CN102898388B - Method for synthesizing substituted benzo[alpha]phenazine compound - Google Patents
Method for synthesizing substituted benzo[alpha]phenazine compound Download PDFInfo
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Abstract
The invention provides a method for synthesizing a substituted benzo[alpha]phenazine compound, which comprises the following steps: synthesizing 2-(2-haloaryl)-3-methyl quinoxaline (I) from 2-haloaryl ethyl ketone and substituted o-phenylenediamine used as raw materials; generating 2-(2-haloaryl)-3-vinyl quinoxaline (II) through the reaction with N-methyl amide in the presence of an iron catalyst; and finally, obtaining the substituted benzo[alpha]phenazine compound (III) through Heck cyclization reaction.
Description
Technical field
The present invention relates to the novel method of a kind of synthesizing substituted also [α] azophenlyene compounds.
Background technology
Benzo [α] azophenlyene compounds is the important organic compound that a class has biologic activity.In recent years, because its outstanding biological activity showing at anti-malarial, anti-hepatitis and the aspect such as antitumor is subject to extensive concern
[1].At present, the traditional technology of synthesizing substituted also [α] azophenlyene compounds mainly contains following several: a): take naphthols as raw material, through steps such as peroxidation chemical combination, obtain replacing benzo [α] azophenlyene compounds, its advantage is that step is short, but shortcoming is also very obvious, as poor in the expansion of substrate, yield is not high, is not the synthetic route of a simple general-purpose
[2]; B): take naphthylamines as raw material is through the coupled reaction with 2-halo-3-nitro-aromatic compound, then obtain product through steps such as reductive ring closures, exist equally the problems such as substrate is difficult to obtain, universality is low, yield is not high
[3].Therefore, one anxious to be developed to solve the above problems by the raw material simple and easy to get synthetic corresponding universal method that replaces benzo [α] azophenlyene compounds of setting out.
Summary of the invention
In recent years, the organic catalyzed reaction with its efficient katalysis and novelty of metal is more and more applied among the structure of some complicated aromatic rings.The present invention is exactly under this background, the coupling carbon-to-carbon coupling synthesizing ethylene based compound of metal catalytic of independent development of take is committed step, again forefathers' work has been changed with application and development one directly take containing various substituent 2-halogenated aryl ethyl ketones be raw material, after α-bromination, generate 2-(2-halogenated aryl with substituted o-phenylenediamine cyclization)-3-methyl-quinoxaline, at iron catalyst and oxygenant, leave the vinylation reaction that " the N-methyl " captured in N-methyl nitrosourea realizes methyl, generate 2-(2-halogenated aryl)-3-vinyl quinoxaline, finally by Heck ring closure reaction, generate and replace benzo [α] azophenlyene.
Concrete, the technical solution used in the present invention is:
A kind of method of synthetic replacement benzo [α] azophenlyene compounds as shown in formula III, , described method is: the 2-halogenated aryl ethyl ketone shown in formula IV of take is raw material, after α-bromination, carry out ring-closure reaction with the substituted o-phenylenediamine shown in formula V, 2-(2-halogenated aryl shown in synthesis type I)-3-methyl-quinoxaline, 2-(2-halogenated aryl shown in formula I)-3-methyl-quinoxaline reacts with the N-methyl nitrosourea shown in formula VI under iron catalyst and oxygenant existence, 2-(2-halogenated aryl shown in production II)-3-vinyl quinoxaline, 2-(2-halogenated aryl shown in formula II)-3-vinyl quinoxaline carries out Heck ring closure reaction under palladium catalyst effect, generate replacement benzo [α] the azophenlyene compounds shown in formula III,
In formula I, formula II, formula III or formula IV, R
1, R
2, R
3, R
4independent is separately H, methyl, methoxyl group, phenyl, F, Cl, Br, I, NO
2, CF
3, COO CH
3, COO C
2h
5, CN; Or R
2, R
3connect into ring with its two carbon that connect on phenyl ring, form a new phenyl ring; Preferably, described R
1, R
2, R
3, R
4be all H; Or R
1, R
3, R
4for H, R
2for methoxyl group; Or R
1, R
4for H, R
2, R
3connect into ring with its two carbon that connect on phenyl ring, form a new phenyl ring;
In formula I, formula II, formula III or formula V, R
5, R
6, R
7, R
8independent is separately H, methyl, Cl, phenyl, COO CH
3; Preferred R
5, R
6, R
7, R
8be all H
In formula I, formula II or formula IV, X is Cl, Br or I, is preferably Br;
In formula VI, R is H, methyl or phenyl, is preferably methyl.
Further, said method comprising the steps of:
(1) after being dissolved with ether or methylene dichloride, the 2-halogenated aryl ethyl ketone shown in formula IV under room temperature, splashes into bromine simple substance, dropwise under room temperature stirring reaction 15 ~ 60 minutes, then in reaction mixture, add saturated sodium thiosulfate solution washing to colourless, it is dry that separatory is got organic phase, decompression desolvation, gained crude product is alpha-brominated 2-halogenated aryl ethyl ketone, and crude product is dissolved with acetonitrile, adds HClO
4siO
2substituted o-phenylenediamine shown in catalyzer and formula V, in room temperature under reflux temperature (preferably 60 ℃) stirring reaction, TLC follow the tracks of to detect to reaction and finishes, gained reaction solution a aftertreatment obtains the 2-(2-halogenated aryl shown in formula I)-3-methyl-quinoxaline; 2-halogenated aryl ethyl ketone shown in described formula IV is 1:1.0 ~ 1.5 with the ratio of the amount of substance of bromine simple substance, preferably 1:1.2; Described alpha-brominated 2-halogenated aryl ethyl ketone is 1:1 ~ 5 with the ratio of the amount of substance of the substituted o-phenylenediamine shown in formula V, preferably 1:2; The amount of substance of described alpha-brominated 2-halogenated aryl ethyl ketone comes in the amount of substance of the 2-halogenated aryl ethyl ketone shown in formula IV;
(2) the 2-(2-halogenated aryl shown in formula I)-3-methyl-quinoxaline is under iron catalyst and oxygenant existence, react with the N-methyl nitrosourea shown in formula VI, 20 ~ 160 ℃ of temperature of reaction, TLC follows the tracks of and detects to reaction end, and reaction solution b aftertreatment obtains the 2-(2-halogenated aryl shown in formula II)-3-vinyl quinoxaline; Described iron catalyst is molysite or ferrous salt, and described oxygenant is persulphate,, the 2-(2-halogenated aryl shown in described formula I) ratio of amount of substance of-3-methyl-quinoxaline, iron catalyst, oxygenant is 1:0.001 ~ 0.3:1 ~ 5; 2-(2-halogenated aryl shown in described formula I) concentration of-3-methyl-quinoxaline in the N-methyl nitrosourea shown in formula VI is 0.01 ~ 2mol/L;
(3) the 2-(2-halogenated aryl shown in formula II)-3-vinyl quinoxaline and palladium catalyst, inorganic silver salt additives rare gas element as argon gas, nitrogen environment in, add tertiary amine compounds and polar non-proton organic solvent, at 50 ~ 160 ℃ of temperature, carry out Heck ring closure reaction, TLC follows the tracks of and detects to reaction end, and reaction solution c separating treatment obtains replacement benzo [α] the azophenlyene compounds shown in formula III; Described palladium catalyst is tetrakis triphenylphosphine palladium or three (dibenzalacetone) two palladiums, is preferably tetrakis triphenylphosphine palladium; The ratio of the amount of substance of the 2-(2-halogenated aryl shown in described formula II)-3-vinyl quinoxaline, palladium catalyst, inorganic silver salt additives, tertiary amine compounds is 1:0.001 ~ 0.15:1 ~ 4:1 ~ 10.
In described step (1), described HClO
4siO
2the quality consumption of catalyzer is counted 20 ~ 150mg/mmol with the amount of substance of alpha-brominated 2-halogenated aryl ethyl ketone, preferred 70mg/mmol, the amount of substance of described alpha-brominated 2-halogenated aryl ethyl ketone comes in the amount of substance of the 2-halogenated aryl ethyl ketone shown in formula IV.
In described step (1), the volumetric usage of described ether or methylene dichloride is counted 1 ~ 5mL/mmol with the amount of substance of the 2-halogenated aryl ethyl ketone shown in formula IV conventionally.
In described step (1), described acetonitrile volumetric usage conventionally with the amount of substance of the 2-halogenated aryl ethyl ketone shown in formula IV, count 1 ~ 10mL/mmol.
HClO in described step (1)
4siO
2be according to document A. K. Chakraborti, the method in R. Gulhane. Chem. Commun. 2003,1896. prepares.
In described step (1), described reaction solution a post-treating method is: after reaction finishes, reaction solution a filters, filtrate decompression is except desolventizing, separated through column chromatography chromatogram method, take sherwood oil or hexanaphthene and ethyl acetate preferred 6 ~ 15 ︰ 1 of 2 ~ 30:1(by volume) solvent that mixes is as eluent, collect elutriant steam desolventize the 2-(2-halogenated aryl obtaining shown in formula I)-3-methyl-quinoxaline.
In described step (2), vinylated reagent is the N-methyl nitrosourea shown in formula VI, under the existence of iron catalyst and oxygenant, capture the carbon atom in " N-methyl " structural unit in N-methyl nitrosourea, thereby realize the vinylated of methyl in substrate, reach the object that increases carbochain, also successfully built the carbon skeleton structure that replaces phenonaphthazine simultaneously.The N-methyl nitrosourea of selecting comprises N, dinethylformamide (DMF), N, N-N,N-DIMETHYLACETAMIDE (DMA) or N, N-dimethyl benzamide etc., also the solvent that conduct is reacted when making vinylated reagent, 2-(2-halogenated aryl shown in substrate formula I) concentration of-3-methyl-quinoxaline in the N-methyl nitrosourea shown in dissolvant type VI is being proper between 0.01 ~ 2mol/L, and best concentration is 0.1 mol/L.The complete solvent of unreacted can be recycled, and has certain industrial prospect.
In described step (2), the 2-(2-halogenated aryl shown in formula I) ratio of the amount of substance of-3-methyl-quinoxaline, iron catalyst, oxygenant is 1:0.001 ~ 0.3:1 ~ 5, is preferably 1:0:01 ~ 0.1:1.5 ~ 3, most preferably is 1:0.025:2.
Described iron catalyst is molysite or ferrous salt, be preferably iron trichloride, ferric sulfate, iron nitrate, ferric acetyl acetonade, ferrous sulfate, iron protochloride, Iron(III) chloride hexahydrate, Iron dichloride tetrahydrate, Fe(NO3)39H2O or ferrous sulfate, Iron(III) chloride hexahydrate (ferric sesquichloride) more preferably, FERRIC CHLORIDE ANHYDROUS, ferrous sulfate, Iron dichloride tetrahydrate or Fe(NO3)39H2O.Containing the benefit of the inorganic molysite of crystal water, be to deposit easy to use, be cheaply easy to get and active high.
Described oxygenant is persulphate, is preferably ammonium persulphate, Potassium Persulphate, Sodium Persulfate or potassium hydrogen persulfate composite salts, more preferably ammonium persulphate or Potassium Persulphate, most preferably Potassium Persulphate.
The vinylation reaction of described step (2) all can be carried out in a wider range of reaction temperature, and recommendation response temperature is 20 ℃ ~ 160 ℃, and preferably 60 ~ 120 ℃, most preferably temperature of reaction is 110 ℃.In reaction process, with TLC, follow the tracks of and detect to reaction end.The time range of reaction is wider, between 0.5 hour to 12 hours, at preferred catalyzer, oxygenant, concentration of substrate and temperature, conventionally at 2 hours to 6 hours, can finish reaction, needs in some instances by extending the reaction times to improve yield.
In described step (2), described reaction solution b post-treating method is: after reaction finishes, reaction solution b filters, filtrate adds ether dilution, with after saturated common salt water washing, to get dry rear steaming of organic phase and desolventize, residuum is through column chromatography for separation, take sherwood oil or hexanaphthene and ethyl acetate preferred 8 ~ 15 ︰ 1 of 2 ~ 30:1(by volume) solvent that mixes is eluent, collect elutriant steam desolventize the 2-(2-halogenated aryl obtaining shown in formula II)-3-vinyl quinoxaline.
In described step (3), the ratio of the amount of substance of the 2-(2-halogenated aryl shown in described formula II)-3-vinyl quinoxaline, palladium catalyst, inorganic silver salt additives, tertiary amine compounds is 1:0.001 ~ 0.15:1 ~ 4:1 ~ 10, preferred 1:0.02 ~ 0.1:1 ~ 2: 2 ~ 4,1:0.05:2 most preferably: 4.
In described step (3), described tertiary amine compounds is triethylamine, Tri-n-Propylamine or DIPEA, preferably triethylamine.
In described step (3), described inorganic silver salt additives is Sulfuric acid disilver salt or Silver Nitrate, preferably sulfuric acid silver.
In described step (3), described polar non-proton organic solvent is N,N-dimethylacetamide or DMF, preferably N,N-dimethylacetamide.The consumption of described polar non-proton organic solvent is with the 2-(2-halogenated aryl shown in formula II) amount of substance of-3-vinyl quinoxaline counts 10 ~ 50mL/mmol.
The temperature of reaction of described step (3) is 50 ~ 160 ℃, is preferably 100-140 ℃, most preferably 140 ℃.
In described step (3), described reaction solution c method for separating and processing is: after reaction finishes, reaction solution c filters, filtrate adds ether dilution, with after saturated common salt water washing, to get dry rear steaming of organic phase and desolventize, residuum is through column chromatography for separation, take sherwood oil and ethyl acetate preferred 8 ~ 15 ︰ 1 of 2 ~ 30:1(by volume) solvent that mixes is eluent, collects elutriant and steams and desolventize replacement benzo [α] the azophenlyene compounds obtaining shown in formula III.
2-halogenated aryl ethyl ketone shown in formula IV of the present invention can be reduced to ketone and make through isonitrosomethyl, ortho position C-H activation halogenation, de-oxime by common substituted aryl ethyl ketone, D. Kalyani, A. R. Dick, W. Q. Anani, M. S. Sanford. Tetrahedron 2006, aforesaid method is disclosed in 62,11483.Reaction formula is as follows:
Concrete, described method is, by aryl ethyl ketone and CH suc as formula shown in VII
3oNH
2hCl, pyridine reflux in methanol solvate, stirring reaction 12 ~ 30 hours, reaction finishes to be cooled to room temperature, reaction solution removes under reduced pressure in the backward resistates of solvent and adds water, by extracted with diethyl ether, get organic phase dry steam to desolventize by column chromatography for separation obtain the compound shown in formula VIII, the compound shown in formula VIII and N-bromosuccinimide (abbreviation NBS) are at Pd(OAc)
2under catalyst action, in acetic acid, be heated to 100 ~ 120 ℃ of stirring reactions 12 ~ 20 hours, after reaction finishes rear reaction solution and removes solvent under reduced pressure, gained residuum is through column chromatography for separation, obtain the compound shown in formula IX, compound shown in formula IX adds in the Isosorbide-5-Nitrae-dioxane solution of hydrogenchloride of excessive 5mol/L, reacting by heating at 80 ℃, TLC detects to reaction end, and after reaction solution removes solvent under reduced pressure, residuum obtains the 2-halogenated aryl ethyl ketone shown in formula IV through column chromatography for separation; Aryl ethyl ketone and CH shown in described formula VII
3oNH
2the ratio of the amount of substance of HCl, pyridine is 1:1.5 ~ 3:6 ~ 10; Compound shown in described formula VIII and NBS, Pd(OAc)
2the ratio of amount of substance be 1:1 ~ 1.5:0.03 ~ 0.1.
Beneficial effect of the present invention is:
(1) reaction reagent comprises the low toxicities such as catalyzer, oxygenant and solvent and is cheaply easy to get.
(2) reaction conditions is gentle, simple to operate.
(3) substrate adaptability is good, and yield is high.
(4) raw material is easy to get, and reactions steps is simple, is a kind of general novel method of synthetic all kinds of replacement benzos [α] azophenlyene.
Replacement benzo [α] the azophenlyene substrate wide adaptability that the present invention synthesizes, substituting group in raw material comprises hydrogen, alkyl, alkoxyl group, ester group, hydroxyl, amido, nitro, trifluoromethyl, halogen or aromatic group etc., can also be polysubstituted substituted aryl, heterocyclic aryl etc.In sum, this reaction provides a general variation route from synthesizing substituted also [α] azophenlyene of simple raw material, has certain industrial prospect.
Embodiment
By embodiment, the present invention will be further described in the present invention below, but protection scope of the present invention is not limited to this.
HClO in the embodiment of the present invention
4siO
2prepare by the following method: by 70% HClO
4the aqueous solution (1.25g) joins in the ether suspension that is mixed with silica gel (24 g, 200-300 order) and stirs and spend the night, and pressurization removes solution, gained solid is incubated to 72 hours in vacuum drying oven at 100 ℃ obtains HClO
4siO
2pressed powder.
Embodiment 1
[1] by 2-bromo Propiophenone (5.0 mmol), be dissolved in 5mL ether, under room temperature, drip bromine (6.0 mmol), wait to dropwise and continue to stir 40 minutes, to adding in system saturated sodium thiosulfate solution washing to after colourless, separatory is got organic phase and is dried, and removal of solvent under reduced pressure obtains alpha-brominated 2-bromo Propiophenone crude product, without purifying, directly carries out ring closure reaction.Alpha-brominated 2-bromo Propiophenone is dissolved with 10mL acetonitrile, add HClO
4siO
2(350 mg) and O-Phenylene Diamine (10 mmol), mixture is stirring reaction at 60 ℃, and TLC detects to reaction end.Mixture is after filtration, obtain faint yellow solid 2-(2-bromophenyl with column chromatography chromatogram method (leacheate proportioning: sherwood oil is to ethyl acetate volume ratio 15 ︰ 1) separation after filtrate decompression desolvation)-3-methyl-quinoxaline 0.998g(yield 67%).
[2] by 2-(2-bromophenyl)-3-methyl-quinoxaline 119.2 mg (0.4 mmol), Iron(III) chloride hexahydrate 2.7 mg (0.01 mmol), Potassium Persulphate 216 mg(0.8 mmol), N,N-dimethylacetamide (4 mL) adds in 25 mL flasks.110 ℃ of reactions of mixture heating after 3 hours TLC detection reaction finish, after adding 20 mL ether dilutions, with saturated aqueous common salt (10 mL X 3), wash, organic phase is sloughed solvent with decompression after anhydrous sodium sulfate drying, with column chromatography chromatogram method (leacheate proportioning: sherwood oil is to ethyl acetate volume ratio 15 ︰ 1) separation, obtains weak yellow liquid 2-(2-bromophenyl)-3-vinyl quinoxaline 107.8 mg(87% yields).
[3] by 2-(2-bromophenyl)-3-vinyl quinoxaline 46.5 mg (0.15 mmol), tetrakis triphenylphosphine palladium 7.3 mg(0.0075 mmol), Sulfuric acid disilver salt 94 mg(0.3 mmol) add successively in the dry reaction pipe of 10 mL.After reaction tubes is vacuumized, be filled with argon gas, repeatable operation three times is used needle cylinder injection triethylamine 61 mg(0.6 mmol under argon atmosphere) and degassed dry N,N-dimethylacetamide 2 mL.By mixture reacting by heating 2 hours in 140 ℃ of oil baths.After TLC detection reaction finishes, reaction solution is with washing with saturated aqueous common salt (10 mL X 3) after 15 mL ether dilutions, organic phase is sloughed solvent with decompression after anhydrous sodium sulfate drying, with column chromatography chromatogram method (leacheate proportioning: sherwood oil is to ethyl acetate volume ratio 15 ︰ 1) separation, obtains yellow solid benzo [α] azophenlyene 28.6 mg(83% yields).
Yellow solid; R
f=0.42 (petroleum ether-EtOAc=6:1); Mp=142-143 ℃;
1h NMR (500 MHz, CDCl
3): δ=9.41 (d, J=8.5 Hz, 1H); 8.38-8.36 (m, 1H), 8.30-8.28 (m; 1H), 8.01 (d, J=9.5 Hz; 1H), 7.97 (d, J=9.5 Hz; 1H), 7.91-7.86 (m, 3H); (7.82-7.76 m, 2H) ppm;
13c NMR (125 MHz, CDCl
3): δ=143.4,142.7,142.6,142.0,133.3,133.2,131.1,130.0,129.8 (2C), 129.7,129.2,128.2,127.9,127.1,125.4 ppm; MS (EI, 70eV): m/z (%)=230 (100) [M+].
Embodiment 2
[1] by the bromo-4-p-methoxy-phenyl of 2-ethyl ketone (5.0 mmol), be dissolved in 5mL methylene dichloride, under room temperature, drip bromine (6.0 mmol), wait to dropwise and continue stirring reaction 20 minutes, to adding in system saturated sodium thiosulfate solution washing to after colourless, separatory is got the dry removal of solvent under reduced pressure of organic phase and is obtained the bromo-4-p-methoxy-phenyl of alpha-brominated 2-ethyl ketone crude product, without purifying, directly carries out ring closure reaction.The bromo-4-p-methoxy-phenyl of alpha-brominated 2-ethyl ketone is dissolved with 10mL acetonitrile, adds HClO4SiO2(350 mg) and O-Phenylene Diamine (10 mmol), mixture is stirring reaction at 60 ℃, and TLC detects to reacting and finishes.Mixture is after filtration, obtain the bromo-4-p-methoxy-phenyl of faint yellow solid 2-(2-with column chromatography chromatogram method (leacheate proportioning: sherwood oil is to ethyl acetate volume ratio 15 ︰ 1) separation after filtrate decompression desolvation)-3-methyl-quinoxaline 1.05g (yield 64 %).
[2] by the bromo-4-p-methoxy-phenyl of 2-(2-)-3-methyl-quinoxaline 131.2 mg (0.4 mmol), Iron(III) chloride hexahydrate 2.7 mg (0.01 mmol), Potassium Persulphate 216 mg(0.8 mmol), N,N-dimethylacetamide (4 mL) adds in 25 mL flasks.110 ℃ of reactions of mixture heating after 3 hours TLC detection reaction finish, after adding 20 mL ether dilutions, with saturated aqueous common salt (10 mL X 3), wash, organic phase is sloughed solvent with decompression after anhydrous sodium sulfate drying, with column chromatography chromatogram method (leacheate proportioning: sherwood oil is to ethyl acetate volume ratio 15 ︰ 1) separation, obtains the bromo-4-p-methoxy-phenyl of weak yellow liquid 2-(2-)-3-vinyl quinoxaline 118.3 mg(87% yields).
[3] by the bromo-4-p-methoxy-phenyl of 2-(2-)-3-vinyl quinoxaline 51.0 mg (0.15 mmol), tetrakis triphenylphosphine palladium 7.3 mg(0.0075 mmol), Sulfuric acid disilver salt 94 mg(0.3 mmol) add successively in the dry reaction pipe of 10 mL.After reaction tubes is vacuumized, be filled with argon gas, repeatable operation three times is used needle cylinder injection triethylamine 61 mg(0.6 mmol under argon atmosphere) and degassed dry N,N-dimethylacetamide 2 mL.By mixture reacting by heating 2 hours in 140 ℃ of oil baths.After TLC detection reaction finishes, reaction solution is with washing with saturated aqueous common salt (10 mL X 3) after 15 mL ether dilutions, organic phase is sloughed solvent with decompression after anhydrous sodium sulfate drying, with column chromatography chromatogram method (leacheate proportioning: sherwood oil is to ethyl acetate volume ratio 15 ︰ 1) separation, obtains yellow solid 3-methoxyl group benzo [α] azophenlyene 32.4 mg(83% yields).
Yellow solid; R
f=0.28 (petroleum ether-EtOAc=6:1); Mp=166-167 ℃;
1h NMR (500 MHz, CDCl
3): δ=9.30 (d, J=8.5 Hz, 1H), 8.33 (dd, J
1=7.3 Hz, J
2=2.3 Hz, 1H), 8.27 (dd, J
1=7.3 Hz, J
2=2.3 Hz, 1H), 7.96 (d, J=9.0 Hz, 1H), 7.93 (d, J=9.0 Hz, 1H), 7.87-7.82 (m, 2 H), 7.38 (dd, J
1=9.0 Hz, J
2=2.5 Hz, 1H), 7.28 (d, J=2.5 Hz, 1H), 4.00 (s, 3H) ppm;
13c NMR (125 MHz, CDCl
3): δ=161.1,142.8,142.7,142.1,142.0,134.9,133.2,129.8,129.6,129.5,129.1,127.6,127.2,124.8,117.1,109.7,55.6 ppm; MS (EI, 70eV): m/z (%)=260 (100) [M+], 245 (7).
Embodiment 3
[1] by 2-naphthyl ethyl ketone (5 g), O-methyl hydroxylamine (4 g), 15 mL pyridines add reflux stirring in methyl alcohol to spend the night, reaction finishes to be cooled to room temperature, under decompression, steam in the backward residue of solvent and add 50mL water, by extracted with diethyl ether, after organic phase drying precipitation, with the separation of column chromatography chromatogram method, obtain 2-naphthalene acetone-O-methyloxime (yield 82 %).By 2-naphthalene acetone-O-methyloxime (5.0 mmol), NBS (5.5 mmol), Pd(OAc)
2(0.25 mmol) joins in 30 mL acetic acid, mixture stirs 12 hours at 100 ℃, question response finishes after rear decompression steams solvent to obtain the bromo-2-naphthalene acetone-O-of 3-methyloxime (yield 84 %) with the separation of column chromatography chromatogram method, the bromo-2-naphthalene acetone-O-of 3-methyloxime (5.0 mmol) adds 1 of 15 mL hydrogenchloride, in 4-dioxane (5M) solution, at 80 ℃, heat 4 hours (TLC detects to reaction end), after decompression steams solvent, the separation of column chromatography chromatogram method obtains the bromo-2-naphthyl of 3-ethyl ketone (yield 87 %).
[2] by the bromo-2-naphthyl of 3-ethyl ketone (5.0 mmol), be dissolved in 5mL methylene dichloride, under room temperature, drip bromine (6.0 mmol), wait to dropwise and continue stirring reaction 60 minutes, to adding in system saturated sodium thiosulfate solution washing to after colourless, separatory is got the dry removal of solvent under reduced pressure of organic phase and is obtained the bromo-2-naphthyl of alpha-brominated 3-ethyl ketone crude product, without purifying, directly carries out ring closure reaction.The bromo-2-naphthyl of alpha-brominated 3-ethyl ketone is dissolved with 10mL acetonitrile, adds HClO4SiO2(350 mg) and formula V shown in substituted o-phenylenediamine (10 mmol), mixture is stirring reaction at 60 ℃, TLC detects to reaction end.Mixture is after filtration, obtain the bromo-2-naphthyl of faint yellow solid 2-(3-with column chromatography chromatogram method (leacheate proportioning: sherwood oil is to ethyl acetate volume ratio 15 ︰ 1) separation after filtrate decompression desolvation)-3-methyl-quinoxaline 1.04g (yield 60 %).
[3] by the bromo-2-naphthyl of 2-(3-)-3-methyl-quinoxaline 139.2 mg (0.4 mmol), Iron(III) chloride hexahydrate 2.7 mg (0.01 mmol), Potassium Persulphate 216 mg(0.8 mmol), N,N-dimethylacetamide (4 mL) adds in 25 mL flasks.110 ℃ of reactions of mixture heating after 3 hours TLC detection reaction finish, after adding 20 mL ether dilutions, with saturated aqueous common salt (10 mL X 3), wash, organic phase is sloughed solvent with decompression after anhydrous sodium sulfate drying, with column chromatography chromatogram method (leacheate proportioning: sherwood oil is to ethyl acetate volume ratio 15 ︰ 1) separation, obtains the bromo-2-naphthyl of weak yellow liquid 2-(3-)-3-vinyl quinoxaline 125.3 mg(87% yields).
[4] by the bromo-2-naphthyl of 2-(3-)-3-vinyl quinoxaline 54.0 mg (0.15 mmol), tetrakis triphenylphosphine palladium 7.3 mg(0.0075 mmol), Sulfuric acid disilver salt 94 mg(0.3 mmol) add successively in the dry reaction pipe of 10 mL.After reaction tubes is vacuumized, be filled with argon gas, repeatable operation three times is used needle cylinder injection triethylamine 61 mg(0.6 mmol under argon atmosphere) and degassed dry N,N-dimethylacetamide 2 mL.By mixture reacting by heating 2 hours in 140 ℃ of oil baths.After TLC detection reaction finishes, reaction solution is with washing with saturated aqueous common salt (10 mL X 3) after 15 mL ether dilutions, organic phase is sloughed solvent with decompression after anhydrous sodium sulfate drying, with column chromatography chromatogram method (leacheate proportioning: sherwood oil is to ethyl acetate volume ratio 15 ︰ 1) separation, obtain yellow solid naphtho-[2,3-α] azophenlyene 34.4 mg(82% yields).
Yellow solid; R
f=0.43 (petroleum ether-EtOAc=6:1); Mp=225-226 ℃;
1h NMR (500 MHz, CDCl
3): δ=9.80 (s, 1H), 8.37-8.35 (m, 1H), 8.28-8.23 (m, 3H), 8.05 (dd, J
1=8.5 Hz, J
2=3.5 Hz, 1 H), 7.98 (d, J=9.5 Hz, 1H), 7.88-7.83 (m, 2H), 7.78 (d, J=9.5 Hz, 1H), 7.65-7.62 (m, 2H) ppm;
13c NMR (125 MHz, CDCl
3): δ=144.6,144.0,142.4,141.6,134.2,133.7,132.4,130.8,129.8,129.7,129.5,129.3,129.0,128.9,128.1,127.3,127.2,127.1,126.7,125.7 ppm; MS (EI, 70eV): m/z (%)=280 (100) [M+].
Claims (5)
1. the method for synthetic replacement benzo [α] azophenlyene compounds as shown in formula III, it is characterized in that described method is: the 2-halogenated aryl ethyl ketone shown in formula IV of take is raw material, after α-bromination, carry out ring-closure reaction with the substituted o-phenylenediamine shown in formula V, 2-shown in synthesis type I (2-halogenated aryl)-3-methyl-quinoxaline, 2-shown in formula I (2-halogenated aryl)-3-methyl-quinoxaline reacts with the N-methyl nitrosourea shown in formula VI under iron catalyst and oxygenant existence, 2-shown in production II (2-halogenated aryl)-3-vinyl quinoxaline, 2-shown in formula II (2-halogenated aryl)-3-vinyl quinoxaline carries out Heck ring closure reaction under palladium catalyst effect, generate replacement benzo [α] the azophenlyene compounds shown in formula III,
In formula I, formula II, formula III or formula IV, R
1, R
2, R
3, R
4independent is separately H, methyl, methoxyl group, phenyl, F, Cl, Br, I, NO
2, CF
3, COOCH
3, COOC
2h
5, CN; Or R
2, R
3connect into ring with its two carbon that connect on phenyl ring, form a new phenyl ring;
In formula I, formula II, formula III or formula V, R
5, R
6, R
7, R
8independent is separately H, methyl, Cl, phenyl or COO CH
3;
In formula I, formula II or formula IV, X is Cl, Br or I;
In formula VI, R is H, methyl or phenyl;
Said method comprising the steps of:
(1) after being dissolved with ether or methylene dichloride, the 2-halogenated aryl ethyl ketone shown in formula IV under room temperature, splashes into bromine simple substance, dropwise under room temperature stirring reaction 15～60 minutes, then in reaction mixture, add saturated sodium thiosulfate solution washing to colourless, it is dry that separatory is got organic phase, decompression desolvation, gained crude product is alpha-brominated 2-halogenated aryl ethyl ketone, and crude product is dissolved with acetonitrile, adds HClO
4siO
2substituted o-phenylenediamine shown in catalyzer and formula V, in room temperature, to stirring reaction under reflux temperature, TLC follows the tracks of to detect to reaction and finishes, and gained reaction solution a aftertreatment obtains the 2-shown in formula I (2-halogenated aryl)-3-methyl-quinoxaline; 2-halogenated aryl ethyl ketone shown in described formula IV is 1:1.0～1.5 with the ratio of the amount of substance of bromine simple substance; Described alpha-brominated 2-halogenated aryl ethyl ketone is 1:1～5 with the ratio of the amount of substance of the substituted o-phenylenediamine shown in formula V; The amount of substance of described alpha-brominated 2-halogenated aryl ethyl ketone comes in the amount of substance of the 2-halogenated aryl ethyl ketone shown in formula IV;
(2) 2-shown in formula I (2-halogenated aryl)-3-methyl-quinoxaline is under iron catalyst and oxygenant existence, react with the N-methyl nitrosourea shown in formula VI, 20～160 ℃ of temperature of reaction, TLC follows the tracks of and detects to reaction end, and reaction solution aftertreatment obtains the 2-shown in formula II (2-halogenated aryl)-3-vinyl quinoxaline; Described iron catalyst is Iron(III) chloride hexahydrate, and described oxygenant is Potassium Persulphate, and the ratio of the amount of substance of the 2-shown in described formula I (2-halogenated aryl)-3-methyl-quinoxaline, iron catalyst, oxygenant is 1:0.001～0.3:1～5; The concentration of 2-shown in described formula I (2-halogenated aryl)-3-methyl-quinoxaline in the N-methyl nitrosourea shown in formula VI is 0.01～2mol/L;
(3) 2-shown in formula II (2-halogenated aryl)-3-vinyl quinoxaline and palladium catalyst, inorganic silver salt additives are in inert gas environment, add tertiary amine compounds and polar non-proton organic solvent, under the temperature of reaction of 50～160 ℃, carry out Heck ring closure reaction, TLC follows the tracks of and detects to reaction end, and reaction solution separating treatment obtains replacement benzo [α] the azophenlyene compounds shown in formula III; Described palladium catalyst is tetrakis triphenylphosphine palladium, and described inorganic silver salt additives is Sulfuric acid disilver salt, and described tertiary amine compounds is triethylamine; The ratio of the amount of substance of the 2-shown in described formula II (2-halogenated aryl)-3-vinyl quinoxaline, palladium catalyst, inorganic silver salt additives, tertiary amine compounds is 1:0.001～0.15:1～4:1～10.
2. the method for claim 1, it is characterized in that in described step (2), reaction solution post-treating method is: after reaction finishes, reacting liquid filtering, filtrate adds ether dilution, with after saturated common salt water washing, getting dry rear steaming of organic phase desolventizes, residuum is through column chromatography for separation, take sherwood oil or hexanaphthene is eluent with the ethyl acetate solvent that 2～30:1 mixes by volume, collects elutriant and steams to desolventize and obtain the 2-shown in formula II (2-halogenated aryl)-3-vinyl quinoxaline.
3. the method for claim 1, is characterized in that, in described step (3), described polar non-proton organic solvent is N,N-dimethylacetamide or DMF.
4. the method for claim 1, it is characterized in that in described step (3), described reaction solution method for separating and processing is: after reaction finishes, reacting liquid filtering, filtrate adds ether dilution, with after saturated common salt water washing, getting dry rear steaming of organic phase desolventizes, residuum is through column chromatography for separation, and the sherwood oil of take is eluent with the ethyl acetate solvent that 2～30:1 mixes by volume, collects elutriant steaming and desolventizes replacement benzo [α] the azophenlyene compounds obtaining shown in formula III.
5. the method for claim 1, is characterized in that, in described step (3), described rare gas element is argon gas or nitrogen.
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