CN109503595A - The method of level-one amine guiding building 10- methoxyl group -6- Phenylindole simultaneously [1,2-a] quinoxaline - Google Patents

The method of level-one amine guiding building 10- methoxyl group -6- Phenylindole simultaneously [1,2-a] quinoxaline Download PDF

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CN109503595A
CN109503595A CN201811576524.XA CN201811576524A CN109503595A CN 109503595 A CN109503595 A CN 109503595A CN 201811576524 A CN201811576524 A CN 201811576524A CN 109503595 A CN109503595 A CN 109503595A
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methoxyl group
quinoxaline
reaction
indoles
base
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蒋光彬
王守才
及方华
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Guilin University of Technology
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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Abstract

The invention discloses a kind of level-one amine to be oriented to building 10- methoxyl group -6- Phenylindole simultaneously [1,2-a] quinoxaline method.In reaction tube, 2- (6- methoxyl group -1 is addedHIndoles -1- base) aniline and benzoyl formic acid be raw material, 10- methoxyl group -6- Phenylindole simultaneously [1,2- is made in high yield through acylation/cyclizationa] quinoxaline.The present invention, for seamless guiding base, increases the step economy of reaction with level-one amine；And the raw materials required for the reaction is cheap and easy to get, mild condition and easy to operate, and selectivity is single, and separation yield is high, is conducive to industrialized production, meets the development need of green organic chemistry.

Description

Level-one amine guiding building 10- methoxyl group -6- Phenylindole simultaneously [1,2-a] quinoxaline Method
Technical field
The present invention relates to medication chemistry synthesis technical fields, and in particular to a kind of level-one amine guiding building 10- methoxyl group- The method of 6- Phenylindole simultaneously [1,2-a] quinoxaline.
Background technique
Organometallic Chemistry has obtained unprecedented development in recent years, becomes building carbon-carbon bond and the important hand of carbon-heterodesmic Section.The C-H function dough reaction of homing device auxiliary has obtained the wide of scientists because of its good selectivity and reactivity General concern.A series of nitrogenous guiding bases are reacted by Successful utilization in C-H function dough after decades of development, they include Level-one amine, pyridine, amide, imines, oxime, enamine and various nitrogen-containing heterocycles.It is worth noting that, level-one amine is realized as guiding base The report of C-H functionalization is considerably less, because level-one amine has very strong sequestering power, it is easy to catalyst poisoning be caused to be lost It is living, it is achieved that the C-H functionalization of level-one amine guiding has very big challenge.Currently, utilizing transition metal-catalyzed level-one Amine guiding strategy is successfully realized alkenyl, alkynyl, arylation and cyclization (Lazareva, A.；Daugulis O.Org.Lett.,2006,8,5211-5213；Liang,D.；Hu,Z.；Peng,J.；et al.Chem.Commun.,2013, 49,173-175；Liang,Z.；Feng,R.；Yin,H.；et al.Org.Lett.,2013,15,4544-4547；Bai,P.； Huang X.-F.；Xu,G.-D.；et al.Org.Lett.,2016,18,3058-3061；Suzuki,C.；Hirano,K.； Satoh,T.；et al.Org.Lett.,2013,15,3990-3993；Liang,Z.；Ju,L.；Xie,Y.；et al.Chem.Eur.J.,2012,18,15816-15821；Jiang,G.；Hu,W.；Zhu,C.；et al.Chem.Commun., 2018,54,1746-1749.)；But level-one amine is used to realize that acylation/cyclization strategy never has for seamless guiding base It is reported.Therefore, realize that acylation/cyclization of level-one amine guiding has very important researching value.
Quinoxaline derivant is important nitrogenous compound, the activity with antitumor, antimycotic and AntiHIV1 RT activity etc., It can also be used as angiotensin receptor inhibitor (Patel, M.；Mc Hugh,R.J.；Cordova,B.C.；Klabe,R.M.； Erickson-Vitanen,S.；Trainor,G.L.；Rodger,J.D.Bioorg.Med.Chem.Lett.2000,10, 1729-1731；Guillon,J.；Dallemagne,P.；Pfeiffer,B.；Renard,P.；Manechez,D.；Kervran, A.；Rault,S.Eur.J.Med.Chem.1998,33,293-308；Ramamohan,M.；Sridhar,R.； Raghavendrarao,K.；Paradesi,N.；Chandrasekhar,K.B.；Jayaprakash,S.Synlett,2015, 26,1096-1100), at the same they be also some natural products important component.Because of the importance of this kind of compound, Scientists have put into a large amount of energy and have carried out synthesizing quinoxaline derivant, after decades of development, achieve plentiful and substantial research Achievement, but simultaneously its synthetic method is very limited as important quinoxaline derivant for [1,2-a] quinoxaline compounds for indoles. (Xie,C.；Feng,L.；Li,W.；Ma,X.；Ma,X.；Liu,Y.；Ma,C.Org.Biomol.Chem.2016,14,8529- 8535；Rubio-Presa,R.；Pedrosa,M.；Fernández-Rodríguez,Arnáiz,F.；Sanz, R.Org.Lett.2017,19,5470-5473；Ramamohan,M.；Sridhar,R.；Raghavendrarao,K.； Paradesi,N.；Chandrasekhar,K.B.；Jayaprakash,S.Synlett,2015,26,1096-1100).And There are reaction temperatures in reaction known to these, and high, substrate was difficult in place of the deficiencies of preparing.Here, we have invented a kind of palladiums It is catalyzed the new method of level-one amine guiding synthesis 10- methoxyl group -6- Phenylindole simultaneously [1,2-a] quinoxaline.This method reaction condition Simply, required raw material is cheap and easy to get, and preparation condition is mild, easy to operate, and selectivity is single, and separation yield is high, is conducive to industry Metaplasia produces, and has in the research and development of drug and the synthesis of natural products and has been widely used.
Summary of the invention
The object of the present invention is to provide a kind of level-one amine to be oriented to building 10- methoxyl group -6- Phenylindole simultaneously [1,2-a] quinoline The method of quinoline.
Thinking of the invention: using 2- (6- methoxyl group -1H- indoles -1- base) aniline, benzoyl formic acid as raw material, persulfuric acid Salt is oxidant, under the catalysis of palladium salt, continuous acylation/cyclization occurs, step building has pharmaceutical activity skeleton Compound 10- methoxyl group -6- Phenylindole simultaneously [1,2-a] quinoxaline.This method avoid the use of the additives such as acid, alkali, Raw materials required for the reaction is cheap and easy to get, and reaction condition is mild, easy to operate, and selectivity is single, and step economy is high, has potential Practical value.
Specific steps are as follows:
2- (6- methoxyl group -1H- indoles -1- base) aniline and benzoyl formic acid are sequentially added, in reaction flask with persulfuric acid Salt is oxidant, using palladium salt as catalyst, using organic solvent as solvent, is stirred 10~24 hours at 70~90 DEG C, reaction knot It is cooled to room temperature after beam, filtering reacting liquid, crude product is obtained after vacuum rotary steam, obtains compound 10- methoxyl group-through column chromatographic purifying 6- Phenylindole simultaneously [1,2-a] quinoxaline.
The molar ratio of 2- (6- methoxyl group -1H- indoles -1- base) aniline and benzoyl formic acid is 1:1~2.
The oxidant is potassium peroxydisulfate, sodium peroxydisulfate or ammonium persulfate；Oxidant and 2- (6- methoxyl group -1H- indoles - 1- yl) aniline molar ratio be 1~2:1.
The catalyst is palladium acetate, palladium trifluoroacetate, two (triphenylphosphine) palladium chlorides or palladium chloride；Catalyst and 2- The molar ratio of (6- methoxyl group -1H- indoles -1- base) aniline is 0.05:1.
The solvent is 1,4- dioxane or diethylene glycol dimethyl ether.
The column chromatography eluent is the mixed solvent of petroleum ether and ethyl acetate, the volume ratio of petroleum ether and ethyl acetate For 100~10:1.
The present invention has the following advantages that compared with the prior art and effect:
The method that the present invention synthesizes 10- methoxyl group -6- Phenylindole simultaneously [1,2-a] quinoxaline, it is raw materials used nontoxic and honest and clean Valence is easy to get；Reaction in air atmosphere carry out can and；The strategy has single selectivity；In addition, reaction also has step The advantages of economy is high, easy to operate, safety, reaction condition is mild, high income.The strategy is 10- methoxyl group -6- Phenylindole And the preparation of [1,2-a] quinoxaline provides effective synthetic method.
Detailed description of the invention
Fig. 1 is the synthesis equation of 10- methoxyl group -6- Phenylindole simultaneously [1,2-a] quinoxaline in the present invention.
Fig. 2 be 10- methoxyl group -6- Phenylindole made from the embodiment of the present invention 14 simultaneously [1,2-a] quinoxaline hydrogen spectrum.
Fig. 3 be 10- methoxyl group -6- Phenylindole made from the embodiment of the present invention 14 simultaneously [1,2-a] quinoxaline carbon spectrum.
Specific embodiment
The invention is further described below by specific embodiment.
Embodiment 1:
0.2 mM of 2- (6- methoxyl group -1H- indoles -1- base) aniline, 0.01 mM of chlorine is sequentially added in reaction tube Change palladium, 0.4 mM of potassium peroxydisulfate and 0.4 mM of benzoyl formic acid.It is solvent that 2 milliliters of Isosorbide-5-Nitrae-dioxane, which are then added, Stopping reaction after being stirred to react under the conditions of 78 DEG C 12 hours, is cooled to room temperature and filters, filtrate is extracted with ethyl acetate 3 times, Merge organic phase and dried, filtered using 0.5 gram of anhydrous magnesium sulfate, vacuum rotary steam obtains crude product, most pure through column chromatography for separation afterwards Change, column chromatographic eluate used is the petroleum ether of volume ratio 18:1: ethyl acetate mixed solvent.Obtain pure 10- methoxyl group- 6- Phenylindole simultaneously [1,2-a] quinoxaline, yield 36%.
Embodiment 2:
0.2 mM of 2- (6- methoxyl group -1H- indoles -1- base) aniline, 0.01 mM of vinegar is sequentially added in reaction tube Sour palladium, 0.4 mM of potassium peroxydisulfate and 0.4 mM of benzoyl formic acid.It is solvent that 2 milliliters of Isosorbide-5-Nitrae-dioxane, which are then added, Stopping reaction after being stirred to react under the conditions of 78 DEG C 12 hours, is cooled to room temperature and filters, filtrate is extracted with ethyl acetate 3 times, Merge organic phase and dried, filtered using 0.5 gram of anhydrous magnesium sulfate, vacuum rotary steam obtains crude product, most pure through column chromatography for separation afterwards Change, column chromatographic eluate used is the petroleum ether of volume ratio 18:1: ethyl acetate mixed solvent.Obtain pure 10- methoxyl group- 6- Phenylindole simultaneously [1,2-a] quinoxaline, yield 57%.
Embodiment 3:
0.2 mM of 2- (6- methoxyl group -1H- indoles -1- base) aniline, 0.01 mM three is sequentially added in reaction tube Fluoroacetic acid palladium, 0.4 mM of potassium peroxydisulfate and 0.4 mM of benzoyl formic acid.It is molten that 2 milliliters of 1,4- dioxane, which are then added, Agent stops reaction, is cooled to room temperature and filters, filtrate is extracted with ethyl acetate 3 after being stirred to react under the conditions of 78 DEG C 12 hours It is secondary, merge organic phase and dried, filtered using 0.5 gram of anhydrous magnesium sulfate, vacuum rotary steam obtains crude product, most afterwards through column chromatography for separation Purifying, column chromatographic eluate used are the petroleum ether of volume ratio 18:1: ethyl acetate mixed solvent.Obtain pure 10- methoxy Base -6- Phenylindole simultaneously [1,2-a] quinoxaline, yield 42%.
Embodiment 4:
0.2 mM of 2- (6- methoxyl group -1H- indoles -1- base) aniline, 0.01 mM four is sequentially added in reaction tube (triphenylphosphine) palladium, 0.4 mM of potassium peroxydisulfate and 0.4 mM of benzoyl formic acid.2 milliliters of 1,4- dioxane are then added For solvent, stop reaction after being stirred to react under the conditions of 78 DEG C 12 hours.TLC (thin-layered chromatography) detection reaction, is not detected To the generation of 10- methoxyl group -6- Phenylindole simultaneously [1,2-a] quinoxaline.
Embodiment 5:
0.2 mM of 2- (6- methoxyl group -1H- indoles -1- base) aniline, 0.01 mM two is sequentially added in reaction tube Chlorine two (triphenylphosphine) palladium, 0.4 mM of potassium peroxydisulfate and 0.4 mM of benzoyl formic acid.2 milliliters of 1,4- dioxies are then added Six rings are solvent, stop reaction after being stirred to react under the conditions of 78 DEG C 12 hours, are cooled to room temperature and filter, filtrate acetic acid second Ester extracts 3 times, merges organic phase and is dried, filtered using 0.5 gram of anhydrous magnesium sulfate, vacuum rotary steam obtains crude product, most afterwards through column Chromatography purifying, column chromatographic eluate used are the petroleum ether of volume ratio 18:1: ethyl acetate mixed solvent.It obtains pure 10- methoxyl group -6- Phenylindole simultaneously [1,2-a] quinoxaline, yield 25%.
Embodiment 6:
0.2 mM of 2- (6- methoxyl group -1H- indoles -1- base) aniline, 0.01 mM of vinegar is sequentially added in reaction tube Sour palladium, 0.4 mM of copper acetate and 0.4 mM of benzoyl formic acid.It is solvent that 2 milliliters of Isosorbide-5-Nitrae-dioxane, which are then added, Stop reaction after being stirred to react under the conditions of 78 DEG C 12 hours.TLC (thin-layered chromatography) detection reaction, there is trace 10- methoxyl group -6- The generation of Phenylindole simultaneously [1,2-a] quinoxaline, but can not be isolated.
Embodiment 7:
0.2 mM of 2- (6- methoxyl group -1H- indoles -1- base) aniline, 0.01 mM of vinegar is sequentially added in reaction tube Sour palladium, 0.4 mM of silver acetate and 0.4 mM of benzoyl formic acid.It is solvent that 2 milliliters of Isosorbide-5-Nitrae-dioxane, which are then added, Stop reaction after being stirred to react under the conditions of 78 DEG C 12 hours.TLC (thin-layered chromatography) detection reaction, there is trace 10- methoxyl group -6- The generation of Phenylindole simultaneously [1,2-a] quinoxaline, can not be isolated.
Embodiment 8:
0.2 mM of 2- (6- methoxyl group -1H- indoles -1- base) aniline, 0.01 mM of vinegar is sequentially added in reaction tube Sour palladium, 0.4 mM of 1,4-benzoquinone and 0.4 mM of benzoyl formic acid.It is solvent that 2 milliliters of Isosorbide-5-Nitrae-dioxane, which are then added, Stop reaction after being stirred to react under the conditions of 78 DEG C 12 hours.TLC (thin-layered chromatography) detection reaction, there is trace 10- methoxyl group -6- The generation of Phenylindole simultaneously [1,2-a] quinoxaline, but can not be isolated.
Embodiment 9:
0.2 mM of 2- (6- methoxyl group -1H- indoles -1- base) aniline, 0.01 mM of vinegar is sequentially added in reaction tube Sour palladium, 0.4 mM of ammonium persulfate and 0.4 mM of benzoyl formic acid.It is solvent that 2 milliliters of Isosorbide-5-Nitrae-dioxane, which are then added, Stopping reaction after being stirred to react under the conditions of 78 DEG C 12 hours, is cooled to room temperature and filters, filtrate is extracted with ethyl acetate 3 times, Merge organic phase and dried, filtered using 0.5 gram of anhydrous magnesium sulfate, vacuum rotary steam obtains crude product, most pure through column chromatography for separation afterwards Change, column chromatographic eluate used is the petroleum ether of volume ratio 18:1: ethyl acetate mixed solvent.Obtain pure 10- methoxyl group- 6- Phenylindole simultaneously [1,2-a] quinoxaline, yield 58%.
Embodiment 10:
0.2 mM of 2- (6- methoxyl group -1H- indoles -1- base) aniline, 0.01 mM of vinegar is sequentially added in reaction tube Sour palladium, 0.4 mM of sodium peroxydisulfate and 0.4 mM of benzoyl formic acid.It is solvent that 2 milliliters of Isosorbide-5-Nitrae-dioxane, which are then added, Stopping reaction after being stirred to react under the conditions of 78 DEG C 12 hours, is cooled to room temperature and filters, filtrate is extracted with ethyl acetate 3 times, Merge organic phase and dried, filtered using 0.5 gram of anhydrous magnesium sulfate, vacuum rotary steam obtains crude product, most pure through column chromatography for separation afterwards Change, column chromatographic eluate used is the petroleum ether of volume ratio 18:1: ethyl acetate mixed solvent.Obtain pure 10- methoxyl group- 6- Phenylindole simultaneously [1,2-a] quinoxaline, yield 46%.
Embodiment 11:
0.2 mM of 2- (6- methoxyl group -1H- indoles -1- base) aniline, 0.01 mM of vinegar is sequentially added in reaction tube Sour palladium, 0.4 mM of ammonium persulfate and 0.4 mM of benzoyl formic acid.It is solvent that 2 milliliters of DMSO, which are then added, in 78 DEG C of items Stop reaction after being stirred to react under part 12 hours.TLC (thin-layered chromatography) detection reaction, does not detect 10- methoxyl group -6- benzene The generation of base indoles simultaneously [1,2-a] quinoxaline.
Embodiment 12:
0.2 mM of 2- (6- methoxyl group -1H- indoles -1- base) aniline, 0.01 mM of vinegar is sequentially added in reaction tube Sour palladium, 0.4 mM of ammonium persulfate and 0.4 mM of benzoyl formic acid.It is solvent that 2 milliliters of DMF, which are then added, in 78 DEG C of conditions Under be stirred to react 12 hours after stop reaction.TLC (thin-layered chromatography) detection reaction, does not detect 10- methoxyl group -6- phenyl The generation of indoles simultaneously [1,2-a] quinoxaline.
Embodiment 13:
0.2 mM of 2- (6- methoxyl group -1H- indoles -1- base) aniline, 0.01 mM of vinegar is sequentially added in reaction tube Sour palladium, 0.4 mM of ammonium persulfate and 0.4 mM of benzoyl formic acid.It is solvent that 2 milliliters of toluene, which are then added, in 78 DEG C of items Stop reaction after being stirred to react under part 12 hours.TLC (thin-layered chromatography) detection reaction, does not detect 10- methoxyl group -6- benzene The generation of base indoles simultaneously [1,2-a] quinoxaline.
Embodiment 14:
0.2 mM of 2- (6- methoxyl group -1H- indoles -1- base) aniline, 0.01 mM of vinegar is sequentially added in reaction tube Sour palladium, 0.4 mM of ammonium persulfate and 0.4 mM of benzoyl formic acid.It is molten that 2 milliliters of diethylene glycol dimethyl ethers, which are then added, Agent stops reaction, is cooled to room temperature and filters, filtrate is extracted with ethyl acetate 3 after being stirred to react under the conditions of 78 DEG C 12 hours It is secondary, merge organic phase and dried, filtered using 0.5 gram of anhydrous magnesium sulfate, vacuum rotary steam obtains crude product, most afterwards through column chromatography for separation Purifying, column chromatographic eluate used are the petroleum ether of volume ratio 18:1: ethyl acetate mixed solvent.Obtain pure 10- methoxy Simultaneously [1,2-a] quinoxaline, yield are up to 82% to base -6- Phenylindole.
Simultaneously the hydrogen spectrum of [1,2-a] quinoxaline and carbon compose as shown in Figures 2 and 3 respectively, knot to 10- methoxyl group -6- Phenylindole Structure indicator data are as follows:
Yellow oil；IR: ν=3056,2930,2840,1681,1609,1534,1478,1388,1309,1227, 816,749,700cm-1；1H NMR(400MHz,CDCl3) δ 8.37 (d, J=8.3Hz, 1H), 8.06 (d, J=7.9Hz, 1H), 8.04-7.97 (m, 2H), 7.85 (s, 1H), 7.78 (d, J=8.8Hz, 1H), 7.57 (dd, J=9.3,5.0Hz, 4H), 7.42 (t, J=7.5Hz, 1H), 7.18-7.09 (m, 2H), 4.01 (s, 3H)；13C NMR(100MHz,CDCl3)δ157.9,156.3, 138.2,136.4,133.8,130.3,130.1,129.9,128.7,128.6,127.9,124.1,123.7,123.4, 114.3,113.4,102.8,97.5,55.9；HRMS(ESI)m/z:calcd for C22H17N2O[M+H]+,325.1335； found 325.1340.
The structure of 10- methoxyl group -6- Phenylindole simultaneously [1,2-a] quinoxaline is as follows:
Embodiment 15:
0.2 mM of 2- (6- methoxyl group -1H- indoles -1- base) aniline, 0.01 mM of vinegar is sequentially added in reaction tube Sour palladium, 0.4 mM of ammonium persulfate and 0.4 mM of benzoyl formic acid.It is molten that 2 milliliters of diethylene glycol dimethyl ethers, which are then added, Agent stops reaction, is cooled to room temperature and filters, filtrate is extracted with ethyl acetate 3 after being stirred to react under the conditions of 70 DEG C 12 hours It is secondary, merge organic phase and dried, filtered using 0.5 gram of anhydrous magnesium sulfate, vacuum rotary steam obtains crude product, most afterwards through column chromatography for separation Purifying, column chromatographic eluate used are the petroleum ether of volume ratio 18:1: ethyl acetate mixed solvent.Obtain pure 10- methoxy Base -6- Phenylindole simultaneously [1,2-a] quinoxaline, yield 66%.
Embodiment 16:
0.2 mM of 2- (6- methoxyl group -1H- indoles -1- base) aniline, 0.01 mM of vinegar is sequentially added in reaction tube Sour palladium, 0.4 mM of ammonium persulfate and 0.4 mM of benzoyl formic acid.It is molten that 2 milliliters of diethylene glycol dimethyl ethers, which are then added, Agent stops reaction, is cooled to room temperature and filters, filtrate is extracted with ethyl acetate 3 after being stirred to react under the conditions of 85 DEG C 12 hours It is secondary, merge organic phase and dried, filtered using 0.5 gram of anhydrous magnesium sulfate, vacuum rotary steam obtains crude product, most afterwards through column chromatography for separation Purifying, column chromatographic eluate used are the petroleum ether of volume ratio 18:1: ethyl acetate mixed solvent.Obtain pure 10- methoxy Base -6- Phenylindole simultaneously [1,2-a] quinoxaline, yield 74%.
Embodiment 17:
0.2 mM of 2- (6- methoxyl group -1H- indoles -1- base) aniline, 0.01 mM of vinegar is sequentially added in reaction tube Sour palladium, 0.4 mM of ammonium persulfate and 0.4 mM of benzoyl formic acid.It is molten that 2 milliliters of diethylene glycol dimethyl ethers, which are then added, Agent, nitrogen protection stop reaction, are cooled to room temperature and filter after being stirred to react under the conditions of 78 DEG C 12 hours, filtrate acetic acid Ethyl ester extracts 3 times, merges organic phase and is dried, filtered using 0.5 gram of anhydrous magnesium sulfate, vacuum rotary steam obtains crude product, most passes through afterwards Column chromatographic isolation and purification, column chromatographic eluate used are the petroleum ether of volume ratio 18:1: ethyl acetate mixed solvent.It obtains pure 10- methoxyl group -6- Phenylindole simultaneously [1,2-a] quinoxaline, yield 73%.
Embodiment 18:
0.2 mM of 2- (6- methoxyl group -1H- indoles -1- base) aniline, 0.01 mM of vinegar is sequentially added in reaction tube Sour palladium, 0.4 mM of ammonium persulfate and 0.2 mM of benzoyl formic acid.It is molten that 2 milliliters of diethylene glycol dimethyl ethers, which are then added, Agent stops reaction, is cooled to room temperature and filters, filtrate is extracted with ethyl acetate 3 after being stirred to react under the conditions of 78 DEG C 12 hours It is secondary, merge organic phase and dried, filtered using 0.5 gram of anhydrous magnesium sulfate, vacuum rotary steam obtains crude product, most afterwards through column chromatography for separation Purifying, column chromatographic eluate used are the petroleum ether of volume ratio 18:1: ethyl acetate mixed solvent.Obtain pure 10- methoxy Base -6- Phenylindole simultaneously [1,2-a] quinoxaline, yield 52%.
Embodiment 19:
0.2 mM of 2- (6- methoxyl group -1H- indoles -1- base) aniline, 0.01 mM of vinegar is sequentially added in reaction tube Sour palladium, 0.2 mM of ammonium persulfate and 0.4 mM of benzoyl formic acid.It is molten that 2 milliliters of diethylene glycol dimethyl ethers, which are then added, Agent stops reaction, is cooled to room temperature and filters, filtrate is extracted with ethyl acetate 3 after being stirred to react under the conditions of 78 DEG C 12 hours It is secondary, merge organic phase and dried, filtered using 0.5 gram of anhydrous magnesium sulfate, vacuum rotary steam obtains crude product, most afterwards through column chromatography for separation Purifying, column chromatographic eluate used are the petroleum ether of volume ratio 18:1: ethyl acetate mixed solvent.Obtain pure 10- methoxy Base -6- Phenylindole simultaneously [1,2-a] quinoxaline, yield 36%.
Embodiment 20:
0.2 mM of 2- (6- methoxyl group -1H- indoles -1- base) aniline, 0.01 mM of vinegar is sequentially added in reaction tube Sour palladium, 0.4 mM of ammonium persulfate and 0.4 mM of benzoyl formic acid.It is molten that 2 milliliters of diethylene glycol dimethyl ethers, which are then added, Agent stops reaction, is cooled to room temperature and filters, filtrate is extracted with ethyl acetate 3 after being stirred to react under the conditions of 78 DEG C 6 hours It is secondary, merge organic phase and dried, filtered using 0.5 gram of anhydrous magnesium sulfate, vacuum rotary steam obtains crude product, most afterwards through column chromatography for separation Purifying, column chromatographic eluate used are the petroleum ether of volume ratio 18:1: ethyl acetate mixed solvent.Obtain pure 10- methoxy Base -6- Phenylindole simultaneously [1,2-a] quinoxaline, yield 55%.
Embodiment 21:
0.2 mM of 2- (6- methoxyl group -1H- indoles -1- base) aniline, 0.01 mM of vinegar is sequentially added in reaction tube Sour palladium, 0.4 mM of ammonium persulfate and 0.4 mM of benzoyl formic acid.It is molten that 2 milliliters of diethylene glycol dimethyl ethers, which are then added, Agent stops reaction, is cooled to room temperature and filters, filtrate is extracted with ethyl acetate 3 after being stirred to react under the conditions of 78 DEG C 24 hours It is secondary, merge organic phase and dried, filtered using 0.5 gram of anhydrous magnesium sulfate, vacuum rotary steam obtains crude product, most afterwards through column chromatography for separation Purifying, column chromatographic eluate used are the petroleum ether of volume ratio 18:1: ethyl acetate mixed solvent.Obtain pure 10- methoxy Base -6- Phenylindole simultaneously [1,2-a] quinoxaline, yield 79%.
Test result in above-described embodiment is shown in Table 1.
Table 1: the conditional FP tree of reactiona
aReaction condition: 0.2 mM of aniline of 2- (6- methoxyl group -1H- indoles -1- base), 0.4 mM of benzoyl formic acid, 0.01 mM of catalyst, 0.4 mM and 2.0 milliliters of solvent of oxidant sequentially adds in test tube, reacts 12 hours in 78 DEG C (being not necessarily to inert gas shielding)；bSeparation yield, n.d. representative do not detect product；cReaction temperature is 70 DEG C；dReaction temperature is 85℃；eNitrogen protection；fBenzoyl formic acid dosage is 0.2 mM；gThe dosage of ammonium persulfate is 0.2 mM；hReaction time It is 6 hours；iReaction time is 24 hours.
The present invention realizes 10- methoxyl group -6- Phenylindole, and simultaneously [1,2-a] quinoxaline efficiently synthesizes.The reaction condition It can simply complete in air；It is raw materials used nontoxic and cheap and easy to get；The reaction has stronger selection to oxidant and solvent Property (persulfate is best oxidant, and diethylene glycol dimethyl ether is best reaction dissolvent)；Step economy is high, selective Safety single, easy to operate, mild condition, high income are the major advantages of reaction, which is 10- methoxyl group -6- phenyl Yin The synthesis of diindyl simultaneously [1,2-a] quinoxaline provides new approaches.

Claims (1)

1. a kind of level-one amine guiding constructs 10- methoxyl group -6- Phenylindole simultaneously [1,2-a] quinoxaline method, it is characterised in that Specific steps are as follows: in reaction tube, 2- (6- methoxyl group -1 is addedHIndoles -1- base) aniline and benzoyl formic acid be raw material, Using persulfate as oxidant, using organic solvent as solvent, 70 ~ 90oIt stirs 10 ~ 24 hours under C, cools down after reaction To room temperature, filtering reacting liquid, after vacuum rotary steam crude product, obtain 10- methoxyl group -6- Phenylindole simultaneously through column chromatographic purifying [1,2-a] quinoxaline；
2- (the 6- methoxyl group -1HIndoles -1- base) molar ratio of aniline and benzoyl formic acid is 1:1 ~ 2；
The oxidant is potassium peroxydisulfate, sodium peroxydisulfate and ammonium persulfate；Oxidant and 2- (6- methoxyl group -1HIndoles -1- base) The molar ratio of aniline is 1 ~ 2:1；
The catalyst is palladium acetate, palladium trifluoroacetate, two (triphenylphosphine) palladium chlorides or palladium chloride；Catalyst and 2- (6- Methoxyl group -1H- indoles -1- base) aniline molar ratio be 0.05:1；
The solvent is 1,4- dioxane or diethylene glycol dimethyl ether；
The column chromatographs eluent as the mixed solvent of petroleum ether and ethyl acetate, and the volume ratio of petroleum ether and ethyl acetate is 100~10:1。
CN201811576524.XA 2018-12-22 2018-12-22 The method of level-one amine guiding building 10- methoxyl group -6- Phenylindole simultaneously [1,2-a] quinoxaline Withdrawn CN109503595A (en)

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Application publication date: 20190322