CN111943903B - Preparation method of 3, 1-benzoxazine derivative started by ketone free radical - Google Patents
Preparation method of 3, 1-benzoxazine derivative started by ketone free radical Download PDFInfo
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Abstract
The invention relates to a catalyst-free, ligand-free and alkali-free system for preparing alkenyl amide compounds and ketone compounds through ketone alpha-C (sp) 3 ) -H functional group generating free radical to start cyclization reaction to prepare 3, 1-benzoxazine derivative. The methodThe target product is obtained by adding alkenyl amide compounds, ketone compounds and an oxidant into a Schlenk reaction bottle and stirring for reaction at a certain temperature.
Description
Technical Field
The application belongs to the field of organic synthesis, and particularly relates to a method for preparing an alkenyl amide compound and a ketone compound through ketone alpha-C (sp) in a catalyst-free, ligand-free and alkali-free system 3 ) -H functional group generating free radical to start cyclization reaction to prepare 3, 1-benzoxazine derivative.
Background
C(sp 3 ) the-H functionalization has changed the logic of chemical synthesis, and has attracted great attention from chemists because of its ability to rapidly convert simple, readily available starting materials directly into complex and valuable products. Methods for transition metal-promoted, metal-catalyzed carbene transfer, hydrogen atom transfer, and radical coupling have been developed to achieve C (sp) 3 ) -H-functionalization strategy. Despite the great advances made in this field, the alpha-C (sp) is due to the ketone 3 ) High bond dissociation energy and low acidity of the-H bond, keto. Alpha. -C (sp) 3 ) The development of-H bond functionalization methods remains a formidable but desirable challenge. In this context, although some are derived from the keto a-C (sp) 3 ) The functionalization of H bonds produces free radicals to initiate reactions with carbon-carbon double bonds, but these processes are still plagued by limitations such as the use of transition metal or acid catalysts, the need for stoichiometric bases, and relatively poor selectivity. Thus, the search continues for highly selective radicals C (sp) of other types of carbon-carbon double bonds with ketones 3 ) an-H functionalization reaction is very necessary.
The 3, 1-benzoxazine derivatives are a key general structure and have wide application in anticonvulsant drugs, bactericides, hypolipidemic drugs, anti-HIV drugs, progesterone receptor agonists and herbicides. Thus, the preparation of 3, 1-benzoxazine derivatives has attracted a long-standing interest in the chemical world. Traditionally, the synthesis of 3, 1-benzoxazines has been largely dependent on the condensation of 2-aminobenzyl alcohol with aldehydes or ketones under harsh reaction conditions. In recent years, electrophilic or free radical cyclization of alkenyl amide compounds has become a powerful and convenient tool for the preparation of 3, 1-benzoxazines. However, to date, it has not been shown to react with ketones via the keto α -C (sp) 3 ) Preparation of 3, 1-benzoxazoles by cyclization reaction initiated by-H functionalization to generate free radicalsThe report of the oxazine derivative. The present inventors have conducted intensive studies on the preparation of 3, 1-benzoxazine by reacting alkenyl amide compounds with ketone compounds, and in the present invention, we have proposed an oxidant-promoted α -C (sp) related ketone 3 ) -H functionalization generates a radical-promoted cyclization reaction process. The method does not need to use a catalyst, a ligand and alkali, and has mild and green reaction conditions.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a method for preparing a 3, 1-benzoxazine derivative from an alkenyl amide compound and a ketone compound with high efficiency and low cost, and the method does not need any catalyst, ligand or alkali, and prepares a target product with high selectivity and high yield.
The invention provides a free radical cyclization reaction method, which takes alkenyl amide compounds and ketone compounds as raw materials and is prepared by the following steps:
adding an alkenyl amide compound shown in a formula 1, a ketone compound shown in a formula 2 and an oxidant into a Schlenk reaction bottle, placing the reaction bottle at a certain temperature, 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 3, 1-benzoxazine (I).
The invention provides a free radical cyclization reaction method of alkenyl amide compounds and ketone compounds, which has a chemical reaction formula (see formula I):
the post-treatment 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 and concentrating under reduced pressure to remove the solvent, and separating the residue by column chromatography, wherein the eluting solvent is as follows: ethyl acetate/n-hexane to obtain a target 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, halogen;
R 2 is selected from C 1 -C 10 Alkyl radical, C 5 -C 14 An aryl group;
R 3 is selected from C 1 -C 10 Alkyl radical, C 5 -C 14 An aryl group;
wherein each R is as defined above 1 -R 3 The aryl and alkyl 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 Selected from hydrogen, halogen;
R 2 is selected from C 1 Alkyl radical, C 6 An aryl group;
R 3 is selected from C 5 -C 14 And (4) an aryl group.
In the reaction of the invention, the oxidant is selected from any one or a mixture of t-butyl peroxide, benzoyl peroxide, di-t-butyl peroxide and tert-butyl peroxybenzoate, and is preferably tert-butyl peroxybenzoate.
In the reaction of the present invention, the amount of the tert-butyl peroxybenzoate used is 1.2 to 3 equivalents, preferably 2 equivalents.
In the reaction of the present invention, the certain temperature is 100 to 120 ℃ and the temperature is most preferably 120 ℃.
The beneficial effects of the invention are: provides a method for preparing alkenyl amide compounds and ketone compounds through ketone alpha-C (sp) 3 ) The method for preparing the 3, 1-benzoxazine derivative by generating free radicals through H functionalization starts a cyclization reaction, does not need to use a catalyst, a ligand and a base, and obtains a series of target products in high yield. 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 1-9 are experiments optimized for reaction conditions.
Example 1
Adding alkenyl amide compound represented by formula 1a (47.4 mg,0.2 mmol), ketone represented by formula 2a (1 mL), t-butyl peroxide (TBHP, 36.0mg, 2eq) into a Schlenk flask, then stirring the reactor at 120 ℃ for reaction, monitoring the progress of the reaction by TLC until the raw materials disappear (reaction time is 20 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 separating the residue by column chromatography (elution solvent: ethyl acetate/n-hexane) to obtain target product I-1 (18 yueld); 1 H NMR(500MHz，CDCl 3 )δ：8.13-8.12(m，2H)，7.52-7.49(m，1H)，7.46-7.43(m，2H)，7.31-7.30(m，2H)，7.21-7.18(m，1H)，7.07(d，J＝7.5Hz，1H)，2.66-2.59(m，1H)，2.48-2.42(m，1H)，2.39-2.31(m，2H)，2.05(s，3H)，1.67(s，3H)； 13 C NMR(125MHz，CDCl 3 )δ：207.8，156.4，139.1，132.8，131.4，128.7(2)，128.3，127.8，126.8，125.5，122.7，80.4，38.4，35.0，30.1，28.7；HRMS m/z(ESI)calcd for C 19 H 20 NO 2 ([M+H] + )294.1489，found 294.1487。
example 2
The oxidant is benzoyl peroxide instead of tert-butyl peroxide, and the other conditions are the same as in example 1, so that the yield of the target product I-1 is 33%.
Example 3
The oxidant used di-tert-butyl peroxide instead of tert-butyl peroxide, and the other conditions were the same as in example 1, to obtain the target product I-1 with a yield of 52%.
Example 4
The oxidant used was tert-butyl peroxybenzoate instead of tert-butyl peroxyhydrate, and the yield of the objective product I-1 was 85% under the same conditions as in example 1.
Example 5
The amount of the oxidant tert-butyl peroxybenzoate used was 1.2eq (46.6 mg), and the other conditions were the same as in example 4, whereby the yield of the objective product I-1 was 41%.
Example 6
The amount of the oxidant tert-butyl peroxybenzoate used was 3.0eq (116.5 mg), and the other conditions were the same as in example 4, whereby the yield of the objective product I-1 was 77%.
Example 7
With the addition of ferric chloride (10 mol%,3.2 mg) as a catalyst and the other conditions being the same as in example 4, the yield of the desired product I-1 was 84%.
Example 8
With the addition of additional copper chloride (10 mol%,2.7 mg) as catalyst and the same conditions as in example 4, the yield of the desired product I-1 was 85%.
Example 9
The reaction temperature was lowered to 100 ℃ to carry out the reaction under the same conditions as in example 4, whereby the yield of the objective product I-1 was 41%.
As can be seen from the above examples 1 to 9, the optimum reaction conditions were the reaction conditions of example 4, i.e., the oxidizing agent was t-butylperoxybenzoate (77.7mg, 2eq), and then the reactor was allowed to react at a reaction temperature of 120 ℃. On the basis of obtaining the optimal reaction condition, the inventor further selects alkenyl amide compounds and ketone compounds with different substituents as raw materials under the optimal reaction condition to develop a method for preparing the 3, 1-benzoxazine derivative through highly selective free radical cyclization reaction.
Example 10
Adding an alkenyl amide compound represented by formula 1b (56.4 mg,0.2 mmol), a ketone represented by formula 2b (1 mL), and an oxidizing agent tert-butyl peroxybenzoate (77.7mg, 2eq) to a Schlenk flask, then stirring the reactor at 120 ℃ to react, monitoring the progress of the reaction by TLC until the raw materials disappear (reaction time is 20 hours), after completion of the reaction, 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 separating the residue by column chromatography (eluting solvent: ethyl acetate/n-hexane) to obtain target products I-2 and I-3 (I-2: I-3= 2: 1) (62% yield); 1 H NMR(500MHz，CDCl 3 )δ：8.94(d，J＝8.5Hz，0.3H)，8.37(d，J＝8.5Hz，0.7H)，8.31-8.27(m，2H)，8.23(d，J＝9.0Hz，0.7H)，7.99(t，J＝6.5Hz，0.7H)，7.66(t，J＝8.0Hz，0.3H)，7.34(d，J＝4.0Hz，1.3H)，7.25-7.21(m，1H)，7.11(d，J＝7.5Hz，1H)，2.74(s，1H)，2.72-2.68(m，1H)，2.61-2.56(m，1H)，2.41-2.36(m，2H)，1.83-1.79(m，1H)，1.70(s，2H)，0.94-0.92(m，2H)，0.81-0.78(m，2H)； 13 C NMR(125MHz，CDCl 3 )δ：209.5，203.7，163.8，154.3，149.9，149.5，140.8，140.3，138.7，138.4，135.6，132.0，128.9，128.7，127.8，125.9，124.0，123.4，123.3，123.0，122.1，120.9，81.4，38.1，35.1，28.7，28.6，20.6，10.9；HRMS m/z(ESI)calcd for C 21 H 21 N 2 O 4 ([M+H] + )365.1496，found 365.1494。
example 11
To a Schlenk flask, an alkenyl amide compound represented by formula 1b (56.4 mg, 0.2mmol), a ketone represented by formula 2c (1 mL) and tert-butyl peroxybenzoate (77.7 mg, 2eq) as an oxidizing agent were added, the reactor was stirred at 120 ℃ and the progress of the reaction was monitored by TLC until the starting material disappeared (reaction time: 20 hours)After the reaction, the reaction solution was extracted with ethyl acetate, the organic phase was dried over 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 (58% yield, d.r. = 1: 1); 1 H NMR(500MHz，CDCl 3 )δ：8.33-8.27(m，4H)，7.34-7.33(m，2H)，7.27-7.23(m，1H)，7.13-7.10(m，1H)，3.54-3.49(m，0.5H)，3.37-3.31(m，0.5H)，3.06-3.00(m，1H)，2.88-2.82(m，1H)，2.55-2.51(m，0.5H)，2.47-2.43(m，0.5H)，2.20-2.14(m，1H)，2.10-2.00(m，1H)，1.76(s，1.5H)，1.75(s，1.5H)，1.70-1.65(m，0.5H)，1.49-1.43(m，0.5H)； 13 C NMR(125MHz，CDCl 3 )δ：209.9，209.6，154.1，154.0，149.5，138.7，138.6，138.3，138.0，129.1，129.0(2)，128.6，128.5，127.9，127.6，125.9(2)，123.5，123.4，123.1(2)，81.6，80.8，56.4，56.0，45.7，45.4，41.6，41.1，28.8，28.0，19.2，18.7；HRMS m/z(ESI)calcd for C 20 H 19 N 2 O 4 ([M+H] + )351.1339，found 351.1341。
example 12
Adding an alkenyl amide compound represented by formula 1b (56.4 mg,0.2 mmol), a ketone represented by formula 2d (1 mL) and tert-butyl peroxybenzoate (77.7 mmg, 2eq) as an oxidizing agent to a Schlenk flask, then stirring the reactor at 120 ℃ for reaction, monitoring the progress of the reaction by TLC until the raw materials disappear (the reaction time is 20 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 separating the residue by column chromatography (the elution solvent is ethyl acetate/n-hexane) to obtain the target product I-5 (56 yield, d.r. > 20: 1); 1 H NMR(500MHz，CDCl 3 )δ：8.31-8.29(m，3H)，7.33(d，J＝4.5Hz，2H)H)，7.25-7.22(m，2H)，7.17(d，J＝7.5Hz，1H)，2.87-2.84(m，1H)，2.29-2.18(m，2H)，2.07-2.01(m，2H)，1.95-1.90(m，2H)，1.68(s，3H)，1.56-1.45(m，2H)； 13 C NMR(125MHz，CDCl 3 )δ：203.7，154.0，149.5，138.8，138.5，129.0，128.5，128.2，128.0，126.0，123.5，123.1，82.4，46.7，40.9，37.1，31.6，30.2，20.7；HRMS m/z(ESI)calcd for C 21 H 21 N 2 O 4 ([M+H] + )365.1496，found 365.1492。
example 13
Adding an alkenyl amide compound represented by formula 1b (56.4 mg,0.2 mmol), a ketone represented by formula 2e (1 mL) and an oxidizing agent tert-butyl peroxybenzoate (77.7 mg, 2eq) into a Schlenk flask, then stirring the reactor at 120 ℃ for reaction, monitoring the progress of the reaction by TLC until the raw materials disappear (the reaction time is 20 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 separating the residue by column chromatography (the eluting solvent is ethyl acetate/n-hexane) to obtain the target product I-6 (71 yield); 1 H NMR(500MHz，CDCl 3 )δ：8.30-8.23(m，5H)，7.37-7.35(m，2H)，7.06(d，J＝7.5Hz，1H)，3.86-3.83(m，1H)，2.82-2.74(m，2H)，2.07(s，3H)，2.02(s，3H)，1.67(s，3H)； 13 C NMR(125MHz，CDCl 3 )δ：203.1，202.5，153.7，149.6，138.2，138.1，129.4，128.6，128.1，127.8，126.3，123.5，123.0，81.5，64.5，39.0，29.9，29.1，28.8；HRMS m/z(ESI)calcd for C 21 H 21 N 2 O 5 ([M+H] + )381.1445，found 381.1447。
example 14
To a Schlenk flask was added an alkenyl amide compound represented by formula 1c (63.0 mg, 0.2mmol), represented by formula 2aThen the reaction vessel was stirred at 120 ℃ and the progress of the reaction was monitored by TLC until the starting material disappeared (reaction time: 20 hours), after the completion of the reaction, the reaction solution was extracted with ethyl acetate, the organic phase was dried over 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 objective product I-7 (76: yield); 1 H NMR(500MHz，CDCl 3 )δ：8.11(d，J＝7.5Hz，2H)，7.51(t，J＝7.5Hz，1H)，7.46-7.40(m，3H)，7.19-7.17(m，2H)，2.63-2.58(m，1H)，2.49-2.42(m，1H)，2.33-2，29(m，2H)，2.07(s，3H)，1.66(s，3H)； 13 C NMR(125MHz，CDCl 3 )δ：207.4，156.7，138.2，132.4，131.8，131.7，130.7，128.4，127.9，127.1，125.8，119.5，80.1，38.2，34.8，30.1，28.5；HRMS m/z(ESI)calcd for C 19 H 19 BrNO 2 ([M+H] + )372.0594，found 372.0592。
example 15
Adding an alkenyl amide compound represented by formula 1d (51.0mg, 0.2mmol), a ketone represented by formula 2a (1 mL) and an oxidizing agent tert-butyl peroxybenzoate (77.7mg, 2eq) into a Schlenk bottle, then stirring the reactor at 120 ℃ for reaction, monitoring the reaction progress by TLC until the raw materials disappear (the reaction time is 20 hours), after the reaction is completed, extracting the reaction liquid with ethyl acetate, drying an organic phase with anhydrous sodium sulfate, filtering and concentrating under reduced pressure to remove a solvent, and separating the residue by column chromatography (an elution solvent is ethyl acetate/n-hexane) to obtain a target product I-8 (74, yield); 1 H NMR(500MHz，CDCl 3 )δ：8.11-8.09(m，2H)，7.52-7.49(m，1H)，7.47-7.44(m，2H)，7.30-7.27(m，1H)，7.02-6.98(m，1H)，6.80-6.78(m，1H)，2.68-2.60(m，1H)，2.49-2.44(m，1H)，2.34-2.29(m，2H)，2.08(s，3H)，1.66(s，3H)； 13 C NMR(125MHz，CDCl 3 )δ：207.5，161.2(d，J C-F ＝244.4Hz)，155.7(d，J C-F ＝1.9Hz)，135.3(d，J C-F ＝2.8Hz)，132.5，131.5，130.4(d，J C-F ＝7.3Hz)，128.3，127.7，127.0(d，J C-F ＝8.3Hz)，115.4(d，J C-F ＝22.0Hz)，109.8(d，J C-F ＝24.1Hz)，80.0，38.2，34.7，30.1，28.4； 19 F NMR(471MHz，CDCl 3 )δ：-114.3；HRMS m/z(ESI)calcd for C 19 H 19 FNO 2 ([M+H] + )312.1394，found 312.1398。
example 16
Adding an alkenyl amide compound (59.8mg, 0.2mmol) represented by formula 1e, a ketone (1 mL) represented by formula 2a, and tert-butyl peroxybenzoate (77.7mg, 2eq) as an oxidizing agent into a Schlenk flask, then stirring the reactor at 120 ℃ for reaction, monitoring the progress of the reaction by TLC until the raw materials disappear (the reaction time is 20 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 separating the residue by column chromatography (the elution solvent is ethyl acetate/n-hexane) to obtain the target product I-9 (64% yield); 1 H NMR(500MHz，CDCl 3 )δ：8.21(d，J＝7.0Hz，2H)，7.52-7.45(m，4H)，7.38-7.32(m，4H)，7.24-7.20(m，4H)，2.76-2.67(m，4H)，2.09(s，3H)； 13 C NMR(125MHz，CDCl 3 )δ：207.7，156.3，143.3，139.6，132.4，131.5，129.3，129.1，128.8，128.4，128.0，127.8，126.6，125.7，125.6，124.4，83.5，38.9，34.2，30.2；HRMS m/z(ESI)calcd for C 24 H 22 NO 2 ([M+H] + )356.1645，found 356.1649。
example 17
Adding an alkenyl amide compound represented by formula 1f (53.4 mg,0.2 mmol), a ketone represented by formula 2a (1 mL), and tert-butyl peroxybenzoate (77.7mg, 2eq) as an oxidizing agent to a Schlenk flask, then stirring the reactor at 120 ℃ to react, monitoring the progress of the reaction by TLC until the raw materials disappear (reaction time: 20 hours), after completion of the reaction, 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 separating the residue by column chromatography (elution solvent: ethyl acetate/n-hexane) to obtain the objective product I-10 (89 th yield); 1 H NMR(500MHz，CDCl 3 )δ：8.08-8.07(m，2H)，7.29-7.28(m，2H)，7.18-7.15(m，1H)，7.05(d，J＝7.5Hz，1H)，6.96-6.94(m，2H)，3.86(s，3H)，2.64-2.58(m，1H)，2.47-2.41(m，1H)，2.35-2.29(m，2H)，2.04(s，3H)，1.65(s，3H)； 13 C NMR(125MHz，CDCl 3 )δ：207.9，162.3，156.3，139.3，129.6，128.7，128.6，126.3，125.2(2)，122.7，113.6，80.2，55.4，38.4，34.9，30.1，28.5；HRMS m/z(ESI)calcd for C 20 H 22 NO 3 ([M+H] + )324.1594，found 324.1590。
example 18
Adding 1g of an alkenyl amide compound represented by the formula (50.2 mg,0.2 mmol), a ketone represented by the formula 2a (1 mL) and an oxidizing agent tert-butyl peroxybenzoate (77.7mg, 2eq) to a Schlenk flask, then stirring the reactor under an air atmosphere at 120 ℃ for reaction, monitoring the progress of the reaction by TLC until the raw material disappears (the reaction time is 20 hours), after completion of the reaction, 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 separating the residue by column chromatography (the elution solvent is ethyl acetate/n-hexane) to obtain the objective product I-11 (88% yield); 1 H NMR(500MHz，CDCl 3 )δ：8.02(d，J＝8.0Hz，2H)，7.30(d，J＝4.0Hz，2H)，7.27-7.24(m，2H)，7.19-7.16(m，1H)，7.06(d，J＝7.5Hz，1H)，2.65-2.58(m，1H)，2.47-2.44(m，1H)，2.41(s，3H)，2.36-2.29(m，2H)，2.04(s，3H)，1.66(s，3H)； 13 C NMR(125MHz，CDCl 3 )δ：207.9，156.6，141.9，139.2，130.0，129.0，128.7，127.8，126.6，125.3，122.7，80.3，38.4，34.9，30.1，28.6，21.6；HRMS m/z(ESI)calcd for C 20 H 22 NO 2 ([M+H] + )308.1645，found 308.1647。
example 19
Adding an alkenyl amide compound (58.6 mg, 0.2mmol) represented by formula 1h, a ketone (1 mL) represented by formula 2a and tert-butyl peroxybenzoate (77.7mg, 2eq) as an oxidizing agent into a Schlenk flask, then stirring the reactor at 120 ℃ for reaction, monitoring the reaction progress by TLC until the raw materials disappear (the reaction time is 20 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 separating the residue by column chromatography (the elution solvent is ethyl acetate/n-hexane) to obtain the target product I-12 (87: yield); 1 H NMR(500MHz，CDCl 3 )δ：7.94(t，J＝8.5Hz，2H)，7.24-7.22(m，2H)，7.20-7.17(m，3H)，6.99(d，J＝7.0Hz，1H)，2.61-2.55(m，3H)，2.41-2.33(m，1H)，2.28-2.23(m，1H)，1.98(s，3H)，1.59(s，3H)，1.57-1.52(m，2H)，1.31-1.26(m，3H)，0.86(t，J＝7.5Hz，3H)； 13 C NMR(125MHz，CDCl 3 )δ：208.0，156.7，146.9，139.2，130.2，128.7，128.5，128.4，127.8，126.6，125.3，122.7，80.3，38.5，35.7，34.9，33.4，30.1，28.6，22.3，13.9；HRMSm/z(ESI)calcd for C 23 H 28 NO 2 ([M+H] + )350.2115，found350.2111。
example 20
Adding an alkenyl amide compound represented by formula 1I (58.6 mg,0.2 mmol), a ketone represented by formula 2a (1 mL), and tert-butyl peroxybenzoate (77.7mg, 2eq) as an oxidizing agent to a Schlenk flask, then stirring the reactor at 120 ℃ to react, monitoring the progress of the reaction by TLC until the raw material disappears (reaction time is 20 hours), after completion of the reaction, 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 separating the residue by column chromatography (elution solvent: ethyl acetate/n-hexane) to obtain the objective product I-13 (86% yield); 1 H NMR(500MHz，CDCl 3 )δ：8.06-8.04(m，2H)，7.50-7.46(m，3H)，7.31-7.29(m，2H)，7.06(d，J＝7.5Hz，1H)，2.66-2.59(m，1H)，2.48-2.41(m，1H)，2.36-2.30(m，2H)，2.05(s，3H)，1.66(s，3H)，1.35(s，9H)； 13 C NMR(125MHz，CDCl 3 )δ：208.0，156.5，154.9，139.2，130.0，129.7，128.7，127.6，126.6，125.4，125.3，122.7，80.2，38.5，35.0，34.9，31.2，30.1，28.7；HRMS m/z(ESI)calcd for C 23 H 28 NO 2 ([M+H] + )350.2115，found 350.2117。
example 21
Adding an alkenyl amide compound represented by formula 1j (51.0mg, 0.2mmol), a ketone represented by formula 2a (1 mL) and an oxidizing agent tert-butyl peroxybenzoate (77.7mg, 2eq) into a Schlenk bottle, stirring the reactor at 120 ℃ for reaction, monitoring the reaction progress by TLC until the raw materials disappear (the reaction time is 20 hours), extracting the reaction liquid with ethyl acetate after the reaction is completed, drying an organic phase with anhydrous sodium sulfate, filtering and concentrating under reduced pressure to remove a solvent, and separating the residue by column chromatography (an eluting solvent is ethyl acetate/n-hexane) to obtain a target product I-14 (83, yield); 1 H NMR(500MHz，CDCl 3 )δ：8.14-8.11(m，2H)，7.31-7.28(m，2H)，7.21-7.18(m，1H)，7.14-7.10(m，2H)，7.07(d，J＝8.0Hz，1H)，2.63-2.57(m，1H)，2.47-2.40(m，1H)，2.36-2.30(m，2H)，2.05(s，3H)，1.67(s，3H)； 13 C NMR(125MHz，CDCl 3 )δ：207.7，164.5(d，J C-F ＝250.4Hz)，155.5，138.9，130.0(d，J C-F ＝8.8Hz)，128.9(d，J C-F ＝3.0Hz)，128.8，128.5，126.8，125.4，122.8，115.3(d，J C-F ＝21.8Hz)，80.6，38.4，34.9，30.1，28.6； 19 F NMR(471MHz，CDCl 3 )δ：-108.5；HRMS m/z(ESI)calcd for C 19 H 19 FNO 2 ([M+H] + )312.1394，found 312.1392。
example 22
Adding an alkenyl amide compound represented by formula 1k (54.2mg, 0.2mmol), a ketone represented by formula 2a (1 mL) and tert-butyl peroxybenzoate (77.7mg, 2eq) as an oxidizing agent into a Schlenk flask, then stirring the reactor at 120 ℃ for reaction, monitoring the progress of the reaction by TLC until the raw materials disappear (the reaction time is 20 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 separating the residue by column chromatography (the elution solvent is ethyl acetate/n-hexane) to obtain a target product I-15 (82, yield); 1 H NMR(500MHz，CDCl 3 )δ：8.06(d，J＝8.5Hz，2H)，7.44-7.41(m，2H)，7.31-7.29(m，2H)，7.22-7.19(m，1H)，7.07(d，J＝7.5Hz，1H)，2.63-2.57(m，1H)，2.48-2.42(m，1H)，2.36-2.30(m，2H)，2.05(s，3H)，1.67(s，3H)； 13 C NMR(125MHz，CDCl 3 )δ：207.8，155.6，138.8，137.6，130.1，129.2，128.8，128.6，128.4，127.0，125.4，122.8，80.8，38.4，34.9，30.1，28.7；HRMS m/z(ESI)calcd for C 19 H 19 ClNO 2 ([M+H] + )328.1099，found 328.1095。
example 23
Adding an alkenyl amide compound represented by the formula 1l (63.0 mg,0.2 mmol), a ketone represented by the formula 2a (1 mL), and tert-butyl peroxybenzoate (77.7mg, 2eq) as an oxidizing agent to a Schlenk flask, then stirring the reactor at 120 ℃ to react, monitoring the progress of the reaction by TLC until the raw material disappears (reaction time: 20 hours), after completion of the reaction, 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 separating the residue by column chromatography (elution solvent: ethyl acetate/n-hexane) to obtain the objective product I-16 (82. Yield); 1 H NMR(500MHz，CDCl 3 )δ：8.00-7.98(m，2H)，7.59-7.56(m，2H)，7.30(d，J＝4.0Hz，2H)，7.22-7.19(m，1H)，7.06(d，J＝7.5Hz，1H)，2.63-2.56(m，1H)，2.47-2.41(m，1H)，2.36-2.30(m，2H)，2.05(s，3H)，1.66(s，3H)； 13 C NMR(125MHz，CDCl 3 )δ：207.8，155.7，138.7，131.5，129.4，128.8，128.6，128.4，127.1，126.2，125.5，122.8，80.8，38.4，34.9，30.1，28.7；HRMS m/z(ESI)calcd for C 19 H 19 BrNO 2 ([M+H] + )372.0594，found 372.0596。
example 24
Adding an alkenyl amide compound represented by the formula 1m (61.0mg, 0.2mmol), a ketone represented by the formula 2a (1 mL) and an oxidizing agent tert-butyl peroxybenzoate (77.7mg, 2eq) into a Schlenk bottle, then stirring the reactor at 120 ℃ for reaction, monitoring the reaction progress by TLC until the raw materials disappear (the reaction time is 20 hours), after the reaction is completed, extracting the reaction liquid with ethyl acetate, drying an organic phase with anhydrous sodium sulfate, filtering and concentrating under reduced pressure to remove a solvent, and separating the residue by column chromatography (an elution solvent is ethyl acetate/n-hexane) to obtain a target product I-17 (71: yield); 1 H NMR(500MHz，CDCl 3 )δ：8.24(d，J＝8.0Hz，2H)，7.70(d，J＝8.5Hz，2H)，7.33(d，J＝4.0Hz，2H)，7.25-7.21(m，1H)，7.08(d，J＝8.0Hz，1H)，2.64-2.57(m，1H)，2.47(t，J＝7.5Hz，1H)，2.41-2.32(m，2H)，2.06(s，3H)，1.69(s，3H)； 13 C NMR(125MHz，CDCl 3 )δ：207.6，155.0，138.6，136.1，132.9(q，J C-F ＝32.3Hz)，128.9，128.6，128.1，127.4，125.7，125.2(q，J C-F ＝3.8Hz)，125.0，122.9，81.0，38.4，34.9，30.1，28.7； 19 F NMR(471MHz，CDCl 3 )δ：-62.8；HRMS m/z(ESI)calcd for C 20 H 19 F 3 NO 2 ([M+H] + )362.1362，found 362.1364。
example 25
Adding an alkenyl amide compound represented by formula 1b (56.4 mg,0.2 mmol), a ketone represented by formula 2a (1 mL), and tert-butyl peroxybenzoate (77.7 mg, 2eq) as an oxidizing agent to a Schlenk flask, then stirring the reactor at 120 ℃ for reaction, monitoring the progress of the reaction by TLC until the raw material disappears (reaction time: 20 hours), after completion of the reaction, 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 separating the residue by column chromatography (elution solvent: ethyl acetate/n-hexane) to obtain the objective product I-18 (73. Yield); 1 H NMR(500MHz，CDCl 3 )δ：8.31-8.27(m，4H)，7.34(d，J＝4.0Hz，2H)，7.27-7.24(m，1H)，7.10(d，J＝7.5Hz，1H)，2.64-2.57(m，1H)，2.49-2.44(m，1H)，2.39-2.34(m，2H)，2.06(s，3H)，1.70(s，3H)； 13 C NMR(125MHz，CDCl 3 )δ：207.4，154.2，149.5，138.6，138.3，129.0，128.6(2)，127.8，125.9，123.4，122.9，81.4，38.3，34.9，30.1，28.7；HRMS m/z(ESI)calcd for C 19 H 19 N 2 O 4 ([M+H] + )339.1339，found 339.1337。
example 26
Adding an alkenyl amide compound represented by formula 1n (50.2mg, 0.2mmol), a ketone represented by formula 2a (1 mL) and tert-butyl peroxybenzoate (77.7mmg, 2eq) as an oxidizing agent into a Schlenk flask, then stirring the reactor at 120 ℃ for reaction, monitoring the progress of the reaction by TLC until the raw materials disappear (the reaction time is 20 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 separating the residue by column chromatography (the elution solvent is ethyl acetate/n-hexane) to obtain the target product I-19 (85 yield); 1 H NMR(500MHz，CDCl 3 )δ：7.95(s，1H)，7.91(d，J＝7.0Hz，1H)，7.36-7.31(m，4H)，7.20-7.15(m，1H)，7.06(d，J＝7.5Hz，1H)，2.66-2.59(m，1H)，2.48-2.45(m，1H)，2.43(s，3H)，2.37-2.26(m，2H)，2.05(s，3H)，1.67(s，3H)； 13 CNMR(125MHz，CDCl 3 )δ：208.0，156.7，139.1，138.0，132.7，132.3，128.7，128.6，128.3，128.2，126.7，125.4，125.0，122.8，80.4，38.5，34.9，30.1，28.7，21.4；HRMS m/z(ESI)calcd for C 20 H 22 NO 2 ([M+H] + )308.1645，found 308.1643。
example 27
Adding an alkenyl amide compound represented by formula 1o (53.4 mg,0.2 mmol), a ketone represented by formula 2a (1 mL) and tert-butyl peroxybenzoate (77.7 mg, 2eq) as an oxidizing agent to a Schlenk flask, then stirring the reactor at 120 ℃ for reaction, monitoring the progress of the reaction by TLC until the raw materials disappear (reaction time: 20 hours), after completion of the reaction, 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 separating the residue by column chromatography (elution solvent: ethyl acetate/n-hexane) to obtain the target product I-20 (86 yield); 1 H NMR(500MHz，CDCl 3 )δ：7.64-7.60(m，2H)，7.447.40(m，1H)，7.30-7.23(m，3H)，7.19-7.11(m，2H)，3.82(s，3H)，2.58-2.51(m，1H)，2.36-2.32(m，1H)，2.29-2.23(m，2H)，1.98(s，3H)，1.60(s，3H)； 13 C NMR(125MHz，CDCl 3 )δ：206.9，158.6，155.3，137.9，133.1，128.3，127.7，125.8，124.4，121.7，119.3，116.6，113.3，111.7，79.5，54.4，37.4，33.9，29.1，27.6；HRMS m/z(ESI)calcd for C 20 H 22 NO 3 ([M+H] + )324.1594，found 324.1592。
example 28
Adding an alkenyl amide compound represented by formula 1p (54.2mg, 0.2mmol), a ketone represented by formula 2a (1 mL) and tert-butyl peroxybenzoate (77.7mg, 2eq) as an oxidizing agent into a Schlenk flask, then stirring the reactor at 120 ℃ for reaction, monitoring the progress of the reaction by TLC until the raw materials disappear (the reaction time is 20 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 separating the residue by column chromatography (the elution solvent is ethyl acetate/n-hexane) to obtain a target product I-21 (81% yield); 1 H NMR(500MHz，CDCl 3 )δ：8.10(t，J＝2.0Hz，1H)，8.02-8.00(m，1H)，7.47-7.45(m，1H)，7.38(t，J＝8.0Hz，1H)，7.33-7.29(m，2H)，7.22-7.19(m，1H)，7.07(d，J＝7.5Hz，1H)，2.64-2.57(m，1H)，2.46-2.41(m，1H)，2.37-2.30(m，2H)，2.06(s，3H)，1.67(s，3H)； 13 C NMR(125MHz，CDCl 3 )δ：207.6，155.1，138.7，134.6，134.4，131.3，129.6，128.8，128.6，127.8，127.2，125.9，125.6，122.8，80.9，38.4，34.9，30.1，28.7；HRMS m/z(ESI)calcd for C 19 H 19 ClNO 2 ([M+H] + )328.1099，found 328.1095。
example 29
Adding an alkenyl amide compound represented by formula 1q (50.2mg, 0.2mmol), a ketone represented by formula 2a (1 mL) and tert-butyl peroxybenzoate (77.7mg, 2eq) as an oxidizing agent into a Schlenk flask, then stirring the reactor at 120 ℃ for reaction, monitoring the progress of the reaction by TLC until the raw materials disappear (the reaction time is 20 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 separating the residue by column chromatography (the elution solvent is ethyl acetate/n-hexane) to obtain a target product I-22 (84: yield); 1 H NMR(500MHz，CDCl 3 )δ：7.78-7.76(m，1H)，7.37-7.34(m，1H)，7.33-7.30(m，1H)，7.29-7.28(m，2H)，7.22-7.18(m，2H)，7.07-7.05(m，1H)，2.69-2.64(m，1H)，2.63(s，3H)，2.50-2.47(m，1H)，2.39-2.29(m，2H)，2.06(s，3H)，1.70(s，3H)； 13 CNMR(125MHz，CDCl 3 )δ：207.9，158.4，138.9，138.1，132.7，131.4，130.4，129.5，128.7，128.1，126.9，125.8，125.4，122.7，80.8，38.6，34.8，30.1，29.0，21.6；HRMS m/z(ESI)calcd for C 20 H 22 NO 2 ([M+H] + )308.1645，found 308.1643。
example 30
Adding an alkenyl amide compound represented by formula 1r (54.2mg, 0.2mmol), a ketone represented by formula 2a (1 mL) and tert-butyl peroxybenzoate (77.7mg, 2eq) as an oxidizing agent into a Schlenk flask, then stirring the reactor at 120 ℃ for reaction, monitoring the progress of the reaction by TLC until the raw materials disappear (the reaction time is 20 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 separating the residue by column chromatography (the elution solvent is ethyl acetate/n-hexane) to obtain a target product I-23 (80% yield); 1 H NMR(500MHz，CDCl 3 )δ：7.75-7.74(m，1H)，7.45-7.43(m，1H)，7.39-7.34(m，2H)，7.32-7.28(m，2H)，7.24-7.21(m，1H)，7.07-7.06(m，1H)，2.75-2.68(m，1H)，2.50-2.41(m，2H)，2.34-2.28(m，1H)，2.07(s，3H)，1.73(s，3H)； 13 CNMR(125MHz，CDCl 3 )δ：207.9，157.1，138.5，133.1，132.9，131.3，131.1，130.7，128.8，128.3，127.4，126.8，125.5，122.8，81.8，38.5，35.0，30.1，29.2；HRMS m/z(ESI)calcd for C 19 H 19 ClNO 2 ([M+H] + )328.1099，found 328.1097。
example 31 experiment for controlling reaction mechanism
To further verify the reaction mechanism of this reaction, the following two sets of control experiments were performed. First, in the experiment in example 4, without the addition of acetone, the product I-24 was not obtained, indicating that the conversion may be by acetone α -C (sp) 3 ) the-H functionalization is initiated by the generation of free radicals. Secondly, when 2.2 equivalents of tetramethylpiperidine nitroxide (TEMPO) or 2, 6-di-tert-butyl-4-methylphenol (BHT) were added as a radical scavenger to the reaction of example 4, only a trace amount of the objective product was detected, and the product I-25 of 2, 6-di-tert-butyl-4-methylphenol bound to acetone radical was obtained in a yield of 64%, 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 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 (3)
1. A method for preparing 3, 1-benzoxazine derivatives by free radical cyclization reaction of alkenyl amide compounds and ketone compounds is characterized by comprising the following steps:
adding an alkenyl amide compound shown in a formula 1, a ketone compound shown in a formula 2 and an oxidant into a Schlenk reaction bottle, placing the reaction bottle at a certain temperature, stirring for reaction, monitoring the reaction process by TLC or GC until the raw materials react completely, and carrying out post-treatment to obtain a cyclized product 3, 1-benzoxazine (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, halogen;
R 2 is selected from C 1 -C 10 Alkyl radical, C 5 -C 14 An aryl group;
R 3 is selected from C 1 -C 10 Alkyl radical, C 5 -C 14 An aryl group;
wherein each R is 1 -R 3 The aryl and alkyl 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 =) -;
and wherein, the ketone compound represented by the formula 2
Selected from the following structures:
the oxidant is tert-butyl peroxybenzoate; the using amount of the tert-butyl peroxybenzoate is 2 equivalents;
the certain temperature is 120 ℃.
2. The method of claim 1, wherein R is 1 Selected from hydrogen, halogen;
R 2 is selected from C 1 Alkyl radical, C 6 An aryl group;
R 3 is selected from C 5 -C 14 And (3) an aryl group.
3. A method according to any one of claims 1-2, characterized in that 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 and concentrating under reduced pressure to remove the solvent, and separating the residue by column chromatography, wherein the eluting solvent is as follows: ethyl acetate/n-hexane to obtain the target cyclization product 3, 1-benzoxazine I.
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