CN110117237A - A kind of preparation method of aromatic nitriles or alkenyl nitrile compounds - Google Patents

Abstract

The invention discloses a preparation method of aromatic nitrile or alkenyl nitrile compound. The preparation method of the present invention comprises the following steps: under the protection of an inert gas, in a solvent, in the presence of nickel complexes, metal zinc and additives, the aryl or heteroaryl sulfonates shown in formula II The compound and the cyanation reagent carry out the cross-coupling reaction shown below, or carry out the cross-coupling reaction shown below with the alkenyl sulfonate compound shown in IV and the cyanation reagent; Wherein, The additive is 4-dimethylaminopyridine (DMAP), and the cyanation agent is zinc cyanide. The preparation method of the present invention can realize the cyanation of aryl sulfonate, heteroaryl sulfonate or alkenyl sulfonate simply and efficiently with a cheap catalytic system, and also has good functional group compatibility and substrate Universality provides better application prospect and use value for realizing the industrial synthesis of aromatic nitrile or alkenyl nitrile compounds.

Description

A kind of preparation method of aromatic nitrile or alkenyl nitrile compound

technical field

The invention relates to the field of organic chemistry, in particular to a method for preparing aromatic nitrile or alkenyl nitrile compounds.

Background technique

As excellent reaction intermediates in organic chemistry, aromatic nitrile compounds have been widely used in biology, medicine, pesticides, functional materials and other fields. For example, 2,4-dinitro-6-cyanoaniline is an important intermediate for the manufacture of excellent bright blue diazo dyes; 4-bromo-2,6-difluorobenzonitrile is a synthetic compound with moderate An important synthetic intermediate of excellent liquid crystal materials with dielectric anisotropy; at the same time, many natural products and clinical drugs contain cyano groups, such as the antineoplastic drug Letrozole, the β inhibitor Bucindolol, the kinase inhibitor Neratinib, the cardiovascular drug cromakalim, Anti-HIV drug Etravirine, anti-gout drug Febuxostat, antidepressant Citalopram, diabetes drug alogliptin, etc. The reason why the cyano group is widely used in medicinal chemistry research is mainly determined by the special properties of the cyano group. The cyano group has a relatively small volume (about 1/8 of the methyl group), and in addition, the cyano group has strong electron-withdrawing characteristics, making the cyano group a good hydrogen bond acceptor, which can penetrate deep into the target protein It forms a strong hydrogen bond interaction with the key amino acid residues in the active site; at the same time, the cyano group has a high degree of polarization and promotes polar interactions, so the introduction of cyano groups into the drug molecule can change the physical and chemical properties of the drug molecule and enhance the drug. The interaction between the molecule and the target protein, thereby improving the efficacy of the drug; in addition, the cyano group also has good metabolic stability and serves as a bioelectron emitter of functional groups such as hydroxyl and carboxyl groups. These characteristics make the cyano group a class in medicinal chemistry research. Very important functional group. At present, more than 30 kinds of cyano-containing drugs have been listed, and as many as 20 kinds of cyano-containing drugs are under research and development.

The cyano group in aromatic nitrile compounds is also an important functional group, which can be converted into other functional groups through chemical reactions to form other important organic compounds, such as: amide compounds can be obtained by hydrogenation reduction; carboxylic acid compounds can be obtained by hydrolysis ; Primary amine compounds or aromatic aldehyde compounds can be obtained by reduction; tetrazole compounds can be obtained by addition reaction; carbonyl compounds can be obtained by nucleophilic addition.

In view of the unique properties and important role of cyano group, the synthesis of cyano group-containing compounds, especially aromatic nitrile compounds, has attracted extensive attention. The traditional method of synthesizing aromatic nitriles is Rosenmund-von Braun reaction and Sandmeyer reaction, because these two kinds of methods all need the cuprous cyanide of equivalent as cyanation reagent, will certainly cause the pollution of heavy metal, and usually require higher The temperature (150 ~ 250 ℃), the post-processing is cumbersome, which limits the application of these two methods. The industrial preparation of aryl nitrile compounds is mainly through the ammoxidation method, but the reaction needs to be carried out under high temperature and pressure, and a large excess of ammonia is used, which is limited to the cyano group of toluene and its derivatives and picoline and its derivatives reaction, which limits the application of this method. Therefore, it is particularly urgent and necessary to develop a mild and efficient cyanation method to meet the development trend of green chemical industry and meet the rapid development of social production of medicine, materials and other related fields.

Transition metal-catalyzed cross-coupling reactions are one of the effective methods for constructing carbon-carbon bonds, and the cross-coupling reactions of transition metal-catalyzed electrophiles and metal cyanides can effectively form aromatic nitrile compounds. In 1973, the Takagi research group first reported the palladium-catalyzed coupling reaction of aryl iodide or aryl bromide with potassium cyanide (Takagi, K.; Okamoto, T.; Sakakiba, Y.; Oka, S. Chem. Lett.1973,471), although only limited substrates in this paper can achieve cyanation reaction, but it is precisely because of this pioneering research work that in the following decades, transition metal catalyzed cyano The cyanation reaction has been extensively researched and developed, and a series of low-toxic cyanation reagents have been developed, such as: TMSCN, Zn(CN) ₂ , K ₄ Fe(CN) ₆ , acetone cyanohydrin, NCTS, etc. Aryl iodides and aryl bromides are often used as electrophiles in such reactions due to their high reactivity. Due to the high bond energy of C-Cl bond and low activity, aryl chloride compounds with relatively wide sources were rarely used as electrophiles in early research. However, through the development of new ligands and catalytic systems, aryl chlorides have gradually been applied in metal-catalyzed cyanation reactions in recent years. However, the application of halogenated hydrocarbons as electrophiles has obvious disadvantages: organic halides are harmful to the environment due to their own toxicity; secondly, aryl halides will produce halogen-containing by-products after coupling reactions; and aryl halides Halides are less readily available directly. Therefore, there is an urgent need to develop some more environmentally friendly and green electrophiles to synthesize aromatic nitriles.

Through literature research, we found that phenolic compounds have the advantages of wide sources, low price, and environmental friendliness, and have been gradually used in cross-coupling reactions. At the same time, due to the difficulty in cleavage of the CO bonds of phenols, the stepwise functionalization of substrates can be achieved by converting phenolic compounds into phenolic derivatives. Therefore, it is of great significance to use phenolic derivatives as electrophiles in coupling reactions. In recent years, there are still few reports on cyanation reactions of phenolic derivatives catalyzed by transition metals. In 1989, the Widdowson research group first reported the nickel-catalyzed coupling reaction of aryl trifluoromethanesulfonate and potassium cyanide, and synthesized a series of aromatic nitrile compounds. Subsequently, the Percec group further developed the nickel-catalyzed coupling reaction of aryl methanesulfonate with potassium cyanide. However, it is necessary to use highly toxic potassium cyanide as a cyanation reagent in this reaction. In addition, when there is steric hindrance in the ortho position of the substrate, the reaction yield is low, such as when the substrate is 2,4,6-trimethyl The yield of the reaction was 32% when phenyl triflate was used as substrate. (References: Chambers, MR; Widdowson, DAJ Chem. Soc. Perkin trans. I 1989, 1366; Percec, V.; Bae, JY; Hill, DHJ Org. Chem. 1995, 60, 6895.). Subsequently, the Neumeyer group and the Fairfax group reported the palladium-catalyzed cyanation reaction of aryl trifluoromethanesulfonate. In the reaction, zinc cyanide with relatively low toxicity was used as the cyanide source, but the temperature required for the reaction was as high as 140°C-200°C. (References: Zhang, A.; Neumeyer, JL Org. Lett. 2003, 5, 201; Srivastava, RR; Zych, AJ; Jenkins, DM; Wang, HJ; Chen, ZJ; Fairfax, DJ Synthetic Communications, 2007, 37, 431). Subsequently, the Kwong research group reported the use of potassium ferrocyanate trihydrate (K ₄ [Fe(CN) ₆ ]·3H ₂ O) as the cyanide source, palladium-catalyzed aryl methanesulfonate or p-toluenesulfonate The coupling reaction of base esters under mild conditions requires the addition of the indole phosphine ligand CM-phos with special electronic effects and steric hindrance effects developed by the group. The ligand has a special structure and is relatively expensive. (References Yeung, PY; So, CM; Lau, CP; Kwong, FY Angew. Chem. Int. Ed. 2010, 49, 8918.). In 2016, Yamaguchi reported the cyanation reaction of aryl carbamate or aryl pivalate using aminoacetonitrile as the cyanide source and nickel catalyzed cyanation. The reaction requires the use of dcype or dcypt with large steric hindrance and electron-rich properties as ligands. And the temperature required for the reaction is as high as 150 °C, which limits the application of this reaction (References: Takise, R.; Itami, K.; Yamaguchi, J. Org. Lett. 2016, 18, 4428.). In view of the above-mentioned transition metal catalyzed cyanation reactions of phenolic derivatives have their own limitations, such as the need for special phosphine ligands, complex operations (pre-preparation of catalysts) and post-treatment, special catalyst precursors and higher reaction temperature and longer reaction time.

Therefore, it is very urgent and necessary to explore and develop a more efficient, simple and mild cyanation method of sulfonate compounds catalyzed by cheap catalysts such as nickel and cheap ligands, and it will be very urgent and necessary for the realization of aromatic nitrile or alkenyl The industrial synthesis of nitrile compounds provides better application prospects.

Contents of the invention

The technical problem to be solved by the present invention is to overcome the shortcomings such as expensive catalysts and ligands used in the preparation methods of existing aromatic nitriles or alkenyl nitriles, poor functional group compatibility, poor substrate universality, etc., thus providing A preparation method of aromatic nitrile or alkenyl nitrile compound is provided. The preparation method of the present invention can realize the cyanation of aryl sulfonate, heteroaryl sulfonate or alkenyl sulfonate simply and efficiently with a cheap catalytic system, and also has good functional group compatibility and substrate universality.

The present invention solves the above-mentioned technical problems through the following technical solutions.

The present invention provides a kind of preparation method of the aromatic nitrile compound shown in formula I, it comprises the following steps: under inert gas protection, in solvent, under the condition that nickel complex, metal zinc and additive exist, will The aryl or heteroaryl sulfonate compound shown in formula II and the cyanation reagent carry out the cross-coupling reaction as shown below; wherein, the additive is 4-dimethylaminopyridine (DMAP ), the cyanation reagent is zinc cyanide;

In the aromatic nitrile compound shown in formula I and the aryl or heteroaryl sulfonate compound shown in formula II,

n is selected from any integer between 0-[M-1], wherein M represents the maximum number of substitutions on ring α, for example, n can be 0, 1 or 2.

R ¹ may be the same or different, each independently selected from halogen, C ₁ -C ₆ linear or branched alkoxy, -CN, -C(=O)OR ^a , -NR ^b R ^c , -C (=O)R ^d , -C(=O)NR ^e R ^f , C ₃ -C ₁₀ aryl or heteroaryl substituted by R ^g , straight or branched C ₁ -C ₆ substituted by ^Rh Alkyl; wherein, R ^a , R ^b , R ^c , R ^d , ^Re , R ^f , R ^g and R ^h are each independently selected from -H, halogen, -OH, -CN, C ₁ -C ₄ One or more of linear or branched alkoxy and C ₁ -C ₄ linear or branched alkyl; wherein, the halogen is preferably fluorine, chlorine, bromine or iodine; the C ₁ - _C4 linear or branched alkoxy is preferably _{C1 -} C3 linear or branched alkoxy, more preferably methoxy, ethoxy, propoxy or isopropoxy; The above C ₁ -C ₄ linear or branched alkyl is preferably a C ₁ -C ₃ linear or branched alkyl, more preferably methyl, ethyl, propyl or isopropyl.

Alternatively, any two adjacently substituted R ¹ (when n>=2) and the atoms on the ring α connected to each other together form a carbocyclic or carbon heterocyclic ring parallel to the ring α, and the carbon The ring or carboheterocycle is a 3-10 membered ring, and said carboheterocycle contains 1-4 heteroatoms selected from O, N and S.

When R ¹ is halogen, said halogen is preferably fluorine, chlorine, bromine or iodine.

When R ¹ is a C ₁ -C ₆ linear or branched alkoxy group, the C ₁ -C ₆ linear or branched alkoxy group is preferably a C ₁ -C ₃ linear or branched chain The alkoxy group is more preferably methoxy, ethoxy, propoxy or isopropoxy.

When R ¹ is -C(=O)OR ^a , R ^a is preferably a C ₁ -C ₄ linear or branched chain alkyl group, more preferably methyl, ethyl, propyl or isopropyl.

When R ¹ is -NR ^b R ^c , R ^b and R ^c are each independently preferably C ₁ -C ₄ linear or branched chain alkyl, more preferably methyl, ethyl, propyl or isopropyl .

When R ¹ is -C(=O)R ^d , R ^d is preferably a C ₁ -C ₄ linear or branched chain alkyl group, more preferably methyl, ethyl, propyl or isopropyl.

When R ¹ is -C(=O)NR ^e R ^f , R ^e and R ^f are each independently preferably C ₁ -C ₄ linear or branched chain alkyl, more preferably methyl, ethyl, propylene base or isopropyl.

When R ¹ is a C ₃ -C ₁₀ aryl or heteroaryl group substituted by R ^g , the C ₃ -C ₁₀ aryl or heteroaryl group is preferably phenyl or thienyl;

When R ¹ is a C ₁ -C ₆ straight chain or branched chain alkyl substituted by ^Rh , the C ₁ -C ₆ straight chain or branched chain alkyl is preferably a C ₁ -C ₃ straight chain or The branched alkyl group is more preferably methyl, ethyl, propyl or isopropyl.

When any two adjacently substituted R ¹ (when n>=2) and the atoms on the ring α connected to each other form a carbocyclic or carbon heterocyclic ring combined with the ring α, the carbocyclic ring Or the carboheterocycle is preferably a 3-5 membered ring, and the carboheterocycle contains 1 or 2 heteroatoms selected from O, N and S.

When n is ¹ , R is further preferably selected from methyl, n-butyl, methoxy, amino, acetyl, methoxycarbonyl, ethoxycarbonyl, cyano and phenyl.

When n is 2, R ¹ can be the same or different, which are further independently preferably selected from methyl or methoxy; or two R ¹ and the atoms on the ring α to which they are respectively connected together form a dioxolyl group .

-OS(=O) ₂ R is a sulfonate ester structure that can be used as a good leaving group conventionally described in the art, wherein R is selected from halogen, C ₁ -C ₆ linear or branched chain alkyl, C ₁ -C ₆ straight chain or branched chain haloalkyl, or R ⁱ substituted phenyl, R ⁱ selected from halogen (such as fluorine, chlorine, bromine or iodine), C ₁ -C ₆ straight chain or branched chain alkyl ( Preferably C ₁ -C ₃ linear or branched chain alkyl, more preferably methyl, ethyl, propyl or isopropyl), or -NR ^j R ^k (R ^j and R ^k are each independently selected from C ₁ - _C4 straight or branched chain alkyl, more preferably methyl, ethyl, propyl or isopropyl).

When R is halogen, said halogen is preferably fluorine, chlorine, bromine or iodine.

When R is a C ₁ -C ₆ straight chain or branched chain alkyl group, the C ₁ -C ₆ straight chain or branched chain alkyl group is preferably a C ₁ -C ₃ straight chain or branched chain alkyl group, further Preferred is methyl, ethyl, propyl or isopropyl.

When R is a C ₁ -C ₆ straight chain or branched chain haloalkyl, said C ₁ -C ₆ straight chain or branched chain haloalkyl is preferably a C ₁ -C ₃ straight chain or branched chain haloalkyl, More preferred is trifluoromethyl.

In the present invention, the -OS(=O) ₂ R is preferably any of the following structures: fluorosulfonyl (-SO ₂ F), trifluoromethanesulfonyl (-Tf), methylsulfonyl (-Ms), p-tolylsulfonyl (-Ts) or aminosulfonyl (-SO ₂ NMe ₂ ).

In the present invention, in the aromatic nitrile compound shown in formula I and the aryl or heteroaryl sulfonate compound shown in formula II, the ring α is an aromatic ring or an aromatic heterocyclic ring.

Wherein, when the ring α is an aromatic ring, the aromatic ring refers to any stable monocyclic or polycyclic carbocyclic ring with up to 6 atoms in each ring, and the polycyclic ring can be bicyclic , a tricyclic or tetracyclic ring structure, and at least one of the rings is an aromatic ring; when the aromatic ring is polycyclic and there are non-aromatic rings, -OS(=O) ₂ R and -CN and their The connection is carried out respectively through the "aromatic ring"; and the connection of n identical or different R ^1s to it is not limited in any way.

Wherein, when the ring α is an aromatic heterocycle, the aromatic heterocycle refers to any stable monocyclic or polycyclic ring with up to 6 atoms in each ring, and the polycyclic ring can be bicyclic , a tricyclic or tetracyclic ring structure, wherein at least one ring is an aromatic ring and contains 1-4 heteroatoms selected from O, N and S. When the aromatic heterocyclic ring is polycyclic and there is a non-aromatic ring or does not contain heteroatoms, the connections of -OS(=O) ₂ R and -CN to it are respectively carried out through "aromatic rings containing heteroatoms"; and the connection of n identical or different -R _1s to them is not limited.

In the present invention, the aromatic ring is preferably a monocyclic aromatic ring or a bicyclic condensed aromatic ring, such as a benzene ring or a naphthalene ring.

In the present invention, the aromatic heterocycle is preferably a monocyclic pyridine-like ring or a bicyclic quinoline-like ring.

In the present invention, the aryl or heteroaryl sulfonate compound shown in formula II and the aromatic nitrile compound shown in formula I are further preferably any pair of compounds as follows:

In the preparation method of the described aromatic nitrile compound shown in formula I, described cross-coupling reaction is carried out under inert gas protection system, and described inert protection gas can be nitrogen, helium, argon and neon One or more of the air.

In the described preparation method of the aromatic nitrile compound shown in formula I, the consumption of described additive DMAP can be routinely used in the art; The present invention preferably described aryl or heteroaryl group shown in formula II The molar ratio of sulfonate compound to DMAP is 1:0.1-1:10, more preferably 1:1-1:1.5.

In the described preparation method of the aromatic nitrile compound shown in formula I, except described additive DMAP, also can add other additive, described other additive is quaternary ammonium salt and/or inorganic salt; Wherein, all The quaternary ammonium salt is preferably tetraethylammonium iodide; the inorganic salt is preferably one or more of sodium iodide, potassium iodide and lithium iodide, more preferably potassium iodide.

In the described preparation method of the aromatic nitrile compound shown in formula I, when also comprising quaternary ammonium salt and/or inorganic salt in described reaction system, the consumption of described quaternary ammonium salt and/or inorganic salt can be It is routinely used in the art; the molar ratio of the preferred aryl or heteroaryl sulfonate compound shown in formula II and the quaternary ammonium salt and/or inorganic salt in the present invention is 1:0.1-1 :10, more preferably 1:0.5-1:1.

In the described preparation method of the aromatic nitrile compound shown in formula I, the consumption of described metal zinc can be this type of reaction conventional use in this area; The present invention preferably described aryl group shown in formula II or The molar ratio of the heteroaryl sulfonate compound to the metal zinc is 1:0.01-1:10, more preferably 1:0.1-1:1, further preferably 1:0.2-1:0.4.

In the preparation method of the aromatic nitrile compound shown in the described formula I, the nickel complex can be conventionally used in this type of cross-coupling reaction in the art, and it can be prepared by a conventionally applicable compound well known in the art. The metal complex form of the nickel precursor catalyst and its conventionally applicable ligand participates in the reaction, and at this time, no other ligands can be added; the conventionally applicable nickel precursor catalyst well known in the art and its conventionally applicable ligand can also be used in the reaction system Participate in the reaction after in situ coordination. The preferred nickel complex of the present invention is NiBr ₂ (PPh ₃ ) ₂ and/or NiCl ₂ (dppf); or, the preferred nickel precursor catalyst of the present invention is selected from Ni(cod) ₂ , NiCl ₂ , NiBr ₂ , one or more of NiI ₂ , NiBr ₂ (diglyme), NiCl ₂ (glyme), NiBr ₂ (DME), NiF ₂ and NiCl ₂ ·6H ₂ O; for example NiBr ₂ (DME), NiI ₂ and One or more of NiCl ₂ ·6H ₂ O.

In the described preparation method of the aromatic nitrile compound shown in formula I, the consumption of described nickel complex can be this kind of reaction conventional use in this area; The present invention preferably described aryl group shown in formula II Or the molar ratio of the heteroaryl sulfonate compound to the nickel complex is 1:0.01-1:1, more preferably 1:0.02-1:0.50, further preferably 1:0.05-1:0.10.

In the described preparation method of the aromatic nitrile compound shown in formula I, if also comprise described conventional suitable part in described reaction system, it can be suitable for nickel catalyst in this kind of cross-coupling reaction in this field The conventional ligands can be selected from triphenylphosphine (PPh ₃ ), triethylphosphine, tributylphosphine (TBUP), tricyclohexylphosphine (TCHP), bisdiphenylphosphine methane (dppm), dimethyl phenylphosphine (PMe ₂ Ph), diphenylmethylphosphine (PMePh ₂ ), 1,2-bis(diphenylphosphine)ethane (dppe), 1,3-bis(diphenylphosphine)propane ( dppp), 1,4-bis(diphenylphosphino)butane (dppb), 1,1'-bis(diphenylphosphino)ferrocene (dppf), 9,9-dimethyl-4,5 -bis-diphenylphosphine-xanthene ( ^xantphos ), 4,5-bis(di-tert-butylphosphine)-9,9-dimethylxanthene (tBu-xantphos) and 3-(dicyclohexylphosphine One or more of -1-methyl-2-phenyl-1H-indole (CM-phos), more preferably bisdiphenylphosphine methane (dppm), diphenylmethylphosphine (PMePh ₂ ), 1,2-bis(diphenylphosphine)ethane (dppe), 1,3-bis(diphenylphosphine)propane (dppp), 1,4-bis(diphenylphosphine)butane (dppb ), 1,1'-bis(diphenylphosphino)ferrocene (dppf) and 9,9-dimethyl-4,5-bisdiphenylphosphoxanthene (xantphos) species; for example one of diphenylmethylphosphine, 1,1'-bis(diphenylphosphino)ferrocene and 9,9-dimethyl-4,5-bisdiphenylphosphoxanthene or more.

In the described preparation method of the aromatic nitrile compound shown in formula I, also comprise described conventional applicable ligand in described reaction system, the molar ratio of described nickel precursor catalyst and described ligand It can be used routinely in this type of cross-coupling reaction in the art. In the present invention, the preferred molar ratio is 1:1 to 1:10, more preferably 1:1 to 1:5, and even more preferably 1:1.2.

In the preparation method of described aromatic nitrile compound shown in formula I, the mol ratio of described aryl or heteroaryl sulfonate compound shown in formula II and described cyanation reagent can be It is a conventional molar ratio for this type of reaction in the art; in the present invention, it is preferably 1:0.1-1:10, more preferably 1:0.5-1:2, further preferably 1:0.6-1:1.2, for example 1:0.8.

In the described preparation method of the aromatic nitrile compound shown in formula I, described solvent can be this type of cross-coupling reaction conventional use in this area, does not participate in reaction and gets final product; The present invention preferably aromatic hydrocarbon solvent, ethers One or more of solvents, halogenated hydrocarbon solvents, nitrile solvents, amide solvents and sulfoxide solvents; the aromatic hydrocarbon solvent is preferably one or more of benzene, toluene and xylene; the One or more of said ether solvent is preferably ether, 1,4-dioxane and tetrahydrofuran; said halogenated hydrocarbon solvent is preferably chlorinated hydrocarbon solvent; said chlorinated hydrocarbon solvent is preferably One or more of dichloromethane, dichloroethane and chloroform; the preferred acetonitrile of the described nitrile solvent; the preferred N,N-dimethylformamide, N,N-dimethylformamide of the described amide solvent One or more of methyl acetamide (DMA) and hexamethylphosphoramide; the sulfoxide solvent is preferably dimethyl sulfoxide. The solvent is more preferably one or more of acetonitrile, N,N-dimethylformamide and N,N-dimethylacetamide.

In the described preparation method of the aromatic nitrile compound shown in formula I, the consumption of described solvent can be the conventional use of this type of cross-coupling reaction in this area; The preferred described aromatic nitrile compound shown in formula II of the present invention The molar volume ratio of the base or heteroaryl sulfonate compound to the solvent is 0.01mmol/mL-1mmol/mL, more preferably 0.1mmol/mL-0.5mmol/mL.

In the preparation method of the aromatic nitrile compound as shown in formula I, the reaction temperature of the cross-coupling reaction can be conventionally used in this type of cross-coupling reaction in the art; in the present invention, it can be -100°C- 500°C, preferably 0°C-150°C, more preferably 50°C-100°C, further preferably 60°C-80°C.

In the described preparation method of the aromatic nitrile compound shown in formula I, the reaction process of described cross-coupling reaction can adopt the conventional monitoring method (such as TLC, HPLC or NMR) is monitored, generally with the described aryl or heteroaryl sulfonate compounds as shown in formula II disappearing or no longer reacting as the reaction end point.

In the preparation method of the aromatic nitrile compound shown in the described formula I, the reaction time of the cross-coupling reaction can be conventionally used in this type of cross-coupling reaction in the art; preferably 0.1-200h in the present invention, further Preferably 3-12h.

In the preparation method of the described aromatic nitrile compound shown in formula I, after the described cross-coupling reaction finishes, the described preparation method can also preferably include the following post-processing steps: after the reaction finishes, filter, remove Solvent, column chromatographic separation to obtain the target compound, and the column chromatographic separation can adopt conventional methods of this type of operation in the art. The eluent is preferably a mixed solvent of an alkane solvent and an ester solvent. Wherein, the volume ratio of the alkane solvent to the ester solvent is preferably 100:1-1:1; the alkane solvent is preferably petroleum ether; the ester solvent is preferably ethyl acetate.

The present invention also provides a method for preparing an alkenyl nitrile compound as shown in formula III, which comprises the following steps: under the protection of an inert gas, in a solvent, in the presence of nickel complexes, metal zinc and additives , carrying out the following cross-coupling reaction with the alkenyl sulfonate compound shown in IV and the cyanation reagent; wherein, the additive is 4-dimethylaminopyridine (DMAP); the Described cyanation reagent is zinc cyanide;

Among them, -OS(=O) ₂ R is a sulfonate structure that can be used as a good leaving group conventionally described in the art, and its definition is the same as mentioned above, that is: R is selected from halogen, C ₁ -C ₆ Straight chain or branched chain alkyl, C ₁ -C ₆ straight chain or branched chain haloalkyl, or R ⁱ substituted phenyl, R ⁱ is selected from halogen (such as fluorine, chlorine, bromine or iodine), C ₁ -C ₆ linear or branched alkyl (preferably C ₁ -C ₃ linear or branched alkyl, more preferably methyl, ethyl, propyl or isopropyl), or -NR ^j R ^k (R ^j and R ^k are each independently selected from C ₁ -C ₄ linear or branched chain alkyl groups, more preferably methyl, ethyl, propyl or isopropyl).

When R is halogen, said halogen is preferably fluorine, chlorine, bromine or iodine.

When R is a C ₁ -C ₆ straight chain or branched chain alkyl group, the C ₁ -C ₆ straight chain or branched chain alkyl group is preferably a C ₁ -C ₃ straight chain or branched chain alkyl group, further Preferred is methyl, ethyl, propyl or isopropyl.

When R is a C ₁ -C ₆ straight chain or branched chain haloalkyl, said C ₁ -C ₆ straight chain or branched chain haloalkyl is preferably a C ₁ -C ₃ straight chain or branched chain haloalkyl, More preferred is trifluoromethyl.

In the present invention, the -OS(=O) ₂ R is preferably any of the following structures: fluorosulfonyl (-SO ₂ F), trifluoromethanesulfonyl (-Tf), methylsulfonyl (-Ms), p-tolylsulfonyl (-Ts) or aminosulfonyl (-SO ₂ NMe ₂ ).

In the alkenyl nitrile compound shown in formula III and the alkenyl sulfonate compound shown in formula IV, R ² , R ³ and R ⁴ are each independently selected from -H, -(CH ₂ )xR ^m substituted C ₃ -C ₁₀ aryl or heteroaryl, or R ⁿ substituted C ₁ -C ₆ straight or branched chain alkyl; wherein, R ^m and R ⁿ are each independently selected from -H, One or more of halogen, -OH, -CN, C ₁ -C ₄ linear or branched alkoxy and C ₁ -C ₄ linear or branched alkyl; wherein the halogen It is preferably fluorine, chlorine, bromine or iodine; the C ₁ -C ₄ linear or branched alkoxy is preferably a C ₁ -C ₃ linear or branched alkoxy, further methoxy, ethyl Oxygen, propoxy or isopropoxy; the C ₁ -C ₄ straight chain or branched chain alkyl is preferably C ₁ -C ₃ straight chain or branched chain alkyl, more preferably methyl, Ethyl, propyl or isopropyl; x is selected from any integer between 0-4, such as 0, 1, 2 or 3.

Wherein, among the C ₃ -C ₁₀ aryl or heteroaryl substituted by -(CH ₂ )xR ^m , the C ₃ -C ₁₀ aryl or heteroaryl is preferably C ₆ -C ₁₀ Aryl such as phenyl or naphthyl.

Wherein, in the C ₁ -C ₆ straight chain or branched chain alkyl substituted by R ⁿ , the C ₁ -C ₆ straight chain or branched chain alkyl is preferably a C ₁ -C ₃ straight chain or branched alkyl, more preferably methyl, ethyl, propyl or isopropyl.

Alternatively, R ² and R ³ , or R ² and R ⁴ jointly form a 5-10 membered monocyclic or polycyclic carbocycle or carboheterocycle, and the carboheterocycle contains 1-4 members selected from O, N and S heteroatoms; the 5-10 membered monocyclic or polycyclic carbocyclic or carboheterocyclic rings may be saturated or semi-saturated rings; and they may be further substituted by R ⁿ .

Wherein, the 5-10 membered monocyclic or polycyclic carbocycle is preferably monocyclic or bicyclic carbocycle, more preferably cyclohexene or benzocyclohexene.

In the present invention, among the alkenyl nitrile compound shown in formula III and the alkenyl sulfonate compound shown in formula IV, it can be Z type and/or E type without any limitation.

In the present invention, the alkenyl sulfonate compound shown in formula IV and the alkenyl nitrile compound shown in formula III are further preferably any pair of compounds as follows:

In the present invention, unless otherwise specified, except that the substrate used is different, each reaction parameter and condition adopted in the preparation method of the alkenyl nitrile compound shown in the formula III are the same as previously described, namely:

In the preparation method of described alkenyl nitrile compounds shown in formula III, described cross-coupling reaction is carried out under inert gas protection system, and described inert protection gas can be nitrogen, helium, argon and One or more of neon gases.

In the preparation method of the described alkenyl nitrile compound shown in formula III, the consumption of described additive DMAP can be routinely used in the art; The present invention preferably described alkenyl sulfonate shown in formula IV The molar ratio of quasi-compound to DMAP is 1:0.1-1:10, more preferably 1:1-1:1.5.

In the described preparation method of the alkenyl nitrile compound shown in formula III, except described additive DMAP, also can add other additive, described other additive is quaternary ammonium salt and/or inorganic salt; Wherein, The quaternary ammonium salt is preferably tetraethylammonium iodide; the inorganic salt is preferably one or more of sodium iodide, potassium iodide and lithium iodide, more preferably potassium iodide.

In the described preparation method of alkenyl nitrile compound shown in formula III, when also comprising quaternary ammonium salt and/or inorganic salt in the described reaction system, the consumption of described quaternary ammonium salt and/or inorganic salt It can be routinely used in the art; the preferred molar ratio of the alkenyl sulfonate compound shown in formula IV in the present invention to the quaternary ammonium salt and/or inorganic salt is 1:0.1-1:10, More preferably 1:0.5-1:1.

In the preparation method of described alkenyl nitrile compound shown in formula III, the consumption of described metal zinc can be conventionally used for this type of reaction in the art; The present invention preferably described alkenyl compound shown in formula IV The molar ratio of the sulfonate compound to the metal zinc is 1:0.01-1:10, more preferably 1:0.1-1:1, further preferably 1:0.2-1:0.4.

In the preparation method of the alkenyl nitrile compound shown in the formula III, the nickel complex can be used conventionally in this type of cross-coupling reaction in the art, and it can be prepared by conventional methods well known in the art. The metal complex form of the nickel precursor catalyst and its conventional applicable ligand participates in the reaction, and at this time, no other ligands can be added; the conventional applicable nickel precursor catalyst well known in the art and its conventional applicable ligand can also be reacted After in-situ coordination in the system, it participates in the reaction. The preferred nickel complex of the present invention is NiBr ₂ (PPh ₃ ) ₂ and/or NiCl ₂ (dppf); or, the preferred nickel precursor catalyst of the present invention is selected from Ni(cod) ₂ , NiCl ₂ , NiBr ₂ , one or more of NiI ₂ , NiBr ₂ (diglyme), NiCl ₂ (glyme), NiBr ₂ (DME), NiF ₂ and NiCl ₂ ·6H ₂ O; for example NiBr ₂ (DME), NiI ₂ and One or more of NiCl ₂ ·6H ₂ O.

In the preparation method of the described alkenyl nitrile compound shown in the formula III, the amount of the nickel complex can be conventionally used in this type of reaction in the art; the present invention preferably describes the alkenyl nitrile compound shown in the formula IV The molar ratio of the sulfonate compound to the nickel complex is 1:0.01-1:1, more preferably 1:0.02-1:0.50, further preferably 1:0.05-1:0.10.

In the preparation method of the alkenyl nitrile compound shown in the described formula III, if the reaction system also includes the described conventional applicable ligand, it can be suitable for nickel in this type of cross-coupling reaction in the art. Conventional ligands for catalysts, which may be selected from triphenylphosphine (PPh ₃ ), triethylphosphine, tributylphosphine (TBUP), tricyclohexylphosphine (TCHP), bisdiphenylphosphinemethane (dppm), di Methylphenylphosphine (PMe ₂ Ph), Diphenylmethylphosphine (PMePh ₂ ), 1,2-bis(diphenylphosphine)ethane (dppe), 1,3-bis(diphenylphosphine)propane (dppp), 1,4-bis(diphenylphosphino)butane (dppb), 1,1'-bis(diphenylphosphino)ferrocene (dppf), 9,9-dimethyl-4, 5-bis-diphenylphosphine-oxanthene (xantphos), 4,5-bis(di-tert-butylphosphine)-9,9-dimethylxanthene ( ^t Bu-xantphos) and 3-(dicyclohexyl One or more of phosphino)-1-methyl-2-phenyl-1H-indole (CM-phos), more preferably bis-diphenylphosphine methane (dppm), diphenylmethylphosphine ( PMePh ₂ ), 1,2-bis(diphenylphosphine)ethane (dppe), 1,3-bis(diphenylphosphine)propane (dppp), 1,4-bis(diphenylphosphine)butane ( dppb), 1,1'-bis(diphenylphosphino)ferrocene (dppf) and 9,9-dimethyl-4,5-bisdiphenylphosphoxanthene (xantphos) or Various; for example one of diphenylmethylphosphine, 1,1'-bis(diphenylphosphino)ferrocene and 9,9-dimethyl-4,5-bisdiphenylphosphoxanthene one or more species.

In the described preparation method of the alkenyl nitrile compound shown in formula III, if also comprise described conventional suitable part in described reaction system, the mole of described nickel precursor catalyst and described part Ratios are routinely used in this type of cross-coupling reaction in the art. In the present invention, the preferred molar ratio is 1:1 to 1:10, more preferably 1:1 to 1:5, and even more preferably 1:1.2.

In the preparation method of the described alkenyl nitrile compound shown in formula III, the molar ratio of described alkenyl sulfonate compound shown in formula IV and the described cyanation reagent can be The conventional molar ratio of this type of reaction; in the present invention, it is preferably 1:0.1-1:10, more preferably 1:0.5-1:2, further preferably 1:0.6-1:1.2, for example 1:0.8.

In the preparation method of the alkenyl nitrile compound shown in the described formula III, the solvent can be conventionally used in this type of cross-coupling reaction in the art, and does not participate in the reaction; the present invention preferably aromatic solvent, ether One or more of solvents, halogenated hydrocarbon solvents, nitrile solvents, amide solvents and sulfoxide solvents; the aromatic hydrocarbon solvent is preferably one or more of benzene, toluene and xylene; The ether solvent is preferably one or more of ether, 1,4-dioxane and tetrahydrofuran; the halogenated hydrocarbon solvent is preferably a chlorinated hydrocarbon solvent; the chlorinated hydrocarbon solvent Preferably one or more of dichloromethane, dichloroethane and chloroform; the preferred acetonitrile of the described nitrile solvent; the preferred N, N-dimethylformamide, N, N-di One or more of methylacetamide (DMA) and hexamethylphosphoramide; the sulfoxide solvent is preferably dimethyl sulfoxide. The solvent is more preferably one or more of acetonitrile, N,N-dimethylformamide and N,N-dimethylacetamide.

In the preparation method of the described alkenyl nitrile compound shown in formula III, the consumption of described solvent can be conventionally used in this type of cross-coupling reaction in the art; The present invention preferably described as shown in formula IV The molar volume ratio of the alkenyl sulfonate compound to the solvent is 0.01mmol/mL-1mmol/mL, more preferably 0.1mmol/mL-0.5mmol/mL.

In the preparation method of the alkenyl nitrile compound shown in formula III, the reaction temperature of the cross-coupling reaction can be conventionally used in this type of cross-coupling reaction in the art; in the present invention, it can be -100°C -500°C, preferably 0°C-150°C, more preferably 50°C-100°C, further preferably 60°C-80°C.

In the preparation method of described alkenyl nitrile compounds shown in formula III, the reaction process of described cross-coupling reaction can adopt the conventional monitoring method (for example TLC, HPLC that this type of cross-coupling reaction is used in the art) or NMR) for monitoring, generally the end point of the reaction is when the alkenyl sulfonate compound shown in formula IV disappears or no longer reacts.

In the preparation method of the alkenyl nitrile compound shown in formula III, the reaction time of the cross-coupling reaction can be conventionally used in this type of cross-coupling reaction in the art; preferably 0.1-200h in the present invention, More preferably 3-12h.

In the preparation method of the described alkenyl nitrile compound shown in formula III, after the described cross-coupling reaction finishes, the described preparation method can also preferably include the following post-processing steps: after the reaction finishes, filter, The solvent is removed, and the target compound is obtained through column chromatography separation, and the column chromatography separation can adopt conventional methods of this type of operation in the art. The eluent is preferably a mixed solvent of an alkane solvent and an ester solvent. Wherein, the volume ratio of the alkane solvent to the ester solvent is preferably 100:1-1:1; the alkane solvent is preferably petroleum ether; the ester solvent is preferably ethyl acetate.

The present invention further provides an aromatic nitrile compound as shown in formula I or an alkenyl nitrile compound as shown in formula III,

Wherein, the definition of each substituent is the same as above.

Specifically, the present invention also provides an aromatic nitrile or alkenyl nitrile compound as shown in the following structure:

On the basis of not violating common knowledge in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain preferred examples of the present invention.

The reagents and raw materials used in the present invention are all commercially available.

The positive and progressive effect of the present invention is that the present invention realizes the cyanation reaction of aryl sulfonate, heteroaryl sulfonate or alkenyl sulfonate by using a simple and easy-to-obtain catalytic system, and has the advantages of simple operation, high reaction efficiency, The advantages of mild conditions, functional group compatibility and substrate universality provide better application prospects and use value for the industrial synthesis of aromatic nitrile or alkenyl nitrile compounds.

Detailed ways

The present invention is further illustrated below by means of examples, but the present invention is not limited to the scope of the examples. For the experimental methods that do not specify specific conditions in the following examples, select according to conventional methods and conditions, or according to the product instructions.

Preparation example 1:

General preparation process: Add p-iodophenol (1 equiv), boric acid (1.2 equiv), 5% Pd/CaCO ₃ (1.5 mol%), K ₂ CO ₃ (2 equiv), EtOH and water to dissolve in the round bottom bottle, and heat to Reflux at 80°C, and detect the reaction by TLC. Return to room temperature, filter with celite to remove the precipitate, quench the reaction with saturated brine, extract with ethyl acetate, wash the organic phase with water, wash with saturated brine, dry over anhydrous magnesium sulfate, separate and purify after filtration and concentration.

Silica gel column chromatography, eluent: petroleum ether/ethyl acetate/dichloromethane=8:1:1 to pure dichloromethane, the product is 1.81g of white solid, yield 91%. mp＝81.0-82.9℃. ¹ H NMR (400MHz, CDCl ₃ ): δ3.85(s,3H),5.47(brs,1H),6.84-6.89(m,3H),7.07(s,1H),7.12 (d, J=7.6Hz, 1H), 7.32 (dd, J=8.0Hz, 1H), 7.45 (d, J=7.6Hz, 2H). ¹³ C NMR (100MHz, CDCl ₃ ): δ55.30, 112.07, 112.48 ,115.62,119.33,128.39,129.72,133.71,142.27,155.17,159.76.IR(neat):3499,3419,3362,1597,1583,1520,1488,1412,1265,1213,1175,1107,1016,860,831,820,781,688. HRMS(ESI) calcd for C ₁₃ H ₁₃ O ₂ [M+H] ⁺ :201.0910, found 201.0910.

Silica gel column chromatography, eluent: petroleum ether/ethyl acetate/dichloromethane=6:1:1 to petroleum ether/dichloromethane=1:1, after recrystallization with dichloromethane/n-hexane, the product is White solid 1.09g, yield 62%. mp＝172.4-174.2℃. ¹ H NMR (400MHz, DMSO-d ₆ ): δ6.81(d, J＝7.6Hz, 2H), 7.44-7.45(m, 1H), 7.53-7.55(m, 3H) ,7.61(s,1H),9.50(s,1H). ¹³ C NMR(100MHz,DMSO-d ₆ ):δ115.61,118.52,125.98,126.42,126.66,127.29,141.62,156.72.IR(neat):3386, 3096,3029,1597,1532,1500,1444,1372,1250,1199,1181,1110,1009,863,833,800,774,714cm ^-1 .HRMS(EI) calcd for C ₁₀ H ₈ OS[M] ⁺ :176.0296,found 295.76.

Preparation example 2:

Phenol (1equiv) was dissolved in ethyl acetate in a round bottom flask, Et ₃ N (2equiv), MsCl (1.3equiv) was added in an ice-water bath, and the ice-water bath was removed after addition, and reacted at room temperature, and the reaction was complete by TLC. Water was added to quench the reaction, extracted with ethyl acetate, the organic phase was washed with water, dried over anhydrous magnesium sulfate, filtered through silica gel, and the filtrate was concentrated and then separated and purified.

Silica gel column chromatography, eluent: petroleum ether/ethyl acetate=4:1, the product was a light yellow liquid with a yield of 98%. ¹ HNMR (400MHz, CDCl ₃ ): δ0.93(t, J=7.2Hz, 3H), 1.32-1.38(m, 2H), 1.55-1.63(m, 2H), 2.61(t, J=7.6Hz, 2H), 3.11(s, 3H), 7.17-7.26(m, 4H). ¹³ C NMR (100MHz, CDCl ₃ ): δ13.83, 22.21, 33.44, 34.94, 37.09, 121.63, 129.79, 142.28, 147.18.IR (neat):3029,2957,2932,2860,1503,1365,1330,1197,1173,1147,1113,1018,968,865,841,814,776,740,681.HRMS(ESI)calcd for C ₁₁ H ₂₀ NO ₃ S[M+NH ₄ ] ⁺ :246.1158, found 246.1157.

Silica gel column chromatography, eluent: petroleum ether/ethyl acetate/dichloromethane=4:1:1, the product was a white solid, and the yield was 94%. mp＝53.8-55.1℃. ¹ H NMR (400MHz, CDCl ₃ ): δ2.35(s,3H),3.14(s,3H),3.86(s,3H),6.74-6.77(m,1H),6.81 (d, J=1.6Hz, 1H), 7.16 (d, J=8.4Hz, 1H). ¹³ C NMR (100MHz, CDCl ₃ ): δ21.35, 37.93, 55.75, 113.56, 121.38, 123.95, 136.02, 138.48 ,150.81.IR(neat):3037,3013,2933,2843,1602,1505,1473,1415,1356,1290,1196,1174,1145,1110,1035,966,850,812,786,684.HRMS(ESI)calcd for C ₉ H ₁ NO ₄ S[M+NH ₄ ] ⁺ :234.0794, found 234.0792.

The product was recrystallized from dichloromethane/n-hexane, and the product was a white solid with a yield of 89%. mp=148.6-149.7℃. ¹ HNMR (400MHz, CDCl ₃ ): δ2.39(s, 3H), 3.15(s, 3H), 7.24(d, J=7.6Hz, 2H), 7.32(d, J= 8.4Hz, 2H), 7.44(d, J=7.2Hz, 2H), 7.59(d, J=7.6Hz, 2H). ¹³ C NMR(100MHz, CDCl ₃ ): 21.04, 37.25, 122.18, 126.89, 128.38, _{129.57,136.75,137.58,140.50,148.31.IR} (neat): _{3039,3026,2944,1611,1491,1360,1334,1173,1151,973,964,867,852,811,788,720,655.HRMS3} for CI8 _H1c +NH ₄ ] ⁺ :280.1002,found 280.0998.

The product was recrystallized from dichloromethane/n-hexane, and the product was a white solid with a yield of 95%. mp＝83.4-85.0℃. ¹ H NMR (400MHz, CDCl ₃ , Me ₄ Si): δ3.16(s, 3H), 3.86(s, 3H), 6.91(d, J＝8.4Hz, 1H), 7.07 (s, 1H), 7.13 (d, J=7.6Hz, 1H), 7.33-7.38 (m, 3H), 7.59-7.61 (m, 2H). ¹³ C NMR (100MHz, CDCl ₃ , Me ₄ Si): 37.31,55,25,112.92,113.01,119.54,122.20,128.67,129.89,140.42,141.15,148.59,159.94.IR(neat):2962,2938,2838,1608,1576,1782,1356,193 ,1147,1056,972,963,862,838,793,735,721,696.HRMS(ESI)calcd for C ₁₄ H ₁₈ NO ₄ S[M+NH ₄ ] ⁺ :296.0951,found 296.0948.

Silica gel column chromatography, dichloromethane/n-hexane recrystallization, the product is a white solid, and the yield is 95%. mp＝120.8-122.2℃. ¹ H NMR (400MHz, DMSO-d ₆ ): δ7.27-7.31(m, 2H), 7.45(d, J＝8.0Hz, 2H), 7.69-7.75(m, 4H) ^.13 C NMR (100MHz, DMSO-d ₆ ): δ37.40, 115.79 ( ² J _CF ＝21.3Hz), 122.73, 128.33, 128.83 ( ³ J _CF ＝7.5Hz), 135.38 ( ⁴ J _CF ＝3.8Hz), 138.31 ,148.56,162.08( ¹ J _CF ＝242.9Hz). ¹⁹ FNMR(376.1MHz,DMSO-d ₆ ):δ-114.95.IR(neat):3062,3029,2944,1735,1599,1491,1370,1336, 1254,1210,1182,1157,1115,1016,1006,968,945,864,825,789,739,719,653.HRMS(ESI)calcd for C ₁₃ H ₁₅ FNO ₃ S[M+NH ₄ ] ⁺ :284.0751,found 284.0750.

The product was recrystallized from dichloromethane/n-hexane, and the product was a white solid with a yield of 84%. mp＝160.8-162.2℃. ¹ HNMR (400MHz, DMSO-d ₆ ): δ3.41(s, 3H), 7.40(d, J＝8.0Hz, 2H), 7.57(d, J＝3.6Hz, 1H) , 7.65(d, J=2.0Hz, 1H), 7.82(d, J=8.0Hz, 2H), 7.91(s, 1H). ¹³ C NMR(100MHz, DMSO-d ₆ ): 37.36, 121.72, 122.70, 126.22,127.36,127.66,134.34,140.15,148.06.IR(neat):3096,3037,3024,2941,1600,1530,1495,11372,1327,1203,1182,1155,1107,1011,970,863,850,819,792,780,729,709.HRMS(ESI )calcd for C ₁₁ H ₁₄ NO ₃ S ₂ [M+NH ₄ ] ⁺ :272.0410,found272.0410.

Preparation example 3:

Dissolve p-aldehyde phenol (1.22g, 10mmol) in 30mL of ethyl acetate in a round bottom flask, add Et ₃ N (2.8mL, 20mmol) and MsCl (1.0mL, 13mmol) at 0°C, remove the ice after the addition is complete Water bath, react at room temperature, and TLC detects that the reaction is complete. Water was added to quench the reaction, extracted with ethyl acetate, the organic phase was washed with water, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered through silica gel, and the filtrate was concentrated for the next step of reaction.

The product from the previous step was dissolved in 20 mL MeOH and 20 mL DCM, NaBH ₄ (491.8 mg, 13 mmol) was added in batches, and reacted at room temperature after the addition was complete. The reaction was complete as detected by TLC. Add saturated ammonium chloride to quench the reaction, extract with DCM, wash the organic phase with water, wash with saturated brine, dry over anhydrous sodium sulfate, filter and concentrate, silica gel column chromatography, eluent: petroleum ether/ethyl acetate=4:1, separate 1.899 g of colorless liquid was obtained, yield 95%. ¹ H NMR (400MHz, CDCl ₃ ): δ1.05(br, 1H), 3.11(s, 3H), 4.65(s, 2H), 7.24(d, J=7.6Hz, 2H), 7.38(d, J ＝8.0Hz, 2H). ¹³ C NMR (100MHz, CDCl ₃ ): δ37.21, 64.02, 121.93, 128.31, 140.26, 148.24. IR (neat): 3561, 3383, 3024, 2939, 2871, 1603, 1504, 1412,1358,1196,1170,1144,1015,969,865,838,812,773,678.HRMS(ESI)calcd for C ₈ H ₁₄ NO ₄ S[M+NH ₄ ] ⁺ :220.0637,found220.0638.

Preparation example 4:

Under argon protection, 4-phenylcyclohexan-1-one (1.39g, 8 and THF (30mL) were added to a standard Schlenk reaction tube. The reaction solution was cooled to -15°C, and KHMDS (0.5M in toluene, 17.6 mL, 8.8mmol), and stirred at -15°C for 1h after the addition was completed. Then, 4-toluenesulfonic anhydride (2.87g, 8.8mmol) was added at one time at -15°C. After the addition was completed, stirred at -15°C for 0.5h, then Return to room temperature and react. After TLC detects that the reaction is complete, add saturated NaHCO ₃ to quench the reaction, extract with EA, wash the organic phase with water, wash with saturated saline, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate before column chromatography. Eluent: Petroleum ether/ethyl acetate=15:1, a white solid was obtained, and ethyl acetate/n-ethane was recrystallized to obtain 841.6 mg of a white solid, with a yield of 32%. Mp: 100.8-101.5°C. ¹ H NMR (400MHz, CDCl ₃ ): δ1.80-1.87(m,1H),1.93-1.96(m,1H),2.16-2.22(m,2H),2.26-2.33(m,2H),2.47(s,3H),2.71- 2.76(m,1H),7.17-7.23(m,3H),7.26-7.32(m,2H),7.36(d,J=8.0Hz,2H),7.83(d,J=7.2Hz,2H). ¹³ C NMR (100MHz, CDCl ₃ ): δ21.67, 27.85, 29.65, 31.57, 38.87, 116.4, 126.35, 126.71, 128.20, 128.44, 129.66, 133.48, 144.92, 145.18, 147.94. IR (neat): 32960, 2920,2892,2840,1735,1681,1593,1493,1371,1290,1190,1174,1081,1036,891,853,815,763,743,696,688,675.HRMS(ESI)calcd for C ₁₉ H 264 NO ₃₄ S[ _M ⁺ NH]: ₄ , found 346.1466.

Preparation example 5:

Under argon protection, 1-acetonaphthone (1.36 g, 8 mmol) and THF (24 mL) were added to a standard Schlenk reaction tube. The reaction solution was cooled to -20°C, and a solution of 1.0M tBuOK (1.27g, 11.2mmol) in THF ( ^11mL ) was added dropwise, and the addition was completed within 10min. Stir at 0°C for 1.5h after the addition is complete. It was then cooled to -20°C, and 4-toluenesulfonic anhydride (3.13 g, 9.6 mmol) was added in one portion. After the addition, stir at -20°C for 1h, then stir at 0°C for 6h, then return to room temperature and react. After TLC detects that the reaction is complete, add saturated NaHCO ₃ to quench the reaction, extract with EA, wash the organic phase with water, wash with saturated saline, and anhydrous sulfuric acid Dry over sodium, filter, and concentrate the filtrate for column chromatography. Eluent: petroleum ether/ethyl acetate=20:1, 1.77 g of yellow liquid was obtained, yield 54%. ¹ H NMR (400MHz, CDCl ₃ ): δ2.24(s, 3H), 5.25(d, J=1.6Hz, 1H), 5.54(d, J=2.0Hz, 1H), 6.90(d, J=8.0 Hz, 2H), 7.28-7.32(t, J=7.2Hz, 1H), 7.37(d, J=7.2Hz, 1H), 7.41-7.45(m, 3H), 7.71-7.75(m, 2H), 8.00 -8.02(m,1H) ^.13 C NMR(100MHz,CDCl ₃ ):δ21.36,108.94,124.62,125.31,125.92,126.56,127.87,127.94,127.99,128.84,129.81,130.39,131.42,913.4 _152.90.IR (neat): _{3117,3052,2944,1655,1590,1505,1451,1364,1234,1190,1171,1125,1089,922,900,851,798,777,731,682,655.HRMS} (ESI)calcd for C ₃ NH ₄ ] ⁺ :342.1158,found 342.1151.

Example 1 compound (1a)

In a glove box filled with N ₂ , NiCl ₂ 6H ₂ O (5.9 mg, 0.025 mmol), dppf (16.6 mg, 0.03 mmol), Zn (6.5 mg, 0.1 mmol), Zn(CN) ₂ (47.0 mg, 0.4 mmol), DMAP (91.6 mg, 0.75 mmol), 4-acetylphenyl mesylate (107.1 mg, 0.5 mmol), CH ₃ CN (5 mL). After covering the lid, remove it from the glove box, place it directly in an oil bath at 80°C for heating reaction, cool to room temperature after 12 hours, filter on silica gel after TLC detection, wash with ethyl acetate, concentrate and perform column chromatography. Eluent: petroleum ether/ethyl acetate=5:1, the product was 67.8 mg of white solid, the yield was 93%, and the ¹ H NMR purity was greater than 98%. ¹ H NMR (400MHz, CDCl ₃ ): δ2.67(s, 3H), 7.80(d, J=8.4Hz, 2H), 8.07(d, J=8.4Hz, 2H). ¹³ C NMR (100MHz, CDCl ₃ ): δ26.61, 116.12, 117.77, 128.53, 132.37, 139.70, 196.43.

Example 2 Compound (1b)

In a glove box filled with N ₂ , NiCl ₂ 6H ₂ O (11.9mg, 0.05mmol), dppf (33.3mg, 0.06mmol), Zn (13.1mg, 0.2mmol), Zn(CN) ₂ (47.0mg, 0.4mmol), DMAP (91.6mg, 0.75mmol), KI (41.5mg, 0.25mmol), 4-methoxyphenyl mesylate (107.1mg, 0.5mmol), DMF (5 mL). After covering the lid, remove it from the glove box, place it directly in an 80°C oil bath for heating reaction, cool to room temperature after 12 hours, and detect the reaction by TLC. After the reaction, quenched with water, extracted three times with Et ₂ O, washed the organic phase with water, washed with saturated brine, combined the aqueous phase, back-extracted twice with Et ₂ O, combined the organic phase, dried over anhydrous magnesium sulfate, filtered and concentrated, and then column chromatography. Silica gel column chromatography, eluent: petroleum ether/ethyl acetate=10:1, the product was 53.6 mg of white solid, the yield was 81%, and the ¹ H NMR purity was greater than 98%. ¹ HNMR (400MHz, CDCl ₃ ): δ3.86(s, 3H), 6.95(d, J=8.8Hz, 2H), 7.58(d, J=9.2Hz, 2H). ¹³ C NMR (100MHz, CDCl ₃ ): δ55.45, 103.81, 114.67, 119.15, 133.87, 162.76.

Example 3 Compound (1c)

Using the scheme of Example 2, the reaction was carried out at 80° C. for 12 h. Silica gel plate chromatography, eluent: petroleum ether/ethyl acetate=40:1, the product was 20.4 mg of light yellow liquid, the yield was 35% and the NMR yield was 72%. ¹ H NMR purity greater than 98%. ¹ H NMR (400MHz, CDCl ₃ ): δ2.42(s, 3H), 7.27(d, J=7.2Hz, 2H), 7.54(d, J=7.2Hz, 2H). ¹³ C NMR (100MHz, CDCl ₃ ): δ21.77, 109.28, 119.11, 129.79, 132.00, 143.65.

Example 4 compound (1d)

Using the scheme of Example 2, the reaction was carried out at 80° C. for 12 hours. Silica gel plate chromatography, eluent: petroleum ether/ethyl acetate/dichloromethane=100:3:1, the product was 33.2 mg of light yellow liquid, the yield was 42% and the NMR yield was 71%. ¹ H NMR purity greater than 98%. ¹ H NMR (400MHz, CDCl ₃ ): δ0.93(t, J=7.2Hz, 3H), 1.29-1.39(m, 2H), 1.57-1.64(m, 2H), 2.66(t, J=7.6Hz , 2H), 7.27(d, J=8.0Hz, 2H), 7.55(d, J=8.0Hz, 2H). ¹³ C NMR (100MHz, CDCl ₃ ): δ13.78, 22.18, 33.01, 35.74, 109.39, 111.13, 129.14, 132.03, 148.52.

Example 5 compound (1e)

Using the protocol of Example 1, the reaction was carried out at 80° C. for 12 h. Silica gel column chromatography, eluent: petroleum ether/ethyl acetate=3:1, the product was 40.7 mg of colorless liquid, and the yield was 61%. ¹ H NMR purity greater than 98%. ¹ H NMR (400MHz, CDCl ₃ ): δ2.70(brs, 1H), 4.76(s, 2H), 7.47(d, J=8.0Hz, 2H), 7.62(d, J=8.0Hz, 2H)

Example 6 Compound (1f)

Using the scheme of Example 2, the reaction was carried out at 80° C. for 12 h. Silica gel plate chromatography, eluent: petroleum ether/ethyl acetate/dichloromethane=15:1:1, the product was 50.9 mg of light yellow solid, and the yield was 69%. ¹ H NMR purity greater than 98%. mp=70.1-71.2℃. ¹ H NMR (400MHz, CDCl ₃ , Me ₄ Si): δ2.41(s, 3H), 3.91(s, 3H), 6.78(s, 1H), 6.81(d, J= 8.0Hz, 1H), 7.41 (d, J=7.6Hz, 1H). ¹³ C NMR (100MHz, CDCl ₃ , Me ₄ Si): δ22.17, 55.78, 98.60, 111.97, 116.75, 121.56, 133.26, 145.69, 161.09.IR(neat):3070,3016,2949,2921,2845,2217,1608,1572,1503,1466,1409,1378,1302,1287,1272,1200,1164,1123,1033,929,864,742,728. )calcd for C ₉ H ₁₀ NO[M+H] ⁺ :148.0757, found 148.0752.

Example 7 compound (1g)

Using the protocol of Example 1, the reaction was carried out at 80° C. for 6 h. Silica gel column chromatography, eluent: petroleum ether/ethyl acetate=12:1, the product was 62.8 mg of colorless liquid, and the yield was 85%. ¹ H NMR purity greater than 98%. ¹ H NMR (400MHz, CDCl ₃ ): δ6.07(s, 2H), 6.87(d, J=8.0Hz, 1H), 7.03(s, 1H), 7.21(d, J=8.0Hz, 1H). ¹³ C NMR (100MHz, CDCl ₃ ): δ102.13, 104.77, 109.00, 111.24, 118.74, 128.07, 147.91, 151.42.

Example 8 compound (1h)

Using the protocol of Example 1, the reaction was carried out at 80° C. for 12 hours. Silica gel column chromatography, eluent: petroleum ether/ethyl acetate=12:1, the product was 56.2 mg of colorless liquid, and the yield was 77%. ¹ H NMR purity greater than 98%. ¹ H NMR (400MHz, CDCl ₃ ): δ2.96(s, 3H), 6.86–6.88(m, 2H), 6.93(d, J=7.2Hz, 1H), 7.26(dd, J=7.6Hz, 1H ). ¹³ C NMR (100MHz, CDCl ₃ ): δ40.00, 112.60, 114.62, 116.11, 119.23, 119.69, 129.61, 150.11.

Example 9 Compound (1i)

Using the protocol of Example 1, the reaction was carried out at 80° C. for 5 h. Column chromatography, eluent: petroleum ether/ethyl acetate=10:1, the product was 74.5 mg of white solid, and the yield was 91%. ¹ H NMR purity greater than 98%. ¹ H NMR(400MHz,CDCl ₃ ,Me ₄ Si):δ3.81(s,6H),6.65(s,1H),6.75(s,2H). ¹³ C NMR(100MHz,CDCl ₃ ,Me ₄ Si) : δ55.52, 105.44, 109.74, 113.23, 118.62, 160.85.

Example 10 Compound (1j)

Using the protocol of Example 1, but replacing the ligands with PMePh ₂ , NiCl ₂ .6H ₂ O (5.9 mg, 0.025 mmol), PMePh ₂ (12.0 mg, 0.06 mmol), Zinc (6.5 mg, 0.1 mmol), Zn ( CN) ₂ (47.0mg, 0.4mmol), DMAP (91.6mg, 0.75mmol), 4-benzoylphenyl mesylate (138.2mg, 0.5mmol) and CH ₃ CN (5mL), after adding Reaction at 80°C for 12h. Silica gel column chromatography, eluent: petroleum ether/ethyl acetate=10:1, the product was 91.5 mg of white solid, and the yield was 88%. ¹ H NMR purity greater than 98%. ¹ H NMR (400MHz, CDCl ₃ ): δ7.52(t, J=7.6Hz, 2H), 7.64(t, J=7.2Hz, 2H), 7.78-7.80(m, 4H), 7.88(d, J ＝8.4Hz, 2H). ¹³ C NMR (100MHz, CDCl ₃ ): δ115.49, 117.89, 128.51, 129.93, 130.10, 132.05, 133.20, 136.18, 141.08, 194.90.

Example 11 Compound (1k)

Using the protocol of Example 1, the reaction was carried out at 80° C. for 9 h. Silica gel plate chromatography, eluent: petroleum ether/dichloromethane=3:2 to 1:1, the product was 52.8 mg of white solid, and the yield was 82%. ¹ H NMR purity greater than 98%. ¹ H NMR (400MHz, CDCl ₃ ): δ7.81(s, 4H). ¹³ C NMR (100MHz, CDCl ₃ ): δ116.66, 116.97, 132.76.

Example 12 compound (11)

Using the protocol of Example 1, the reaction was carried out at 80° C. for 3 h. Silica gel column chromatography, eluent: petroleum ether/ethyl acetate=10:1, the product was 73.9 mg of white solid, and the yield was 92%. ¹ H NMR purity greater than 98%. ¹ H NMR (400MHz, CDCl ₃ ): δ3.97(s, 3H), 7.76(d, J=8.4Hz, 2H), 8.15(d, J=8.4Hz, 2H). ¹³ C NMR (100MHz, CDCl ₃ ): δ52.58, 116.21, 117.82, 129.94, 132.09, 133.75, 165.26.

Example 13 compound (1m)

Using the protocol of Example 1, the reaction was carried out at 80° C. for 7 h. Silica gel column chromatography, eluent: petroleum ether/ethyl acetate=12:1, the product was 77.4 mg of white solid, and the yield was 88%. ¹ H NMR purity greater than 98%. ¹ H NMR (400MHz, CDCl ₃ ): δ1.43(t, J=6.8Hz, 3H), 4.43(q, J=6.8Hz, 2H), 7.60(t, J=8.0Hz, 1H), 7.84( d, J＝7.6Hz, 1H), 8.28(d, J＝8.0Hz, 1H), 8.33(s, 1H). ¹³ C NMR (100MHz, CDCl ₃ ): δ14.09, 61.64, 112.72, 117.79, 129.28 ,131.60,133.06,133.48,135.72,164.43.

Example 14 compound (1n)

Using the protocol of Example 1, the reaction was carried out at 80° C. for 12 h. Silica gel column chromatography, eluent: petroleum ether/ethyl acetate=3:1, the product was 35.6 mg of white solid, and the yield was 68%. ¹ H NMR purity greater than 98%. ¹ H NMR (400MHz, CDCl ₃ ): δ7.46-7.49(m, 1H), 8.00(d, J=8.0Hz, 1H), 8.84(d, J=4.0Hz, 1H), 8.91(s, 1H ). ¹³ C NMR (100MHz, CDCl ₃ ): δ110.02, 116.39, 123.55, 139.17, 152.35, 152.89.

Example 15 Compound (1o)

Using the scheme of Example 2, the reaction was carried out at 80° C. for 12 hours. Silica gel plate chromatography, eluent: petroleum ether/ethyl acetate=2:1, the product was 34.3 mg of white solid, and the yield was 44%. ¹ H NMR purity greater than 98%. ¹ H NMR (400MHz, CDCl ₃ ): δ7.57 (dd, J = 8.0, 4.0Hz, 1H), 7.63 (t, J = 8.0Hz, 1H), 8.10 (d, J = 8.4Hz, 1H), 8.14(d, J=7.2Hz, 1H), 8.27(d, J=8.0Hz, 1H), 9.10-9.11(m, 1H). ¹³ C NMR(100MHz, CDCl ₃ ): δ112.98, 117.19, 122.72, 125.80 ,128.05,132.86,135.47,136.45,147.38,152.43.

Example 16 Compound (1p)

Using the protocol of Example 1, the reaction was carried out at 80° C. for 12 h. Silica gel column chromatography, eluent: petroleum ether/ethyl acetate=7:1 to 5:1, the product was 57.9 mg of white solid, and the yield was 41%. ¹ H NMR purity greater than 98%. ¹ H NMR (400MHz, CDCl ₃ , Me ₄ Si): δ0.92(s, 3H), 1.48-1.65(m, 6H), 1.98-2.19(m, 4H), 2.40-2.41(m, 2H), 2.52(dd,J＝18.8,9.2Hz,1H),2.93-2.96(m,2H),7.38–7.43(m,2H). ¹³ C NMR(100MHz,CDCl ₃ ,Me ₄ Si):δ13.65, 21.41, 25.28, 25.82, 28.83, 31.31, 35.65, 37.42, 44.40, 47.67, 50.29, 109.41, 119.04, 126.09, 129.17, 132.38, 137.79, 145.25, 220.19.

Example 17 Compound (1q)

Using the protocol of Example 1, the reaction was carried out at 50° C. for 8 h. Silica gel plate chromatography, eluent: petroleum ether/ethyl acetate=35:1, the product was 71.6 mg of white solid, and the yield was 93%. ¹ H NMR purity greater than 98%. ¹ H NMR(400MHz, CDCl ₃ ):δ7.54-7.64(m,3H),7.82-7.87(m,3H),8.15(s,1H). ¹³ C NMR(100MHz,CDCl ₃ ):δ109.12,119.11 ,126.11,127.49,127.88,128.22,128.89,129.01,132.01,133.94,134.42.

Example 18 Compound (1r)

Using the protocol of Example 1, the reaction was carried out at 50° C. for 6 h. Silica gel plate chromatography, eluent: petroleum ether/ethyl acetate=35:1, the product was 70.9 mg of light yellow liquid, and the yield was 93%. ¹ H NMR purity greater than 98%. ¹ H NMR (400MHz, CDCl ₃ , Me ₄ Si): δ7.48(dd, J=7.6Hz, 1H), 7.58(dd, J=7.6Hz, 1H), 7.65(dd, J=7.6Hz, 1H ), 7.87(d, J＝8.4Hz, 2H), 8.03(d, J＝8.4Hz, 1H), 78.29(d, J＝8.4Hz, 1H). ¹³ C NMR (100MHz, CDCl ₃ , Me ₄ Si ): δ109.93, 117.70, 124.76, 124.91, 127.39, 128.43, 128.52, 132.13, 132.46, 132.72, 133.14.

Example 19 Compound (1s)

Using the protocol of Example 1, the reaction was carried out at 80° C. for 9 h. Silica gel column chromatography, eluent: petroleum ether/ethyl acetate=30:1, the product was 66.3 mg of white solid, and the yield was 74%. ¹ H NMR purity greater than 98%. ¹ H NMR (400MHz, CDCl ₃ ): δ7.42-7.50(m, 3H), 7.57-7.59(m, 2H), 7.66(d, J=8.8Hz, 2H), 7.71(d, J=8.4Hz ,2H). ¹³ C NMR (100MHz, CDCl ₃ ): δ110.78, 118.87, 127.13, 127.63, 128.58, 129.03, 132.50, 139.04, 145.54.

Example 20 Compound (1t)

Using the protocol of Example 1, the reaction was carried out at 80° C. for 12 hours. Silica gel plate chromatography, eluent: petroleum ether/ethyl acetate/dichloromethane=100:3:1, the product was 71.3 mg of white solid, and the yield was 74%. ¹ H NMR purity greater than 98%. ¹ H NMR (400MHz, CDCl ₃ ): δ2.40(s, 3H), 7.27(d, J=8.8Hz, 2H), 7.47(d, J=7.2Hz, 2H), 7.62-7.68(m, 4H ). ¹³ CNMR (100MHz, CDCl ₃ ): δ21.06, 110.38, 118.93, 126.92, 127.30, 129.73, 132.42, 136.09, 138.63, 145.43.

Example 21 compound (1u)

Using the protocol of Example 1, the reaction was carried out at 80° C. for 12 hours. Silica gel column chromatography, eluent: petroleum ether/ethyl acetate=30:1, the product was 86.7 mg of white solid, and the yield was 83%. ¹ H NMR purity greater than 98%. ¹ H NMR (400MHz, CDCl ₃ ): δ3.85(s, 3H), 6.95(d, J=8.0Hz, 1H), 7.09(s, 1H), 7.15(d, J=7.2Hz, 2H), 7.38(t, J=7.6Hz, 1H), 7.63-7.69(m, 4H). ¹³ C NMR (100MHz, CDCl ₃ ): δ55.22, 110.84, 112.94, 113.73, 118.78, 119.49, 127.60, 130.02, 132.39, 140.43 ,145.32,159.99.

Example 22 compound (1v)

Using the protocol of Example 1, the reaction was carried out at 80° C. for 12 h. Silica gel column chromatography, eluent: petroleum ether/ethyl acetate=30:1, the product was 78.9 mg of white solid, and the yield was 80%. ¹ H NMR purity greater than 98%. ¹ H NMR (400MHz, CDCl ₃ ): δ7.14-7.18(m, 2H), 7.54-7.57(m, 2H), 7.63(d, J=8.0Hz, 2H), 7.70(d, J=7.6Hz ,2H). ¹³ C NMR (100MHz, CDCl ₃ ): δ110.81, 115.98( ² J _CF ＝21.5Hz), 118.71, 127.43, 128.84( ³ J _CF ＝8.2Hz), 132.51, 135.15( ⁴ J _CF ＝3.7Hz ), 144.44, 163.05 ( ¹ J _CF ＝246.9Hz). ¹⁹ F NMR (376.1MHz, CDCl ₃ ) δ-113.13.

Example 23 compound (1w)

Using the protocol of Example 1, the reaction was carried out at 80° C. for 12 hours. Silica gel column chromatography, eluent: petroleum ether/dichloromethane/ethyl acetate=10:1.5:1, the product was 90.6 mg of white solid, and the yield was 89%. ¹ H NMR purity greater than 98%. ¹ H NMR (400MHz, CDCl ₃ ): δ7.71 (d, J=7.6Hz, 4H), 7.79 (d, J=7.6Hz, 4H). ¹³ C NMR (100MHz, CDCl ₃ ): δ112.33, 118.36, 127.89, 132.82, 143.49.

Example 24 compound (1x)

Using the protocol of Example 1, the reaction was carried out at 80° C. for 12 hours. Silica gel column chromatography, eluent: petroleum ether/ethyl acetate=30:1, the product was 78.4 mg of white solid, and the yield was 85%. ¹ H NMR purity greater than 98%. ¹ H NMR (400MHz, CDCl ₃ ): δ7.40 (d, J=13.2Hz, 2H), 7.55 (s, 1H), 7.65 (m, 4H). ¹³ C NMR (100MHz, CDCl ₃ ): δ110. 29, 118.83, 122.51, 125.78, 126.67, 127.03, 132.54, 139.82, 140.16.

Example 25 Compound (2a)

Using the scheme of Example 1, react at 80°C for 12h. Silica gel plate chromatography, eluent: petroleum ether/ethyl acetate=20:1, the product was 50.3 mg of white solid, and the yield was 65%. ¹ H NMR purity greater than 98%. ¹ H NMR (400MHz, CDCl ₃ ): δ2.49(t, J=13.2, 4.8Hz, 2H), 2.84(t, J=8.4Hz, 2H), 6.87(t, J=4.8Hz, 1H), 7.13-7.15(m,1H),7.23-7.29(m,2H),7.43-7.45(m,1H). ¹³ C NMR(100MHz,CDCl ₃ ):δ23.63,25.96,114.29,117.04,124.64,127.12 ,127.87,128.59,129.04,134.09,143.81.

Example 26 Compound (2b)

Using the protocol of Example 1, the reaction was carried out at 80° C. for 8 h. Silica gel plate chromatography, eluent: petroleum ether/ethyl acetate=20:1, the product was 70.5 mg of white solid, and the yield was 91%. ¹ H NMR purity greater than 98%. ¹ H NMR (400MHz, CDCl ₃ ): δ2.52(t, J=8.4Hz, 2H), 2.88(t, J=8.4Hz, 2H), 7.12-7.16(m, 3H), 7.20-7.29(m ,2H). ¹³ C NMR (100MHz, CDCl ₃ ): δ24.52, 26.52, 109.47, 119.54, 126.99, 127.86, 130.14, 131.01, 135.26, 141.54.

Example 27 Compound (2c)

Using the protocol of Example 1, the reaction was carried out at 80° C. for 7 h. Silica gel plate chromatography, eluent: petroleum ether/ethyl acetate=15:1, the product was 78.9 mg of white solid, and the yield was 86%. ¹ H NMR purity greater than 98%. Mp:59.3-61.2℃. ¹ H NMR(400MHz,CDCl ₃ ):δ6.14(s,1H),6.39(s,1H),7.43-7.44(m,2H),7.50-7.58(m,2H) ,7.85-7.87(m,2H),8.10(t,J＝8.4Hz,2H). ¹³ C NMR(100MHz,CDCl ₃ ):δ118.33,122.01,124.09,125.13,126.42,126.90,127.04,128.60,130.02, 130.09,131.62,133.49,134.69.IR(neat):3028,2211,1635,1601,1492,1452,1434,1417,1077,1027,976,945,926,834,761,699.HRMS(EI)for C ₁₃ H ⁺ ₁₃ N[M calcd 183.1048, found 183.1042.

Example 28 Compound (2d)

Using the protocol of Example 1, the reaction was carried out at 80° C. for 7 h. Silica gel plate chromatography, eluent: petroleum ether/ethyl acetate=30:1, the product was 68.0 mg of white solid, and the yield was 76%. ¹ H NMR purity greater than 98%. ¹ H NMR (400MHz, CDCl ₃ ): δ1.76-1.83(m,1H),1.98-2.03(m,1H),2.23-2.33(m,1H),2.35-2.39(m,2H),2.46- 2.52 (m, 1H), 2.79-2.80 (m, 1H), 6.69-6.70 (m, 1H), 7.17-7.25 (m, 3H), 7.32 (t, J=7.6Hz, 2H). ¹³ C NMR ( 100MHz, CDCl ₃ ):δ27.08,28.47,33.41,38.18,112.15,119.40,126.53,126.57,128.54,144.50,144.82.IR(neat):3057,2226,1590,1508,1402,1340,12052 ,944,859,802,774,658,660.HRMS(ESI)calcd for C ₁₃ H ₁₀ N[M+H] ⁺ :180.0808,found 180.0808.

Example 29 Compound (2e)

Using the protocol of Example 1, the reaction was carried out at 80° C. for 7 h. Silica gel plate chromatography, eluent: petroleum ether/ethyl acetate=20:1, the product was 99.2 mg of white solid, and the yield was 90% (Z:E=3.2:1). ¹ H NMR purity greater than 98%. ¹ H NMR (400MHz, CDCl ₃ ): δ3.66(s,2H),3.78(s,0.63H),6.94(s,1H),7.24-7.38(m,11H),7.69-7.71(m,2H ). ¹³ C NMR (100MHz, CDCl ₃ ): δ35.33, 42.01, 110.56, 113.83, 118.58, 120.16, 127.10, 127.21, 128.20, 128.54, 128.67, 128.70, 128.75, 128.77, 1128.89, 4, 133.39, 133.54, 136.24, 136.32, 143.92, 145.11.

Example 30 Compound (1a)

Using the protocol of Example 1, the substrate was changed to 4-acetylphenyl 4-methylbenzenesulfonate (145.2 mg, 0.5 mmol). Reaction at 80°C for 12h. Silica gel plate chromatography, eluent: petroleum ether/ethyl acetate=5:1, the product was 69.0 mg of white solid, and the yield was 95%. ¹ H NMR purity greater than 98%.

Example 31 Compound (1a)

Using the protocol of Example 1, the substrate was changed to 4-acetylphenyl trifluoromethanesulfonate (134.1 mg, 0.5 mmol). Reaction at 80°C for 12h. Silica gel plate chromatography, eluent: petroleum ether/ethyl acetate=5:1, the product was 67.2 mg of white solid, and the yield was 93%. ¹ H NMR purity greater than 98%.

Example 32 Compound (1a)

Using the protocol of Example 2, the substrate was changed to 4-acetylphenyl dimethylsulfamate (121.6 mg, 0.5 mmol). Reaction at 100°C for 9h. Silica gel plate chromatography, eluent: petroleum ether/ethyl acetate=6:1, the product was 45.5 mg of white solid, and the yield was 63%. ¹ H NMR purity greater than 98%.

Example 32 Compound (1b)

Using the protocol of Example 2, the substrate was changed to 4-methoxyphenyl sulfurofluoridate (103.1 mg, 0.5 mmol) (121.6 mg, 0.5 mmol). Reaction at 80°C for 12h. Silica gel plate chromatography, eluent: petroleum ether/ethyl acetate=12:1, the product was 51.1 mg of white solid, and the yield was 77%. ¹ H NMR purity greater than 98%.

Example 33 Compound (1k)

In a glove box filled with N ₂ , NiCl ₂ 6H ₂ O (11.9 mg, 0.05 mmol), dppf (33.3 mg, 0.06 mmol), Zinc (13.1 mg, 0.2 mmol), Zn(CN) ₂ (93.9 mg, 0.8 mmol), DMAP (183.3 mg, 1.50 mmol), 4-chlorophenyl sulfurofluoridate (105.3 mg, 0.5 mmol) and CH ₃ CN (5 mL). After covering the lid, remove it from the glove box, place it directly in an oil bath at 80°C for heating reaction, cool to room temperature after 12 hours, filter on silica gel after TLC detection, wash with ethyl acetate, concentrate and perform column chromatography. Silica gel plate chromatography, eluent: petroleum ether/dichloromethane=3:2 to 1:1, the product was 58.7 mg of white solid, and the yield was 92%. ¹ H NMR purity greater than 98%.

Example 34 Compound (1a)

In a glove box filled with N ₂ , NiCl ₂ 6H ₂ O (5.9 mg, 0.025 mmol), dppf (16.6 mg, 0.03 mmol), Zn (6.5 mg, 0.1 mmol), Zn(CN) ₂ (47.0 mg, 0.4 mmol), DMAP (61.1 mg, 0.5 mmol), 4-acetylphenyl mesylate (107.1 mg, 0.5 mmol), CH ₃ CN (5 mL). After covering the lid, remove it from the glove box, place it directly in an oil bath at 80°C for heating reaction, cool to room temperature after 12 hours, filter on silica gel after TLC detection, wash with ethyl acetate, concentrate and perform column chromatography. Eluent: petroleum ether/ethyl acetate=5:1, the product is 64.0 mg of white solid, the yield is 88%, and the ¹ H NMR purity is greater than 98%.

Example 35 Compound (1a)

Using the protocol of Example 34, the ligand was changed to dppb (12.8mg, 0.03mmol). Reaction at 80°C for 12h. Silica gel column chromatography, eluent: petroleum ether/ethyl acetate=5:1, the product was 64.8 mg of white solid, the yield was 89%, and the ¹ H NMR purity was greater than 98%.

Example 36 Compound (1a)

Using the protocol of Example 34, the ligand was changed to Xantphos (17.4mg, 0.03mmol). Reaction at 80°C for 12h. Silica gel column chromatography, eluent: petroleum ether/ethyl acetate=5:1. The product was white solid 16.4 mg, yield 23%. ¹ H NMR purity greater than 98%.

Example 37 Compound (1a)

Using the protocol of Example 34, the ligand was changed to DPEphos (16.2 mg, 0.03 mmol). Reaction at 80°C for 12h. Silica gel column chromatography, eluent: petroleum ether/ethyl acetate=5:1. The product is 43.3mg of white solid, the yield is 60%. ¹ H NMR purity greater than 98%

Example 38 Compound (1a)

Using the protocol of Example 34, the ligand was changed to PMe ₂ Ph (8.3 mg, 0.06 mmol). Reaction at 80°C for 12h. Silica gel column chromatography, eluent: petroleum ether/ethyl acetate=5:1. The product was 52.9 mg of white solid, and the yield was 73%. ¹ H NMR purity greater than 98%.

Example 39 Compound (1a)

Using the protocol of Example 34, the ligand was changed to PMePh ₂ (12.0 mg, 0.06 mmol). Reaction at 80°C for 12h. Silica gel column chromatography, eluent: petroleum ether/ethyl acetate=5:1. The product was 52.9 mg of white solid, and the yield was 73%. ¹ H NMR purity greater than 98%.

Example 40 Compound (1a)

Using the protocol of Example 34, the ligand was changed to PPh ₃ (12.0 mg, 0.06 mmol). Reaction at 80°C for 12h. Silica gel column chromatography, eluent: petroleum ether/ethyl acetate=5:1. The product was white solid 13.2mg, yield 18%. ¹ H NMR purity greater than 98%.

Example 41 Compound (1a)

Using the protocol of Example 34, the catalyst was changed to NiBr ₂ ·DME (7.7 mg, 0.06 mmol). Reaction at 80°C for 12h. Silica gel column chromatography, eluent: petroleum ether/ethyl acetate=5:1. The product was 63.1 mg of white solid, and the yield was 87%. ¹ HNMR purity greater than 98%.

Example 42 Compound (1a)

Using the protocol of Example 34, the catalyst was changed to NiI ₂ (7.8mg, 0.06mmol). Reaction at 80°C for 12h. Silica gel column chromatography, eluent: petroleum ether/ethyl acetate=5:1. The product was 59.7 mg of white solid, and the yield was 82%. ¹ H NMR purity greater than 98%

Example 43 Compound (1a)

Using the protocol of Example 34, the solvent was changed to DMA (5 mL). Reaction at 80°C for 12h. Silica gel column chromatography, eluent: petroleum ether/ethyl acetate=5:1. The product was 62.5 mg of white solid, and the yield was 87%. ¹ H NMR purity greater than 98%

Example 44 Compound (1a)

Using the protocol of Example 34, the solvent was changed to NMP (5 mL). Reaction at 80°C for 12h. Silica gel column chromatography, eluent: petroleum ether/ethyl acetate=5:1. The product was 42.4 mg of white solid, and the yield was 58%. ¹ H NMR purity greater than 98%.

Example 45 Compound (1a)

Using the scheme of Example 34, the temperature was changed to 60°C. Reaction at 60°C for 12h. Silica gel column chromatography, eluent: petroleum ether/ethyl acetate=5:1. The product was 61.9 mg of white solid, and the yield was 85%. ¹ H NMR purity greater than 98%.

Example 46 Compound (1b)

In a glove box filled with N ₂ , NiCl ₂ 6H ₂ O (11.9mg, 0.05mmol), dppf (33.3mg, 0.06mmol), Zn (13.1mg, 0.2mmol), Zn(CN) ₂ (47.0mg, 0.4mmol), DMAP (91.6mg, 0.75mmol), NaI (37.5mg, 0.25mmol), 4-methoxyphenyl mesylate (107.1mg, 0.5mmol), DMF (5 mL). After covering the lid, remove it from the glove box, place it directly in an 80°C oil bath for heating reaction, cool to room temperature after 12 hours, and detect the reaction by TLC. After the reaction, quenched with water, extracted three times with Et ₂ O, washed the organic phase with water, washed with saturated brine, combined the aqueous phase, back-extracted twice with Et ₂ O, combined the organic phase, dried over anhydrous magnesium sulfate, filtered and concentrated, and then column chromatography. Silica gel column chromatography, eluent: petroleum ether/ethyl acetate=10:1, the product was 43.2 mg of white solid, the yield was 65%, and the ¹ H NMR purity was greater than 98%.

Example 47 Compound (1b)

Using the protocol of Example 46, the additive was changed to Et ₄ NI (64.3 mg, 0.25 mmol). Silica gel column chromatography, eluent: petroleum ether/ethyl acetate=10:1, the product was 45.9 mg of white solid, and the yield was 70%. ¹ H NMR purity greater than 98%.

Claims (13)

1. A preparation method of an aromatic nitrile compound shown as a formula I comprises the following steps: under the protection of inert gas, in a solvent and in the presence of a nickel complex, metal zinc and an additive, carrying out cross coupling reaction on an aryl or heteroaryl sulfonate compound shown as a formula II and a cyanation reagent as shown in the specification; wherein the additive is 4-dimethylamino pyridine, and the cyanation reagent is zinc cyanide;

in the aromatic nitrile compounds shown in the formula I and the aryl or heteroaryl sulfonate compounds shown in the formula II,

n is selected from any integer between 0- [ M-1], wherein M represents the maximum number of substitutions on ring α;

R¹identical or different, each independently selected from halogen, C₁-C₆Linear OR branched alkoxy, -CN, -C (═ O) OR^a、-NR^bR^c、-C(＝O)R^d、-C(＝O)NR^eR^f、R^gSubstituted C₃-C₁₀Or R is aryl or heteroaryl, or^hSubstituted C₁-C₆Linear or branched alkyl of (a); wherein R is^a、R^b、R^c、R^d、R^e、R^f、R^gAnd R^hEach independently selected from-H, halogen, -OH, -CN, C₁-C₄A straight or branched alkoxy group of (A), and C₁-C₄One or more of linear or branched alkyl groups of (a);

or, any two adjacently substituted R¹Together with the atoms of ring α to which they are each attached, form a carbocyclic or carbocyclic heterocyclic ring fused to ring α, said carbocyclic or carbocyclic heterocyclic ring being a 3-10 membered ring, said carbocyclic or carbocyclic heterocyclic ring containing 1-4 heteroatoms selected from O, N and S;

-OS(＝O)₂r in R is selected from halogen and C₁-C₆Straight or branched alkyl of (2), C₁-C₆Or R is a linear or branched haloalkyl groupⁱSubstituted phenyl; wherein R isⁱSelected from halogen, C₁-C₆Straight or branched alkyl of, or-NR^jR^kWherein R is^jAnd R^kEach independently selected from C₁-C₄Linear or branched alkyl of (a);

ring α is an aromatic or heteroaromatic ring, wherein when ring α is an aromatic ring, the aromatic ring is any stable monocyclic or polycyclic carbocyclic ring of up to 6 atoms in each ring, at least one ring of the polycyclic rings being aromatic, and when ring α is an aromatic ring, the aromatic ring is optionally substituted with one or more substituents selected from the group consisting of alkyl, aryl, heteroaryl, and optionally substitutedWhen the aromatic ring is polycyclic and a non-aromatic ring is present, -OS (═ O)₂Wherein when ring α is an aromatic heterocycle, the aromatic heterocycle is any stable monocyclic or polycyclic ring of up to 6 atoms in each ring, at least one ring of the polycyclic ring is aromatic and contains 1 to 4 heteroatoms selected from O, N and S, and when the aromatic heterocycle is polycyclic and wherein a non-aromatic ring is present or contains no heteroatoms, -OS (═ O)₂The attachment of R and-CN to each other is via a "heteroatom-containing aromatic ring".

2. The method according to claim 1, wherein,

n is 0, 1 or 2;

and/or when R^a、R^b、R^c、R^d、R^e、R^f、R^gAnd R^hWhen any one of the halogen is fluorine, chlorine, bromine or iodine;

and/or when R^a、R^b、R^c、R^d、R^e、R^f、R^gAnd R^hAny one of them is C₁-C₄Said C is a straight or branched alkoxy group of₁-C₄Is C₁-C₃Is preferably methoxy, ethoxy, propoxy or isopropoxy;

and/or when R^a、R^b、R^c、R^d、R^e、R^f、R^gAnd R^hAny one of them is C₁-C₄When the alkyl group is a straight or branched alkyl group, said C₁-C₄Is C₁-C₃Preferably methyl, ethyl, propyl or isopropyl;

and/or when R¹When the halogen is fluorine, chlorine, bromine or iodine;

and/or when R¹Is C₁-C₆Said C is a straight or branched alkoxy group of₁-C₆Is C₁-C₃Is preferably methoxy, ethoxy, propoxy or isopropoxy;

and/or when R¹is-C (═ O) OR^aWhen R is^aIs C₁-C₄Preferably methyl, ethyl, propyl or isopropyl;

and/or when R¹is-NR^bR^cWhen R is^bAnd R^cEach independently is C₁-C₄Preferably methyl, ethyl, propyl or isopropyl;

and/or when R¹is-C (═ O) R^dWhen R is^dIs C₁-C₄Preferably methyl, ethyl, propyl or isopropyl;

and/or when R¹is-C (═ O) NR^eR^fWhen R is^eAnd R^fEach independently is C₁-C₄Preferably methyl, ethyl, propyl or isopropyl;

and/or when R¹Is R^gSubstituted C₃-C₁₀Aryl or heteroaryl of (A), said C₃-C₁₀Aryl or heteroaryl of (a) is phenyl or thienyl;

and/or when R¹Is R^hSubstituted C₁-C₆When the alkyl group is a straight or branched alkyl group, said C₁-C₆Is C₁-C₃Preferably methyl, ethyl, propyl or isopropyl;

and/or, when any two of adjacently substituted R are¹When the atoms of ring α to which each is attached form a carbocyclic or carbocyclic ring fused to ring α, said carbocyclic or carbocyclic ring is a 3-5 membered ring and said carbocyclic ring contains 1 or 2 heteroatoms selected from O, N and S;

and/or, when n is 1, R¹Preferably selected from methyl, n-butyl, methoxyA group, amino, acetyl, methoxycarbonyl, ethoxycarbonyl, cyano or phenyl; when n is 2, R¹Identical or different, each of which is independently preferably selected from methyl or methoxy; or two R¹Taken together with the atom on ring α to which each is attached to form a dioxolanyl group;

and/or when RⁱWhen the halogen is fluorine, chlorine, bromine or iodine;

and/or when RⁱIs C₁-C₆When the alkyl group is a straight or branched alkyl group, said C₁-C₆Is C₁-C₃Preferably methyl, ethyl, propyl or isopropyl;

and/or when Rⁱis-NR^jR^kWhen said is-NR^jR^kIn R^jAnd R^kEach independently is methyl, ethyl, propyl or isopropyl;

and/or, when R is halogen, said halogen is fluorine, chlorine, bromine or iodine;

and/or, when R is C₁-C₆When the alkyl group is a straight or branched alkyl group, said C₁-C₆Is C₁-C₃Preferably methyl, ethyl, propyl or isopropyl;

and/or, when R is C₁-C₆When said alkyl is a straight or branched chain haloalkyl, said C₁-C₆Is C₁-C₃Preferably trifluoromethyl, is used as the straight or branched chain haloalkyl group of (1).

3. The method according to claim 1, wherein,

said-OS (═ O)₂R is fluorosulfonyl, trifluoromethanesulfonyl, methanesulfonyl, p-tolylsulfonyl or aminosulfonyl;

and/or the aromatic ring is a monocyclic aromatic ring or a bicyclic fused ring aromatic ring, preferably a benzene ring or a naphthalene ring;

and/or the aromatic heterocycle is a monocyclic pyridine ring or a bicyclic quinoline ring.

4. The method according to claim 1, wherein the aryl or heteroaryl sulfonate compound of formula II and the aromatic nitrile compound of formula I are any pair of compounds selected from the group consisting of:

5. the method according to claim 1, wherein in the method for producing an aromatic nitrile compound represented by the formula I,

the inert protective gas is one or more of nitrogen, helium, argon and neon;

and/or the molar ratio of the aryl or heteroaryl sulfonate compound shown as the formula II to DMAP is 1:0.1-1:10, preferably 1:1-1: 1.5;

and/or the molar ratio of the aryl or heteroaryl sulfonate compound shown as the formula II to the metal zinc is 1:0.01-1:10, more preferably 1:0.1-1:1, and further preferably 1:0.2-1: 0.4;

and/or, the nickel complex is NiBr₂(PPh₃)₂And/or NiCl₂(dppf)；

And/or the molar ratio of the aryl or heteroaryl sulfonate compound shown as the formula II to the nickel complex is 1:0.01-1:1, more preferably 1:0.02-1:0.50, and further preferably 1:0.05-1: 0.10;

and/or the molar ratio of the aryl or heteroaryl sulfonate compound shown as the formula II to the cyanation reagent is 1:0.1-1:10, more preferably 1:0.5-1:2, further preferably 1:0.6-1:1.2, or preferably 1: 0.8;

and/or the solvent is one or more of aromatic hydrocarbon solvent, ether solvent, halogenated hydrocarbon solvent, nitrile solvent, amide solvent and sulfoxide solvent; the aromatic hydrocarbon solvent is preferably one or more of benzene, toluene and xylene; the ether solvent is preferably one or more of diethyl ether, 1, 4-dioxane and tetrahydrofuran; the halogenated hydrocarbon solvent is preferably a chlorinated hydrocarbon solvent; the chlorinated hydrocarbon solvent is preferably one or more of dichloromethane, dichloroethane and chloroform; the nitrile solvent is preferably acetonitrile; the amide solvent is preferably one or more of N, N-dimethylformamide, N-Dimethylacetamide (DMA) and hexamethylphosphoramide; the sulfoxide solvent is preferably dimethyl sulfoxide; the solvent is more preferably one or more of acetonitrile, N-dimethylformamide and N, N-dimethylacetamide;

and/or the molar volume ratio of the aryl or heteroaryl sulfonate compound shown in the formula II to the solvent is 0.01mmol/mL-1mmol/mL, preferably 0.1mmol/mL-0.5 mmol/mL;

and/or the reaction temperature of the cross-coupling reaction is-100 ℃ to 500 ℃, preferably 0 ℃ to 150 ℃, more preferably 50 ℃ to 100 ℃, and further preferably 60 ℃ to 80 ℃;

and/or the reaction time of the cross-coupling reaction is 0.1-200h, preferably 3-12 h.

6. The method according to claim 1, wherein in the method for producing an aromatic nitrile compound represented by the formula I,

the reaction system also comprises other additives besides the additive DMAP, wherein the other additives are quaternary ammonium salt and/or inorganic salt; wherein, the quaternary ammonium salt is preferably tetraethyl ammonium iodide; the inorganic salt is preferably one or more of sodium iodide, potassium iodide and lithium iodide, and more preferably potassium iodide; when the reaction system further comprises quaternary ammonium salt and/or inorganic salt, the molar ratio of the aryl or heteroaryl sulfonate compound shown as the formula II to the quaternary ammonium salt and/or the inorganic salt is preferably 1:0.1-1:10, and more preferably 1:0.5-1: 1;

and/or the nickel complex is subjected to in-situ coordination in a reaction system by a nickel precursor catalyst and a suitable ligand thereof and then participates in the reaction; wherein the nickel precursor catalyst is selected from the group consisting of Ni (cod)₂、NiCl₂、NiBr₂、NiI₂、NiBr₂(diglyme)、NiCl₂(glyme)、NiBr₂(DME)、NiF₂And NiCl₂·6H₂One or more of O, preferably NiBr₂(DME)、NiI₂And NiCl₂·6H₂One or more of O; suitable ligands for the nickel precursor catalyst are selected from one or more of triphenylphosphine, triethylphosphine, tributylphosphine, tricyclohexylphosphine, bisdiphenylphosphinomethane, dimethylphenylphosphine, diphenylmethylphosphine, 1, 2-bis (diphenylphosphino) ethane, 1, 3-bis (diphenylphosphino) propane, 1, 4-bis (diphenylphosphino) butane, 1' -bis (diphenylphosphino) ferrocene, 9-dimethyl-4, 5-bisdiphenylphosphine xanthene, 4, 5-bis (di-tert-butylphosphino) -9, 9-dimethylxanthene and 3- (dicyclohexylphosphino) -1-methyl-2-phenyl-1H-indole, more preferably bisdiphenylphosphinomethane, diphenylmethylphosphine, 1, 2-bis (diphenylphosphino) ethane, tris (diphenylphosphino) methane, bis (diphenylphosphino) ethane, bis (diphenylphosphino) methane, bis (diphenylphosphino) ferrocene, bis (diphenylphosphino, One or more of 1, 3-bis (diphenylphosphino) propane, 1, 4-bis (diphenylphosphino) butane, 1 '-bis (diphenylphosphino) ferrocene and 9, 9-dimethyl-4, 5-bisdiphenylphosphinoanthracene, further preferably one or more of diphenylmethylphosphine, 1' -bis (diphenylphosphino) ferrocene and 9, 9-dimethyl-4, 5-bisdiphenylphosphinoanthracene; the molar ratio of the nickel precursor catalyst to the suitable ligand is preferably 1:1 to 1:10, more preferably 1:1 to 1:5, and even more preferably 1: 1.2.

7. A preparation method of alkenyl nitrile compounds shown in formula III comprises the following steps: under the protection of inert gas, under the condition of existence of a nickel complex, metal zinc and an additive, an alkenyl sulfonate compound shown as IV and a cyanation reagent are subjected to cross coupling reaction shown as follows; wherein the additive is 4-dimethylaminopyridine; the cyanation reagent is zinc cyanide;

in the alkenyl nitrile compounds shown in the formula III and the alkenyl sulfonate compounds shown in the formula IV,

R²、R³and R⁴Each independently selected from-H, - (CH)₂)x-R^mSubstituted C₃-C₁₀Or R is aryl or heteroaryl, orⁿSubstituted C₁-C₆Linear or branched alkyl of (a); wherein R is^mAnd RⁿEach independently selected from-H, halogen, -OH, -CN, C₁-C₄Linear or branched alkoxy and C₁-C₄One or more of linear or branched alkyl groups of (a); x is selected from any integer between 0 and 4;

or, R²And R³Or R²And R⁴Together form a quilt RⁿA substituted 5-10 membered monocyclic or polycyclic carbocyclic or carbocyclic ring containing 1-4 heteroatoms selected from O, N and S; the 5-10 membered monocyclic or polycyclic carbocyclic or carbocyclic ring is a saturated or semi-saturated ring;

-OS(＝O)₂r in R is selected from halogen and C₁-C₆Straight or branched alkyl of (2), C₁-C₆Or R is a linear or branched haloalkyl groupⁱSubstituted phenyl; wherein R isⁱSelected from halogen, C₁-C₆Straight or branched alkyl of, or-NR^jR^kWherein R is^jAnd R^kEach independently selected from C₁-C₄Linear or branched alkyl.

8. The method according to claim 7, wherein,

x is 0, 1,2 or 3;

and/or when R^mAnd RⁿWhen any one of the above is halogen, the halogen is preferably fluorine, chlorine, bromine or iodine;

and/or when R^mAnd RⁿAny one of them is C₁-C₄Of a straight chain orWhen the alkoxy group is branched, said C₁-C₄Is C₁-C₃Is preferably methoxy, ethoxy, propoxy or isopropoxy;

and/or when R^mAnd RⁿAny one of them is C₁-C₄When the alkyl group is a straight or branched alkyl group, said C₁-C₄Is C₁-C₃Preferably methyl, ethyl, propyl or isopropyl;

and/or when RⁱWhen the halogen is fluorine, chlorine, bromine or iodine;

and/or when RⁱIs C₁-C₆When the alkyl group is a straight or branched alkyl group, said C₁-C₆Is C₁-C₃Preferably methyl, ethyl, propyl or isopropyl;

and/or when Rⁱis-NR^jR^kWhen said is-NR^jR^kIn R^jAnd R^kEach independently is methyl, ethyl, propyl or isopropyl;

and/or, when R is halogen, said halogen is fluorine, chlorine, bromine or iodine;

and/or, when R is C₁-C₆When the alkyl group is a straight or branched alkyl group, said C₁-C₆Is C₁-C₃Preferably methyl, ethyl, propyl or isopropyl;

and/or, when R is C₁-C₆When said alkyl is a straight or branched chain haloalkyl, said C₁-C₆Is C₁-C₃Preferably trifluoromethyl, is used as the straight or branched chain haloalkyl group of (1).

9. The method according to claim 7, wherein,

said-OS (═ O)₂R is fluorosulfonyl, trifluoromethanesulfonyl or methylsulfonylAcyl, p-tolylsulfonyl or aminosulfonyl;

and/or, said- (CH)₂)x-R^mSubstituted C₃-C₁₀In the aryl or heteroaryl group of (a), said C₃-C₁₀Aryl or heteroaryl of (A) is C₆-C₁₀Aryl of (a), preferably phenyl or naphthyl;

and/or, said RⁿSubstituted C₁-C₆In the straight or branched alkyl group of (1), said C₁-C₆Is C₁-C₃Preferably methyl, ethyl, propyl or isopropyl;

and/or said 5-to 10-membered monocyclic or polycyclic carbocycle is preferably a monocyclic or bicyclic carbocycle, preferably cyclohexene or benzocycloalkene.

10. The method according to claim 7, wherein the alkenyl sulfonate compound of formula IV and the alkenyl nitrile compound of formula III are any pair of compounds selected from the group consisting of:

11. the method according to claim 7, wherein, in the method for producing an alkenylnitrile compound represented by the formula III,

the inert protective gas is one or more of nitrogen, helium, argon and neon;

and/or the molar ratio of the alkenyl sulfonate compound shown as the formula IV to DMAP is 1:0.1-1:10, preferably 1:1-1: 1.5;

and/or the molar ratio of the alkenyl sulfonate compound shown as the formula IV to the metal zinc is 1:0.01-1:10, preferably 1:0.1-1:1, and further preferably 1:0.2-1: 0.4;

and/or, the nickel complex is NiBr₂(PPh₃)₂And/or NiCl₂(dppf)；

And/or the molar ratio of the alkenyl sulfonate compound shown as the formula IV to the nickel complex is 1:0.01-1:1, preferably 1:0.02-1:0.50, and further preferably 1:0.05-1: 0.10;

and/or the molar ratio of the alkenyl sulfonate compound shown as the formula IV to the cyanation reagent is 1:0.1-1:10, more preferably 1:0.5-1:2, further preferably 1:0.6-1:1.2, or preferably 1: 0.8;

and/or the solvent is one or more of aromatic hydrocarbon solvent, ether solvent, halogenated hydrocarbon solvent, nitrile solvent, amide solvent and sulfoxide solvent; the aromatic hydrocarbon solvent is preferably one or more of benzene, toluene and xylene; the ether solvent is preferably one or more of diethyl ether, 1, 4-dioxane and tetrahydrofuran; the halogenated hydrocarbon solvent is preferably a chlorinated hydrocarbon solvent; the chlorinated hydrocarbon solvent is preferably one or more of dichloromethane, dichloroethane and chloroform; the nitrile solvent is preferably acetonitrile; the amide solvent is preferably one or more of N, N-dimethylformamide, N-Dimethylacetamide (DMA) and hexamethylphosphoramide; the sulfoxide solvent is preferably dimethyl sulfoxide; the solvent is more preferably one or more of acetonitrile, N-dimethylformamide and N, N-dimethylacetamide;

and/or the mol volume ratio of the alkenyl sulfonate compound shown in the formula IV to the solvent is 0.01mmol/mL-1mmol/mL, preferably 0.1mmol/mL-0.5 mmol/mL;

and/or the reaction temperature of the cross-coupling reaction is-100 ℃ to 500 ℃, preferably 0 ℃ to 150 ℃, more preferably 50 ℃ to 100 ℃, and further preferably 60 ℃ to 80 ℃;

and/or the reaction time of the cross-coupling reaction is 0.1-200h, preferably 3-12 h.

12. The method according to claim 7, wherein, in the method for producing an alkenylnitrile compound represented by the formula III,

the reaction system also comprises other additives besides the additive DMAP, wherein the other additives are quaternary ammonium salt and/or inorganic salt; wherein, the quaternary ammonium salt is preferably tetraethyl ammonium iodide; the inorganic salt is preferably one or more of sodium iodide, potassium iodide and lithium iodide, and more preferably potassium iodide; when the reaction system further comprises quaternary ammonium salt and/or inorganic salt, the molar ratio of the alkenyl sulfonate compound shown as the formula IV to the quaternary ammonium salt and/or the inorganic salt is 1:0.1-1:10, preferably 1:0.5-1: 1;

and/or the nickel complex is subjected to in-situ coordination in a reaction system by a nickel precursor catalyst and a suitable ligand thereof and then participates in the reaction; wherein the nickel precursor catalyst is selected from the group consisting of Ni (cod)₂、NiCl₂、NiBr₂、NiI₂、NiBr₂(diglyme)、NiCl₂(glyme)、NiBr₂(DME)、NiF₂And NiCl₂·6H₂One or more of O, preferably NiBr₂(DME)、NiI₂And NiCl₂·6H₂One or more of O; suitable ligands for the nickel precursor catalyst are selected from one or more of triphenylphosphine, triethylphosphine, tributylphosphine, tricyclohexylphosphine, bisdiphenylphosphinomethane, dimethylphenylphosphine, diphenylmethylphosphine, 1, 2-bis (diphenylphosphino) ethane, 1, 3-bis (diphenylphosphino) propane, 1, 4-bis (diphenylphosphino) butane, 1' -bis (diphenylphosphino) ferrocene, 9-dimethyl-4, 5-bisdiphenylphosphine xanthene, 4, 5-bis (di-tert-butylphosphino) -9, 9-dimethylxanthene and 3- (dicyclohexylphosphino) -1-methyl-2-phenyl-1H-indole, more preferably bisdiphenylphosphinomethane, diphenylmethylphosphine, 1, 2-bis (diphenylphosphino) ethane, tris (diphenylphosphino) methane, bis (diphenylphosphino) ethane, bis (diphenylphosphino) methane, bis (diphenylphosphino) ferrocene, bis (diphenylphosphino, One or more of 1, 3-bis (diphenylphosphino) propane, 1, 4-bis (diphenylphosphino) butane, 1 '-bis (diphenylphosphino) ferrocene and 9, 9-dimethyl-4, 5-bisdiphenylphosphinoanthracene, further preferably one or more of diphenylmethylphosphine, 1' -bis (diphenylphosphino) ferrocene and 9, 9-dimethyl-4, 5-bisdiphenylphosphinoanthracene; of said nickel precursor catalyst with said ligandThe molar ratio is preferably 1:1 to 1:10, more preferably 1:1 to 1:5, and still more preferably 1: 1.2.

13. An aromatic or alkenyl nitrile compound represented by the following structure: