CN114907252A - Synthesis method of silver-mediated 3, 3-disubstituted indole-2-ketone derivative - Google Patents
Synthesis method of silver-mediated 3, 3-disubstituted indole-2-ketone derivative Download PDFInfo
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- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 title claims abstract description 13
- 229910052709 silver Inorganic materials 0.000 title claims abstract description 13
- 239000004332 silver Substances 0.000 title claims abstract description 13
- 230000001404 mediated effect Effects 0.000 title claims abstract description 8
- 238000001308 synthesis method Methods 0.000 title abstract description 11
- 238000006243 chemical reaction Methods 0.000 claims abstract description 24
- 238000000034 method Methods 0.000 claims abstract description 12
- -1 3, 3-disubstituted indol-2-one Chemical class 0.000 claims abstract description 9
- 229940126062 Compound A Drugs 0.000 claims abstract description 3
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 claims abstract description 3
- 238000010438 heat treatment Methods 0.000 claims abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 27
- ZXSQEZNORDWBGZ-UHFFFAOYSA-N 1,3-dihydropyrrolo[2,3-b]pyridin-2-one Chemical compound C1=CN=C2NC(=O)CC2=C1 ZXSQEZNORDWBGZ-UHFFFAOYSA-N 0.000 claims description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- 229910001958 silver carbonate Inorganic materials 0.000 claims description 9
- LKZMBDSASOBTPN-UHFFFAOYSA-L silver carbonate Substances [Ag].[O-]C([O-])=O LKZMBDSASOBTPN-UHFFFAOYSA-L 0.000 claims description 9
- 239000003054 catalyst Substances 0.000 claims description 8
- 238000003786 synthesis reaction Methods 0.000 claims description 7
- 230000015572 biosynthetic process Effects 0.000 claims description 6
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 6
- NDVLTYZPCACLMA-UHFFFAOYSA-N silver oxide Chemical compound [O-2].[Ag+].[Ag+] NDVLTYZPCACLMA-UHFFFAOYSA-N 0.000 claims description 6
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 claims description 6
- 230000035484 reaction time Effects 0.000 claims description 5
- 125000003118 aryl group Chemical group 0.000 claims description 4
- 125000004185 ester group Chemical group 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- CQLFBEKRDQMJLZ-UHFFFAOYSA-M silver acetate Chemical compound [Ag+].CC([O-])=O CQLFBEKRDQMJLZ-UHFFFAOYSA-M 0.000 claims description 3
- 229940071536 silver acetate Drugs 0.000 claims description 3
- 229910001961 silver nitrate Inorganic materials 0.000 claims description 3
- 229910001923 silver oxide Inorganic materials 0.000 claims description 3
- 229910000367 silver sulfate Inorganic materials 0.000 claims description 3
- YPNVIBVEFVRZPJ-UHFFFAOYSA-L silver sulfate Chemical compound [Ag+].[Ag+].[O-]S([O-])(=O)=O YPNVIBVEFVRZPJ-UHFFFAOYSA-L 0.000 claims description 3
- 150000005840 aryl radicals Chemical class 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 238000003756 stirring Methods 0.000 claims description 2
- 230000002194 synthesizing effect Effects 0.000 claims description 2
- 238000006555 catalytic reaction Methods 0.000 abstract description 3
- 238000002360 preparation method Methods 0.000 abstract description 3
- 239000000654 additive Substances 0.000 abstract 1
- 230000000996 additive effect Effects 0.000 abstract 1
- 125000000524 functional group Chemical group 0.000 abstract 1
- 239000003921 oil Substances 0.000 description 9
- 239000002904 solvent Substances 0.000 description 6
- 239000002994 raw material Substances 0.000 description 4
- 239000000758 substrate Substances 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 239000012230 colorless oil Substances 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- WLWNRAWQDZRXMB-YLFCFFPRSA-N (2r,3r,4r,5s)-n,3,4,5-tetrahydroxy-1-(4-phenoxyphenyl)sulfonylpiperidine-2-carboxamide Chemical compound ONC(=O)[C@H]1[C@@H](O)[C@H](O)[C@@H](O)CN1S(=O)(=O)C(C=C1)=CC=C1OC1=CC=CC=C1 WLWNRAWQDZRXMB-YLFCFFPRSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 2
- 150000001336 alkenes Chemical class 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- IMOLAGKJZFODRK-UHFFFAOYSA-N 2-phenylprop-2-enamide Chemical compound NC(=O)C(=C)C1=CC=CC=C1 IMOLAGKJZFODRK-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 206010010904 Convulsion Diseases 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 239000002147 L01XE04 - Sunitinib Substances 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- YLEIFZAVNWDOBM-ZTNXSLBXSA-N ac1l9hc7 Chemical compound C([C@H]12)C[C@@H](C([C@@H](O)CC3)(C)C)[C@@]43C[C@@]14CC[C@@]1(C)[C@@]2(C)C[C@@H]2O[C@]3(O)[C@H](O)C(C)(C)O[C@@H]3[C@@H](C)[C@H]12 YLEIFZAVNWDOBM-ZTNXSLBXSA-N 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000036461 convulsion Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000007306 functionalization reaction Methods 0.000 description 1
- 150000005625 indol-2-ones Chemical class 0.000 description 1
- 239000003999 initiator Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 238000012803 optimization experiment Methods 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- WINHZLLDWRZWRT-ATVHPVEESA-N sunitinib Chemical compound CCN(CC)CCNC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C WINHZLLDWRZWRT-ATVHPVEESA-N 0.000 description 1
- 229960001796 sunitinib Drugs 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
- 150000004917 tyrosine kinase inhibitor derivatives Chemical class 0.000 description 1
- 210000003556 vascular endothelial cell Anatomy 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/32—Oxygen atoms
- C07D209/34—Oxygen atoms in position 2
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Indole Compounds (AREA)
Abstract
The invention discloses a synthesis method of a silver-mediated 3, 3-disubstituted indole-2-ketone derivative. The synthesis method comprises the steps of adding an N-aryl alkene amide compound A and a bromo-carboxylic ester compound B into a reaction tube under the catalysis of a silver additive, heating to 90-130 ℃, and reacting for 6-24 hours to obtain a 3, 3-disubstituted indole-2-ketone derivative C. The method of the invention has simple operation, good functional group tolerance and high yield.
Description
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to a synthesis method of a silver-mediated 3, 3-disubstituted indole-2-ketone derivative.
Background
The indole-2-ketone derivative is an important synthetic intermediate, is a structural unit skeleton of natural product molecules and a plurality of medicaments, and has various pharmacological activities of resisting senile paralysis agitans, convulsion, virus, fungus, tumor and the like. Many anticancer drug molecules contain indole-2-ketone structures, such as sunitinib which is used as a multi-target tyrosine kinase inhibitor can directly inhibit the growth and proliferation of vascular endothelial cells, thereby exerting high-efficiency antitumor effect, so that the synthesis of indole-2-ketone derivatives has important significance for the research of pharmaceutical synthesis, pharmacology and application (Acc. chem. Res. 2020, 53, 8, 1605-.
The existing reported methods for 3, 3-disubstituted indol-2-one derivatives mainly focus on the joint participation of catalysts and ligands or free radical initiators, for example, Jin-Heng Li and the like report that bromo-carbonyl compounds perform double-functionalization on olefin oxidation to construct indol-2-one derivatives, and the reaction requires the addition of palladium catalysts and bidentate phosphine ligands (angelw. chem. int. ed. 2014, 53, 6650-; fuwei Li and the like use diazoate and phenylacrylamide as raw materials, the reaction needs the co-catalysis of metal nickel and peroxide, the diazoate needs to be prepared, and the raw materials have certain danger and are not beneficial to the amplification of the reaction (org. Lett. 2019, 21, 9386-doped 9390); chengming Wang et al constructed 3, 3-disubstituted indol-2-one derivatives (org. Lett. 2021, 23, 4662-one 4666) with quaternary carbon centers by the combined action of carbene catalysts and cesium carbonate. In conclusion, the existing method needs the catalyst to participate in other reagents, has the defects of inconvenient raw material preparation, limited substrate application range and the like, and has very important significance in developing a method for synthesizing the 3, 3-disubstituted indol-2-one derivative efficiently and simply.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a novel silver-mediated synthesis method of 3, 3-disubstituted indole-2-ketone derivatives, without adding various reagents for co-catalysis.
The synthesis method of the silver-mediated 3, 3-disubstituted indole-2-ketone derivative comprises the following implementation processes: adding an N-aryl alkene amide compound A, a bromo-carboxylic ester compound B, a silver catalyst and an organic solvent into a reaction tube, then placing the reaction tube into an oil bath pot, heating to 90-130 ℃, stirring for reacting for 6-24 hours, and carrying out post-treatment to obtain a 3, 3-disubstituted indole-2-ketone derivative C, wherein the reaction formula is as follows:
in the synthesis process, R 1 Is selected from C 1 ~C 6 Alkyl of (C) 6 ~C 14 Aryl radical, C 2 ~C 10 An ester group of (a); r 2 Is selected from C 1 ~C 6 Alkyl of (C) 6 ~C 14 An aryl group; r 3 One, two or three substituents representing ortho, meta or para positions on the phenyl ring, each R 3 The substituents are independently of one another selected from hydrogen, halogen, C 1 ~C 6 Alkyl of (C) 1 ~C 6 Halogenated alkyl group of (C) 1 ~C 6 Alkyl of (2)Oxy radical, C 2 ~C 6 An ester group of (a); r 4 Is selected from C 1 ~C 6 Alkyl of (C) 6 ~C 14 An aryl group; r 5 Selected from hydrogen, C 1 ~C 6 Alkyl groups of (a); r 6 Selected as hydrogen atoms.
In the synthesis method, the silver catalyst is selected from any one of silver carbonate, silver oxide, silver nitrate, silver sulfate and silver acetate, wherein the silver carbonate is preferred.
In the synthesis method, the organic solvent is any one of ethyl acetate, 1, 4-dioxane, methanol, dichloromethane and normal hexane, wherein ethyl acetate is preferred.
In the synthesis method, the reaction temperature ranges from 90 to 130 degrees, and 110 degrees is preferred.
In the synthesis method, the reaction time ranges from 6 to 24 hours, and 12 hours is preferred.
Detailed Description
The present invention will be described in further detail with reference to specific examples. In the following, unless otherwise indicated, all the procedures involved are conventional in the art, and the reagents used are commercially available and/or prepared using synthetic methods known in the art.
Examples 1-15 optimization experiments of reaction conditions
The N-aryl alkene amide compound 1a and the bromo-carboxylic ester compound 2a are used as raw materials, the influence of different preparation process conditions on the yield of the target product 3a is discussed, and representative examples are shown in examples 1-15.
Example 1
To the reaction tube were added N-arylalkenylamide compound 1a (0.3 mmol), bromocarboxylic acid ester compound represented by formula 2a (0.9 mmol), silver carbonate (0.6 mmol) and ethyl acetate (2.0 ml), and the reaction tube was placed in an oil bath at 110 ℃ and stirred to reactAfter 12 hours, the reaction mixture was quenched, extracted, and the organic phase was dried over anhydrous sodium sulfate or anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a residue, which was separated by silica gel column chromatography (eluting solvent was petroleum ether/ethyl acetate) to obtain the objective product 3a as a pale yellow liquid with a yield of 93%. Structural characterization: 1 H NMR (400 MHz, CDCl 3 ) δ: 7.33-7.21 (m, 1H), 7.16 (d, J = 6.8 Hz, 1H), 7.06 (t, J = 7.6 Hz, 1H), 6.84 (d, J = 8.0 Hz, 1H), 3.52 (s, 3H), 3.20 (s, 3H), 2.25-2.16 (m, 1H), 2.15-2.00 (m, 2H), 1.90-1.80 (m, 1H), 1.37 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ: 179.9, 173.2, 143.2, 132.8, 128.1, 122.7, 122.7, 108.2, 51.6, 47.6, 33.0, 29.4, 26.2, 23.6。
example 2
The same procedure and conditions were used without addition of silver carbonate as in example 1, with a yield of 3% of the desired product of formula 3 a.
Example 3
The silver carbonate was replaced by silver acetate under the same conditions and in the same operation as in example 1, and the yield of the desired product of formula 3a was 6%.
Example 4
The silver carbonate is replaced by silver sulfate under the same conditions and operation as in example 1, and the yield of the target product of formula 3a is 5%.
Example 5
Silver carbonate was replaced with silver nitrate, and the remaining conditions and operation were the same as in example 1, with a target product yield of 10% of formula 3 a.
Example 6
The silver carbonate was replaced by silver oxide under the same conditions and in the same operation as in example 1, and the yield of the target product of formula 3a was 75%.
Example 7
1, 4-dioxane was used as a solvent instead of ethyl acetate, and the rest of the conditions and operation were the same as in example 1, with a yield of 43% of the objective product of formula 3 a.
Example 8
The solvent used was methanol instead of ethyl acetate, and the remaining conditions and operation were the same as in example 1, with a yield of 33% of the desired product of formula 3 a.
Example 9
N-hexane was used as a solvent instead of ethyl acetate, and the remaining conditions and operation were the same as in example 1, with a yield of 63% of the objective product of formula 3 a.
Example 10
The solvent was dichloromethane instead of ethyl acetate, and the remaining conditions and operation were the same as in example 1, with a yield of 28% of the desired product of formula 3 a.
Example 11
The reaction temperature was replaced with 130 ℃ and the remaining conditions and operation were the same as in example 1, resulting in a yield of 71% of the desired product of formula 3 a.
Example 12
The reaction temperature was replaced with 90 ℃ and the remaining conditions and operation were the same as in example 1, with a yield of 20% of the desired product of formula 3 a.
Example 13
The reaction time was changed to 24 hours, and the remaining conditions and operation were the same as in example 1, and the yield of the objective product of formula 3a was 73%.
Example 14
The reaction time was changed to 10 hours, and the remaining conditions and operation were the same as in example 1, with a yield of 81% of the desired product of formula 3 a.
Example 15
The reaction time was changed to 6 hours, and the remaining conditions and operation were the same as in example 1, with a yield of 55% of the desired product of formula 3 a.
Substrate development experiment
According to the experimental results of reaction condition optimization of the present invention, the inventors selected the reaction condition of example 1 as the optimal reaction condition, further expanded various types of reaction substrates, and examined the tolerance of the optimal reaction condition to different types of reaction substrates, and the results are shown in the following chemical formula.
The characterization data for representative products 3d, 3f, 3h, 3p, 3s, 3w, 3aa, 3ae, 3aj, 3al are as follows.
3d: Yield: 80.5mg, 84%; Colorless oil; 1 H NMR (400 MHz, CDCl 3 ) δ: 7.26-7.18 (m, 2H), 7.08 (td, J = 7.6, 0.8 Hz, 1H), 6.72 (d, J = 7.6 Hz, 1H), 4.59 (d, J = 17.6 Hz, 1H), 4.32 (d, J = 17.2 Hz, 1H), 4.20 (q, J = 7.2 Hz, 2H), 3.53 (s, 3H), 2.31-2.24 (m, 1H), 2.22-2.11 (m, 2H), 1.91-1.83 (m, 1H), 1.41 (s, 3H), 1.24 (t, J = 7.2 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ: 180.1, 173.4, 167.6, 142.1, 132.7, 128.2, 123.2, 123.1, 108.2, 61.9, 51.6, 47.8, 41.4, 33.3, 29.5, 23.9, 14.2; HRMS m/z (ESI) calcd for C 17 H 21 NO 5 ([M+Na] + ) 342.1312, found 342.1316.
3f: Yield: 86.0mg, 93%; Colorless oil; 1 H NMR (400 MHz, CDCl 3 ) δ: 7.39-7.35 (m, 2H), 7.35-7.27 (m, 3H), 7.26-7.21 (m, 2H), 7.11 (td, J = 7.6, 0.8 Hz, 1H), 6.91 (d, J = 8.0 Hz, 1H), 3.56 (s, 3H), 3.23 (s, 3H), 2.78-2.68 (m, 1H), 2.62-2.52 (m, 1H), 2.23-2.13 (m, 1H), 2.04-1.94 (m, 1H); 13 C NMR (100 MHz, CDCl 3 ) δ: 178.0, 173.1, 143.9, 139.5, 131.3, 128.7, 128.6, 127.6, 126.9, 125.0, 122.9, 108.5, 55.9, 51.7, 32.6, 29.7, 26.5; HRMS m/z (ESI) calcd for C 19 H 19 NO 3 ([M+H] + ) 310.1438, found 310.1437.
3h:Yield: 76.5mg, 88%; Yellow oil; 1 H NMR (400 MHz, CDCl 3 ) δ: 6.79-6.75 (m, 2H), 6.74-6.70 (m, 1H), 3.99 (q, J = 14.0,7.2 Hz, 2H), 3.54 (s, 3H), 3.17 (s, 3H), 2.26-2.15 (m, 1H), 2.12-1.98 (m, 2H), 1.94-1.82 (m, 1H), 1.40 (t, J = 6.8 Hz, 3H), 1.35 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ: 179.6, 173.3, 155.6, 136.8, 134.4, 112.9, 111.1, 108.5, 64.2, 51.6, 48.1, 33.1, 29.5, 26.3, 23.7, 15.0.
3p:Yield: 57.8mg, 88%; Yellow oil; 1 H NMR (400 MHz, CDCl 3 ) δ: 7.18 (dd, J = 8.0,1.2 Hz, 1H), 7.04 (dd, J = 7.2,1.2 Hz, 1H), 6.99-6.93 (m, 1H), 3.57 (s, 3H), 3.54 (s, 3H), 2.27-2.16 (m, 1H), 2.12-2.00 (m, 2H), 1.91-1.81 (m, 1H), 1.36 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ: 180.2, 173.1, 139.3, 135.9, 130.5, 123.6, 121.3, 115.7, 51.7, 47.5, 33.3, 29.6, 29.4, 24.0; HRMS m/z (ESI) calcd for C 14 H 16 35 ClNO 3 ([M+H] + ) 282.0891, found 282.0889.
3s:Yield: 81.0mg, 86%; Yellow oil; 1 H NMR (400 MHz, CDCl 3 ) δ: 7.00 (d, J = 1.6 Hz, 1H), 6.75 (d, J = 1.6 Hz, 1H), 3.55 (s, 3H), 3.18 (s, 3H), 2.58-2.47 (m, 1H), 2.31-2.21 (m, 1H), 2.00-1.82 (m, 2H), 1.49 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ: 179.3, 172.8, 146.0, 134.8, 131.3, 127.3, 123.3, 107.7, 51.8, 49.2, 30.2, 29.8, 26.6, 21.3; HRMS m/z (ESI) calcd for C 14 H 15 Cl 2 NO 3 ([M+H] + ) 316.0502, found 316.0497.
3w:Yield: 70.5mg, 90%; Colorless oil; 1 H NMR (400 MHz, CDCl 3 ) δ: 7.26 (td, J = 7.6, 1.2 Hz, 1H), 7.16 (d, J = 7.2 Hz, 1H), 7.05 (t, J = 7.6 Hz, 1H), 6.83 (d, J = 8.0 Hz, 1H), 4.04-3.90 (m, 2H), 3.20 (s, 3H), 2.27-2.16 (m, 1H), 2.15-1.98 (m, 2H), 1.89-1.78 (m, 1H), 1.37 (s, 3H), 1.14 (t, J = 7.2 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ: 180.0, 172.8, 143.3, 133.0, 128.1, 122.8, 122.7, 108.1, 60.4, 47.6, 33.0, 29.7, 26.2, 23.7, 14.2.
3aa:Yield: 84.3mg, 97%; Yellow oil; 1 H NMR (400 MHz, CDCl 3 ) δ: 7.25-7.18 (m, 1H), 7.18-7.13 (m, 1H), 7.06-6.97 (m, 1H), 6.81 (d, J = 7.6 Hz, 1H), 3.20 (s, 1.5H), 3.17 (s, 1.5H),2.47-2.33 (m, 1H), 2.27-2.12 (m, 0.5H), 1.94-1.83 (m, 1H), 1.64 (dd, J = 14.0, 4.4 Hz, 0.5H), 1.36 (s, 4H), 1.31 (d, J = 2.8 Hz, 3H), 1.19 (s, 5H), 0.95 (d, J = 6.8 Hz, 1.5H), 0.84 (d, J = 7.2 Hz, 1.5H); 13 C NMR(100 MHz, CDCl 3 ) δ: 180.6, 180.0, 175.6, 175.5, 143.3, 143.3, 134.1, 132.8, 128.0, 123.9, 122.8, 122.7, 122.5, 108.1, 108.0, 80.1, 80.0, 48.1, 47.5, 41.2, 40.8, 37.6, 37.2, 28.0, 27.9, 26.3, 26.3, 25.2, 24.3, 19.5, 19.2.
3ae:Yield: 93.7mg, 93%; Yellow oil; 1 H NMR (400 MHz, CDCl 3 ) δ: 7.21 (ddd, J = 8.0, 6.0, 2.0 Hz, 1H), 7.13 (t, J = 2.4 Hz, 1H), 6.74 (d, J = 8.4 Hz, 1H), 3.19 (s, 1.6H), 3.15 (s, 1.4H), 2.47-2.31 (m, 1H), 2.24-2.13 (m, 0.5H), 1.90-1.80 (m, 1H), 1.63 (dd, J = 14.4, 4.0 Hz, 0.5H), 1.36 (s, 4H), 1.31 (d, J = 3.2 Hz, 3H), 1.22 (s, 5H), 0.97 (d, J = 7.2 Hz, 1.6H), 0.89 (d, J = 7.2 Hz, 1.4H); 13 C NMR (100 MHz, CDCl 3 ) δ: 180.0, 179.5, 175.4, 142.0, 141.9, 135.8, 134.5, 128.1, 128.0, 127.9, 127.9, 124.6, 123.4, 109.1, 109.0, 80.3, 80.2, 48.5, 47.7, 41.1, 40.6, 37.6, 37.2, 28.0, 27.9, 26.4, 26.4, 25.1, 24.2, 19.6, 19.4;HRMS m/z (ESI) calcd for C 18 H 24 35 ClNO 3 ([M+Na] + ) 360.1337, found 360.1329.
3aj:Yield: 97.5mg, 96%; Yellow oil; 1 H NMR (400 MHz, CDCl 3 ) δ: 7.16 (t, J = 7.2 Hz, 1H), 7.05 (t, J = 6.8 Hz, 1H), 6.94 (q, J = 7.2 Hz, 1H), 3.58 (s, 1.5H), 3.55 (s, 1.5H), 2.44 (dd, J = 14.4, 8.0 Hz, 0.5H), 2.39-2.30 (m, 0.5H), 2.25-2.14 (m, 0.5H), 1.96-1.85 (m, 1H), 1.62 (dd, J = 14.4, 4.4 Hz, 0.5H), 1.38 (s, 4.5H), 1.32 (s, 3H), 1.21 (s, 4.5H), 0.98 (d, J = 6.4 Hz, 1.5H), 0.88 (d, J = 7.2 Hz, 1.5H); 13 C NMR (100 MHz, CDCl 3 ) δ: 180.7, 180.2, 175.4, 175.3, 139.2, 136.9, 135.7, 130.2, 123.5, 123.2, 122.4, 121.3, 115.5, 115.4, 80.2, 80.0, 47.9, 47.2, 41.4, 41.0, 37.4, 37.1, 29.6, 29.6,28.0, 27.9, 25.4, 24.6, 19.5, 19.3; (30C) HRMS m/z (ESI) calcd for C 18 H 24 35 ClNO 3 ([M+Na] + ) 360.1337, found 360.1329.
3al:Yield: 69.3mg, 89%; Yellow oil; 1 H NMR (400 MHz, CDCl 3 ) δ: 7.30-7.20 (m, 1H), 7.17-7.11 (m, 1H), 7.08-7.00 (m, 1H), 6.84 (dd, J = 7.6, 4.8 Hz, 1H), 3.57 (s, 1.4H), 3.23 (s, 1.6H), 3.17 (s, 1.4H), 3.15 (s, 1.6H), 2.46 (dd, J = 14.0, 8.4 Hz, 0.5H), 2.35 (dd, J = 13.6, 9.2 Hz, 0.5H), 2.22-2.12 (m, 0.5H), 2.09-1.95 (m, 1H), 1.78 (dd, J = 14.0, 4.0 Hz, 0.5H), 1.33 (d, J = 1.6 Hz, 3H), 1.01 (d, J = 6.8 Hz, 1.6H), 0.92 (d, J = 7.2 Hz, 1.4H); 13 C NMR (100 MHz, CDCl 3 ) δ: 180.31, 179.81, 176.70, 176.55, 143.56, 143.38, 133.54, 132.23, 128.12, 128.08, 123.92, 122.63, 122.55, 122.38, 108.23, 108.09, 51.76.
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 (4)
1. A method for synthesizing a silver-mediated 3, 3-disubstituted indol-2-one derivative, which is characterized by comprising the following steps: adding an N-aryl alkene amide compound A, a bromo-carboxylic ester compound B, a silver catalyst and an organic solvent into a reaction tube, then placing the reaction tube into an oil bath pot, heating to 90-130 ℃, stirring for reacting for 6-24 hours, and carrying out post-treatment to obtain a 3, 3-disubstituted indole-2-ketone derivative C, wherein the reaction formula is as follows.
2. The method of synthesis according to claim 1, characterized in that: r is 1 Is selected from C 1 ~C 6 Alkyl of (C) 6 ~C 14 Aryl radical, C 2 ~C 10 An ester group of (a); r is 2 Is selected from C 1 ~C 6 Alkyl of (C) 6 ~C 14 An aryl group; r 3 One, two or three substituents representing ortho, meta or para positions on the phenyl ring, each R 3 The substituents are independently of one another selected from hydrogen, halogen, C 1 ~C 6 Alkyl of (C) 1 ~C 6 Halogenoalkyl of, C 1 ~C 6 Alkoxy group of (C) 2 ~C 6 An ester group of (a); r 4 Is selected from C 1 ~C 6 Alkyl of (C) 6 ~C 14 An aryl group; r 5 Selected from hydrogen, C 1 ~C 6 Alkyl groups of (a); r 6 Selected as hydrogen atoms.
3. The method of synthesis according to claim 1, characterized in that: the silver catalyst is selected from any one of silver carbonate, silver oxide, silver nitrate, silver sulfate and silver acetate, and the organic solvent is selected from any one of ethyl acetate, 1, 4-dioxane, methanol, dichloromethane and n-hexane.
4. The method of synthesis according to claim 1, characterized in that: the reaction temperature ranges from 90 to 130 degrees and the reaction time ranges from 6 to 24 hours.
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