CN110511175B - Free radical cyclization reaction method of 1, 6-eneyne compound and azo alkyl nitrile - Google Patents
Free radical cyclization reaction method of 1, 6-eneyne compound and azo alkyl nitrile Download PDFInfo
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Abstract
The invention relates to a method for the regioselective free-radical cyclization reaction of 1, 6-eneyne compounds and azoalkylnitriles under mild conditions. Adding a 1, 6-eneyne compound, an azoalkyl nitrile compound, a catalyst, alkali and a solvent into a Schlenk reaction bottle, and stirring for reaction at a certain temperature under the air atmosphere condition to obtain a cyclized product.
Description
Technical Field
The application belongs to the field of organic synthesis, and particularly relates to a regioselective free radical cyclization reaction method of a 1, 6-eneyne compound and azo alkyl nitrile under mild conditions.
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 this context, chemists have developed cyanation reactions of azoalkylnitriles with alkenes, alkynes and enyne derivatives. However, it has been reported that an azoalkylnitrile further participates in a radical ring addition reaction as a dicarbon unit by means of intramolecular cyclization reaction after the cyanation reaction.
The inventor carries out intensive research on the radical cyclization reaction of azoalkyl nitrile under mild conditions, and in the invention, the inventor provides a novel method for high-regioselectivity cyanation/cyclization reaction through a radical process by using a 1, 6-eneyne compound and the azoalkyl nitrile as reaction raw materials under a cheap and easily-obtained catalyst and a base catalytic system.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a green, efficient, low-cost and high-selectivity cyanation/cyclization reaction method of 1, 6-eneyne compounds and azo alkyl nitriles, and the method can prepare cyclization products with high selectivity and high yield under mild conditions.
The invention provides a free radical cyclization reaction method, which takes 1, 6-eneyne compounds and azo alkyl nitrile as raw materials and is prepared by the following steps:
adding a 1, 6-eneyne compound shown in formula 1, an azoalkyl nitrile shown in formula 2, a catalyst, a base and a solvent into a Schlenk reaction bottle, placing the reaction bottle at a certain temperature under the condition of an air atmosphere, 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 a cyclized product (I).
The chemical reaction formula of the high-selectivity free radical cyclization reaction method of the 1, 6-enyne and the azo alkyl nitrile provided by the invention 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 give the desired cyclized product (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 among 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 =) -.
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 selected from hydrogen, 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 catalyst is selected from any one or a mixture of cuprous iodide, cuprous bromide, cuprous chloride, cupric bromide and cupric acetate, and is preferably cuprous iodide.
In the reaction of the invention, the base is any one or a mixture of triethylamine, 1, 8-diazabicycloundecen-7-ene, potassium acetate and tetra-n-butylammonium acetate, and is preferably triethylamine.
In the reaction of the invention, the solvent is selected from any one or a mixture of acetonitrile and water, and the solvent is preferably H 2 O/MeCN(v∶v＝4∶1，2.0mL)。
In the reaction of the present invention, the certain temperature is 40 to 80 ℃ and the temperature is most preferably 60 ℃.
In the reaction of the present invention, the molar ratio of the 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 the 1, 6-enyne compound of formula 1 to the azoalkylnitrile of formula 2 is 1: 2.
The invention has the beneficial effects that: a method for the radical cyclization reaction of 1, 6-eneyne compounds and azo alkyl nitriles under mild conditions is provided, and a series of target products are obtained at high yield through twice intramolecular radical cyclization. The method has the advantages of wide application range of reaction substrates, simplicity and high efficiency, 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 1-16 were experiments optimized for reaction conditions.
Example 1
To a Schlenk flask were added a 1, 6-enyne compound represented by formula 1a (39.8mg, 0.2mmol), an azoalkylnitrile represented by formula 2a (65.6mg, 0.4mmol), cuprous iodide (CuI, 7.6mg, 0.04mmol), and triethylamine (Et 3 N，4.0mg，0.04 mmol)，H 2 O/MeCN (v: v = 4: 1,2.0 ml), then the reactor was stirred to react under an air atmosphere at 60 ℃, the progress of the reaction was monitored by TLC until the raw material disappeared (reaction time 16 hours), after the reaction was completed, the reaction solution was extracted with ethyl acetate, the organic phase was dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to remove the solvent, and the residue was subjected to column chromatography (elution solvent: ethyl acetate/n-hexane) to obtain the target product I-1 (71% yield); 1 H NMR(500MHz，CDCl 3 )δ： 7.66(d，J＝7.5Hz，2H)，7.40(t，J＝8.0Hz，2H)，7.19(t，J＝7.5Hz，1H)，6.01(s，1H)，4.75(d，J ＝14.0Hz，1H)，4.37(d，J＝14.0Hz，1H)，2.18-2.08(m，2H)，1.60(s，3H)，1.35(s，3H)，1.21(s， 3H)； 13 C NMR(125MHz，CDCl 3 )δ：202.8，175.3，159.0，138.6，129.1，125.1，121.9，119.7，50.7， 45.1，42.9，40.9，29.4，27.9，24.0；HRMS m/z(ESI)calcd for C 17 H 20 NO 2 ([M+H] + )270.1489，found 270.1490。
example 2
The base was replaced by 1, 8-diazabicycloundec-7-ene for triethylamine under the same conditions as in example 1, giving the desired product I-1 in a yield of 61%.
Example 3
The base was potassium acetate instead of triethylamine under the same conditions as in example 1, giving the desired product I-1 in a yield of 52%.
Example 4
The triethylamine was replaced by tetra-n-butylammonium acetate under the same conditions as in example 1, whereby the yield of the objective product I-1 was 59%.
Example 5
The amount of triethylamine used was 10mol% (2.0 mg, 0.02mmol), and the other conditions were the same as in example 1, whereby the yield of the objective product I-1 was 43%.
Example 6
The amount of triethylamine was 40mol% (8.0 mg, 0.08mmol), and the other conditions were the same as in example 1, whereby the yield of the objective product I-1 was 72%.
Example 7
Cuprous bromide is used as the catalyst instead of cuprous iodide, and the yield of the target product I-1 is 68% under the same conditions as example 1.
Example 8
The cuprous iodide is replaced by cuprous chloride in the catalyst, and the yield of the target product I-1 is 65% under the same conditions as in example 1.
Example 9
The catalyst uses cupric bromide to replace cuprous iodide, and the rest conditions are the same as example 1, so that the yield of the target product I-I is 67%.
Example 10
The catalyst uses copper acetate to replace cuprous iodide, the other conditions are the same as example 1, and the yield of the target product I-1 is 63%.
Example 11
The amount of cuprous iodide used was 10mol% (3.8mg, 0.02mmol), and the yield of the objective product I-1 was 58% under the same conditions as in example 1.
Example 12
The amount of cuprous iodide used was 40mol% (15.2mg, 0.08mmol), and the other conditions were the same as in example 1, giving the desired product I-1 in a yield of 72%.
Example 13
H for solvent 2 O/MeCN (v: v = 9: 1, 2.0mL) instead of H 2 O/MeCN (v: v = 4: 1,2.0 mL), the other conditions were the same as in example 1, and the yield of the objective product I-1 was 42%.
Example 14
H for solvent 2 O (2.0 mL) instead of H 2 O/MeCN (v: v = 4: 1,2.0 mL), and the other conditions were the same as in example 1, whereby the yield of the objective product I-1 was 14%.
Example 15
The reaction temperature was reduced to 40 ℃ and the other conditions were the same as in example 1, giving a yield of the target product I-1 of 33%.
Example 16
The reaction temperature was raised to 80 ℃ and the other conditions were the same as in example 1, giving the desired product I-1 in a yield of 72%.
As can be seen from the above-mentioned examples 1 to 16, the optimum reaction conditions were those of example 1, i.e., the amount of cuprous iodide was 20mol% (7.6 mg, 0.04mmol), the amount of triethylamine was 20mol% (4.0 mg, 0.04mmol), and the solvent was selected to be H 2 O/MeCN (v: v = 4: 1, 2.0mL), the reaction temperature was 60 ℃. On the basis of obtaining the optimal reaction conditions, the inventor further selects 1, 6-eneyne compounds with different substituents as raw materials under the optimal reaction conditions to develop a high-selectivity free radical cyclization reaction method.
Example 17
To a Schlenk flask were added a 1, 6-enyne compound represented by formula 1b (45.8mg, 0.2mmol), an azoalkylnitrile represented by formula 2a (65.6mg, 0.4mmol), cuprous iodide (CuI, 7.6mg, 0.04mmol), and triethylamine (Et 3 N，4.0mg，0.04 mmol)，H 2 O/MeCN (v: v = 4: 1,2.0 ml), then the reactor was stirred to react under an air atmosphere at 60 ℃, the progress of the reaction was monitored by TLC until the raw material disappeared (reaction time was 16 hours), after the reaction was completed, the reaction solution was extracted with ethyl acetate, the organic phase was dried with anhydrous sodium sulfate, filtered and 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-2 (74% yield); 1 H NMR(500MHz，CDCl 3 )δ： 7.54(d，J＝9.0Hz，2H)，6.93(d，J＝9.0Hz，2H)，5.98(s，1H)，4.73-4.69(m，1H)，4.31(d，J＝14.0 Hz，1H)，3.81(s，3H)，2.17-2.06(m，2H)，1.59(s，3H)，1.35(s，3H)，1.21(s，3H)； 13 C NMR(125 MHz，CDCl 3 )δ：202.9，174.9，159.3，157.0，131.7，121.8，121.6，114.3，55.5，51.1，44.8，42.9，40.9， 29.7，27.9，24.0；HRMS m/z(ESI)calcd for C 18 H 22 NO 3 ([M+H] + )300.1594，found 300.1597。
example 18
To a Schlenk flask were added a 1, 6-enyne compound represented by formula 1c (42.6 mg, 0.2mmol), an azoalkylnitrile represented by formula 2a (65.6 mg,0.4 mmol), cuprous iodide (CuI, 7.6mg, 0.04mmol), triethylamine (Et 3 N，4.0mg，0.04 mmol)，H 2 O/MeCN (v: v = 4: 1,2.0 mL), the reaction vessel was stirred under an air atmosphere at 60 ℃ for reaction, the progress of the reaction was monitored by TLC until the starting material disappeared (reaction time: 16 hours), and after completion of the reaction, the reaction solution was extracted with ethyl acetateExtracting, drying the organic phase with anhydrous sodium sulfate, filtering, concentrating under reduced pressure to remove solvent, and separating the residue by column chromatography (eluting solvent is ethyl acetate/n-hexane) to obtain target product I-3 (72% yield); 1 H NMR(500MHz，CDCl 3 )δ： 7.52(d，J＝8.5Hz，2H)，7.20(d，J＝8.5Hz，2H)，5.99(s，1H)，4.74-4.70(m，1H)，4.33(d，J＝14.5 Hz，1H)，2.34(s，3H)，2.17-2.07(m，2H)，1.59(s，3H)，1.35(s，3H)，1.21(s，3H)； 13 C NMR(125 MHz，CDCl 3 )δ：202.9，175.1，159.2，136.1，134.9，129.6，121.8，119.8，50.9，45.0，42.9，40.9，29.4， 27.9，24.0，20.9；HRMS m/z(ESI)calcd for C 18 H 22 NO 2 ([M+H] + )284.1645，found 284.1647。
example 19
To a Schlenk flask were added 1, 6-enyne compound represented by formula 1d (43.4 mg, 0.2mmol), azoalkylnitrile represented by formula 2a (65.6 mg,0.4 mmol), cuprous iodide (CuI, 7.6mg, 0.04mmol), triethylamine (Et) 3 N，4.0mg，0.04 mmol)，H 2 O/MeCN (v: v = 4: 1,2.0 ml), then the reactor was stirred to react under an air atmosphere at 60 ℃, the progress of the reaction was monitored by TLC until the raw material disappeared (reaction time 16 hours), after the reaction was completed, the reaction solution was extracted with ethyl acetate, the organic phase was dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to remove the solvent, and the residue was subjected to column chromatography (elution solvent: ethyl acetate/n-hexane) to obtain the target product I-4 (68% yield); 1 H NMR(500MHz，CDCl 3 )δ： 7.63-7.61(m，2H)，7.12-7.06(m，2H)，6.01(s，1H)，4.73(d，J＝14.0Hz，1H)，4.34(d，J＝14.0Hz， 1H)，2.18-2.07(m，2H)，1.60(s，3H)，1.35(s，3H)，1.21(s，3H)； 13 C NMR(125MHz，CDCl 3 )δ： 202.7，175.2，160.7，158.6，134.7，122.0，121.6(d，J C-F ＝7.5Hz)，115.8(d，J C-F ＝21.3Hz)，51.0， 44.9，42.9，40.9，29.4，27.9，24.0； 19 F NMR(471MHz，CDCl 3 )δ：-116.7；HRMS m/z(ESI)calcd for C 17 H 19 FNO 2 ([M+H] + )288.1394，found 288.1396。
example 20
To a Schlenk flask were added a 1, 6-enyne compound represented by formula 1e (46.6 mg, 0.2mmol), an azoalkylnitrile represented by formula 2a (65.6 mg,0.4 mmol), cuprous iodide (CuI, 7.6mg, 0.04mmol), triethylamine (Et 3 N，4.0mg，0.04 mmol)，H 2 O/MeCN (v: v = 4: 1,2.0 ml), then the reactor was stirred to react under an air atmosphere at 60 ℃, the progress of the reaction was monitored by TLC until the raw material disappeared (reaction time was 16 hours), after the reaction was completed, the reaction solution was extracted with ethyl acetate, the organic phase was dried with anhydrous sodium sulfate, filtered and 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-5 (67% yield); 1 H NMR(500MHz，CDCl 3 )δ： 7.62(d，J＝9.0Hz，2H)，7.36(d，J＝9.0Hz，2H)，6.01(s，1H)，4.74-4.70(m，1H)，4.34(d，J＝14.5 Hz，1H)，2.17-2.07(m，2H)，1.59(s，3H)，1.35(s，3H)，1.21(s，3H)； 13 C NMR(125MHz，CDCl 3 ) δ：202.6，175.3，158.3，137.2，130.2，129.2，122.1，120.8，50.6，45.0，42.9，40.9，29.4，27.9，24.0； HRMS m/z(ESI)calcd for C 17 H 19 ClNO 2 ([M+H] + )304.1099，found 304.1101。
example 21
To a Schlenk flask were added 1, 6-enyne compound represented by formula 1f (53.4 mg, 0.2mmol), an azoalkylnitrile represented by formula 2a (65.6 mg,0.4 mmol), cuprous iodide (CuI, 7.6mg, 0.04mmol)Triethylamine (Et) 3 N，4.0mg，0.04 mmol)，H 2 O/MeCN (v: v = 4: 1,2.0 ml), then the reactor was stirred to react under an air atmosphere at 60 ℃, the progress of the reaction was monitored by TLC until the raw material disappeared (reaction time was 16 hours), after the reaction was completed, the reaction solution was extracted with ethyl acetate, the organic phase was dried with anhydrous sodium sulfate, filtered and 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-6 (61% yield); 1 H NMR(500MHz，CDCl 3 )δ： 7.82(d，J＝8.5Hz，2H)，7.66(d，J＝9.0Hz，2H)，6.04(s，1H)，4.79-4.75(m，1H)，4.41(d，J＝14.5 Hz，1H)，2.19-2.09(m，2H)，1.61(s，3H)，1.36(s，3H)，1.22(s，3H)； 13 C NMR(125MHz，CDCl 3 ) δ：202.5，175.7，157.8，141.6，129.7，126.6(q，J C-F ＝36.9Hz)，126.3(q，J C-F ＝2.8Hz)，122.3， 119.1，50.4，45.2，42.8，40.9，29.3，27.9，24.1； 19 F NMR(471MHz，CDCl 3 )δ：-62.3；HRMS m/z (ESI)calcd for C 18 H 19 F 3 NO 2 ([M+H] + )338.1362，found 338.1364。
example 22
A Schlenk bottle was charged with 1g of a 1, 6-eneyne compound represented by formula 1 (44.8mg, 0.2mmol), an azoalkylnitrile represented by formula 2a (65.6 mg, 0.4mmol), cuprous iodide (CuI, 7.6mg, 0.04mmol), and triethylamine (Et) 3 N，4.0mg，0.04 mmol)，H 2 O/MeCN (v: v = 4: 1,2.0 ml), then the reactor was stirred to react under an air atmosphere at 60 ℃, the progress of the reaction was monitored by TLC until the raw material disappeared (reaction time 16 hours), after the reaction was completed, the reaction solution was extracted with ethyl acetate, the organic phase was dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to remove the solvent, and the residue was subjected to column chromatography (elution solvent: ethyl acetate/n-hexane) to obtain the target product I-7 (58% yield); 1 H NMR(500MHz，CDCl 3 )δ： 7.83(d，J＝8.5Hz，2H)，7.69(d，J＝9.0Hz，2H)，6.05(s，1H)，4.77-4.74(m，1H)，4.40(d，J＝14.0 Hz，1H)，2.19-2.08(m，2H)，1.61(s，3H)，1.36(s，3H)，1.22(s，3H)； 13 C NMR(125MHz，CDCl 3 ) δ：202.4，175.9，157.2，142.4，133.3，122.5，119.2，118.5，107.9，50.3，45.3，42.8，40.9，29.3，27.9， 24.1；HRMS m/z(ESI)calcd for C 18 H 19 N 2 O 2 ([M+H] + )295.1441，found 295.1443。
example 23
To a Schlenk bottle, 1, 6-enyne compound represented by formula 1h (42.6 mg, 0.2mmol), azoalkylnitrile represented by formula 2a (65.6 mg,0.4 mmol), cuprous iodide (CuI, 7.6mg, 0.04mmol), triethylamine (Et) 3 N，4.0mg，0.04 mmol)，H 2 O/MeCN (v: v = 4: 1,2.0 ml), then the reactor was stirred to react under an air atmosphere at 60 ℃, the progress of the reaction was monitored by TLC until the raw material disappeared (reaction time 16 hours), after the reaction was completed, the reaction solution was extracted with ethyl acetate, the organic phase was dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to remove the solvent, and the residue was subjected to column chromatography (elution solvent: ethyl acetate/n-hexane) to obtain the target product I-8 (60% yield); 1 H NMR(500MHz，CDCl 3 )δ： 7.37-7.31(m，3H)，7.24(d，J＝7.5Hz，2H)，5.84(s，1H)，4.66(d，J＝15.0Hz，1H)，4.36(d，J＝ 14.5Hz，1H)，4.09-4.06(m，1H)，3.77(d，J＝15.0Hz，1H)，2.13(d，J＝14.5Hz，1H)，1.98(d，J＝ 14.0Hz，1H)，1.48(s，3H)，1.32(s，3H)，1.18(s，3H)； 13 C NMR(125MHz，CDCl 3 )δ：203.0，176.1， 160.6，135.6，129.0，128.2，128.0，121.6，48.9，46.3，43.8，42.7，40.9，29.7，27.9，23.8；HRMS m/z (ESI)calcd for C 18 H 22 NO 2 ([M+H] + )284.1645，found 284.1647。
example 24
To a Schlenk flask were added 1, 6-eneyne compound represented by formula 1i (55.0 mg, 0.2mmol), azoalkylnitrile represented by formula 2a (65.6 mg,0.4 mmol), cuprous iodide (CuI, 7.6mg, 0.04mmol), triethylamine (Et) 3 N，4.0mg，0.04 mmol)，H 2 O/MeCN (v: v = 4: 1,2.0 ml), then the reactor was stirred to react under an air atmosphere at 60 ℃, the progress of the reaction was monitored by TLC until the raw material disappeared (reaction time 16 hours), after the reaction was completed, the reaction solution was extracted with ethyl acetate, the organic phase was dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to remove the solvent, and the residue was subjected to column chromatography (elution solvent: ethyl acetate/n-hexane) to obtain the target product I-9 (56% yield); 1 H NMR(500MHz，CDCl 3 )δ： 7.30(t，J＝8.0Hz，2H)，7.23-7.20(m，3H)，7.17-7.11(m，5H)，6.07(s，1H)，3.89(d，J＝14.5Hz， 1H)，3.29-3.23(m，3H)，2.36(d，J＝14.5Hz，1H)，2.10(d，J＝14.0Hz，1H)，1.52(s，3H)，1.25(s， 3H)； 13 C NMR(125MHz，CDCl 3 )δ：203.3，173.7，158.7，137.7，135.6，129.6，128.9，128.4，127.5， 125.3，122.7，120.5，52.0，51.0，45.6，43.1，41.0，31.3，28.6；HRMS m/z(ESI)calcd for C 23 H 24 NO 2 ([M+H] + )346.1802，found 346.1805。
example 25
To a Schlenk bottle, 1, 6-enyne compound represented by formula 1j (52.2mg, 0.2mmol), azoalkylnitrile represented by formula 2a (65.6 mg,0.4 mmol), cuprous iodide (CuI, 7.6mg, 0.04mmol), triethylamine (Et) 3 N，4.0mg，0.04 mmol)，H 2 O/MeCN (v: v = 4: 1,2.0 mL), the reaction was then stirred under an air atmosphere at 60 ℃ and monitored by TLCProceeding until the raw material disappears (reaction time is 16 hours), after the reaction is completed, extracting the reaction solution with ethyl acetate, drying the organic phase with anhydrous sodium sulfate, filtering and concentrating under reduced pressure to remove the solvent, and subjecting the residue to column chromatography (elution solvent: ethyl acetate/n-hexane) to obtain the target product I-10 (52% yield); 1 H NMR(500MHz，CDCl 3 )δ： 7.60-7.55(m，4H)，7.37-7.33(m，4H)，7.30(d，J＝7.5Hz，1H)，7.14(t，J＝7.5Hz，1H)，6.36(s， 1H)，4.83-4.80(m，1H)，4.49(d，J＝14.0Hz，1H)，2.67(d，J＝14.0Hz，1H)，2.40(d，J＝14.0Hz， 1H)，1.16(s，3H)，0.61(s，3H)； 13 C NMR(125MHz，CDCl 3 )δ：202.9，172.8，156.3，138.8，138.6， 129.1，129.0，128.1，127.0，125.0，125.0，119.6，52.6，51.5，45.9，41.4，28.6，25.8；HRMS m/z(ESI) calcd for C 22 H 22 NO 2 ([M+H] + )332.1645，found 332.1647。
example 26
To a Schlenk flask were added 1, 6-enyne compound represented by formula 1k (37.0mg, 0.2mmol), azoalkylnitrile represented by formula 2a (65.6 mg,0.4 mmol), cuprous iodide (CuI, 7.6mg, 0.04mmol), triethylamine (Et 3 N，4.0mg，0.04 mmol)，H 2 O/MeCN (v: v = 4: 1,2.0 ml), then the reactor was stirred to react under an air atmosphere at 60 ℃, the progress of the reaction was monitored by TLC until the raw material disappeared (reaction time 16 hours), after the reaction was completed, the reaction solution was extracted with ethyl acetate, the organic phase was dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to remove the solvent, and the residue was subjected to column chromatography (elution solvent: ethyl acetate/n-hexane) to obtain the target product I-11 (45% yield); 1 H NMR(500MHz，CDCl 3 )δ： 7.65(d，J＝7.5Hz，2H)，7.43(t，J＝8.0Hz，2H)，7.24(t，J＝7.5Hz，1H)，6.38(s，1H)，4.90-4.86 (m，1H)，4.47(d，J＝14.5Hz，1H)，3.82-3.68(m，1H)，2.29(d，J＝15.5Hz，1H)，2.20(d，J＝15.5 Hz，1H)，1.51(s，3H)，1.49(s，3H)； 13 C NMR(125MHz，CDCl 3 )δ：202.2，171.3，150.0，137.7， 129.3，123.9，121.1，120.6，52.2，44.3，41.6，40.9，25.9，22.9；HRMSm/z(ESI)calcd for C 16 H 18 NO 2 ([M+H] + )256.1332，found 256.1334。
example 27 reaction mechanism control experiment
To the reaction of example 1, 2.4 equivalents of tetramethylpiperidine nitroxide (TEMPO) or 2, 6-di-t-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.
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 invention and are not exhaustive of the possible implementations of the invention. Any obvious modifications to the above would be obvious to those of ordinary skill in the art, but would not bring the invention so modified beyond the spirit and scope of the present invention.
Claims (6)
1. A method for the free radical cyclization reaction of 1, 6-eneyne compounds and azo alkyl nitriles is characterized by comprising the following steps:
adding a 1, 6-eneyne compound shown in formula 1, an azoalkyl nitrile shown in formula 2, a catalyst, alkali 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 carrying out post-treatment to obtain a cyclized product I;
in the compounds represented by formula 1, formula 2 and formula I, R 1 Is selected from C 5 -C 14 Aryl radical, C 1 -C 10 Alkyl radical, wherein said 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, halogen substituted C 1 -C 6 Alkyl, -NO 2 -CN, said C 1 -C 10 Alkyl is optionally substituted by C 5 -C 14 Aryl substitution;
R 2 is hydrogen;
R 3 selected from hydrogen, C 1 -C 8 Alkyl radical, C 5 -C 14 Aryl, wherein said C 1 -C 8 Alkyl is optionally substituted by C 5 -C 14 Aryl substitution;
R 4 is selected from C 1 -C 6 An alkyl group;
R 5 is selected from C 1 -C 6 An alkyl group;
the catalyst is selected from any one or a mixture of more of cuprous iodide, cuprous bromide, cuprous chloride, copper bromide and copper acetate; the alkali is selected from one or a mixture of more of triethylamine, 1, 8-diazabicycloundecen-7-ene, potassium acetate and tetra-n-butylammonium acetate;
the solvent is H with the volume ratio of 4: 1 2 O/MeCN, the dosage of the solvent is 2.0mL;
the certain temperature is 60-80 ℃.
2. The process of claim 1 wherein the catalyst is cuprous iodide.
3. The process of claim 1, wherein the base is triethylamine.
4. The process according to claim 1, wherein the molar ratio of the 1, 6-enyne compound of formula 1 to the azoalkylnitrile of formula 2 is from 1: 1.2 to 1: 3.
5. The process according to claim 4, wherein the molar ratio of the 1, 6-enyne compound of formula 1 to the azoalkylnitrile of formula 2 is 1: 2.
6. The method of claim 1, 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 cyclized product I.
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