1H)，3.50-3.47(m，1H)，2.36(d，J＝14.5Hz，1H)，2.13(d，J＝14.5Hz， 1H)，1.46(s，3H)，1.36(s，3H)； 13 C NMR(125MHz，CDCl 3 )δ：174.4，141.3，135.1，130.4，128.9， 127.9，127.0，125.4，124.8，121.2，118.3，112.2，54.8，48.6，46.1，31.4，30.4，27.2；HRMS m/z(ESI) calcd for C 22 H 23 N 2 O([M+H] + )331.1805，found 331.1807。
example 19
A Schlenk flask was charged with 1,6-enyne compound represented by formula 1a (39.8mg, 0.2mmol), an azoalkylnitrile represented by formula 2b (76.8mg, 0.4mmol), and ethyl acetate (2 mL), and the reactor was stirred under an air atmosphere at 60 ℃ to react via TLC, monitoring the reaction process until the raw materials disappear (the reaction time is 16 hours), concentrating the reaction liquid under reduced pressure to remove the solvent after the reaction is finished, and separating the residue by column chromatography (the elution solvent is ethyl acetate/n-hexane) to obtain a target product I-10 (65 percent yield, d.r. > 20: 1); 1 H NMR(500MHz，CDCl 3 )δ：7.70-7.68(m，2H)，7.41-7.38(m，2H)，7.18(t，J＝7.0Hz，1H)，5.40 (t，J＝2.0Hz，1H)，5.31(t，J＝2.5Hz，1H)，4.68-4.65(m，1H)，4.54-4.51(m，1H)，2.29(d，J＝14.5 Hz，1H)，1.87(d，J＝15.0Hz，1H)，1.71-1.67(m，1H)，1.50-1.46(m，1H)，1.37(s，3H)，1.35(s， 3H)，1.00(t，J＝7.5Hz，3H)； 13 C NMR(125MHz，CDCl 3 )δ：175.9，143.5，138.8，129.0，125.0， 123.4，120.4，110.6，52.3，48.6，46.4，35.4，33.0，31.9，26.7，9.1；HRMS m/z(ESI)calcd for C 18 H 23 N 2 O([M+H] + )283.1805，found 283.1806。
example 20
Adding 1,6-enyne compound (39.8mg, 0.2mmol) represented by formula 1a, azo compound (92.0mg, 0.4mmol) represented by formula 2c, and ethyl acetate (2 mL) to a Schlenk flask, then stirring the reactor under an air atmosphere at 60 ℃ to react, monitoring the progress of the reaction by TLC until the raw material disappears (the reaction time is 16 hours), after completion of the reaction, concentrating the reaction solution under reduced pressure to remove the solvent, and separating the residue by column chromatography (the elution solvent is ethyl acetate/n-hexane) to obtain the target product I-11 (78 yield); 1 H NMR (500MHz，CDCl 3 )δ：7.62(d，J＝8.5Hz，2H)，7.31(t，J＝8.0Hz，2H)，7.08(t，J＝7.5Hz，1H)， 5.15(t，J＝2.0Hz，1H)，4.97(t，J＝2.5Hz，1H)，4.44-4.41(m，1H)，4.34-4.31(m，1H)，3.46(s， 3H)，2.12(d，J＝2.5Hz，2H)，1.25(s，3H)，1.11(s，3H)，1.00(s，3H)； 13 C NMR(125MHz，CDCl 3 )δ：178.1，176.9，144.2，139.0，128.9，124.7，120.0，109.4，51.8，51.4，48.9，48.5，41.6，29.3，29.2， 23.4；HRMS m/z(ESI)calcd for C 18 H 24 NO 3 ([M+H] + )302.1751，found 302.1753。
example 21 reaction mechanism control experiment
To the reaction of example 2, 2.4 equivalents of tetramethylpiperidine nitroxide (TEMPO) or 2,6-di-tert-butyl-4-methylphenol (BHT) were added as a radical scavenger, and the yield of the target product of the reaction was almost 0%, indicating that the reaction did proceed through the radical reaction process.
It follows that the possible reaction mechanism of the present invention can be deduced as shown in the following formula:
the embodiments described above are only preferred embodiments of the present invention and are not exhaustive of the possible implementations of the present invention. Any obvious modifications thereof, which would occur to one skilled in the art, without departing from the principles and spirit of the invention, are to be considered as included within the scope of the appended claims.
Claims (8)
1. A method for cyanoalkylation/cyclization reaction of 1,6-enyne compounds and azoalkyl nitriles is characterized by comprising the following steps:
adding 1,6-enyne compound shown in formula 1, a compound shown in formula 2 and a solvent into a Schlenk reaction bottle, placing the reaction bottle at a certain temperature under the air atmosphere condition, stirring for reaction, monitoring the reaction process by TLC or GC until the raw materials are completely reacted, and performing post-treatment to obtain a cyclized product 2-pyrrolidone compound (I);
in the compounds represented by formula 1, formula 2 and formula I, R 1 Selected from hydrogen, C 5 -C 14 Aryl radical, C 1 -C 10 Alkyl radical, C 1 -C 6 An acyl group;
R 2 selected from hydrogen, C 1 -C 6 Alkyl radical, C 5 -C 14 An aryl group;
R 3 is selected from C 1 -C 8 Alkyl radical, C 5 -C 14 An aryl group;
R 4 is selected from C 1 -C 6 Alkyl radical, C 5 -C 14 An aryl group;
R 5 is selected from C 1 -C 6 Alkyl radical, C 5 -C 14 An aryl group;
wherein each R is 1 -R 5 The aryl, alkyl and acyl groups having the number of carbon atoms in the substituents are optionally substituted by a substituent selected from the group consisting of halogen, C 1 -C 6 Alkyl radical, C 1 -C 6 Alkoxy radical, C 5 -C 14 Aryl, halogen substituted C 1 -C 6 Alkyl, -NO 2 、-CN、C 1 -C 6 alkyl-C (= O) -, C 1 -C 6 alkyl-OC (O =) -;
EWG = CN or COOMe.
2. The method of claim 1, wherein R is 1 Is selected from C 1 -C 10 Alkyl radical, C 5 -C 14 An aryl group; wherein said C 1 -C 10 Alkyl radical, C 5 -C 14 Aryl is optionally substituted by a substituent selected from halogen, C 1 -C 6 Alkyl radical, C 1 -C 6 Alkoxy radical, C 5 -C 14 Aryl, halogen substituted C 1 -C 6 Alkyl, -NO 2 、-CN、C 1 -C 6 alkyl-C (= O) -, C 1 -C 6 alkyl-OC (O =) -;
R 2 selected from hydrogen;
R 3 is selected from C 1 -C 8 Alkyl radical, C 5 -C 14 Aryl, wherein said C 1 -C 6 Alkyl radical, C 5 -C 14 Aryl is optionally substituted by a substituent selected from halogen, C 1 -C 6 Alkyl radical, C 1 -C 6 Alkoxy radical, C 5 -C 14 Aryl, halogen substituted C 1 -C 6 Alkyl, -NO 2 、-CN、C 1 -C 6 alkyl-C (= O) -, C 1 -C 6 alkyl-OC (O =) -;
R 4 is selected from C 1 -C 6 An alkyl group;
R 5 is selected from C 1 -C 6 An alkyl group.
3. The method according to any one of claims 1-2, wherein the solvent is selected from one or more of ethyl acetate, acetonitrile, toluene, N-dimethylformamide, and water.
4. The process according to claim 3, wherein the solvent is acetonitrile.
5. The method according to any one of claims 1, 2 or 4, wherein the certain temperature is 40-80 ℃.
6. The method according to any one of claims 1, 2 and 4, wherein the time required for complete reaction of the starting materials is 12 to 20 hours.
7. The method of any one of claims 1, 2, 4, wherein the molar ratio of 1,6-enyne compound of formula 1 to the compound of formula 2 is 1: 1.2 to 1: 3.
8. The method according to any one of claims 1, 2 and 4, wherein the post-processing operation is as follows: extracting the reaction solution after the reaction is finished with ethyl acetate, drying an organic phase with anhydrous sodium sulfate, filtering, concentrating under reduced pressure to remove a solvent, and separating the residue by column chromatography, wherein the elution solvent is: ethyl acetate/n-hexane to obtain the target product 2-pyrrolidone compound (I).
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