CN108623495A - A kind of preparation method of aromatic nitriles or miscellaneous aromatic nitrile compounds - Google Patents

A kind of preparation method of aromatic nitriles or miscellaneous aromatic nitrile compounds Download PDF

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CN108623495A
CN108623495A CN201710154605.XA CN201710154605A CN108623495A CN 108623495 A CN108623495 A CN 108623495A CN 201710154605 A CN201710154605 A CN 201710154605A CN 108623495 A CN108623495 A CN 108623495A
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aromatic
hydrocarbon
haloheteroaromatic
nmr
halogenated
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刘元红
张兴杰
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Shanghai Institute of Organic Chemistry of CAS
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Shanghai Institute of Organic Chemistry of CAS
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    • C07D241/44—Benzopyrazines with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
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Abstract

The invention discloses the preparation methods of a kind of aromatic nitriles or miscellaneous aromatic nitrile compounds comprising following steps：Under inert gas protection, in solvent, in Raney nickel and ligand, under metallic zinc and Additive, cyanylation agent is reacted with halogenated aryl hydrocarbon or haloheteroaromatic.Preparation method provided by the invention, use Raney nickel and ligand cheap and easy to get, it can mildly, efficiently realize and cheap and easy to get but reaction low activity chlorinated aromatic hydrocarbons or chloro heteroaryl the hydrocarbon cyanylation agent smaller with toxicity can especially be reacted to halogenated aryl hydrocarbon or haloheteroaromatic, aromatic nitriles or miscellaneous aromatic nitrile compounds are prepared.The preparation method of the present invention not only has many advantages, such as simple to operation, mild, efficient, but also has many characteristics, such as good functional group compatibility and substrate universality.

Description

A kind of preparation method of aromatic nitriles or miscellaneous aromatic nitrile compounds
Technical field
The present invention relates to the preparation methods of a kind of aromatic nitriles or miscellaneous aromatic nitrile compounds.
Background technology
Aromatic nitrile compounds are a kind of very important organic synthesis intermediates, are widely present in medicine, pesticide, weeding In agent, insecticide, dyestuff, fragrance and natural products.It such as can be used for manufacturing the 2,4- dinitros of excellent sapphirine diazo colours Base -6- cyano-anilines and novel nitrile perfume lemonile in the world of strong similar citris aromas etc. with sharp.In addition, Cyano is a kind of functional group containing three key of carbon-to-nitrogen, and bond distance is shorter, with relatively small volume (about the 1/8 of methyl) and The highly polar and strong features such as electron-withdrawing can be deep into target proteins so cyano is a kind of good hydrogen bond receptor The key amino acid of depths and active site forms strong interaction of hydrogen bond；Meanwhile cyano also due to its in activity research The metabolic stability shown and the bioisostere as functional groups such as hydroxyl, carboxyls, it is small can to enhance drug Molecule thus is also widely used in pharmaceutical chemistry research with the interaction of target proteins.Such as Anti-HIV agents Etravirine, gout suppressant Febuxostat, antineoplastic Letrozole and antidepressants Citalopram etc. are owned by Important functional group of the aromatic nitriles as the drug molecule.In addition, diversified functional group conversions can also occur for cyano, formed Other important organic compounds, such as carboxylic acid, aldehyde, ketone, amide, amine, tetrazolium and other nitrogen heterocyclics.
It is based on these peculiar properties and important function of cyano, the conjunction of the synthesis especially aromatic nitriles of organic nitrile compound At the extensive concern and dense research interest for causing organic chemist.The synthetic method of traditional aromatic nitriles is Rosenmund-von Braun reactions and Sandmeyer reactions, the former is sub- by aryl halide and equivalent or excessive cyaniding (150-250 DEG C) is made at high temperature in copper, and reaction condition is more harsh；And the latter is sub- with the cyaniding of equivalent by aryl diazonium salts Copper reaction is made, due to needing to use diazols compound, so there is the security risk of explosion.In addition, both are reacted It is required for the cuprous cyanide of equivalent, so it is bound to cause the waste of heavy metal, and since reaction temperature is excessively high, post-processing is cumbersome And the reasons such as reactivity is poor of aryl chlorine bromine, also further limit the development and application of such reaction.And it is industrial The method of another large-scale production aromatic nitrile compounds is led at high temperature under high pressure by toluene derivative and oxygen and ammonia Ammonia oxidation is crossed to be made, but since this method needs higher reaction temperature, pressure and a large amount of ammonia, so functional group Compatibility it is bad, be only applicable to the toluene derivative without containing labile functional groups, while there is also equipment to want in production technology Ask high, the drawbacks such as three-waste pollution is big.Therefore, the cyanalation method efficient, green non-poisonous with Development of Novel is probed into, to meet society The needs of each related field fast development such as traditional Chinese medicine, pesticide, dyestuff and material are produced, then are even more seemed particularly urgently and again It wants.
The fast development of Organometallic Chemistry provides simple, efficient, strong synthesis to construct C-C keys and C-X keys The cross-coupling reaction of method, especially palladium chtalyst, since it is with easy to operate, functional group compatibility is good, and reaction is efficiently etc. Series of advantages, and be widely used in the synthesis of complicated natural products and the design studies of drug.Since these are important Application value A.Suzuki, R.F.Heck and E.Negishi obtained Nobel chemistry Prize in 2010.Development transition metal is urged The cross-coupling reaction of the same metal cyanides of halogenated aryl hydrocarbon (such as NaCN, KCN) of change forms aryl cyanide by being undoubtedly Most effective and succinct synthetic method.Takagi seminars in 1973 report the aryl iodide and aryl bromide of palladium chtalyst for the first time Compound is with the cyanalation reaction of potassium cyanide, but there is also more defects for the reaction, such as need higher reaction temperature (140 DEG C) could realize the substrate universality of good conversion ratio and reaction also poor (Takagi, K.；Okamoto,T.； Sakakiba,Y.；Oka,S.Chem.Lett.1973,471).However, just because of the research work of this initiative, then Decades in, transition metal (such as Pd, Ni, Cu) catalysis halogenated aryl hydrocarbon obtained extensively with the cross-coupling reaction of cyanide The cyanalation reaction of general research and development, especially palladium chtalyst since its reactivity worth is mild, functional group compatibility it is good and The series of advantages such as the good stability of catalyst are even more the cyano for having obtained vigorous growth, and having developed some low toxicities in turn Change reagent such as TMSCN, ZnCN2、K4Fe(CN)6, acetone cyanohydrin, NCTS etc..And nickel is then since its stability is poor (such as to air And moisture-sensitive), the defects of reactivity is excessively strong, functional group compatibility is bad then develop more slowly, primary limitation It is not very good in the coupling reaction with highly toxic cyanylation agent (KCN, NaCN) and substrate universality.
It is investigated based on document above, it has been found that although the cyanalation reaction of nickel catalysis makes some progress, still It is more slow compared to what is then developed for Pd, Cu, it is mainly limited to use highly toxic cyanylation agent (KCN, NaCN, Ni (CN)2And acetone cyanohydrin) research in, and react the universality especially universality of heteroaryl hydrocarbon and yield be not very yet It is good.Metastable nickelous NiBr is utilized as K.Takagi seminars in 1988 report for the first time2(PPh3)2Exist for catalyst PPh3Be the cyanalation reaction under conditions of reducing agent for ligand and Zn powder, but the reaction need use severe toxicity Cymag or Potassium cyanide and to human body have carcinogenesis 6-methyl phosphonic triamide be solvent, in addition, the reaction is not suitable for heteroaryl hydrocarbon Cyanalation reaction, if 3- bromopyridine yields are only 19%.An another piece is more relevant to be, Y.Sakakibara seminars in 1993 Report the cyanalation reaction of the haloheteroaromatic using the zero-valent nickel catalysis being formed in situ.Although the reaction can with it is medium extremely Good yield obtains corresponding cyanalation product, but the universality of the reaction is bad, is only applicable to part bromo heteroaryl hydrocarbon, And when for example 2- chlorine pyrimidine acts on the reaction system to chloro heteroaryl hydrocarbon, reaction cannot then occur.Equally, the reaction system also office It is limited to Cymag, potassium cyanide and the 6-methyl phosphonic triamide with carcinogenesis of severe toxicity.(bibliography：Sakakibara, Y.；Okuda,F.；Shimobayashi,A.；Kirino,K.；Sakai,M.；Uchino,N.；Takagi,K.Bull.Chem.S ℃.Jpn.1988,61,1985.Sakakibara,Y.；Ido,Y.；Sasaki,K.；Sakai,K.；Uchino, N.Bull.Chem.S℃.Jpn.1993,66,2776.).And the cyanalation reaction of the halogenated aryl hydrocarbon of palladium, copper catalysis is in recent years Although having obtained vigorous growth, reaction substrate be mostly confined to price costly, the higher aryl iodide of reactivity Or aryl bromide, and as aryl chloride that is cheap, being easy to get, then due to its lower reactivity, stronger C-Cl keys The Reason-studies such as bond energy it is less, be limited only to be connected with the aryl chloride of the activation of electron-withdrawing group, and the temperature reacted is usual Higher (120-160 DEG C), substrate universality are not very good, and are not suitable for chloro heteroaryl hydrocarbon (Jin, F.Q.；Confalone, P.N.Tetrahedron Lett.2000,41,3271.).In recent years, the chlorinated aromatic hydrocarbons or miscellaneous of transition metal especially palladium chtalyst Although the cyanalation reaction of aromatic hydrocarbons achieves certain progress, but have larger own limitations, such as need it is special and Expensive Phosphine ligands：Phosphine ligands (binaphthyl) P (t-Bu) of the Buchwald types of big steric hindrance electron rich2Or CM-Phos (Littke,A.；Soumeillant,M.；Kaltenbach,R.F.；Cherney,R.J.；Tarby,C.M.；Kiau, S.Org.Lett.2007,9,1711.Yeung,P.Y.；So,C.M.；Lau,C.P.；Kwong,F.Y.Org.Lett.2011, 13,648.), complicated operation (pre-prepared catalyst) and post-processing, special catalyst precarsor is such as：The Buchwald of the third generation Ring palladium complex limits such reaction as catalyst precarsor and higher reaction temperature and longer reaction time etc. Development and application.(Littke,A.；Soumeillant,M.；Kaltenbach,R.F.；Cherney,R.J.；Tarby,C.M.； Kiau,S.Org.Lett.2007,9,1711.Yeung,P.Y.；So,C.M.；Lau,C.P.；Kwong, F.Y.Org.Lett.2011,13,648.Senecal,T.D.；Shu,W.；Buchwald, S.L.Angew.Chem.Int.Ed.2013,52,10035.) (in addition the synthesis summary in relation to aromatic nitriles is shown in Anbarasan, P.； Schareina,T.；Beller,M.Chem.S℃.Rev.2011,40,5049.Yan,G.B.；Yu,J.；Zhang, L.Chin.J.Org.Chem.2012,32,294.Wen,Q.D.；Jin,J.S.；Zhang,L.P.；Luo,Y.；Lu,P.；Wang, Y.G.Tetrahedron Lett.2014,55,1271.Sundermeier,M.；Zapf,A.；Beller, M.Eur.J.Inorg.Chem.2003,3513).Therefore, probe into and develop cheap catalyst such as nickel and cheap ligand catalysis The cyanalation method of more efficient, simple and direct, mild aryl chloride then seem very urgent and needs, and will be realization The commercial synthesis of aromatic nitriles or miscellaneous aromatic nitrile compounds provides better application prospect.
Invention content
The technical problem to be solved by the present invention is in order to overcome existing aromatic nitriles or miscellaneous aromatic nitrile compounds to prepare The catalyst used and ligand encountered in process are expensive, functional group compatibility is poor, substrate universality is bad, Yi Ji great The defects of being all confined to the cyanalation reaction of expensive bromo or iodo aromatic hydrocarbon, and provide a kind of can be urged with cheap Change system, cyanalation preparation method that is simple and direct, efficiently realizing halogenated aryl hydrocarbon or haloheteroaromatic.
The present invention provides the preparation methods of a kind of aromatic nitriles or miscellaneous aromatic nitrile compounds comprising following steps： Under inert gas protection, in solvent, under Raney nickel and ligand, metallic zinc (Zn) and Additive, by cyanalation examination Agent carries out cross-coupling reaction with halogenated aryl hydrocarbon or haloheteroaromatic, obtains the aromatic nitriles or miscellaneous aromatic nitrile compounds i.e. Can,
The additive is one or more in inorganic base, organic base, quaternary ammonium salt and inorganic salts；The inorganic base It is preferred that potassium carbonate, wrong sour potassium, zinc carbonate；The organic base preferably unsubstituted or C1-C5Alkyl-substituted pyridine (for example, It is one or more in pyridine, 4-aminopyridine, 4-dimethylaminopyridine (DMAP) and 4- picolines) and/or C1-C5Alkyl Substituted amine (such as tri-butylamine)；The preferred tetrabutylammonium chloride of the quaternary ammonium salt；The preferred sodium chloride of the inorganic salts, chlorine Change one or more in potassium, lithium chloride or lead chloride；The additive most preferably 4-dimethylaminopyridine and/or potassium carbonate.
The molar ratio of substituted halogen and the additive can be 1 in the halogenated aryl hydrocarbon or haloheteroaromatic: 0.1~1:10, preferably 1:0.5~1:5, best is 1:1.
The molar ratio of substituted halogen and the metallic zinc can be 1 in the halogenated aryl hydrocarbon or haloheteroaromatic: 0.01~1:10, preferably 1:0.1~1:1, best is 1:0.2.
The Raney nickel can be such cross-coupling reaction routine Raney nickel of this field, particularly preferred in of the invention Ni(cod)2、NiCl2、NiBr2、NiI2、Ni(acac)2、NiBr2(diglyme)、NiBr2(PPh3)2、NiCl2(dppf)、NiCl2 (glyme)、NiBr2(DME)、NiF2And NiCl2·6H2It is one or more in O；Further preferred NiCl2、NiBr2(DME)、 NiBr2(diglyme)、NiBr2(PPh3)2、NiCl2(dppf)、NiCl2(glyme)、NiBr2、NiI2And NiCl2·6H2In O It is one or more.
The molar ratio of substituted halogen and the Raney nickel can be in the halogenated aryl hydrocarbon or haloheteroaromatic The conventional molar ratio of such reaction of this field, particularly preferred molar ratio is 1 in of the invention:0.01~1:1, further preferred 1: 0.02~1:0.5, most preferably 1:0.02~1:0.05.
The ligand can be such cross-coupling reaction conventional ligands of this field, particularly preferred triphenylphosphine in the present invention (PPh3), triethyl phosphine, tributylphosphine (TBUP), tricyclohexyl phosphine (TCHP), double diphenylphosphine methane (dppm), dimethyl benzene Base phosphine (PMe2Ph), diphenyl methyl phosphine (PMePh2), bis- (diphenyl phosphine) ethane (dppe) of 1,2-, 1,3- bis- (diphenylphosphines) third Bis- (diphenylphosphine) butane (dppb) of alkane (dppp), 1,4-, bis- (diphenylphosphine) ferrocene (dppf) of 1,1'-, 9,9- dimethyl- The bis- diphenylphosphine xanthenes (xantphos) of 4,5-, (the di-t-butyl phosphine) -9,9- of 4,5- bis- xanthphos (tBu- Xantphos one or more) and in 3- (dicyclohexyl phosphino-) -1- methyl -2- phenyl -1H- indoles (CM-phos), into one Step preferably double diphenylphosphine methane (dppm), diphenyl methyl phosphine (PMePh2), bis- (diphenyl phosphine) ethane (dppe) of 1,2-, 1,3- Bis- (diphenylphosphine) propane (dppp), bis- (diphenylphosphine) butane (dppb) of 1,4-, bis- (diphenylphosphine) ferrocene of 1,1'- (dppf) one or more and in the double diphenylphosphine xanthenes (xantphos) of 9,9- dimethyl -4,5-；Most preferably diphenyl One kind or more in bis- (diphenylphosphine) ferrocene of methylphosphine, 1,1'- and the double diphenylphosphine xanthenes of 9,9- dimethyl -4,5- Kind.
The Raney nickel such can react conventional molar ratio, this hair with the molar ratio of the ligand for this field Particularly preferred molar ratio can be 1 in bright:1~1:10, further preferred 1:1~1:5, more preferable 1:1.2.
When what the Raney nickel was well known in the art itself includes ligand, such as NiCl2(dppf)、NiBr2 (PPh3)2When, it can be not added with and/or add the ligand.
The cyanylation agent can be metal cyanides, particularly preferred alkali metal cyanide and/or transition in of the invention Metal cyanides；The alkali metal cyanide can be Cymag and/or potassium cyanide；The transition metal cyanide compound can be cyanogen Change one or more in nickel, zinc cyanide and cuprous cyanide etc.；The cyanylation agent is most preferably zinc cyanide.
Substituted halogen can with the molar ratio of the cyanylation agent in the halogenated aryl hydrocarbon or haloheteroaromatic For the conventional molar ratio of such reaction of this field, particularly preferred 1 in the present invention:0.1~1:10, further preferred 1:0.5~1: 2, most preferably 1:0.6~1:1.2.
The solvent can be that such reaction of this field is conventional, especially excellent in of the invention to be not involved in reaction Select one kind in aromatic hydrocarbon solvent, ether solvent, halogenated hydrocarbon solvent, nitrile solvents, amide solvent and sulfoxide type solvents or It is a variety of；It is one or more in the preferred benzene of the aromatic hydrocarbon solvent, toluene and dimethylbenzene；The preferred second of the ether solvent It is one or more in ether, Isosorbide-5-Nitrae-dioxane and tetrahydrofuran；The preferred chlorinated hydrocarbon solvent of the halogenated hydrocarbon solvent；Institute It is one or more in the preferred dichloromethane of chlorinated hydrocarbon solvent, dichloroethanes and the chloroform stated；The nitrile solvents are preferred Acetonitrile；The preferred n,N-Dimethylformamide of the amide solvent, n,N-dimethylacetamide (DMA) and hexamethyl phosphoramide In it is one or more；The preferred dimethyl sulfoxide (DMSO) of the sulfoxide type solvents.The more preferable acetonitrile of the solvent, N, N- dimethyl It is one or more in formamide and n,N-dimethylacetamide.
The molal volume ratio of the halogenated aryl hydrocarbon or haloheteroaromatic compound and the solvent can be somebody's turn to do for this field The conventional molar ratio of class reaction, particularly preferred 0.01mmol/mL~1mmol/mL, further preferred 0.15mmol/ in of the invention ML~0.5mmol/mL.
The reaction temperature can be the conventional temperature of such reaction of this field, such as -100 DEG C to 500 DEG C, preferably 0 DEG C To 150 DEG C, more preferable 60 DEG C to 80 DEG C.
In the reaction, the process of the reaction may be used in this field routine monitoring method (such as TLC, HPLC or NMR) it is monitored, it is reaction when generally disappearing or no longer react with halogenated aryl hydrocarbon or haloheteroaromatic compound Terminal.
The reaction time such can react the conventional reaction time for this field, and particularly preferred 0.1 is small in the present invention Up to 200 hours, further preferred 30 minutes to 20 hours.
The inert protective gas can be one or more in nitrogen, helium, argon gas and neon.
In the present invention, " halogen " can be selected from fluorine, chlorine, bromine or iodine.
It is described it is halogenated replaced by arbitrary fluorine, chlorine, bromine or iodine for hydrogen, preferably replaced by arbitrary chlorine, bromine or iodine.
The halogenated aromatic hydrocarbons or halogenated heteroaryl hydrocarbon refer to the one or more in aromatic hydrocarbons or heteroaryl hydrocarbon on aromatic rings Hydrogen is arbitrarily replaced by the halogen, and preferably one to three hydrogen in the aromatic hydrocarbons or heteroaryl hydrocarbon on aromatic rings is arbitrary Chlorine, bromine or iodine substitution.
In the present invention, " aromatic hydrocarbons " refers to the monocycle or double that may be up to 6 atoms in each ring of any stabilization Ring carbon ring, wherein at least one ring are aromatic rings；It is appreciated that be two ring substituents in aryl substituent, and one of ring In the case of being non-aromatic ring, connection is carried out by aromatic ring.The halogenated aromatic hydrocarbons preferably contains one to two fragrance The aromatic hydrocarbon of ring, more preferably halogenated benzene or naphthalene.
In the present invention, " the heteroaryl hydrocarbon " indicates to may be up to the stabilization monocycle or two rings of 6 atoms in each ring, wherein At least one ring is aromatic rings and the miscellaneous aromatic hydrocarbon that the hetero atom selected from O, N and S replaces containing 1~4；In this range of definition Interior heteroaryl hydrocarbon includes but not limited to：Acridine, carbazole, cinnolines, quinoxaline, pyrazoles, indoles, benzotriazole, furans, thiophene, benzene Bithiophene, benzofuran, quinoline, isoquinolin, oxazole, isoxazoles, pyrazine, pyridazine, pyridine, pyrimidine, 1,2,4- triazoles, pyrimido Pyridine, benzo [d] oxazole, benzo [d] thiazole, pyrroles or tetrahydroquinoline." heterocyclic arene " is it should also be understood that it includes any nitrogen to be The N- oxides of heteroaryl hydrocarbon.Substituent group is two ring substituents on heteroaryl hydrocarbon wherein and a ring is non-aromatic ring or does not wrap In the case of heteroatomic, it will be understood that connection is carried out by aromatic ring or by wrapping ring-containing hetero atom respectively.Described is miscellaneous N- oxides, thiophene, furans, pyridine, pyrroles, nitrogenous azole, pyrimido pyridine, the benzo [d] of the preferred azepine aromatic hydrocarbons of aromatic hydrocarbons are disliked Azoles or benzo [d] thiazole.
In the present invention, the halogenated aromatic hydrocarbons or halogenated heteroaryl hydrocarbon can not connect, or can be connected with one or more suctions Electron substituent group and/or electron substituent group；Such as：C1-C10Alkyl, the C of linear chain or branched chain1-C10The alcoxyl of linear chain or branched chain Base, C1-C10Alkoxy carbonyl group, the C of linear chain or branched chain1-C10The alkyl amine group of linear chain or branched chain, C1-C10The alkyl of linear chain or branched chain Carbonyl, C1-C10Alkyl amine group formoxyl, the C of linear chain or branched chain1-C10Alkyl amine group sulfonyl, the C of linear chain or branched chain1-C10Directly Methyl, the C that the alkyl silicon ether of chain or branch, phenyl replace5~C6Heteroaryl substitution methyl, (the C5~C6It is miscellaneous The preferred pyrazoles of aryl, indoles, furans, thiophene, oxazole, isoxazoles, pyrazine, pyridazine, pyridine, pyrimidine or 1,2,4- triazoles), cyanogen One or more of base, carbamoyl, amino-sulfonyl, amino and aldehyde radical；It is preferred that C1-C4The alkyl of linear chain or branched chain, C1-C4Alkoxy, the C of linear chain or branched chain1-C4Alkoxy carbonyl group, the C of linear chain or branched chain1-C4The alkyl amine group of linear chain or branched chain, C1- C4Alkyl-carbonyl, the C of linear chain or branched chain1-C4Alkyl amine group formoxyl, the C of linear chain or branched chain1-C4The alkylamine of linear chain or branched chain Base sulfonyl, C1-C4The alkyl silicon ether of linear chain or branched chain, the methyl of phenyl substitution, the methyl of 1,2,4- triazoles substitution, cyano, One or more of carbamoyl, amino-sulfonyl, amino and aldehyde radical；More preferable methyl, normal-butyl, tertiary butyl, methoxy Base, amido, acetyl group, methoxycarbonyl, ethoxy carbonyl, tert-butyldimethyl silyl ether, trimethyl silicane ether, carbamyl One or more in base, amino-sulfonyl, the methyl of phenyl substitution, the methyl of 1,2,4- triazoles substitution, cyano, amino and aldehyde radical It is a.
Heretofore described halogenated aryl hydrocarbon and the aromatic nitriles chemical combination being prepared by the halogenated aryl hydrocarbon Object is following a pair of of compound：
Heretofore described haloheteroaromatic and the miscellaneous aromatic nitriles being prepared by the haloheteroaromatic Class compound is following a pair of of compound：
The reaction may also include following post-processing step：After reaction, it filters, removes solvent, pillar layer separation Target compound is obtained, the conventional method of the generic operation in this field may be used in the pillar layer separation.Eluant, eluent is preferred The volume ratio of the mixed solvent of alkane solvents and esters solvent, the alkane solvents and the esters solvent is preferred 30:1~10:1.The preferred petroleum ether of the alkane solvents.The esters solvent ethyl acetate.
Without prejudice to the field on the basis of common sense, above-mentioned each optimum condition can be combined arbitrarily each preferably to get the present invention Example.
The reagents and materials used in the present invention are commercially available.
The positive effect of the present invention is that：The present invention using catalyst system and catalyzing simple and easy to get realize halogenated aryl hydrocarbon or The cyanalation reaction of haloheteroaromatic.The chloro that reactivity is relatively poor but cheap, raw material is easy to get can especially be used Aromatic hydrocarbons or chloro heteroaryl hydrocarbon are reacted with the cyanylation agent of hypotoxicity, and corresponding cyano compound is prepared.With it is simple to operation, The advantages that reaction is efficiently, mild condition, functional group compatibility and substrate universality are good, to realize aromatic nitriles or miscellaneous aromatic nitriles The commercial synthesis for closing object provides better application prospect and use value.
Specific implementation mode
It is further illustrated the present invention below by the mode of embodiment, but does not therefore limit the present invention to the reality It applies among a range.In the following examples, the experimental methods for specific conditions are not specified, according to conventional methods and conditions, or according to quotient Product specification selects.
1 compound of embodiment (1a)
Under argon gas protection, NiCl is sequentially added into the tube sealing of 25.0mL2·6H2O (0.05mmol, 11.9mg), dppf (0.06mmol, 33.3mg), Zn (0.2mmol, 13.0mg), DMAP (1.0mmol, 122.2mg), Zn (CN)2(0.8mmol, 93.9mg), it to chloroanisole (1.0mmol, 140.6mg) and acetonitrile (5.0mL), is then directly placed into 60 DEG C of oil bath pan anti- It answers, stops heating after 6h, be cooled to room temperature, the directly too short silicagel column of reaction solution is filtered, is rinsed, is concentrated, directly with dichloromethane Silica gel column chromatography purifying (is largely easily pumped in view of the product, is wet method if without specified otherwise to avoid mixing sample loss Fill sample.) eluent：Petrol ether/ethyl acetate=20:1, product be white solid 117.2mg, yield 88%,1H NMR purity More than 98%.1H NMR(400MHz,CDCl3,Me4Si):δ3.81(s,3H),6.89-6.93(m,2H),7.51-7.55(m, 2H).13C NMR(100MHz,CDCl3,Me4Si):δ55.34,103.60,114.55,119.03,133.72,162.64.
2 compound of embodiment (1b)
Using 1 scheme of embodiment, 4h, silica gel plate layer chromatography, eluent are reacted at 60 DEG C：Petrol ether/ethyl acetate=40:1, Product be light yellow liquid 82.4mg, yield 70%, and nuclear-magnetism yield be 95%,1H NMR purity is more than 98%.1H NMR (400MHz,CDCl3,Me4Si):δ 2.42 (s, 3H), 7.27 (d, J=8.0Hz, 2H), 7.52 (d, J=8.0Hz, 2H)13C NMR(100MHz,CDCl3,Me4Si):δ21.65,109.05,119.00,129.67,131.83,143.56.
3 compound of embodiment (1c)
Using 1 scheme of embodiment, 4h, silica gel plate layer chromatography, eluent are reacted at 60 DEG C：Petrol ether/ethyl acetate=100: 1, product be light yellow/close colourless liquid 143.2mg, yield 90%,1H NMR purity is more than 98%.1H NMR(400MHz, CDCl3,Me4Si):δ 0.93 (t, J=7.2Hz, 3H), 1.30-1.39 (m, 2H), 1.56-1.64 (m, 2H), 2.66 (t, J= 8.0Hz, 2H), 7.27 (d, J=8.4Hz, 2H), 7.54 (d, J=8.4Hz, 2H)13C NMR(100MHz,CDCl3,Me4Si): δ13.65,22.03,32.87,35.57,109.21,118.97,129.01,131.84,148.38.
4 compound of embodiment (1d)
Using 1 scheme of embodiment, 14h, silica gel plate layer chromatography, eluent are reacted at 60 DEG C：Petrol ether/ethyl acetate/dichloro Methane=15:1:1, product be light yellow liquid 128.2mg, yield 81%,1H NMR purity is more than 98%.1H NMR (400MHz,CDCl3,Me4Si):δ 1.31 (s, 9H), 7.47 (d, J=8.4Hz, 2H), 7.56 (d, J=8.4Hz, 2H)13C NMR(100MHz,CDCl3,Me4Si):δ30.78,35.10,109.13,119.00,126.04,131.80,156.49.
5 compound of embodiment (1e)
Using 1 scheme of embodiment, 4h, silica gel plate layer chromatography, eluent are reacted at 60 DEG C：Petrol ether/ethyl acetate=50:1, Product be nearly colourless liquid 212.5mg, yield 86%,1H NMR purity is more than 98%.1H NMR(400MHz,CDCl3, Me4Si):δ 0.09 (s, 6H), 0.93 (s, 9H), 4.77 (s, 2H), 7.41 (d, J=8.8Hz, 2H), 7.58 (d, J=8.0Hz, 2H).13C NMR(100MHz,CDCl3,Me4Si):δ-5.54,18.15,25.69,63.95,110.38,118.82,126.12, 131.86,146.83.
6 compound of embodiment (1f)
Using 1 scheme of embodiment, 5h, silica gel plate layer chromatography, eluent are reacted at 60 DEG C：Petrol ether/ethyl acetate=5:1, Product is nearly colourless liquid 90.2mg, and yield 77% and nuclear-magnetism yield are 97%,1H NMR purity is more than 98%.1H NMR (400MHz,CDCl3,Me4Si):δ 2.54 (s, 3H), 7.27 (t, J=7.6Hz, 1H), 7.31 (d, J=7.6Hz, 1H), 7.48 (t, J=7.6Hz, 1H), 7.58 (d, J=7.6Hz, 1H)13C NMR(100MHz,CDCl3,Me4Si):δ20.31,112.57, 118.01,126.09,130.10,132.34,132.53,141.76.
7 compound of embodiment (1g)
Using 1 scheme of embodiment, 7h, silica gel column chromatography, eluent are reacted at 60 DEG C：Petrol ether/ethyl acetate=15:1, Product be white solid 143.5mg, yield 88%,1H NMR purity is more than 98%.1H NMR(400MHz,CDCl3,Me4Si):δ 3.80 (s, 6H), 6.64 (t, J=2.4Hz, 1H), 6.74 (d, J=2.4Hz, 2H)13C NMR(100MHz,CDCl3, Me4Si):δ55.42,105.29,109.63,113.11,118.54,160.76.
8 compound of embodiment (1h)
Using 1 scheme of embodiment, 4h, silica gel plate layer chromatography, eluent are reacted at 60 DEG C：Petrol ether/ethyl acetate=100: 1, product be light yellow liquid 153.7mg, yield 88%,1H NMR purity is more than 98%.1H NMR(400MHz,CDCl3, Me4Si):δ0.28(s,9H),7.58-7.62(m,4H).13C NMR(100MHz,CDCl3,Me4Si):δ-1.62,112.21, 118.90,130.80,133.66,147.20.
9 compound of embodiment (1i)
Using 1 scheme of embodiment, 4h, silica gel column chromatography, eluent are reacted at 60 DEG C：Petrol ether/ethyl acetate=3:1, Product be white solid 62.7mg, yield 53%,1H NMR purity is more than 98%.1H NMR(400MHz,CDCl3,Me4Si):δ 4.33 (br, 2H), 6.65 (d, J=7.6Hz, 2H), 7.39 (d, J=7.6Hz, 2H)13C NMR(100MHz,CDCl3, Me4Si):δ99.32,114.21,120.24,133.58,150.59.
10 compound of embodiment (1j)
Solvent replacement is N, N-dimethylacetylamide (5.0mL), under argon gas protection, is sequentially added into the tube sealing of 25.0mL NiCl2·6H2O (0.05mmol, 11.9mg), dppf (0.06mmol, 33.3mg), Zn (0.2mmol, 13.0mg), DMAP (1.2mmol, 146.6mg), Zn (CN)2(0.6mmol, 70.5mg), 4-chloro-benzaldehyde (1.0mmol, 140.6mg) and acetonitrile (5.0mL) is then directly placed into 80 DEG C of oil bath pan and reacts, and stops heating after 20h, is cooled to room temperature, by the direct mistake of reaction solution Short silicagel column filtering, is rinsed with dichloromethane, is concentrated, silica gel column chromatography, eluent：Petrol ether/ethyl acetate=10:1, product For white solid 122.0mg, yield 93%,1H NMR purity is more than 98%.1H NMR(400MHz,CDCl3,Me4Si):δ7.80 (d, J=7.6Hz, 2H), 7.95 (d, J=8.4Hz, 2H), 10.05 (s, 1H)13C NMR(100MHz,CDCl3,Me4Si):δ 117.18,117.54,129.65,132.66,138.43,190.61.
11 compound of embodiment (1j)
Using 10 scheme of embodiment, solvent replacement N, N-dimethylacetylamide (5.0mL) react 20h, silica gel at 80 DEG C Column chromatography, eluent：Petrol ether/ethyl acetate=10:1, product be white solid 93.9mg, yield 72%,1H NMR purity More than 98%..
12 compound of embodiment (1j)
Using 10 scheme of embodiment, solvent replacement is N-Methyl pyrrolidone (5.0mL), reacts 20h, silicagel column at 80 DEG C Chromatography, eluent：Petrol ether/ethyl acetate=10:1, product be white solid 104.2mg, yield 79%,1H NMR purity is big In 98%.
13 compound of embodiment (1j)
Under argon gas protection, NiCl is sequentially added into the tube sealing of 25.0mL2(glyme) (0.05mmol, 11.0mg), dppf (0.06mmol, 33.3mg), Zn (0.2mmol, 13.0mg), DMAP (1.0mmol, 122.2mg), Zn (CN)2(0.6mmol, 70.5mg), 4-chloro-benzaldehyde (1.0mmol, 140.6mg) and acetonitrile (5.0mL) are then directly placed into 80 DEG C of oil bath pan anti- It answers, stops heating after 20h, be cooled to room temperature, the directly too short silicagel column of reaction solution is filtered, is rinsed, is concentrated, directly with dichloromethane Silica gel column chromatography purifying (is largely easily pumped in view of the product, is wet method if without specified otherwise to avoid mixing sample loss Fill sample.) eluent：Petrol ether/ethyl acetate=10:1, product be white solid 114.3mg, yield 87%,1H NMR purity More than 98%.
14 compound of embodiment (1j)
Using 13 scheme of embodiment, catalyst change NiBr2(diglyme) (0.05mmol, 17.6mg), it is anti-at 80 DEG C Answer 20h, silica gel column chromatography, eluent：Petrol ether/ethyl acetate=10:1, product is white solid 106.8mg, yield 81% ,1H NMR purity is more than 98%.
15 compound of embodiment (1j)
Using 13 scheme of embodiment, catalyst change NiI2(0.05mmol, 15.6mg) reacts 20h, silica gel at 80 DEG C Column chromatography, eluent：Petrol ether/ethyl acetate=10:1, product be white solid 106.0mg, yield 81%,1H NMR purity More than 98%.
16 compound of embodiment (1j)
Under argon gas protection, NiCl is sequentially added into the tube sealing of 25.0mL2(dppf) (0.05mmol, 34.2mg), Zn (0.2mmol, 13.0mg), DMAP (1.0mmol, 122.2mg), Zn (CN)2(0.6mmol, 70.5mg), 4-chloro-benzaldehyde (1.0mmol, 140.6mg) and acetonitrile (5.0mL), is then directly placed into 80 DEG C of oil bath pan and reacts, and stops heating after 20h, It is cooled to room temperature, the directly too short silicagel column of reaction solution is filtered, is rinsed, is concentrated with dichloromethane, direct silica gel column chromatography purifying (mirror It is largely easily pumped in the product, is wet method dress sample if without specified otherwise to avoid mixing sample loss.) eluent：Oil Ether/ethyl acetate=10:1, product be white solid 91.6mg, yield 70%,1H NMR purity is more than 98%.
17 compound of embodiment (1j)
Under argon gas protection, NiCl is sequentially added into the tube sealing of 25.0mL2·6H2O (0.05mmol, 11.9mg), PMePh2 (0.1mmol, 18.6uL), Zn (0.2mmol, 13.0mg), DMAP (1.0mmol, 122.2mg), Zn (CN)2(0.6mmol, 70.5mg), 4-chloro-benzaldehyde (1.0mmol, 140.6mg) and acetonitrile (5.0mL) are then directly placed into 80 DEG C of oil bath pan anti- It answers, stops heating after 20h, be cooled to room temperature, the directly too short silicagel column of reaction solution is filtered, is rinsed, is concentrated, directly with dichloromethane Silica gel column chromatography purifies, eluent：Petrol ether/ethyl acetate=10:1, product be white solid 87.9mg, yield 67%,1H NMR purity is more than 98%.
18 compound of embodiment (1j)
Using 17 scheme of embodiment, ligand is changed to Xantphos (0.06mmol, 34.7mg), reacts 20h, silicon at 80 DEG C Plastic column chromatography, eluent：Petrol ether/ethyl acetate=10:1, product be white solid 109.5mg, yield 84%,1H NMR are pure Degree is more than 98%.
19 compound of embodiment (1j)
Under argon gas protection, NiCl is sequentially added into the tube sealing of 25.0mL2·6H2O (0.05mmol, 11.9mg), dppf (0.06mmol, 33.3mg), Zn (0.2mmol, 13.0mg), potassium carbonate (1.0mmol, 138.2mg), Zn (CN)2(0.6mmol, 70.5mg), 4-chloro-benzaldehyde (1.0mmol, 140.6mg) and acetonitrile (5.0mL) are then directly placed into 80 DEG C of oil bath pan anti- It answers, stops heating after 20h, be cooled to room temperature, the directly too short silicagel column of reaction solution is filtered, is rinsed, is concentrated, directly with dichloromethane Silica gel column chromatography purifies, eluent：Petrol ether/ethyl acetate=10:1, product be white solid 83.7mg, yield 64%,1H NMR purity is more than 98%.
20 compound of embodiment (1j)
Additive is changed to tri-n-butylamine (1.0mmol, 238.0uL), other to use 19 scheme of embodiment, is reacted at 80 DEG C 20h, silica gel column chromatography, eluent：Petrol ether/ethyl acetate=10:1, product be white solid 67.5mg, yield 51%,1H NMR purity is more than 98%.
21 compound of embodiment (1j)
Additive is changed to tetrabutylammonium chloride (1.0mmol, 277.9mg), other to use 19 schemes of embodiment, at 80 DEG C React 20h, silica gel column chromatography, eluent：Petrol ether/ethyl acetate=10:1, product is white solid 27.4mg, yield 21%, 1H NMR purity are more than 98%.
22 compound of embodiment (1j)
Experimental procedure is same as above, but the dosage of additive is changed to 0.5equiv (0.5mmol, 61.1mg), is reacted at 80 DEG C 20h, silica gel column chromatography, eluent：Petrol ether/ethyl acetate=10:1, product be white solid 66.6mg, yield 51%,1H NMR purity is more than 98%.
23 compound of embodiment (1j)
Under argon gas protection, NiCl is sequentially added into the tube sealing of 25.0mL2·6H2O (0.02mmol, 4.8mg), dppf (0.03mmol, 16.6mg), Zn (0.2mmol, 13.0mg), DMAP (1.0mmol, 122.2mg), Zn (CN)2(0.6mmol, 70.5mg), 4-chloro-benzaldehyde (1.0mmol, 140.6mg) and acetonitrile (5.0mL) are then directly placed into 80 DEG C of oil bath pan anti- It answers, stops heating after 20h, be cooled to room temperature, the directly too short silicagel column of reaction solution is filtered, is rinsed, is concentrated with dichloromethane, silicon Plastic column chromatography, eluent：Petrol ether/ethyl acetate=10:1, product be white solid 68.8mg, yield 52%,1H NMR are pure Degree is more than 98%.
24 compound of embodiment (1j)
Under argon gas protection, NiCl is sequentially added into the tube sealing of 25.0mL2·6H2O (0.05mmol, 11.9mg), dppf (0.06mmol, 33.3mg), Zn (1.0mmol, 65.0mg), DMAP (1.0mmol, 122.2mg), Zn (CN)2(0.6mmol, 70.5mg), 4-chloro-benzaldehyde (1.0mmol, 140.6mg) and acetonitrile (5.0mL) are then directly placed into 80 DEG C of oil bath pan anti- It answers, stops heating after 20h, be cooled to room temperature, the directly too short silicagel column of reaction solution is filtered, is rinsed, is concentrated, silica gel with dichloromethane Column chromatography, eluent：Petrol ether/ethyl acetate=10:1, product be white solid 77.0mg, yield 59%,1H NMR purity More than 98%.
25 compound of embodiment (1j)
Under argon gas protection, NiCl is sequentially added into the tube sealing of 25.0mL2·6H2O (0.05mmol, 11.9mg), dppf (0.06mmol, 33.3mg), Zn (0.2mmol, 13.0mg), DMAP (1.0mmol, 122.2mg), Zn (CN)2(0.8mmol, 93.9mg), 4-chloro-benzaldehyde (1.0mmol, 140.6mg) and acetonitrile (5.0mL) are then directly placed into 80 DEG C of oil bath pan anti- It answers, stops heating after 20h, be cooled to room temperature, the directly too short silicagel column of reaction solution is filtered, is rinsed, is concentrated, silica gel with dichloromethane Column chromatography, eluent：Petrol ether/ethyl acetate=10:1, product be white solid 121.9mg, yield 93%,1H NMR purity More than 98%.
26 compound of embodiment (1j)
Under argon gas protection, NiCl is sequentially added into the tube sealing of 25.0mL2·6H2O (0.05mmol, 11.9mg), dppf (0.06mmol, 33.3mg), Zn (0.2mmol, 13.0mg), DMAP (1.0mmol, 122.2mg), Zn (CN)2(0.6mmol, 70.5mg), 4-chloro-benzaldehyde (1.0mmol, 140.6mg) and acetonitrile (5.0mL) are then directly placed into 60 DEG C of oil bath pan anti- It answers, stops heating after 20h, be cooled to room temperature, the directly too short silicagel column of reaction solution is filtered, is rinsed, is concentrated, silica gel with dichloromethane Column chromatography, eluent：Petrol ether/ethyl acetate=10:1, product be white solid 29.5mg, yield 22%,1H NMR purity More than 98%.
27 compound of embodiment (1j)
Under argon gas protection, NiCl is sequentially added into the tube sealing of 25.0mL2·6H2O (0.05mmol, 11.9mg), dppf (0.06mmol, 33.3mg), Zn (0.2mmol, 13.0mg), DMAP (1.0mmol, 122.2mg), Zn (CN)2(0.8mmol, 93.9mg), 4-chloro-benzaldehyde (1.0mmol, 140.6mg) and acetonitrile (10.0mL), are then directly placed into 80 DEG C of oil bath pan It reacts, stops heating after 20h, be cooled to room temperature, the directly too short silicagel column of reaction solution is filtered, is rinsed, is concentrated, silicon with dichloromethane Plastic column chromatography, eluent：Petrol ether/ethyl acetate=10:1, product be white solid 119.9mg, yield 91%,1H NMR are pure Degree is more than 98%.
28 compound of embodiment (1j)
Under argon gas protection, NiBr is sequentially added into the tube sealing of 25.0mL2·(PPh3)2(0.05mmol), PPh3 (0.1mmol), Zn (0.2mmol, 13.0mg), DMAP (1.0mmol, 122.2mg), Zn (CN)2(0.6mmol), to chlorobenzene first Aldehyde (1.0mmol, 140.6mg) and acetonitrile (10.0mL), are then directly placed into 80 DEG C of oil bath pan and react, and stop adding after 20h Heat is cooled to room temperature, and the directly too short silicagel column of reaction solution is filtered, is rinsed, is concentrated, silica gel column chromatography, eluent with dichloromethane： Petrol ether/ethyl acetate=10:1, product is white solid, yield 49%,1H NMR purity is more than 98%.
29 compound of embodiment (1k)
Using 1 scheme of embodiment, 8h, silica gel column chromatography, eluent are reacted at 80 DEG C：Petrol ether/ethyl acetate=8:1, Product be white solid 117.8mg, yield 81%,1H NMR purity is more than 98%.1H NMR(400MHz,CDCl3,Me4Si):δ 2.60 (s, 3H), 7.73 (d, J=8.0Hz, 2H), 8.00 (d, J=8.4Hz, 2H)13C NMR(100MHz,CDCl3, Me4Si):δ26.61,116.08,117.76,128.51,132.31,139.66,196.44.
30 compound of embodiment (1l)
Using 1 scheme of embodiment, 10h, silica gel column chromatography, eluent are reacted at 80 DEG C：Gradient elution, pentane/dichloro Methane=4:1 to 3:1, product be white solid 133.0mg, yield 83%,1H NMR purity is more than 98%.1H NMR (400MHz,CDCl3,Me4Si):δ 3.90 (s, 3H), 7.69 (d, J=8.0Hz, 2H), 8.08 (d, J=8.0Hz, 2H)13C NMR(100MHz,CDCl3,Me4Si):δ52.52,116.13,117.15,129.87,132.03,133.67,165.18.
31 compound of embodiment (1m)
Using 1 scheme of embodiment, 6h is reacted at 80 DEG C, (due to the product dissolubility difference and polarity is big, so being used when filtering THF is rinsed) silica gel column chromatography, eluent：Petroleum ether/tetrahydrofuran=1:1, product is white solid 117.6mg, yield 80%,1H NMR purity is more than 98%.1H NMR(400MHz,DMSO-d6,Me4Si):δ 7.70 (br, 1H), 7.93 (d, J= 8.4Hz, 2H), 8.02 (d, J=8.4Hz, 2H), 8.23 (br, 1H)13C NMR(100MHz,DMSO-d6,Me4Si):δ 113.74,118.46,128.34,132.45,138.34,166.57.
32 compound of embodiment (1n)
Using 1 scheme of embodiment, 7h, silica gel column chromatography, eluent are reacted at 80 DEG C：Gradient elution petroleum ether/acetic acid second Ester=3:1 to 1:1, product be white solid 145.0mg, yield 80%,1H NMR purity is more than 98%.1H NMR(400MHz, CD3OD,Me4Si):δ 4.81 (br, 2H), 7.92 (d, J=8.4Hz, 2H), 8.05 (d, J=8.0Hz, 2H)13C NMR (100MHz,CD3OD,Me4Si):δ116.72,118.74,128.06,134.23,149.12.
33 compound of embodiment (1o)
Using 1 scheme of embodiment, 6h, silica gel column chromatography, eluent are reacted at 80 DEG C：Petrol ether/ethyl acetate=3:1, Product be white solid 107.7mg, yield 74%,1H NMR purity is more than 98%.1H NMR(400MHz,CDCl3,Me4Si):δ 2.62 (s, 3H), 7.62 (dt, J=1.2,7.6Hz, 1H), 7.69 (dt, J=1.2,7.6Hz, 1H), 7.74 (dd, J=1.2, 7.4Hz, 1H), 7.94 (d, J=8.0Hz, 1H)13C NMR(100MHz,CDCl3,Me4Si):δ27.43,110.37, 117.95,129.89,132.41,132.56,135.04,139.14,196.00.
34 compound of embodiment (1p)
Using 1 scheme of embodiment, using 2- chlorobenzonitriles as raw material, 6h, silica gel plate layer chromatography, eluent are reacted at 80 DEG C：Stone Oily ether/ethyl acetate=3:1, product be white solid 106.1mg, yield 83%,1H NMR purity is more than 98%.1H NMR (400MHz,CDCl3,Me4Si):δ7.76-7.80(m,2H),7.81-7.86(m,2H).13C NMR(100MHz,CDCl3, Me4Si):δ115.32,115.57,133.23,133.47.
35 compound of embodiment (1q)
Using 1 scheme of embodiment, 10h, silica gel column chromatography, eluent are reacted at 80 DEG C：Petrol ether/ethyl acetate=10: 1, product be white solid 78.6mg, yield 60%,1H NMR purity is more than 98%.1H NMR(400MHz,CDCl3,Me4Si): δ 7.73-7.84 (m, 3H), 8.02 (dd, J=1.2,7.4Hz, 1H), 10.30 (s, 1H)13C NMR(100MHz,CDCl3, Me4Si):δ113.40,115.94,129.73,133.17,134.06,134.19,136.58,188.54.
36 compound of embodiment (1r)
Under argon gas protection, NiCl is sequentially added into the tube sealing of 25.0mL2·6H2O (0.1mmol, 23.8mg), dppf (0.12mmol, 66.5mg), Zn (0.4mmol, 26.0mg), DMAP (2.0mmol, 244.3mg), Zn (CN)2(1.6mmol, 187.9mg), 2,4- dichlorobenzonitriles (1.0mmol, 172.0mg) and acetonitrile (10.0mL), are then directly placed into 80 DEG C of oil bath It is reacted in pot, stops heating after 13.5h, be cooled to room temperature, the directly too short silicagel column of reaction solution is filtered, is rinsed with dichloromethane, Concentration, the purifying of direct silica gel column chromatography (it is largely easily pumped in view of the product, to avoid mixing sample loss, if without specified otherwise, It is wet method dress sample).Eluent：Petrol ether/ethyl acetate=5:1, product is white solid 127.6mg, yield 83%, 1H NMR purity is more than 98%.1H NMR(400MHz,CDCl3,Me4Si):δ 8.01 (d, J=8.4Hz, 1H), 8.07 (dd, J= 1.2,8.2Hz,1H),8.13-8.14(m,1H).13C NMR(100MHz,CDCl3,Me4Si):δ113.57,113.98, 115.14,117.10,117.46,119.38,134.30,136.36.IR(neat):3111,3079,3053,2240,1487, 1401,1291,1277,1233,1203,1155,1096,982,921,857,729cm-1.HRMS(EI)calcd for C9H3N3 [M]+:153.0327,found 153.0330.
37 compound of embodiment (1s)
Using 1 scheme of embodiment, 11h, silica gel column chromatography, eluent are reacted at 50 DEG C：Petroleum ether, product are white solid 129.9mg, yield 85%,1H NMR purity is more than 98%.1H NMR(400MHz,CDCl3,Me4Si):δ7.53-7.64(m, 3H),7.81-7.86(m,3H),8.14(s,1H).13C NMR(100MHz,CDCl3,Me4Si):δ109.06,119.06, 126.04,127.44,127.82,128.16,128.84,128.95,131.95,133.87,134.36.
38 compound of embodiment (1t)
Using 1 scheme of embodiment, 6h, silica gel column chromatography, eluent are reacted at 80 DEG C：Petrol ether/ethyl acetate/dichloromethane Alkane=20:1:1, product be white solid 186.0mg, yield 79%,1H NMR purity is more than 98%.1H NMR(400MHz, CDCl3,Me4Si):δ 7.39-7.43 (m, 1H), 7.48-7.52 (m, 1H), 7.67 (d, J=8.8Hz, 2H), 7.87 (d, J= 8.0Hz,1H),8.04-8.10(m,3H).13C NMR(100MHz,CDCl3,Me4Si):δ113.82,118.11,121.62, 123.59,125.92,126.65,127.62,132.49,135.08,137.13,153.76,165.07.IR(neat):3064, 2227,1608,1558,1515,1480,1461,1433,1406,1315,1292,1251,1226,1124,1111,1074, 1020,966,838,824,763,729,711,695cm-1.HRMS(ESI)calcd for C14H9N2S[M+H]+: 237.0481,found 237.0482.
39 compound of embodiment (1u)
Using 1 scheme of embodiment, 20h, silica gel column chromatography, eluent are reacted at 60 DEG C：Petrol ether/ethyl acetate/acetone =3:3:1, product be shallow white solid 140.3mg, yield 83%,1H NMR purity is more than 98%.1H NMR(400MHz, CDCl3,Me4Si):δ 7.17 (s, 1H), 7.31 (s, 1H), 7.49 (d, J=8.4Hz, 2H), 7.73 (d, J=8.4Hz, 2H), 7.90(s,1H).13C NMR(100MHz,CDCl3,Me4Si):δ110.59,117.35,117.66,121.03,131.16, 133.85,135.07,140.19.IR(neat):3130,3080,2225,1608,1577,1520,1487,1425,1373, 1332,1303,1263,1184,1132,1100,1056,960,903,833,782,729,712,653cm-1.HRMS(ESI) calcd for C10H8N3[M+H]+:170.0713,found 170.0714.
40 compound of embodiment (1a)
Using 1 scheme of embodiment, 4- methoxybromobenzenes are substrate, react 4h, silica gel column chromatography, eluent at 60 DEG C：Stone Oily ether/ethyl acetate=20:1, product be white solid 107.4mg, yield 81%,1H NMR purity is more than 98%.
41 compound of embodiment (1m)
Using 1 scheme of embodiment, 4- brombenzamides are substrate, react 6h at 80 DEG C, (due to product dissolubility difference and Polarity is big, so being rinsed with THF when filtering) silica gel column chromatography gradient elution, eluent：Petroleum ether/tetrahydrofuran=2:3 to 1: 2, product be white solid 120.0mg, yield 82%,1H NMR purity is more than 98%.1H NMR(400MHz,DMSO-d6, Me4Si):δ 7.70 (br, 1H), 7.92 (d, J=7.2Hz, 2H), 8.02 (d, J=7.6Hz, 2H), 8.24 (br, 1H)13C NMR(100MHz,DMSO-d6,Me4Si):δ113.80,118.50,128.39,132.48,138.36,166.66.
42 compound of embodiment (1a)
Using 1 scheme of embodiment, 4- methoxyl group iodobenzenes are substrate, react 2h, silica gel column chromatography, eluent at 60 DEG C：Stone Oily ether/ethyl acetate=20:1, product be white solid 106.1mg, yield 80%,1H NMR purity is more than 98%.
43 compound of embodiment (1y)
Using 1 scheme of embodiment, 4- iodo ethyl benzoates are substrate, react 3h, silica gel column chromatography, eluent at 80 DEG C： Petrol ether/ethyl acetate=20:1, product be white solid 146.3mg, yield 84%,1H NMR purity is more than 98%.1H NMR (400MHz,CDCl3,Me4Si):δ 1.33 (t, J=7.2Hz, 3H), 4.33 (q, J=7.2Hz, 2H), 7.66-7.68 (m, 2H), 8.05-8.07(m,2H).13C NMR(100MHz,CDCl3,Me4Si):δ13.93,61.49,115.91,117.71,129.74, 131.90,133.93,164.58.
44 compound of embodiment (2a)
Using 1 scheme of embodiment, using the chloro- nicotinonitriles of 2- as raw material, 6h, silica gel column chromatography, elution are reacted at 80 DEG C Agent：Petrol ether/ethyl acetate=2:1, product be white solid 115.8mg, yield 90%,1H NMR purity is more than 98%.1H NMR(400MHz,CDCl3,Me4Si):δ 7.77 (dd, J=4.8,8.0Hz, 1H), 8.20 (d, J=8.0Hz, 1H), 8.94 (d, J =4.8Hz, 1H)13C NMR(100MHz,CDCl3,Me4Si):δ113.56,114.13,114.31,126.73,135.91, 140.57,153.61.IR(neat):3069,2925,2850,2238,1976,1574,1558,1449,1425,1274, 1170,1100,1057,1007,831,816,759,707,687cm-1.HRMS(ESI)calcd for C7H4N3[M+H]+: 130.0400,found 130.0398.
45 compound of embodiment (2b)
Using 1 scheme of embodiment, 6h, silica gel column chromatography, eluent are reacted at 80 DEG C：Petrol ether/ethyl acetate=3:1, Product be light yellow liquid 88.0mg, yield 85%,1H NMR purity is more than 98%.1H NMR(400MHz,CDCl3,Me4Si): δ 7.59-7.62 (m, 1H), 7.76 (d, J=8.0Hz, 1H), 7.92 (t, J=8.0Hz, 1H), 8.75 (d, J=4.0Hz, 1H) .13C NMR(100MHz,CDCl3,Me4Si):δ117.02,126.89,128.37,133.53,136.99,150.88.
46 compound of embodiment (2c)
Using with apply 1 scheme of example, react 3h, silica gel column chromatography, eluent at 80 DEG C：Petrol ether/ethyl acetate=10:1, Product be white solid 100.7mg, yield 75%,1H NMR purity is more than 98%.1H NMR(400MHz,CDCl3,Me4Si):δ 3.94 (s, 3H), 6.78 (d, J=8.8Hz, 1H), 7.72-7.75 (m, 1H), 8.44 (s, 1H)13C NMR(100MHz, CDCl3,Me4Si):δ54.10,102.21,111.67,117.12,140.73,151.81,165.86.
47 compound of embodiment (2d)
Under argon gas protection, NiCl is sequentially added into the tube sealing of 25.0mL2·6H2O (0.1mmol, 23.8mg), dppf (0.12mmol, 66.5mg), Zn (0.4mmol, 26.0mg), DMAP (2.0mmol, 244.3mg), Zn (CN)2(1.6mmol, 187.9mg), 3,5- dichloropyridines (1.0mmol, 148.0mg) and acetonitrile (10.0mL), are then directly placed into 80 DEG C of oil bath pan Middle reaction stops heating after 23h, is cooled to room temperature, and the directly too short silicagel column of reaction solution is filtered, is rinsed, is concentrated with dichloromethane, Direct silica gel column chromatography purifying (is largely easily pumped in view of the product, to avoid mixing sample loss, if without specified otherwise, is Wet method fills sample).Silica gel column chromatography, eluent：Petrol ether/ethyl acetate=3:1, product is white solid 64.2mg, yield 50%,1H NMR purity is more than 98%.1H NMR(400MHz,CDCl3,Me4Si):δ 8.28 (t, J=2.0Hz, 1H), 9.07 (d, J=1.6Hz, 2H)13C NMR(100MHz,CDCl3,Me4Si):δ110.64,114.38,142.23,154.94.IR (neat):3053,3029,3004,2912,2245,1958,1948,1902,1593,1558,1445,1433,1421,1341, 1145,1022,977,926,698cm-1.HRMS(EI)calcd for C7H3N3[M]+:129.0327,found 129.0322.
48 compound of embodiment (2e)
Using 1 scheme of embodiment, 4h, silica gel column chromatography, eluent are reacted at 80 DEG C：Petrol ether/ethyl acetate=5:1, Product be white solid 107.5mg, yield 80%,1H NMR purity is more than 98%.1H NMR(400MHz,CDCl3,Me4Si):δ 4.15 (s, 3H), 7.09 (d, J=9.2Hz, 1H), 7.70 (d, J=9.2Hz, 1H)13C NMR(100MHz,CDCl3, Me4Si):δ55.62,115.47,116.98,132.25,134.74,165.06.
Embodiment 49
Using 1 scheme of embodiment, 4h, silica gel column chromatography, eluent are reacted at 80 DEG C：Petrol ether/ethyl acetate=5:1, Product be light yellow liquid 74.3mg, yield 71%,1H NMR purity is more than 98%.1H NMR(400MHz,CDCl3,Me4Si): δ 8.71 (s, 1H), 8.79 (d, J=2.4Hz, 1H), 8.91 (s, 1H)13C NMR(100MHz,CDCl3,Me4Si):δ 115.16,130.81,145.39,147.31,148.17.
50 compound of embodiment (2g)
Using 1 scheme of embodiment, 4h is reacted at 80 DEG C, (note：Reaction needs can be smooth under the conditions of relatively diluted Occur, acetonitrile is 10.0mL at this time) silica gel column chromatography, eluent：Petrol ether/ethyl acetate=5:1, product is white solid 63.2mg, yield 60%,1H NMR purity is more than 98%.1H NMR(400MHz,CDCl3,Me4Si):δ9.00(s,2H),9.37 (s,1H).13C NMR(100MHz,CDCl3,Me4Si):δ109.98,113.93,159.35,160.30.
51 compound of embodiment (2h)
Using 1 scheme of embodiment, 4h, silica gel column chromatography, eluent are reacted at 80 DEG C：Petrol ether/ethyl acetate=3:1, Product be white solid 122.4mg, yield 79%,1H NMR purity is more than 98%.1H NMR(400MHz,CDCl3,Me4Si):δ 7.47 (dd, J=4.0,8.6Hz, 1H), 7.76 (dd, J=2.0,8.8Hz, 1H), 8.10 (d, J=8.4Hz, 1H), 8.14- 8.16 (m, 2H), 8.98 (dd, J=1.6,4.4Hz, 1H)13C NMR(100MHz,CDCl3,Me4Si):δ110.06, 118.29,122.52,127.27,129.85,130.77,133.92,136.17,148.80,153.05.
52 compound of embodiment (2i)
Using 1 scheme of embodiment, 9h, silica gel column chromatography, eluent are reacted at 80 DEG C：Petrol ether/ethyl acetate=3:1, Product be white solid 135.6mg, yield 81%,1H NMR purity is more than 98%.1H NMR(400MHz,CDCl3,Me4Si):δ 2.68 (s, 3H), 7.33 (d, J=8.4Hz, 1H), 7.50 (dd, J=1.2,8.4Hz, 1H), 7.76 (d, J=8.4Hz, 1H), 8.00 (d, J=8.8Hz, 1H), 8.22 (s, 1H)13C NMR(100MHz,CDCl3,Me4Si):δ25.19,112.33, 118.44,124.42,126.14,128.32,128.73,134.18,135.69,146.37,161.09.IR(neat):3067, 2912,2228,1829,1769,1604,1557,1504,1447,1407,1372,1342,1305,1267,1222,1200, 1151,1127,1036,979,969,950,938,922,853,780,772,661cm-1.HRMS(ESI)calcd for C11H9N2[M+H]+:169.0760,found 169.0760.
53 compound of embodiment (2j)
Using 1 scheme of embodiment, 3h, silica gel column chromatography, eluent are reacted at 80 DEG C：Petrol ether/ethyl acetate=10:1, Product be white solid 106.0mg, yield 69%,1H NMR purity is more than 98%.1H NMR(400MHz,CDCl3,Me4Si):δ 7.62-7.67 (m, 2H) .7.77-7.81 (m, 1H), 7.85 (d, J=8.0Hz, 1H), 8.08 (d, J=8.4Hz, 1H), 8.26 (d, J=8.4Hz, 1H)13C NMR(100MHz,CDCl3,Me4Si):δ117.42,123.08,127.66,128.43, 129.30,129.62,131.09,133.27,137.38,147.89.
54 compound of embodiment (2k)
Using 1 scheme of embodiment, 6.5h, silica gel column chromatography, eluent are reacted at 80 DEG C：Petrol ether/ethyl acetate=10: 1, product be light yellow solid 119.4mg, yield 71%,1H NMR purity is more than 98%.1H NMR(400MHz,CDCl3, Me4Si):δ 2.62 (s, 3H), 7.33 (s, 1H), 7.60 (dt, J=0.8,8.4Hz, 1H), 7.00 (dt, J=1.2,7.0Hz, 1H), 7.89 (d, J=8.0Hz, 1H), 7.97 (d, J=8.4Hz, 1H)13C NMR(100MHz,CDCl3,Me4Si):δ 18.38,117.38,123.40,123.61,128.26,128.87,129.99,130.49,132.84,146.38, 147.30.IR(neat):3065,2984,2914,2235,2005,1974,1930,1694,1647,1614,1590,1554, 1505,1449,1432,1406,1375,1340,1321,1261,1225,1178,1133,1038,954,873,851,784, 771,734,676cm-1.HRMS(ESI)calcd for C11H9N2[M+H]+:169.0760,found 169.0761.
55 compound of embodiment (2l)
Using 1 scheme of embodiment, 6h, silica gel column chromatography, eluent are reacted at 80 DEG C：Petrol ether/ethyl acetate=10:1, Product be white solid 115.7mg, yield 75%,1H NMR purity is more than 98%.1H NMR(400MHz,CDCl3,Me4Si):δ 7.70-7.79 (m, 2H), 7.84-7.90 (m, 2H), 8.20 (d, J=8.0Hz, 1H), 8.57 (d, J=5.6Hz, 1H)13C NMR(100MHz,CDCl3,Me4Si):δ115.65,124.33,124.83,127.14,128.96,129.67,131.56, 134.35,135.56,142.99.
56 compound of embodiment (2m)
Using 1 scheme of embodiment, 6.5h, silica gel column chromatography, eluent are reacted at 80 DEG C：Petrol ether/ethyl acetate/dichloro Methane=10:1:5, product be white solid 102.3mg, yield 72%,1H NMR purity is more than 98%.1H NMR(400MHz, CDCl3,Me4Si):δ 6.62-6.63 (m, 1H), 7.36 (t, J=3.2Hz, 1H), 7.41 (dd, J=1.2,8.2Hz, 1H), 7.50 (d, J=8.4Hz, 1H), 9.05 (br, 1H)13C NMR(100MHz,CDCl3,Me4Si):δ102.07,103.02, 112.08,121.04,124.50,126.22,126.65,127.52,137.52.
57 compound of embodiment (2n)
Using 1 scheme of embodiment, 6h, silica gel column chromatography, eluent are reacted at 80 DEG C：Petrol ether/ethyl acetate=10:1, Product be white solid 126.1mg, yield 81%,1H NMR purity is more than 98%.1H NMR(400MHz,CDCl3,Me4Si):δ 7.89 (t, J=8.4Hz, 2H), 8.11 (t, J=8.4Hz, 2H), 9.01 (s, 1H)13C NMR(100MHz,CDCl3, Me4Si):δ115.74,129.42,129.54,129.71,131.84,133.19,141.77,142.64,145.46.IR (neat):3065,3049,3015,2231,1847,1610,1564,1502,1489,1464,1411,1371,1329,1209, 1194,1125,1013,978,930,890,868,798,758,671cm-1.HRMS(ESI)calcd for C9H6N3[M+H]+: 156.0556,found 156.0554.
58 compound of embodiment (2o)
Using 1 scheme of embodiment, 4h, silica gel column chromatography, eluent are reacted at 80 DEG C：Petrol ether/ethyl acetate/dichloromethane Alkane=10:1:5, product be white solid 133.6mg, yield 86%,1H NMR purity is more than 98%.1H NMR(400MHz, CDCl3,Me4Si):δ 7.91 (dd, J=1.6,8.8Hz, 1H), 8.20 (d, J=8.4Hz, 1H), 8.48 (d, J=1.6Hz, 1H),8.96(s,2H).13C NMR(100MHz,CDCl3,Me4Si):δ113.60,117.73,130.71,131.15, 135.49,141.96,144.24,146.69,147.28.
59 compound of embodiment (2p)
Using 1 scheme of embodiment, 4h, silica gel column chromatography, eluent are reacted at 80 DEG C：Ethyl acetate, product are that white is solid Body 100.3mg, yield 70%,1H NMR purity is more than 98%.1H NMR(400MHz,CDCl3,Me4Si):δ 6.83 (dd, J= 1.2,7.2Hz, 1H), 7.69 (s, 1H), 7.73 (s, 1H), 7.90 (s, 1H), 8.19 (d, J=6.8Hz, 1H)13C NMR (100MHz,CDCl3,Me4Si):δ106.62,112.05,114.48,117.28,123.67,126.44,136.21, 142.71.IR(neat):3140,3103,3082,3065,2225,1792,1759,1621,1518,1497,1458,1386, 1314,1298,1272,1172,1141,1120,1071,950,911,899,861,811,801,748,726,652cm- 1.HRMS(ESI)calcd for C8H6N3[M+H]+:144.0556,found 144.0556.
60 compound of embodiment (2q)
Using 1 scheme of embodiment, 2h, silica gel column chromatography, eluent are reacted at 80 DEG C：Petrol ether/ethyl acetate=10:1, Product be white solid 121.8mg, yield 77%,1H NMR purity is more than 98%.1H NMR(400MHz,CDCl3,Me4Si):δ 2.62(s,3H),7.48-7.53(m,2H),7.87(s,1H).13C NMR(100MHz,CDCl3,Me4Si):δ14.34, 107.79,111.31,118.54,123.77,128.46,141.72,153.09,166.03.
61 compound of embodiment (2r)
Using 1 scheme of embodiment, 3.5h, silica gel column chromatography, eluent are reacted at 80 DEG C：Petrol ether/ethyl acetate/dichloro Methane=15:1:5, product be white solid 141.2mg, yield 81%,1H NMR purity is more than 98%.1H NMR(400MHz, CDCl3,Me4Si):δ 2.79 (s, 3H), 7.46 (dd, J=1.6,8.4Hz, 1H), 7.83 (d, J=8.0Hz, 1H), 8.10 (d, J =0.8Hz, 1H)13C NMR(100MHz,CDCl3,Me4Si):δ20.02,109.22,118.54,122.26,126.11, 126.77,140.38,152.66,169.58.
62 compound of embodiment (2s)
Using 1 scheme of embodiment, 7h, silica gel column chromatography, eluent are reacted at 80 DEG C：Petrol ether/ethyl acetate=5:1, Product be white solid 98.5mg, yield 65%,1H NMR purity is more than 98%.1H NMR(400MHz,CDCl3,Me4Si):δ 2.54 (s, 3H), 7.81 (d, J=1.2Hz, 1H), 8.16 (d, J=1.2Hz, 1H)13C NMR(100MHz,CDCl3, Me4Si):δ26.54,111.25,113.82,132.76,141.84,145.90,189.54.
63 compound of embodiment (2t)
Using 1 scheme of embodiment, 5h, silica gel column chromatography, gradient elution, eluent are reacted at 80 DEG C：Petroleum ether/acetic acid second Ester=1:2 to ethyl acetate, and product is white solid 136.9mg, yield 74%,1H NMR purity is more than 98%.1H NMR (400MHz,CDCl3,Me4Si):δ 2.64 (s, 3H), 7.43 (d, J=8.8Hz, 1H), 7.63-7.66 (m, 2H), 7.90 (d, J =8.4Hz, 1H), 8.99 (s, 1H)13C NMR(100MHz,CDCl3,Me4Si):δ18.52,113.01,117.83, 124.00,125.25,125.83,128.46,129.37,130.87,140.56,147.13.IR(neat):3080,2230, 1620,1590,1550,1516,1461,1438,1372,1334,1314,1266,1248,1218,1151,1101,1028, 978,952,918,896,843,793,767,753,734,663,660cm-1.HRMS(ESI)calcd for C11H9N2O[M+ H]+:185.0709,found 185.0709。
64 Letrozole of embodiment it is fully synthetic
In the glove box full of nitrogen, NiCl is sequentially added into the bottle of 4.0mL2·6H2O(0.03mmol, 7.1mg), dppf (0.036mmol, 20.0mg), Zn (0.12mmol, 7.8mg), DMAP (0.6mmol, 73.3mg), Zn (CN)2 (0.48mmol, 56.4mg), Letrozole precursor 5 (0.3mmol, 91.3mg) and acetonitrile (3.0mL), then tighten bottle cap and use 3M Insulating tape seals lid, takes out to be directly placed into 80 DEG C of oil bath pan outside glove box and react, stops heating after 4h, be cooled to room Temperature filters the directly too short diatomite of reaction solution, with ethyl acetate rinse, concentration, direct silica gel plate chromatographic purifying.Silica gel plate layer Analysis, eluent：Petroleum ether/tetrahydrofuran=1:1, product be white solid 58.6mg, yield 68%,1H NMR purity is more than 98%.1H NMR(400MHz,CDCl3):δ 6.87 (s, 1H), 7.32 (d, J=8.4Hz, 4H), 7.71 (d, J=8.4Hz, 4H), 8.06(s,1H),8.15(s,1H).13C NMR(100MHz,CDCl3):δ66.04,112.92,117.81,128.81, 132.75,141.73,143.68,152.83.
1 compound of comparative example (1j)
Under argon gas protection, NiCl is sequentially added into the tube sealing of 25.0mL2·6H2O (0.05mmol, 11.9mg), dppf (0.06mmol, 33.3mg), Zn (0.2mmol, 13.0mg), Zn (CN)2(0.8mmol, 93.9mg), 4-chloro-benzaldehyde (1.0mmol, 140.6mg) and acetonitrile (10.0mL), is then directly placed into 80 DEG C of oil bath pan and reacts, and stops heating after 20h, It is cooled to room temperature, the directly too short silicagel column of reaction solution is filtered, is rinsed, is concentrated, silica gel column chromatography, eluent with dichloromethane：Stone Oily ether/ethyl acetate=10:1, product is white solid 15.3mg, and yield 12%, 1H NMR purity is more than 98%.
2 compound of comparative example (1j)
Under argon gas protection, NiBr is sequentially added into the tube sealing of 25.0mL2(PPh3)2(0.05mmol), PPh3 (0.1mmol), Zn (0.15mmol), Zn (CN)2(0.6mmol), 4-chloro-benzaldehyde (1.0mmol, 140.6mg) and acetonitrile (10.0mL) is then directly placed into 80 DEG C of oil bath pan and reacts, and stops heating after 20h, is cooled to room temperature, by the direct mistake of reaction solution Short silicagel column filtering, is rinsed with dichloromethane, is concentrated, silica gel column chromatography, eluent：Petrol ether/ethyl acetate=10:1, product For white solid, yield 24%,1H NMR purity is more than 98%.
3 compound of comparative example (1j)
Under argon gas protection, NiCl is sequentially added into the tube sealing of 25.0mL2·6H2O (0.05mmol, 11.9mg), dppf (0.06mmol, 33.3mg), Zn (0.2mmol, 13.0mg), TMSCN (1.5mmol, 148.8mg), 4-chloro-benzaldehyde (1.0mmol, 140.6mg) and acetonitrile (10.0mL), is then directly placed into 80 DEG C of oil bath pan and reacts, and stops heating after 20h, It is cooled to room temperature, the directly too short silicagel column of reaction solution is filtered, is rinsed, is concentrated, silica gel column chromatography, eluent with dichloromethane：Stone Oily ether/ethyl acetate=10:1, reaction cannot occur, and required cyanalation product does not generate.

Claims (10)

1. the preparation method of a kind of aromatic nitriles or miscellaneous aromatic nitrile compounds, it is characterised in that：Under inert gas protection, solvent In, in Raney nickel and ligand, under the action of metallic zinc and additive, by metal cyanylation agent and halogenated aryl hydrocarbon or halogenated Heteroaryl hydrocarbon is reacted, and the aromatic nitriles or miscellaneous aromatic nitriles are obtained, and the additive is inorganic base, organic base, season It is one or more in ammonium salt and inorganic salts,
2. the preparation method of aromatic nitriles as described in claim 1 or miscellaneous aromatic nitrile compounds, which is characterized in that the nothing Machine alkali is potassium carbonate, wrong sour potassium, zinc carbonate, preferably potassium carbonate；
And/or the organic base is unsubstituted or C1-C5Alkyl-substituted pyridine and/or C1-C5Alkyl-substituted amine；
And/or the quaternary ammonium salt is tetrabutylammonium chloride；
And/or the inorganic salts are one or more in sodium chloride, potassium chloride, lithium chloride and lead chloride；
And/or the molar ratio of substituted halogen and the additive is 1 in the halogenated aryl hydrocarbon or haloheteroaromatic:0.1 ~1:10；
And/or the molar ratio of substituted halogen and the metallic zinc is 1 in the halogenated aryl hydrocarbon or haloheteroaromatic: 0.01~1:10；
And/or the Raney nickel is Ni (cod)2、NiCl2、NiBr2、NiI2、Ni(acac)2、NiBr2(diglyme)、 NiBr2(PPh3)2、NiCl2(dppf)、NiCl2(glyme)、NiBr2(DME)、NiF2And NiCl2·6H2One kind or more in O Kind；
And/or the molar ratio of substituted halogen and the Raney nickel is in the halogenated aryl hydrocarbon or haloheteroaromatic 1:0.01~1:1；
And/or the ligand is triphenylphosphine, triethyl phosphine, tributylphosphine, tricyclohexyl phosphine, double diphenylphosphine methane, two Bis- (diphenyl phosphine) ethane of aminomethyl phenyl phosphine, diphenyl methyl phosphine, 1,2-, bis- (diphenylphosphine) propane of 1,3-, the bis- (diphenyl of 1,4- Phosphine) butane, bis- (diphenylphosphine) ferrocene of 1,1'-, the double diphenylphosphine xanthenes of 9,9- dimethyl -4,5-, (the two tertiary fourths of 4,5- bis- Base phosphine) it is one or more in -9,9- xanthphos and 3- (dicyclohexyl phosphino-) -1- methyl -2- phenyl -1H- indoles；
And/or the molar ratio of the Raney nickel and the ligand is 1:1~1:10；
And/or the Raney nickel is not added with and/or adds the ligand when being complex compound containing the ligand；
And/or it is alkali metal cyanide and/or transition metal cyanide compound that the cyanylation agent, which is metal cyanides,；
And/or in the halogenated aryl hydrocarbon or haloheteroaromatic substituted halogen and the cyanylation agent molar ratio It is 1:0.1~1:10；
And/or the solvent be aromatic hydrocarbon solvent, ether solvent, halogenated hydrocarbon solvent, nitrile solvents, amide solvent and It is one or more in sulfoxide type solvents；
And/or the molal volume ratio of the halogenated aryl hydrocarbon or haloheteroaromatic and the solvent be 0.01mmol/mL~ 1mmol/mL；
And/or the reaction temperature is -100 DEG C to 500 DEG C.
3. the preparation method of aromatic nitriles as claimed in claim 2 or miscellaneous aromatic nitrile compounds, which is characterized in that described adds Add the unsubstituted or C described in agent1-C5Alkyl-substituted pyridine is pyridine, 4-aminopyridine, 4-dimethylaminopyridine and 4- It is one or more in picoline；
And/or the C described in the additive1-C5Alkyl-substituted amine is tri-butylamine；
And/or the molar ratio of substituted halogen and the additive is 1 in the halogenated aryl hydrocarbon or haloheteroaromatic:0.5 ~1:5；
And/or the molar ratio of substituted halogen and the metallic zinc is 1 in the halogenated aryl hydrocarbon or haloheteroaromatic:0.1 ~1:1；
The Raney nickel is NiCl2(glyme)、NiBr2(DME)、NiCl2、NiBr2、NiBr2(diglyme)、NiBr2 (PPh3)2、NiCl2(dppf)、NiI2And NiCl2·6H2It is one or more in O；
And/or the molar ratio of substituted halogen and the Raney nickel is in the halogenated aryl hydrocarbon or haloheteroaromatic 1:0.02~1:0.5；
And/or the ligand is bis- for double diphenylphosphine methane, diphenyl methyl phosphine, bis- (diphenyl phosphine) ethane of 1,2-, 1,3- Bis- (diphenylphosphine) butane of (diphenylphosphine) propane, 1,4-, bis- (diphenylphosphine) ferrocene of 1,1'- and 9,9- dimethyl -4,5- It is one or more in double diphenylphosphine xanthenes；
And/or the molar ratio of the Raney nickel and the ligand is 1:1~1:5, preferably 1:1.2；
And/or the alkali metal cyanide is Cymag and/or potassium cyanide；
And/or the transition metal cyanide compound is one or more in nickel cyanide, zinc cyanide and cuprous cyanide etc.；
And/or in the halogenated aryl hydrocarbon or haloheteroaromatic substituted halogen and the cyanylation agent molar ratio It is 1:0.5~1:2；
And/or it is second that the aromatic hydrocarbon solvent, which is one or more in benzene, toluene and dimethylbenzene, described ether solvent, One or more in ether, Isosorbide-5-Nitrae-dioxane and tetrahydrofuran, the halogenated hydrocarbon solvent is chlorinated hydrocarbon solvent, described Chlorinated hydrocarbon solvent be one or more in dichloromethane, dichloroethanes and chloroform, the nitrile solvents are acetonitrile, institute The amide solvent stated is n,N-Dimethylformamide, N-Methyl pyrrolidone, n,N-dimethylacetamide and hexamethyl phosphinylidyne One or more in amine, the sulfoxide type solvents are dimethyl sulfoxide (DMSO)；
And/or the molal volume ratio of the halogenated aryl hydrocarbon or haloheteroaromatic and the solvent be 0.15mmol/mL~ 0.5mmol/mL；
And/or the reaction temperature is 0 DEG C~150 DEG C.
4. the preparation method of aromatic nitriles as claimed in claim 3 or miscellaneous aromatic nitrile compounds, which is characterized in that described adds It is 4-dimethylaminopyridine and/or potassium carbonate to add agent；
And/or the molar ratio of substituted halogen and the additive is 1 in the halogenated aryl hydrocarbon or haloheteroaromatic:1；
And/or the molar ratio of substituted halogen and the metallic zinc is 1 in the halogenated aryl hydrocarbon or haloheteroaromatic: 0.2；
And/or the molar ratio of substituted halogen and the Raney nickel is in the halogenated aryl hydrocarbon or haloheteroaromatic 1:0.02~1:0.05；
And/or the ligand is diphenyl methyl phosphine, bis- (diphenylphosphine) ferrocene of 1,1'- and 9,9- dimethyl -4,5- is bis- It is one or more in diphenylphosphine xanthene；
And/or the cyanylation agent is zinc cyanide；
And/or in the halogenated aryl hydrocarbon or haloheteroaromatic substituted halogen and the cyanylation agent molar ratio It is 1:0.6~1:1.2；
And/or the preferred acetonitrile of solvent, n,N-Dimethylformamide, n,N-dimethylacetamide and N- crassitudes It is one or more in ketone,
And/or the reaction temperature is 60 DEG C~80 DEG C.
5. the preparation method of aromatic nitriles as described in claim 1 or miscellaneous aromatic nitrile compounds, which is characterized in that the halogen Replaced by arbitrary fluorine, chlorine, bromine or iodine on behalf of hydrogen；
And/or the halogenated aromatic hydrocarbons or halogenated heteroaryl hydrocarbon refer in the aromatic hydrocarbons or heteroaryl hydrocarbon on aromatic rings one A or multiple hydrogen are arbitrarily replaced by the halogen；
And/or the aromatic hydrocarbons in the halogenated aromatic hydrocarbons is the aromatic hydrocarbon containing one to two aromatic rings；
And/or the heteroaryl hydrocarbon in the halogenated heteroaryl hydrocarbon be containing one to two aromatic rings and containing 1-4 selected from O, The miscellaneous aromatic hydrocarbon of any heteroatom substitution of N and S；
And/or the halogenated aryl hydrocarbon and/or haloheteroaromatic, do not connect, or be connected with one or more electron-withdrawing substituents And/or electron substituent group.
6. the preparation method of aromatic nitriles as claimed in claim 5 or miscellaneous aromatic nitrile compounds, which is characterized in that the halogen The aromatic hydrocarbons in generation or halogenated heteroaryl hydrocarbon refer to that one to three hydrogen in the aromatic hydrocarbons or heteroaryl hydrocarbon on aromatic rings is arbitrary Chlorine, bromine or iodine substitution；
And/or the aromatic hydrocarbons in the halogenated aromatic hydrocarbons is benzene or naphthalene；
And/or N- oxides, acridine, carbazole, cinnolines, the quinoline that the heteroaryl hydrocarbon in the halogenated heteroaryl hydrocarbon is azepine aromatic hydrocarbons Quinoline, pyrazoles, indoles, benzotriazole, furans, thiophene, benzothiophene, benzofuran, quinoline, isoquinolin, oxazole, isoxazoles, Pyrazine, pyridazine, pyridine, pyrimidine, 1,2,4- triazoles, pyrimido pyridine, benzo [d] oxazole, benzo [d] thiazole, pyrroles or tetrahydrochysene Quinoline；
And/or the halogenated aryl hydrocarbon and/or haloheteroaromatic, do not connect, or be connected with C1-C10Alkyl, the C of linear chain or branched chain1- C10Alkoxy, the C of linear chain or branched chain1-C10Alkoxy carbonyl group, the C of linear chain or branched chain1-C10The alkyl amine group of linear chain or branched chain, C1- C10Alkyl-carbonyl, the C of linear chain or branched chain1-C10Alkyl amine group formoxyl, the C of linear chain or branched chain1-C10The alkyl of linear chain or branched chain Amido sulfonyl, C1-C10The alkyl silicon ether of linear chain or branched chain, methyl, the C of phenyl substitution5~C6Heteroaryl substitution first One or more of base, cyano, carbamoyl, amino-sulfonyl, amino and aldehyde radical.
7. the preparation method of aromatic nitriles as claimed in claim 6 or miscellaneous aromatic nitrile compounds, which is characterized in that the halogen For N- oxides thiophene, furans, pyridine, pyrroles, nitrogenous azole, the pyrimido pyrrole that the heteroaryl hydrocarbon in heteroaryl hydrocarbon is azepine aromatic hydrocarbons Pyridine, benzo [d] oxazole or benzo [d] thiazole；
And/or the C5~C6The preferred pyrazoles of heteroaryl, indoles, furans, thiophene, oxazole, isoxazoles, pyrazine, pyridazine, pyrrole Pyridine, pyrimidine or 1,2,4- triazoles；
And/or the halogenated aryl hydrocarbon and/or haloheteroaromatic, do not connect, or be connected with C1-C4Alkyl, the C of linear chain or branched chain1-C4 Alkoxy, the C of linear chain or branched chain1-C4Alkoxy carbonyl group, the C of linear chain or branched chain1-C4The alkyl amine group of linear chain or branched chain, C1-C4Directly The alkyl-carbonyl of chain or branch, C1-C4Alkyl amine group formoxyl, the C of linear chain or branched chain1-C4The alkyl amine group sulphur of linear chain or branched chain Acyl group, C1-C4Methyl, cyano, the amino that the alkyl silicon ether of linear chain or branched chain, the methyl of phenyl substitution, 1,2,4- triazoles replace One or more of formoxyl, amino-sulfonyl, amino and aldehyde radical.
8. the preparation method of aromatic nitriles as claimed in claim 7 or miscellaneous aromatic nitrile compounds, which is characterized in that the halogen For aromatic hydrocarbons and/or haloheteroaromatic, do not connect, or is connected with methyl, normal-butyl, tertiary butyl, methoxyl group, amino, acetyl group, methoxyl group Carbonyl, ethoxy carbonyl, tert-butyldimethyl silyl ether, trimethyl silicane ether, carbamoyl, amino-sulfonyl, phenyl take The methyl in generation, one or more of methyl, cyano and the aldehyde radical of the substitution of 1,2,4- triazoles.
9. the preparation method of aromatic nitriles according to claims 1-8 or miscellaneous aromatic nitrile compounds, which is characterized in that described Halogenated aryl hydrocarbon is following a pair of of compound with the aromatic nitrile compounds being prepared by the halogenated aryl hydrocarbon,
10. the preparation method of aromatic nitriles according to claims 1-8 or miscellaneous aromatic nitrile compounds, which is characterized in that described Haloheteroaromatic with the miscellaneous aromatic nitrile compounds being prepared by the haloheteroaromatic be following a pairization Object is closed,
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