CN109400629A - Indoles spirooxazine heterocycle compound and preparation method thereof - Google Patents

Indoles spirooxazine heterocycle compound and preparation method thereof Download PDF

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CN109400629A
CN109400629A CN201811541656.9A CN201811541656A CN109400629A CN 109400629 A CN109400629 A CN 109400629A CN 201811541656 A CN201811541656 A CN 201811541656A CN 109400629 A CN109400629 A CN 109400629A
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indoles
reaction
spirooxazine
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compound
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CN109400629B (en
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陈知远
韩翠芬
袁建军
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Jiangxi Normal University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
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  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
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Abstract

The present invention provides a kind of new indoles spirooxazine heterocycle compounds and preparation method thereof.This method, as reaction substrate, makes it react under the catalysis of transition metal using indoles diazonium compound and benzene isoxazole, and indoles spirooxazine heterocycle compound is made by single step reaction high efficiency.There is potential medical active using the resulting indoles spiro-heterocycle compound of this method; various additional conversions are easy to happen containing halogen, carbon nitrogen imine double bond and sulfonyl group in product molecule, thus the organic compound of the more complicated ring system containing indoles of preparation structure.This method raw material is easy to get, and reaction system is simple, and chemo-selective is good, and without stringent anhydrous and oxygen-free condition, strong operability, the ten gram-grade scales for being easy amplification also not appreciably affect the yield of reaction.The functional group compatibility of reaction is good, and substrate applicability is wide, and product is stablized, and can be easily separated purification, is suitable for industry amplification preparation, has preferable application potential.

Description

Indoles spirooxazine heterocycle compound and preparation method thereof
Technical field
The present invention relates to the derivatives of indoles skeleton, and in particular to indoles spirooxazine heterocycle compound and its preparation side Method.
Background technique
Indoles volution compound is present in natural products and biologically active drug molecule, this kind of nitrogen-containing heterocycle Skeleton with loop coil quaternary carbon center due to making it have significant bioactivity: (a) Lin, H. in drug research； Danishefsky,S.J.Angew.Chem.,Int.Ed.2003,42,36.(b)Ding,K.；Lu,Y.；Nikolovska- Coleska,Z.；Qiu,S.；Ding,Y.；Gao,W.；Stuckey,J.；Krajewski,K.；Roller,P.P.；Tomita, Y.；Parrish,D.A.；Deschamps,J.R.；Wang,S.J.Am.Chem.Soc.2005,127,10130.(c) C.V.Galliford,K.A.Scheidt,Angew.Chem.Int.Ed.,2007,46,8748.(d)Y.C.Lee,S.Patil, C.Golz,C.Strohmann,S.Ziegler,K.Kumar and H.Waldmann,Nat.Commun.,2017,8,14043. (e)Shangary,S.；Qin,D.；McEachern,D.；Liu,M.；Miller,R.S.；Qiu,S.；Nikolovska- Coleska,Z.；Ding,K.；Wang,G.；Chen,J.；Bernard,D.；Zhang,J.；Lu,Y.；Gu,Q.；Shah,R.B.； Pienta,K.J.；Ling,X.；Kang,S.；Guo,M.；Sun,Y.；Yang,D.；Wang, S.Proc.Natl.Acad.Sci.U.S.A.2008,105,3933. for example, the MI-219 containing skeleton can effectively inhibit swollen Interaction between p53 the and E3 ubiquitin ligase MDM2 of oncocyte.
The some simple effective method synthesis of indole volution compounds of research and development have highly important science meaning Justice and application value.Such as: in 2014, Du. seminar was intermolecular by rhodium catalysis epoxy olefins and imine compound The synthesis of [3+2] cycloaddition reaction has compound (Z.Q.Liu, the X.Q.Feng and of indolone spiral shell oxazoline ring skeleton H.F.Du,Org.Lett.2012,14,3154；), in 2014, Tang seminar passed through Louis acid catalysis intramolecular [3+2] Cycloaddition reaction obtained indolone spiroperidol ring skeleton compound (J.Zhu, Y.Liang, L.J.Wang, Z.B.Zheng, K.N.Houk and Y.Tang,J.Am.Chem.Soc.2014,136,6900.).2017, Ashfeld etc. utilized indoles weight Nitrogen ketone compounds and alkene obtain indolone spiral shell pyrroles by [4+1] cycloaddition reaction in acetic acid rhodium catalysis Toluene solvent Alkanone skeleton cyclics (J.L.Meloche and B.L.Ashfeld, Angew.Chem.Int.Ed.2017,56, 6604.).The place of not doing of this method is that reaction profile carries out and the reaction time is longer.Recently, Wang seminar reports The C-N/C-O coupling reaction of copper catalysis, which is anti-with 3- diazonium indoles -2- imine compound and diethyl alcohol compound Object is answered, using Isosorbide-5-Nitrae-dioxane aqueous solution as solvent, 2h is reacted under the conditions of 60 DEG C and obtains indolone spiral shell oxazoline product (Sheng,G.,Ma,S.,Bai,S.,Mao,J,Lu,P.,&Wang,Y.Chem.Commun.2018,54,1529-1532.)。
The above method provides many alternative approach for synthesis of indole spiral shell or nitrogen-containing hetero cyclics, so And existing document shows that the method for synthesizing the indoles spirooxazine class compound containing hexa-atomic nitrogen oxa- ring structure is not really common, It there is no effective method that can obtain such compound at present.Therefore, the present invention is directed to protect a kind of new synthesis of indole spirooxazine miscellaneous The preparation method of cyclics.This method raw material is easy to get, and reaction system is simple, and chemo-selective is good, strong operability, is easy Ten gram-grade scales of amplification also not appreciably affect the yield of reaction.Product stabilization can be easily separated purification, be suitable for industry amplification system It is standby.
Summary of the invention
It is an object of that present invention to provide new indoles spirooxazine heterocycle compounds and preparation method thereof.
The present invention uses following technical scheme.
Indoles spirooxazine heterocycle compound, which is characterized in that there is structure shown in lower formula (III):
In formula, R1Selected from fragrant sulfonyl, alkyl sulphonyl；R2、R3、R4Independently selected from hydrogen, alkyl, alkoxy, fluorine, Chlorine, bromine, cyano, nitro, ester group, silicon substrate.
In above-mentioned indoles spirooxazine heterocycle compound molecule containing halogen, carbon nitrogen imine double bond or easily leave away to toluene The reactivity of sulfonyl group, these groups is very high, for example, imine linkage can do asymmetric catalysis synthesis obtain it is active Molecule can also occur hydrolysis and obtain the carbonyl that can further react.Therefore above-mentioned indoles spirooxazine heterocyclic chemical combination Further conversion can occur by other organic chemical reactions for object, in above-mentioned indoles spirooxazine heterocycle compound molecule The other functional groups of middle introducing, obtain novel organic compound.Above-mentioned indoles spirooxazine heterocycle compound can be used in giving birth to Produce the drug for the treatment of disease.Additionally due to contain indole structure segment and benzoxazine structural framework in product molecule simultaneously, These groups itself all with good biological medicine activity or material in terms of purposes, and resulting product can pass through it Further conversion occurs for his organic reaction, generates indoles or oxazines structure analog, therefore have considerable application prospect.
The preparation method of above-mentioned indoles spirooxazine heterocycle compound, which is characterized in that make 3- indoles diazonium -2- imines Compound reacts under the action of transition-metal catalyst with the different azole compounds of benzene, obtains indoles spirooxazine heterocyclic chemical combination Object.Reaction equation is as follows:
In formula, R1Selected from fragrant sulfonyl, alkyl sulphonyl；R2、R3、R4Independently selected from hydrogen, alkyl, alkoxy, fluorine, Chlorine, bromine, cyano, nitro, ester group, silicon substrate.
In the above method, transition-metal catalyst can for dimerization rhodium acetate, rhodium caprylate, it is bis- [(Α, Α, Α ', Α '-four Methyl-1,3- benzene dipropionic acid) rhodium], acetylacetone,2,4-pentanedione (1,5- cyclo-octadiene) rhodium, bis- (diphenylphosphine propane) Nickel Chlorides of 1,3-, (1,1'- bis- (diphenylphosphine) ferrocene) Nickel Chloride or copper trifluoromethanesulfcomposite etc., wherein bis- [(Α, Α, Α ', Α '-tetramethyl Base -1,3- benzene dipropionic acid) rhodium] (it is labeled as Rh2(esp)2) catalytic effect it is best.
In the above method, the solvent that uses can for 1,2- dichloroethanes, methylene chloride, chloroform, acetonitrile, to diformazan Benzene, toluene, N,N-dimethylformamide, n-hexane, tetrahydrofuran, 1,4- dioxane or dimethyl sulfoxide.Wherein with dichloro Reaction effect is best when methane is solvent.
In the above method, reaction can carry out in a nitrogen environment.
In the above method, the temperature of reaction can be 60 DEG C, and the reaction time can be 2~4h.
In the above method, the molar ratio of reactant 3- indoles diazonium -2- imine compound and the different azole compounds of benzene It can be 3:1.
Specific behaviour's step conduct of the above method: under nitrogen atmosphere that transition-metal catalyst, 3- indoles diazonium -2- is sub- Aminated compounds and the different azole compounds of benzene are dissolved in solvent, and 2~4h is reacted under the conditions of 60 DEG C, use TLC plate after reaction (triethylamine detection is added dropwise, otherwise can not detect product) in detection；When post-processing, first passes through the sand core funnel suction filtration equipped with silica gel and remove Fall transition-metal catalyst, then gained filtrate is separated by rapid column chromatography, obtains pure product indoles spirooxazine heterocyclic Compound.
Beneficial effects of the present invention: contain halogen, carbon in indoles spirooxazine heterocycle compound molecule of the invention simultaneously Nitrogen imine double bond or the tolysulfonyl group easily left away, these groups itself all have good reactivity, therefore gained Product further conversion can occur by other organic reactions, in the molecule of synthesising biological or pharmaceutical activity, natural The fields such as product have extraordinary application prospect.In method of the invention, the Atom economy of reaction is very high, reactant 3- Yin The ratio of diindyl diazonium -2- imines and benzene isoxazole is that 3:1 can be carried out very wellly, and use the amount of catalyst fewer, Thus reaction embodies good greenization.Meanwhile operation is easy, post-processing is simple, and chemo-selective is high, and substrate is applicable in Property it is wide, product yield is medium, and this reaction can effectively be amplified to ten gram-grade scales preparation without influence reaction efficiency, can fit For fairly large preparation.
Detailed description of the invention
Fig. 1 is the general structure of indoles spirooxazine heterocycle compound of the invention.
Fig. 2 is the mono-crystalline structures schematic diagram of indoles spirooxazine heterocycle compound 3a.
Specific embodiment
The following examples are not intended to limit the scope of the invention to further explanation of the invention.
Embodiment one:
In a 25mLSchlenk reaction tube equipped with magnetic stir bar, catalyst Rh is added2(esp)2(0.01mmol, 0.02equiv.), N- (3- diazonium -1- methyl indoline -2- subunit) -4- methyl benzenesulfonamide (1.5mmol, 3.0equiv), benzene isoxazole (0.5mmol, 1.0equiv.) and methylene chloride (5mL), nitrogen protection.Place reaction liquid into 60 DEG C Oil bath pan in react about 2~4h, TLC is detected to fully reacting, is then cooled to room temperature reaction solution.It is first passed through when post-processing Sand core funnel suction filtration equipped with silica gel removes catalyst, the product 4- first that gained filtrate separates pure by rapid column chromatography Base-N- (1'- methylspiro [benzo [e] [1,3] oxazines -2,3'- indoline] -2'- methylene) benzsulfamide.Yield: 74%.With Under be product 3a nuclear magnetic resonance experiment data:
1H NMR (400MHz, DMSO) δ: 8.50 (s, 1H), 7.69 (d, J=8.2Hz, 2H), 7.53 (d, J=6.6Hz, 1H), 7.48 (t, J=7.7Hz, 2H), 7.34 (d, J=8.0Hz, 2H), 7.27 (t, J=6.0Hz, 1H), 7.15-7.07 (m, 3H), 6.85 (d, J=8.1Hz, 1H), 3.34 (s, 3H), 2.37 (s, 3H)
13C NMR(100MHz,DMSO)δ:164.6,156.7,152.9,142.8,140.9,140.8,135.1,132.1, 129.8,129.7,128.9,126.6,125.0,122.9,122.7,116.4,116.1,111.5,94.0,29.4,21.4.
Embodiment two:
In a 25mLSchlenk reaction tube equipped with magnetic stir bar, catalyst Rh is added2(esp)2(0.01mmol, 0.02equiv.), N- (3- diazonium -1- methyl indoline -2- subunit) -4- methyl benzenesulfonamide (1.5mmol, 3.0equiv), 5- methylbenzene isoxazole (0.5mmol, 1.0equiv.) and methylene chloride (5mL), nitrogen protection.Reaction solution is set About 2~4h is reacted in 60 DEG C of oil bath pan, TLC is detected to fully reacting, is then cooled to room temperature reaction solution.When post-processing It first passes through the sand core funnel suction filtration equipped with silica gel and removes catalyst, the product that gained filtrate separates pure by rapid column chromatography N- (1', 6- dimethyl spiral shell [benzo [e] [1,3] oxazines -2,3'- indoline] -2'- methylene) -4- methyl benzenesulfonamide.It produces Rate: 58%.It is the nuclear magnetic resonance experiment data of product 3b below:
1H NMR (400MHz, DMSO) δ: 8.44 (s, 1H), 7.69 (d, J=8.2Hz, 2H), 7.46 (t, J=7.3Hz, 1H), 7.33 (d, J=7.6Hz, 3H), 7.30-7.24 (m, 2H), 7.13 (d, J=7.1Hz, 1H), 7.06 (t, J=7.4Hz, 1H), 6.74 (d, J=8.2Hz, 1H), 3.33 (s, 3H), 2.37 (s, 3H), 2.31 (s, 3H)
13C NMR(100MHz,DMSO)δ:164.7,156.8,150.7,142.8,140.9,140.8,135.5,132.0, 131.7,129.7,128.9,126.7),125.0,122.9,116.2,115.9,111.4,93.9,29.4,21.4,20.5.
Embodiment three:
In a 25mLSchlenk reaction tube equipped with magnetic stir bar, catalyst Rh is added2(esp)2(0.01mmol, 0.02equiv.), N- (3- diazonium -1- methyl indoline -2- subunit) -4- methyl benzenesulfonamide (1.5mmol, 3.0equiv), 5- chlorobenzene isoxazole (0.5mmol, 1.0equiv.) and methylene chloride (5mL), nitrogen protection.It places reaction liquid into About 2~4h is reacted in 60 DEG C of oil bath pan, TLC is detected to fully reacting, is then cooled to room temperature reaction solution.It is first when post-processing Catalyst, the product N- that gained filtrate separates pure by rapid column chromatography are removed by the sand core funnel suction filtration equipped with silica gel (the chloro- 1'- methylspiro of 6- [benzo [e] [1,3] oxazines -2,3'- indoline] -2'- methylene) -4- methyl benzenesulfonamide.Yield: 52%.It is the nuclear magnetic resonance experiment data of product 3c below:
1H NMR(400MHz,DMSO)δ:8.49(s,1H),7.72–7.66(m,3H),7.53–7.47(m,2H),7.35(t,J =9.3Hz, 2H), 7.28-7.22 (m, 2H), 7.09 (t, J=7.5Hz, 1H), 6.89 (d, J=8.7Hz, 1H), 3.34 (s, 3H),2.37(s,3H).
13C NMR(100MHz,DMSO)δ:164.2,155.7,151.7,142.9,140.9,140.6,134.6,132.3, 129.8,128.4,126.6,126.1,126.1,125.1,123.2,118.1,117.3,111.5,94.1,29.5,21.4.
Example IV:
In a 25mLSchlenk reaction tube equipped with magnetic stir bar, catalyst Rh is added2(esp)2(0.01mmol, 0.02equiv.), N- (3- diazonium -1- methyl indoline -2- subunit) -4- methyl benzenesulfonamide (1.5mmol, 3.0equiv), 6- methylbenzene isoxazole (0.5mmol, 1.0equiv.) and methylene chloride (5mL), nitrogen protection.Reaction solution is set About 2~4h is reacted in 60 DEG C of oil bath pan, TLC is detected to fully reacting, is then cooled to room temperature reaction solution.When post-processing It first passes through the sand core funnel suction filtration equipped with silica gel and removes catalyst, the product that gained filtrate separates pure by rapid column chromatography N- (1', 7- dimethyl spiral shell [benzo [e] [1,3] oxazines -2,3'- indoline] -2'- methylene) -4- methyl benzenesulfonamide.It produces Rate: 58%.It is the nuclear magnetic resonance experiment data of product 3d below:
1H NMR (400MHz, DMSO) δ: 8.43 (s, 1H), 7.69 (d, J=7.6Hz, 2H), 7.47 (t, J=7.1Hz, 1H), 7.40 (d, J=7.4Hz, 1H), 7.34 (d, J=7.5Hz, 2H), 7.26 (s, 1H), 7.13 (s, 1H), 7.08 (d, J= 7.2Hz, 1H), 6.93 (d, J=7.0Hz, 1H), 6.67 (s, 1H), 3.33 (s, 3H), 2.37 (s, 3H), 2.32 (s, 3H)
13C NMR(100MHz,DMSO)δ:164.7,156.5,152.9,145.9,142.8,140.9,140.8,132.0, 129.9,129.7,128.6,126.6,125.0,123.4,122.9,116.4,114.2,111.4,93.9,29.4,22.0, 21.4.
Embodiment five:
In a 25mLSchlenk reaction tube equipped with magnetic stir bar, catalyst Rh is added2(esp)2(0.01mmol, 0.02equiv.), N- (3- diazonium -1- methyl indoline -2- subunit) -4- methyl benzenesulfonamide (1.5mmol, 3.0equiv), 7- methoxybenzene isoxazole (0.5mmol, 1.0equiv.) and methylene chloride (5mL), nitrogen protection.By reaction solution It is placed in 60 DEG C of oil bath pan and reacts about 2~4h, TLC is detected to fully reacting, is then cooled to room temperature reaction solution.Post-processing When first pass through equipped with silica gel sand core funnel suction filtration remove catalyst, the production that gained filtrate separates pure by rapid column chromatography Product N- (8- methoxyl group -1'- methylspiro [benzo [e] [1,3] oxazines -2,3'- indoline] -2'- methylene) -4- Methyl benzenesulfonyl Amine.Yield: 47%.It is the nuclear magnetic resonance experiment data of product 3e below:
1H NMR (400MHz, DMSO) δ: 8.47 (s, 1H), 7.70 (d, J=8.1Hz, 2H), 7.46 (t, J=7.6Hz, 1H), 7.32 (d, J=8.0Hz, 2H), 7.25 (d, J=7.9Hz, 1H), 7.21 (d, J=7.9Hz, 1H), 7.13-7.10 (m, 2H), 7.06 (t, J=7.7Hz, 2H), 3.74 (s, 3H), 3.33 (s, 3H), 2.36 (s, 3H)
13C NMR(100MHz,DMSO)δ:164.6,156.6,147.3,142.8,142.0,140.9,140.6,132.1, 129.8,129.7,126.8,125.0,122.9,122.4,120.2,117.9,116.8,111.5,93.8,56.2,29.4, 21.4.
Embodiment six:
In a 25mLSchlenk reaction tube equipped with magnetic stir bar, catalyst Rh is added2(esp)2(0.01mmol, 0.02equiv.), the bromo- N- of 4- (3- diazonium -1- methyl indol quinoline -2- ethylidene) benzsulfamide (1.5mmol, 3.0equiv), Benzene isoxazole (0.5mmol, 1.0equiv.) and methylene chloride (5mL), nitrogen protection.It places reaction liquid into 60 DEG C of oil bath pan About 2~4h is reacted, TLC is detected to fully reacting, is then cooled to room temperature reaction solution.It first passes through when post-processing equipped with silica gel Sand core funnel suction filtration removes catalyst, product 4- bromo- N- (the 1'- methyl that gained filtrate separates pure by rapid column chromatography Spiral shell [benzo [e] [1,3] oxazines -2,3'- indoline] -2'- methylene) benzsulfamide.Yield: 40%.It is product 3f below Nuclear magnetic resonance experiment data:
1H NMR (400MHz, DMSO) δ 8.50 (s, 1H), 7.75 (s, 4H), 7.54-7.49 (m, 3H), 7.29 (d, J= 7.3Hz, 1H), 7.14-7.07 (m, 3H), 6.85 (d, J=7.5Hz, 1H), 3.35 (s, 3H)
13C NMR(100MHz,DMSO)δ:165.2,156.9,152.8,142.8,140.8,135.2,132.4,132.2, 129.8,128.9,128.6,126.3,125.3,122.9,122.8,116.4,116.1,111.7,94.0,29.5.
Embodiment seven:
In a 25mLSchlenk reaction tube equipped with magnetic stir bar, catalyst Rh is added2(esp)2(0.01mmol, 0.02equiv.), the chloro- N- of 4- (3- diazonium -1- methyl indol quinoline -2- ethylidene) benzsulfamide (1.5mmol, 3.0equiv), Benzene isoxazole (0.5mmol, 1.0equiv.) and methylene chloride (5mL), nitrogen protection.It places reaction liquid into 60 DEG C of oil bath pan About 2~4h is reacted, TLC is detected to fully reacting, is then cooled to room temperature reaction solution.It first passes through when post-processing equipped with silica gel Sand core funnel suction filtration removes catalyst, product 4- chloro- N- (the 1'- methyl that gained filtrate separates pure by rapid column chromatography Spiral shell [benzo [e] [1,3] oxazines -2,3'- indoline] -2'- methylene) benzsulfamide.Yield: 28%.It is product 3g below Nuclear magnetic resonance experiment data:
1H NMR (400MHz, DMSO) δ: 8.51 (s, 1H), 7.81 (d, J=7.9Hz, 2H), 7.61 (d, J=7.9Hz, 2H), 7.54-7.47 (m, 3H), 7.29 (d, J=7.7Hz, 1H), 7.14-7.09 (m, 3H), 6.85 (d, J=7.9Hz, 1H), 3.36 (s,3H).
13C NMR(100MHz,DMSO)δ:165.1,156.9,152.8,142.4,140.8,137.4,135.2,132.2, 129.8,129.5,128.9,128.5,125.3,122.9,122.8,116.4,116.1,111.7,94.0,29.5.
Embodiment eight:
In a 25mLSchlenk reaction tube equipped with magnetic stir bar, catalyst Rh is added2(esp)2(0.01mmol, 0.02equiv.), N- (3- diazonium -1- methyl indol quinoline -2- ethylidene) -4- methoxybenzenesulphoismide (1.5mmol, 3.0equiv), benzene isoxazole (0.5mmol, 1.0equiv.) and methylene chloride (5mL), nitrogen protection.Place reaction liquid into 60 DEG C Oil bath pan in react about 2~4h, TLC is detected to fully reacting, is then cooled to room temperature reaction solution.It is first passed through when post-processing Sand core funnel suction filtration equipped with silica gel removes catalyst, the product 4- methoxy that gained filtrate separates pure by rapid column chromatography Base-N- (1'- methylspiro [benzo [e] [1,3] oxazines -2,3'- indoline] -2'- methylene) benzsulfamide.Yield: 50%.With Under be product 3h nuclear magnetic resonance experiment data:
1H NMR (400MHz, DMSO) δ: 8.49 (s, 1H), 7.74 (d, J=8.5Hz, 2H), 7.54-7.45 (m, 3H), 7.25 (d, J=7.8Hz, 1H), 7.13 (t, J=7.8Hz, 2H), 7.06 (t, J=7.5Hz, 3H), 6.86 (d, J=8.1Hz, 1H), 3.83(s,3H),3.33(s,3H).
13C NMR(100MHz,DMSO)δ:164.3,162.4,156.6,152.9,140.9,135.4,135.1,132.1, 129.7,128.9,128.8,125.0,122.9,122.7,116.4,116.1,114.5,111.4,56.1,29.3.
Embodiment nine:
In a 25mLSchlenk reaction tube equipped with magnetic stir bar, catalyst Rh is added2(esp)2(0.01mmol, 0.02equiv.), N- (3- diazonium -1- methyl indol quinoline -2- ethylidene) Methanesulfomide (1.5mmol, 3.0equiv), benzene isoxazole (0.5mmol, 1.0equiv.) and methylene chloride (5mL), nitrogen protection.It places reaction liquid into 60 DEG C of oil bath pan and reacts about 2 ~4h, TLC are detected to fully reacting, are then cooled to room temperature reaction solution.The sand core leakage equipped with silica gel is first passed through when post-processing Bucket filters and removes catalyst, the product N- (1'- methylspiro [benzo [e] that gained filtrate separates pure by rapid column chromatography [1,3] oxazines -2,3'- indoline] -2'- methylene) Methanesulfomide.Yield: 34%.It is the nuclear magnetic resonance reality of product 3i below Test data:
1H NMR (400MHz, DMSO) δ: 8.43 (s, 1H), 7.50-7.42 (m, 3H), 7.27 (d, J=7.9Hz, 1H), 7.13- 7.04 (m, 3H), 6.85 (d, J=8.1Hz, 1H), 3.37 (s, 3H), 3.02 (s, 3H)
13C NMR(100MHz,DMSO)δ:165.1,156.7,152.9,141.1,135.1,132.1,129.8,128.7, 124.8,122.9,122.6,116.3,116.1,111.3,94.1,43.7,29.3.
Embodiment ten:
In a 25mLSchlenk reaction tube equipped with magnetic stir bar, catalyst Rh is added2(esp)2(0.01mmol, 0.02equiv.), N- (1- butyl -3- diazonium indoles -2- ethylidene) -4- methyl benzenesulfonamide (1.5mmol, 3.0equiv), Benzene isoxazole (0.5mmol, 1.0equiv.) and methylene chloride (5mL), nitrogen protection.It places reaction liquid into 60 DEG C of oil bath pan About 2~4h is reacted, TLC is detected to fully reacting, is then cooled to room temperature reaction solution.It first passes through when post-processing equipped with silica gel Sand core funnel suction filtration removes catalyst, product N- (the 1'- butyl spiral shell [benzene that gained filtrate separates pure by rapid column chromatography And [e] [1,3] oxazines -2,3'- indoline] -2'- methylene) -4- methyl benzenesulfonamide.Yield: 65%.It is product 3j below Nuclear magnetic resonance experiment data:
1H NMR (400MHz, DMSO) δ: 8.49 (s, 1H), 7.70 (d, J=8.0Hz, 2H), 7.53 (d, J=7.3Hz, 1H), 7.47-7.42 (m, 2H), 7.34 (d, J=7.9Hz, 2H), 7.27 (d, J=7.9Hz, 1H), 7.12 (t, J=7.9Hz, 2H), 7.04 (t, J=7.4Hz, 1H), 6.86 (d, J=8.1Hz, 1H), 3.84 (d, J=5.9Hz, 2H), 2.36 (s, 3H), 1.60- 1.53 (m, 2H), 1.24-1.20 (m, 2H), 0.80 (t, J=7.3Hz, 3H)
13C NMR(100MHz,DMSO)δ:164.4,156.5,152.9,142.7,140.7,140.1,135.1,132.1, 129.9,129.7,128.9,126.6,124.9,123.0,122.7,116.4,116.1,111.5,93.9,41.8,28.7, 21.4,19.7,14.0
Embodiment 11:
In a 25mLSchlenk reaction tube equipped with magnetic stir bar, catalyst Rh is added2(esp)2(0.01mmol, 0.02equiv.), N- (3- diazonium -1- ethyl indoline -2- subunit) -4- methyl benzenesulfonamide (1.5mmol, 3.0equiv), benzene isoxazole (0.5mmol, 1.0equiv.) and methylene chloride (5mL), nitrogen protection.Place reaction liquid into 60 DEG C Oil bath pan in react about 2~4h, TLC is detected to fully reacting, is then cooled to room temperature reaction solution.It is first passed through when post-processing Sand core funnel suction filtration equipped with silica gel removes catalyst, the product N- (1'- that gained filtrate separates pure by rapid column chromatography Ethyl spiral shell [benzo [e] [1,3] oxazines -2,3'- indoline] -2'- methylene) -4- methyl benzenesulfonamide.Yield: 45%.Below It is the nuclear magnetic resonance experiment data of product 3k:
1H NMR (400MHz, DMSO) δ: 8.48 (s, 1H), 7.68 (d, J=8.1Hz, 2H), 7.52 (d, J=7.4Hz, 1H), 7.49-7.44 (m, 2H), 7.35-7.29 (m, 3H), 7.15-7.10 (m, 2H), 7.05 (t, J=7.5Hz, 1H), 6.85 (d, J =8.1Hz, 1H), 3.88 (q, J=6.8Hz, 2H), 2.36 (s, 3H), 1.16 (t, J=7.0Hz, 3H)
13C NMR(100MHz,DMSO)δ:164.0,156.6,152.9,142.7,140.8,139.7,135.1,132.2, 130.0,129.7,128.9,126.6,125.0,123.1,122.7,116.4,116.1,111.4,93.9,37.3,21.4, 12.1.
Embodiment 12:
In a 25mLSchlenk reaction tube equipped with magnetic stir bar, catalyst Rh is added2(esp)2(0.01mmol, 0.02equiv.), N- (1- allyl -3- azepindole -2- subunit) -4- methyl benzenesulfonamide (1.5mmol, 3.0equiv), benzene Isoxazole (0.5mmol, 1.0equiv.) and methylene chloride (5mL), nitrogen protection.It places reaction liquid into anti-in 60 DEG C of oil bath pan Should about 2~4h, TLC detects to fully reacting, is then cooled to room temperature reaction solution.The sand equipped with silica gel is first passed through when post-processing Core funnel suction filtration removes catalyst, product N- (the 1'- allyl spiral shell [benzene that gained filtrate separates pure by rapid column chromatography And [e] [1,3] oxazines -2,3'- indoline] -2'- methylene) -4- methyl benzenesulfonamide.Yield: 60%.It is product 3l below Nuclear magnetic resonance experiment data:
1H NMR (400MHz, DMSO) δ: 8.54 (s, 1H), 7.72 (d, J=8.2Hz, 2H), 7.59-7.56 (m 1H), 7.54- 7.45 (m, 2H), 7.37 (d, J=8.0Hz, 2H), 7.25 (d, J=7.9Hz, 1H), 7.19-7.16 (m, 2H), 7.10 (d, J= 7.9Hz, 1H), 6.89 (d, J=8.1Hz, 1H), 5.88 (tt, J=10.2,6.2Hz, 1H), 5.24 (s, 1H), 5.20 (d, J= 6.0Hz, 1H), 4.53 (d, J=3.4Hz, 2H), 2.40 (s, 3H)
13C NMR(100MHz,DMSO)δ:164.4,156.6,152.9,142.8,140.6,139.8,135.2,132.1, 130.5,129.7,128.9,126.6,125.0,123.0,122.8),118.3,116.4,116.2,111.7,94.0,44.2, 21.4.
Embodiment 13:
In a 25mLSchlenk reaction tube equipped with magnetic stir bar, catalyst Rh is added2(esp)2(0.01mmol, 0.02equiv.), N- (the chloro- 3- diazonium -1- methyl indol quinoline -2- ethylidene of 4-) -4- methyl benzenesulfonamide (1.5mmol, 3.0equiv), benzene isoxazole (0.5mmol, 1.0equiv.) and methylene chloride (5mL), nitrogen protection.Place reaction liquid into 60 DEG C Oil bath pan in react about 2~4h, TLC is detected to fully reacting, is then cooled to room temperature reaction solution.It is first passed through when post-processing Sand core funnel suction filtration equipped with silica gel removes catalyst, the product N- (4'- that gained filtrate separates pure by rapid column chromatography Chloro- 1'- methylspiro [benzo [e] [1,3] oxazines -2,3'- indoline] -2'- methylene) -4- methyl benzenesulfonamide.Yield: 20%.It is the nuclear magnetic resonance experiment data of product 3m below:
1H NMR (400MHz, DMSO) δ: 8.49 (s, 1H), 7.63 (d, J=8.1Hz, 2H), 7.50-7.43 (m, 3H), 7.32 (d, J=8.0Hz, 2H), 7.27 (d, J=7.9Hz, 1H), 7.21 (d, J=8.1Hz, 1H), 7.05 (d, J=7.3Hz, 1H), 6.77 (d, J=8.5Hz, 1H), 3.32 (s, 3H), 2.36 (s, 3H)
13C NMR(100MHz,DMSO)δ:163.3,158.7,153.7,143.5,142.9,140.6,135.1,133.2, 130.5,129.8,128.6,127.9,126.4,125.8,122.1,116.1,114.9,110.4,95.2,29.9,21.4.
Embodiment 14:
In a 25mLSchlenk reaction tube equipped with magnetic stir bar, catalyst Rh is added2(esp)2(0.01mmol, 0.02equiv.), N- (3- azo -5- methoxyl group -1- methyl indoline -2- subunit) -4- methyl benzenesulfonamide (1.5mmol, 3.0equiv), benzene isoxazole (0.5mmol, 1.0equiv.) and methylene chloride (5mL), nitrogen protection.Place reaction liquid into 60 DEG C Oil bath pan in react about 2~4h, TLC is detected to fully reacting, is then cooled to room temperature reaction solution.It is first passed through when post-processing Sand core funnel suction filtration equipped with silica gel removes catalyst, the product N- (5'- that gained filtrate separates pure by rapid column chromatography Methoxyl group -1'- methylspiro [benzo [e] [1,3] oxazines -2,3'- indoline] -2'- methylene) -4- methyl benzenesulfonamide.It produces Rate: 45%.It is the nuclear magnetic resonance experiment data of product 3n below:
1H NMR (400MHz, DMSO) δ: 8.48 (s, 1H), 7.65 (d, J=8.1Hz, 2H), 7.52-7.46 (m, 2H), 7.31 (d, J=8.0Hz, 2H), 7.20 (d, J=8.6Hz, 1H), 7.12 (t, J=7.4Hz, 1H), 7.06-7.03 (m, 1H), 6.84 (d, J=8.1Hz, 1H), 6.68 (d, J=2.3Hz, 1H), 3.65 (s, 3H), 3.32 (s, 3H), 2.36 (s, 3H)
13C NMR(100MHz,DMSO)δ:164.1,157.2,157.0,152.8,142.6,141.0,135.1,134.2, 131.1,129.7,128.9,126.5,122.7,116.4,116.1,112.3,110.1,94.0,56.3,29.7,21.4.
Embodiment 15:
In a 25mLSchlenk reaction tube equipped with magnetic stir bar, catalyst Rh is added2(esp)2(0.01mmol, 0.02equiv.), N- (the chloro- 3- diazonium -1- methyl indol quinoline -2- ethylidene of 6-) -4- methyl benzenesulfonamide (1.5mmol, 3.0equiv), benzene isoxazole (0.5mmol, 1.0equiv.) and methylene chloride (5mL), nitrogen protection.Place reaction liquid into 60 DEG C Oil bath pan in react about 2~4h, TLC is detected to fully reacting, is then cooled to room temperature reaction solution.It is first passed through when post-processing Sand core funnel suction filtration equipped with silica gel removes catalyst, the product N- (6'- that gained filtrate separates pure by rapid column chromatography Chloro- 1'- methylspiro [benzo [e] [1,3] oxazines -2,3'- indoline] -2'- methylene) -4- methyl benzenesulfonamide.Yield: 16%.It is the nuclear magnetic resonance experiment data of product 3o below:
1H NMR (400MHz, DMSO) δ: 8.50 (s, 1H), 7.69 (d, J=8.2Hz, 2H), 7.54-7.46 (m, 2H), 7.44 (d, J=1.3Hz, 1H), 7.34 (d, J=8.1Hz, 2H), 7.12 (dt, J=8.0,4.7Hz, 3H), 6.86 (d, J=8.1Hz, 1H),3.32(s,3H),2.37(s,3H).
13C NMR(100MHz,DMSO)δ:164.7,157.0,152.7,143.0,142.6,140.4,136.5,135.3, 129.8,129.0,128.4,126.7,124.6,124.3,122.9,116.3,116.1,112.1,93.4,29.6,21.4.
Embodiment 16:
In a 25mLSchlenk reaction tube equipped with magnetic stir bar, catalyst Rh is added2(esp)2(0.01mmol, 0.02equiv.), N- (3- diazonium -1,7- dimethyl indole quinoline -2- ethylidene) -4- methyl benzenesulfonamide (1.5mmol, 3.0equiv), benzene isoxazole (0.5mmol, 1.0equiv.) and methylene chloride (5mL), nitrogen protection.Place reaction liquid into 60 DEG C Oil bath pan in react about 2~4h, TLC is detected to fully reacting, is then cooled to room temperature reaction solution.It is first passed through when post-processing Sand core funnel suction filtration equipped with silica gel removes catalyst, product N- that gained filtrate separates pure by rapid column chromatography (1', 7'- dimethyl spiral shell [benzo [e] [1,3] oxazines -2,3'- indoline] -2'- methylene) -4- methyl benzenesulfonamide.Yield: 58%.It is the nuclear magnetic resonance experiment data of product 3p below:
1H NMR (400MHz, DMSO) δ: 8.47 (s, 1H), 7.69 (d, J=8.2Hz, 2H), 7.52-7.44 (m, 2H), 7.34 (d, J=8.1Hz, 2H), 7.22-7.20 (m, 1H), 7.10 (s, 1H), 6.95 (t, J=4.6Hz, 2H), 6.81 (d, J= 8.1Hz,1H),3.57(s,3H),2.57(s,3H),2.37(s,3H).
13C NMR(100MHz,DMSO)δ:165.4,156.4,152.9,142.7,141.0,138.3,135.7,135.1, 130.6,129.7,128.8,126.6,125.0,122.9,122.6,120.7,116.3,116.1,93.2,32.5,21.4, 19.2.
Embodiment 17:
In a 100mL Schlenk reaction tube equipped with magnetic stir bar, catalyst Rh is added2(esp)2(0.1mmol)、 N- (3- diazonium -1- methyl indoline -2- subunit) -4- methyl benzenesulfonamide (4.89g, 15mmol), benzene isoxazole (0.6g, 5mmol) and methylene chloride (50mL), nitrogen protection.Place reaction liquid into 60 DEG C of oil bath pan and react about 4h, TLC detect to Then reaction solution is cooled to room temperature by fully reacting.The sand core funnel suction filtration equipped with silica gel is first passed through when post-processing removes catalysis Agent, the product 4- methyl-N- that gained filtrate separates pure by rapid column chromatography ([dislike 1'- methylspiro by benzo [e] [1,3] Piperazine -2,3'- indoline] -2'- methylene) benzsulfamide.Yield: 1.42g, 68%.It is the nuclear magnetic resonance experiment of product 3a below Data:
1H NMR (400MHz, DMSO) δ: 8.50 (s, 1H), 7.69 (d, J=8.2Hz, 2H), 7.53 (d, J=6.6Hz, 1H), 7.48 (t, J=7.7Hz, 2H), 7.34 (d, J=8.0Hz, 2H), 7.27 (t, J=6.0Hz, 1H), 7.15-7.07 (m, 3H), 6.85 (d, J=8.1Hz, 1H), 3.34 (s, 3H), 2.37 (s, 3H)
13C NMR(100MHz,DMSO)δ:164.6,156.7,152.9,142.8,140.9,140.8,135.1,132.1, 129.8,129.7,128.9,126.6,125.0,122.9,122.7,116.4,116.1,111.5,94.0,29.4,21.4.
Embodiment 18:
In a 250mL Schlenk reaction tube equipped with magnetic stir bar, catalyst Rh is added2(esp)2(0.3mmol)、 N- (3- diazonium -1- methyl indoline -2- subunit) -4- methyl benzenesulfonamide (14.67g, 45mmol), benzene isoxazole (1.8g, 15mmol) and methylene chloride (150mL), nitrogen protection.It places reaction liquid into 60 DEG C of oil bath pan and reacts about 4h, TLC detection To fully reacting, then reaction solution is cooled to room temperature.The sand core funnel suction filtration equipped with silica gel is first passed through when post-processing to remove and urge Agent, the product 4- methyl-N- that gained filtrate separates pure by rapid column chromatography ([dislike 1'- methylspiro by benzo [e] [1,3] Piperazine -2,3'- indoline] -2'- methylene) benzsulfamide.Yield: 4.13g, 66%.It is the nuclear magnetic resonance experiment of product 3a below Data:
1H NMR (400MHz, DMSO) δ: 8.50 (s, 1H), 7.69 (d, J=8.2Hz, 2H), 7.53 (d, J=6.6Hz, 1H), 7.48 (t, J=7.7Hz, 2H), 7.34 (d, J=8.0Hz, 2H), 7.27 (t, J=6.0Hz, 1H), 7.15-7.07 (m, 3H), 6.85 (d, J=8.1Hz, 1H), 3.34 (s, 3H), 2.37 (s, 3H)
13C NMR(100MHz,DMSO)δ:164.6,156.7,152.9,142.8,140.9,140.8,135.1,132.1, 129.8,129.7,128.9,126.6,125.0,122.9,122.7,116.4,116.1,111.5,94.0,29.4,21.4.
Embodiment 19:
In a 1.0L Schlenk reaction tube equipped with magnetic stir bar, catalyst Rh is added2(esp)2(0.45mmol)、 N- (3- diazonium -1- methyl indoline -2- subunit) -4- methyl benzenesulfonamide (45g), benzene isoxazole (5.4g) and methylene chloride (500mL), nitrogen protection.It places reaction liquid into 60 DEG C of oil bath pan and reacts about 4h, TLC is detected to fully reacting, then will Reaction solution is cooled to room temperature.The sand core funnel suction filtration equipped with silica gel is first passed through when post-processing and removes catalyst, and gained filtrate passes through Product 4- methyl-N- (the 1'- methylspiro [benzo [e] [1,3] oxazines -2,3'- indoline]-that rapid column chromatography separates pure 2'- methylene) benzsulfamide.Yield: 11.7g, 62%.It is the nuclear magnetic resonance experiment data of product 3a below:
1H NMR (400MHz, DMSO) δ: 8.50 (s, 1H), 7.69 (d, J=8.2Hz, 2H), 7.53 (d, J=6.6Hz, 1H), 7.48 (t, J=7.7Hz, 2H), 7.34 (d, J=8.0Hz, 2H), 7.27 (t, J=6.0Hz, 1H), 7.15-7.07 (m, 3H), 6.85 (d, J=8.1Hz, 1H), 3.34 (s, 3H), 2.37 (s, 3H)
13C NMR(100MHz,DMSO)δ:164.6,156.7,152.9,142.8,140.9,140.8,135.1,132.1, 129.8,129.7,128.9,126.6,125.0,122.9,122.7,116.4,116.1,111.5,94.0,29.4,21.4.

Claims (7)

1. indoles spirooxazine heterocycle compound, which is characterized in that have the structure as shown in formula (III):
In formula, R1Selected from fragrant sulfonyl, alkyl sulphonyl；R2、R3、R4Independently selected from hydrogen, alkyl, alkoxy, fluorine, chlorine, bromine, Cyano, nitro, ester group, silicon substrate.
2. the preparation method of indoles spirooxazine heterocycle compound according to claim 1, which is characterized in that using such as formula (I) indoles shown in weight nitrogen compound and the structure different azole compounds of benzene as shown in formula (II) as reactant, make its It reacts under conditions of transition metal-catalyzed, obtains the indoles spirooxazine heterocycle compound；
In formula, R1Selected from fragrant sulfonyl, alkyl sulphonyl；R2、R3、R4Independently selected from hydrogen, alkyl, alkoxy, fluorine, chlorine, bromine, Cyano, nitro, ester group, silicon substrate.
3. according to the method described in claim 2, it is characterized in that, transition-metal catalyst be dimerization rhodium acetate, it is rhodium caprylate, double [(Α, Α, Α ', Α '-tetramethyl -1,3- benzene dipropionic acid) rhodium], acetylacetone,2,4-pentanedione (1,5- cyclo-octadiene) rhodium, the bis- (hexichol of 1,3- Base phosphine propane) Nickel Chloride, (bis- (diphenylphosphine) ferrocene of 1,1'-) Nickel Chloride or copper trifluoromethanesulfcomposite.
4. according to the method described in claim 2, it is characterized in that, the solvent that reaction uses is 1,2- dichloroethanes, dichloromethane Alkane, chloroform, acetonitrile, paraxylene, toluene, N,N-dimethylformamide, n-hexane, tetrahydrofuran, 1,4- dioxane, Or dimethyl sulfoxide.
5. according to the method described in claim 2, the reaction time is 2~4h it is characterized in that, the temperature of reaction is 60 DEG C.
6. according to the method described in claim 2, it is characterized in that, reactant 3- indoles diazonium -2- imine compound and benzene The molar ratio of different azole compounds is 3:1.
7. the application of indoles spirooxazine heterocycle compound according to claim 1.
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CN102336769A (en) * 2011-07-06 2012-02-01 华东理工大学 Simple and novel method for synthesizing spiro[oxoindole-3,5'-oxazoline] heterocyclic compound

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