CN105646326B - A kind of preparation method of the ketone compounds of polysubstituted indoles 2 - Google Patents
A kind of preparation method of the ketone compounds of polysubstituted indoles 2 Download PDFInfo
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- CN105646326B CN105646326B CN201610037331.1A CN201610037331A CN105646326B CN 105646326 B CN105646326 B CN 105646326B CN 201610037331 A CN201610037331 A CN 201610037331A CN 105646326 B CN105646326 B CN 105646326B
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- 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
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Abstract
The present invention discloses a kind of preparation method of the ketone compounds of polysubstituted indoles 2, and by the effect of radical initiator and oxidant, with the alkyl diradical that fatty aldehyde decarbonylation is formed addition cascade reaction occurs for nitrogen aryl acrylamide, obtains target product.Raw material nitrogen aryl acrylamide used in the present invention is easily largely prepared and stablized at room temperature easy to maintain, secondly, aldehyde wide variety and cheap and easy to get, alkyl diradical is translated into by radical mechanism, and applied to the decarbonylation addition reaction of unsaturated multiple bond, a kind of construction method of brand-new, economic, environment-friendly carbon-carbon bond will be established；Any metallic catalyst is not used, it is environment-friendly；Reaction condition is gentleer, and productivity ratio is higher, the easily separated purifying of product.Formulas I,
Description
Technical field
The present invention relates to a kind of similar Benzazole compounds, more particularly to a kind of polysubstituted indole-2-ketone chemical combination
The preparation method of thing.
Background technology
Indole ketone compound is widely used, is intermediate indispensable in modern organic synthesis, even more many functions
The important source material of material or medical, its skeleton are present in many natural products and the compound with bioactivity.
Wherein, polysubstituted indole-2-ketone compound is one kind by suppressing tyrosine kinase receptor（RTKs）And play a role
Vascular targeting agents.For example, SU 5416 is a kind of target vascular therapy endothelial growth factor researched and developed by Sugen companies
Acceptor 2（VEGFR-2）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 such compound is having
Closing not only needs multistep to synthesize but also needs to add metallic catalyst also or reaction condition is harsher in document report.Than
Such as：Wu, Tao. Mu, Xin. Liu, Guosheng. Tetrahedron, 2012,68,5229-5233. this method is not only
Reaction raw materials are complicated and also need to add part and metal salt compound.Therefore there is an urgent need to develop new efficient method
To synthesize polysubstituted indole-2-ketone compound.
SU 5416。
The content of the invention
It is an object of the invention to provide a kind of preparation method of polysubstituted indole-2-ketone.
The method provided by the invention for preparing polysubstituted indole-2-ketone compound, it is in radical initiator/oxidation
Under the conditions of agent is existing, fatty aldehyde decarbonylation forms alkyl diradical and the nitrogen aryl acrylamide class shown in Formula II general structure
Free radical addition and cascade reaction occur in a solvent for compound, obtain polysubstituted indole-2-ketone compound.The Formula II structure
In formula, R1：Methyl, fluorine, chlorine, bromine, iodine, methoxyl group, trifluoromethyl, phenyl.R2：Methyl, benzyl, phenyl, ethyl.R3：Hydrogen is former
Son, methoxyl group, acetate groups.
Formula II
Fatty aldehyde and oxidation-decarbonylation-coupling string with the nitrogen Activities of Arylacrylamide Compounds shown in Formula II general structure
It is as follows to join reaction equation：
Formula II Formulas I
In above-mentioned preparation method, the reactant shown in Formula II general structure is nitrogen Activities of Arylacrylamide Compounds.Contain
The above-mentioned nitrogen Activities of Arylacrylamide Compounds of various substituents can largely be prepared according to the method for following document reports：Wu,
Tao. Mu, Xin. Liu,Guosheng. Angew. Chem., Int. Ed. 2011, 130, 12578–12581.Institute
With any one of radical initiator/oxidant in following compounds：DCP (cumyl peroxide), DTBP（Peroxide
Change di-t-butyl）、TBHP（TBHP, the organic phase of 5.0M-6.0M concentration）、BPO（Benzoyl peroxide）、30%
Hydrogen peroxide, iodobenzene diacetate.Any one of solvent for use in following compounds：Chlorobenzene, face difluorobenzene, fluorobenzene, face two
Chlorobenzene, toluene, benzene, 1,2- dichloroethanes.
The dosage of the radical initiator/oxidant is the 50- of the mole dosage of compound shown in Formula II general structure
250%, the dosage of fatty aldehyde is the 100%-500% of the mole dosage of compound shown in Formula II general structure.In addition, the addition-
The reaction temperature of rearrangement reaction is 80-150 DEG C, and the reaction time is 0.1-120 hours.
Raw material nitrogen Activities of Arylacrylamide Compounds used in the present invention is easily largely prepared and stablized at room temperature easy
Preserve, secondly, aldehyde wide variety and cheap and easy to get is translated into alkyl diradical, and used by radical mechanism
In decarburization-addition reaction of unsaturated multiple bond, a kind of construction method of brand-new, economic, environment-friendly carbon-carbon bond will be established；
Any metallic catalyst is not used, it is environment-friendly；Reaction condition is gentleer, and productivity ratio is higher, the easily separated purifying of product.
Embodiment
With reference to specific embodiment, the invention will be further described, but the present invention is not limited to following examples.
Embodiment 1
Polysubstituted indole-2-ketone compound shown in formula Ia general structures, the reaction equation are as follows:
Formula II a Formulas I a
Specifically preparation method is：Under the conditions of air at room temperature, magnetic is sequentially added into drying, clean 5ml glass reaction tubes
Son, the N-methyl pyridyl acrylamide shown in Formula II a structural formulas（35mg, 0.2mmol）, add the chlorobenzene of molecular sieve drying
1.5ml, special valeral is added after dissolving completely（51.6mg 0.6mmol）, it is eventually adding DCP（54mg, 0.2mmol）1300C is anti-
After answering 12 hours, reaction system is cooled to room temperature, and thin-layer chromatographic analysis show that raw material II a consumption is complete.Directly use 200-300 mesh
The mixed solvent of silica gel column chromatography, ethyl acetate and petroleum ether（1：8）Elution.Separate to obtain compound shown in Formulas I a structural formulas
35.1mg, yield 76%；
The product is faint yellow solid；Fusing point mp：104-1050C；
1H NMR (400 MHz, CDCl3) δ 7.26 (t, J = 7.2 Hz, 1H), 7.20 (d, J = 6.8
Hz, 1H), 7.03 (t, J = 7.2 Hz, 1H), 6.85 (d, J = 7.6Hz, 1H), 3.22 (s, 4H),
2.16 (d, J = 14.4 Hz, 1H), 1.86 (d, J = 14.4 Hz, 1H), 1.29 (s, 3H), 0.61 (s,
9H).
13C NMR (101 MHz, CDCl3) δ 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.
Elemental Analysis: C15H21NO:C, 77.88; H, 9.15; N, 6.05; O, 6.92。
Embodiment 2
Polysubstituted indole-2-ketone compound shown in formula Ia general structures, the reaction equation are as follows:
Formula II a Formulas I a
Specifically preparation method is：Under the conditions of air at room temperature, magnetic is sequentially added into drying, clean 5ml glass reaction tubes
Son, the N-methyl pyridyl acrylamide shown in Formula II a structural formulas（35mg, 0.2mmol）, add the chlorobenzene of molecular sieve drying
1.5ml, special valeral is added after dissolving completely（51.6mg 0.6mmol）, it is eventually adding TBHP（34mg, 0.2mmol）1300C is anti-
After answering 12 hours, reaction system is cooled to room temperature, and thin-layer chromatographic analysis show that raw material II a consumption is complete.Directly use 200-300 mesh
The mixed solvent of silica gel column chromatography, ethyl acetate and petroleum ether（1：8）Elution.Separate to obtain compound shown in Formulas I a structural formulas
35.1mg, yield 76%；Compound structure analyzes and identifies data consistent with Example 1.
Embodiment 3
Polysubstituted indole-2-ketone compound shown in formula Ia general structures, the reaction equation are as follows：
Formula II a Formulas I a
Specifically preparation method is：Under the conditions of air at room temperature, magnetic is sequentially added into drying, clean 5ml glass reaction tubes
Son, the N-methyl pyridyl acrylamide shown in Formula II a structural formulas（35mg, 0.2mmol）, add the chlorobenzene of molecular sieve drying
1.5ml, special valeral is added after dissolving completely（51.6mg 0.6mmol）, it is eventually adding BPO（48.4mg, 0.2mmol）1300C
After reaction 12 hours, reaction system is cooled to room temperature, and thin-layer chromatographic analysis show that raw material II a consumption is complete.Directly use 200-300
The mixed solvent of mesh silica gel column chromatography, ethyl acetate and petroleum ether（1：8）Elution.Separate to obtain compound shown in Formulas I a structural formulas
33.2mg, yield 72%；Compound structure analyzes and identifies data consistent with Example 1.
Embodiment 4
Polysubstituted indole-2-ketone compound shown in formula Ia general structures, the reaction equation are as follows：
Formula II a Formulas I a
Specifically preparation method is：Under the conditions of air at room temperature, magnetic is sequentially added into drying, clean 5ml glass reaction tubes
Son, the N-methyl pyridyl acrylamide shown in Formula II a structural formulas（35mg, 0.2mmol）, add the chlorobenzene of molecular sieve drying
1.5ml, special valeral is added after dissolving completely（51.6mg 0.6mmol）, it is eventually adding TBP（29.2mg, 0.2mmol）1300C
After reaction 12 hours, reaction system is cooled to room temperature, and thin-layer chromatographic analysis show that raw material II a consumption is complete.Directly use 200-300
The mixed solvent of mesh silica gel column chromatography, ethyl acetate and petroleum ether（1：8）Elution.Separate to obtain compound shown in Formulas I a structural formulas
35.1mg, yield 76%；Compound structure analyzes and identifies data consistent with Example 1.
Embodiment 5
Polysubstituted indole-2-ketone compound shown in formula Ia general structures, the reaction equation are as follows：
Formula II a Formulas I a
Specifically preparation method is：Under the conditions of air at room temperature, magnetic is sequentially added into drying, clean 5ml glass reaction tubes
Son, the N-methyl pyridyl acrylamide shown in Formula II a structural formulas（35mg, 0.2mmol）, add the chlorobenzene of molecular sieve drying
1.5ml, special valeral is added after dissolving completely（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 show that raw material II a consumption is complete.
Directly use the mixed solvent of 200-300 mesh silica gel column chromatographies, ethyl acetate and petroleum ether（1：8）Elution.Separate to obtain Formulas I a structures
Compound 34.2mg shown in formula, yield 74%；Compound structure analyzes and identifies data consistent with Example 1.
Embodiment 6
Polysubstituted indole-2-ketone compound shown in formula Ia general structures, the reaction equation are as follows：
Formula II a Formulas I a
Specifically preparation method is：Under the conditions of air at room temperature, magnetic is sequentially added into drying, clean 5ml glass reaction tubes
Son, the N-methyl pyridyl acrylamide shown in Formula II a structural formulas（35mg, 0.2mmol）, add the fluorobenzene of molecular sieve drying
1.5ml, special valeral is added after dissolving completely（51.6mg 0.6mmol）, it is eventually adding TBP（29.2mg, 0.2mmol）1300C
After reaction 12 hours, reaction system is cooled to room temperature, and thin-layer chromatographic analysis show that raw material II a consumption is complete.Directly use 200-300
The mixed solvent of mesh silica gel column chromatography, ethyl acetate and petroleum ether（1：8）Elution.Separate to obtain compound shown in Formulas I a structural formulas
31.0mg, yield 67%；Compound structure analyzes and identifies data consistent with Example 1.
Embodiment 7
Polysubstituted indole-2-ketone compound shown in formula Ia general structures, the reaction equation are as follows：
Formula II a Formulas I a
Specifically preparation method is：Under the conditions of air at room temperature, magnetic is sequentially added into drying, clean 5ml glass reaction tubes
Son, the N-methyl pyridyl acrylamide shown in Formula II a structural formulas（35mg, 0.2mmol）, add the toluene of molecular sieve drying
1.5ml, special valeral is added after dissolving completely（51.6mg 0.6mmol）, it is eventually adding TBP（29.2mg, 0.2mmol）1300C
After reaction 12 hours, reaction system is cooled to room temperature, and thin-layer chromatographic analysis show that raw material II a consumption is complete.Directly use 200-300
The mixed solvent of mesh silica gel column chromatography, ethyl acetate and petroleum ether（1：8）Elution.Separate to obtain compound shown in Formulas I a structural formulas
28.6mg, yield 62%；Compound structure analyzes and identifies data consistent with Example 1.
Embodiment 8
Polysubstituted indole-2-ketone compound shown in formula Ia general structures, the reaction equation are as follows：
Formula II a Formulas I a
Specifically preparation method is：Under the conditions of air at room temperature, magnetic is sequentially added into drying, clean 5ml glass reaction tubes
Son, the N-methyl pyridyl acrylamide shown in Formula II a structural formulas（35mg, 0.2mmol）, add molecular sieve drying
DCE1.5ml, special valeral is added after dissolving completely（51.6mg 0.6mmol）, it is eventually adding TBP（29.2mg, 0.2mmol）
After 1300C reacts 12 hours, reaction system is cooled to room temperature, and thin-layer chromatographic analysis show that raw material II a consumption is complete.Directly use
The mixed solvent of 200-300 mesh silica gel column chromatographies, ethyl acetate and petroleum ether（1：8）Elution.Separate shown in Formulas I a structural formulas
Compound 31.0mg, yield 67%；Compound structure analyzes and identifies data consistent with Example 1.
Embodiment 9
Polysubstituted indole-2-ketone compound shown in formula Ia general structures, the reaction equation are as follows：
Formula II a Formulas I a
Specifically preparation method is：Under the conditions of air at room temperature, magnetic is sequentially added into drying, clean 5ml glass reaction tubes
Son, the N-methyl pyridyl acrylamide shown in Formula II a structural formulas（35mg, 0.2mmol）, add the benzene of molecular sieve drying
1.5ml, special valeral is added after dissolving completely（51.6mg 0.6mmol）, it is eventually adding TBP（29.2mg, 0.2mmol）1300C
After reaction 12 hours, reaction system is cooled to room temperature, and thin-layer chromatographic analysis show that raw material II a consumption is complete.Directly use 200-300
The mixed solvent of mesh silica gel column chromatography, ethyl acetate and petroleum ether（1：8）Elution.Separate to obtain compound shown in Formulas I a structural formulas
31.0mg, yield 67%；Compound structure analyzes and identifies data consistent with Example 1.
Embodiment 10
Polysubstituted indole-2-ketone compound shown in formula Ia general structures, the reaction equation are as follows：
Formula II a Formulas I a
Specifically preparation method is：Under the conditions of air at room temperature, magnetic is sequentially added into drying, clean 5ml glass reaction tubes
Son, the N-methyl pyridyl acrylamide shown in Formula II a structural formulas（35mg, 0.2mmol）, add the benzene of molecular sieve drying
1.5ml, special valeral is added after dissolving completely（51.6mg 0.6mmol）, it is eventually adding TBP（29.2mg, 0.2mmol）1000C
After reaction 12 hours, reaction system is cooled to room temperature, and thin-layer chromatographic analysis show that raw material II a consumption is complete.Directly use 200-300
The mixed solvent of mesh silica gel column chromatography, ethyl acetate and petroleum ether（1：8）Elution.Separate to obtain compound shown in Formulas I a structural formulas
31.0mg, yield 67%；Compound structure analyzes and identifies data consistent with Example 1.
Embodiment 11
Polysubstituted indole-2-ketone compound shown in formula Ia general structures, the reaction equation are as follows：
Formula II a Formulas I a
Specifically preparation method is：Under the conditions of air at room temperature, magnetic is sequentially added into drying, clean 5ml glass reaction tubes
Son, the N-methyl pyridyl acrylamide shown in Formula II a structural formulas（35mg, 0.2mmol）, add the benzene of molecular sieve drying
1.5ml, special valeral is added after dissolving completely（51.6mg 0.6mmol）, it is eventually adding TBP（29.2mg, 0.2mmol）1200C
After reaction 12 hours, reaction system is cooled to room temperature, and thin-layer chromatographic analysis show that raw material II a consumption is complete.Directly use 200-300
The mixed solvent of mesh silica gel column chromatography, ethyl acetate and petroleum ether（1：8）Elution.Separate to obtain compound shown in Formulas I a structural formulas
30.5mg, yield 66%；Compound structure analyzes and identifies data consistent with Example 1.
Embodiment 12
Polysubstituted indole-2-ketone compound shown in formula Ia general structures, the reaction equation are as follows：
Formula II a Formulas I a
Specifically preparation method is：Under the conditions of air at room temperature, magnetic is sequentially added into drying, clean 5ml glass reaction tubes
Son, the N-methyl pyridyl acrylamide shown in Formula II a structural formulas（35mg, 0.2mmol）, add the benzene of molecular sieve drying
1.5ml, special valeral is added after dissolving completely（51.6mg 0.6mmol）, it is eventually adding TBP（29.2mg, 0.2mmol）1500C
After reaction 12 hours, reaction system is cooled to room temperature, and thin-layer chromatographic analysis show that raw material II a consumption is complete.Directly use 200-300
The mixed solvent of mesh silica gel column chromatography, ethyl acetate and petroleum ether（1：8）Elution.Separate to obtain compound shown in Formulas I a structural formulas
30.0mg, yield 65%；Compound structure analyzes and identifies data consistent with Example 1.
Embodiment 13
Polysubstituted indole-2-ketone compound shown in formula Ia general structures, the reaction equation are as follows：
Formula II a Formulas I a
Specifically preparation method is：Under the conditions of air at room temperature, magnetic is sequentially added into drying, clean 5ml glass reaction tubes
Son, the N-methyl pyridyl acrylamide shown in Formula II a structural formulas（35mg, 0.2mmol）, add the chlorobenzene of molecular sieve drying
1.5ml, special valeral is added after dissolving completely（17.2mg 0.2mmol）, it is eventually adding TBP（29.2mg, 0.2mmol）1300C
After reaction 12 hours, reaction system is cooled to room temperature, and thin-layer chromatographic analysis show that raw material II a consumption is complete.Directly use 200-300
The mixed solvent of mesh silica gel column chromatography, ethyl acetate and petroleum ether（1：8）Elution.Separate to obtain compound shown in Formulas I a structural formulas
24.9mg, yield 54%；Compound structure analyzes and identifies data consistent with Example 1.
Embodiment 14
Polysubstituted indole-2-ketone compound shown in formula Ia general structures, the reaction equation are as follows：
Formula II a Formulas I a
Specifically preparation method is：Under the conditions of air at room temperature, magnetic is sequentially added into drying, clean 5ml glass reaction tubes
Son, the N-methyl pyridyl acrylamide shown in Formula II a structural formulas（35mg, 0.2mmol）, add the chlorobenzene of molecular sieve drying
1.5ml, special valeral is added after dissolving completely（86.0mg 1mmol）, it is eventually adding TBP（29.2mg, 0.2mmol）1300C is anti-
After answering 12 hours, reaction system is cooled to room temperature, and thin-layer chromatographic analysis show that raw material II a consumption is complete.Directly use 200-300 mesh
The mixed solvent of silica gel column chromatography, ethyl acetate and petroleum ether（1：8）Elution.Separate to obtain compound shown in Formulas I a structural formulas
35.6mg, yield 77%；Compound structure analyzes and identifies data consistent with Example 1.
Embodiment 15
Polysubstituted indole-2-ketone compound shown in formula Ia general structures, the reaction equation are as follows：
Formula II a Formulas I a
Specifically preparation method is：Under the conditions of air at room temperature, magnetic is sequentially added into drying, clean 5ml glass reaction tubes
Son, the N-methyl pyridyl acrylamide shown in Formula II a structural formulas（35mg, 0.2mmol）, add the chlorobenzene of molecular sieve drying
1.5ml, special valeral is added after dissolving completely（51.6mg 0.6mmol）, it is eventually adding TBP（14.6mg, 0.1mmol）1300C
After reaction 12 hours, reaction system is cooled to room temperature, and thin-layer chromatographic analysis show that raw material II a consumption is complete.Directly use 200-300
The mixed solvent of mesh silica gel column chromatography, ethyl acetate and petroleum ether（1：8）Elution.Separate to obtain compound shown in Formulas I a structural formulas
28.2mg, yield 61%；Compound structure analyzes and identifies data consistent with Example 1.
Embodiment 16
Polysubstituted indole-2-ketone compound shown in formula Ia general structures, the reaction equation are as follows：
Formula II a Formulas I a
Specifically preparation method is：Under the conditions of air at room temperature, magnetic is sequentially added into drying, clean 5ml glass reaction tubes
Son, the N-methyl pyridyl acrylamide shown in Formula II a structural formulas（35mg, 0.2mmol）, add the chlorobenzene of molecular sieve drying
1.5ml, special valeral is added after dissolving completely（51.6mg 0.6mmol）, it is eventually adding TBP（71.5mg, 5mmol）1300C is anti-
After answering 12 hours, reaction system is cooled to room temperature, and thin-layer chromatographic analysis show that raw material II a consumption is complete.Directly use 200-300 mesh
The mixed solvent of silica gel column chromatography, ethyl acetate and petroleum ether（1：8）Elution.Separate to obtain compound shown in Formulas I a structural formulas
34.2mg, yield 74%；Compound structure analyzes and identifies data consistent with Example 1.
Embodiment 17
Polysubstituted indole-2-ketone compound shown in formula Ia general structures, the reaction equation are as follows：
Formula II a Formulas I a
Specifically preparation method is：Under the conditions of air at room temperature, magnetic is sequentially added into drying, clean 5ml glass reaction tubes
Son, the N-methyl pyridyl acrylamide shown in Formula II a structural formulas（35mg, 0.2mmol）, add the chlorobenzene of molecular sieve drying
1.5ml, special valeral is added after dissolving completely（51.6mg 0.6mmol）, it is eventually adding TBP（29.2mg, 0.2mmol）800C is anti-
After answering 12 hours, reaction system is cooled to room temperature, and thin-layer chromatographic analysis show that raw material II a consumption is complete.Directly use 200-300 mesh
The mixed solvent of silica gel column chromatography, ethyl acetate and petroleum ether（1：8）Elution.Separate to obtain compound shown in Formulas I a structural formulas
26.3mg, yield 52%；Compound structure analyzes and identifies data consistent with Example 1.
Embodiment 18
Polysubstituted indole-2-ketone compound shown in formula Ia general structures, the reaction equation are as follows：
Formula II a Formulas I a
Specifically preparation method is：Under the conditions of air at room temperature, magnetic is sequentially added into drying, clean 5ml glass reaction tubes
Son, the N-methyl pyridyl acrylamide shown in Formula II a structural formulas（35mg, 0.2mmol）, add the chlorobenzene of molecular sieve drying
1.5ml, special valeral is added after dissolving completely（51.6mg 0.6mmol）, it is eventually adding TBP（29.2mg, 0.2mmol）1500C
After reaction 12 hours, reaction system is cooled to room temperature, and thin-layer chromatographic analysis show that raw material II a consumption is complete.Directly use 200-300
The mixed solvent of mesh silica gel column chromatography, ethyl acetate and petroleum ether（1：8）Elution.Separate to obtain compound shown in Formulas I a structural formulas
34.6mg, yield 75%；Compound structure analyzes and identifies data consistent with Example 1.
Embodiment 19
Polysubstituted indole-2-ketone compound shown in formula Ia general structures, the reaction equation are as follows：
Formula II a Formulas I a
Specifically preparation method is：Under the conditions of air at room temperature, magnetic is sequentially added into drying, clean 5ml glass reaction tubes
Son, the N-methyl pyridyl acrylamide shown in Formula II a structural formulas（35mg, 0.2mmol）, add the chlorobenzene of molecular sieve drying
1.5ml, special valeral is added after dissolving completely（51.6mg 0.6mmol）, it is eventually adding TBP（29.2mg, 0.2mmol）1300C
After reaction 0.1 hour, reaction system is cooled to room temperature, and thin-layer chromatographic analysis show that raw material II a consumption is complete.Directly use 200-
The mixed solvent of 300 mesh silica gel column chromatographies, ethyl acetate and petroleum ether（1：8）Elution.Separate to obtain chemical combination shown in Formulas I a structural formulas
Thing 5.5mg, yield 12%；Compound structure analyzes and identifies data consistent with Example 1.
Embodiment 20
Polysubstituted indole-2-ketone compound shown in formula Ia general structures, the reaction equation are as follows：
Formula II a Formulas I a
Specifically preparation method is：Under the conditions of air at room temperature, magnetic is sequentially added into drying, clean 5ml glass reaction tubes
Son, the N-methyl pyridyl acrylamide shown in Formula II a structural formulas（35mg, 0.2mmol）, add the chlorobenzene of molecular sieve drying
1.5ml, special valeral is added after dissolving completely（51.6mg 0.6mmol）, it is eventually adding TBP（29.2mg, 0.2mmol）1300C
After reaction 120 hours, reaction system is cooled to room temperature, and thin-layer chromatographic analysis show that raw material II a consumption is complete.Directly use 200-
The mixed solvent of 300 mesh silica gel column chromatographies, ethyl acetate and petroleum ether（1：8）Elution.Separate to obtain chemical combination shown in Formulas I a structural formulas
Thing 34.2mg, yield 74%；Compound structure analyzes and identifies data consistent with Example 1.
According to the operating method described in embodiment 3, the present invention has also synthesized following compound：
It shown below is the chemical structure analysis data of section Example compound of the present invention：
Embodiment 21
New penta indol-2-ones of the fluoro- 1,3- dimethyl -3- of 5-
M.p. 121-123 C;1H NMR (400 MHz, CDCl3) δ 6.981-6.937 (m,2H), 6.76
(dd, J = 8.0, 4.0 Hz, 1H), 3.21 (s, 3H), 2.16 (d, J = 14.4 Hz, 1H), 1.82 (d,
J = 14.4 Hz, 1H), 1.29 (s, 3H), 0.63 (s, 9H).
13C NMR (101 MHz, CDCl3) δ 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.
Elemental Analysis: C15H20FNO: C, 72.26; H, 8.09; F, 7.62; N, 5.62;
O, 6.42。
Embodiment 25
New penta indol-2-ones of 1,3,5- trimethyls -3-
M.p. 120-121 C;1H NMR (400 MHz, CDCl3) δ 7.05 (d, J = 8.0 Hz, 1H),
7.01 (s, 1H), 6.73 (d, J = 8.0 Hz, 1H), 3.20 (s, 3H), 2.34 (s, 3H), 2.14 (d,
J = 14.4 Hz, 1H), 1.83 (d, J = 14.4 Hz, 1H), 1.28 (s, 3H), 0.61 (s, 9H).
13C NMR (101 MHz, CDCl3) δ 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.
Elemental Analysis: C16H23NO:C, 78.32; H, 9.45; N, 5.71; O, 6.52。
Embodiment 28
1,3- dimethyl -3- neopentyls -5-（Trifluoromethyl）Indol-2-one
1H NMR (400 MHz, CDCl3) δ 7.55 (d, J = 8.0 Hz, 1H), 7.42 (s, 1H),
6.91 (d, J = 8.0 Hz, 1H), 3.25 (s, 3H), 2.19 (d, J = 14.4 Hz, 1H), 1.89 (d, J
= 14.4 Hz, 1H), 1.32 (s, 3H), 0.60 (s, 9H).
13CNMR (101 MHz, CDCl3) δ 181.04 , 181.04 , 145.97 , 135.02 , 131.36 –
131.16 (m), 126.01 , 125.49 (q, J = 3.9 Hz), 124.67 , 124.35 , 123.31 ,
121.02 (q, J = 3.6 Hz), 107.87 , 50.98 , 47.53 , 31.92 , 30.93 , 28.26 ,
26.58 .
Elemental Analysis: C16H20F3NO:C, 64.20; H, 6.73; F, 19.04; N, 4.68;
O, 5.35。
Embodiment 29
New penta indol-2-ones of the chloro- 1,3- dimethyl -3- of 7-
1H NMR (400 MHz, CDCl3) δ 7.18 (d, J = 7.6Hz, 1H), 7.07 (d, J = 6.8
Hz, 1H), 6.93 (t, J = 7.6 Hz, 1H), 3.59 (s, 3H), 2.15 (d, J = 14.4 Hz, 1H),
1.83 (d, J = 14.3 Hz, 1H), 1.28 (s, 3H), 0.62 (s, 9H).
13C NMR (101 MHz, CDCl3) δ 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.
Elemental Analysis: C15H20ClNO:C, 67.79; H, 7.58; Cl, 13.34; N, 5.27;
O, 6.02。
Embodiment 30
New penta indol-2-ones of the chloro- 1,3- dimethyl -3- of 6,7- bis-
M.p. 75-76 C;1H NMR (400 MHz, CDCl3) δ 7.14 (d, J = 8.0 Hz, 1H), 7.01
(d, J = 7.6Hz, 1H), 3.62 (s, 3H), 2.16 (d, J = 14.4 Hz, 1H), 1.82 (d, J =
14.4 Hz, 1H), 1.27 (s, 3H), 0.63 (s, 9H).
13C NMR (101 MHz, CDCl3) δ 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.
Elemental Analysis: 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. 103-104 C;1H NMR (400 MHz, CDCl3) δ 7.52 (t, J = 7.6 Hz, 2H),
7.40 (dd, J = 13.6, 7.6 Hz, 3H), 7.27 (d, J = 7.6 Hz, 1H), 7.18 (t, J = 7.6
Hz, 1H), 7.07 (t, J = 7.6 Hz, 1H), 6.86 (d, J = 8.0 Hz, 1H), 2.25 (d, J =
14.4 Hz, 1H), 1.95 (d, J = 14.4 Hz, 1H), 1.42 (s, 3H), 0.73 (s, 9H).
13C NMR (101 MHz, CDCl3) δ 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.
Elemental Analysis: C20H23NO:C, 81.87; H, 7.90; N, 4.77; O, 5.45。
Embodiment 33
New penta indol-2-ones of 1- ethyl -3- methyl -3-
M.p. 60-61 C;1H NMR (400 MHz, CDCl3) δ 7.22 (dd, J = 13.6, 8.0 Hz,
2H), 7.02 (t, J = 7.6 Hz, 1H), 6.87 (d, J = 7.6 Hz, 1H), 3.915-3.826(m, 1H),
3.730-3.641 (m,1H),2.16 (d, J = 14.4 Hz, 1H), 1.86 (d, J = 14.4 Hz, 1H), 1.36
– 1.20 (m, 3H), 0.63 (s, 9H).
13C NMR (101 MHz, CDCl3) δ 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.
Elemental Analysis: C16H23NO: C, 78.32; H, 9.45; N, 5.71; O, 6.52。
Embodiment 35
3-（Methoxy）New penta indol-2-ones of -1- methyl -3-
M.p. 73-74 C;1H NMR (400 MHz, CDCl3) δ 7.30 – 7.27 (m, 2H), 7.03 (t,
J = 7.6 Hz, 1H), 6.84 (d, J = 8.0 Hz, 1H), 3.54 (d, J = 8.4 Hz, 1H), 3.44 (d,
J = 8.8 Hz, 1H), 3.20 (d, J = 16.4 Hz, 6H), 2.02 (d, J = 14.0 Hz, 1H), 1.92
(d, J = 14.4 Hz, 1H), 0.62 (s, 9H).
13C NMR (101 MHz, DMSO) δ 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.
Elemental Analysis: C16H23NO2:C, 73.53; H, 8.87; N, 5.36; O, 12.24。
Embodiment 37
The different tert-butyl group -1,3- dimethyl -2- the indol-2-ones of 3-
1H NMR (400 MHz, CDCl3) δ 7.26 (t, J = 7.6 Hz, 1H), 7.16 (d, J = 7.2
Hz, 1H), 7.06 (t, J = 7.6 Hz,1H), 6.84 (d, J = 7.6Hz, 1H), 3.22 (s, 3H), 1.94
(dd, J =14.0, 7.6 Hz, 1H), 1.76 (dd, J = 14, 5.6 Hz, 1H), 1.32 (s, 3H), 1.24
(m, 1H), 0.65 (d, J = 6.8 Hz, 3H), 0.61 (d, J = 6.4 Hz, 3H).
13C NMR (101 MHz, CDCl3) δ 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.
Elemental Analysis: C14H19NO: C, 77.38; H, 8.81; N, 6.45; O, 7.36。
Embodiment 40
3-（Cyclohexyl methyl）- 1,3- dimethyl indole -2- ketone
1H NMR (400 MHz, CDCl3) δ 7.26 (s, 1H), 7.15 (d, J = 6.4 Hz, 1H),
7.06 (d, J = 6.4 Hz, 1H), 6.84 (d, J = 6.8 Hz, 1H), 3.22 (s, 3H), 1.92 (dd, J
= 13.6, 6.0 Hz, 1H), 1.72 (d, J = 13.6 Hz, 1H), 1.46 (d, J = 9.2 Hz, 3H),
1.31 (s, 3H), 1.20 (d, J = 12.4 Hz, 1H), 1.09 – 0.65 (m, 7H).
13C NMR(101 MHz, CDCl3) δ181.27, 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.
Elemental Analysis: C17H23NO: C, 79.33; H, 9.01; N, 5.44; O, 6.22。
Embodiment 42
1,3- dimethyl -3- phenethyl indol-2-ones
1H NMR (400 MHz, CDCl3) δ 7.29 (dd, J = 15.8,7.6 Hz, 1H), 7.21 (dd, J
= 13.6,6.8 Hz, 3H), 7.12 (dd, J = 14.8, 7.2 Hz, 2H), 7.02 (d, J = 7.2 Hz,
2H), 6.87 (d, J = 7.6Hz, 1H), 3.21 (s, 3H), 2.43 – 2.20 (m, 2H), 2.19 – 2.08
(m, 1H), 2.07 – 1.91 (m, 1H), 1.40 (s, 3H).
13C NMR (101 MHz, CDCl3) δ 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.
Elemental Analysis: C18H19NO: C, 81.47; H, 7.22; N, 5.28; O, 6.03。
Claims (3)
1. a kind of method for preparing polysubstituted indole-2-ketone compound, this method is in certain reaction temperature and reaction
Under the conditions of time and oxidant/radical initiator are existing, alkyl diradical and Formula II structure that special valeral decarbonylation is formed
Free radical addition and cascade reaction occur in a solvent for the nitrogen Activities of Arylacrylamide Compounds shown in formula, obtain polysubstituted
Indole-2-ketone compound, R1 are selected from methyl, fluorine, chlorine, bromine, iodine, methoxyl group, trifluoromethyl, phenyl；R2 is selected from methyl, benzyl
Base, phenyl, ethyl；R3 is selected from hydrogen atom, methoxyl group, acetate groups, and the oxidant/radical initiator is selected from following chemical combination
Thing：Cumyl peroxide (DCP), TBHP (TBHP), di-t-butyl peroxide (DTBP), benzoyl peroxide
(BPO), 30% hydrogen peroxide, iodobenzene diacetate, any one of the solvent in following compounds：Chlorobenzene, o-difluoro-benzene,
Fluorobenzene, o-dichlorohenzene, toluene, benzene, 1,2- dichloroethanes, the reaction temperature are 80-150 DEG C, and the reaction time is 0.1-120
Hour, the structural formula of the special valeral is formula III, and the structural formula of the polysubstituted indole-2-ketone compound is formula IV,
A kind of 2. method for preparing polysubstituted indole-2-ketone compound according to claim 1, it is characterised in that institute
The dosage for stating special valeral is the 100%-500% of the mole dosage of compound shown in Formula II general structure.
A kind of 3. method for preparing polysubstituted indole-2-ketone compound according to claim 1, it is characterised in that institute
The dosage for stating oxidant/radical initiator is the 50%-250% of the mole dosage of compound shown in Formula II general structure.
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