Synthesis method of copper-catalyzed aryl nitrile compound

Abstract

The invention discloses a synthesis method of a copper-catalyzed aryl nitrile compound. Specifically, the method comprises the following steps: cuprous cyanide, aryl halide, ligand and alkali are placed in an organic solvent, heating and stirring reaction are performed to obtain the aryl nitrile compound, the reaction process is shown in the specification, and the definition of each group is shown in the specification. The synthesis method has the advantages of cheap and easily available raw materials, low catalyst cost, mild reaction conditions, low production cost, high raw material conversion rate, good selectivity, good product purity, stability, high efficiency, simple operation, compatibility with almost all common functional groups, and good industrial production prospect.

Description

Technical Field

[0001] This invention belongs to the fields of chemical synthesis and pharmaceutical synthesis. Specifically, this invention relates to a copper-catalyzed method for synthesizing aryl nitrile compounds. Background Technology

[0002] Aromatic ring cyanation, which involves introducing a cyano group onto an aromatic ring, is an important type of carbon-adding reaction. Its importance lies primarily in two aspects: firstly, aryl nitrile compounds are widely used in the pharmaceutical and pesticide fields; and secondly, aryl nitrile compounds can undergo a wide variety of transformations.

[0003] The cyano group, a linear functional group consisting of a nitrogen atom bonded to a sp-hybridized carbon atom, has a spatial volume only 1 / 8 that of a methyl group. This allows it to penetrate deeper into protein cavities and better tolerate target mutations. Simultaneously, the lone pair of electrons on the nitrogen atom acts as a good hydrogen bond acceptor, contributing to a tight binding affinity to the target. Furthermore, the strong electron-withdrawing ability of the cyano group can modulate the electronegativity of the aromatic ring it occupies, potentially leading to significant π-π stacking interactions with amino acid residues containing aromatic rings. Beyond the inherent chemical properties of the cyano group, introducing aryl nitrile functional groups into drug molecules can significantly alter their pharmacokinetic properties. On one hand, the water solubility of the drug molecule is improved to some extent, thereby enhancing its bioavailability. On the other hand, the half-life of the drug molecule is prolonged, allowing for fuller efficacy.

[0004]

[0005] Formula 0-1: Examples of pharmaceutical active ingredients containing aryl nitrile fragments

[0006] Due to the aforementioned special properties, aryl nitrile fragments are commonly found in various anticancer, antiviral, and psychotropic drugs (Formula 0-1). Compounds 1 and 2 are two anticancer drug molecules, named alectinib and serpercatinib, respectively. They are two clinically used drugs for non-small cell lung cancer with different targets. Serpercatinib can also be used to treat refractory RET fusion-positive advanced or metastatic thyroid cancer. Compounds 3 and 4 are two antidepressants, named (S)-citalopram and vilazodone, respectively, both of which are highly selective serotonin reuptake inhibitors. Compounds 5 and 6 are two commonly used drugs for treating HIV / AIDS, named etravirine and doravirine, respectively, both of which belong to the non-nucleoside reverse transcriptase inhibitors.

[0007] Besides their wide application in medicine, aryl nitrile fragments are also common in pesticides. As shown in Formula 0-2, cyhalofop-butyl (7) is a herbicide that degrades rapidly in the natural environment. Azoxystrobin (8) is a broad-spectrum fungicide with good systemic conductivity, strong penetration, and long-lasting effect. Isotianil (9) is an antifungal agent that can induce and stimulate rice to produce its own defense mechanism against rice blast, and also has some insecticidal efficacy, making it suitable for early-stage control of rice diseases with minimal impact on the natural environment. Cyantraniliprole (10) is a ryanodine receptor inhibitor in insects; after absorption by insects, it triggers Ca2+ receptor activating enzymes. 2+ It is released in large quantities and accumulates in muscle tissue, leading to severe muscle contraction and death of the insect.

[0008]

[0009] Formula 0-2: Examples of pesticide active ingredients containing aryl nitrile fragments

[0010] Furthermore, aryl nitrile compounds can undergo a variety of transformations (Equations 0-3). For example, through hydrolysis, hydration, reduction, nucleophilic addition, and amination reactions, they can generate benzoic acid, benzamide, and other benzoyl derivatives, as well as benzylamine and benzamide compounds. Moreover, they can readily construct various nitrogen-containing heterocyclic compounds through cyclization reactions. For instance, aryl nitrile compounds can undergo 1,3-dipolar cycloaddition with sodium azide to construct 5-aryl-1-H-tetrazole, react with optically active ethanolamine to synthesize chiral oxazoline compounds, and under copper catalysis, can react with 2-aminopyridine and benzamide compounds to synthesize triazole derivatives, respectively.

[0011]

[0012] Formula 0-3: Examples of aryl nitrile compounds transformed into various functional groups and nitrogen heterocycles

[0013] In summary, aryl nitrile compounds play an irreplaceable role in many fields, including pharmaceutical manufacturing and chemical production. Therefore, exploring simple and efficient methods for synthesizing these compounds is of paramount importance.

[0014] Numerous synthetic methods for aryl nitrile compounds have been reported, and researchers are continuously exploring new synthetic approaches to obtain high-yield, high-purity nitriles, reduce raw material consumption, shorten reaction time, and achieve milder reaction conditions, thereby improving economic efficiency. As shown in Formula 0-4, commonly used synthetic methods include redox methods, elimination methods, and addition methods. However, these methods have not yet achieved the desired results. Poor atom economy and demanding reaction conditions are their obvious drawbacks.

[0015]

[0016] Formula 0-4: Examples of synthetic methods for aryl nitrile compounds

[0017] In modern times, researchers have launched a research boom in transition metal catalysis. Transition metal catalysis boasts advantages such as high efficiency and atom economy. Therefore, the synthesis of aryl nitrile compounds via transition metal catalysis is of great significance for chemical production and drug development. Among these methods, the coupling reaction of aryl halides with cyano reagents catalyzed by transition metals is the most efficient.

[0018] The reaction can be catalyzed by three main types of catalysts: Pd, nickel (Ni), and Cu. The cyaniding reagents used include metal cyanides, potassium ferrocyanide, and organic cyanide reagents. The earliest reported reaction was the cyanation of aryl halides catalyzed by Pd. In 1973, Tagaki et al. used KCN as the cyano source and DMF as the solvent to achieve the cyanation of aryl halides at 140°C (Equation 0-5). However, this system could not achieve the conversion of aryl chlorides.

[0019]

[0020] Equations 0-5: Early Pd-catalyzed cyanidation reactions of aryl halides

[0021] In 2000, Confalone et al. first achieved Pd-catalyzed cyanation of aryl chlorides (Formula 0-6). The catalyst system used was Pd₂dba₃ and dppf, with Zn(CN)₂ as the cyano source, and a certain amount of Zn powder was also added. The tested substrates yielded yields of over 85%. However, for electron-rich substrates such as 4-chloroanisole, a larger catalyst dosage was required to obtain good yields.

[0022]

[0023] Formula 0-6: Cyanide of aryl chlorides

[0024] It is worth mentioning that in 2004, Beller's research group successfully achieved the conversion of aryl halides into aryl nitrile compounds using the almost non-toxic K4[Fe(CN)6] as a cyano source (Equation 0-7). This cyano source is even used as an additive in the food industry, as well as a flavoring agent in table salt and red wine. Therefore, it has a great advantage over highly toxic metal cyanides.

[0025]

[0026] Formula 0-7: Cyanidation of aryl halides with non-toxic K4[Fe(CN)6] as the cyano source

[0027] Regarding Ni-catalyzed cyanation of aryl halides, Cassar first reported the Ni-catalyzed cyanation reaction of aryl halides in 1973 (Equation 0-8). Meta- and para-substituted aryl halides can be readily converted to the corresponding aryl nitrile. However, ortho-substituted aryl halides, such as 2-methylbromobenzene, can only proceed via oxidative addition (In1) or the transmetallized species (In2).

[0028]

[0029] Equation 0-8: First Ni-catalyzed cyanidation of aryl halides

[0030] In 2017, Professor Liu Yuanhong's research group at the Shanghai Institute of Organic Chemistry reported a catalytic system using NiCl2·6H2O as a catalyst and dppf as a ligand, which can efficiently convert (hetero)aryl halides into (hetero)aryl nitrile compounds (Formulas 0-9) under mild conditions. It is noteworthy that the reaction cannot proceed if anhydrous NiCl2 is used in this system. Without the addition of DMAP, the yield drops sharply to around 10%.

[0031]

[0032] Formula 0-9: Ni-catalyzed cyanidation of heterocyclic aryl chlorides

[0033] In the area of ​​Cu-catalyzed cyanation of aryl halides, the first report appeared in 2003, with Buchwald et al. using DMEDA as a ligand and CuI-catalyzed aryl ring cyanation (Equation 0-10). A catalytic amount of KI was added to the system to promote the conversion of aryl bromides to iodides, thereby accelerating the reaction. The addition of an equivalent amount of ligand was to prevent catalyst poisoning and deactivation caused by the extremely strong complexing ability of cyanide anions with the metal catalyst.

[0034]

[0035] Formula 0-10: Cu-catalyzed cyanidation of aryl halides

[0036] In 2007, inspired by the metal coordination of the imidazole ring on the side chain of histidine in nature, Beller's group utilized commercially available alkylimidazolium as ligands or solvents to promote cyanation reactions (Equation 0-11). This discovery partially compensated for the limitations of previous CuI / DMEDA catalytic systems for electron-deficient substrates and those with highly sterically hindered substitutions. However, this system requires high temperatures and a large amount of alkylimidazolium.

[0037]

[0038] Formula 0-11: Cu-catalyzed cyanidation of aryl halides with K4[Fe(CN)6] as the cyano source

[0039] In summary, current transition metal-catalyzed aryl cyanation reactions mainly focus on Pd. Although Pd catalysis currently holds a leading advantage over other metals in terms of efficiency and substrate diversity, Pd-catalyzed systems have significant drawbacks. First, Pd-catalyzed systems often require the participation of P ligands; the participation of N ligands cannot facilitate effective conversion, and P ligands are often highly toxic and expensive. Second, Pd is a precious metal, resulting in a significant cost disadvantage compared to Ni and Cu. Third, currently reported palladium-catalyzed reaction systems generally suffer from excessively high reaction temperatures. While Ni catalysis significantly lowers the reaction temperature, it also has many difficult-to-compensate drawbacks. First, Ni-catalyzed reaction systems often require the addition of additives. Second, the substrate universality is poor, and the selection of cyano sources is quite demanding. Furthermore, the reaction system is overly sensitive to water and oxygen; slight errors in operation or reaction conditions can lead to extremely poor reaction results.

[0040] In summary, there is an urgent need in this field to develop green, inexpensive, and simple metal-catalyzed synthesis methods for aryl nitrile compounds. Summary of the Invention

[0041] One object of the present invention is to provide a green, inexpensive, and simple reaction system for the metal-catalyzed synthesis of aryl cyanide compounds.

[0042] The technical problem this invention aims to solve is to overcome the shortcomings of existing methods for synthesizing aryl nitrile compounds, such as high cost of catalysts or raw materials, and / or harsh reaction conditions, and / or high production costs, and / or low raw material conversion rates, and / or poor selectivity, and / or low product purity, and / or complex operations. Simultaneously, it overcomes the shortcomings of existing copper-catalyzed methods for synthesizing aryl nitrile compounds, such as poor substrate universality and the inability to complete the conversion of aryl chlorides.

[0043] In a first aspect of the invention, use is provided for a compound of formula I, or an isomer thereof.

[0044]

[0045] In the formula,

[0046] W represents -NR4R5, -(C1-6 alkylene)-R8, substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted 5-20 heteroaryl;

[0047] R8 is selected from the following group: C6-14 aryl, 5-10 heteroaryl;

[0048] R4 and R5 are each independently selected from the group consisting of: substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3-7-membered heterocyclic group, substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted 5-20-membered heteroaryl; or, R4 and R5 together with the N atom they are connected to form a substituted or unsubstituted saturated or unsaturated 3-20-membered heterocycle or heteroaromatic ring (such as substituted or unsubstituted pyrrole, indole, azole, benzoazole and aromatic heterocycle), wherein the heteroaryl and heterocycle contain 1-3 heteroatoms each independently selected from N, O and S;

[0049] R6 and R7 are each independently selected from the group consisting of C1-C6 alkyl or C6-10 aryl;

[0050] As a ligand for the preparation of aryl nitrile compounds from copper-catalyzed aryl halides, wherein the aryl halides are selected from the group consisting of aryl chlorides, aryl bromides, aryl iodides, or combinations thereof;

[0051] Unless otherwise specified, the substitution refers to one or more hydrogen atoms on the group being substituted by a substituent selected from the group consisting of: C1-C6 alkyl, C1-C6 alkoxy, halo-C1-6 alkyl, C1-C6 haloalkoxy, C1-6 hydroxyalkyl, C6-C10 aryl, 3- to 20-membered heteroaryl, C6-C10 aryl-oxy, halogen, nitro, hydroxy, cyano, C2-C10 ester (C1-C10 alkyl-COO-), C2-C10 acyl (C1-C10 alkyl-CO-), sulfonate, or two hydrogen atoms on two adjacent carbon atoms of the group being replaced by -(CH2). q - Replacement, where q is 1, 2, 3, 4, 5, or 6.

[0052] In another preferred embodiment, the aryl halide refers to a cyclic structure comprising at least one 5-6 membered heteroaryl or phenyl group, wherein the 5-6 membered heteroaryl or phenyl group comprises at least one halogen.

[0053] In another preferred embodiment, W is -NR4R5, -(CH2)-R8, substituted or unsubstituted C6-C14 aryl, substituted or unsubstituted 5-10 heteroaryl.

[0054] In another preferred embodiment, R8 is selected from the group consisting of C6-10 aryl and 5-7 heteroaryl.

[0055] In another preferred embodiment, R4 and R5 are each independently selected from the group consisting of C6-14 aryl and 5-14 heteroaryl; or, R4 and R5 together with the N atom they are connected to form a substituted or unsubstituted 5-13 nitrogen-containing heteroaryl ring.

[0056] Wherein, the substitution refers to one or more hydrogen atoms on the substituent group being substituted by a substituent selected from the group consisting of: hydroxyl, cyano, nitro, halogen, C1-6 alkyl, C1-6 alkoxy, haloC1-6 alkyl, C1-C6 haloalkoxy, and C1-6 hydroxyalkyl, and the heteroaryl and heteroaromatic ring contain 1 to 3 heteroatoms each independently selected from N, O, and S.

[0057] In another preferred embodiment, W is selected from -N(phenyl)2, -(CH2)-pyridyl, C1-3 alkyl-substituted C10-C14 aryl, and C1-3 alkyl-substituted 9-membered heteroaryl.

[0058] In another preferred embodiment, R8 is selected from a 6-membered heteroaryl group (e.g., pyridyl).

[0059] In another preferred embodiment, R6 and R7 are each independently selected from the group consisting of C1-C3 alkyl or phenyl groups.

[0060] In another preferred embodiment, R6 and R7 are each independently selected from the group consisting of methyl, ethyl, isopropyl or phenyl, preferably, R6 and R7 are each independently methyl.

[0061] In another preferred embodiment, R4 is hydrogen and R5 is not hydrogen.

[0062] In another preferred embodiment, R4 and R5, along with their commonly attached N atom, together form a substituted or unsubstituted 5-13-membered heteroaryl group; the substitution refers to substitution by one or more groups selected from the group consisting of: halogen, nitro, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkoxy, C6 aryl, 3- to 7-membered heteroaryl, C6 aryl-O-, C2-C6 ester (C1-C6 alkyl-COO-), C2-C6 acyl (C1-C6 alkyl-CO-), sulfonate, or two hydrogen atoms on two adjacent carbon atoms of said group being replaced by -(CH2). q - Replacement, where q is 1, 2, 3, 4, 5, or 6.

[0063] In another preferred embodiment, the compound has the structure shown in formula Ia:

[0064]

[0065] Wherein, W is as described in the first aspect of the present invention.

[0066] In another preferred embodiment, W is selected from the following group:

[0067]

[0068] In another preferred embodiment, the compound of formula I is selected from the group consisting of:

[0069]

[0070] In a second aspect of the present invention, a method for preparing an aryl nitrile compound is provided, comprising the following steps:

[0071]

[0072] In an inert solvent, in the presence of an alkali, a cuprous cyanide catalyst, and the ligand shown in Formula I, the halogenated aryl compound shown in Formula II reacts to give the aryl nitrile compound shown in Formula III; wherein the ligand is as described in the first aspect of the present invention.

[0073]

[0074] in,

[0075] W, R6 and R7 are as described in the first aspect of the present invention;

[0076] X is a halogen, preferably Cl, Br or I;

[0077] It is a benzene ring or a 5-6 membered aromatic ring, or a 9-20 membered fused polycyclic system, wherein the fused polycyclic system includes at least one benzene ring or a 5-6 membered heteroaromatic ring (preferably a benzene ring) as a fusion unit, and the benzene ring or the 5-6 membered heteroaromatic ring is substituted by one or more X (preferably substituted by one X).

[0078] The polycyclic system is formed by one or more (e.g., 2, 3, 4 or 5) cyclic structures, each independently selected from 5-6-membered heteroaryl, phenyl, 5-7-membered heterocyclic and C3-7 cycloalkyl groups, through fusion, screwing, or bridging, or by the above cyclic structures being connected by one or more divalent groups L.

[0079] Wherein, each L is independently selected from the group consisting of: none, C1-6 alkylene, C2-4 alkenylene, -O-, -S-, -NH, -C(O)-, -C(O)O-, -SO-, -S(O)2-, or combinations thereof;

[0080] Optionally substituted with one or more R groups selected from the group consisting of: H, D, halogen, amino, oxo (=O), nitro, hydroxyl, cyano, carboxyl (-COOH), C1-6 alkyl-NH-, -C1-6 alkylene-OH, acyl, amide, C1-6 alkyl-S(O)2-, ester, C1-6 alkyl, C2-6 alkenyl, C2-6 alkoxy, halo-C1-6 alkoxy, (C1-6 alkyl)3 silyl, C1-6 alkyl-(L) z - C6-10 aryl-(L) z -, 5-10 aryl-(L) z - C3-10 cycloalkyl-(L) z -, 3-10 membered heterocyclic group-(L) z -;

[0081] z can be 0, 1, 2, 3, 4, 5, or 6;

[0082] Wherein, the cycloalkyl and heterocyclic groups are optionally substituted with groups selected from the group consisting of: halogen, cyano, oxo, phenyl, C1-6 alkyl, ester, N(C1-6 alkyl)2.

[0083] In another preferred embodiment, the halogenated aryl compound represented by Formula II is an aryl chloride, an aryl bromide, or an aryl iodide.

[0084] In another preferred embodiment, when multiple halogens are present in the halogenated aryl compound represented by Formula II, the halogen atoms undergoing cyanidation reaction have the following priority order: aryl iodide, aryl bromide, and aryl chloride.

[0085] In another preferred embodiment, the Selected from the following group:

[0086]

[0087] Wherein, R and X are as described in the second aspect of the present invention;

[0088] Y is -NH-, -O-, or -S-.

[0089] Ring B is selected from the group consisting of 5-7 membered heterocyclic groups, 5-7 membered heteroaryl groups, C3-7 cycloalkyl groups, or phenyl groups;

[0090] The ring C is selected from the following group: 5-7 membered heterocyclic group, 5-7 membered heteroaryl group, C3-7 cycloalkyl group, or C6-10 aryl group;

[0091] n is 1, 2, or 3; and

[0092] m is 0, 1, 2 or 3;

[0093] *express It can also be located at the para position of the X substituent;

[0094] Wherein, when a substituent R is present, the substituent R is located at a substitutable site on any ring in the above polycyclic system.

[0095] In another preferred embodiment, the haloaryl compound represented by Formula II is selected from the group consisting of:

[0096]

[0097]

[0098] In another preferred embodiment, the alkali is selected from the group consisting of sodium phosphate, potassium phosphate, sodium carbonate, potassium carbonate, sodium acetate, potassium acetate, sodium hydroxide, potassium hydroxide, or combinations thereof; and / or

[0099] The inert solvent is selected from the group consisting of: aromatic solvents, halogenated hydrocarbon solvents, ether solvents, alkane solvents, sulfone solvents, sulfoxide solvents, amide solvents, halogenated aromatic solvents, or combinations thereof; preferably, the inert solvent is selected from the group consisting of: dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, or combinations thereof.

[0100] In another preferred embodiment, the method further includes adding potassium iodide to participate in the reaction, wherein the amount of potassium iodide is 10% of the molar amount of the compound represented by Formula II.

[0101] In another preferred embodiment, adding 1-10 mol% potassium iodide as an additive can reduce the reaction temperature by 5%-20% or the amount of catalyst by 10-15%.

[0102] In another preferred embodiment, the molar ratio of the haloaryl compound represented by Formula II to the base is 1:(0.25-1), more preferably 1:(0.5-0.75); and / or

[0103] The molar ratio of the haloaryl compound represented by Formula II to cuprous cyanide is 1:(1±0.5), preferably 1:(1±0.5), and more preferably 1:1; and / or

[0104] The molar ratio of the haloaryl compound to the ligand represented by Formula II is 1:(0.005-0.1), preferably 1:(0.01-0.1), and more preferably 1:(0.02-0.05); and / or

[0105] The molar volume ratio (mol / L) of the haloaryl compound represented by Formula II to the solvent is (1-10):1, preferably (2-8):1, and more preferably (3-5):1; and / or

[0106] The reaction time is 1-48 h, preferably 12-24 h; and / or

[0107] The reaction temperature is 20-140℃, preferably 60-130℃.

[0108] In another preferred embodiment, the compound of formula III is selected from the group consisting of:

[0109]

[0110]

[0111] In a third aspect of the invention, a compound of Formula I is provided:

[0112]

[0113] in,

[0114] W, R6, and R7 are as described in the first aspect of the present invention.

[0115] In another preferred embodiment, the compound is selected from the group consisting of:

[0116]

[0117] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here. Detailed Implementation

[0118] Through extensive and in-depth research, the inventors have, for the first time, provided a novel system using cuprous cyanide as a catalyst and cyanide source, along with pyridine amide ligands as shown in Formula I, for catalyzing the conversion of aryl halides to aryl cyanides. The method provided by this invention exhibits good substrate compatibility, being compatible with almost all common functional groups, and overcomes the shortcomings of existing technologies. It features mild reaction conditions, readily available raw materials, good selectivity, and high raw material conversion rate, making it suitable for industrial production. Based on these findings, the inventors completed this invention.

[0119] the term

[0120] As used in this article, the term "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0121] The term "halogenated" refers to the replacement of one or more hydrogen atoms in a group with a halogen.

[0122] The term "multiple" refers to 1, 2, 3, 4, 5, or 6.

[0123] The term "alkyl" refers to a straight-chain or branched alkyl group. When an alkyl group is preceded by a carbon number limit (e.g., C1-C6), it means that the alkyl group contains 1-6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, or similar groups.

[0124] The term "cycloalkyl" refers to a bicyclic or tricyclic (fused, bridged, or spirocyclic) ring system having a saturated or partially saturated unit. The cycloalkyl group may have 3-20 carbon atoms. When a cycloalkyl group is preceded by a carbon number limitation (e.g., C3-C20), it indicates that the cycloalkyl group contains 3-20 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cycloheptyl, or similar groups. Preferably, the cycloalkyl group contains 3-10 carbon atoms, more preferably 3-6 carbon atoms. The cycloalkyl group may be monocyclic, polycyclic, spirocyclic, or bridged.

[0125] As used herein, the term "alkoxy" refers to an alkyl group (e.g., -O-alkyl, wherein the alkyl group is as described above) linked by an oxygen atom, such as (but not limited to) methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, or similar groups. When an alkoxy group is preceded by a carbon number limitation (e.g., C1-C6), it means that the alkoxy group contains 1-6 carbon atoms.

[0126] The term "aryl" refers to an aromatic hydrocarbon group that is monocyclic, bicyclic, tricyclic, or fused-ring, and may be substituted or unsubstituted. When an aryl group is preceded by a carbon number limit (e.g., C6-C20), it means that the aryl group contains 6-20 carbon atoms. Examples of aryl groups include (but are not limited to): phenyl, biphenyl, naphthyl, or similar groups (each carbon atom of which may be arbitrarily substituted); preferably, the aryl group contains 6-14 carbon atoms (more preferably 6-10 carbon atoms).

[0127] The term "heteroaryl" refers to a monocyclic, bicyclic, tricyclic, or fused-ring aromatic group comprising at least one heteroatom selected from N, O, or S. The heteroaryl can be 3- to 20-membered, having 1-5 heteroatoms, each independently selected from N, O, or S. Examples of heteroaryl groups include (but are not limited to): pyridine, pyrimidine, pyrrole, indazole, indole, furan, benzofuran, thiophene, or similar groups; preferably, the heteroaryl contains 5-13 carbon atoms. Preferably, the heteroaryl refers to a 5-12-membered (more preferably 5-9- or 5-7-membered) heterocyclic group having 1-3 heteroatoms, each independently selected from N, O, or S.

[0128] The term "heterocyclic group" refers to a saturated or partially saturated substituent of a monocyclic or fused ring, wherein the group comprises at least one identical or different heteroatom selected from N, O, or S. The heterocyclic group can be 3- to 20-membered, having 1-5 heteroatoms, each independently selected from N, O, or S. Examples of heterocyclic groups include (but are not limited to): nitrogen heterocyclic groups, oxygen heterocyclic groups, sulfur heterocyclic groups, nitrogen-oxygen heterocyclic groups, etc. Preferably, the heterocyclic group refers to a 5-12-membered (more preferably 5-9- or 5-7-membered) heterocyclic group having 1-3 heteroatoms, each independently selected from N, O, or S.

[0129] The term "carbocyclic group" refers to a cyclic hydrocarbon structure consisting of 3 to 10 carbon atoms, wherein the cyclic hydrocarbon structure is saturated, unsaturated, or partially unsaturated, and may optionally contain one or more double or triple bonds. Preferably, the carbocyclic group consists of 3 to 6 carbon atoms.

[0130] The term "polycyclic system" refers to a group consisting of 1, 2, 3, 4 or 5 saturated or unsaturated carbon rings or heterocyclic groups through screwing, bridging, fusion (co-fusion). Furthermore, in the polycyclic system, the individual carbon rings or heterocyclic groups can be connected by divalent bonds, such as bonds, C1-4 alkylene groups, -O-, -S-, -NH, -C(O)-, -SO-, -S(O)2-.

[0131] The term "ester group" refers to a group having a "C1-6 alkyl-C(O)O-" structure, wherein the alkyl group is defined as described above.

[0132] The term "acyl" refers to a group having a "C1-6 alkyl-CO-" structure, wherein the alkyl group is defined as described above.

[0133] The term "amide group" refers to a group having a "C1-6 alkyl-NHC(O)-" or "aryl-NHC(O)-" structure, wherein alkyl and aryl are defined as described above.

[0134] As used in this article, the term "isomer" includes stereoisomers, tautomers, geometric isomers, etc.

[0135] ligands

[0136] Unless otherwise specified, the ligands mentioned in this article refer to ligands used in copper-catalyzed aryl chloride / bromine coupling reactions.

[0137] The ligands available in this invention have the structure shown in formula (I) above. In a preferred embodiment of this invention, the ligand has the following structure (the definitions of each group are as described above):

[0138]

[0139] In the formula,

[0140] W represents -NR4R5, -(C1-6 alkylene)-R8, substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted 5-20 heteroaryl;

[0141] R8 is selected from the following group: C6-14 aryl, 5-10 heteroaryl;

[0142] R4 and R5 are each independently selected from the following group: H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3-6 membered heterocyclic, substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted 5-20 membered heteroaryl, -(C1-6 alkylene)-C6-10 aryl, -(C1-6 alkylene)-5-10 membered heteroaryl;

[0143] Alternatively, R4 and R5 together with the N atom they are connected to form substituted or unsubstituted saturated or unsaturated 3-20 membered heterocycles or heteroaromatic rings (such as substituted or unsubstituted pyrroles, indoles, azoles, benzoxazoles, and aromatic heterocycles), wherein the heteroaryl group and heterocycle contain 1-3 heteroatoms, each independently selected from N, O, and S.

[0144] R6 and R7 are each independently selected from the group consisting of C1-C6 alkyl or C6-10 aryl;

[0145] As a ligand for the preparation of aryl nitrile compounds from copper-catalyzed aryl halides, wherein the aryl halides are selected from the group consisting of aryl chlorides, aryl bromides, aryl iodides, or combinations thereof;

[0146] Unless otherwise specified, the substitution refers to one or more hydrogen atoms on the group being substituted by a substituent selected from the group consisting of: C1-C6 alkyl, C1-C6 alkoxy, halo-C1-6 alkyl, C1-C6 haloalkoxy, C1-6 hydroxyalkyl, C6-C10 aryl, 3- to 20-membered heteroaryl, C6-C10 aryl-oxy, halogen, nitro, hydroxy, cyano, C2-C10 ester (C1-C10 alkyl-COO-), C2-C10 acyl (C1-C10 alkyl-CO-), sulfonate, or two hydrogen atoms on two adjacent carbon atoms of the group being replaced by -(CH2). n - Replacement (n is 1, 2, 3, 4, 5 or 6).

[0147] As a ligand for copper-catalyzed aryl halide coupling reactions; wherein the aryl halide is selected from the group consisting of aryl chlorides, aryl bromides, aryl iodides, or combinations thereof.

[0148] The ligands of the present invention can be obtained through commercial channels or prepared according to the preferred method provided in the present invention.

[0149] Copper-catalyzed preparation of aryl halides from aryl nitrile compounds

[0150] This invention provides a method for synthesizing aryl nitrile compounds from copper-catalyzed aryl halides, the method comprising using a compound of formula (I) as described above as a ligand to carry out the above reaction.

[0151] In contrast, Cu-catalyzed reaction systems overcome almost all the drawbacks of Pd and Ni. For example, Cu-catalyzed systems are compatible with almost all cyano sources, including the non-toxic potassium ferrocyanide. Furthermore, as an inexpensive metal, Cu offers significant advantages over Ni in terms of reaction system simplicity and catalyst stability. Additionally, Cu-catalyzed systems generally use N ligands to modulate reaction activity, avoiding the use of highly toxic and expensive P ligands. Moreover, Cu-catalyzed systems are effective not only for aryl halides but also for other aryl parent compounds, such as arylboronic acids and aryl aldehydes.

[0152] For example, some drug molecules or drug intermediates containing chlorine, bromine or iodine in their structure can be converted into corresponding cyano compounds using the method of the present invention. For example, the anti-allergy drug loratadine, the drug perphenazine for treating mental illness, the lipid-lowering drug fenofibrate, the antimalarial drug chloroquine, the drug nicergoline for treating cerebrovascular disease, the anticonvulsant serotonin, and intermediates of the active pharmaceutical ingredients for treating diabetes such as ipalliptin, canagliflozin and ioggliflozin can all be successfully converted into corresponding cyano compounds using the method of the present invention.

[0153]

[0154] For different reactants, the ligands and reaction conditions can be optimized within the scope of the disclosure of this invention to select the most suitable ligand type and reaction conditions (such as temperature, solvent, reactant ratio and reaction time). After reading the disclosure of this application, the above optimization is within the skill of those skilled in the art.

[0155] A typical method includes the following steps:

[0156]

[0157] In an inert solvent, in the presence of a base, a cuprous cyanide catalyst, and the ligand shown in Formula I, the halogenated aryl compound shown in Formula II reacts to give the aryl nitrile compound shown in Formula III; wherein, the ligand is not particularly limited and can be any of the ligands mentioned above.

[0158] It is a benzene ring or a 5-6 membered aromatic ring, or a 9-20 membered fused polycyclic system, wherein the fused polycyclic system includes at least one benzene ring or a 5-6 membered heteroaromatic ring (preferably a benzene ring) as a fusion unit, and the benzene ring or the 5-6 membered heteroaromatic ring is substituted by one or more X (preferably substituted by one X).

[0159] The polycyclic system is formed by one or more (e.g., 2, 3, 4 or 5) cyclic structures, each independently selected from 5-6-membered heteroaryl, phenyl, 5-7-membered heterocyclic and C3-7 cycloalkyl groups, through fusion, screwing, or bridging, or by the above cyclic structures being connected by one or more divalent groups L.

[0160] Wherein, each L is independently selected from the group consisting of: none, C1-6 alkylene, C2-4 alkenylene, -O-, -S-, -NH, -C(O)-, -C(O)O-, -SO-, -S(O)2-, or combinations thereof;

[0161] Optionally substituted with one or more R groups selected from the group consisting of: H, D, halogen, amino, oxo (=O), nitro, hydroxyl, cyano, carboxyl (-COOH), C1-6 alkyl-NH-, -C1-6 alkylene-OH, acyl, amide, C1-6 alkyl-S(O)2-, ester, C1-6 alkyl, C2-6 alkenyl, C2-6 alkoxy, halo-C1-6 alkoxy, (C1-6 alkyl)3 silyl, C1-6 alkyl-(L) z - C6-10 aryl-(L) z -, 5-10 aryl-(L) z - C3-10 cycloalkyl-(L) z -, 3-10 membered heterocyclic group-(L) z -;

[0162] z can be 0, 1, 2, 3, 4, 5, or 6;

[0163] Wherein, the cycloalkyl and heterocyclic groups are optionally substituted with groups selected from the group consisting of: halogen, cyano, oxo, phenyl, C1-6 alkyl, ester, N(C1-6 alkyl)2.

[0164] Preferably, the Selected from the following group:

[0165]

[0166] R and X are as described above;

[0167] Y is -NH-, -O-, or -S-.

[0168] Ring B is selected from the group consisting of 5-7 membered heterocyclic groups, 5-7 membered heteroaryl groups, C3-7 cycloalkyl groups, or phenyl groups;

[0169] The ring C is selected from the following group: 5-7 membered heterocyclic group, 5-7 membered heteroaryl group, C3-7 cycloalkyl group, or C6-10 aryl group;

[0170] n is 1, 2, or 3; and

[0171] m is 0, 1, 2 or 3;

[0172] *express It can also be located at the para position of the X substituent;

[0173] Wherein, when a substituent R is present, the substituent R is located at a substitutable site on any ring in the above polycyclic system.

[0174] In a preferred embodiment, under the reaction conditions of the present invention, when multiple halogens are present in the aryl halide, the priority order of the halogen atoms undergoing the cyanation reaction is as follows: aryl iodide, aryl bromide, aryl chloride.

[0175] The reaction conditions of the method of the present invention are not particularly limited. For example, the base can be a commonly used alkaline substance selected from the group consisting of sodium phosphate, potassium phosphate, sodium carbonate, potassium carbonate, sodium acetate, potassium acetate, sodium hydroxide, potassium hydroxide, or a combination thereof; and / or

[0176] There are no particular restrictions on the reaction solvent, which is generally an inert solvent. For example, the inert solvent is selected from the group consisting of: aromatic solvents, halogenated hydrocarbon solvents, ether solvents, alkane solvents, sulfone solvents, sulfoxide solvents, amide solvents, halogenated aromatic solvents, or combinations thereof; preferably, the inert solvent is selected from the group consisting of: dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, or combinations thereof.

[0177] In particular, an appropriate amount of potassium iodide may be added to the method of the present invention, wherein the amount of potassium iodide is 1-10% of the molar amount of the compound represented by Formula II; preferably 10%.

[0178] For the same substrate, adding an appropriate amount of potassium iodide can reduce the temperature of the reaction system by 5%-20% (preferably 10%), or reduce the amount of catalyst required by 5%-20% (preferably 10%). At the same time, adding potassium iodide helps to increase the product yield.

[0179] There are no particular restrictions on the ratios of the reactants; those skilled in the art can choose according to the reaction type. For example, the molar ratio of the halogenated aryl compound shown in Formula II to the base is 1:(0.25-1), preferably 1:(0.5-0.75); and / or

[0180] The molar ratio of the haloaryl compound represented by Formula II to cuprous cyanide is 1:(1±0.5), preferably 1:(1±0.5), and more preferably 1:1; and / or

[0181] The molar ratio of the haloaryl compound to the ligand represented by Formula II is 1:(0.005-0.1), preferably 1:(0.01-0.1), and more preferably 1:(0.02-0.05); and / or

[0182] The molar volume ratio (mol / L) of the haloaryl compound represented by Formula II to the solvent is (1-10):1, preferably (2-8):1, and more preferably (3-5):1; and / or

[0183] The reaction time is 1-48 h, preferably 12-24 h; and / or

[0184] The reaction temperature is 20-140℃, preferably 60-130℃.

[0185] use

[0186] The aryl cyanides prepared by the method of this invention can be used as intermediates to prepare other important drug molecules and chemical raw materials.

[0187] For example, compound P24 can be used as an intermediate in the preparation of the anti-HIV drug eztravirine;

[0188]

[0189] Compound P43 can be used as an intermediate in the preparation of doravirine;

[0190]

[0191] Compound P39 can be used as an intermediate in the preparation of the antidepressant citalopram;

[0192]

[0193] Compound P36 can be used as an intermediate in the preparation of trelagliptin, a drug for treating diabetes.

[0194]

[0195] Compound P42 can be used as an intermediate in the preparation of the insecticide bromocyanamide.

[0196]

[0197] In addition to the compounds mentioned above, for example, compounds P33 and P37 can be used as intermediates in drugs for treating multiple sclerosis and ulcerative colitis, and compound P44 is an important chemical raw material, and so on.

[0198]

[0199] Compared with the prior art, the main advantages of the present invention include:

[0200] (1) The method for preparing aryl cyanide of the present invention is based on pyridine amide ligand, copper catalyst has low cost and good substrate compatibility, and is compatible with almost all common functional groups.

[0201] (2) The synthesis method of the present invention has mild reaction conditions, cheap and readily available raw materials, low catalyst cost, simple operation, and good prospects for industrial production.

[0202] (3) The method of the present invention is stable and efficient, has good selectivity, high raw material conversion rate and high product purity.

[0203] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, were performed according to conventional reaction conditions in the art or as recommended by the manufacturer. Percentages and parts are by weight unless otherwise stated.

[0204] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as are familiar to those skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to the methods of this invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0205] Example of ligand preparation:

[0206]

[0207] Reaction 1: A (4-(dimethylamino)pyridine-2-carboxylic acid, 10 mmol), B (2-methyl-1-naphthylamine, 10 mmol), HATU (15 mmol), DIPEA (40 mmol), and DMF (30 mL) were added sequentially to a 100 mL round-bottom flask. After stirring at room temperature for 24 h, the reaction system was directly quenched with water. The aqueous phase was extracted with DCM, the organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated under vacuum with silica gel. Column chromatography was used to separate the organic phase to obtain C (89%, white solid).

[0208] Reaction 2: C (2 mmol), LiCl (20 mmol), PTSA (20 mmol), and DMF (4 mL) were added sequentially to a 15 mL thick-walled pressure-resistant tube. The reaction flask was then placed in an oil bath preheated to 120 °C and stirred for 24 h. Finally, the reaction flask was removed and cooled to room temperature. The sample was then extracted, and after separation and purification, product L3 (76%, white solid) was obtained.

[0209] Example 1:

[0210]

[0211] Under nitrogen atmosphere, potassium iodide (0.5 mmol), sodium phosphate (3.75 mmol), cuprous cyanide (5 mmol), ligand L3 (0.25 mmol), dimethyl sulfoxide (1 mL), and compound S1 (loratadine) (5 mmol) as shown above were added sequentially to a 25 mL reaction flask (explosion-proof flask). The reaction flask was then placed in an oil bath preheated to 135 °C and stirred for 24 h. Finally, the reaction flask was removed and cooled to room temperature. The sample was then extracted, separated, and purified to obtain product P1 (71%, yellow solid).

[0212] 1 H NMR (400MHz, CDCl3) δ8.43(dd,J=4.8,1.5Hz,1H),7.63–7.39(m,3H),7.30(d,J=7.7Hz,1H),7.14(dd,J=7.7,4.8Hz,1H),4.14(q,J=7.1Hz,2H),3.8 3(br.s,2H),3.59–3.30(m,2H),3.17(ddd,J=13.1,9.4,3.9Hz,2H),3.00– 2.72(m,2H),2.64–2.45(m,1H),2.41–2.23(m,3H),1.25(t,J=7.1Hz,3H).

[0213] 13 C NMR (101MHz, CDCl3) δ155.97,155.44,146.95,144.39,139.24,138.69,137.80,133.94,133.1 7,132.64,129.97,129.83,122.62,118.81,111.15,61.39,44.72,31.45,30.83,30.54,14.68.

[0214] 13C dept135 NMR (101MHz, CDCl3) δpositive 61.39, 44.72, 31.45, 30.83, 30.54; negative 146.95, 137.80, 132.64, 129.97, 129.83, 122.62, 14.68.

[0215] HRMS(ESI): [M+H]+calcd for C 23 H 24 N3O2,374.18685; found,374.18532.

[0216] 13 C dept135 NMR (101MHz, CDCl3) δpositive 61.39, 44.72, 31.45, 30.83, 30.54; negative 146.95, 137.80, 132.64, 129.97, 129.83, 122.62, 14.68.

[0217] HRMS(ESI): [M+H]+calcd for C 23 H 24 N3O2,374.18685; found,374.18532.

[0218] Example 2:

[0219]

[0220] Under nitrogen atmosphere, potassium iodide (0.5 mmol), sodium phosphate (3.75 mmol), cuprous cyanide (5 mmol), ligand L3 (0.25 mmol), dimethyl sulfoxide (1 mL), and compound S2 (perphenazine) (5 mmol) as shown above were added sequentially to a 25 mL reaction flask (explosion-proof flask). The reaction flask was then placed in an oil bath preheated to 135 °C and stirred for 24 h. Finally, the reaction flask was removed and cooled to room temperature. The sample was then extracted, separated, and purified to obtain product P2 (65%, yellow viscous gel).

[0221] 1 H NMR (600MHz, CDCl3) δ7.33–6.85(m,7H),4.00(t,J=6.8Hz,2H),3.84(br.s,1H),3.73(t,J=5.4Hz,2H),3.03–2.21(m,12H),2.01(p,J=6.8Hz,2H).

[0222] 13C NMR (151MHz, CDCl3) δ145.68,143.75,132.03,127.90,127.69,127.52,125.85,123.37,1 23.34,119.05,117.80,116.03,110.61,59.45,57.72,55.19,53.12,52.91,45.32,23.98.

[0223] HRMS(ESI): [M+H]+calcd for C 22 H 27 N4OS,395.19001; found,395.18917.

[0224] Example 3:

[0225]

[0226] Under nitrogen atmosphere, sodium phosphate (0.75 mmol), cuprous cyanide (1 mmol), ligand L3 (0.02 mmol), dimethyl sulfoxide (1 mL), and compound S3 (nimergoline) (1 mmol) as shown above were added sequentially to a 10 mL reaction flask (explosion-proof flask). The reaction flask was then placed in an oil bath preheated to 80 °C and stirred for 24 h. Finally, the reaction flask was removed and cooled to room temperature. The sample was then extracted, separated, and purified to obtain product P3 (91%, a light yellow viscous gel).

[0227] 1 H NMR (400MHz, CDCl3) δ9.40(d,J=2.0Hz,1H),9.02(d,J=2.1Hz,1H),8.56(t,J=2.1Hz ,1H),7.27–7.12(m,2H),7.11–6.92(m,1H),6.79(d,J=1.1Hz,1H),4.59–4.16(m,2H ),3.76(s,3H),3.21(dd,J=14.3,4.3Hz,2H),3.07–2.97(m,2H),2.99(s,3H),2.49( s,3H),2.36(dd,J=11.2,4.5Hz,1H),2.11(t,J=11.2Hz,1H),1.39(t,J=13.3Hz,1H).

[0228] 13C NMR (151MHz, CDCl3) δ163.26,155.52,153.57,140.22,135.11,129.53,126.32,126.30,123.36,121.42,115 .66,114.93,110.27,110.18,109.06,73.57,69.98,68.98,60.52,49.59,43.89,32.80,31.56,30.14,22.34.

[0229] 13 C dept135 NMR(101MHz, CDCl3)δpositive 155.52,153.56,140.22,123.36,121.42,114.92,109.05,69.99,49.59,43.88,32.80,31.56; negative 68.98,60.53,30.16,22.34.

[0230] Example 4:

[0231]

[0232] Under nitrogen atmosphere, sodium phosphate (1.125 mmol), cuprous cyanide (1.5 mmol), ligand L3 (0.03 mmol), dimethyl sulfoxide (1 mL), and compound S5 (1.5 mmol) as shown above were added sequentially to a 10 mL reaction flask (explosion-proof flask). The reaction flask was then placed in an oil bath preheated to 60 °C and stirred for 24 h. Finally, the reaction flask was removed and cooled to room temperature. The sample was then extracted, separated, and purified to obtain product P5 (70%, white solid).

[0233] 1 H NMR (400MHz, CDCl3) δ7.66–7.41(m,4H),7.30(d,J=7.8Hz,1H),7.17–6.95(m,3H),6.72(d,J=3.5Hz,1H),4.16(s,2H),2.42(s,3H).

[0234] 13C NMR (101MHz, CDCl3) δ163.46, 161.01, 142.34, 141.70 (d, J = 110.6Hz), 139.72, 132.73, 131.25, 130.62, 130. 58(d,J=3.7Hz),127.24(d,J=8.0Hz),126.66,122.88,119.11,115.82(d,J=21.8Hz),110.09,33.64,19.93.

[0235] 13 C dept135 NMR (101MHz, CDCl3) δpositive 132.73, 131.25, 130.62, 127.24 (d, J = 8.0Hz), 126.66, 122.88, 115.83 (d, J = 21.8Hz), 19.93; negative 33.64.

[0236] 19 F NMR (377MHz, CDCl3) δ-114.61 (s, 1F).

[0237] HRMS(ESI): [M+H]+calcd for C 19 H 15 NFS,308.09307; found,308.08995.

[0238] Example 5:

[0239]

[0240] Under nitrogen atmosphere, potassium iodide (0.5 mmol), sodium phosphate (3.75 mmol), cuprous cyanide (5 mmol), ligand L3 (0.1 mmol), dimethyl sulfoxide (1 mL), and compound S6 (fenofibrate) (5 mmol) as shown above were added sequentially to a 25 mL reaction flask (explosion-proof flask). The reaction flask was then placed in an oil bath preheated to 120 °C and stirred for 24 h. Finally, the reaction flask was removed and cooled to room temperature. The sample was then extracted, separated, and purified to obtain product P6 (60%, colorless viscous gel).

[0241] 1H NMR (600MHz, CDCl3) δ7.83(d,J=8.2Hz,2H),7.79(d,J=7.9Hz,2H),7.75(d,J=8.7Hz,2H ),6.89(d,J=8.6Hz,2H),5.10(hept,J=6.2Hz,1H),1.68(s,6H),1.22(d,J=6.3Hz,6H).

[0242] 13 C NMR (101MHz, CDCl3) δ193.55,172.82,160.24,141.89,132.08,129.89,129.26,118.03,117.30,115.12,79.48,69.32,25.31,21.47.

[0243] HRMS(ESI): [M+H]+calcd for C 21 H 22 O4N,352.15433; found,352.15371.

[0244] Example 6:

[0245]

[0246] Under nitrogen atmosphere, sodium phosphate (1.125 mmol), cuprous cyanide (1.5 mmol), ligand L3 (0.03 mmol), dimethyl sulfoxide (1 mL), and compound S7 (aluminopropylamide) (1.5 mmol) as shown above were added sequentially to a 10 mL reaction flask (explosion-proof flask). The reaction flask was then placed in an oil bath preheated to 60 °C and stirred for 24 h. Finally, the reaction flask was removed and cooled to room temperature. The sample was then extracted, separated, and purified to obtain product P7 (70%, white solid).

[0247] 1 H NMR(400MHz, CDCl3)δ7.76(s,1H),7.68(d,J=7.9Hz,1H),7.64–7.54(m,2H),7.47(t,J=7.8Hz,1 H),6.52(d,J=15.6Hz,1H),6.23(br.s,1H),3.45(qd,J=7.3,5.8Hz,2H),1.23(t,J=7.3Hz,3H).

[0248] 13C NMR (101MHz, CDCl3) δ164.99,138.06,136.27,132.52,132.12,130.63,129.77,123.64,118.37,113.08,34.76,14.80.

[0249] HRMS(ESI): [M+H]+calcd for C 12 H 13 ON2,201.10224; found,201.10186.

[0250] Example 7:

[0251]

[0252] Under nitrogen atmosphere, sodium phosphate (1.125 mmol), cuprous cyanide (1.5 mmol), ligand L3 (0.03 mmol), dimethyl sulfoxide (1 mL), and compound S8 (1.5 mmol) as shown above were added sequentially to a 10 mL reaction flask (explosion-proof flask). The reaction flask was then placed in an oil bath preheated to 60 °C and stirred for 24 h. Finally, the reaction flask was removed and cooled to room temperature. The sample was then extracted, separated, and purified to obtain product P8 (54%, colorless viscous gel).

[0253] 1 H NMR (400MHz, CDCl3) δ7.53–7.39(m,2H),7.35(d,J=1.6Hz,1H),7.08(d,J=8.6Hz,2H),6.82(d,J= 8.6Hz,2H),5.01–4.73(m,1H),4.27–3.94(m,5H),3.89(td,J=8.2,4.6Hz,1H),2.31–2.10(m,2H).

[0254] 13 C NMR (101MHz, CDCl3) δ156.02,140.69,139.00,133.74,130.60,130.14,12 9.87,129.60,117.84,115.35,110.59,76.51,72.80,66.88,37.71,32.67.

[0255] HRMS(ESI): [M+H]+calcd for C 18 H 17 O2NCl,314.09423; found,314.09363.

[0256] HRMS(ESI): [M+Na]+calcd for C 18 H 16 O2NClNa,336.07618; found,336.07556.

[0257] Example 8:

[0258]

[0259] Under nitrogen atmosphere, sodium phosphate (1.125 mmol), cuprous cyanide (1.5 mmol), ligand L3 (0.03 mmol), dimethyl sulfoxide (1 mL), and compound S9 (1.5 mmol) as shown above were added sequentially to a 10 mL reaction flask (explosion-proof flask). The reaction flask was then placed in an oil bath preheated to 60 °C and stirred for 24 h. Finally, the reaction flask was removed and cooled to room temperature. The sample was then extracted, separated, and purified to obtain product P9 (68%, white solid).

[0260] 1 H NMR(600MHz, CDCl3)δ7.78(d,J=7.8Hz,1H),7.71(d,J=7.8Hz,1H),7.64–7.56(m,1H), 7.57–7.49(m,1H),7.42–7.27(m,2H),7.16(t,J=8.8Hz,1H),7.07(s,1H),4.26(s,2H).

[0261] 13 C NMR (151MHz, CDCl3) δ 162.89 (d, J = 256.9Hz), 140.95, 139.63 (d, J = 7.6Hz), 134.86 (d, J = 5.8Hz), 132.93 (d, J = 9.5Hz), 128.6 4(d,J=16.7Hz),124.35,124.07,123.09,122.56,122.09,117.87,116.80,116.64,108.55(d,J=4.1Hz),29.28(d,J=3.2Hz).

[0262] 19 F NMR (565MHz, CDCl3) δ-107.42 (s, 1F).

[0263] Example 9:

[0264]

[0265] Under nitrogen atmosphere, potassium iodide (0.25 mmol), sodium phosphate (1.875 mmol), cuprous cyanide (2.5 mmol), ligand L3 (0.05 mmol), dimethyl sulfoxide (0.5 mL), and compound S10 (2.5 mmol) as shown above were added sequentially to a 10 mL reaction flask (explosion-proof flask). The reaction flask was then placed in an oil bath preheated to 120 °C and stirred for 24 h. Finally, the reaction flask was removed and cooled to room temperature. The sample was then extracted, separated, and purified to obtain product P10 (64%, white solid).

[0266] 1 H NMR (400MHz, methanol-d4) δ7.83–7.73(m,2H),7.71–7.58(m,2H),2.17(s,3H).

[0267] 13 C NMR (101MHz, methanol-d4) δ170.59,143.05,132.79,119.38,118.44,106.12,22.64.

[0268] Example 10:

[0269]

[0270] Under nitrogen atmosphere, sodium phosphate (1.125 mmol), cuprous cyanide (1.5 mmol), ligand L3 (0.03 mmol), dimethyl sulfoxide (0.75 mL), and compound S10-1 (1.5 mmol) as shown above were added sequentially to a 10 mL reaction flask (explosion-proof flask). The reaction flask was then placed in an oil bath preheated to 60 °C and stirred for 24 h. Finally, the reaction flask was removed and cooled to room temperature. The sample was then extracted, separated, and purified to obtain product P10 (73%, white solid).

[0271] Example 11:

[0272]

[0273] Under nitrogen atmosphere, potassium iodide (0.25 mmol), sodium phosphate (1.875 mmol), cuprous cyanide (2.5 mmol), ligand L3 (0.05 mmol), dimethyl sulfoxide (0.5 mL), and compound S11 (2.5 mmol) as shown above were added sequentially to a 10 mL reaction flask (explosion-proof flask). The reaction flask was then placed in an oil bath preheated to 120 °C and stirred for 24 h. Finally, the reaction flask was removed and cooled to room temperature. The sample was then extracted, separated, and purified to obtain product P11 (85%, white solid).

[0274] 1 H NMR (400MHz, CDCl3) δ7.79 (s, 4H).

[0275] 13 C NMR (101MHz, CDCl3) δ132.76, 116.96, 116.70.

[0276] Example 12:

[0277]

[0278] Under nitrogen atmosphere, sodium phosphate (1.125 mmol), cuprous cyanide (1.5 mmol), ligand L3 (0.03 mmol), dimethyl sulfoxide (0.75 mL), and compound S11-1 (1.5 mmol) as shown above were added sequentially to a 10 mL reaction flask (explosion-proof flask). The reaction flask was then placed in an oil bath preheated to 60 °C and stirred for 24 h. Finally, the reaction flask was removed and cooled to room temperature. The sample was then extracted, separated, and purified to obtain product P11 (82%, white solid).

[0279] Example 13:

[0280]

[0281] Under nitrogen atmosphere, potassium iodide (0.25 mmol), sodium phosphate (1.875 mmol), cuprous cyanide (2.5 mmol), ligand L3 (0.05 mmol), dimethyl sulfoxide (0.5 mL), and compound S13 (2.5 mmol) as shown above were added sequentially to a 10 mL reaction flask (explosion-proof flask). The reaction flask was then placed in an oil bath preheated to 120 °C and stirred for 24 h. Finally, the reaction flask was removed and cooled to room temperature. The sample was then extracted, separated, and purified to obtain product P13 (71%, white solid).

[0282] 1 H NMR (400MHz, CDCl3) δ8.10(d,J=8.6Hz,1H),7.70(d,J=8.6Hz,1H),4.38(q,J=7.1Hz,1H),1.37(t,J=7.2Hz,2H).

[0283] 13 C NMR (101MHz, CDCl3) δ164.85,134.24,132.15,130.01,117.96,116.21,61.75,14.19.

[0284] Example 14:

[0285]

[0286] Under nitrogen atmosphere, sodium phosphate (1.875 mmol), cuprous cyanide (2.5 mmol), ligand L3 (0.05 mmol), dimethyl sulfoxide (0.5 mL), and compound S13-1 (2.5 mmol) as shown above were added sequentially to a 10 mL reaction flask (explosion-proof flask). The reaction flask was then placed in an oil bath preheated to 60 °C and stirred for 24 h. Finally, the reaction flask was removed and cooled to room temperature. The sample was then extracted, purified, and the product P13 (75%, white solid) was obtained.

[0287] Example 15:

[0288]

[0289] Under nitrogen atmosphere, potassium iodide (0.15 mmol), sodium phosphate (1.125 mmol), cuprous cyanide (1.5 mmol), ligand L3 (0.45 mmol), dimethyl sulfoxide (0.5 mL), and compound S14 (1.5 mmol) as shown above were added sequentially to a 10 mL reaction flask (explosion-proof flask). The reaction flask was then placed in an oil bath preheated to 120 °C and stirred for 24 h. Finally, the reaction flask was removed and cooled to room temperature. The sample was then extracted, separated, and purified to obtain product P14 (60%, colorless liquid).

[0290] 1 H NMR (600MHz, CDCl3) δ7.72 (d, J = 8.8 Hz, 2H), 7.32 (d, J = 8.4 Hz, 2H).

[0291] 13 C NMR (151MHz, CDCl3) δ152.16, 134.13, 121.17, 120.13 (q, J = 259.6Hz), 119.27, 110.81.

[0292] Example 16:

[0293]

[0294] Under nitrogen atmosphere, sodium phosphate (1.875 mmol), cuprous cyanide (2.5 mmol), ligand L3 (0.05 mmol), dimethyl sulfoxide (0.5 mL), and compound S14-1 (2.5 mmol) as shown above were added sequentially to a 10 mL reaction flask (explosion-proof flask). The reaction flask was then placed in an oil bath preheated to 60 °C and stirred for 24 h. Finally, the reaction flask was removed and cooled to room temperature. The sample was then extracted, separated, and purified to obtain product P14 (69%, colorless liquid).

[0295] Example 17:

[0296]

[0297] Under nitrogen atmosphere, potassium iodide (0.25 mmol) was added sequentially to a 10 mL reaction flask (explosion-proof flask).

[0298]

[0299] Sodium phosphate (1.875 mmol), cuprous cyanide (2.5 mmol), ligand L3 (0.05 mmol), dimethyl sulfoxide (0.5 mL), and compound S15 (2.5 mmol) as shown above were prepared. The reaction flask was then placed in an oil bath preheated to 120 °C and stirred for 24 h. Finally, the reaction flask was removed and cooled to room temperature. The sample was then extracted and purified to obtain product P15 (61%, colorless liquid).

[0300] 1 H NMR (600MHz, CDCl3) δ7.38–7.24(m,1H),7.15(d,J=7.5Hz,1H),7.08–7.03(m,2H),3.75(s,3H).

[0301] 13 C NMR (151MHz, CDCl3) δ159.57,130.24,124.38,119.21,118.63,116.79,113.10,55.44.

[0302] Example 18:

[0303]

[0304] Under nitrogen atmosphere, sodium phosphate (1.875 mmol), cuprous cyanide (2.5 mmol), ligand L3 (0.05 mmol), dimethyl sulfoxide (0.5 mL), and compound S15-1 (2.5 mmol) as shown above were added sequentially to a 10 mL reaction flask (explosion-proof flask). The reaction flask was then placed in an oil bath preheated to 60 °C and stirred for 24 h. Finally, the reaction flask was removed and cooled to room temperature. The sample was then extracted, separated, and purified to obtain product P15 (87%, colorless liquid).

[0305] Example 19:

[0306]

[0307] Under nitrogen atmosphere, potassium iodide (0.25 mmol), sodium phosphate (1.875 mmol), cuprous cyanide (2.5 mmol), ligand L3 (0.05 mmol), dimethyl sulfoxide (0.5 mL), and compound S16 (2.5 mmol) as shown above were added sequentially to a 10 mL reaction flask (explosion-proof flask). The reaction flask was then placed in an oil bath preheated to 120 °C and stirred for 24 h. Finally, the reaction flask was removed and cooled to room temperature. The sample was then extracted, purified, and the product P16 (71%, white solid) was obtained.

[0308] 1 H NMR (600MHz, CDCl3) δ7.40 (d, J = 8.6 Hz, 2H), 6.64 (d, J = 8.6 Hz, 2H), 4.16 (br.s, 2H).

[0309] 13 C NMR (151MHz, CDCl3) δ150.36,133.77,120.06,114.41,100.21.

[0310] Example 20:

[0311]

[0312] Under nitrogen atmosphere, sodium phosphate (1.125 mmol), cuprous cyanide (1.5 mmol), ligand L3 (0.45 mmol), dimethyl sulfoxide (0.75 mL), and compound S16-1 (1.5 mmol) as shown above were added sequentially to a 10 mL reaction flask (explosion-proof flask). The reaction flask was then placed in an oil bath preheated to 60 °C and stirred for 24 h. Finally, the reaction flask was removed and cooled to room temperature. The sample was then extracted, separated, and purified to obtain product P16 (61%, white solid).

[0313] Example 21:

[0314]

[0315] Under nitrogen atmosphere, potassium iodide (0.25 mmol), sodium phosphate (1.875 mmol), cuprous cyanide (2.5 mmol), ligand L3 (0.05 mmol), dimethyl sulfoxide (0.5 mL), and compound S18 (2.5 mmol) as shown above were added sequentially to a 10 mL reaction flask (explosion-proof flask). The reaction flask was then placed in an oil bath preheated to 120 °C and stirred for 24 h. Finally, the reaction flask was removed and cooled to room temperature. The sample was then extracted, separated, and purified to obtain product P18 (76%, white solid).

[0316] 1H NMR (600MHz, CDCl3) δ8.23 (s, 1H), 7.91 (dd, J = 13.6, 8.6Hz, 3H), 7.71–7.52 (m, 3H).

[0317] 13 C NMR (151MHz, CDCl3) δ134.63,134.13,132.23,129.17,129.01,128.39,128.03,127.63,126.32,119.22,109.37.

[0318] Example 22:

[0319]

[0320] Under nitrogen atmosphere, sodium phosphate (1.875 mmol), cuprous cyanide (2.5 mmol), ligand L3 (0.05 mmol), dimethyl sulfoxide (0.5 mL), and compound S18-1 (2.5 mmol) as shown above were added sequentially to a 10 mL reaction flask (explosion-proof flask). The reaction flask was then placed in an oil bath preheated to 60 °C and stirred for 24 h. Finally, the reaction flask was removed and cooled to room temperature. The sample was then extracted, separated, and purified to obtain product P18 (85%, white solid).

[0321] Example 23:

[0322]

[0323] Under nitrogen atmosphere, sodium phosphate (1.875 mmol), cuprous cyanide (2.5 mmol), ligand L3 (0.05 mmol), dimethyl sulfoxide (0.5 mL), and compound S19 (2.5 mmol) as shown above were added sequentially to a 10 mL reaction flask (explosion-proof flask). The reaction flask was then placed in an oil bath preheated to 60 °C and stirred for 24 h. Finally, the reaction flask was removed and cooled to room temperature. The sample was then extracted, separated, and purified to obtain product P19 (89%, white crystals).

[0324] 1 H NMR (400MHz, CDCl3) δ7.67 (ddd, J=9.8, 5.0, 2.4Hz, 2H), 7.23–6.82 (m, 2H).

[0325] 13 C NMR (151MHz, CDCl3) δ 164.97 (d, J = 256.2Hz), 134.61 (d, J = 9.5Hz), 117.93, 116.78 (d, J = 22.8Hz), 108.53 (d, J = 3.7Hz).

[0326] 19 F NMR (377MHz, CDCl3) δ-102.45 (s, 1F).

[0327] Example 24:

[0328]

[0329] Under nitrogen atmosphere, potassium iodide (0.15 mmol), sodium phosphate (1.125 mmol), cuprous cyanide (1.5 mmol), ligand L3 (0.45 mmol), dimethyl sulfoxide (0.5 mL), and compound S20 (1.5 mmol) as shown above were added sequentially to a 10 mL reaction flask (explosion-proof flask). The reaction flask was then placed in an oil bath preheated to 120 °C and stirred for 24 h. Finally, the reaction flask was removed and cooled to room temperature. The sample was then extracted, separated, and purified to obtain product P20 (72%, white solid).

[0330] 1 H NMR (600MHz, CDCl3) δ7.73(d,J=8.4Hz,2H),7.69(d,J=8.4Hz,2H),7.59(d,J=7.4Hz,2H),7.49(t,J=7.6Hz,2H),7.43(t,J=7.3Hz,1H).

[0331] 13 C NMR (151MHz, CDCl3) δ145.63,139.14,132.54,129.07,128.62,127.69,127.18,118.88,110.90.

[0332] Example 25:

[0333]

[0334] Under nitrogen atmosphere, sodium phosphate (1.125 mmol), cuprous cyanide (1.5 mmol), ligand L3 (0.3 mmol), dimethyl sulfoxide (0.75 mL), and compound S20-1 (1.5 mmol) as shown above were added sequentially to a 10 mL reaction flask (explosion-proof flask). The reaction flask was then placed in an oil bath preheated to 60 °C and stirred for 24 h. Finally, the reaction flask was removed and cooled to room temperature. The sample was then extracted, separated, and purified to obtain product P20 (72%, white solid).

[0335] Example 26:

[0336]

[0337] Under nitrogen atmosphere, sodium phosphate (1.875 mmol), cuprous cyanide (2.5 mmol), ligand L3 (0.05 mmol), dimethyl sulfoxide (0.5 mL), and compound S21 (2.5 mmol) as shown above were added sequentially to a 10 mL reaction flask (explosion-proof flask). The reaction flask was then placed in an oil bath preheated to 60 °C and stirred for 24 h. Finally, the reaction flask was removed and cooled to room temperature. The sample was then extracted, separated, and purified to obtain product P21 (62%, colorless liquid).

[0338] 1 H NMR (600MHz, CDCl3) δ7.46 (ddd, J=7.3, 4.3, 2.7Hz, 2H), 7.08–6.65 (m, 2H), 3.84 (s, 3H).

[0339] 13 C NMR (151MHz, CDCl3) δ161.11,134.31,133.58,120.65,116.38,111.24,101.62,55.89.

[0340] Example 27:

[0341]

[0342] Under nitrogen atmosphere, sodium phosphate (1.125 mmol), cuprous cyanide (1.5 mmol), ligand L3 (0.3 mmol), dimethyl sulfoxide (0.75 mL), and compound S22 (2.5 mmol) as shown above were added sequentially to a 10 mL reaction flask (explosion-proof flask). The reaction flask was then placed in an oil bath preheated to 60 °C and stirred for 24 h. Finally, the reaction flask was removed and cooled to room temperature. The sample was then extracted, separated, and purified to obtain product P22 (91%, light yellow solid).

[0343] 1 H NMR (400MHz, CDCl3) δ8.02–7.79(m,2H),7.69(s,1H),7.60–7.43(m,3H),7.36(ddd,J=8.1,5.5,2.8Hz,1H).

[0344] 13 C NMR (101MHz, CDCl3) δ156.86,154.50,129.02,128.22,126.18,123.37,122.34,121.22,121.05,118.81,115.25,111.81,109.38.

[0345] Example 28:

[0346]

[0347] Under nitrogen atmosphere, potassium iodide (0.25 mmol), sodium phosphate (1.875 mmol), cuprous cyanide (2.5 mmol), ligand L3 (0.05 mmol), dimethyl sulfoxide (0.5 mL), and compound S23 (2.5 mmol) as shown above were added sequentially to a 10 mL reaction flask (explosion-proof flask). The reaction flask was then placed in an oil bath preheated to 120 °C and stirred for 24 h. Finally, the reaction flask was removed and cooled to room temperature. The sample was then extracted, separated, and purified to obtain product P23 (81%, white solid).

[0348] 1 H NMR (400MHz, CDCl3) δ7.97–7.80(m,2H),7.81–7.68(m,4H),7.66–7.56(m,1H),7.55–7.43(m,2H).

[0349] 13 C NMR (101MHz, CDCl3) δ194.84,141.03,136.15,133.17,132.02,130.08,129.90,128.48,117.87,115.46.

[0350] Example 29:

[0351]

[0352] Under nitrogen atmosphere, sodium phosphate (1.125 mmol), cuprous cyanide (1.5 mmol), ligand L3 (0.3 mmol), dimethyl sulfoxide (0.75 mL), and compound S23-1 (1.5 mmol) as shown above were added sequentially to a 10 mL reaction flask (explosion-proof flask). The reaction flask was then placed in an oil bath preheated to 60 °C and stirred for 24 h. Finally, the reaction flask was removed and cooled to room temperature. The sample was then extracted, separated, and purified to obtain product P23 (86%, white solid).

[0353] Example 30:

[0354]

[0355] Under nitrogen atmosphere, potassium iodide (0.25 mmol), sodium phosphate (1.875 mmol), cuprous cyanide (2.5 mmol), ligand L3 (0.05 mmol), dimethyl sulfoxide (0.5 mL), and compound S24 (2.5 mmol) as shown above were added sequentially to a 10 mL reaction flask (explosion-proof flask). The reaction flask was then placed in an oil bath preheated to 120 °C and stirred for 24 h. Finally, the reaction flask was removed and cooled to room temperature. The sample was then extracted, separated, and purified to obtain product P24 (80%, yellow solid).

[0356] 1 H NMR (400MHz, CDCl3) δ7.29(s,2H),5.80(s,1H),2.28(s,6H).

[0357] 13 C NMR (101MHz, CDCl3) δ156.56,132.55,124.51,119.55,102.68,15.79.

[0358] Example 31:

[0359]

[0360] Under nitrogen atmosphere, sodium phosphate (1.125 mmol), cuprous cyanide (1.5 mmol), ligand L3 (0.3 mmol), dimethyl sulfoxide (0.75 mL), and compound S24-1 (1.5 mmol) as shown above were added sequentially to a 10 mL reaction flask (explosion-proof flask). The reaction flask was then placed in an oil bath preheated to 60 °C and stirred for 24 h. Finally, the reaction flask was removed and cooled to room temperature. The sample was then extracted, separated, and purified to obtain product P24 (70%, yellow solid).

[0361] Example 32:

[0362]

[0363] Under nitrogen atmosphere, potassium iodide (0.25 mmol), sodium phosphate (1.875 mmol), cuprous cyanide (2.5 mmol), ligand L3 (0.05 mmol), dimethyl sulfoxide (0.5 mL), and compound S25 (2.5 mmol) as shown above were added sequentially to a 10 mL reaction flask (explosion-proof flask). The reaction flask was then placed in an oil bath preheated to 120 °C and stirred for 24 h. Finally, the reaction flask was removed and cooled to room temperature. The sample was then extracted, separated, and purified to obtain product P25 (82%, yellow solid).

[0364] 1H NMR (600MHz, CDCl3) δ8.43–8.27(m,2H),7.99–7.79(m,2H).

[0365] 13 C NMR (151MHz, CDCl3) δ149.92,133.41,124.17,118.18,116.72.

[0366] Example 33:

[0367]

[0368] Under nitrogen atmosphere, sodium phosphate (1.875 mmol), cuprous cyanide (2.5 mmol), ligand L3 (0.05 mmol), dimethyl sulfoxide (0.5 mL), and compound S25-1 (2.5 mmol) as shown above were added sequentially to a 10 mL reaction flask (explosion-proof flask). The reaction flask was then placed in an oil bath preheated to 60 °C and stirred for 24 h. Finally, the reaction flask was removed and cooled to room temperature. The sample was then extracted, separated, and purified to obtain product P25 (85%, yellow solid).

[0369] Example 34:

[0370]

[0371] Under nitrogen atmosphere, sodium phosphate (1.875 mmol), cuprous cyanide (2.5 mmol), ligand L3 (0.05 mmol), dimethyl sulfoxide (0.5 mL), and compound S26 (2.5 mmol) as shown above were added sequentially to a 10 mL reaction flask (explosion-proof flask). The reaction flask was then placed in an oil bath preheated to 60 °C and stirred for 24 h. Finally, the reaction flask was removed and cooled to room temperature. The sample was then extracted, separated, and purified to obtain product P26 (82%, yellow solid).

[0372] 1 H NMR (400MHz, CDCl3) δ7.83–7.53(m,2H),7.53–7.32(m,2H).

[0373] 13 C NMR (101MHz, CDCl3) δ139.49,133.33,129.64,117.92,110.72.

[0374] Example 35:

[0375]

[0376] Under nitrogen atmosphere, sodium phosphate (1.125 mmol), cuprous cyanide (1.5 mmol), ligand L3 (0.3 mmol), dimethyl sulfoxide (0.75 mL), and compound S27 (1.5 mmol) as shown above were added sequentially to a 10 mL reaction flask (explosion-proof flask). The reaction flask was then placed in an oil bath preheated to 60 °C and stirred for 24 h. Finally, the reaction flask was removed and cooled to room temperature. The sample was then extracted, separated, and purified to obtain product P27 (65%, white solid).

[0377] 1 H NMR (400MHz, CDCl3) δ7.90–7.68(m,2H),7.67–7.42(m,2H),3.84(t,J=7.1Hz,2H),2.60(t,J=8.1Hz,2H),2.17(p,J=7.6Hz,2H).

[0378] 13 C NMR (101MHz, CDCl3) δ174.70,143.00,132.70,119.01,118.70,106.67,48.08,32.62,17.54.

[0379] Example 36:

[0380]

[0381] Under nitrogen atmosphere, sodium phosphate (1.125 mmol), cuprous cyanide (1.5 mmol), ligand L3 (0.3 mmol), dimethyl sulfoxide (0.75 mL), and compound S28 (1.5 mmol) as shown above were added sequentially to a 10 mL reaction flask (explosion-proof flask). The reaction flask was then placed in an oil bath preheated to 60 °C and stirred for 24 h. Finally, the reaction flask was removed and cooled to room temperature. The sample was then extracted, separated, and purified to obtain product P28 (88%, white solid).

[0382] 1 H NMR (400MHz, CDCl3) δ7.72–7.55(m,2H),7.44–7.29(m,2H),1.99–1.70(m,2H),1.60–1.31(m,2H).

[0383] 13 C NMR (101MHz, CDCl3) δ141.47,132.59,125.83,121.12,118.12,111.32,19.47,14.00.

[0384] Example 37:

[0385]

[0386] Under nitrogen atmosphere, sodium phosphate (1.125 mmol), cuprous cyanide (1.5 mmol), ligand L3 (0.3 mmol), dimethyl sulfoxide (0.75 mL), and compound S29 (1.5 mmol) as shown above were added sequentially to a 10 mL reaction flask (explosion-proof flask). The reaction flask was then placed in an oil bath preheated to 60 °C and stirred for 24 h. Finally, the reaction flask was removed and cooled to room temperature. The sample was then extracted, separated, and purified to obtain product P29 (77%, white solid).

[0387] Example 38:

[0388]

[0389] Under nitrogen atmosphere, sodium phosphate (1.125 mmol), cuprous cyanide (1.5 mmol), ligand L3 (0.3 mmol), dimethyl sulfoxide (0.75 mL), and compound S30 (1.5 mmol) as shown above were added sequentially to a 10 mL reaction flask (explosion-proof flask). The reaction flask was then placed in an oil bath preheated to 60 °C and stirred for 24 h. Finally, the reaction flask was removed and cooled to room temperature. The sample was then extracted, separated, and purified to obtain product P30 (87%, white solid).

[0390] 1 H NMR (400MHz, CDCl3) δ7.23–7.00(m,2H),6.98–6.46(m,1H),4.40–4.29(m,2H),4.29–4.23(m,2H).

[0391] 13 C NMR (101MHz, CDCl3) δ147.66,143.71,125.83,121.16,118.84,118.18,104.34,64.51,64.03.

[0392] Example 39:

[0393]

[0394] Under nitrogen atmosphere, sodium phosphate (1.125 mmol), cuprous cyanide (1.5 mmol), ligand L3 (0.3 mmol), dimethyl sulfoxide (0.75 mL), and compound S31 (1.5 mmol) as shown above were added sequentially to a 10 mL reaction flask (explosion-proof flask). The reaction flask was then placed in an oil bath preheated to 60 °C and stirred for 24 h. Finally, the reaction flask was removed and cooled to room temperature. The sample was then extracted, separated, and purified to obtain product P31 (60%, light yellow solid).

[0395] 1 H NMR (400MHz, CDCl3) δ8.96 (s, 2H), 8.65–8.33 (m, 1H), 8.20 (d, J = 8.7Hz, 1H), 7.91 (dd, J = 8.7, 1.6Hz, 1H).

[0396] 13 C NMR (101MHz, CDCl3) δ147.29,146.69,144.25,141.97,135.50,131.15,130.71,117.73,113.60.

[0397] Example 40:

[0398]

[0399] Under nitrogen atmosphere, sodium phosphate (1.875 mmol), cuprous cyanide (2.5 mmol), ligand L3 (0.05 mmol), dimethyl sulfoxide (0.5 mL), and compound S32 (2.5 mmol) as shown above were added sequentially to a 10 mL reaction flask (explosion-proof flask). The reaction flask was then placed in an oil bath preheated to 60 °C and stirred for 24 h. Finally, the reaction flask was removed and cooled to room temperature. The sample was then extracted, separated, and purified to obtain product P32 (96%, white solid).

[0400] 1 H NMR (400MHz, CDCl3) δ7.47 (dd, J=8.3, 1.6Hz, 1H), 7.36 (d, J=1.5Hz, 1H), 7.18 (d, J=8.3Hz, 1H).

[0401] 13 C NMR (101MHz, CDCl3) δ146.75, 143.75, 131.57 (t, J = 259.4Hz), 129.51, 117.49, 112.94, 110.46, 107.75.

[0402] 19F NMR (377MHz, CDCl3) δ-49.68 (s, 2F).

[0403] Example 41:

[0404]

[0405] Under nitrogen atmosphere, potassium iodide (0.25 mmol), sodium phosphate (1.875 mmol), cuprous cyanide (2.5 mmol), ligand L3 (0.05 mmol), N,N-dimethylformamide (0.5 mL), and compound S33 (2.5 mmol) as shown above were added sequentially to a 10 mL reaction flask (explosion-proof flask). The reaction flask was then placed in an oil bath preheated to 120 °C and stirred for 24 h. Finally, the reaction flask was removed and cooled to room temperature. The sample was then extracted, separated, and purified to obtain product P33 (80%, colorless oily liquid).

[0406] 1 H NMR(400MHz, CDCl3) δ8.19(d,J=2.2Hz,1H),8.14(dd,J=8.9,2.2Hz,1H),6.97( d,J=8.9Hz,1H),4.72(hept,J=6.1Hz,1H),3.87(s,3H),1.40(d,J=6.1Hz,7H).

[0407] 13 C NMR (101MHz, CDCl3) δ164.97,162.88,135.67,135.58,122.39,115.55,112.59,102.76,72.33,52.20,21.59.

[0408] Example 42:

[0409]

[0410] Under nitrogen atmosphere, sodium phosphate (1.875 mmol), cuprous cyanide (2.5 mmol), ligand L3 (0.05 mmol), dimethyl sulfoxide (0.5 mL), and compound S34 (2.5 mmol) as shown above were added sequentially to a 10 mL reaction flask (explosion-proof flask). The reaction flask was then placed in an oil bath preheated to 60 °C and stirred for 24 h. Finally, the reaction flask was removed and cooled to room temperature. The sample was then extracted, separated, and purified to obtain product P34 (91%, white powder).

[0411] 1H NMR (400MHz, CDCl3) δ7.02–6.92 (m, 2H), 6.87 (dt, J = 10.4, 2.3Hz, 1H), 3.85 (s, 3H).

[0412] 13 C NMR (101MHz, CDCl3) δ163.16 (d, J = 249.1Hz), 161.33 (d, J = 11.4Hz), 117.66 (d, J = 4.0Hz), 113 .92(d,J=11.9Hz), 113.77(d,J=3.4Hz), 111.40(d,J=25.2Hz), 107.03(d,J=24.7Hz), 56.00.

[0413] 19 F NMR (377MHz, CDCl3) δ-108.27 (s, 1F).

[0414] Example 43:

[0415]

[0416] Under nitrogen atmosphere, sodium phosphate (1.125 mmol), cuprous cyanide (1.5 mmol), ligand L3 (0.3 mmol), dimethyl sulfoxide (0.75 mL), and compound S35 (1.5 mmol) as shown above were added sequentially to a 10 mL reaction flask (explosion-proof flask). The reaction flask was then placed in an oil bath preheated to 60 °C and stirred for 24 h. Finally, the reaction flask was removed and cooled to room temperature. The sample was then extracted, separated, and purified to obtain product P35 (88%, light yellow powder).

[0417] 1 H NMR (400MHz, CDCl3) δ8.14–6.76 (m, 8H).

[0418] 13 C NMR (101MHz, CDCl3) δ158.98 (d, J = 251.5Hz), 134.10 (d, J = 13.2Hz), 133.63, 131.54 (d, J = 3.9Hz), 128.80 (d, J = 1.5Hz), 128.76, 128.62, 128.20 (d, J = 4.1Hz), 119.76 (d, J = 26.7Hz), 117.47 (d, J = 2.7Hz), 112.08 (d, J = 9.6Hz).

[0419] 19 F NMR (377MHz, CDCl3) δ-114.59 (s, 1F).

[0420] Example 44:

[0421]

[0422] Under nitrogen atmosphere, potassium iodide (0.25 mmol), sodium phosphate (1.875 mmol), cuprous cyanide (2.5 mmol), ligand L3 (0.05 mmol), N,N-dimethylformamide (0.5 mL), and compound S36 (2.5 mmol) as shown above were added sequentially to a 10 mL reaction flask (explosion-proof flask). The reaction flask was then placed in an oil bath preheated to 120 °C and stirred for 24 h. Finally, the reaction flask was removed and cooled to room temperature. The sample was then extracted, separated, and purified to obtain product P36 (80%, white solid).

[0423] 1 H NMR (400MHz, CDCl3) δ7.62 (dd, J=8.5, 5.6Hz, 1H), 7.18–6.81 (m, 2H), 2.57 (s, 3H).

[0424] 13 C NMR (101MHz, CDCl3) δ164.87 (d, J = 255.8Hz), 145.36 (d, J = 9.3Hz), 134.80 (d, J = 9.9Hz), 117 .61(d,J=22.4Hz), 117.42, 114.01(d,J=22.7Hz), 108.95(d,J=3.3Hz), 20.59(d,J=1.2Hz).

[0425] 19 F NMR (377MHz, CDCl3) δ-103.68 (s, 1F).

[0426] Example 45:

[0427]

[0428] Under nitrogen atmosphere, potassium iodide (0.25 mmol), sodium phosphate (1.875 mmol), cuprous cyanide (2.5 mmol), ligand L3 (0.05 mmol), N,N-dimethylformamide (0.5 mL), and compound S37 (2.5 mmol) as shown above were added sequentially to a 10 mL reaction flask (explosion-proof flask). The reaction flask was then placed in an oil bath preheated to 120 °C and stirred for 24 h. Finally, the reaction flask was removed and cooled to room temperature. The sample was then extracted, separated, and purified to obtain product P37 (80%, light yellow solid).

[0429] 1H NMR (400MHz, CDCl3) δ10.51(br.s,1H),8.31(d,J=2.0Hz,1H),8.24(dd,J=8.9,2. 1Hz, 1H), 7.03 (d, J = 9.0Hz, 1H), 4.77 (hept, J = 6.1Hz, 1H), 1.46 (d, J = 6.1Hz, 6H).

[0430] 13 C NMR (101MHz, CDCl3) δ170.03,163.70,136.62,136.31,121.46,115.44,112.70,103.20,72.65,21.70.

[0431] Example 46:

[0432]

[0433] Under nitrogen atmosphere, sodium phosphate (1.125 mmol), cuprous cyanide (1.5 mmol), ligand L3 (0.3 mmol), dimethyl sulfoxide (0.75 mL), and compound S38 (1.5 mmol) as shown above were added sequentially to a 10 mL reaction flask (explosion-proof flask). The reaction flask was then placed in an oil bath preheated to 60 °C and stirred for 24 h. Finally, the reaction flask was removed and cooled to room temperature. The sample was then extracted, separated, and purified to obtain product P38 (69%, colorless oily liquid).

[0434] 1 H NMR (600MHz, CDCl3) δ7.59 (s, 1H), 7.38 (d, J = 1.1Hz, 2H), 1.70 (s, 4H), 1.28 (s, 12H).

[0435] 13 C NMR (151MHz, CDCl3) δ150.55,146.25,130.81,128.74,127.46,119.46,109.29,34.69,34.45,34.32,31.61,31.47.

[0436] Example 47:

[0437]

[0438] Under nitrogen atmosphere, sodium phosphate (1.125 mmol), cuprous cyanide (1.5 mmol), ligand L3 (0.3 mmol), dimethyl sulfoxide (0.75 mL), and compound S39 (1.5 mmol) as shown above were added sequentially to a 10 mL reaction flask (explosion-proof flask). The reaction flask was then placed in an oil bath preheated to 60 °C and stirred for 24 h. Finally, the reaction flask was removed and cooled to room temperature. The sample was then extracted, separated, and purified to obtain product P39 (61%, white solid).

[0439] 1 H NMR (600MHz, CDCl3) δ8.05 (d, J = 8.2Hz, 1H), 7.84 (d, J = 5.8Hz, 2H), 5.39 (s, 2H).

[0440] 13 C NMR (151MHz, CDCl3) δ168.88,146.65,132.87,129.52,126.74,126.34,117.64,117.40,69.22.

[0441] Example 48:

[0442]

[0443] Under nitrogen atmosphere, potassium iodide (0.25 mmol), sodium phosphate (1.875 mmol), cuprous cyanide (2.5 mmol), ligand L3 (0.05 mmol), dimethyl sulfoxide (0.5 mL), and compound S40 (2.5 mmol) as shown above were added sequentially to a 10 mL reaction flask (explosion-proof flask). The reaction flask was then placed in an oil bath preheated to 120 °C and stirred for 24 h. Finally, the reaction flask was removed and cooled to room temperature. The sample was then extracted, separated, and purified to obtain product P40 (71%, white solid).

[0444] 1 H NMR (400MHz, CDCl3) δ8.19–8.08(m,1H),7.97(d,J=8.4Hz,1H),7.62(d,J=5.5Hz,1H),7.56(dd,J=8.4,1.5Hz,1H),7.46–7.35(m,1H).

[0445] 13 C NMR (101MHz, CDCl3) δ143.72,139.23,129.03,128.08,126.04,123.62,123.37,119.32,107.84.

[0446] Example 49:

[0447]

[0448] Under nitrogen atmosphere, sodium phosphate (1.125 mmol), cuprous cyanide (1.5 mmol), ligand L3 (0.3 mmol), dimethyl sulfoxide (0.75 mL), and compound S40-1 (1.5 mmol) as shown above were added sequentially to a 10 mL reaction flask (explosion-proof flask). The reaction flask was then placed in an oil bath preheated to 60 °C and stirred for 24 h. Finally, the reaction flask was removed and cooled to room temperature. The sample was then extracted, purified, and the product P40 (71%, white solid) was obtained.

[0449] Example 50:

[0450]

[0451] Under nitrogen atmosphere, sodium phosphate (1.875 mmol), cuprous cyanide (2.5 mmol), ligand L3 (0.05 mmol), dimethyl sulfoxide (0.5 mL), and compound S41 (2.5 mmol) as shown above were added sequentially to a 10 mL reaction flask (explosion-proof flask). The reaction flask was then placed in an oil bath preheated to 60 °C and stirred for 24 h. Finally, the reaction flask was removed and cooled to room temperature. The sample was then extracted, separated, and purified to obtain product P41 (86%, colorless oily liquid).

[0452] 1 H NMR (400MHz, CDCl3) δ7.69 (d, J = 1.3Hz, 1H), 7.03–6.70 (m, 1H), 2.49 (d, J = 1.2Hz, 3H).

[0453] 13 C NMR (101MHz, CDCl3) δ141.82,133.46,126.01,115.22,109.92,14.79.

[0454] Example 51:

[0455]

[0456] Under nitrogen atmosphere, sodium phosphate (3.75 mmol), cuprous cyanide (5 mmol), ligand L3 (0.25 mmol), dimethyl sulfoxide (1 mL), and compound S1 (loratadine) (5 mmol) as shown above were added sequentially to a 25 mL reaction flask (explosion-proof flask). The reaction flask was then placed in an oil bath preheated to 150 °C and stirred for 24 h. Finally, the reaction flask was removed and cooled to room temperature. The sample was then extracted, separated, and purified to obtain product P1 (20%, yellow solid).

[0457] Example 52:

[0458]

[0459] Under nitrogen atmosphere, sodium phosphate (3.75 mmol), cuprous cyanide (5 mmol), ligand L3 (0.5 mmol), dimethyl sulfoxide (1 mL), and compound S2 (perphenazine) (5 mmol) as shown above were added sequentially to a 25 mL reaction flask (explosion-proof flask). The reaction flask was then placed in an oil bath preheated to 150 °C and stirred for 24 h. Finally, the reaction flask was removed and cooled to room temperature. The sample was then extracted, separated, and purified to obtain product P2 (22%, a yellow viscous gel).

[0460] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. Use of a compound of Formula I, or an isomer thereof, In the formula, W represents -NR4R5, -(C1-6 alkylene)-R8, substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted 5-20 heteroaryl; R8 is selected from the following group: C6-14 aryl, 5-10 heteroaryl; R4 and R5 are each independently selected from the group consisting of: substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3-7-membered heterocyclic group, substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted 5-20-membered heteroaryl; or, R4 and R5 together with the N atom they are connected to form a substituted or unsubstituted saturated or unsaturated 3-20-membered heterocycle or heteroaromatic ring (such as substituted or unsubstituted pyrrole, indole, azole, benzoazole and aromatic heterocycle), wherein the heteroaryl and heterocycle contain 1-3 heteroatoms each independently selected from N, O and S; R6 and R7 are each independently selected from the group consisting of C1-C6 alkyl or C6-10 aryl; Its features are, As a ligand for the preparation of aryl nitrile compounds from copper-catalyzed aryl halides, wherein the aryl halides are selected from the group consisting of aryl chlorides, aryl bromides, aryl iodides, or combinations thereof; Unless otherwise specified, the substitution refers to one or more hydrogen atoms on the group being substituted by a substituent selected from the group consisting of: C1-C6 alkyl, C1-C6 alkoxy, halo-C1-6 alkyl, C1-C6 haloalkoxy, C1-6 hydroxyalkyl, C6-C10 aryl, 3- to 20-membered heteroaryl, C6-C10 aryl-oxy, halogen, nitro, hydroxy, cyano, C2-C10 ester (C1-C10 alkyl-COO-), C2-C10 acyl (C1-C10 alkyl-CO-), sulfonate, or two hydrogen atoms on two adjacent carbon atoms of the group being replaced by -(CH2). q - Replacement, where q is 1, 2, 3, 4, 5, or 6.

2. The use as described in claim 1, characterized in that, W is -NR4R5, -(CH2)-R8, substituted or unsubstituted C6-C14 aryl, substituted or unsubstituted 5-10 heteroaryl; R8 is selected from the following group: C6-10 aryl, 5-7 membered heteroaryl; R6 and R7 are each independently selected from the group consisting of C1-C3 alkyl or phenyl groups; R4 and R5 are each independently selected from the following group: C6-14 aryl, 5-14 membered heteroaryl; or, R4 and R5 together with the N atom they are connected to form a substituted or unsubstituted 5-13 membered nitrogen-containing heteroaryl ring. Wherein, the substitution refers to one or more hydrogen atoms on the substituent group being substituted by a substituent selected from the group consisting of: hydroxyl, cyano, nitro, halogen, C1-6 alkyl, C1-6 alkoxy, haloC1-6 alkyl, C1-C6 haloalkoxy, and C1-6 hydroxyalkyl, and the heteroaryl and heteroaromatic ring contain 1 to 3 heteroatoms each independently selected from N, O, and S.

3. The use as described in claim 1, characterized in that, The compound of formula I is selected from the following group:

4. A method for preparing an aryl nitrile compound, characterized in that, Includes the following steps: In an inert solvent, in the presence of a base, a cuprous cyanide catalyst, and the ligand shown in Formula I, the halogenated aryl compound shown in Formula II reacts to give the aryl nitrile compound shown in Formula III; wherein the ligand is as described in claim 1. in, W, R6 and R7 are as described in claim 1; X is a halogen, preferably Cl, Br or I; It is a benzene ring or a 5-6 membered aromatic ring, or a 9-20 membered fused polycyclic system, wherein the fused polycyclic system includes at least one benzene ring or a 5-6 membered heteroaromatic ring (preferably a benzene ring) as a fusion unit, and the benzene ring or the 5-6 membered heteroaromatic ring is substituted by one or more X (preferably substituted by one X). The polycyclic system is formed by one or more (e.g., 2, 3, 4 or 5) cyclic structures, each independently selected from 5-6-membered heteroaryl, phenyl, 5-7-membered heterocyclic and C3-7 cycloalkyl groups, through fusion, screwing, or bridging, or by the above cyclic structures being connected by one or more divalent groups L. Wherein, each L is independently selected from the group consisting of: none, C1-6 alkylene, C2-4 alkenylene, -O-, -S-, -NH, -C(O)-, -C(O)O-, -SO-, -S(O)2-, or combinations thereof; Optionally substituted with one or more R groups selected from the group consisting of: H, D, halogen, amino, oxo (=O), nitro, hydroxyl, cyano, carboxyl (-COOH), C1-6 alkyl-NH-, -C1-6 alkylene-OH, acyl, amide, C1-6 alkyl-S(O)2-, ester, C1-6 alkyl, C2-6 alkenyl, C2-6 alkoxy, halo-C1-6 alkoxy, (C1-6 alkyl)3 silyl, C1-6 alkyl-(L) z - C6-10 aryl-(L) z -, 5-10 aryl-(L) z - C3-10 cycloalkyl-(L) z -, 3-10 membered heterocyclic group-(L) z -; z can be 0, 1, 2, 3, 4, 5, or 6; Wherein, the cycloalkyl and heterocyclic groups are optionally substituted with groups selected from the group consisting of: halogen, cyano, oxo, phenyl, C1-6 alkyl, ester, N(C1-6 alkyl)2.

5. The method as described in claim 4, characterized in that, The Selected from the following group: Wherein, R and X are as described in claim 4; Y is -NH-, -O-, or -S-. Ring B is selected from the group consisting of 5-7 membered heterocyclic groups, 5-7 membered heteroaryl groups, C3-7 cycloalkyl groups, or phenyl groups; The ring C is selected from the following group: 5-7 membered heterocyclic group, 5-7 membered heteroaryl group, C3-7 cycloalkyl group, or C6-10 aryl group; n is 1, 2, or 3; and m is 0, 1, 2 or 3; *express It can also be located at the para position of the X substituent; Wherein, when a substituent R is present, the substituent R is located at a substitutable site on any ring in the above polycyclic system.

6. The method as described in claim 4, characterized in that, The haloaryl compounds represented by Formula II are selected from the following group:

7. The method as described in claim 4, characterized in that, The alkali is selected from the group consisting of sodium phosphate, potassium phosphate, sodium carbonate, potassium carbonate, sodium acetate, potassium acetate, sodium hydroxide, potassium hydroxide, or combinations thereof; and / or The inert solvent is selected from the group consisting of: aromatic solvents, halogenated hydrocarbon solvents, ether solvents, alkane solvents, sulfone solvents, sulfoxide solvents, amide solvents, halogenated aromatic solvents, or combinations thereof; preferably, the inert solvent is selected from the group consisting of: dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, or combinations thereof.

8. The method as described in claim 4, characterized in that, The method further includes adding potassium iodide to participate in the reaction, wherein the amount of potassium iodide used is 10% of the molar amount of the compound represented by Formula II.

9. The method as described in claim 4, characterized in that, The molar ratio of the haloaryl compound represented by Formula II to the base is 1:(0.25-1), preferably 1:(0.5-0.75); and / or The molar ratio of the haloaryl compound represented by Formula II to cuprous cyanide is 1:(1±0.5), preferably 1:(1±0.5), and more preferably 1:1; and / or The molar ratio of the haloaryl compound to the ligand represented by Formula II is 1:(0.005-0.1), preferably 1:(0.01-0.1), and more preferably 1:(0.02-0.05); and / or The molar volume ratio (mol / L) of the haloaryl compound represented by Formula II to the solvent is (1-10):1, preferably (2-8):1, and more preferably (3-5):1; and / or The reaction time is 1-48 h, preferably 12-24 h; and / or The reaction temperature is 20-140℃, preferably 60-130℃.

10. A compound represented by Formula I: in, W, R6, and R7 are as described in claim 1.

Images