CN109503600A - The method of the level-one amine guiding building fluoro- 6- Phenylindole of 2- simultaneously [1,2-a] quinoxaline - Google Patents

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

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CN109503600A
CN109503600A CN201811576556.XA CN201811576556A CN109503600A CN 109503600 A CN109503600 A CN 109503600A CN 201811576556 A CN201811576556 A CN 201811576556A CN 109503600 A CN109503600 A CN 109503600A
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fluoro
quinoxaline
indoles
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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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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 the synthesis fluoro- 6- Phenylindole of 2- simultaneously [1,2-a] quinoxaline method.In reaction tube, the fluoro- 2- (1 of 4- is addedHIndoles -1- base) aniline and benzoyl formic acid be raw material, the fluoro- 6- Phenylindole of 2- 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

The method of the level-one amine guiding building fluoro- 6- Phenylindole of 2- simultaneously [1,2-a] quinoxaline
Technical field
The present invention relates to medication chemistry synthesis technical fields, and in particular to a kind of level-one amine guiding building fluoro- 6- benzene of 2- The method of base indoles 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 the level-one amine guiding synthesis fluoro- 6- Phenylindole of 2- simultaneously [1,2-a] quinoxaline.This method reaction condition is simple, 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 industrial metaplasia It produces, has in the research and development of drug and the synthesis of natural products and have 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 2- fluoro- 6- Phenylindole simultaneously [1,2-a] quinoxaline Method.
Thinking of the present invention: using the fluoro- 2- of 4- (1H- indoles -1- base) aniline, benzoyl formic acid as raw material, persulfate is oxygen Under the catalysis of palladium salt continuous acylation/cyclization occurs for agent, and step building has the chemical combination of pharmaceutical activity skeleton The fluoro- 6- Phenylindole of object 2- simultaneously [1,2-a] quinoxaline.This method avoid the use of the additives such as acid, alkali, raw materials required for the reactions Cheap and easy to get, 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:
The fluoro- 2- of 4- (1H- indoles -1- base) aniline and benzoyl formic acid are sequentially added in reaction flask, are with persulfate Oxidant using organic solvent as solvent, stirs 10~24 hours, after reaction using palladium salt as catalyst at 70~90 DEG C It is cooled to room temperature, filtering reacting liquid, crude product is obtained after vacuum rotary steam, obtains the fluoro- 6- phenyl Yin of compound 2- through column chromatographic purifying Diindyl simultaneously [1,2-a] quinoxaline.
The molar ratio of the fluoro- 2- of 4- (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 the fluoro- 2- of 4- (1H- indoles -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 4- The molar ratio of fluoro- 2- (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 the fluoro- 6- Phenylindole of 2- simultaneously [1,2-a] quinoxaline, it is raw materials used nontoxic and it is cheap easily ?；Reaction in air atmosphere carry out can and；The strategy has single selectivity；In addition, reaction also has step economy Property high, easy to operate, safety, the advantages of reaction condition is mild, high income.The strategy be the fluoro- 6- Phenylindole of 2- simultaneously [1,2-a] The preparation of quinoxaline provides effective synthetic method.
Detailed description of the invention
Fig. 1 is the synthesis equation of the fluoro- 6- Phenylindole of 2- simultaneously [1,2-a] quinoxaline in the present invention.
Fig. 2 be the fluoro- 6- Phenylindole of 2- made from the embodiment of the present invention 14 simultaneously [1,2-a] quinoxaline hydrogen spectrum.
Fig. 3 be the fluoro- 6- Phenylindole of 2- 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 fluoro- 2- of 4- (1H- indoles -1- base) aniline, 0.01 mM of chlorination is sequentially added in reaction tube 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, Stop reaction after being stirred to react under the conditions of 78 DEG C 12 hours, be cooled to room temperature and filter, filtrate is extracted with ethyl acetate 3 times, closes And organic phase and dried, filtered using 0.5 gram of anhydrous magnesium sulfate, vacuum rotary steam obtains crude product, most afterwards through column chromatographic isolation and purification, Column chromatographic eluate used is the petroleum ether of volume ratio 50:1: ethyl acetate mixed solvent.Obtain the fluoro- 6- phenyl Yin of pure 2- Diindyl simultaneously [1,2-a] quinoxaline, yield 27%.
Embodiment 2:
0.2 mM of fluoro- 2- of 4- (1H- indoles -1- base) aniline, 0.01 mM of acetic acid is sequentially added in reaction tube 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, Stop reaction after being stirred to react under the conditions of 78 DEG C 12 hours, be cooled to room temperature and filter, filtrate is extracted with ethyl acetate 3 times, closes And organic phase and dried, filtered using 0.5 gram of anhydrous magnesium sulfate, vacuum rotary steam obtains crude product, most afterwards through column chromatographic isolation and purification, Column chromatographic eluate used is the petroleum ether of volume ratio 50:1: ethyl acetate mixed solvent.Obtain the fluoro- 6- phenyl Yin of pure 2- Diindyl simultaneously [1,2-a] quinoxaline, yield 41%.
Embodiment 3:
0.2 mM of fluoro- 2- of 4- (1H- indoles -1- base) aniline, 0.01 mM of trifluoro second 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 50:1: ethyl acetate mixed solvent.Obtain the fluoro- 6- benzene of pure 2- Base indoles simultaneously [1,2-a] quinoxaline, yield 25%.
Embodiment 4:
0.2 mM of fluoro- 2- of 4- (1H- indoles -1- base) aniline, 0.01 mM four (three is sequentially added in reaction tube Phenylphosphine) palladium, 0.4 mM of potassium peroxydisulfate and 0.4 mM of benzoyl formic acid.2 milliliters of 1,4- dioxane, which are then added, is Solvent stops reaction after being stirred to react under the conditions of 78 DEG C 12 hours.TLC (thin-layered chromatography) detection reaction, does not detect The generation of the fluoro- 6- Phenylindole of 2- simultaneously [1,2-a] quinoxaline.
Embodiment 5:
0.2 mM of fluoro- 2- of 4- (1H- indoles -1- base) aniline, 0.01 mM of dichloro two 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, stops reaction after being stirred to react under the conditions of 78 DEG C 12 hours, be cooled to room temperature and filter, filtrate is extracted with ethyl acetate It takes 3 times, merge organic phase and is dried, filtered using 0.5 gram of anhydrous magnesium sulfate, vacuum rotary steam obtains crude product, most chromatographs afterwards through column It isolates and purifies, column chromatographic eluate used is the petroleum ether of volume ratio 50:1: ethyl acetate mixed solvent.Obtain pure 2- Fluoro- 6- Phenylindole simultaneously [1,2-a] quinoxaline, yield 18%.
Embodiment 6:
0.2 mM of fluoro- 2- of 4- (1H- indoles -1- base) aniline, 0.01 mM of acetic acid is sequentially added in reaction tube 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, 78 Stop reaction after being stirred to react under the conditions of DEG C 12 hours.TLC (thin-layered chromatography) detection reaction, no fluoro- 6- Phenylindole of 2- is simultaneously [1,2-a] quinoxaline generates.
Embodiment 7:
0.2 mM of fluoro- 2- of 4- (1H- indoles -1- base) aniline, 0.01 mM of acetic acid is sequentially added in reaction tube 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, 78 Stop reaction after being stirred to react under the conditions of DEG C 12 hours.TLC (thin-layered chromatography) detection reaction, no fluoro- 6- Phenylindole of 2- is simultaneously [1,2-a] quinoxaline generates.
Embodiment 8:
0.2 mM of fluoro- 2- of 4- (1H- indoles -1- base) aniline, 0.01 mM of acetic acid is sequentially added in reaction tube 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, 78 Stop reaction after being stirred to react under the conditions of DEG C 12 hours.TLC (thin-layered chromatography) detection reaction, no fluoro- 6- Phenylindole of 2- is simultaneously [1,2-a] quinoxaline generates.
Embodiment 9:
0.2 mM of fluoro- 2- of 4- (1H- indoles -1- base) aniline, 0.01 mM of acetic acid is sequentially added in reaction tube 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, Stop reaction after being stirred to react under the conditions of 78 DEG C 12 hours, be cooled to room temperature and filter, filtrate is extracted with ethyl acetate 3 times, closes And organic phase and dried, filtered using 0.5 gram of anhydrous magnesium sulfate, vacuum rotary steam obtains crude product, most afterwards through column chromatographic isolation and purification, Column chromatographic eluate used is the petroleum ether of volume ratio 50:1: ethyl acetate mixed solvent.Obtain the fluoro- 6- phenyl Yin of pure 2- Diindyl simultaneously [1,2-a] quinoxaline, yield 54%.
Embodiment 10:
0.2 mM of fluoro- 2- of 4- (1H- indoles -1- base) aniline, 0.01 mM of acetic acid is sequentially added in reaction tube 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, Stop reaction after being stirred to react under the conditions of 78 DEG C 12 hours, be cooled to room temperature and filter, filtrate is extracted with ethyl acetate 3 times, closes And organic phase and dried, filtered using 0.5 gram of anhydrous magnesium sulfate, vacuum rotary steam obtains crude product, most afterwards through column chromatographic isolation and purification, Column chromatographic eluate used is the petroleum ether of volume ratio 50:1: ethyl acetate mixed solvent.Obtain the fluoro- 6- phenyl Yin of pure 2- Diindyl simultaneously [1,2-a] quinoxaline, yield 35%.
Embodiment 11:
0.2 mM of fluoro- 2- of 4- (1H- indoles -1- base) aniline, 0.01 mM of acetic acid is sequentially added in reaction tube 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 conditions Under be stirred to react 12 hours after stop reaction.TLC (thin-layered chromatography) detection reaction, does not detect the fluoro- 6- Phenylindole of 2- And the generation of [1,2-a] quinoxaline.
Embodiment 12:
0.2 mM of fluoro- 2- of 4- (1H- indoles -1- base) aniline, 0.01 mM of acetic acid is sequentially added in reaction tube 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, under the conditions of 78 DEG C Stop reaction after being stirred to react 12 hours.TLC (thin-layered chromatography) detection reaction, does not detect the fluoro- 6- Phenylindole of 2- simultaneously The generation of [1,2-a] quinoxaline.
Embodiment 13:
0.2 mM of fluoro- 2- of 4- (1H- indoles -1- base) aniline, 0.01 mM of acetic acid is sequentially added in reaction tube 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 conditions Under be stirred to react 12 hours after stop reaction.TLC (thin-layered chromatography) detection reaction, does not detect the fluoro- 6- Phenylindole of 2- And the generation of [1,2-a] quinoxaline.
Embodiment 14:
0.2 mM of fluoro- 2- of 4- (1H- indoles -1- base) aniline, 0.01 mM of acetic acid is sequentially added in reaction tube Palladium, 0.4 mM of ammonium persulfate and 0.4 mM of benzoyl formic acid.It is solvent that 2 milliliters of diethylene glycol dimethyl ethers, 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 50:1: ethyl acetate mixed solvent.Obtain the fluoro- 6- benzene of pure 2- Simultaneously [1,2-a] quinoxaline, yield are up to 70% to base indoles.
Simultaneously the hydrogen spectrum of [1,2-a] quinoxaline and carbon compose as shown in Figures 2 and 3, structure indicator respectively to the fluoro- 6- Phenylindole of 2- Data are as follows:
Yellow solid；mp 204-205℃；IR: ν=3057,2921,2851,1622,1449,1386,1332, 1210,1160,1065,819,733,691,607cm-1；1H NMR (400MHz, CDCl3) δ 8.37 (d, J=8.7Hz, 1H), 8.18 (dd, J=10.4,2.5Hz, 1H), 8.03 (ddd, J=9.4,7.1,4.2Hz, 3H), 7.92 (d, J=8.0Hz, 1H), 7.57 (dd, J=7.2,5.2Hz, 4H), 7.46 (t, J=7.5Hz, 1H), 7.25 (s, 1H), 7.16 (m, J=8.6,2.5Hz, 1H)；13C NMR(100MHz,CDCl3) δ 161.9 (d, J=246.4Hz), 155.3,137.9,132.9,132.8 (d, J= 1.8Hz), 131.9 (d, J=9.8Hz), 130.7 (d, J=11.4Hz), 130.1,129.3,128.7,128.6,128.5, 124.7,123.0 (d, J=16.2Hz), 114.2,111.6,111.4,103.0,102.0 (d, J=28.4Hz)；HRMS(ESI) m/z:calcd for C21H14FN2[M+H]+,313.1136；found 313.1139.
The structure of the fluoro- 6- Phenylindole of 2- simultaneously [1,2-a] quinoxaline is as follows:
Embodiment 15:
0.2 mM of fluoro- 2- of 4- (1H- indoles -1- base) aniline, 0.01 mM of acetic acid is sequentially added in reaction tube Palladium, 0.4 mM of ammonium persulfate and 0.4 mM of benzoyl formic acid.It is solvent that 2 milliliters of diethylene glycol dimethyl ethers, which are then added, Stopping reaction after being stirred to react under the conditions of 70 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 50:1: ethyl acetate mixed solvent.Obtain the fluoro- 6- benzene of pure 2- Base indoles simultaneously [1,2-a] quinoxaline, yield 59%.
Embodiment 16:
0.2 mM of fluoro- 2- of 4- (1H- indoles -1- base) aniline, 0.01 mM of acetic acid is sequentially added in reaction tube Palladium, 0.4 mM of ammonium persulfate and 0.4 mM of benzoyl formic acid.It is solvent that 2 milliliters of diethylene glycol dimethyl ethers, which are then added, Stopping reaction after being stirred to react under the conditions of 85 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 50:1: ethyl acetate mixed solvent.Obtain the fluoro- 6- benzene of pure 2- Base indoles simultaneously [1,2-a] quinoxaline, yield 67%.
Embodiment 17:
0.2 mM of fluoro- 2- of 4- (1H- indoles -1- base) aniline, 0.01 mM of acetic acid is sequentially added in reaction tube Palladium, 0.4 mM of ammonium persulfate and 0.4 mM of benzoyl formic acid.It is solvent that 2 milliliters of diethylene glycol dimethyl ethers, which are then added, Nitrogen protection stops reaction, is cooled to room temperature and filters after being stirred to react under the conditions of 78 DEG C 12 hours, filtrate ethyl acetate Extraction 3 times is merged organic phase and is dried, filtered using 0.5 gram of anhydrous magnesium sulfate, and vacuum rotary steam obtains crude product, most afterwards through column layer Analysis isolates and purifies, and column chromatographic eluate used is the petroleum ether of volume ratio 50:1: ethyl acetate mixed solvent.Obtain pure 2- Fluoro- 6- Phenylindole simultaneously [1,2-a] quinoxaline, yield 66%.
Embodiment 18:
0.2 mM of fluoro- 2- of 4- (1H- indoles -1- base) aniline, 0.01 mM of acetic acid is sequentially added in reaction tube Palladium, 0.4 mM of ammonium persulfate and 0.2 mM of benzoyl formic acid.It is solvent that 2 milliliters of diethylene glycol dimethyl ethers, 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 50:1: ethyl acetate mixed solvent.Obtain the fluoro- 6- benzene of pure 2- Base indoles simultaneously [1,2-a] quinoxaline, yield 38%.
Embodiment 19:
0.2 mM of fluoro- 2- of 4- (1H- indoles -1- base) aniline, 0.01 mM of acetic acid is sequentially added in reaction tube Palladium, 0.2 mM of ammonium persulfate and 0.4 mM of benzoyl formic acid.It is solvent that 2 milliliters of diethylene glycol dimethyl ethers, 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 50:1: ethyl acetate mixed solvent.Obtain the fluoro- 6- benzene of pure 2- Base indoles simultaneously [1,2-a] quinoxaline, yield 30%.
Embodiment 20:
0.2 mM of fluoro- 2- of 4- (1H- indoles -1- base) aniline, 0.01 mM of acetic acid is sequentially added in reaction tube Palladium, 0.4 mM of ammonium persulfate and 0.4 mM of benzoyl formic acid.It is solvent that 2 milliliters of diethylene glycol dimethyl ethers, which are then added, Stop reaction after being stirred to react under the conditions of 78 DEG C 6 hours, be cooled to room temperature and filter, filtrate is extracted with ethyl acetate 3 times, closes And organic phase and dried, filtered using 0.5 gram of anhydrous magnesium sulfate, vacuum rotary steam obtains crude product, most afterwards through column chromatographic isolation and purification, Column chromatographic eluate used is the petroleum ether of volume ratio 50:1: ethyl acetate mixed solvent.Obtain the fluoro- 6- phenyl Yin of pure 2- Diindyl simultaneously [1,2-a] quinoxaline, yield 42%.
Embodiment 21:
0.2 mM of fluoro- 2- of 4- (1H- indoles -1- base) aniline, 0.01 mM of acetic acid is sequentially added in reaction tube Palladium, 0.4 mM of ammonium persulfate and 0.4 mM of benzoyl formic acid.It is solvent that 2 milliliters of diethylene glycol dimethyl ethers, which are then added, Stopping reaction after being stirred to react under the conditions of 78 DEG C 24 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 50:1: ethyl acetate mixed solvent.Obtain the fluoro- 6- benzene of pure 2- Base indoles simultaneously [1,2-a] quinoxaline, yield 64%.
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 the fluoro- 2- of 4- (1H- indoles -1- base), 0.4 mM of benzoyl formic acid, catalysis 0.01 mM of agent, 0.4 mM and 2.0 milliliters of solvent of oxidant sequentially adds in test tube, reacts 12 hours and (is not necessarily in 78 DEG C Inert gas shielding)；bSeparation yield, n.d. representative do not detect product；cReaction temperature is 70 DEG C；dReaction temperature is 85 DEG C；e Nitrogen protection；fBenzoyl formic acid dosage is 0.2 mM；gThe dosage of ammonium persulfate is 0.2 mM；hReaction time is 6 small When；iReaction time is 24 hours.
The present invention realizes 2- fluoro- 6- Phenylindole, and simultaneously [1,2-a] quinoxaline efficiently synthesizes.The reaction condition simply exists It can be completed in air；It is raw materials used nontoxic and cheap and easy to get；The reaction has stronger selectivity (over cure to oxidant and solvent Hydrochlorate is best oxidant, and diethylene glycol dimethyl ether is best reaction dissolvent)；Step economy is high, selectivity is single, behaviour Make simple and safe, mild condition, high income be reaction major advantage, which is the fluoro- 6- Phenylindole of 2- simultaneously [1,2-a] quinoline The synthesis of quinoline provides new approaches.

Claims (1)

1. a kind of level-one amine guiding constructs the fluoro- 6- Phenylindole of 2- simultaneously [1,2-a] quinoxaline method, it is characterised in that specific step Suddenly are as follows: in reaction tube, the fluoro- 2- (1 of 4- is addedHIndoles -1- base) aniline and benzoyl formic acid be raw material, with persulfate For oxidant, using organic solvent as solvent, 70 ~ 90oIt stirs 10 ~ 24 hours under C, is cooled to room temperature after reaction, filter Reaction solution, after vacuum rotary steam crude product, obtain the fluoro- 6- Phenylindole of 2- simultaneously [1,2- through column chromatographic purifyinga] quinoxaline；
The fluoro- 2- (1 of 4-HIndoles -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 the fluoro- 2- (1 of 4-HIndoles -1- base) aniline Molar ratio be 1 ~ 2:1；
The catalyst is palladium acetate, palladium trifluoroacetate, two (triphenylphosphine) palladium chlorides or palladium chloride；Catalyst is fluoro- with 4- 2-(1HIndoles -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。
CN201811576556.XA 2018-12-22 2018-12-22 The method of the level-one amine guiding building fluoro- 6- Phenylindole of 2- simultaneously [1,2-a] quinoxaline Withdrawn CN109503600A (en)

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