CN115504921A - C (sp) 3 ) Method for preparing pyrrolidine-2,4-diketone derivative from (E) -H-functionalized initiated 1,5-alkenenitrile - Google Patents
C (sp) 3 ) Method for preparing pyrrolidine-2,4-diketone derivative from (E) -H-functionalized initiated 1,5-alkenenitrile Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 25
- 238000006243 chemical reaction Methods 0.000 claims abstract description 98
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims abstract description 57
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims abstract description 56
- 239000007800 oxidant agent Substances 0.000 claims abstract description 18
- 230000001590 oxidative effect Effects 0.000 claims abstract description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 11
- DOQJUNNMZNNQAD-UHFFFAOYSA-N pyrrolidine-2,4-dione Chemical class O=C1CNC(=O)C1 DOQJUNNMZNNQAD-UHFFFAOYSA-N 0.000 claims abstract description 4
- 238000003756 stirring Methods 0.000 claims abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 156
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 51
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 37
- 229910052700 potassium Inorganic materials 0.000 claims description 37
- 239000011591 potassium Substances 0.000 claims description 37
- 239000002904 solvent Substances 0.000 claims description 36
- 150000001875 compounds Chemical class 0.000 claims description 28
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 26
- 238000004440 column chromatography Methods 0.000 claims description 26
- 239000012074 organic phase Substances 0.000 claims description 26
- 239000002994 raw material Substances 0.000 claims description 26
- 238000001914 filtration Methods 0.000 claims description 22
- 125000003118 aryl group Chemical group 0.000 claims description 9
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 9
- 230000008569 process Effects 0.000 claims description 7
- GJBRNHKUVLOCEB-UHFFFAOYSA-N tert-butyl benzenecarboperoxoate Chemical compound CC(C)(C)OOC(=O)C1=CC=CC=C1 GJBRNHKUVLOCEB-UHFFFAOYSA-N 0.000 claims description 4
- USHAGKDGDHPEEY-UHFFFAOYSA-L potassium persulfate Chemical compound [K+].[K+].[O-]S(=O)(=O)OOS([O-])(=O)=O USHAGKDGDHPEEY-UHFFFAOYSA-L 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- DORMTBIPKNPJPY-UHFFFAOYSA-N acetic acid;iodobenzene Chemical compound CC(O)=O.IC1=CC=CC=C1 DORMTBIPKNPJPY-UHFFFAOYSA-N 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims description 2
- 238000012544 monitoring process Methods 0.000 claims description 2
- 238000012805 post-processing Methods 0.000 claims description 2
- 239000012298 atmosphere Substances 0.000 abstract description 26
- 239000003054 catalyst Substances 0.000 abstract description 8
- 238000005481 NMR spectroscopy Methods 0.000 description 50
- 239000000047 product Substances 0.000 description 40
- 230000035484 reaction time Effects 0.000 description 24
- 239000012156 elution solvent Substances 0.000 description 20
- 239000012295 chemical reaction liquid Substances 0.000 description 13
- 238000006460 hydrolysis reaction Methods 0.000 description 8
- -1 amino acid esters Chemical class 0.000 description 7
- 238000007306 functionalization reaction Methods 0.000 description 7
- 229910052723 transition metal Inorganic materials 0.000 description 6
- 150000003624 transition metals Chemical class 0.000 description 6
- 239000000654 additive Substances 0.000 description 4
- 239000003513 alkali Substances 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 238000007154 radical cyclization reaction Methods 0.000 description 4
- 150000003254 radicals Chemical class 0.000 description 4
- 238000007363 ring formation reaction Methods 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 description 3
- 230000000996 additive effect Effects 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 230000007246 mechanism Effects 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 150000003997 cyclic ketones Chemical class 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- LSXWFXONGKSEMY-UHFFFAOYSA-N di-tert-butyl peroxide Chemical compound CC(C)(C)OOC(C)(C)C LSXWFXONGKSEMY-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000005805 hydroxylation reaction Methods 0.000 description 2
- QNXSIUBBGPHDDE-UHFFFAOYSA-N indan-1-one Chemical compound C1=CC=C2C(=O)CCC2=C1 QNXSIUBBGPHDDE-UHFFFAOYSA-N 0.000 description 2
- 230000009257 reactivity Effects 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- YZMVLKJJJCMVGX-UHFFFAOYSA-N 1,2,3,4-tetrahydroquinoline-2,4-dione Chemical compound C1=CC=C2NC(=O)CC(=O)C2=C1 YZMVLKJJJCMVGX-UHFFFAOYSA-N 0.000 description 1
- VUZNLSBZRVZGIK-UHFFFAOYSA-N 2,2,6,6-Tetramethyl-1-piperidinol Chemical group CC1(C)CCCC(C)(C)N1O VUZNLSBZRVZGIK-UHFFFAOYSA-N 0.000 description 1
- FXZXTDVGVWWRLT-UHFFFAOYSA-M C(C)(=O)[O-].C1=CC=CC=C1.[I+] Chemical compound C(C)(=O)[O-].C1=CC=CC=C1.[I+] FXZXTDVGVWWRLT-UHFFFAOYSA-M 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 238000007259 addition reaction Methods 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 150000001723 carbon free-radicals Chemical class 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000004880 explosion Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 231100001261 hazardous Toxicity 0.000 description 1
- 230000033444 hydroxylation Effects 0.000 description 1
- 150000002466 imines Chemical class 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- GDOPTJXRTPNYNR-UHFFFAOYSA-N methyl-cyclopentane Natural products CC1CCCC1 GDOPTJXRTPNYNR-UHFFFAOYSA-N 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 231100000956 nontoxicity Toxicity 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 244000045947 parasite Species 0.000 description 1
- 125000000864 peroxy group Chemical group O(O*)* 0.000 description 1
- 230000001699 photocatalysis Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002516 radical scavenger Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- CIHOLLKRGTVIJN-UHFFFAOYSA-N tert‐butyl hydroperoxide Chemical compound CC(C)(C)OO CIHOLLKRGTVIJN-UHFFFAOYSA-N 0.000 description 1
- 238000006257 total synthesis reaction Methods 0.000 description 1
- 229930195735 unsaturated hydrocarbon Natural products 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 150000003953 γ-lactams Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/36—Oxygen or sulfur atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a metal-free catalyst and alkali-free C (sp) in green system 3 ) -H-functionalized initiated 1,5-enenitriles to pyrrolidine-2,4-dione derivatives. The method comprises the steps of adding 1,5-alkene nitrile compounds, acetone/acetonitrile, an oxidant and water into a Schlenk reaction bottle, and stirring and reacting at a certain temperature under an air atmosphere to obtain the pyrrolidine-2,4-diketone derivative.
Description
Technical Field
The application belongs to the field of organic synthesis, and particularly relates to acetone/acetonitrile C (sp) under a metal-free and alkali-free green system 3 ) A green method for preparing pyrrolidine-2,4-diketone derivatives by-H functionalized 1,5-alkene nitrile compound free radical cyclization/hydrolysis reaction.
Background
In the last years, C (sp) 3 ) Direct functionalization of the-H bond has greatly stimulated interest of synthetic organic chemists. However, the difficulty is C (sp) 3 ) The high bond of the-H bond can lead to poor reactivity, which at present times has been activated by organic chemists, usually by the addition of transition metal catalysts or by the use of bases. Although transition metal catalysts are used in many reactionsWhile there are good performance and efficiency in these applications, there are some inherent drawbacks to these transition metal catalyzed functional reactions, for example, most transition metal catalysts and their supporting ligands are often very expensive; most transition metals are toxic and their complete removal from the product is very difficult. In addition, the use of alkali additives has certain limitations on groups that are poorly alkali-tolerant, and the waste products from post-treatment are also environmentally hazardous. Thus, a C (sp) in a metal-free catalyst and base-free system is achieved 3 ) H-bond functionalization reactions remain an attractive but challenging task in current green organic synthesis. Oxone, because it has the advantages of low cost, good stability under different reaction conditions, easy treatment, no toxicity, and the ability to obtain pollution-free by-products under reaction conditions with moderate operating conditions, is a good choice for this simple and versatile oxidant in organic synthesis processes. Furthermore, oxone is in C (sp) 3 ) The functionalization reaction of the-H bond has been preliminarily reported. One achieves inert alkane C (sp) in various compounds through Oxone mediation 3 ) Hydroxylation of-H, selective monohalogenation, alpha-hydroxylation of beta-dicarbonyl compounds and ketones C (sp) 3 ) Functionalization of the H bond, etc. Thus, C (sp) is oxidized by Oxone 3 ) The cleavage of the-H bond and its direct functionalization is an alternative green approach.
The skeleton structure of pyrrolidine-2,4-dione is commonly present in various natural/non-natural products with medicinal activity, and has the effects of resisting tumor, virus, fungus, expelling parasites and the like. Traditionally, the compound is prepared by performing multiple steps of substitution, acylation, cyclization, acidification and the like on amino acid esters. But the total yield is lower, and the defects of limited synthesis, complicated total synthesis steps and the like exist. Therefore, a synthesis method which is efficient, convenient and low in cost is developed. Because of its low price and easy availability, cyano is widely used in the introduction reaction of various functional groups, and one important application is in the formation of cyclic ketone compounds through addition reaction with a free radical source to generate imine free radicals and further hydrolysis. In recent years, cyano groups on electron-rich aromatic rings or nitrogen atoms have been widely used for the preparation of cyclic ketone compounds. Quinoline-2,4-dione, gamma-lactam, 1-indanone and other cyclic ketone frameworks are prepared by a transition metal catalytic system or a photocatalytic system such as Cu, fe, ag and the like; in fact, at the end of the early 20 th century, it was reported that cyano groups attached to alkyl groups participate in free radical cyclization to produce cyclic ketone compounds, which typically were obtained in relatively low yields by the addition of active organotin reagents or zinc powders which are prone to explosion. On the one hand, however, the recent participation of the cyano group attached to the alkyl group in the serial cyclization of unsaturated hydrocarbons to cyclic ketones has been reported less frequently mainly because of its relatively poor reactivity; on the other hand, the early cyclized hydrolysis reaction of a cyano group bonded to an alkyl group often uses an excessively reactive and toxic organotin reagent, resulting in a low yield and a large amount of by-products, which has made the progress of the research still difficult.
To solve the above problems, the inventors designed to achieve C (sp) by using Oxone as the green oxidant 3 ) Direct functionalization of the-H bond realizes series cyclization/hydrolysis reaction of 1,5-alkene nitriles and acetone/acetonitrile, thereby efficiently preparing pyrrolidine-2,4-diketone with important application value. The scheme has the following outstanding advantages: (1) no metal catalyst and no alkali; (2) use Oxone as green oxidant; (3) C (sp) 3 ) -direct functionalization of the H bond; and (4) cyclizing hydrolysis of the alkyl cyanide is realized.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a green and efficient acetone/acetonitrile C (sp) 3 ) The method for preparing pyrrolidine-2,4-diketone derivatives by the-H functionalized 1,5-alkene nitrile compound free radical cyclization/hydrolysis reaction does not need any metal catalyst or alkali, and prepares the target products with higher yield under the condition of adding a little water and temperature.
C (sp) provided by the invention 3 ) A process for the preparation of pyrrolidine-2,4-dione derivatives from-H-functionalized initiated 1,5-alkenenitriles comprising the steps of:
adding 1,5-alkene nitrile compounds (formula 1), acetone/acetonitrile (formula 2), an oxidant and water 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 obtaining a product pyrrolidine-2,4-diketone derivative (I) through aftertreatment;
in the compounds represented by the formulae 1, 2 and formula I, R 1 Is selected from C 1 -C 10 Alkyl radical, C 5 -C 14 An aryl group;
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 3 Acyl radical, C 1 -C 3 A cyano group.
Preferably, R 1 Is selected from C 5 -C 14 An aryl group;
R 2 is selected from C 5 -C 14 An aryl group;
R 3 is selected from C 1 -C 3 Acyl radical, C 1 -C 3 A cyano group.
Preferably, said certain temperature is 90-110 ℃.
Preferably, the oxidant is selected from any one or a mixture of more of tert-butyl peroxybenzoate, tert-butyl peroxide, iodobenzene acetate, potassium persulfate and potassium peroxymonosulfonate.
Preferably, the amount of the potassium peroxymonosulfonate is 1.2 to 3.0 equivalents.
Preferably, the amount of water is 5.0 to 15.0 equivalents.
Preferably, the amount of the acetone/acetonitrile solvent is 1.0mL-2.0mL.
Preferably, 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 pyrrolidine-2,4-diketone derivative (I).
Preferably, the certain temperature is 90 ℃, the oxidant is potassium peroxymonosulfonate, the using amount of the potassium peroxymonosulfonate is 2.0 equivalents, the using amount of water is 10.0 equivalents, and the using amount of the acetone/acetonitrile solvent is 1.0mL.
The beneficial effects of the invention are: proposes acetone/acetonitrile C (sp) 3 ) The method for the (E) -H-functionalized initiated 1,5-alkene nitrile compound free radical cyclization/hydrolysis reaction does not need any metal catalyst and alkali, only needs an oxidant and trace water, can be carried out in an air atmosphere, and can obtain a series of target products with high yield. The method has the advantages of wide application range of reaction substrates, greenness 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 1-10 are experiments optimized for reaction conditions.
Example 1
A Schlenk flask was charged with a compound represented by formula 1a (46.0 mg, 0.2mmol), acetone represented by formula 2a (1.0 mL), H 2 O (36.0mg, 10.0eq), potassium peroxymonosulfonate (Oxone, 245.9mg, 2.0eq), then the reactor is stirred at 90 ℃ under an air atmosphere, the reaction progress is monitored by TLC until the raw materials disappear (the reaction time is 4 hours), after the reaction is finished, the reaction liquid is extracted by ethyl acetate, an organic phase is dried by anhydrous sodium sulfate, the solvent is removed by filtration and concentration under reduced pressure, and the residue is separated by column chromatography (the elution solvent is ethyl acetate/n-hexane) to obtain a target product I-1 (88 yield); 1 H NMR (400MHz,CDCl 3 )δ:7.56-7.54(m,2H),6.96-6.93(m,2H),4.33-4.21(m,2H),3.82(s,3H),2.55 (t,J＝7.2Hz,2H),2.12(s,3H),2.08-2.03(m,2H),1.33(s,3H)； 13 C NMR(101MHz,CDCl 3 )δ: 209.0,207.3,173.5,157.2,130.9,122.3,114.3,56.3,55.5,51.1,38.0,29.8,28.9,19.8；HRMS m/z(ESI)calcd for C 16 H 20 NO 4 ([M+H] + )290.1387,found 290.1381。
example 2
The reaction temperature was lowered to 80 ℃ to carry out the reaction under the same conditions as in example 1, whereby the yield of the objective product I-1 was 42%.
Example 3
The oxidizing agent tert-butyl peroxybenzoate (TBPB) was used in place of potassium peroxymonosulfonate (Oxone), and the same procedure as in example 1 was repeated to give the desired product I-1 in a yield of 8%.
Example 4
Oxidizing agent tert-butyl peroxide (TBHP) was used in place of potassium peroxymonosulfonate (Oxone), and the same procedure as in example 1 was repeated to obtain the desired product I-1 in a yield of 12%.
Example 5
Iodine benzene acetate (PhI (OAc) as oxidant 2 ) The same procedure as in example 1 was repeated except for using potassium peroxymonosulfonate (Oxone) in place of it, to obtain the objective product I-1 in a yield of 17%.
Example 6
Potassium persulfate (K) as oxidant 2 S 2 O 8 ) The same procedure as in example 1 was repeated except for using potassium peroxymonosulfonate (Oxone) in place of it, to obtain the objective product I-1 in a yield of 64%.
Example 7
The oxidizing agent potassium peroxymonosulfonate (Oxone) was used in an amount of 1.2 equivalents (147.5 mg), and the other conditions were the same as in example 1, whereby the yield of the objective product I-1 was 72%.
Example 8
The amount of the oxidizing agent potassium peroxymonosulfonate (Oxone) was 3.0 equivalents (368.9 mg), and the remaining conditions were the same as in example 1, giving the target product I-1 a yield of 88%.
Example 9
The amount of additive water used was 5.0 equivalents (18 mg), and the other conditions were the same as in example 1, giving the desired product I-1 in a yield of 62%.
Example 10
The amount of additive water used was 15.0 equivalents (54 mg), and the other conditions were the same as in example 1, giving the desired product I-1 in 73% yield.
As can be seen from the above examples 1-10, the optimum reaction conditions were those of example 1, i.e., the amount of oxidant Oxone used was 2.0eq (245.9 mg), H 2 O (36.0 mg) as an additive and 2a as a solvent, and then the reactor was reacted at 90 ℃. On the basis of obtaining the optimal reaction condition, the inventor further selects 1,5-alkene nitrile compounds with different substituents and acetone or acetonitrile as raw materials to develop a green cyclization/hydrolysis reaction to prepare pyrrolidine-2,4-diketone under the optimal reaction condition.
Example 11
A Schlenk flask was charged with a compound represented by formula 1b (51.2 mg,0.2 mmol), acetone represented by formula 2a (1.0 mL), H 2 O (36.0 mg, 10.0eq), potassium peroxymonosulfonate (Oxone, 245.9mg, 2.0eq), then the reactor was stirred at 90 ℃ under an air atmosphere to react, the progress of the reaction was monitored by TLC until the raw material disappeared (reaction time was 4 hours), after completion of the reaction, the reaction solution was extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, the solvent was removed by filtration and concentration under reduced pressure, and the residue was separated by column chromatography (elution solvent: ethyl acetate/n-hexane) to obtain the objective product I-2 (85 yield); 1 H NMR (400MHz,CDCl 3 )δ:7.59(d,J＝8.8Hz,2H),7.44(d,J＝8.8Hz,2H),4.36-4.24(m,2H), 2.56-2.51(m,2H),2.11(s,3H),2.08-2.03(m,2H),1.33(s,3H),1.32(s,9H)； 13 C NMR(101 MHz,CDCl 3 )δ:208.9,207.2,173.6,148.5,135.2,126.0,120.1,55.9,51.3,38.0,34.4,31.2,29.8, 28.9,19.9；HRMS m/z(ESI)calcd for C 19 H 26 NO 3 ([M+H] + )316.1907,found 316.1913。
example 12
A Schlenk flask was charged with a compound represented by formula 1c (42.8mg, 0.2mmol), acetone represented by formula 2a (1.0 mL), and H 2 O (36.0mg, 10.0eq), potassium peroxymonosulfonate (Oxone, 245.9mg, 2.0eq), then the reactor is stirred at 90 ℃ under an air atmosphere, the reaction progress is monitored by TLC until the raw materials disappear (the reaction time is 4 hours), after the reaction is finished, the reaction liquid is extracted by ethyl acetate, an organic phase is dried by anhydrous sodium sulfate, the solvent is removed by filtration and concentration under reduced pressure, and the residue is separated by column chromatography (the elution solvent is ethyl acetate/n-hexane) to obtain a target product I-3 (83 yield); 1 H NMR (400MHz,CDCl 3 )δ:7.54-7.52(m,2H),7.24-7.20(m,2H),4.34-4.22(m,2H),2.56-2.52(m, 2H),2.35(s,3H),2.11(s,3H),2.08-2.03(m,2H),1.33(s,3H)； 13 C NMR(101MHz,CDCl 3 )δ: 208.9,207.3,173.6,135.3,129.7(2),120.5,56.0,51.3,38.0,29.8,28.9,20.9,19.8；HRMS m/z (ESI)calcd for C 16 H 20 NO 3 ([M+H] + )274.1438,found 274.1444。
example 13
A Schlenk flask was charged with a compound represented by formula 1d (40.0 mg, 0.2mmol), acetone represented by formula 2a (1.0 mL), H 2 O (36.0mg, 10.0eq), potassium peroxymonosulfonate (Oxone, 245.9mg, 2.0eq), then the reactor is stirred at 90 ℃ under an air atmosphere, the reaction progress is monitored by TLC until the raw materials disappear (the reaction time is 4 hours), after the reaction is finished, the reaction liquid is extracted by ethyl acetate, an organic phase is dried by anhydrous sodium sulfate, the solvent is removed by filtration and concentration under reduced pressure, and the residue is separated by column chromatography (the elution solvent is ethyl acetate/n-hexane) to obtain a target product I-4 (80 yield); 1 H NMR (400MHz,CDCl 3 )δ:7.67(d,J＝7.6Hz,2H),7.43(t,J＝8.0Hz,2H),7.23(t,J＝7.2Hz,1H), 4.37-4.25(m,2H),2.57-2.53(m,2H),2.12(s,3H),2.09-2.05(m,2H),1.34(s,3H)； 13 C NMR (101MHz,CDCl 3 )δ:208.7,207.3,173.8,137.9,129.2,125.5,120.5,55.8,51.4,38.0,29.9,28.9, 19.9；HRMS m/z(ESI)calcd for C 15 H 18 NO 3 ([M+H] + )260.1281,found 260.1289。
example 14
A Schlenk flask was charged with a compound represented by formula 1e (46.9mg, 0.2mmol), acetone represented by formula 2a (1.0 mL), H 2 O (36.0mg, 10.0eq), potassium peroxymonosulfonate (Oxone, 245.9mg, 2.0eq), then the reactor was stirred at 90 ℃ under an air atmosphere, the progress of the reaction was monitored by TLC until the raw material disappeared (the reaction time was 4 hours), after the completion of the reaction, the reaction solution was extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, the solvent was removed by filtration and concentration under reduced pressure, and the residue was separated by column chromatography (the eluting solvent was ethyl acetate/n-hexane) to obtain the objective product I-5 (75 yield); 1 H NMR (400MHz,CDCl 3 )δ:7.64-7.62(m,2H),7.39-7.37(m,2H),4.35-4.22(m,2H),2.55(t,J＝7.2 Hz,2H),2.12(s,3H),2.08-2.03(m,2H),1.33(s,3H)； 13 C NMR(101MHz,CDCl 3 )δ:208.0, 207.4,173.9,136.5,130.6,129.2,121.5,55.7,51.3,37.9,29.9,28.9,19.8；HRMS m/z(ESI) calcd for C 15 H 17 ClNO 3 ([M+H] + )294.0891,found 294.0895。
example 15
A Schlenk flask was charged with a compound represented by formula 1f (55.8mg, 0.2mmol), acetone represented by formula 2a (1.0 mL), and H 2 O (36.0 mg,10.0 eq), potassium peroxymonosulfonate (Oxone, 245.9mg,2.0 eq), then the reactor was stirred at 90 ℃ under an air atmosphere for reaction, the progress of the reaction was monitored by TLC until the raw material disappeared (reaction time was 4 hours), after the reaction was completed, 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 isolated by column chromatography (see (R) (R))The elution solvent is: ethyl acetate/n-hexane) to yield the target product I-6 (71% yield); 1 H NMR (400MHz,CDCl 3 )δ:7.60-7.52(m,4H),4.35-4.22(m,2H),2.55(t,J＝7.2Hz,2H),2.12(s,3H), 2.08-2.03(m,2H),1.34(s,3H)； 13 C NMR(101MHz,CDCl 3 )δ:208.0,207.4,173.9,137.0, 132.1,121.8,118.3,55.6,51.3,37.9,29.9,28.8,19.8；HRMS m/z(ESI)calcd for C 15 H 17 BrNO 3 ([M+H] + )338.0386,found 338.0384。
example 16
A Schlenk flask was charged with compound represented by formula 1g (42.8mg, 0.2mmol), acetone represented by formula 2a (1.0 mL), and H 2 O (36.0mg, 10.0eq), potassium peroxymonosulfonate (Oxone, 245.9mg, 2.0eq), then the reactor was stirred at 90 ℃ under an air atmosphere, the progress of the reaction was monitored by TLC until the raw material disappeared (the reaction time was 4 hours), after the completion of the reaction, the reaction solution was extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, the solvent was removed by filtration and concentration under reduced pressure, and the residue was separated by column chromatography (the eluting solvent was ethyl acetate/n-hexane) to obtain the objective product I-7 (77 yueld); 1 H NMR (500MHz,CDCl 3 )δ:7.53(s,1H),7.42-7.40(m,1H),7.30(t,J＝7.5Hz,1H),7.05-7.03(m,1H), 4.35-4.24(m,2H),2.56-2.52(m,2H),2.39(s,3H),2.11(s,3H),2.07-2.04(m,2H),1.33(s,3H)； 13 C NMR(126MHz,CDCl 3 )δ:208.8,207.2,173.8,139.1,137.8,129.0,126.3,121.3,117.5, 56.0,51.4,38.0,29.8,28.9,21.6,19.8；HRMS m/z(ESI)calcd for C 16 H 20 NO 3 ([M+H] + ) 274.1438,found 274.1442。
example 17
A Schlenk flask was charged with a compound of formula 1h (45.6 mg, 0.2mmol), formula 2aAcetone (1.0 mL), H 2 O (36.0mg, 10.0eq), potassium peroxymonosulfonate (Oxone, 245.9mg, 2.0eq), then the reactor is stirred at 90 ℃ under an air atmosphere, the reaction progress is monitored by TLC until the raw materials disappear (the reaction time is 4 hours), after the reaction is finished, the reaction liquid is extracted by ethyl acetate, an organic phase is dried by anhydrous sodium sulfate, the solvent is removed by filtration and concentration under reduced pressure, and the residue is separated by column chromatography (the elution solvent is ethyl acetate/n-hexane) to obtain a target product I-8 (72) which is obtained by purifying; 1 H NMR (500MHz,CDCl 3 )δ:7.47(s,1H),7.33-7.31(m,1H),7.18-7.16(m,1H),4.33-4.22(m,2H), 2.56-2.52(m,2H),2.29(s,3H),2.26(s,3H),2.11(s,3H),2.07-2.03(m,2H),1.33(s,3H)； 13 C NMR(126MHz,CDCl 3 )δ:209.0,207.2,173.6,137.6,135.6,134.1,130.1,122.0,118.0,56.1, 51.3,38.1,29.8,28.9,20.0,19.8,19.2；HRMS m/z(ESI)calcd for C 17 H 22 NO 3 ([M+H] + ) 288.1594,found 288.1598。
example 18
A Schlenk flask was charged with a compound represented by formula 1i (50.0 mg, 0.2mmol), acetone represented by formula 2a (1.0 mL), H 2 O (36.0mg, 10.0eq), potassium peroxymonosulfonate (Oxone, 245.9mg, 2.0eq), then the reactor is stirred at 90 ℃ under an air atmosphere, the reaction progress is monitored by TLC until the raw materials disappear (the reaction time is 4 hours), after the reaction is finished, the reaction liquid is extracted by ethyl acetate, an organic phase is dried by anhydrous sodium sulfate, the solvent is removed by filtration and concentration under reduced pressure, and the residue is separated by column chromatography (the elution solvent is ethyl acetate/n-hexane) to obtain a target product I-9 (83 yield); 1 H NMR (500MHz,CDCl 3 )δ:7.92-7.88(m,2H),7.72-7.68(m,1H),7.57-7.51(m,3H),7.46-7.44(m, 1H),4.43-4.39(m,1H),4.30-4.27(m,1H),2.69(t,J＝7.5Hz,2H),2.24-2.19(m,1H),2.17(s, 3H),2.14-2.10(m,1H),1.47(s,3H)； 13 C NMR(126MHz,CDCl 3 )δ:209.4,207.9,174.8,134.5, 133.5,129.4,129.0,128.7,127.2,126.5,125.6,125.0,121.9,58.9,50.1,38.1,29.8,28.6,20.4； HRMS m/z(ESI)calcd for C 19 H 20 NO 3 ([M+H] + )310.1438,found 310.1434。
example 19
A Schlenk flask was charged with a compound represented by formula 1j (48.8mg, 0.2mmol), acetone represented by formula 2a (1.0 mL), and H 2 O (36.0mg, 10.0eq), potassium peroxymonosulfonate (Oxone, 245.9mg, 2.0eq), then the reactor was stirred at 90 ℃ under an air atmosphere, the progress of the reaction was monitored by TLC until the raw material disappeared (the reaction time was 4 hours), after the completion of the reaction, the reaction solution was extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, the solvent was removed by filtration and concentration under reduced pressure, and the residue was separated by column chromatography (elution solvent: ethyl acetate/n-hexane) to obtain the objective product I-10 (89 yield); 1 H NMR (500MHz,CDCl 3 )δ:7.20-7.18(m,2H),6.89-6.88(m,2H),4.57(s,2H),3.80(s,3H),3.71-3.63 (m,2H),2.48-2.43(m,2H),2.09(s,3H),1.99-1.94(m,2H),1.23(s,3H)； 13 C NMR(126MHz, CDCl 3 )δ:209.8,207.1,174.4,159.4,129.6,127.2,114.3,55.3,54.0,49.9,45.3,38.0,29.7,28.6, 19.5；HRMS m/z(ESI)calcd for C 17 H 22 NO 4 ([M+H] + )304.1543,found 304.1541。
example 20
A Schlenk flask was charged with a compound represented by formula 1k (45.6 mg, 0.2mmol), acetone represented by formula 2a (1.0 mL), H 2 O (36.0mg, 10.0eq), potassium peroxymonosulfonate (Oxone, 245.9mg, 2.0eq), then the reactor was stirred at 90 ℃ under an air atmosphere for reaction, the progress of the reaction was monitored by TLC until the raw materials disappeared (the reaction time was 4 hours), after the reaction was completed, the reaction solution was extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, the solvent was removed by filtration and concentration under reduced pressure, and the residue was removedSeparating the residue by column chromatography (eluting with ethyl acetate/n-hexane) to obtain target product I-11 (84% yield); 1 H NMR (500MHz,CDCl 3 )δ:7.18-7.14(m,4H),4.59(s,2H),3.72-3.64(m,2H),2.48-2.43(m,2H),2.34 (s,3H),2.09(s,3H),1.99-1.94(m,2H),1.24(s,3H)； 13 C NMR(126MHz,CDCl 3 )δ:209.8, 207.1,174.4,137.8,132.1,129.6,128.2,54.0,49.9,45.6,38.0,29.7,28.5,21.0,19.5；HRMS m/z (ESI)calcd for C 17 H 22 NO 3 ([M+H] + )288.1594,found 288.1590。
example 21
A Schlenk bottle was charged with the compound represented by formula 1l (42.8mg, 0.2mmol), acetone represented by formula 2a (1.0 mL), H 2 O (36.0 mg, 10.0eq), potassium peroxymonosulfonate (Oxone, 245.9mg, 2.0eq), then the reactor was stirred at 90 ℃ under an air atmosphere to react, the progress of the reaction was monitored by TLC until the raw material disappeared (reaction time was 4 hours), after 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 separated by column chromatography (elution solvent: ethyl acetate/n-hexane) to obtain the objective product I-12 (80 yield); 1 H NMR (500MHz,CDCl 3 )δ:7.38-7.33(m,3H),7.27-7.26(m,1H),7.26-7.25(m,1H),4.63(s,2H), 3.74-3.65(m,2H),2.49-2.44(m,2H),2.09(s,3H),2.00-1.95(m,2H),1.25(s,3H)； 13 C NMR (126MHz,CDCl 3 )δ:209.7,207.1,174.5,135.2,129.0,128.2,128.1,54.1,49.8,45.9,38.0,29.7, 28.6,19.5；HRMS m/z(ESI)calcd for C 16 H 20 NO 3 ([M+H] + )274.1438,found 274.1446。
example 22
A Schlenk flask was charged with a compound represented by formula 1m (49.9mg2 mmol), acetone of formula 2a (1.0 mL), H 2 O (36.0mg, 10.0eq), potassium peroxymonosulfonate (Oxone, 245.9mg, 2.0eq), then the reactor was stirred at 90 ℃ under an air atmosphere, the progress of the reaction was monitored by TLC until the raw material disappeared (the reaction time was 4 hours), after the completion of the reaction, the reaction solution was extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, the solvent was removed by filtration and concentration under reduced pressure, and the residue was separated by column chromatography (the eluting solvent was ethyl acetate/n-hexane) to obtain the objective product I-13 (73 yield); 1 H NMR (500MHz,CDCl 3 )δ:7.36-7.32(m,2H),7.23-7.20(m,2H),4.59(s,2H),3.75-3.65(m,2H), 2.50-2.45(m,2H),2.10(s,3H),1.99-1.93(m,2H),1.24(s,3H)； 13 C NMR(126MHz,CDCl 3 )δ: 209.2,207.1,174.6,134.0,133.7,129.6,129.1,54.0,49.7,45.2,37.9,29.7,28.5,19.5；HRMS m/z(ESI)calcd for C 16 H 19 ClNO 3 ([M+H] + )308.1048,found 308.1056。
example 23
A Schlenk bottle was charged with a compound represented by formula 1n (58.8mg, 0.2mmol), acetone represented by formula 2a (1.0 mL), H 2 O (36.0mg, 10.0eq), potassium peroxymonosulfonate (Oxone, 245.9mg, 2.0eq), then the reactor was stirred at 90 ℃ under an air atmosphere, the progress of the reaction was monitored by TLC until the raw material disappeared (the reaction time was 4 hours), after the completion of the reaction, the reaction solution was extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, the solvent was removed by filtration and concentration under reduced pressure, and the residue was separated by column chromatography (the eluting solvent was ethyl acetate/n-hexane) to obtain the objective product I-14 (68 yield); 1 H NMR (400MHz,CDCl 3 )δ:7.52-7.47(m,2H),7.17-7.14(m,2H),4.58(s,2H),3.76-3.65(m,2H),2.47 (t,J＝7.2Hz,2H),2.10(s,3H),1.99-1.93(m,2H),1.24(s,3H)； 13 C NMR(101MHz,CDCl 3 )δ: 209.2,207.3,174.6,134.2,132.0,129.9,122.0,54.0,49.7,45.2,37.9,29.7,28.4,19.5；HRMS m/z(ESI)calcd for C 16 H 19 BrNO 3 ([M+H] + )352.0543,found 352.0537。
example 24
A Schlenk flask was charged with a compound represented by formula 1o (45.6 mg, 0.2mmol), acetone represented by formula 2a (1.0 mL), H 2 O (36.0mg, 10.0eq), potassium peroxymonosulfonate (Oxone, 245.9mg, 2.0eq), then the reactor is stirred at 90 ℃ under an air atmosphere, the reaction progress is monitored by TLC until the raw materials disappear (the reaction time is 4 hours), after the reaction is finished, the reaction liquid is extracted by ethyl acetate, an organic phase is dried by anhydrous sodium sulfate, the solvent is removed by filtration and concentration under reduced pressure, and the residue is separated 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:7.30(t,J＝7.5Hz,2H),7.25-7.21(m,3H),3.86-3.81(m,1H),3.72-3.68 (m,1H),3.67-3.59(m,2H),2.93(t,J＝7.0Hz,2H),2.27(t,J＝7.5Hz,2H),2.06(s,3H), 1.86-1.82(m,2H),1.12(s,3H)； 13 C NMR(126MHz,CDCl 3 )δ:210.0,207.2,174.5,137.8, 128.6(2),126.8,55.0,49.8,42.8,37.9,33.3,29.7,28.4,19.5；HRMS m/z(ESI)calcd for C 17 H 22 NO 3 ([M+H] + )288.1594,found 288.1590。
example 25
A Schlenk flask was charged with a compound represented by formula 1p (58.0 mg, 0.2mmol), acetone represented by formula 2a (1.0 mL), H 2 O (36.0mg, 10.0eq), potassium peroxymonosulfonate (Oxone, 245.9mg, 2.0eq), then the reactor is stirred at 90 ℃ under the air atmosphere for reaction, the reaction progress is monitored by TLC until the raw material disappears (the reaction time is 4 hours), after the reaction is finished, the reaction liquid is extracted by ethyl acetate, the organic phase is dried by anhydrous sodium sulfate, the solvent is removed by filtration and concentration under reduced pressure, and the residue is separated by column chromatography (the elution solvent is ethyl acetate)N-hexane) to yield the target product I-16 (74% yield); 1 H NMR (500MHz,CDCl 3 )δ:6.80-6.78(m,2H),6.76-6.74(m,1H),3.88(s,3H),3.84(s,3H),3.78-3.71 (m,2H),3.68-3.63(m,2H),2.88(t,J＝7.0Hz,2H),2.28(t,J＝7.5Hz,2H),2.07(s,3H), 1.86-1.82(m,2H),1.13(s,3H)； 13 C NMR(126MHz,CDCl 3 )δ:210.0,207.1,174.4,148.9, 147.7,130.1,120.5,111.5,111.1,55.8,55.7,54.8,49.7,42.5,37.8,32.8,29.6,28.4,19.4；HRMS m/z(ESI)calcd for C 19 H 26 NO 5 ([M+H] + )348.1805,found 348.1807。
example 26
A Schlenk flask was charged with a compound represented by formula 1q (55.2 mg,0.2 mmol), acetone represented by formula 2a (1.0 mL), and H 2 O (36.0mg, 10.0eq), potassium peroxymonosulfonate (Oxone, 245.9mg, 2.0eq), then the reactor is stirred at 90 ℃ under an air atmosphere, the reaction progress is monitored by TLC until the raw materials disappear (the reaction time is 4 hours), after the reaction is finished, the reaction liquid is extracted by ethyl acetate, an organic phase is dried by anhydrous sodium sulfate, the solvent is removed by filtration and concentration under reduced pressure, and the residue is separated by column chromatography (the elution solvent is ethyl acetate/n-hexane) to obtain a target product I-17 (84 yield); 1 H NMR (400MHz,CDCl 3 )δ:7.35-7.32(m,4H),7.20-7.17(m,4H),7.14-7.12(m,2H),3.96-3.91(m, 1H),3.21-3.18(m,1H),3.16-3.12(m,1H),3.02-2.98(m,1H),2.58-2.50(m,2H),2.23-2.17(m, 2H),2.12(s,3H)； 13 C NMR(101MHz,CDCl 3 )δ:209.3,207.2,172.5,137.4,134.7,129.6,129.1, 128.5,127.4,125.8,121.2,58.3,57.4,43.0,38.4,29.8,28.4；HRMS m/z(ESI)calcd for C 21 H 22 NO 3 ([M+H] + )336.1594,found 336.1598。
example 27
A Schlenk flask was charged with a compound represented by formula 1a (46.0 mg, 0.2mmol), acetonitrile represented by formula 2b (1.0 mL), H 2 O (36.0mg, 10.0eq), potassium peroxymonosulfonate (Oxone, 245.9mg, 2.0eq), then the reactor is stirred at 110 ℃ under an air atmosphere for reaction, the progress of the reaction is monitored by TLC until the raw materials disappear (the reaction time is 8 hours), after the reaction is completed, the reaction liquid is extracted by ethyl acetate, an organic phase is dried by anhydrous sodium sulfate, the solvent is removed by filtration and concentration under reduced pressure, and the residue is separated by column chromatography (the elution solvent is ethyl acetate/n-hexane) to obtain a target product I-18 (75 yield); 1 H NMR(500MHz,CDCl 3 )δ:7.56-7.54(m,2H),6.97-6.95(m,2H),4.36-4.34(m,2H),3.83(s, 3H),2.52-2.47(m,2H),2.24-2.11(m,2H),1.39(s,3H)； 13 C NMR(126MHz,CDCl 3 )δ:208.0, 172.2,157.5,130.5,122.6,118.3,114.4,56.4,55.5,51.1,29.7,20.8,12.9；HRMS m/z(ESI)calcd for C 15 H 17 N 2 O 3 ([M+H] + )273.1234,found 273.1238。
example 28
A Schlenk flask was charged with a compound represented by formula 1b (51.2 mg,0.2 mmol), acetonitrile (1.0 mL) represented by formula 2b, and H 2 O (36.0mg, 10.0eq), potassium peroxymonosulfonate (Oxone, 245.9mg, 2.0eq), then the reactor is stirred at 110 ℃ under an air atmosphere for reaction, the progress of the reaction is monitored by TLC until the raw materials disappear (the reaction time is 8 hours), after the reaction is completed, the reaction liquid is extracted by ethyl acetate, an organic phase is dried by anhydrous sodium sulfate, the solvent is removed by filtration and concentration under reduced pressure, and the residue is separated by column chromatography (the elution solvent is ethyl acetate/n-hexane) to obtain a target product I-19 (72) which is a product of yield); 1 H NMR(400MHz,CDCl 3 )δ:7.59-7.57(m,2H),7.47-7.44(m,2H),4.38-4.36(m,2H),2.50-2.46 (m,2H),2.23-2.11(m,2H),1.39(s,3H),1.33(s,9H)； 13 C NMR(101MHz,CDCl 3 )δ:207.9, 172.3,149.0,134.8,126.1,120.4,118.3,56.0,51.3,34.5,31.2,29.6,20.8,12.9；HRMS m/z(ESI) calcd for C 18 H 23 N 2 O 2 ([M+H] + )299.1754,found 299.1750。
example 29
A Schlenk flask was charged with a compound represented by formula 1c (42.8mg, 0.2mmol), acetonitrile (1.0 mL) represented by formula 2b, and H 2 O (36.0mg, 10.0eq), potassium peroxymonosulfonate (Oxone, 245.9mg, 2.0eq), then the reactor is stirred at 110 ℃ under an air atmosphere for reaction, the progress of the reaction is monitored by TLC until the raw materials disappear (the reaction time is 8 hours), after the reaction is completed, the reaction liquid is extracted by ethyl acetate, an organic phase is dried by anhydrous sodium sulfate, the solvent is removed by filtration and concentration under reduced pressure, and the residue is separated by column chromatography (the elution solvent is ethyl acetate/n-hexane) to obtain a target product I-20 (70 yield); 1 H NMR(500MHz,CDCl 3 )δ:7.54-7.52(m,2H),7.25-7.22(m,2H),4.37-4.35(m,2H),2.51-2.47 (m,2H),2.36(s,3H),2.22-2.11(m,2H),1.39(s,3H)； 13 C NMR(126MHz,CDCl 3 )δ:207.9, 172.3,135.9,135.0,129.8,120.7,118.3,56.1,51.3,29.7,20.9,20.8,12.9；HRMS m/z(ESI) calcd for C 15 H 17 N 2 O 2 ([M+H] + )257.1285,found 257.1289。
example 30
A Schlenk flask was charged with a compound represented by formula 1d (40.0 mg, 0.2mmol), acetonitrile represented by formula 2b (1.0 mL), H 2 O (36.0 mg,10.0 eq), potassium peroxymonosulfonate (Oxone, 245.9mg,2.0 eq), the reaction vessel was then stirred at 110 ℃ under an air atmosphere, the progress of the reaction was monitored by TLC until the starting material disappeared (reaction time was 8 hours), after 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 isolated by column chromatography (elution solvent: ethyl acetate)Ester/n-hexane) to yield the target product I-21 (67% yield); 1 H NMR(500MHz,CDCl 3 )δ:7.67-7.65(m,2H),7.44(t,J＝8.0Hz,2H),7.26-7.24(m,1H), 4.39-4.37(m,2H),2.51-2.47(m,2H),2.25-2.11(m,2H),1.40(s,3H)； 13 C NMR(126MHz, CDCl 3 )δ:207.7,172.5,137.6,129.3,126.0,120.7,118.3,56.0,51.4,29.7,20.8,12.9；HRMS m/z (ESI)calcd for C 14 H 15 N 2 O 2 ([M+H] + )243.1128,found 243.1132。
example 31
A Schlenk flask was charged with a compound represented by formula 1e (46.9mg, 0.2mmol), acetonitrile represented by formula 2b (1.0 mL), H 2 O (36.0mg, 10.0eq), potassium peroxymonosulfonate (Oxone, 245.9mg, 2.0eq), then the reactor is stirred at 110 ℃ under an air atmosphere for reaction, the progress of the reaction is monitored by TLC until the raw materials disappear (the reaction time is 8 hours), after the reaction is completed, the reaction liquid is extracted by ethyl acetate, an organic phase is dried by anhydrous sodium sulfate, the solvent is removed by filtration and concentration under reduced pressure, and the residue is separated by column chromatography (the elution solvent is ethyl acetate/n-hexane) to obtain a target product I-22 (59: yield); 1 H NMR(500MHz,CDCl 3 )δ:7.64-7.62(m,2H),7.41-7.40(m,2H),4.37-4.36(m,2H),2.51-2.47 (m,2H),2.23-2.14(m,2H),1.41(s,3H)； 13 C NMR(126MHz,CDCl 3 )δ:207.1,172.6,136.1, 131.2,129.4,121.8,118.2,55.8,51.4,29.6,20.9,12.9；HRMS m/z(ESI)calcd for C 14 H 14 ClN 2 O 2 ([M+H] + )277.0738,found 277.0744。
example 32
A Schlenk flask was charged with compound represented by formula 1g (42.8mg, 0.2mmol), acetonitrile (1.0 mL) represented by formula 2b, and H 2 O (36.0mg, 10.0eq), peroxy monosulfonic acidPotassium (Oxone, 245.9mg, 2.0eq), then the reactor was stirred at 110 ℃ under an air atmosphere for reaction, progress of the reaction was monitored by TLC until the raw material disappeared (reaction time was 8 hours), after completion of the reaction, 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-23 (61% yield); 1 H NMR(400MHz,CDCl 3 )δ:7.51(s,1H),7.43-7.39(m,1H),7.32(t,J＝7.6Hz,1H),7.09-7.04 (m,1H),4.38-4.33(m,2H),2.53-2.46(m,2H),2.40(s,3H),2.23-2.11(m,2H),1.40(s,3H)； 13 C NMR(101MHz,CDCl 3 )δ:207.8,172.5,139.3,137.4,129.1,126.8,121.5,118.3,117.8,56.1, 51.4,29.7,21.6,20.8,12.9；HRMS m/z(ESI)calcd for C 15 H 17 N 2 O 2 ([M+H] + )257.1285,found 257.1289。
example 33
A Schlenk flask was charged with a compound represented by formula 1H (45.6 mg, 0.2mmol), acetonitrile (1.0 mL) represented by formula 2b, H 2 O (36.0mg, 10.0eq), potassium peroxymonosulfonate (Oxone, 245.9mg, 2.0eq), then the reactor is stirred at 110 ℃ under an air atmosphere for reaction, the progress of the reaction is monitored by TLC until the raw materials disappear (the reaction time is 8 hours), after the reaction is completed, the reaction liquid is extracted by ethyl acetate, an organic phase is dried by anhydrous sodium sulfate, the solvent is removed by filtration and concentration under reduced pressure, and the residue is separated by column chromatography (the elution solvent is ethyl acetate/n-hexane) to obtain a target product I-24 (72) which is obtained by purifying; 1 H NMR(500MHz,CDCl 3 )δ:7.45(s,1H),7.33-7.31(m,1H),7.19-7.17(m,1H),4.36-4.34(m, 2H),2.50-2.46(m,2H),2.30(s,3H),2.27(s,3H),2.22-2.19(m,1H),2.15-2.09(m,1H),1.39(s, 3H)； 13 C NMR(126MHz,CDCl 3 )δ:208.0,172.3,137.7,135.2,134.7,130.2,122.1,118.3(2), 56.3,51.3,29.7,20.7,20.0,19.3,12.9；HRMS m/z(ESI)calcd for C 16 H 19 N 2 O 2 ([M+H] + ) 271.1441,found 271.1445。
example 34 reaction mechanism control experiment
To further verify the mechanism of this reaction, the following two sets of control experiments were performed. First, when 2.2 equivalents of the radical scavenger 2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO) or Butylhydroxytoluene (BHT) were reacted in the reaction of example 1, the process was completely inhibited, and Nuclear Magnetic Resonance (NMR) analysis could detect the products 5a and 5b in which BHT was combined with carbon radicals. The above results indicate that the reaction involves a free radical 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 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 (9)
1. C (sp) 3 ) A process for the preparation of pyrrolidine-2,4-dione derivatives from-H functionalized initiated 1,5-alkenenitriles comprising the steps of:
adding 1,5-alkene nitrile compounds (formula 1), acetone/acetonitrile (formula 2), an oxidant and water 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 aftertreatment to obtain pyrrolidine-2,4-diketone derivatives (I);
in the compounds represented by the formulas 1 and 2 and the formula I, R 1 Is selected from C 1 -C 10 Alkyl radical, C 5 -C 14 An aryl group;
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 3 Acyl radical, C 1 -C 3 A cyano group.
2. The method of claim 1, wherein R is 1 Is selected from C 5 -C 14 An aryl group;
R 2 is selected from C 5 -C 14 An aryl group;
R 3 is selected from C 1 -C 3 Acyl radical, C 1 -C 3 A cyano group.
3. The method according to any one of claims 1-2, wherein the certain temperature is 90-110 ℃.
4. The method according to any one of claims 1-2, wherein the oxidant is selected from any one or more of tert-butyl peroxybenzoate, iodobenzene acetate, potassium persulfate, and potassium peroxymonosulfonate.
5. The process according to any one of claims 1 to 2, wherein the potassium peroxymonosulfonate is used in an amount of 1.2 to 3.0 equivalents.
6. The method according to any one of claims 1-2, wherein the amount of water is 5.0-15.0 equivalents.
7. The method of any one of claims 1-2, wherein the acetone/acetonitrile solvent is present in an amount of 1.0mL to 2.0mL.
8. A method according to any 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 pyrrolidine-2,4-diketone derivative (I).
9. The process according to any one of claims 1-2, wherein the certain temperature is 90 ℃, the oxidizing agent is potassium peroxymonosulfonate, the amount of potassium peroxymonosulfonate is 2.0 equivalents, the amount of water is 10.0 equivalents, and the amount of acetone/acetonitrile solvent is 1.0mL.
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