CN105646326A - Preparation method of multi-substituted indole-2-ketone compounds - Google Patents
Preparation method of multi-substituted indole-2-ketone compounds Download PDFInfo
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- CN105646326A CN105646326A CN201610037331.1A CN201610037331A CN105646326A CN 105646326 A CN105646326 A CN 105646326A CN 201610037331 A CN201610037331 A CN 201610037331A CN 105646326 A CN105646326 A CN 105646326A
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- 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
Abstract
The invention discloses a preparation method of multi-substituted indole-2-ketone compounds. Due to radical initiator and oxidant, an addition-cascade reaction happens to azo-arylacrylamide and alkyl radicals formed by fatty aldehyde through decarbonylation, and the target products are obtained. The raw material azo-arylacrylamide used in the preparation method can be prepared on a large scale easily, and is stable and easy to preserve at room temperature; secondarily, aldehyde is various in variety, low in price and easy to obtain and is converted into alkyl radicals through the radical process, the alkyl radicals are applied to a decarbonylation-addition reaction of unsaturated multiple bonds, and a brand-new, economical and environment-friendly carbon-carbon bond building method will is built; no metal catalysts are used, and the method is environmentally friendly; reaction conditions are mild, the yield is high, and the products are easy to separate and purify. Please see the formula I and the formula II in the description.
Description
Technical field
The present invention relates to a kind of similar Benzazole compounds, the preparation method particularly relating to a kind of polysubstituted indole-2-ketone compound.
Background technology
Indole ketone compound is of many uses, is intermediate indispensable in modern organic synthesis, the important source material of many functional materials or medical especially, and its skeleton is present in many natural products and has in bioactive compound. Wherein, polysubstituted indole-2-ketone compound is the vascular targeting agents that a class is played a role by suppression tyrosine kinase receptor (RTKs). Such as, SU5416 is a kind of target vascular therapy endothelial cell growth factor receptor 2 body 2(VEGFR-2 researched and developed by Sugen company) tyrosine kinase inhibitor (Sun, L.; Tran, N.; Tang, F.; App, H.; Hirth, P.; McMahon, G.; Tang, C.J.Med.Chem.1998,41,2588). The synthesis of this compounds not only need in relevant bibliographical information multistep synthesis and also need add metallic catalyst also or reaction condition harsher. Such as: Wu, Tao.Mu, Xin.Liu, Guosheng.Tetrahedron, 2012,68,5229-5233. this method not only reaction raw materials is complicated but also needs to add part and metal salt compound. Therefore in the urgent need to developing new efficient method to synthesize polysubstituted indole-2-ketone compound.
SU5416��
Summary of the invention
The preparation method that it is an object of the invention to provide a kind of polysubstituted indole-2-ketone.
The method preparing polysubstituted indole-2-ketone compound provided by the invention, it is under radical initiator/oxidant existent condition, fatty aldehyde decarbonylation forms alkyl diradical, with the nitrogen Activities of Arylacrylamide Compounds shown in Formula II general structure, free radical addition and cascade reaction occurs in a solvent, obtains polysubstituted indole-2-ketone compound. In this Formula II general structure, R1: methyl, fluorine, chlorine, bromine, iodine, methoxyl group, trifluoromethyl, phenyl. R2: methyl, benzyl, phenyl, ethyl. R3: hydrogen atom, methoxyl group, acetate groups.
Formula II
Fatty aldehyde is with as follows with the oxidation-decarbonylation-coupling cascade reaction equation of the nitrogen Activities of Arylacrylamide Compounds shown in Formula II general structure:
Formula II Formulas I
In above-mentioned preparation method, the reactant shown in Formula II general structure is nitrogen Activities of Arylacrylamide Compounds. Above-mentioned nitrogen Activities of Arylacrylamide Compounds containing various substituent groups all can be prepared according to the method for following bibliographical information in a large number: Wu, Tao.Mu, Xin.Liu, Guosheng.Angew.Chem., Int.Ed.2011,130,12578 12581. Any one in following compound of radical initiator/oxidant used: DCP (cumyl peroxide), DTBP(di-t-butyl peroxide), TBHP(tert-butyl hydroperoxide, the organic facies of 5.0M-6.0M concentration), BPO(benzoyl peroxide), 30% hydrogen peroxide, iodobenzene diacetate. Any one in the following compound of solvent for use: chlorobenzene, face difluorobenzene, fluorobenzene, face dichloro-benzenes, toluene, benzene, 1,2-dichloroethanes.
The consumption of described radical initiator/oxidant is the 50-250% of the mole dosage of compound shown in Formula II general structure, and the consumption of fatty aldehyde is the 100%-500% of the mole dosage of compound shown in Formula II general structure. It addition, the reaction temperature of this addition-rearrangement reaction is 80 150 DEG C, the response time is 0.1 120 hours.
The raw material nitrogen Activities of Arylacrylamide Compounds used in the present invention prepares very easily in a large number and room-temperature stable easily preserves, secondly, aldehyde wide variety and cheap and easy to get, it is translated into alkyl diradical by radical mechanism, and applied to the decarburization-additive reaction of unsaturated multiple bond, the construction method of a kind of brand-new, economic, eco-friendly carbon-carbon bond will be set up; Do not use any metallic catalyst, environmental friendliness; Reaction condition is gentleer, and productivity ratio is higher, the easily separated purification of product.
Detailed description of the invention
Below in conjunction with specific embodiment, the invention will be further described, but the present invention is not limited to following example.
Embodiment 1
The preparation polysubstituted indole-2-ketone compound shown in Formulas I a general structure, this reaction equation is as follows:
Formula II a Formulas I a
Concrete preparation method is: when air at room temperature, it is sequentially added into magneton in dry, clean 5ml glass reaction tube, N-methyl pyridyl acrylamide (35mg shown in Formula II a structural formula, 0.2mmol), add the chlorobenzene 1.5ml of molecular sieve drying, dissolve and after completely, add special valeral (51.6mg, 0.6mmol), it is eventually adding DCP(54mg, 0.2mmol) 1300After C reacts 12 hours, reaction system is cooled to room temperature, and thin-layer chromatographic analysis display raw material II a consumes completely. Directly with 200-300 order silica gel column chromatography, mixed solvent (1:8) drip washing of ethyl acetate and petroleum ether. Separate to obtain compound 35.1mg shown in Formulas I a structural formula, productivity 76%;
This product is faint yellow solid; Fusing point mp:104-1050C;
1HNMR(400MHz,CDCl3)��7.26(t,J=7.2Hz,1H),7.20(d,J=6.8Hz,1H),7.03(t,J=7.2Hz,1H),6.85(d,J=7.6Hz,1H),3.22(s,4H),2.16(d,J=14.4Hz,1H),1.86(d,J=14.4Hz,1H),1.29(s,3H),0.61(s,9H).
13CNMR(101MHz,CDCl3)��181.12,142.96,134.30,127.64,123.96,122.08,108.12,50.89,47.49,31.87,30.92,28.38,26.33.
ElementalAnalysis:C15H21NO:C,77.88;H,9.15;N,6.05;O,6.92��
Embodiment 2
The preparation polysubstituted indole-2-ketone compound shown in Formulas I a general structure, this reaction equation is as follows:
Formula II a Formulas I a
Concrete preparation method is: when air at room temperature, it is sequentially added into magneton in dry, clean 5ml glass reaction tube, N-methyl pyridyl acrylamide (35mg shown in Formula II a structural formula, 0.2mmol), add the chlorobenzene 1.5ml of molecular sieve drying, dissolve and after completely, add special valeral (51.6mg, 0.6mmol), it is eventually adding TBHP(34mg, 0.2mmol) 1300After C reacts 12 hours, reaction system is cooled to room temperature, and thin-layer chromatographic analysis display raw material II a consumes completely.Directly with 200-300 order silica gel column chromatography, mixed solvent (1:8) drip washing of ethyl acetate and petroleum ether. Separate to obtain compound 35.1mg shown in Formulas I a structural formula, productivity 76%; Compound structure Analysis and Identification data consistent with Example 1.
Embodiment 3
The preparation polysubstituted indole-2-ketone compound shown in Formulas I a general structure, this reaction equation is as follows:
Formula II a Formulas I a
Concrete preparation method is: when air at room temperature, it is sequentially added into magneton in dry, clean 5ml glass reaction tube, N-methyl pyridyl acrylamide (35mg shown in Formula II a structural formula, 0.2mmol), add the chlorobenzene 1.5ml of molecular sieve drying, dissolve and after completely, add special valeral (51.6mg, 0.6mmol), it is eventually adding BPO(48.4mg, 0.2mmol) 1300After C reacts 12 hours, reaction system is cooled to room temperature, and thin-layer chromatographic analysis display raw material II a consumes completely. Directly with 200-300 order silica gel column chromatography, mixed solvent (1:8) drip washing of ethyl acetate and petroleum ether. Separate to obtain compound 33.2mg shown in Formulas I a structural formula, productivity 72%; Compound structure Analysis and Identification data consistent with Example 1.
Embodiment 4
The preparation polysubstituted indole-2-ketone compound shown in Formulas I a general structure, this reaction equation is as follows:
Formula II a Formulas I a
Concrete preparation method is: when air at room temperature, it is sequentially added into magneton in dry, clean 5ml glass reaction tube, N-methyl pyridyl acrylamide (35mg shown in Formula II a structural formula, 0.2mmol), add the chlorobenzene 1.5ml of molecular sieve drying, dissolve and after completely, add special valeral (51.6mg, 0.6mmol), it is eventually adding TBP(29.2mg, 0.2mmol) 1300After C reacts 12 hours, reaction system is cooled to room temperature, and thin-layer chromatographic analysis display raw material II a consumes completely. Directly with 200-300 order silica gel column chromatography, mixed solvent (1:8) drip washing of ethyl acetate and petroleum ether. Separate to obtain compound 35.1mg shown in Formulas I a structural formula, productivity 76%; Compound structure Analysis and Identification data consistent with Example 1.
Embodiment 5
The preparation polysubstituted indole-2-ketone compound shown in Formulas I a general structure, this reaction equation is as follows:
Formula II a Formulas I a
Concrete preparation method is: when air at room temperature, it is sequentially added into magneton in dry, clean 5ml glass reaction tube, N-methyl pyridyl acrylamide (35mg shown in Formula II a structural formula, 0.2mmol), add the chlorobenzene 1.5ml of molecular sieve drying, dissolve and after completely, add special valeral (51.6mg, 0.6mmol), it is eventually adding iodobenzene diacetate (64.4mg, 0.2mmol) 1300After C reacts 12 hours, reaction system is cooled to room temperature, and thin-layer chromatographic analysis display raw material II a consumes completely. Directly with 200-300 order silica gel column chromatography, mixed solvent (1:8) drip washing of ethyl acetate and petroleum ether. Separate to obtain compound 34.2mg shown in Formulas I a structural formula, productivity 74%; Compound structure Analysis and Identification data consistent with Example 1.
Embodiment 6
The preparation polysubstituted indole-2-ketone compound shown in Formulas I a general structure, this reaction equation is as follows:
Formula II a Formulas I a
Concrete preparation method is: when air at room temperature, it is sequentially added into magneton in dry, clean 5ml glass reaction tube, N-methyl pyridyl acrylamide (35mg, 0.2mmol) shown in Formula II a structural formula, adds the fluorobenzene 1.5ml of molecular sieve drying, dissolve and after completely, add special valeral (51.6mg, 0.6mmol), it being eventually adding TBP(29.2mg, 0.2mmol) 1300C reacts after 12 hours, reaction system is cooled to room temperature, and thin-layer chromatographic analysis display raw material II a consumes completely.Directly with 200-300 order silica gel column chromatography, mixed solvent (1:8) drip washing of ethyl acetate and petroleum ether. Separate to obtain compound 31.0mg shown in Formulas I a structural formula, productivity 67%; Compound structure Analysis and Identification data consistent with Example 1.
Embodiment 7
The preparation polysubstituted indole-2-ketone compound shown in Formulas I a general structure, this reaction equation is as follows:
Formula II a Formulas I a
Concrete preparation method is: when air at room temperature, it is sequentially added into magneton in dry, clean 5ml glass reaction tube, N-methyl pyridyl acrylamide (35mg, 0.2mmol) shown in Formula II a structural formula, adds the toluene 1.5ml of molecular sieve drying, dissolve and after completely, add special valeral (51.6mg, 0.6mmol), it being eventually adding TBP(29.2mg, 0.2mmol) 1300C reacts after 12 hours, reaction system is cooled to room temperature, and thin-layer chromatographic analysis display raw material II a consumes completely. Directly with 200-300 order silica gel column chromatography, mixed solvent (1:8) drip washing of ethyl acetate and petroleum ether. Separate to obtain compound 28.6mg shown in Formulas I a structural formula, productivity 62%; Compound structure Analysis and Identification data consistent with Example 1.
Embodiment 8
The preparation polysubstituted indole-2-ketone compound shown in Formulas I a general structure, this reaction equation is as follows:
Formula II a Formulas I a
Concrete preparation method is: when air at room temperature, it is sequentially added into magneton in dry, clean 5ml glass reaction tube, N-methyl pyridyl acrylamide (35mg, 0.2mmol) shown in Formula II a structural formula, adds the DCE1.5ml of molecular sieve drying, dissolve and after completely, add special valeral (51.6mg, 0.6mmol), it being eventually adding TBP(29.2mg, 0.2mmol) 1300C reacts after 12 hours, reaction system is cooled to room temperature, and thin-layer chromatographic analysis display raw material II a consumes completely. Directly with 200-300 order silica gel column chromatography, mixed solvent (1:8) drip washing of ethyl acetate and petroleum ether. Separate to obtain compound 31.0mg shown in Formulas I a structural formula, productivity 67%; Compound structure Analysis and Identification data consistent with Example 1.
Embodiment 9
The preparation polysubstituted indole-2-ketone compound shown in Formulas I a general structure, this reaction equation is as follows:
Formula II a Formulas I a
Concrete preparation method is: when air at room temperature, it is sequentially added into magneton in dry, clean 5ml glass reaction tube, N-methyl pyridyl acrylamide (35mg shown in Formula II a structural formula, 0.2mmol), add the benzene 1.5ml of molecular sieve drying, dissolve and after completely, add special valeral (51.6mg, 0.6mmol), it is eventually adding TBP(29.2mg, 0.2mmol) 1300After C reacts 12 hours, reaction system is cooled to room temperature, and thin-layer chromatographic analysis display raw material II a consumes completely. Directly with 200-300 order silica gel column chromatography, mixed solvent (1:8) drip washing of ethyl acetate and petroleum ether. Separate to obtain compound 31.0mg shown in Formulas I a structural formula, productivity 67%; Compound structure Analysis and Identification data consistent with Example 1.
Embodiment 10
The preparation polysubstituted indole-2-ketone compound shown in Formulas I a general structure, this reaction equation is as follows:
Formula II a Formulas I a
Concrete preparation method is: when air at room temperature, it is sequentially added into magneton in dry, clean 5ml glass reaction tube, N-methyl pyridyl acrylamide (35mg, 0.2mmol) shown in Formula II a structural formula, adds the benzene 1.5ml of molecular sieve drying, dissolve and after completely, add special valeral (51.6mg, 0.6mmol), it being eventually adding TBP(29.2mg, 0.2mmol) 1000C reacts after 12 hours, reaction system is cooled to room temperature, and thin-layer chromatographic analysis display raw material II a consumes completely.Directly with 200-300 order silica gel column chromatography, mixed solvent (1:8) drip washing of ethyl acetate and petroleum ether. Separate to obtain compound 31.0mg shown in Formulas I a structural formula, productivity 67%; Compound structure Analysis and Identification data consistent with Example 1.
Embodiment 11
The preparation polysubstituted indole-2-ketone compound shown in Formulas I a general structure, this reaction equation is as follows:
Formula II a Formulas I a
Concrete preparation method is: when air at room temperature, it is sequentially added into magneton in dry, clean 5ml glass reaction tube, N-methyl pyridyl acrylamide (35mg, 0.2mmol) shown in Formula II a structural formula, adds the benzene 1.5ml of molecular sieve drying, dissolve and after completely, add special valeral (51.6mg, 0.6mmol), it being eventually adding TBP(29.2mg, 0.2mmol) 1200C reacts after 12 hours, reaction system is cooled to room temperature, and thin-layer chromatographic analysis display raw material II a consumes completely. Directly with 200-300 order silica gel column chromatography, mixed solvent (1:8) drip washing of ethyl acetate and petroleum ether. Separate to obtain compound 30.5mg shown in Formulas I a structural formula, productivity 66%; Compound structure Analysis and Identification data consistent with Example 1.
Embodiment 12
The preparation polysubstituted indole-2-ketone compound shown in Formulas I a general structure, this reaction equation is as follows:
Formula II a Formulas I a
Concrete preparation method is: when air at room temperature, it is sequentially added into magneton in dry, clean 5ml glass reaction tube, N-methyl pyridyl acrylamide (35mg, 0.2mmol) shown in Formula II a structural formula, adds the benzene 1.5ml of molecular sieve drying, dissolve and after completely, add special valeral (51.6mg, 0.6mmol), it being eventually adding TBP(29.2mg, 0.2mmol) 1500C reacts after 12 hours, reaction system is cooled to room temperature, and thin-layer chromatographic analysis display raw material II a consumes completely. Directly with 200-300 order silica gel column chromatography, mixed solvent (1:8) drip washing of ethyl acetate and petroleum ether. Separate to obtain compound 30.0mg shown in Formulas I a structural formula, productivity 65%; Compound structure Analysis and Identification data consistent with Example 1.
Embodiment 13
The preparation polysubstituted indole-2-ketone compound shown in Formulas I a general structure, this reaction equation is as follows:
Formula II a Formulas I a
Concrete preparation method is: when air at room temperature, it is sequentially added into magneton in dry, clean 5ml glass reaction tube, N-methyl pyridyl acrylamide (35mg, 0.2mmol) shown in Formula II a structural formula, adds the chlorobenzene 1.5ml of molecular sieve drying, dissolve and after completely, add special valeral (17.2mg, 0.2mmol), it being eventually adding TBP(29.2mg, 0.2mmol) 1300C reacts after 12 hours, reaction system is cooled to room temperature, and thin-layer chromatographic analysis display raw material II a consumes completely. Directly with 200-300 order silica gel column chromatography, mixed solvent (1:8) drip washing of ethyl acetate and petroleum ether. Separate to obtain compound 24.9mg shown in Formulas I a structural formula, productivity 54%; Compound structure Analysis and Identification data consistent with Example 1.
Embodiment 14
The preparation polysubstituted indole-2-ketone compound shown in Formulas I a general structure, this reaction equation is as follows:
Formula II a Formulas I a
Concrete preparation method is: when air at room temperature, it is sequentially added into magneton in dry, clean 5ml glass reaction tube, N-methyl pyridyl acrylamide (35mg, 0.2mmol) shown in Formula II a structural formula, adds the chlorobenzene 1.5ml of molecular sieve drying, dissolve and after completely, add special valeral (86.0mg, 1mmol), it being eventually adding TBP(29.2mg, 0.2mmol) 1300C reacts after 12 hours, reaction system is cooled to room temperature, and thin-layer chromatographic analysis display raw material II a consumes completely.Directly with 200-300 order silica gel column chromatography, mixed solvent (1:8) drip washing of ethyl acetate and petroleum ether. Separate to obtain compound 35.6mg shown in Formulas I a structural formula, productivity 77%; Compound structure Analysis and Identification data consistent with Example 1.
Embodiment 15
The preparation polysubstituted indole-2-ketone compound shown in Formulas I a general structure, this reaction equation is as follows:
Formula II a Formulas I a
Concrete preparation method is: when air at room temperature, it is sequentially added into magneton in dry, clean 5ml glass reaction tube, N-methyl pyridyl acrylamide (35mg, 0.2mmol) shown in Formula II a structural formula, adds the chlorobenzene 1.5ml of molecular sieve drying, dissolve and after completely, add special valeral (51.6mg, 0.6mmol), it being eventually adding TBP(14.6mg, 0.1mmol) 1300C reacts after 12 hours, reaction system is cooled to room temperature, and thin-layer chromatographic analysis display raw material II a consumes completely. Directly with 200-300 order silica gel column chromatography, mixed solvent (1:8) drip washing of ethyl acetate and petroleum ether. Separate to obtain compound 28.2mg shown in Formulas I a structural formula, productivity 61%; Compound structure Analysis and Identification data consistent with Example 1.
Embodiment 16
The preparation polysubstituted indole-2-ketone compound shown in Formulas I a general structure, this reaction equation is as follows:
Formula II a Formulas I a
Concrete preparation method is: when air at room temperature, it is sequentially added into magneton in dry, clean 5ml glass reaction tube, N-methyl pyridyl acrylamide (35mg, 0.2mmol) shown in Formula II a structural formula, adds the chlorobenzene 1.5ml of molecular sieve drying, dissolve and after completely, add special valeral (51.6mg, 0.6mmol), it being eventually adding TBP(71.5mg, 5mmol) 1300C reacts after 12 hours, reaction system is cooled to room temperature, and thin-layer chromatographic analysis display raw material II a consumes completely. Directly with 200-300 order silica gel column chromatography, mixed solvent (1:8) drip washing of ethyl acetate and petroleum ether. Separate to obtain compound 34.2mg shown in Formulas I a structural formula, productivity 74%; Compound structure Analysis and Identification data consistent with Example 1.
Embodiment 17
The preparation polysubstituted indole-2-ketone compound shown in Formulas I a general structure, this reaction equation is as follows:
Formula II a Formulas I a
Concrete preparation method is: when air at room temperature, it is sequentially added into magneton in dry, clean 5ml glass reaction tube, N-methyl pyridyl acrylamide (35mg, 0.2mmol) shown in Formula II a structural formula, adds the chlorobenzene 1.5ml of molecular sieve drying, dissolve and after completely, add special valeral (51.6mg, 0.6mmol), it being eventually adding TBP(29.2mg, 0.2mmol) 800C reacts after 12 hours, reaction system is cooled to room temperature, and thin-layer chromatographic analysis display raw material II a consumes completely. Directly with 200-300 order silica gel column chromatography, mixed solvent (1:8) drip washing of ethyl acetate and petroleum ether. Separate to obtain compound 26.3mg shown in Formulas I a structural formula, productivity 52%; Compound structure Analysis and Identification data consistent with Example 1.
Embodiment 18
The preparation polysubstituted indole-2-ketone compound shown in Formulas I a general structure, this reaction equation is as follows:
Formula II a Formulas I a
Concrete preparation method is: when air at room temperature, it is sequentially added into magneton in dry, clean 5ml glass reaction tube, N-methyl pyridyl acrylamide (35mg, 0.2mmol) shown in Formula II a structural formula, adds the chlorobenzene 1.5ml of molecular sieve drying, dissolve and after completely, add special valeral (51.6mg, 0.6mmol), it being eventually adding TBP(29.2mg, 0.2mmol) 1500C reacts after 12 hours, reaction system is cooled to room temperature, and thin-layer chromatographic analysis display raw material II a consumes completely.Directly with 200-300 order silica gel column chromatography, mixed solvent (1:8) drip washing of ethyl acetate and petroleum ether. Separate to obtain compound 34.6mg shown in Formulas I a structural formula, productivity 75%; Compound structure Analysis and Identification data consistent with Example 1.
Embodiment 19
The preparation polysubstituted indole-2-ketone compound shown in Formulas I a general structure, this reaction equation is as follows:
Formula II a Formulas I a
Concrete preparation method is: when air at room temperature, it is sequentially added into magneton in dry, clean 5ml glass reaction tube, N-methyl pyridyl acrylamide (35mg, 0.2mmol) shown in Formula II a structural formula, adds the chlorobenzene 1.5ml of molecular sieve drying, dissolve and after completely, add special valeral (51.6mg, 0.6mmol), it being eventually adding TBP(29.2mg, 0.2mmol) 1300C reacts after 0.1 hour, reaction system is cooled to room temperature, and thin-layer chromatographic analysis display raw material II a consumes completely. Directly with 200-300 order silica gel column chromatography, mixed solvent (1:8) drip washing of ethyl acetate and petroleum ether. Separate to obtain compound 5.5mg shown in Formulas I a structural formula, productivity 12%; Compound structure Analysis and Identification data consistent with Example 1.
Embodiment 20
The preparation polysubstituted indole-2-ketone compound shown in Formulas I a general structure, this reaction equation is as follows:
Formula II a Formulas I a
Concrete preparation method is: when air at room temperature, it is sequentially added into magneton in dry, clean 5ml glass reaction tube, N-methyl pyridyl acrylamide (35mg, 0.2mmol) shown in Formula II a structural formula, adds the chlorobenzene 1.5ml of molecular sieve drying, dissolve and after completely, add special valeral (51.6mg, 0.6mmol), it being eventually adding TBP(29.2mg, 0.2mmol) 1300C reacts after 120 hours, reaction system is cooled to room temperature, and thin-layer chromatographic analysis display raw material II a consumes completely. Directly with 200-300 order silica gel column chromatography, mixed solvent (1:8) drip washing of ethyl acetate and petroleum ether. Separate to obtain compound 34.2mg shown in Formulas I a structural formula, productivity 74%; Compound structure Analysis and Identification data consistent with Example 1.
According to the operational approach described in embodiment 3, the present invention has also synthesized following compound:
Shown below is the chemical structure analysis data of section Example compound of the present invention:
Embodiment 21
New penta indol-2-one of 5-fluoro-1,3-dimethyl-3-
M.p.121-123C;1HNMR(400MHz,CDCl3)��6.981-6.937(m,2H),6.76(dd,J=8.0,4.0Hz,1H),3.21(s,3H),2.16(d,J=14.4Hz,1H),1.82(d,J=14.4Hz,1H),1.29(s,3H),0.63(s,9H).
13CNMR(101MHz,CDCl3)��180.69,160.41,158.03,138.93,136.22,136.14,113.95,113.72,112.10,111.85,108.54,108.46,50.91,47.99,47.97,31.87,30.92,28.30,26.45.
ElementalAnalysis:C15H20FNO:C,72.26;H,8.09;F,7.62;N,5.62;O,6.42��
Embodiment 25
New penta indol-2-one of 1,3,5-trimethyl-3-
M.p.120-121C;1HNMR(400MHz,CDCl3)��7.05(d,J=8.0Hz,1H),7.01(s,1H),6.73(d,J=8.0Hz,1H),3.20(s,3H),2.34(s,3H),2.14(d,J=14.4Hz,1H),1.83(d,J=14.4Hz,1H),1.28(s,3H),0.61(s,9H).
13CNMR(101MHz,CDCl3)��181.08,140.63,134.37,131.48,127.83,124.80,107.80,50.88,47.53,31.86,30.92,28.41,26.34,21.23.
ElementalAnalysis:C16H23NO:C,78.32;H,9.45;N,5.71;O,6.52��
Embodiment 28
1,3-dimethyl-3-neopentyl-5-(trifluoromethyl) indol-2-one
1HNMR(400MHz,CDCl3)��7.55(d,J=8.0Hz,1H),7.42(s,1H),6.91(d,J=8.0Hz,1H),3.25(s,3H),2.19(d,J=14.4Hz,1H),1.89(d,J=14.4Hz,1H),1.32(s,3H),0.60(s,9H).
13CNMR(101MHz,CDCl3)��181.04,181.04,145.97,135.02,131.36�C131.16(m),126.01,125.49(q,J=3.9Hz),124.67,124.35,123.31,121.02(q,J=3.6Hz),107.87,50.98,47.53,31.92,30.93,28.26,26.58.
ElementalAnalysis:C16H20F3NO:C,64.20;H,6.73;F,19.04;N,4.68;O,5.35��
Embodiment 29
New penta indol-2-one of 7-chloro-1,3-dimethyl-3-
1HNMR(400MHz,CDCl3)��7.18(d,J=7.6Hz,1H),7.07(d,J=6.8Hz,1H),6.93(t,J=7.6Hz,1H),3.59(s,3H),2.15(d,J=14.4Hz,1H),1.83(d,J=14.3Hz,1H),1.28(s,3H),0.62(s,9H).
13CNMR(101MHz,CDCl3)��181.31,138.88,137.17,129.97,122.87,122.48,115.58,51.17,47.31,31.93,30.98,29.71,28.70.
ElementalAnalysis:C15H20ClNO:C,67.79;H,7.58;Cl,13.34;N,5.27;O,6.02��
Embodiment 30
New penta indol-2-one of 6,7-bis-chloro-1,3-dimethyl-3-
M.p.75-76C;1HNMR(400MHz,CDCl3)��7.14(d,J=8.0Hz,1H),7.01(d,J=7.6Hz,1H),3.62(s,3H),2.16(d,J=14.4Hz,1H),1.82(d,J=14.4Hz,1H),1.27(s,3H),0.63(s,9H).
13CNMR(101MHz,CDCl3)��181.31,140.68,135.22,132.96,123.63,122.66,114.77,51.10,47.14,31.95,31.02,30.01,28.67.
ElementalAnalysis:C15H19Cl2NO:C,60.01;H,6.38;Cl,23.62;N,4.67;O,5.33��
Embodiment 32
3-methyl-3-neopentyl-1-Phenylindole-2-ketone
M.p.103-104C;1HNMR(400MHz,CDCl3)��7.52(t,J=7.6Hz,2H),7.40(dd,J=13.6,7.6Hz,3H),7.27(d,J=7.6Hz,1H),7.18(t,J=7.6Hz,1H),7.07(t,J=7.6Hz,1H),6.86(d,J=8.0Hz,1H),2.25(d,J=14.4Hz,1H),1.95(d,J=14.4Hz,1H),1.42(s,3H),0.73(s,9H).
13CNMR(101MHz,CDCl3)��180.43,142.83,135.00,134.12,129.67,127.91,127.55,126.42,124.39,122.56,109.57,51.13,47.73,32.10,31.15,29.03.
ElementalAnalysis:C20H23NO:C,81.87;H,7.90;N,4.77;O,5.45��
Embodiment 33
1-ethyl new penta indol-2-one of-3-methyl-3-
M.p.60-61C;1HNMR(400MHz,CDCl3)��7.22(dd,J=13.6,8.0Hz,2H),7.02(t,J=7.6Hz,1H),6.87(d,J=7.6Hz,1H),3.915-3.826(m,1H),3.730-3.641(m,1H),2.16(d,J=14.4Hz,1H),1.86(d,J=14.4Hz,1H),1.36�C1.20(m,3H),0.63(s,9H).
13CNMR(101MHz,CDCl3)��180.70,142.08,134.59,127.55,124.22,121.83,108.29,50.70,47.53,34.64,31.98,31.02,28.76,12.37.
ElementalAnalysis:C16H23NO:C,78.32;H,9.45;N,5.71;O,6.52��
Embodiment 35
3-(methoxy) new penta indol-2-one of-1-methyl-3-
M.p.73-74C;1HNMR(400MHz,CDCl3)��7.30�C7.27(m,2H),7.03(t,J=7.6Hz,1H),6.84(d,J=8.0Hz,1H),3.54(d,J=8.4Hz,1H),3.44(d,J=8.8Hz,1H),3.20(d,J=16.4Hz,6H),2.02(d,J=14.0Hz,1H),1.92(d,J=14.4Hz,1H),0.62(s,9H).
13CNMR(101MHz,DMSO)��178.83,144.02,131.24,128.03,124.89,121.98,108.04,79.48,59.69,53.02,45.66,31.76,31.12,26.40.
ElementalAnalysis:C16H23NO2:C,73.53;H,8.87;N,5.36;O,12.24��
Embodiment 37
The 3-different tert-butyl group-1,3-dimethyl-2-indol-2-one
1HNMR(400MHz,CDCl3)��7.26(t,J=7.6Hz,1H),7.16(d,J=7.2Hz,1H),7.06(t,J=7.6Hz,1H),6.84(d,J=7.6Hz,1H),3.22(s,3H),1.94(dd,J=14.0,7.6Hz,1H),1.76(dd,J=14,5.6Hz,1H),1.32(s,3H),1.24(m,1H),0.65(d,J=6.8Hz,3H),0.61(d,J=6.4Hz,3H).
13CNMR(101MHz,CDCl3)��181.19,143.29,134.31,127.66,122.91,122.43,108.05,48.18,46.84,26.28,26.24,25.63,24.22,22.93.
ElementalAnalysis:C14H19NO:C,77.38;H,8.81;N,6.45;O,7.36��
Embodiment 40
3-(cyclohexyl methyl)-1,3-dimethyl indole-2-ketone
1HNMR(400MHz,CDCl3)��7.26(s,1H),7.15(d,J=6.4Hz,1H),7.06(d,J=6.4Hz,1H),6.84(d,J=6.8Hz,1H),3.22(s,3H),1.92(dd,J=13.6,6.0Hz,1H),1.72(d,J=13.6Hz,1H),1.46(d,J=9.2Hz,3H),1.31(s,3H),1.20(d,J=12.4Hz,1H),1.09�C0.65(m,7H).
13CNMR(101MHz,CDCl3)��181.27,143.15,134.45,127.61,122.80,122.44,108.06,47.95,45.48,34.82,34.53,33.58,26.31,26.17,26.11.
ElementalAnalysis:C17H23NO:C,79.33;H,9.01;N,5.44;O,6.22��
Embodiment 42
1,3-dimethyl-3-phenethyl indol-2-one
1HNMR(400MHz,CDCl3)��7.29(dd,J=15.8,7.6Hz,1H),7.21(dd,J=13.6,6.8Hz,3H),7.12(dd,J=14.8,7.2Hz,2H),7.02(d,J=7.2Hz,2H),6.87(d,J=7.6Hz,1H),3.21(s,3H),2.43�C2.20(m,2H),2.19�C2.08(m,1H),2.07�C1.91(m,1H),1.40(s,3H).
13CNMR(101MHz,CDCl3)��180.46,143.53,141.50,133.86,128.39,128.34,127.95,125.95,122.71,122.59,108.13,48.49,40.35,31.08,26.24,24.07.
ElementalAnalysis:C18H19NO:C,81.47;H,7.22;N,5.28;O,6.03��
Claims (8)
1. the method preparing polysubstituted indole-2-ketone compound, the method is under certain reaction temperature and response time and oxidant/radical initiator existent condition, there is free radical addition and cascade reaction in the alkyl diradical that fatty aldehyde decarbonylation is formed and the nitrogen Activities of Arylacrylamide Compounds shown in Formula II general structure, obtains polysubstituted indole-2-ketone compound in a solvent
Formula II.
2. a kind of method preparing polysubstituted indole-2-ketone compound according to claim 1, it is characterized in that in the nitrogen Activities of Arylacrylamide Compounds shown in described Formula II general structure, R1 is selected from methyl, fluorine, chlorine, bromine, iodine, methoxyl group, trifluoromethyl, phenyl; R2 is selected from methyl, benzyl, phenyl, ethyl; R3 is selected from hydrogen atom, methoxyl group, acetate groups.
3. a kind of method preparing polysubstituted indole-2-ketone compound according to claim 1, it is characterised in that the consumption of described fatty aldehyde is the 100%-500% of the mole dosage of compound shown in Formula II general structure.
4. a kind of method preparing polysubstituted indole-2-ketone compound according to claim 1, it is characterized in that described oxidant/radical initiator is selected from following compound: DCP (cumyl peroxide), TBHP(tert-butyl hydroperoxide, the organic facies of 5.0M-6.0M concentration), DTBP(tert-butyl peroxide), BPO(benzoyl peroxide), 30% hydrogen peroxide, iodobenzene diacetate.
5. a kind of method preparing polysubstituted indole-2-ketone compound according to claim 4, it is characterised in that the consumption of described oxidant/radical initiator is the 50%-250% of the mole dosage of compound shown in Formula II general structure.
6. a kind of method preparing polysubstituted indole-2-ketone compound according to claim 1, it is characterized in that any one in the following compound of described solvent: chlorobenzene, face difluorobenzene, fluorobenzene, face dichloro-benzenes, toluene, benzene, 1,2-dichloroethanes.
7. a kind of method preparing polysubstituted indole-2-ketone compound according to claim 1, it is characterised in that described reaction temperature is 80 150 DEG C.
8. a kind of method preparing polysubstituted indole-2-ketone compound according to claim 1, it is characterised in that the response time is 0.1 120 hours.
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| CN108440378A (en) * | 2018-03-27 | 2018-08-24 | 宁波大学 | A kind of preparation method for the 3- amino -2- indolone derivatives that hydrogen peroxide iodo- at room temperature promotes |
| CN112062706A (en) * | 2020-10-26 | 2020-12-11 | 南京先进生物材料与过程装备研究院有限公司 | Method for continuously preparing indolone compounds by using microchannel reaction device |
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Non-Patent Citations (3)
| Title |
|---|
| JIN XIE ET AL.: "A room temperature decarboxylation/C–H functionalization cascade by visible-light photoredox catalysis", 《CHEM. COMMUN.》 * |
| MING-BO ZHOU ET AL.: "Metal-free oxidative tandem coupling of activated alkenes with carbonyl C(sp2)–H bonds and aryl C(sp2)–H bonds using TBHP", 《CHEMICAL SCIENCE》 * |
| 周明波: "炔烃环加成反应及N-芳基烯酰胺1,2-双官能团化反应的研究", 《万方数字资源平台》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108440378A (en) * | 2018-03-27 | 2018-08-24 | 宁波大学 | A kind of preparation method for the 3- amino -2- indolone derivatives that hydrogen peroxide iodo- at room temperature promotes |
| CN108440378B (en) * | 2018-03-27 | 2021-03-12 | 宁波大学 | Preparation method of iodine-hydrogen peroxide promoted 3-amino-2-indolone derivative at room temperature |
| CN112062706A (en) * | 2020-10-26 | 2020-12-11 | 南京先进生物材料与过程装备研究院有限公司 | Method for continuously preparing indolone compounds by using microchannel reaction device |
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