A recyclable and highly reactive hypervalent iodine reagent

Abstract

The present invention provides a recyclable, highly reactive hypervalent iodine reagent. Specifically, the present invention provides a highly selective hypervalent iodine reagent and a method for preparing the reagent. The method of the present invention features mild conditions, simple operation, a wide substrate range, low cost, high selectivity and reactivity in subsequent application reactions, and recyclable raw materials, making it suitable for large-scale production.

Description

Technical Field

[0001] The present invention belongs to the field of organic synthesis. Specifically, the present invention provides a method for preparing a high-valent iodine reagent containing 3,5-dimethyl-4-iodoisoxazole, which has high selectivity and high reactivity in the synthesis of medicines, pesticide intermediates and polymer monomers. Background Art

[0002] Hypervalent iodine reagents have been widely used in organic synthesis since the 1990s due to their wide applicability, non-toxicity, and environmental friendliness. These reagents are primarily used to replace toxic heavy metal oxidants. In addition to simple oxidations, hypervalent iodine reagents have also been applied to various oxidative rearrangement reactions.

[0003] Structurally, they consistently adopt a distorted trigonal bipyramidal geometry, with the less electronegative aromatic ring and two lone pairs occupying equatorial positions, while the electronegative ligands are located at the apical positions. Trivalent iodine(III) reagents are inherently electrophilic, formed by a node in a high-valent nonbonding orbital, a 3-center-4-electron (3c-4e) bond (LIL), formed by the overlap of the iodine atom's 5p orbital with the orbitals of the two ligands. Due to their electrophilicity and excellent leaving group ability, CN and CC migration reactions are particularly common. Their unique reactivity has inspired the continuous exploration of new synthetic transformations.

[0004] However, the types of high-valent iodine salts are significantly limited due to their preparation methods, and their atom economy is poor. The present invention combines multiple known methods to prepare a variety of high-valent iodine reagents containing 3,5-dimethyl-4-iodoisoxazole from phenylboronic acid or non-functionalized aromatic rings. The recyclable nature of these reagents also addresses the issue of poor atom economy to a certain extent.

[0005] In summary, the art still lacks a method for preparing a high-valent iodine reagent containing 3,5-dimethyl-4-iodoisoxazole. Summary of the Invention

[0006] The present invention provides a high-valent iodine reagent for preparing 3,5-dimethyl-4-iodoisoxazole, as well as a preparation method and application thereof.

[0007] In a first aspect of the present invention, a hypervalent iodine reagent is provided, wherein the reagent comprises an effective amount of a compound having the structure of the following formula I:

[0008]

[0009] In the formula, R is a group containing an aromatic ring; preferably, R is a group selected from the following group: a substituted or unsubstituted C6-C30 aryl group, a substituted or unsubstituted 5-30-membered heteroaryl group, a substituted or unsubstituted 9-30-membered carbocyclic ring, or a substituted or unsubstituted 8-30-membered heterocyclic group, wherein the carbocyclic ring or heterocyclic group has a paracyclic or condensed ring structure, and the paracyclic or condensed ring structure has at least one aryl or heteroaryl unit;

[0010] The substituted group is substituted by one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C10 aryl, 5-12 membered heteroaryl, C6-C10 aryloxy, 5-12 membered heteroaryloxy, benzyloxy, CN, NO2, OR 1 SR 1 NR 1 R 2 、C(O)R 1 、O(CH2) p R 1 、C(O)OR 1 、C(O)NR 1 R 2 NR 1 C(O)R 2 , or S(O)2R 1 ; Among them, R 1 and R 2 Each is independently selected from the group consisting of hydrogen, OH, COOH, C1-C4 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C10 aryl, 5-12 membered heteroaryl, C3-C8 cycloalkyl, 5-12 membered heterocyclyl; and said alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, aryloxy, heteroaryloxy or benzyloxy is optionally substituted with one or more substituents selected from the group consisting of =O, halogen, COOH, C1-C4 alkyl, C1-C4 alkoxy, C6-C10 aryloxy, 5-12 membered heteroaryloxy, benzyloxy, C6-C10 aryl, 5-12 membered heteroaryl, -CH(Ph)2, p is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7 or 8.

[0011] In another preferred embodiment, the reagent includes a base; preferably, the base is selected from the following group: Cs2CO3, NaH.

[0012] In another preferred embodiment, R is not

[0013] The second aspect of the present invention provides a method for preparing the hypervalent iodine reagent according to the first aspect of the present invention, wherein the method comprises the steps of:

[0014]

[0015] In an inert solvent, in the presence of compounds IV and V, a compound of formula ⅠI reacts with a compound of formula ⅡI to obtain a hypervalent iodine reagent I; wherein R is as described in the first aspect of the present invention.

[0016] In another preferred embodiment, the reaction is carried out at -20°C to 70°C.

[0017] In another preferred embodiment, the reaction time is 3 hours to 9 hours.

[0018] In another preferred embodiment, the inert solvent is selected from the group consisting of DCM, DCE, or a combination thereof.

[0019] In another preferred embodiment, the method comprises: reacting at -30 to -10°C for a period of time, and then heating to 20 to 40°C and reacting for a period of time.

[0020] In another preferred embodiment, the reaction comprises: reacting at -30 to -10°C for 0.5 to 2 hours, and then reacting at 20 to 40°C for 1.5 to 8 hours.

[0021] In another preferred embodiment, the method comprises:

[0022] (a) preparing a hypervalent iodine reagent using the method described above; and

[0023] (b) Cooling the system to -30 to -10°C, then sequentially adding the compound of formula III and the compound of formula IV to the solution of formula II, and finally adding the compound of formula V to perform ion exchange to obtain a hypervalent iodine reagent.

[0024] In another preferred embodiment, the method further comprises the steps of: extracting the prepared hypervalent iodine reagent with dichloromethane, and separating the organic phase to obtain the hypervalent iodine reagent.

[0025] In another preferred embodiment, the method further comprises: purifying the obtained organic phase.

[0026] In another preferred embodiment, the purification step includes concentration and / or recrystallization.

[0027] The third aspect of the present invention provides a method for preparing the hypervalent iodine reagent according to the first aspect of the present invention, wherein the method comprises the steps of:

[0028]

[0029] In an inert solvent, a compound of formula VI is reacted with a compound of formula VII to obtain a hypervalent iodine reagent I; wherein R is as described above.

[0030] In another preferred embodiment, the reaction is carried out at room temperature.

[0031] In another preferred embodiment, the reaction time is 8-12 hours.

[0032] In another preferred embodiment, the inert solvent is selected from the group consisting of TFE, DCM, HFIP, or a combination thereof.

[0033] A fourth aspect of the present invention provides a method for preparing the hypervalent iodine reagent according to the first aspect of the present invention, characterized in that the method comprises the steps of:

[0034]

[0035] In an inert solvent, a compound of formula VI is reacted with a compound of formula VII to obtain a hypervalent iodine reagent I; wherein R is as described in the first aspect of the present invention.

[0036] In another preferred embodiment, the reaction is carried out at room temperature.

[0037] In another preferred embodiment, the reaction time is 8-12 hours.

[0038] In another preferred embodiment, the solvent is selected from the group consisting of trifluoroacetic acid, trifluoromethanesulfonic acid, or a combination thereof.

[0039] A fifth aspect of the present invention provides a coupling reaction method, comprising the steps of:

[0040]

[0041] In an inert solvent, a compound of formula I and R a XH reaction to obtain formula RXR a Compounds;

[0042] in,

[0043] M is H, Na or K;

[0044] X is selected from the following group: O, S, NR b 、C(R b )2、(R b )PO、(R b )P(O)O, S(O)2, S(O)3, C(O)O, SCN;

[0045] R is a group containing an aromatic ring; preferably, R is a group selected from the group consisting of a sulfonyl group, a substituted or unsubstituted C6-C30 aryl group, a substituted or unsubstituted 5-30-membered heteroaryl group, and a substituted or unsubstituted 8-30-membered heterocyclic group, wherein the heterocyclic group has a paracyclic or condensed ring structure, and the paracyclic or condensed ring structure contains at least one aryl or heteroaryl unit;

[0046] R a is a group selected from the group consisting of none, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C6-C30 aryl, substituted or unsubstituted 5-20 membered heteroaryl, substituted or unsubstituted 8-20 membered heterocyclyl;

[0047] R b is a group selected from the group consisting of H, a substituted or unsubstituted C1-C10 alkyl group, a substituted or unsubstituted C2-C10 ester group, a substituted or unsubstituted C6-C30 aryl group, a substituted or unsubstituted 5-20 membered heteroaryl group, and a substituted or unsubstituted 8-20 membered heterocyclic group;

[0048] The substituted group is substituted by one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C10 aryl, 5-12 membered heteroaryl, C6-C10 aryloxy, 5-12 membered heteroaryloxy, benzyloxy, CN, NO2, OR 1 SR 1 NR 1 R 2 、C(O)R 1 、O(CH2) p R 1 、C(O)OR 1 、C(O)NR 1 R 2 NR 1 C(O)R 2 , or S(O)2R 1 ; Among them, R 1 and R 2Each is independently selected from the following group: hydrogen, OH, COOH, C1-C4 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C10 aryl, 5-12 membered heteroaryl, C3-C8 cycloalkyl, 5-12 membered heterocyclyl; and the aryl, heteroaryl, cycloalkyl or heterocyclyl is optionally substituted by one or more substituents selected from the following group: =O, halogen, C1-C4 alkyl, C1-C4 alkoxy, C6-C10 aryloxy, 5-12 membered heteroaryloxy, benzyloxy; p is selected from the following group: 0, 1, 2, 3, 4, 5, 6, 7 or 8.

[0049] In another preferred embodiment, the method does not generate or substantially does not generate dimethylisoxazole substituent X.

[0050] In another preferred embodiment, the method further comprises: after the reaction is completed, recovering the compound of formula XII in the system and using it to re-prepare the hypervalent iodine reagents I, III, and VII.

[0051] A sixth aspect of the present invention provides a fluorination reaction method, comprising the steps of:

[0052]

[0053] In an inert solvent, reacting a compound of formula V with CsF to obtain a compound of formula RF;

[0054] Wherein, R is a group containing an aromatic ring; preferably, R is a group selected from the following group: a substituted or unsubstituted C6-C30 aryl group, a substituted or unsubstituted 5-30-membered heteroaryl group, a substituted or unsubstituted 8-30-membered heterocyclic group, wherein the heterocyclic group has a paracyclic or condensed ring structure, and the paracyclic or condensed ring structure contains at least one aryl or heteroaryl unit;

[0055] The substituted group is substituted by one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C10 aryl, 5-12 membered heteroaryl, C6-C10 aryloxy, 5-12 membered heteroaryloxy, benzyloxy, CN, NO2, OR 1 SR 1 NR 1 R 2 、C(O)R 1 、O(CH2) p R 1 、C(O)OR 1 、C(O)NR 1 R 2 NR 1C(O)R 2 , or S(O)2R 1 ; Among them, R 1 and R 2 Each is independently selected from the following group: hydrogen, OH, COOH, C1-C4 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C10 aryl, 5-12 membered heteroaryl, C3-C8 cycloalkyl, 5-12 membered heterocyclyl; and the aryl, heteroaryl, cycloalkyl or heterocyclyl is optionally substituted by one or more substituents selected from the following group: =O, halogen, C1-C4 alkyl, C1-C4 alkoxy, C6-C10 aryloxy, 5-12 membered heteroaryloxy, benzyloxy; p is selected from the following group: 0, 1, 2, 3, 4, 5, 6, 7 or 8.

[0056] In another preferred embodiment, the method does not generate or substantially does not generate dimethylisoxazole fluoride.

[0057] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features described in detail 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 listed here one by one. DETAILED DESCRIPTION

[0058] After extensive and in-depth research, the inventors unexpectedly discovered and prepared a class of recyclable hypervalent iodine reagents. The preparation method for this reagent features mild conditions, simple operation, a wide range of substrates, low cost, and recyclability. Because the 3,5-dimethyl-4-iodoisoxazole group exhibits very low reactivity in a range of reactions using hypervalent iodine reagents, coupling reactions using this reagent can yield various functionalized products with high selectivity and high yields. The reactions are also simple to operate and have broad applicability.

[0059] the term

[0060] As used herein, the term "C1-C6 alkyl" refers to a straight or branched chain alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, or the like, and "C1-C4 alkyl" has a similar definition.

[0061] The term "C6-C30 aryl group" refers to an aryl group having 6 to 30 carbon atoms, including a monocyclic or bicyclic aryl group, such as a phenyl group, a naphthyl group, or the like.

[0062] The term "5-30 membered heteroaryl" refers to a heteroaryl group having 5-30 ring atoms including 1-10 heteroatoms and the remainder carbon atoms, such as pyrrolyl, pyridyl, furyl, or the like.

[0063] The term "8-30 membered heterocyclic group" refers to a heterocyclic group having 8-30 ring atoms (including 1-10 heteroatoms and the remaining carbon atoms) (including fully saturated or partially unsaturated cases), such as tetrahydrofuranyl,

[0064] The term "substituted" means that one or more hydrogen atoms on the group are replaced by a substituent selected from the group consisting of: C1-C10 alkyl, C3-C10 cycloalkyl, C1-C10 alkoxy, halogen, hydroxy, carboxyl (-COOH), C1-C10 aldehyde, C2-C10 acyl, C2-C10 ester, phenyl; the phenyl group includes an unsubstituted phenyl group or a substituted phenyl group having 1-3 substituents selected from the group consisting of: halogen, C1-C10 alkyl, cyano, OH, nitro, C3-C10 cycloalkyl, C1-C10 alkoxy, and amino.

[0065] The term "halogen" refers to F, Cl, Br and I.

[0066] High-valent iodine reagent containing 3,5-dimethyl-4-iodoisoxazole and its preparation

[0067] Hypervalent iodine reagents, as important electrophilic arylation reagents, share the advantages of widespread application, non-toxicity, and environmental friendliness over traditional hypervalent iodine reagents. Furthermore, hypervalent iodine reagents containing 3,5-dimethyl-4-iodoisoxazole are readily available from a wide range of sources, including phenylboronic acid and non-functionalized aromatic rings, significantly expanding the range of hypervalent iodine reagents and their applications. Their recyclability also addresses, to a certain extent, the poor atom economy and high cost associated with the use of periodine salts.

[0068] The present invention provides a method for preparing a high-valent iodine reagent containing 3,5-dimethyl-4-iodoisoxazole, the method comprising:

[0069] Method A:

[0070]

[0071] Method B:

[0072]

[0073] Method C:

[0074]

[0075] In an inert solvent, a compound of formula ⅠI reacts with a compound of formula III to obtain a hypervalent iodine reagent I under the action of compounds IV and V; a compound of formula VI reacts with a compound of formula VII to obtain a hypervalent iodine reagent I.

[0076] In the above formulae, the definitions of the groups are the same as those described in the first aspect of the present invention.

[0077] In another preferred embodiment A, the reaction is carried out at -20°C to 70°C; in B, the reaction is carried out at room temperature.

[0078] In another preferred embodiment A, the reaction time is 3 to 9 hours; in B, the reaction time is 8 to 12 hours.

[0079] In another preferred embodiment A, the inert solvent is selected from the group consisting of DCM and DCE. In another preferred embodiment B, the solvent is selected from the group consisting of TFE, TFE / DCM and HFIP.

[0080] In another preferred embodiment A, the reaction is carried out at -20°C for 0.5 to 2 hours and at room temperature for 1.5 to 8 hours; in B, the reaction is carried out at room temperature for 8 to 12 hours.

[0081] In another preferred embodiment A, at low temperature, the compound of formula III and the compound of formula IV are first added to the solution of formula II, and finally the compound of formula V is added for ion exchange. The product is extracted with dichloromethane, the organic phase is separated, and the obtained organic phase is purified to obtain a hypervalent iodine reagent. In B, the compound of formula VI is reacted with the compound of formula VII at room temperature, and the obtained organic phase is purified to obtain a hypervalent iodine reagent I. In C, the compound of formula VI is reacted with the compound of formula III in an acidic solvent at room temperature, and the obtained organic phase is purified to obtain a hypervalent iodine reagent I.

[0082] In another preferred embodiment, the purification step includes concentration and / or recrystallization.

[0083] The raw materials II and VI in methods A, B and C can be purchased from commercial sources or prepared by known methods. In a preferred embodiment of the present application, a method for preparing a compound of formula III comprises the steps of:

[0084]

[0085] Reacting the compound of formula XII with an oxidizing agent to obtain a compound of formula III;

[0086] In another preferred embodiment, the reaction is carried out in a protic solvent.

[0087] In another preferred embodiment, the reaction is carried out without the need for an inert gas protective atmosphere.

[0088] In another preferred embodiment, the oxidant is sodium perborate tetrahydrate.

[0089] In a preferred embodiment of the present application, a method for preparing a compound as shown in Formula VII comprises the steps of:

[0090]

[0091] Under acidic conditions, reacting the compound of formula XII with TsOH·H2O and an oxidant to obtain a compound of formula VII;

[0092] In another preferred embodiment, the reaction is carried out in a protic solvent.

[0093] In another preferred embodiment, the reaction is carried out under the protection of an inert gas.

[0094] In another preferred embodiment, the oxidant is m-chloroperbenzoic acid.

[0095] In another preferred embodiment, the acid-providing reagent is p-toluenesulfonic acid monohydrate.

[0096] In the reaction method of the present invention, iodinated 3,5-dimethyl-4-iodoisoxazole, which is a raw material for preparing 3,5-dimethyl-4-iodoisoxazole reagents III and VII, can be recovered in a very high yield. Therefore, the reaction raw material can be recycled, improving the atom economy of the reaction. The recycling process is shown below:

[0097]

[0098] 3,5-dimethyl-4-iodoisoxazole XII is used to prepare a compound of formula III or formula VII, and then a hypervalent iodine reagent represented by formula I is prepared. The byproduct 3,5-dimethyl-4-iodoisoxazole reagent XII obtained after the reaction of the hypervalent iodine reagent can be reused to prepare a compound of formula III or formula VII, thereby completing the reaction cycle.

[0099] The main advantages of the present invention are:

[0100] (1) The reagent of the present invention can carry out CC coupling, CO coupling, CN coupling and other reactions with high selectivity and high yield, the separation method is simple, and the product purity is high.

[0101] (2) The reagent of the present invention is simple to prepare, does not require column chromatography purification, and is easy to obtain.

[0102] (3) The method of the present invention can be widely applied to the synthesis of high-valent iodine reagents. The raw materials can be recovered in the later reaction to achieve a recyclable process. It has great application value in the fields of drug design and synthesis, pesticide preparation, etc.

[0103] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention only and are not intended to limit the scope of the invention. The experimental methods in the following examples, for which specific conditions are not specified, are generally based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0104] Experimental part

[0105] Synthesis method of hypervalent iodine reagent precursor:

[0106]

[0107] 3.00 g of XII (13.5 mmol, 1.0 equiv.) was added to a 250 mL round-bottom flask, along with 150 mL of AcOH and 20.7 g of sodium perborate tetrahydrate (134.5 mmol, 10.0 equiv.). The mixture was heated to 40°C and stirred for 24 hours. Heating was stopped, 100 mL of water was added, and the mixture was extracted with 3 50 mL of dichloromethane. The resulting organic phase was dried over anhydrous magnesium sulfate, filtered, and the filtrate was spin-dried and then precipitated in petroleum ether to afford 4.36 g of product III as a white solid in a 95% yield. 1 H NMR (600MHz, DMSO-d6) δ2.71(s,3H),2.41(s,3H),1.92(s,6H). 13 C NMR (151MHz, DMSO-d6) δ176.0,175.5,161.0,96.1,21.4,20.4,12.9,11.3.

[0108]

[0109] Under nitrogen, 4.00 g of III (17.9 mmol, 1.0 equiv.) was added to a mixed solvent of 20 mL of DCM and 20 mL of TFE, followed by 4.01 g of m-chloroperbenzoic acid (m-CPBA) (19.7 mmol, 1.1 equiv.) and 3.75 g of p-toluenesulfonic acid monohydrate (TsOH·H2O) (19.7 mmol, 1.1 equiv.). The mixture was heated to 40°C and stirred for 10 hours. The solvent was removed by vortexing, the mixture was precipitated in diethyl ether, filtered, and washed with diethyl ether to afford VII as a white solid (5.41 g, 74% yield). 1 H NMR (600MHz, Methanol-d4) δ7.61(d,J=8.1Hz,2H),7.23(d,J=7.9Hz,2H),2.79(s,3H),2.47(s,3H),2.37(s,3H). 13 C NMR (151MHz, Methanol-d4) δ179.0,160.8,141.2,140.8,128.6,125.5,93.3,19.9,11.6,9.8.

[0110] Synthesis method of high iodine salt I

[0111] Example 1

[0112] Under nitrogen protection, (0.198 g, 1.0 mmol, 1.0 equiv.) was added to 6 mL of dichloromethane. Placed in a -20°C constant temperature cold bath, stirred for 5 minutes, added boron trifluoride etherate (0.394 g, 1.3 mmol, 1.3 equiv.), stirred for 15 minutes, added III (0.341 g, 1.0 mmol, 1.0 equiv.) in batches, slowly warmed to room temperature, continued stirring for 1.5 hours, added 10 mL of water and sodium p-toluenesulfonate (3.44 g, 20.0 mmol, 20.0 equiv.), stirred for 20 minutes. Extracted with 20 mL of dichloromethane * 3 times, the obtained organic phase was dried over anhydrous magnesium sulfate, filtered, the filtrate was spin-dried, and recrystallized from MeOH / Et2O to obtain the product 0.514 g of white solid, yield 94%. 1 H NMR(400MHz,Chloroform-d)δ7.87(d,J=8.3Hz,2H),7.51–7.38(m,7H),7.35( d,J=7.9Hz,2H),7.01(d,J=7.9Hz,2H),2.64(s,3H),2.31(s,3H),2.25(s,3H).

[0113] Example 2

[0114] Under nitrogen protection, 0.122g phenylboronic acid (1.0mmol, 1.0equiv.) was added to 6mL of dichloromethane. Placed in a -20℃ constant temperature cold bath, stirred for 5 minutes, added boron trifluoride etherate (0.394g, 1.3mmol, 1.3equiv.), stirred for 15 minutes, added III (0.341g, 1.0mmol, 1.0equiv.) in batches, slowly warmed to room temperature, continued stirring for 2.5 hours, added 10mL of water and sodium p-toluenesulfonate (3.44g, 20.0mmol, 20.0equiv.), stirred for 20 minutes. Extracted with 20mL*3 of dichloromethane, the obtained organic phase was dried over anhydrous magnesium sulfate, filtered, the filtrate was spin-dried, and recrystallized from MeOH / Et2O to obtain the product. 0.329 g of white solid, yield 70%. 1 H NMR(400MHz,Chloroform-d)δ7.82(dd,J=8.4,1.2Hz,2H),7.48(t,J=7.5Hz,1H), 7.38–7.29(m,4H),7.03(d,J=8.0Hz,2H),2.61(s,3H),2.30(s,3H),2.26(s,3H).

[0115] Example 3

[0116] Under nitrogen protection, (0.282 g, 1.0 mmol, 1.0 equiv.) was added to 6 mL of dichloromethane. Placed in a -20°C constant temperature cold bath, stirred for 5 minutes, added boron trifluoride etherate (0.394 g, 1.3 mmol, 1.3 equiv.), stirred for 15 minutes, added III (0.341 g, 1.0 mmol, 1.0 equiv.) in batches, slowly warmed to room temperature, continued heating to 45°C, maintained for about 8 hours, added 10 mL of water and sodium p-toluenesulfonate (3.88 g, 20.0 mmol, 20.0 equiv.), stirred for 20 minutes. Extracted with 20 mL of dichloromethane * 3 times, the obtained organic phase was dried over anhydrous magnesium sulfate, filtered, the filtrate was spin-dried, and recrystallized from MeOH / Et2O to obtain the product 0.454 g of white solid, yield 81%. 1 H NMR(400MHz,Chloroform-d)δ8.13(dd,J=8.0,1.0Hz,1H),8.00(dd,J=7.8,1.0Hz,1H),7.89(d,J=7.8Hz,1H),7.53(d,J=3.8Hz,2H), 7.43–7.37(m,1H),7.27(dd,J=7.9,0.9Hz,1H),7.20(d,J=7.9Hz,2H),6.83(d,J=7.8Hz,2H),2.70(s,3H),2.40(s,3H),2.13(s,3H).

[0117] Example 4

[0118] Under nitrogen protection, (0.238 g, 1.0 mmol, 1.0 equiv.) was added to 6 mL of dichloromethane. Placed in a -20°C constant temperature cold bath, stirred for 5 minutes, added boron trifluoride etherate (0.394 g, 1.3 mmol, 1.3 equiv.), stirred for 15 minutes, added III (0.341 g, 1.0 mmol, 1.0 equiv.) in batches, slowly warmed to room temperature, continued heating to 45°C, maintained for about 6 hours, added 10 mL of water and sodium p-toluenesulfonate (3.88 g, 20.0 mmol, 20.0 equiv.), stirred for 20 minutes. Extracted with 20 mL of dichloromethane * 3 times, the obtained organic phase was dried over anhydrous magnesium sulfate, filtered, the filtrate was spin-dried, and recrystallized from MeOH / Et2O to obtain the product. 0.335 g of white solid, yield 57%. 1H NMR(400MHz,Chloroform-d)δ8.01(d,J=1.7Hz,1H),7.68(td,J=8.2,1.9Hz,2H),7.59(d,J=8.2Hz,1H),7.42– 7.34(m,3H),7.32(d,J=8.2Hz,2H),6.94(d,J=7.9Hz,2H),2.64(s,3H),2.31(s,3H),2.20(s,3H),1.38(s,6H).

[0119] Example 5

[0120] Under nitrogen protection, (0.172 g, 1.0 mmol, 1.0 equiv.) was added to 6 mL of dichloromethane. Placed in a -20°C constant temperature cold bath, stirred for 5 minutes, added boron trifluoride etherate (0.394 g, 1.3 mmol, 1.3 equiv.), stirred for 15 minutes, added III (0.341 g, 1.0 mmol, 1.0 equiv.) in batches, slowly warmed to room temperature, continued to heat to 40°C, maintained for about 4 hours, added 10 mL of water and sodium p-toluenesulfonate (3.88 g, 20.0 mmol, 20.0 equiv.), stirred for 20 minutes. Extracted with 20 mL of dichloromethane * 3 times, the obtained organic phase was dried over anhydrous magnesium sulfate, filtered, the filtrate was spin-dried, and recrystallized from MeOH / Et2O to obtain the product. 0.364 g of white solid, yield 70%. 1 H NMR(400MHz,Chloroform-d)δ8.42(s,1H),7.80(d,J=8.2Hz,1H),7.74–7.68(m,3H),7.63–7.5 1(m,2H),7.26(d,J=8.2Hz,2H),6.86(d,J=7.9Hz,2H),2.63(s,3H),2.28(s,3H),2.21(s,3H).

[0121] Example 6

[0122] Under nitrogen protection, (0.152 g, 1.0 mmol, 1.0 equiv.) was added to 20 mL of dichloromethane. Placed in a -20°C constant temperature cold bath, stirred for 5 minutes, added boron trifluoride etherate (0.394 g, 1.3 mmol, 1.3 equiv.), stirred for 15 minutes, added III (0.341 g, 1.0 mmol, 1.0 equiv.) in batches, slowly warmed to room temperature, continued to heat to 40°C, maintained for about 3 hours, added 10 mL of water and sodium p-toluenesulfonate (3.88 g, 20.0 mmol, 20.0 equiv.), stirred for 20 minutes. Extracted with 20 mL of dichloromethane * 3 times, the obtained organic phase was dried over anhydrous magnesium sulfate, filtered, the filtrate was spin-dried, and recrystallized from MeOH / Et2O to obtain the product. 0.361 g of white solid, yield 72%. 1 H NMR(400MHz,Chloroform-d)δ7.71(d,J=9.1Hz,2H),7.31(d,J=8.0Hz,2H),7.01(d,J= 7.9Hz,2H),6.76(d,J=9.0Hz,2H),3.76(s,3H),2.58(s,3H),2.30(s,3H),2.25(s,3H).

[0123] Example 7

[0124] Under nitrogen protection, (0.214 g, 1.0 mmol, 1.0 equiv.) was added to 6 mL of dichloromethane. Placed in a -20°C constant temperature cold bath, stirred for 5 minutes, added boron trifluoride etherate (0.394 g, 1.3 mmol, 1.3 equiv.), stirred for 15 minutes, added III (0.341 g, 1.0 mmol, 1.0 equiv.) in batches, slowly warmed to room temperature, continued heating to 40°C, maintained for about 2.5 hours, added 10 mL of water and sodium p-toluenesulfonate (3.88 g, 20.0 mmol, 20.0 equiv.), stirred for 20 minutes. Extracted with 20 mL of dichloromethane * 3 times, the obtained organic phase was dried over anhydrous magnesium sulfate, filtered, the filtrate was spin-dried, and recrystallized from MeOH / Et2O to obtain the product. 0.456 g of white solid, yield 81%. 1 H NMR(400MHz,Chloroform-d)δ7.73–7.68(m,2H),7.39–7.29(m,4H),7.22–7.16(m,1H),7.04( d,J=8.0Hz,2H),7.00–6.96(m,2H),6.84–6.78(m,2H),2.58(s,3H),2.31(s,3H),2.27(s,3H).

[0125] Example 8

[0126] Under nitrogen protection, (0.194 g, 1.0 mmol, 1.0 equiv.) was added to 6 mL of dichloromethane. Placed in a -20°C constant temperature cold bath, stirred for 5 minutes, added boron trifluoride etherate (0.394 g, 1.3 mmol, 1.3 equiv.), stirred for 15 minutes, added III (0.341 g, 1.0 mmol, 1.0 equiv.) in batches, slowly warmed to room temperature, continued heating to 35°C, maintained for about 1.5 hours, added 10 mL of water and sodium p-toluenesulfonate (3.88 g, 20.0 mmol, 20.0 equiv.), stirred for 20 minutes. Extracted with 20 mL of dichloromethane * 3 times, the obtained organic phase was dried over anhydrous magnesium sulfate, filtered, the filtrate was spin-dried, and recrystallized from MeOH / Et2O to obtain the product. 0.499 g of white solid, yield 92%. 1 H NMR(400MHz,Chloroform-d)δ7.88(q,J=8.7Hz,4H),7.29(d,J=8.2Hz,2H),7.02(d,J=8.0H z,2H),4.35(q,J=7.1Hz,2H),2.58(s,3H),2.30(s,3H),2.24(s,3H),1.36(t,J=7.1Hz,3H).

[0127] Example 9

[0128] Under nitrogen protection, (0.167 g, 1.0 mmol, 1.0 equiv.) was added to 20 mL of dichloromethane. Placed in a -20°C constant temperature cold bath, stirred for 5 minutes, added boron trifluoride etherate (0.394 g, 1.3 mmol, 1.3 equiv.), stirred for 15 minutes, added III (0.341 g, 1.0 mmol, 1.0 equiv.) in batches, slowly warmed to room temperature, continued heating to 35°C, maintained for about 3.5 hours, added 10 mL of water and sodium p-toluenesulfonate (3.88 g, 20.0 mmol, 20.0 equiv.), stirred for 20 minutes. Extracted with 20 mL of dichloromethane * 3 times, the obtained organic phase was dried over anhydrous magnesium sulfate, filtered, the filtrate was spin-dried, and recrystallized from MeOH / Et2O to obtain the product. 0.346 g of white solid, yield 67%. 1H NMR(400MHz,Chloroform-d)δ8.51(d,J=7.5Hz,1H),7.82–7.70(m,2H),7.53–7.44(m,2 H),7.28(d,J=6.8Hz,1H),7.10(d,J=7.8Hz,2H),2.70(s,3H),2.36(s,3H),2.33(s,3H).

[0129] Example 10

[0130] Under nitrogen protection, (0.206 g, 1.0 mmol, 1.0 equiv.) was added to 6 mL of dichloromethane. Placed in a -20°C constant temperature cold bath, stirred for 5 minutes, added boron trifluoride etherate (0.394 g, 1.3 mmol, 1.3 equiv.), stirred for 15 minutes, added III (0.341 g, 1.0 mmol, 1.0 equiv.) in batches, slowly warmed to room temperature, continued to heat to 50°C, maintained for about 5 hours, added 10 mL of water and sodium p-toluenesulfonate (3.88 g, 20.0 mmol, 20.0 equiv.), stirred for 20 minutes. Extracted with 20 mL of dichloromethane * 3 times, the obtained organic phase was dried over anhydrous magnesium sulfate, filtered, the filtrate was spin-dried, and recrystallized from MeOH / Et2O to obtain the product White solid 0.311 g, yield 56%. 1 H NMR(400MHz,Chloroform-d)δ7.84(d,J=9.0Hz,2H),7.29(d,J=8.2Hz,2H),7. 15–7.08(m,2H),7.04(d,J=7.9Hz,2H),2.59(s,3H),2.31(s,3H),2.26(s,3H). 19 F NMR(376MHz,Chloroform-d)δ-57.64.

[0131] Example 11

[0132] Under nitrogen protection, (0.170 g, 1.0 mmol, 1.0 equiv.) was added to 6 mL of dichloromethane. Placed in a -20°C constant temperature cold bath, stirred for 5 minutes, added boron trifluoride etherate (0.394 g, 1.3 mmol, 1.3 equiv.), stirred for 15 minutes, added III (0.341 g, 1.0 mmol, 1.0 equiv.) in batches, slowly warmed to room temperature, continued to heat to 40°C, maintained for about 4 hours, added 10 mL of water and sodium p-toluenesulfonate (3.88 g, 20.0 mmol, 20.0 equiv.), stirred for 20 minutes. Extracted with 20 mL of dichloromethane * 3 times, the obtained organic phase was dried over anhydrous magnesium sulfate, filtered, the filtrate was spin-dried, and recrystallized from MeOH / Et2O to obtain the product. 0.249 g of white solid, yield 36%. 1 H NMR(400MHz,Chloroform-d)δ7.72(d,J=4.0Hz,1H),7.36(d,J=4.1Hz,1H),7.33(d,J= 8.2Hz,2H),7.07(d,J=7.9Hz,2H),2.59(s,3H),2.48(s,3H),2.32(s,3H),2.31(s,3H).

[0133] Example 12

[0134] Under nitrogen protection, (0.152 g, 1.0 mmol, 1.0 equiv.) was added to 6 mL of dichloromethane. Placed in a -20°C constant temperature cold bath, stirred for 5 minutes, added boron trifluoride etherate (0.394 g, 1.3 mmol, 1.3 equiv.), stirred for 15 minutes, added III (0.341 g, 1.0 mmol, 1.0 equiv.) in batches, slowly warmed to room temperature, maintained for about 3.5 hours, added 10 mL of water and sodium p-toluenesulfonate (3.88 g, 20.0 mmol, 20.0 equiv.), stirred for 20 minutes. Extracted with 20 mL of dichloromethane * 3 times, the obtained organic phase was dried over anhydrous magnesium sulfate, filtered, the filtrate was spin-dried, and recrystallized from MeOH / Et2O to obtain the product 0.370 g of white solid, yield 74%. 1 H NMR(400MHz,Chloroform-d)δ7.93(d,J=7.0Hz,1H),7.47(td,J=8.0,7.6,1.6Hz,1H),7.35(t,J=7.3Hz,2H ),7.03(d,J=7.9Hz,2H),6.92(td,J=8.9,7.4Hz,2H),3.85(s,3H),2.58(s,3H),2.32(s,3H),2.30(s,3H).

[0135] Example 13

[0136] Under nitrogen protection, (0.198 g, 1.0 mmol, 1.0 equiv.) was added to 6 mL of dichloromethane. Placed in a -20°C constant temperature cold bath, stirred for 5 minutes, added boron trifluoride etherate (0.394 g, 1.3 mmol, 1.3 equiv.), stirred for 15 minutes, added III (0.341 g, 1.0 mmol, 1.0 equiv.) in batches, slowly warmed to room temperature, continued to heat to 50°C, maintained for about 4 hours, added 10 mL of water and sodium p-toluenesulfonate (3.88 g, 20.0 mmol, 20.0 equiv.), stirred for 20 minutes. Extracted with 20 mL of dichloromethane * 3 times, the obtained organic phase was dried over anhydrous magnesium sulfate, filtered, the filtrate was spin-dried, and recrystallized from MeOH / Et2O to obtain the product. White solid 0.323 g, yield 59%. 1 H NMR(400MHz,Chloroform-d)δ8.07(t,J=1.8Hz,1H),7.74–7.69(m,1H),7.65(dt,J=7.9,1.3Hz,1H),7 .41–7.33(m,6H),7.30(d,J=8.2Hz,2H),6.95(d,J=7.9Hz,2H),2.62(s,3H),2.29(s,3H),2.24(s,3H).

[0137] Example 14

[0138] Under nitrogen protection, (0.206 g, 1.0 mmol, 1.0 equiv.) was added to 6 mL of dichloromethane. Placed in a -20°C constant temperature cold bath, stirred for 5 minutes, added boron trifluoride etherate (0.394 g, 1.3 mmol, 1.3 equiv.), stirred for 15 minutes, added III (0.341 g, 1.0 mmol, 1.0 equiv.) in batches, slowly warmed to room temperature, maintained for about 2.5 hours, added 10 mL of water and sodium p-toluenesulfonate (3.88 g, 20.0 mmol, 20.0 equiv.), stirred for 20 minutes. Extracted with 20 mL of dichloromethane * 3 times, the obtained organic phase was dried over anhydrous magnesium sulfate, filtered, the filtrate was spin-dried, and recrystallized from MeOH / Et2O to obtain the product 0.355 g of white solid, yield 64%. 1H NMR(400MHz,Chloroform-d)δ8.22(dd,J=8.1,1.5Hz,1H),7.54–7.49(m,1H),7.35–7.30(m,1H),7.25 (d,J=5.8Hz,2H),7.19(t,J=7.8Hz,1H),7.01(d,J=7.8Hz,2H),2.53(s,3H),2.30(s,3H),2.24(s,3H). 19 F NMR(376MHz,Chloroform-d)δ-56.43.

[0139] Example 15

[0140] Under nitrogen protection, (0.180 g, 1.0 mmol, 1.0 equiv.) was added to 6 mL of dichloromethane. Placed in a -20°C constant temperature cold bath, stirred for 5 minutes, added boron trifluoride etherate (0.394 g, 1.3 mmol, 1.3 equiv.), stirred for 15 minutes, added III (0.341 g, 1.0 mmol, 1.0 equiv.) in batches, slowly warmed to room temperature, maintained for about 4 hours, added 10 mL of water and sodium p-toluenesulfonate (3.88 g, 20.0 mmol, 20.0 equiv.), stirred for 20 minutes. Extracted with 20 mL of dichloromethane * 3 times, the obtained organic phase was dried over anhydrous magnesium sulfate, filtered, the filtrate was spin-dried, and recrystallized from MeOH / Et2O to obtain the product 0.333 g of white solid, yield 63%. 1 H NMR(400MHz,Chloroform-d)δ8.30(dd,J=7.5,1.9Hz,1H),7.75–7.63(m,2H),7.58(d, J=8.0Hz,2H),7.16–7.02(m,3H),4.13(s,3H),2.65(s,3H),2.33(s,4H),2.32(s,3H).

[0141] Example 16

[0142] Under nitrogen protection, (0.158 g, 1.0 mmol, 1.0 equiv.) was added to 6 mL of dichloromethane. Placed in a -20°C constant temperature cold bath, stirred for 5 minutes, added boron trifluoride etherate (0.394 g, 1.3 mmol, 1.3 equiv.), stirred for 15 minutes, added III (0.341 g, 1.0 mmol, 1.0 equiv.) in batches, slowly warmed to room temperature, continued heating to 35°C, maintained for about 4 hours, added 10 mL of water and sodium p-toluenesulfonate (3.88 g, 20.0 mmol, 20.0 equiv.), stirred for 20 minutes. Extracted with 20 mL of dichloromethane * 3 times, the obtained organic phase was dried over anhydrous magnesium sulfate, filtered, the filtrate was spin-dried, and recrystallized from MeOH / Et2O to obtain the product 0.400 g of white solid, yield 79%. 1 H NMR(400MHz,Chloroform-d)δ7.42(tt,J=8.4,6.4Hz,1H),7.27(d,J=8.2Hz,2H),7.04 (d,J=7.9Hz,2H),6.95(dd,J=8.5,6.4Hz,2H),2.58(s,3H),2.31(s,3H),2.31(s,3H). 19 F NMR(376MHz,Chloroform-d)δ-94.38(t,J=6.8Hz).

[0143] Example 17

[0144] Under nitrogen protection, (0.140 g, 1.0 mmol, 1.0 equiv.) was added to 6 mL of dichloromethane. Placed in a -20°C constant temperature cold bath, stirred for 5 minutes, added boron trifluoride etherate (0.394 g, 1.3 mmol, 1.3 equiv.), stirred for 15 minutes, added III (0.341 g, 1.0 mmol, 1.0 equiv.) in batches, slowly warmed to room temperature, continued to heat to 35°C, maintained for about 3 hours, added 10 mL of water and sodium p-toluenesulfonate (3.88 g, 20.0 mmol, 20.0 equiv.), stirred for 20 minutes. Extracted with 20 mL of dichloromethane * 3 times, the obtained organic phase was dried over anhydrous magnesium sulfate, filtered, the filtrate was spin-dried, and recrystallized from MeOH / Et2O to obtain the product. White solid 0.391 g, yield 80%. 1H NMR(400MHz,Chloroform-d)δ8.07(dd,J=7.8,5.8Hz,1H),7.47(dd,J=14.6,7.9Hz,1H),7.26(d,J=8.1H z,2H),7.19–7.13(m,1H),7.13–7.07(m,1H),7.02(d,J=7.9Hz,2H),2.59(s,3H),2.30(d,J=1.6Hz,6H). 19 FNMR(376MHz,Chloroform-d)δ-96.73(q,J=7.6Hz).

[0145] Example 18

[0146] Under nitrogen protection, (0.190 g, 1.0 mmol, 1.0 equiv.) was added to 6 mL of dichloromethane. Placed in a -20°C constant temperature cold bath, stirred for 5 minutes, added boron trifluoride etherate (0.394 g, 1.3 mmol, 1.3 equiv.), stirred for 15 minutes, added III (0.341 g, 1.0 mmol, 1.0 equiv.) in batches, slowly warmed to room temperature, continued to heat to 35°C, maintained for about 6 hours, added 10 mL of water and sodium p-toluenesulfonate (3.88 g, 20.0 mmol, 20.0 equiv.), stirred for 20 minutes. Extracted with 20 mL of dichloromethane * 3 times, the obtained organic phase was dried over anhydrous magnesium sulfate, filtered, the filtrate was spin-dried, and recrystallized from MeOH / Et2O to obtain the product. 0.216 g of white solid, yield 40%. 1 H NMR(400MHz,Chloroform-d)δ7.93(d,J=8.3Hz,2H),7.50(d,J=8.3Hz,2H),7.28 (d,J=8.0Hz,2H),7.03(d,J=8.0Hz,2H),2.60(s,3H),2.30(s,3H),2.26(s,3H). 19 F NMR(376MHz,Chloroform-d)δ-63.36.

[0147] Example 19

[0148] Under nitrogen protection, (0.136 g, 1.0 mmol, 1.0 equiv.) was added to 6 mL of dichloromethane. Placed in a -20°C constant temperature cold bath, stirred for 5 minutes, added boron trifluoride etherate (0.394 g, 1.3 mmol, 1.3 equiv.), stirred for 15 minutes, added III (0.341 g, 1.0 mmol, 1.0 equiv.) in batches, slowly warmed to room temperature, continued to heat to 35°C, maintained for about 2 hours, added 10 mL of water and sodium p-toluenesulfonate (3.88 g, 20.0 mmol, 20.0 equiv.), stirred for 20 minutes. Extracted with 20 mL of dichloromethane * 3 times, the obtained organic phase was dried over anhydrous magnesium sulfate, filtered, the filtrate was spin-dried, and recrystallized from MeOH / Et2O to obtain the product. 0.407 g of white solid, yield 84%. 1 H NMR(400MHz,Chloroform-d)δ7.67(d,J=8.4Hz,2H),7.35(d,J=8.1Hz,2H),7.09(d,J= 8.2Hz,2H),7.03(d,J=8.0Hz,2H),2.59(s,3H),2.32(s,3H),2.30(s,3H),2.26(s,3H).

[0149] Example 20

[0150] Under nitrogen protection, (0.147 g, 1.0 mmol, 1.0 equiv.) was added to 6 mL of dichloromethane. Placed in a -20°C constant temperature cold bath, stirred for 5 minutes, added boron trifluoride etherate (0.394 g, 1.3 mmol, 1.3 equiv.), stirred for 15 minutes, added III (0.341 g, 1.0 mmol, 1.0 equiv.) in batches, slowly warmed to room temperature, continued to heat to 40°C, maintained for about 4 hours, added 10 mL of water and sodium p-toluenesulfonate (3.88 g, 20.0 mmol, 20.0 equiv.), stirred for 20 minutes. Extracted with dichloromethane 20 mL*3, the obtained organic phase was dried over anhydrous magnesium sulfate, filtered, the filtrate was spin-dried, and recrystallized from MeOH / Et2O to obtain the product. 0.173 g of white solid, yield 35%. 1 H NMR (400MHz, Chloroform-d) δ7.92(d,J=8.3Hz,2H),7.54–7.47(m,2H),7.32–7.26(m,2H),7.06(d,J=7.9Hz,2H),2.59(s,3H),2.34(s,3H),2.25(s,3H).

[0151] Example 21

[0152] Under nitrogen protection, (0.164 g, 1.0 mmol, 1.0 equiv.) was added to 6 mL of dichloromethane. Placed in a -20°C constant temperature cold bath, stirred for 5 minutes, added boron trifluoride etherate (0.394 g, 1.3 mmol, 1.3 equiv.), stirred for 15 minutes, added III (0.341 g, 1.0 mmol, 1.0 equiv.) in batches, slowly warmed to room temperature, continued heating to 65°C, maintained for about 4 hours, added 10 mL of water and sodium p-toluenesulfonate (3.88 g, 20.0 mmol, 20.0 equiv.), stirred for 20 minutes. Extracted with 20 mL of dichloromethane * 3 times, the obtained organic phase was dried over anhydrous magnesium sulfate, filtered, the filtrate was spin-dried, and recrystallized from MeOH / Et2O to obtain the product 0.303 g of white solid, yield 59%. 1 H NMR(400MHz,Chloroform-d)δ8.43(t,J=1.7Hz,1H),7.99(dd,J=7.8,1.6Hz,1H),7.94(dd,J=8.1,1.9Hz,1H),7.4 0(t,J=7.9Hz,1H),7.29(d,J=8.2Hz,2H),7.04–6.98(m,2H),2.61(s,3H),2.48(s,3H),2.30(s,3H),2.27(s,3H).

[0153] Example 22

[0154] Under nitrogen protection, (0.156 g, 1.0 mmol, 1.0 equiv.) was added to 6 mL of dichloromethane. Placed in a -20°C constant temperature cold bath, stirred for 5 minutes, added boron trifluoride etherate (0.394 g, 1.3 mmol, 1.3 equiv.), stirred for 15 minutes, added III (0.341 g, 1.0 mmol, 1.0 equiv.) in batches, slowly warmed to room temperature, continued to heat to 70°C, maintained for about 4 hours, added 10 mL of water and sodium p-toluenesulfonate (3.88 g, 20.0 mmol, 20.0 equiv.), stirred for 20 minutes. Extracted with 20 mL of dichloromethane * 3 times, the obtained organic phase was dried over anhydrous magnesium sulfate, filtered, the filtrate was spin-dried, and recrystallized from MeOH / Et2O to obtain the product. 0.298 g of white solid, yield 58%. 1H NMR(400MHz,Chloroform-d)δ7.91(d,J=8.3Hz,2H),7.81(d,J=8.3Hz,2H),7.31(d,J=7.9H z,2H),7.03(d,J=7.9Hz,2H),2.60(s,3H),2.54(d,J=1.1Hz,3H),2.30(s,3H),2.26(s,3H).

[0155] Example 23

[0156] Under nitrogen protection, (0.156 g, 1.0 mmol, 1.0 equiv.) was added to 6 mL of dichloromethane. Placed in a -20°C constant temperature cold bath, stirred for 5 minutes, added boron trifluoride etherate (0.394 g, 1.3 mmol, 1.3 equiv.), stirred for 15 minutes, added III (0.341 g, 1.0 mmol, 1.0 equiv.) in batches, slowly warmed to room temperature, continued to heat to 35°C, maintained for about 4 hours, added 10 mL of water and sodium p-toluenesulfonate (3.88 g, 20.0 mmol, 20.0 equiv.), stirred for 20 minutes. Extracted with 20 mL of dichloromethane * 3 times, the obtained organic phase was dried over anhydrous magnesium sulfate, filtered, the filtrate was spin-dried, and recrystallized from MeOH / Et2O to obtain the product. 0.465 g of white solid, yield 92%. 1 H NMR (400MHz, Chloroform-d) δ7.74–7.68(m,2H),7.31–7.27(m,2H),7.24–7.19(m,2H),7.04(d,J=7.9Hz,2H),2.58(s,3H),2.32(s,3H),2.25(s,3H).

[0157] Example 24

[0158] Under nitrogen protection, (0.178 g, 1.0 mmol, 1.0 equiv.) was added to 6 mL of dichloromethane. Placed in a -20°C constant temperature cold bath, stirred for 5 minutes, added boron trifluoride etherate (0.394 g, 1.3 mmol, 1.3 equiv.), stirred for 15 minutes, added III (0.341 g, 1.0 mmol, 1.0 equiv.) in batches, slowly warmed to room temperature, continued to heat to 40°C, maintained for about 4 hours, added 10 mL of water and sodium p-toluenesulfonate (3.88 g, 20.0 mmol, 20.0 equiv.), stirred for 20 minutes. Extracted with 20 mL of dichloromethane * 3 times, the obtained organic phase was dried over anhydrous magnesium sulfate, filtered, the filtrate was spin-dried, and recrystallized from MeOH / Et2O to obtain the product. 0.227 g of white solid, yield 43%. 1 H NMR(400MHz,Chloroform-d)δ7.72(d,J=8.4Hz,2H),7.32(dd,J=13.0,8.3Hz,4 H),7.02(d,J=7.9Hz,2H),2.61(s,3H),2.29(s,3H),2.28(s,3H),1.25(s,9H).

[0159] Example 25

[0160] Under nitrogen protection, (0.156 g, 1.0 mmol, 1.0 equiv.) was added to 6 mL of dichloromethane. Placed in a -20°C constant temperature cold bath, stirred for 5 minutes, added boron trifluoride etherate (0.394 g, 1.3 mmol, 1.3 equiv.), stirred for 15 minutes, added III (0.341 g, 1.0 mmol, 1.0 equiv.) in batches, slowly warmed to room temperature, continued to heat to 40°C, maintained for about 4 hours, added 10 mL of water and sodium p-toluenesulfonate (3.88 g, 20.0 mmol, 20.0 equiv.), stirred for 20 minutes. Extracted with 20 mL of dichloromethane * 3 times, the obtained organic phase was dried over anhydrous magnesium sulfate, filtered, the filtrate was spin-dried, and recrystallized from MeOH / Et2O to obtain the product. 0.465 g of white solid, yield 92%. 1 H NMR(400MHz,Chloroform-d)δ7.72(d,J=8.8Hz,2H),7.42–7.30(m,7H),7.03(d,J=8. 0Hz, 2H), 6.87 (d, J = 8.8Hz, 2H), 5.01 (s, 1H), 2.61 (s, 3H), 2.30 (s, 3H), 2.28 (s, 3H).

[0161] Example 26

[0162] Under nitrogen protection, (0.228 g, 1.0 mmol, 1.0 equiv.) was added to 6 mL of dichloromethane. Placed in a -20°C constant temperature cold bath, stirred for 5 minutes, added boron trifluoride etherate (0.394 g, 1.3 mmol, 1.3 equiv.), stirred for 15 minutes, added III (0.341 g, 1.0 mmol, 1.0 equiv.) in batches, slowly warmed to room temperature, maintained for about 3 hours, added 10 mL of water and sodium p-toluenesulfonate (3.88 g, 20.0 mmol, 20.0 equiv.), stirred for 20 minutes. Extracted with 20 mL of dichloromethane * 3 times, the obtained organic phase was dried over anhydrous magnesium sulfate, filtered, the filtrate was spin-dried, and recrystallized from MeOH / Et2O to obtain the product 0.450 g of white solid, yield 78%. 1 H NMR(400MHz,Chloroform-d)δ7.73(d,J=8.8Hz,2H),7.39(d,J=7.9Hz,7H),7.05(d,J= 8.0Hz,2H),6.89(d,J=8.8Hz,2H),5.03(s,2H),2.63(s,3H),2.32(s,3H),2.29(s,3H).

[0163] Example 27

[0164] Under nitrogen protection, (0.140 g, 1.0 mmol, 1.0 equiv.) was added to 6 mL of dichloromethane. Placed in a -20°C constant temperature cold bath, stirred for 5 minutes, added boron trifluoride etherate (0.394 g, 1.3 mmol, 1.3 equiv.), stirred for 15 minutes, added III (0.341 g, 1.0 mmol, 1.0 equiv.) in batches, slowly warmed to room temperature, maintained for about 4 hours, added 10 mL of water and sodium p-toluenesulfonate (3.88 g, 20.0 mmol, 20.0 equiv.), stirred for 20 minutes. Extracted with 20 mL of dichloromethane * 3 times, the obtained organic phase was dried over anhydrous magnesium sulfate, filtered, the filtrate was spin-dried, and recrystallized from MeOH / Et2O to obtain the product 0.323 g of white solid, yield 66%. 1 H NMR(400MHz,Chloroform-d)δ7.80(dd,J=9.1,4.8Hz,2H),7.28(d,J=8.1Hz,2H),7.04 (d,J=7.9Hz,2H),6.97(dd,J=9.0,8.1Hz,2H),2.59(s,3H),2.31(s,3H),2.26(s,3H). 19F NMR(376MHz,Chloroform-d)δ-104.51–-108.42(m).

[0165] Example 28

[0166] Under nitrogen protection, (0.164 g, 1.0 mmol, 1.0 equiv.) was added to 6 mL of dichloromethane. Placed in a -20°C constant temperature cold bath, stirred for 5 minutes, added boron trifluoride etherate (0.394 g, 1.3 mmol, 1.3 equiv.), stirred for 15 minutes, added III (0.341 g, 1.0 mmol, 1.0 equiv.) in batches, slowly warmed to room temperature, maintained for about 4 hours, added 10 mL of water and sodium p-toluenesulfonate (0.341 g, 1.0 mmol, 1.0 equiv.), stirred for 20 minutes. Extracted with 20 mL of dichloromethane * 3 times, the obtained organic phase was dried over anhydrous magnesium sulfate, filtered, the filtrate was spin-dried, and recrystallized from MeOH / Et2O to obtain the product White solid 0.410 g, yield 80%. 1 H NMR(400MHz,Chloroform-d)δ7.72(d,J=8.5Hz,2H),7.31(d,J=8.1Hz,2H),7.15(d,J=8.5Hz, 2H),7.01(d,J=7.9Hz,2H),2.60(s,3H),2.29(s,3H),2.27(s,3H),1.19(s,3H),1.17(s,3H).

[0167] Example 29

[0168] Under nitrogen protection, VII (0.41 g, 1.00 mmol, 1.0 equiv.) was added to a mixed solution of 6 mL trifluoroethanol and 0.6 mL dichloromethane. (0.19 g, 1.00 mmol, 1.0 equiv.), stirred at room temperature overnight. The solvent was removed and recrystallized from MeOH / Et2O to obtain the product. 0.216 g of white solid, yield 40%. 1H NMR(600MHz,Chloroform-d)δ7.67(d,J=8.0Hz,2H),7.39(d,J=7.8Hz,2H),7.06(d,J=8.0Hz,2H),7.00(d,J=7.8Hz,2H),2. 56(s,3H),2.50(t,J=7.9Hz,2H),2.26(s,3H),2.21(s,3H),1.49(p,J=7.5Hz,2H),1.36–1.10(m,4H),0.81(t,J=7.0Hz,3H).

[0169] Example 30

[0170] Under nitrogen protection, (0.200 g, 1.0 mmol, 1.0 equiv.) was added to 6 mL of dichloromethane. Placed in a -20°C constant temperature cold bath, stirred for 5 minutes, added boron trifluoride etherate (0.394 g, 1.3 mmol, 1.3 equiv.), stirred for 15 minutes, added III in batches, slowly warmed to room temperature, maintained for about 4 hours, added 10 mL of water and sodium p-toluenesulfonate (0.341 g, 1.0 mmol, 1.0 equiv.), stirred for 20 minutes. Extracted with 20 mL of dichloromethane * 3 times, the obtained organic phase was dried over anhydrous magnesium sulfate, filtered, the filtrate was spin-dried, and recrystallized from MeOH / Et2O to obtain the product 0.170 g of white solid, yield 31%. 1 H NMR(400MHz,Chloroform-d)δ7.70–7.62(m,2H),7.38(d,J=8.7Hz,2H),7.28( d,J=8.2Hz,2H),7.04(d,J=7.8Hz,2H),2.58(s,3H),2.32(s,3H),2.25(s,3H).

[0171] Example 31

[0172] Under nitrogen protection, VII (0.411 g, 1.00 mmol, 1.0 equiv.) was added to a mixed solution of 6 mL trifluoroethanol and 0.6 mL dichloromethane. (0.166 g, 1.00 mmol, 1.0 equiv.), stirred at room temperature overnight. The solvent was removed and recrystallized from MeOH / Et2O to obtain the product. 0.406 g of white solid, yield 79%. 1H NMR(400MHz,Chloroform-d)δ7.69(dd,J=2.0,0.8Hz,1H),7.35(d,J=8.2Hz,2H),7.24–7.21(m,1H),7.03 (d,J=7.9Hz,2H),6.81(d,J=8.4Hz,1H),3.81(s,3H),2.58(s,3H),2.31(s,3H),2.30(s,3H),2.21(s,3H).

[0173] Example 32

[0174] Under nitrogen protection, VII (0.370 g, 0.90 mmol, 1.0 equiv.) was added to a mixed solution of 6 mL trifluoroethanol and 0.6 mL dichloromethane. (0.245 g, 0.90 mmol, 1.0 equiv.), stirred at room temperature overnight. The solvent was removed and recrystallized from MeOH / Et2O to obtain the product. White solid 0.2780 g, yield 57%. 1 HNMR(400MHz,Chloroform-d)δ8.19–8.11(m,1H),7.47(t,J=7.8Hz,1H),7.36(d,J=7.7Hz,1H),7.22( d,J=7.8Hz,1H),6.96(d,J=2.4Hz,2H),6.75(d,J=7.4Hz,2H),2.27(s,3H),2.01(s,3H),1.99(s,3H).

[0175] Example 33

[0176] Under nitrogen protection, VII (0.411 g, 1.0 mmol, 1.0 equiv.) was added to a mixed solution of 6 mL trifluoroethanol and 0.6 mL dichloromethane. (0.155 g, 1.00 mmol, 1.0 equiv.), stirred at room temperature overnight. The solvent was removed and recrystallized from MeOH / Et2O to obtain the product. 0.3755 g of white solid, yield 75%. 1H NMR(400MHz,Chloroform-d)δ7.93(d,J=7.0Hz,1H),7.47(td,J=8.0,7.6,1.6Hz,1H),7.35(t,J=7.3Hz,2H ),7.03(d,J=7.9Hz,2H),6.92(td,J=8.9,7.4Hz,2H),3.85(s,3H),2.58(s,3H),2.32(s,3H),2.30(s,3H).

[0177] Example 34

[0178] Under nitrogen protection, VII (0.411 g, 1.00 mmol, 1.0 equiv.) was added to a mixed solution of 6 mL trifluoroethanol and 0.6 mL dichloromethane. (0.234 g, 1.00 mmol, 1.0 equiv.), stirred at room temperature overnight. The solvent was removed and recrystallized from MeOH / Et2O to obtain the product. 0.461 g of white solid, yield 92%. 1 H NMR(400MHz,Chloroform-d)δ7.71(d,J=9.1Hz,2H),7.31(d,J=8.0Hz,2H),7.01(d,J= 7.9Hz,2H),6.76(d,J=9.0Hz,2H),3.76(s,3H),2.58(s,3H),2.30(s,3H),2.25(s,3H).

[0179] Example 35

[0180] Under nitrogen protection, VII (0.411 g, 1.0 mmol, 1.0 equiv.) was added to a mixed solution of 6 mL trifluoroethanol and 0.6 mL dichloromethane. (0.184 g, 1.00 mmol, 1.0 equiv.), stirred at room temperature overnight. The solvent was removed and recrystallized from MeOH / Et2O to obtain the product. White solid 0.3072 g, yield 57%. 1 H NMR(400MHz,Chloroform-d)δ8.45(d,J=8.0Hz,1H),8.08(s,1H),7.75(d,J=7.8Hz,1H),7.64(t,J =7.7Hz,1H),7.50(t,J=7.7Hz,2H),7.01(d,J=7.9Hz,2H),2.55(s,3H),2.30(s,3H),2.28(s,3H). 19F NMR(376MHz,Chloroform-d)δ-59.51.

[0181] Example 36

[0182] Under nitrogen protection, (0.180 g, 0.50 mmol, 1.0 equiv.) was added to 10 mL of dichloromethane. Placed in a -20°C constant temperature cold bath, stirred for 5 minutes, added boron trifluoride etherate (0.197 g, 0.65 mmol, 1.3 equiv.), stirred for 15 minutes, added III (0.188 g, 0.55 mmol, 1.1 equiv.) in batches, slowly warmed to room temperature, continued heating to 35°C, maintained for about 1.5 hours, added 10 mL of water and sodium p-toluenesulfonate (1.94 g, 10.0 mmol, 20.0 equiv.), stirred for 20 minutes. Extracted with dichloromethane 20 mL*3, the obtained organic phase was dried over anhydrous magnesium sulfate, filtered, the filtrate was spin-dried, and recrystallized from MeOH / Et2O to obtain the product. 0.652 g of white solid, yield 92%. 1 H NMR (400MHz, Methanol-d4) δ8.09(s,2H),8.01(d,J=7.7Hz,1H),7.96(d,J=7.6Hz,2H),7.64(d,J=7.9Hz,1H),7.48–7.39(m,5H),7.24(t ,J=7.6Hz,1H),7.20(s,2H),7.13(t,J=7.6Hz,2H),6.70(d,J=7.7Hz,1H),6.59(d,J=7.6Hz,2H),2.48(s,3H),2.33(s,3H),2.12(s,3H).

[0183] Example 37

[0184] Under nitrogen protection, (0.150 g, 1.0 mmol, 1.0 equiv.) was added to 20 mL of dichloromethane. Placed in a -20°C constant temperature cold bath, stirred for 5 minutes, added boron trifluoride ether solution (0.394 g, 1.3 mmol, 1.3 equiv.), stirred for 15 minutes, added III in batches, slowly warmed to room temperature, continued to heat to 35°C, maintained for about 1.5 hours, added 10 mL of water and sodium p-toluenesulfonate (3.88 g, 20 mmol, 20.0 equiv.), stirred for 20 minutes. Extracted with 20 mL of dichloromethane * 3 times, the obtained organic phase was dried over anhydrous magnesium sulfate, filtered, the filtrate was spin-dried, and recrystallized from MeOH / Et2O to obtain the product 0.665 g of white solid, yield 92%. 1H NMR (600MHz, Chloroform-d) δ7.29–7.28(m,3H),7.17(d,J=7.4Hz,3H),7.01(d,J=7.8Hz,3H),2.64(s,6H),2.56(s,3H),2.31(s,3H),2.17(s,3H).

[0185] Example 38

[0186] Under nitrogen protection, VII (0.822 g, 2.0 mmol, 1.0 equiv.) was added to a mixed solution of 12 mL trifluoroethanol and 1.2 mL dichloromethane. (0.28 mL, 2.0 mmol, 1.0 equiv.), stirred at room temperature overnight. The solvent was removed and recrystallized from MeOH / Et2O to obtain the product. 0.892 g of white solid, yield 87%. 1 H NMR (400MHz, Chloroform-d) δ7.25(d,J=5.0Hz,2H),6.97(d,J=7.8Hz,2H),6.89(s,2H),2.56(s,6H),2.53(s,3H),2.29(s,3H),2.25(s,3H),2.14(s,3H).

[0187] Example 39

[0188] Under nitrogen protection, VII (1.23 g, 3.00 mmol, 1.0 equiv.) was added to a mixed solution of 18 mL trifluoroethanol and 1.8 mL dichloromethane. (0.252 g, 3.00 mmol, 1.0 equiv.), stirred at room temperature overnight. The solvent was removed and recrystallized from MeOH / Et2O to obtain the product. 1.19 g of white solid, yield 83%. 1 H NMR (400MHz, Methanol-d4) δ7.99(d,J=3.3Hz,1H),7.86(d,J=5.0Hz,1H),7.63(d,J=7.9 Hz,2H),7.21(d,J=7.9Hz,2H),7.15–7.10(m,1H),2.72(s,3H),2.41(s,3H),2.35(s,3H).

[0189] Example 40

[0190] Under nitrogen protection, VII (0.411 g, 1.0 mmol, 1.0 equiv.) was added to a mixed solution of 6 mL trifluoroethanol and 0.6 mL dichloromethane. (0.216 g, 1.0 mmol, 1.0 equiv.), stirred at room temperature overnight. The solvent was removed and recrystallized from MeOH / Et2O to obtain the product. 0.488 g of white solid, yield 96%. 1 H NMR(400MHz,Chloroform-d)δ7.44(d,J=7.9Hz,2H),7.07(d,J=7.9Hz,2H),6.78(d,J=2.5Hz, 1H), 6.33 (d, J = 2.5Hz, 1H), 3.86 (s, 3H), 3.79 (s, 3H), 2.63 (s, 3H), 2.34 (s, 3H), 2.33 (s, 3H).

[0191] Example 41

[0192] Under nitrogen protection, VII (0.411 g, 1.0 mmol, 1.0 equiv.) was added to a mixed solution of 6 mL trifluoroethanol and 0.6 mL dichloromethane. Metaxalone was then added. (0.221 g, 1.0 mmol, 1.0 equiv.), stirred at room temperature overnight. The solvent was removed and recrystallized from MeOH / Et2O to obtain the product. 0.479 g of white solid, yield 78%. 1 H NMR(400MHz, Methanol-d4)δ7.66(d,J=8.0Hz,2H),7.21(d,J=7.9Hz,2H),6.99(s,2H),4.98(s,1H),4.33–4.10 (m,2H),3.73(t,J=9.2Hz,1H),3.50(dd,J=9.1,6.4Hz,1H),2.64(s,6H),2.35(s,3H),2.25(s,3H),1.88(s,3H).

[0193] Example 42

[0194] Under nitrogen protection, VII (0.411 g, 1.0 mmol, 1.0 equiv.) was added to a mixed solution of 6 mL trifluoroethanol and 0.6 mL dichloromethane. Ethylbenzene was then added. (0.106, 1.0 mmol, 1.0 equiv.), stirred at room temperature overnight. The solvent was removed and recrystallized from MeOH / Et2O to obtain the product. 0.429 g of white solid, yield 86%. 1H NMR(400MHz,Chloroform-d)δ7.74(d,J=8.1Hz,2H),7.40(d,J=7.8Hz,2H),7.14(d,J=8.1Hz,2H),7.05 (d,J=7.8Hz,2H),2.64(q,J=7.7Hz,2H),2.61(s,3H),2.32(s,3H),2.28(s,3H),1.19(t,J=7.4Hz,3H).

[0195] Example 43

[0196] Under nitrogen protection, VII (0.411 g, 1.0 mmol, 1.0 equiv.) was added to a mixed solution of 6 mL trifluoroethanol and 0.6 mL dichloromethane. (0.134 g, 1.0 mmol, 1.0 equiv.), stirred at room temperature overnight. The solvent was removed and recrystallized from MeOH / Et2O to obtain the product. 0.442 g of white solid, yield 84%. 1 H NMR(400MHz,Chloroform-d)δ7.73(d,J=8.6Hz,2H),7.33(d,J=7.8Hz,2H),7.02(d,J=7.8Hz,2H),6.78(d,J=8.5H z,2H),5.98(m,1H),5.34(dd,J=29.1,13.9Hz,2H),4.48(d,J=5.3Hz,2H),2.59(s,3H),2.31(s,3H),2.27(s,3H).

[0197] Example 44

[0198] Under nitrogen protection, VII (0.411 g, 1.0 mmol, 1.0 equiv.) was added to a mixed solution of 6 mL trifluoroethanol and 0.6 mL dichloromethane. Then dimethoxypyridine was added. (0.221 g, 1.0 mmol, 1.0 equiv.), stirred at room temperature overnight. The solvent was removed and recrystallized from MeOH / Et2O to obtain the product. 0.462 g of white solid, yield 87%. 1HNMR(400MHz,Chloroform-d)1H NMR(600MHz,Chloroform-d)δ8.18(d,J=8.4Hz,1H),7.40(d,J=7.6Hz,2H),7.06(d,J= 7.7Hz,2H),6.21(d,J=8.4Hz,1H),3.91(s,3H),3.88(s,3H),2.58(s,3H),2.32(s,6H).

[0199] Example 45

[0200] Under nitrogen protection, VII (0.411 g, 1.0 mmol, 1.0 equiv.) was added to a mixed solution of 6 mL trifluoroethanol and 0.6 mL dichloromethane. (0.110 g, 1.0 mmol, 1.0 equiv.), stirred at room temperature overnight. The solvent was removed and recrystallized from MeOH / Et2O to obtain the product. White solid 0.412 g, yield 82%. 1 H NMR (400MHz, Chloroform-d) δ7.36(d,J=8.0Hz,2H),7.08(d,J=7.9Hz,2H),2.57(s,3H),2.38(s,3H),2.33(s,3H),2.26(s,3H),2.24(s,3H).

[0201] Example 46

[0202] Under nitrogen protection, VII (0.411 g, 1.0 mmol, 1.0 equiv.) was added to a mixed solution of 6 mL trifluoroethanol and 0.6 mL dichloromethane. Then o-methoxybromobenzene was added. (0.186 g, 1.00 mmol, 1.0 equiv.) was stirred at room temperature overnight. The solvent was removed and the product was recrystallized from MeOH / Et2O. 0.531 g of white solid, yield 94%. 1 HNMR(600MHz,Chloroform-d)δ7.89(s,1H),7.86(d,J=8.8Hz,1H),7.40(d,J=7.7Hz,2H),7.0 7(d,J=7.7Hz,2H),6.79(d,J=8.7Hz,1H),3.87(s,3H),2.62(s,3H),2.33(s,3H),2.30(s,3H).

[0203] Example 47

[0204] Under nitrogen protection, VII (0.411 g, 1.0 mmol, 1.0 equiv.) was added to a mixed solution of 6 mL trifluoroethanol and 0.6 mL dichloromethane. (0.184 g, 1.0 mmol, 1.0 equiv.), stirred at room temperature overnight. The solvent was removed and recrystallized from MeOH / Et2O to obtain the product. 0.496 g of white solid, yield 84%. 1 H NMR(600MHz,Chloroform-d)δ7.77(d,J=8.0Hz,1H),7.44(d,J=7.3Hz,1H),7.17(d,J=8.0Hz,1H),7.08(d,J=7.7 Hz,1H),3.34(t,J=6.3Hz,1H),2.77(t,J=7.4Hz,1H),2.62(s,1H),2.34(s,1H),2.29(s,1H),2.13–2.08(m,1H).

[0205] Example 48

[0206] Under nitrogen protection, VII (0.411 g, 1.0 mmol, 1.0 equiv.) was added to a mixed solution of 6 mL trifluoroethanol and 0.6 mL dichloromethane. (0.204 g, 1.0 mmol, 1.0 equiv.), stirred at room temperature overnight. The solvent was removed and recrystallized from MeOH / Et2O to obtain the product. 0.513 g of white solid, yield 86%. 1 H NMR(400MHz,Chloroform-d)δ7.47(d,J=8.0Hz,2H),7.08–7.05(m,4H),3.31(p,J=6.6Hz, 2H),2.91(p,J=6.9Hz,1H),2.60(s,3H),2.31(s,3H),2.21(s,3H),1.22(d,J=6.8Hz,18H).

[0207] Example 49

[0208] Under nitrogen protection, VII (0.411 g, 1.0 mmol, 1.0 equiv.) was added to a mixed solution of 6 mL trifluoroethanol and 0.6 mL dichloromethane. (0.254 g, 1.0 mmol, 1.0 equiv.), stirred at room temperature overnight. The solvent was removed and recrystallized from MeOH / Et2O to obtain the product. 0.491 g of white solid, yield 76%. 1HNMR(400MHz,Chloroform-d)δ7.91(s,1H),7.48–7.46(m,1H),7.40–7.34(m,4H),7.30(d ,J=7.9Hz,1H),7.02(m,6H),6.67(d,J=7.9Hz,2H),2.55(s,3H),2.25(s,3H),2.23(s,3H).

[0209] Example 50

[0210] Under nitrogen protection, VII (0.411 g, 1.0 mmol, 1.0 equiv.) was added to a mixed solution of 6 mL trifluoroethanol and 0.6 mL dichloromethane. (0.166 g, 1.0 mmol, 1.0 equiv.), stirred at room temperature overnight. The solvent was removed and recrystallized from MeOH / Et2O to obtain the product. 0.464 g of white solid, yield 83%. 1 H NMR (400MHz, Methanol-d4) δ8.47(d,J=2.5Hz,1H),8.24(dd,J=9.1,2.5Hz,1H),7.68(d,J=8.2Hz,2H),7. 27(d,J=9.1Hz,1H),7.23–7.21(m,2H),3.94(s,3H),3.88(s,3H),2.75(s,3H),2.39(s,3H),2.36(s,3H).

[0211] Example 51

[0212] Under nitrogen protection, VII (0.411 g, 1.0 mmol, 1.0 equiv.) was added to a mixed solution of 6 mL trifluoroethanol and 0.6 mL dichloromethane. (0.168 g, 1.0 mmol, 1.0 equiv.), stirred at room temperature overnight. The solvent was removed and recrystallized from MeOH / Et2O to obtain the product. 0.549 g of white solid, yield 98%. 1 H NMR (400MHz, Chloroform-d) δ7.48(d,J=8.1Hz,2H),7.07(d,J=7.9Hz,2H),6.08(s,2H),3.87(s,6H),3.82(s,3H),2.61(s,3H),2.34(s,3H),2.32(s,3H).

[0213] Example 52

[0214] Under nitrogen protection, VII (0.411 g, 1.00 mmol, 1.0 equiv.) was added to a mixed solution of 6 mL trifluoroethanol and 0.6 mL dichloromethane. (0.147 g, 1.0 mmol, 1.0 equiv.), stirred at room temperature overnight. The solvent was removed and recrystallized from MeOH / Et2O to obtain the product. 0.475 g of white solid, yield 88%. 1 H NMR (400MHz, Methanol-d4) δ8.25(d,J=9.0Hz,1H),7.67(d,J=8.2Hz,2H),7.32(d,J=3.0Hz,1H),7.22(d,J =8.2Hz,2H),7.05(dd,J=9.0,3.0Hz,1H),4.22(s,2H),3.90(s,3H),2.75(s,3H),2.37(s,3H),2.36(s,3H).

[0215] Example 53

[0216] Under nitrogen protection, VII (0.411 g, 1.0 mmol, 1.0 equiv.) was added to a mixed solution of 6 mL trifluoroethanol and 0.6 mL dichloromethane. (0.244 g, 1.0 mmol, 1.0 equiv.), stirred at room temperature overnight. The solvent was removed and recrystallized from MeOH / Et2O to obtain the product. 0.465 g of white solid, yield 73%. 1 H NMR(400MHz,Chloroform-d)δ7.71(d,J=8.5Hz,2H),7.37(d,J=8.0Hz,2H),7.31–7.28(m,3H),7.25–7.2 1(m,3H),7.07(d,J=8.5Hz,2H),7.04–6.99(m,6H),5.49(s,1H),2.59(s,3H),2.30(s,3H),2.27(s,3H).

[0217] Example 54

[0218] Under nitrogen protection, VII (0.411 g, 1.0 mmol, 1.0 equiv.) was added to a mixed solution of 6 mL trifluoroethanol and 0.6 mL dichloromethane. (0.132 g, 1.0 mmol, 1.0 equiv.), stirred at room temperature overnight. The solvent was removed and recrystallized from MeOH / Et2O to obtain the product. 0.323 g of white solid, yield 62%. 1H NMR(400MHz,Chloroform-d)δ7.50(s,1H),7.47(dd,J=8.2,2.0Hz,1H),7.34(d,J=8.1Hz,2H),7.03(d,J=7.9Hz,2H),6.95( d,J=8.2Hz,1H),2.70(d,J=6.5Hz,2H),2.63(d,J=7.0Hz,2H),2.59(s,3H),2.31(s,3H),2.28(s,3H),1.73(q,J=3.4Hz,4H).

[0219] Example 55

[0220] Under nitrogen protection, VII (0.411 g, 1.00 mmol, 1.0 equiv.) was added to a mixed solution of 6 mL trifluoroethanol and 0.6 mL dichloromethane. (0.166 g, 1.0 mmol, 1.0 equiv.), stirred at room temperature overnight. The solvent was removed and recrystallized from MeOH / Et2O to obtain the product. 0.397 g of white solid, yield 71%. 1 H NMR(400MHz, Methanol-d4)δ8.05(dd,J=8.8,2.5Hz,1H),8.01(d,J=2.4Hz,1H),7.69(d,J=8.2Hz,2H),7.2 2(d,J=8.1Hz,2H),7.12(d,J=8.9Hz,1H),3.89(s,3H),3.66(s,2H),2.74(s,3H),2.39(s,3H),2.36(s,3H).

[0221] Example 56

[0222] Under nitrogen protection, VII (0.411 g, 1.0 mmol, 1.0 equiv.) was added to a mixed solution of 6 mL trifluoroethanol and 0.6 mL dichloromethane. (0.277 g, 1.0 mmol, 1.0 equiv.), stirred at room temperature overnight. The solvent was removed and recrystallized from MeOH / Et2O to obtain the product. 0.509 g of white solid, yield 76%. 1H NMR(400MHz, Methanol-d4)δ8.20(s,1H),8.05(d,J=8.5Hz,1H),7.70(s,1H),7.67–7.67(m,2H),7.65(s,1H),7.55(dd ,J=9.0,7.2Hz,1H),7.22(d,J=7.9Hz,2H),6.59(d,J=8.5Hz,1H),3.95(s,2H),2.77(s,3H),2.42(s,3H),2.36(s,3H).

[0223] Example 57

[0224] Under nitrogen protection, VII (0.411 g, 1.0 mmol, 1.0 equiv.) was added to a mixed solution of 6 mL trifluoroethanol and 0.6 mL dichloromethane. (0.250 g, 1.0 mmol, 1.0 equiv.), stirred at room temperature overnight. The solvent was removed and recrystallized from MeOH / Et2O to obtain the product. 0.456 g of white solid, yield 71%.

[0225] 1 H NMR(400MHz,Chloroform-d)δ7.62(s,1H),7.38(d,J=7.8Hz,2H),7.02(d,J=7.8Hz,2H),6.63(s,1H),δ3.87(t,J=6 .0Hz,2H).2.59(s,3H),2.50(s,3H),2.30(s,3H),2.26(s,3H),2.06(s,3H),1.73(m,2H),1.65(m,2H),1.19(s,6H).

[0226] Example 58

[0227] Under nitrogen protection, VII (0.411 g, 1.0 mmol, 1.0 equiv.) was added to a mixed solution of 6 mL trifluoroethanol and 0.6 mL dichloromethane. (0.184 g, 1.0 mmol, 1.0 equiv.), stirred at room temperature overnight. The solvent was removed and recrystallized from MeOH / Et2O to obtain the product. 0.570 g of white solid, yield 89%. 1H NMR (400MHz, DMSO-d6) δ8.22(d,J=9.0Hz,2H),7.62(d,J=8.8Hz,2H),7.46(d,J=7.9Hz,2H),7.17–7.03(m,6H),2.71(s,3H),2.35(s,3H),2.28(s,3H).

[0228] Example 69

[0229] Under nitrogen protection, VII (0.411 g, 1.0 mmol, 1.0 equiv.) was added to a mixed solution of 6 mL trifluoroethanol and 0.6 mL dichloromethane. (0.173 g, 1.0 mmol, 1.0 equiv.), stirred at room temperature overnight. The solvent was removed and recrystallized from MeOH / Et2O to obtain the product. 0.470 g of white solid, yield 83%. 1 H NMR (400MHz, Methanol-d4) δ8.24(d,J=8.9Hz,2H), δ7.69(d,J=7.9Hz,2H),7.65(d,J=8 .9Hz,2H).,7.22(d,J=7.9Hz,2H),7.02(s,2H),2.77(s,3H),2.41(s,3H),2.36(s,3H).

[0230] Example 60

[0231] Under nitrogen protection, VII (0.411 g, 1.0 mmol, 1.0 equiv.) was added to a mixed solution of 6 mL trifluoroethanol and 0.6 mL dichloromethane. (0.166 g, 1.0 mmol, 1.0 equiv.), stirred at room temperature overnight. The solvent was removed and recrystallized from MeOH / Et2O to obtain the product. 0.391 g of white solid, yield 70%. 1 H NMR(400MHz,Chloroform-d)δ10.07(s,1H),7.35(d,J=7.7Hz,2H),7.04(d,J=7.6Hz,2H),6 .94(s,1H),6.65(s,1H),3.88(s,3H),3.84(s,3H),2.57(s,3H),2.32(s,3H),2.26(s,3H).

[0232] Example 61

[0233] Under nitrogen protection, VII (0.411 g, 1.0 mmol, 1.0 equiv.) was added to 6 mL of hexafluoroisopropanol. (0.184 g, 1.0 mmol, 1.0 equiv.), stirred at room temperature overnight. The solvent was removed and recrystallized from MeOH / Et2O to obtain the product. 0.508 g of white solid, yield 88%. 1 H NMR(400MHz,Chloroform-d)δ7.85(s,1H),7.38(s,1H),7.33(d,J=7.9Hz,2H),7.02 (d,J=7.8Hz,2H),2.61(s,3H),2.32(s,3H),2.30(s,3H),2.19(s,3H),2.11(s,3H).

[0234] Example 62

[0235] Under nitrogen protection, VII (0.411 g, 1.0 mmol, 1.0 equiv.) was added to a mixed solution of 6 mL trifluoroethanol and 0.6 mL dichloromethane. (0.196 g, 1.0 mmol, 1.0 equiv.), stirred at room temperature overnight. The solvent was removed and recrystallized from MeOH / Et2O to obtain the product. 0.365 g of white solid, yield 62%. 1 H NMR(400MHz,Chloroform-d)δ10.08(s,1H),7.29(d,J=7.9Hz,2H),7.17(s,1H),7.03(d,J= 7.8Hz,2H),4.07(s,3H),3.90(s,3H),3.91(s,3H),2.61(s,3H),2.31(s,3H),2.29(s,3H).

[0236] Example 63

[0237] Under nitrogen protection, VII (0.411 g, 1.0 mmol, 1.0 equiv.) was added to a mixed solution of 6 mL trifluoroethanol and 0.6 mL dichloromethane. (0.376 g, 1.0 mmol, 1.0 equiv.), stirred at room temperature overnight. The solvent was removed and recrystallized from MeOH / Et2O to obtain the product. 0.546 g of white solid, yield 71%. 1H NMR(400MHz,Chloroform-d)δ8.01(s,1H),7.44(d,J=8.4Hz,1H),7.40–7.31( m,4H),7.14–7.07(m,1H),7.00(t,J=8.0Hz,4H),6.93(d,J=7.5Hz,1H),6.90– 6.85(m,1H),6.85–6.78(m,3H),4.37(s,3H),4.05(q,J=7.0Hz,2H),3.34(s,3 H),2.53(s,3H),2.28(s,3H),2.27(s,3H),1.39(t,J=7.0Hz,3H),1.23(s,6H).

[0238] Example 64

[0239] Under nitrogen protection, VII (0.205 g, 0.5 mmol, 1.0 equiv.) was added to 2 mL of trifluoroacetic acid. (0.078 g, 0.5 mmol, 1.0 equiv.), stirred at room temperature overnight. The solvent was removed and recrystallized from MeOH / Et2O to obtain the product. 0.422 g of white solid, yield 77%. 1 H NMR(400MHz,Chloroform-d)δ7.67(d,J=8.7Hz,2H),7.43(d,J=8.6Hz,2H),7.29 (d,J=7.6Hz,2H),7.05(d,J=7.8Hz,2H),2.62(s,3H),2.33(s,3H),2.28(s,3H).

[0240] Example 65

[0241] Under nitrogen protection, VII (0.411 g, 1.0 mmol, 1.0 equiv.) was added to 6 mL of hexafluoroisopropanol. (0.242 g, 1.0 mmol, 1.0 equiv.), stirred at room temperature overnight. The solvent was removed and recrystallized from MeOH / Et2O to obtain the product. 0.578 g of white solid, yield 91%. 1 H NMR (400MHz, Chloroform-d) δ7.51(s,1H),7.30(d,J=8.1Hz,2H),7.08(d,J=7.8Hz,2H),2.65(s,3H),2.38(s,3H),2.34(s,3H).

[0242] Example 66

[0243] Under nitrogen protection, VII (0.411 g, 1.0 mmol, 1.0 equiv.) was added to a mixed solution of 6 mL trifluoroethanol and 0.6 mL dichloromethane. (0.178 g, 1.0 mmol, 1.0 equiv.), stirred at room temperature overnight. The solvent was removed and recrystallized from MeOH / Et2O to obtain the product. 0.274 g of white solid, yield 48%. 1 H NMR(400MHz,Chloroform-d)δ7.58(s,1H),7.44(s,2H),7.08(d,J=7.5Hz,2H),6.90( s,1H),4.68(s,2H),4.59(s,2H),2.60(s,3H),2.48(s,3H),2.32(s,3H),2.29(s,3H).

[0244] Example 67

[0245] Under nitrogen protection, VII (0.205 g, 0.5 mmol, 1.0 equiv.) was added to 2 mL of trifluoroacetic acid. (0.039 g, 0.5 mmol, 1.0 equiv.), stirred at room temperature overnight. The solvent was removed and recrystallized from MeOH / Et2O to obtain the product. White solid 0.223 g, yield 95%. 1 H NMR(400MHz,Chloroform-d)δ7.81(d,J=7.9Hz,2H),7.44(t,J=7.5Hz,1H),7.29 (d,J=7.9Hz,4H),7.00(d,J=7.8Hz,2H),2.55(s,3H),2.28(s,3H),2.22(s,3H).

[0246] Example 68

[0247] Under nitrogen protection, VII (0.411 g, 1.0 mmol, 1.0 equiv.) was added to a mixed solution of 6 mL trifluoroethanol and 0.6 mL dichloromethane. (0.144 g, 1.0 mmol, 1.0 equiv.), stirred at room temperature overnight. The solvent was removed and recrystallized from MeOH / Et2O to obtain the product. 0.4385 g of white solid, yield 73%. 1H NMR (400MHz, DMSO-d6) δ8.29(t,J=8.8,6.5Hz,2H),7.46(d,J=7.8Hz,2H),7.38(t,J=73.3H z,1H),7.32(d,J=8.8Hz,2H),7.11(d,J=7.7Hz,2H),2.73(s,3H),2.36(s,3H),2.29(s,3H).

[0248] Example 69

[0249] Under nitrogen protection, VII (0.206 g, 0.5 mmol, 1.0 equiv.) was added to 2.0 mL of trifluoroacetic acid. (0.075 g, 0.5 mmol, 1.0 equiv.), stirred at room temperature overnight. The solvent was removed and recrystallized from MeOH / Et2O to obtain the product. White solid 0.231 g, yield 85%. 1 H NMR(400MHz,Chloroform-d)δ7.75(s,1H),7.58(d,J=7.7Hz,2H),7.18(d,J=9.0,1H),7.10(d,J=7 .7Hz,2H),6.97(d,J=8.9Hz,1H),3.92(s,3H),2.83(s,3H),2.64(s,3H),2.33(s,3H),2.32(s,3H).

[0250] Example 70

[0251] Under nitrogen protection, VII (0.205 g, 0.5 mmol, 1.0 equiv.) was added to a mixed solution of 6 mL trifluoroethanol and 0.6 mL dichloromethane. (0.063 g, 0.5 mmol, 1.0 equiv.), stirred at room temperature overnight. The solvent was removed and recrystallized from MeOH / Et2O to obtain the product. White solid 0.223 g, yield 81%. 1 H NMR (400MHz, Methanol-d4) δ8.20(d,J=8.6Hz,1H),7.62(d,J=8.2Hz,2H),7.60(d,J=2.6Hz,1 H),7.32(dd,J=8.5,2.4Hz,1H),7.19(d,J=8.0Hz,2H),2.69(s,3H),2.61(s,3H),2.33(s,6H).

[0252] Example 71

[0253] Under nitrogen protection, VII (0.411 g, 1.0 mmol, 1.0 equiv.) was added to a mixed solution of 6 mL trifluoroethanol and 0.6 mL dichloromethane. (0.216 g, 1.0 mmol, 1.0 equiv.), stirred at room temperature overnight. The solvent was removed and recrystallized from MeOH / Et2O to obtain the product. 0.4689 g of orange solid, yield 77%. 1 H NMR(400MHz,Chloroform-d)δ8.19(d,J=9.9Hz,1H),7.81(d,J=2.2Hz,1H),7.04(d,J=2.3Hz,1H),7.00(d,J= 7.9Hz,2H),6.89(d,J=7.8Hz,2H),6.50(d,J=9.8Hz,1H),4.35(s,3H),2.61(s,3H),2.29(s,3H),2.21(s,3H).

[0254] Example 72

[0255] Under nitrogen protection, VII (0.411 g, 1.0 mmol, 1.0 equiv.) was added to a mixed solution of 6 mL trifluoroethanol and 0.6 mL dichloromethane. (0.210 g, 1.0 mmol, 1.0 equiv.), stirred at room temperature overnight. The solvent was removed and recrystallized from MeOH / Et2O to obtain the product. White solid 0.4522 g, yield 75%. 1 HNMR(400MHz,Chloroform-d)δ8.57–8.54(m,1H),8.04(d,J=8.9Hz,1H),7.82(d,J=7.6Hz,1H),7.59(t,J=7.4Hz,1H),7.49(t,J= 7.5Hz,1H),7.36(d,J=7.3Hz,1H),7.31(d,J=7.0Hz,2H),6.96-6.92(m,3H),5.15(s,2H),2.65(s,3H),2.32(s,3H),2.20(s,3H).

[0256] Example 73

[0257] Under nitrogen protection, VII (0.411 g, 1.0 mmol, 1.0 equiv.) was added to a mixed solution of 6 mL trifluoroethanol and 0.6 mL dichloromethane. (0.352 g, 1.0 mmol, 1.0 equiv.), stirred at room temperature overnight. The solvent was removed and recrystallized from MeOH / Et2O to obtain the product. White solid 0.4842 g, yield 65%. 1 H NMR (400MHz, Methanol-d4) δ7.63(d,J=8.3Hz,2H),7.24(d,J=7.9Hz,2H),5.69(s,1H),4.43(s,3H),4.3 5(s,3H),4.01(d,J=36.3Hz,1H),3.69(s,3H),3.02–2.81(m,1H),2.73(s,3H),2.43(s,3H),2.38(s,3H).

[0258] Example 74

[0259] Under nitrogen protection, VII (0.411 g, 1.0 mmol, 1.0 equiv.) was added to a mixed solution of 6 mL trifluoroethanol and 0.6 mL dichloromethane. (0.234 g, 1.0 mmol, 1.0 equiv.), stirred at room temperature overnight. The solvent was removed and recrystallized from MeOH / Et2O to obtain the product. White solid 0.5204g, yield 83%. 1 H NMR(400MHz,Chloroform-d)δ7.99(dd,J=8.5,1.2Hz,2H),7.32(d,J=7.7Hz,2H),7.02(d, J=7.8Hz,2H),6.73(d,J=8.7Hz,1H),3.80(s,3H),2.61(s,3H),2.30(s,6H),1.31(s,12H).

[0260] Example 75

[0261] Under nitrogen protection, VII (0.411 g, 1.0 mmol, 1.0 equiv.) was added to a mixed solution of 6 mL trifluoroethanol and 0.6 mL dichloromethane. (0.112 g, 1.0 mmol, 1.0 equiv.), stirred at room temperature overnight. The solvent was removed and recrystallized from MeOH / Et2O to obtain the product. White solid 0.3441 g, yield 68%. 1H NMR (400MHz, Methanol-d4) δ7.64(d,J=8.2Hz,2H),7.41(d,J=3.5Hz,1H),7.22(d,J=7 .9Hz,2H),6.56(d,J=3.6Hz,1H),5.59(s,1H),2.73(s,3H),2.43(s,3H),2.36(s,3H).

[0262] Example 76

[0263] Under nitrogen protection, III (0.170 g, 0.5 mmol, 1.0 equiv.) was added to a mixed solution of 2 mL trifluoroacetic acid and 0.2 mL trifluoromethanesulfonic acid. (0.056 g, 0.5 mmol, 1.0 equiv.), stirred at room temperature overnight. The solvent was removed and recrystallized from MeOH / Et2O to obtain the product. White solid 0.210 g, yield 87%. 1 H NMR (400MHz, Methanol-d4) δ8.13(d,J=8.7Hz,2H),7.59(d,J=8.7Hz,2H),3.31(s,3H),2.76(s,3H),2.40(s,3H). 19 F NMR(376MHz,Methanol-d4)δ-80.09.

[0264] Example 77

[0265] Under nitrogen protection, III (0.170 g, 0.5 mmol, 1.0 equiv.) was added to a mixed solution of 2 mL trifluoroacetic acid and 0.2 mL trifluoromethanesulfonic acid. (0.073 g, 0.5 mmol, 1.0 equiv.), stirred at room temperature overnight. The solvent was removed and recrystallized from MeOH / Et2O to obtain the product. 0.165 g of white solid, yield 62%. 1 H NMR (400MHz, Methanol-d4) δ8.44(d,J=2.1Hz,1H),8.05(dd,J=8.7,2.2Hz,1H),7.70(d,J=8.7Hz,1H),2.75(s,3H),2.38(s,3H). 19 F NMR(376MHz,Chloroform-d)δ-80.09.

[0266] Example 78

[0267] Under nitrogen protection, III (0.170 g, 0.5 mmol, 1.0 equiv.) was added to a mixed solution of 2 mL trifluoroacetic acid and 0.2 mL trifluoromethanesulfonic acid. (0.087 g, 0.5 mmol, 1.0 equiv.), stirred at room temperature overnight. The solvent was removed and recrystallized from MeOH / Et2O to obtain the product. White solid 0.2044 g, yield 90%. 1 HNMR (400MHz, Methanol-d4) δ8.13(d,J=8.7Hz,2H),7.70(d,J=8.7Hz,2H),4.33(d,J=9.3Hz,1H),2.8 5(dt,J=8.1,4.7Hz,1H),2.77(s,3H),2.40(s,3H),1.75(dd,J=7.9,5.0Hz,1H),1.47(t,J=4.9Hz,1H). 19 F NMR(376MHz,Methanol-d4)δ-80.13.

[0268] Example 79

[0269] Under nitrogen protection, III (0.170 g, 0.5 mmol, 1.0 equiv.) was added to a mixed solution of 2 mL trifluoroacetic acid and 0.2 mL trifluoromethanesulfonic acid. (0.073 g, 0.5 mmol, 1.0 equiv.), stirred at room temperature overnight. The solvent was removed and recrystallized from MeOH / Et2O to obtain the product. White solid 0.1886 g, yield 58%. 1 H NMR (400MHz, Methanol-d4) δ8.56(s,1H),8.36(d,J=8.2Hz,1H),8.00(d,J=7.9Hz,1H),7.73(t,J=8.0Hz,1H),2.73(s,3H),2.36(s,3H). 19 F NMR(376MHz,Methanol-d4)δ-64.36,-80.12.

[0270] Example 80

[0271] Under nitrogen protection, III (0.170 g, 0.5 mmol, 1.0 equiv.) was added to a mixed solution of 2 mL trifluoroacetic acid and 0.2 mL trifluoromethanesulfonic acid. (0.156 g, 0.5 mmol, 1.0 equiv.), stirred at room temperature overnight. The solvent was removed and recrystallized from MeOH / Et2O to obtain the product. 0.232 g of white solid, yield 68%. 1 HNMR(400MHz,Methanol-d4)δ8.23(s,2H),2.78(s,3H),2.44(s,3H). 19 F NMR(376MHz,Methanol-d4)δ-80.13.

[0272] Example 81

[0273] Under nitrogen protection, III (0.170 g, 0.5 mmol, 1.0 equiv.) was added to a mixed solution of 2 mL trifluoroacetic acid and 0.2 mL trifluoromethanesulfonic acid. (0.105 g, 0.5 mmol, 1.0 equiv.), stirred at room temperature overnight. The solvent was removed and recrystallized from MeOH / Et2O to obtain the product. 0.232 g of white solid, yield 82%. 1 H NMR (400MHz, Methanol-d4) δ8.04(s,1H),7.91(m,2H),7.81(s,1H),7.68(d,J=7.8Hz,2H),7.16(s,1H),2.76(s,3H),2.40(s,6H),2.40(s,3H). 19 F NMR(376MHz,Methanol-d4)δ-80.14.

[0274] Example 82

[0275] Under nitrogen protection, III (0.170 g, 0.5 mmol, 1.0 equiv.) was added to a mixed solution of 2 mL trifluoroacetic acid and 0.2 mL trifluoromethanesulfonic acid. (0.098 g, 0.5 mmol, 1.0 equiv.), stirred at room temperature overnight. The solvent was removed and recrystallized from MeOH / Et2O to obtain the product. 0.258 g of white solid, yield 84%. 1 H NMR (400MHz, Methanol-d4) δ8.96(d,J=2.4Hz,1H),8.48(dd,J=9.0,2.4Hz,1H),8.25(dd,J=8.1,1.5Hz,1H),7. 88(dd,J=8.7,7.2Hz,1H),7.76(d,J=9.0Hz,1H),7.63(d,J=8.0Hz,1H),7.50(m,1H),2.80(s,3H),2.43(s,3H). 19F NMR(376MHz,Methanol-d4)δ-80.12.

[0276] Example 83

[0277] Under nitrogen protection, III (0.170 g, 0.5 mmol, 1.0 equiv.) was added to a mixed solution of 2 mL trifluoroacetic acid and 0.2 mL trifluoromethanesulfonic acid. (0.066 g, 0.5 mmol, 1.0 equiv.), stirred at room temperature overnight. The solvent was removed and recrystallized from MeOH / Et2O to obtain the product. 0.1932 g of white solid, yield 77%. 1 H NMR (400MHz, Methanol-d4) δ7.73(s,2H),2.75(s,3H),2.73(s,3H),2.44(s,3H),2.34(s,3H). 19 F NMR(376MHz,Methanol-d4)δ-80.14.

[0278] Example 84

[0279] Under nitrogen protection, III (0.170 g, 0.5 mmol, 1.0 equiv.) was added to a mixed solution of 2 mL trifluoroacetic acid and 0.2 mL trifluoromethanesulfonic acid. (0.080 g, 0.5 mmol, 1.0 equiv.), stirred at room temperature overnight. The solvent was removed and recrystallized from MeOH / Et2O to obtain the product. 0.219 g of white solid, yield 83%. 1 H NMR (400MHz, Methanol-d4) δ9.44(d,J=8.7Hz,1H),9.19(d,J=4.1Hz,1H),8.51(d,J=9. 5Hz,1H),8.25(dd,J=11.7,6.5Hz,2H),4.29(d,J=1.0Hz,3H),2.71(s,3H),2.34(s,3H). 19 FNMR(376MHz,Methanol-d4)δ-80.11.

[0280] Example 85

[0281] Under nitrogen protection, III (0.170 g, 0.5 mmol, 1.0 equiv.) was added to a mixed solution of 2 mL trifluoroacetic acid and 0.2 mL trifluoromethanesulfonic acid. (0.057 g, 0.5 mmol, 1.0 equiv.), stirred at room temperature overnight. The solvent was removed and recrystallized from MeOH / Et2O to obtain the product. White solid 0.2061 g, yield 85%. 1 H NMR (400MHz, Methanol-d4) δ8.55–8.04(m,1H),7.43(t,J=8.9Hz,1H),7.28–7.16(m,1H),2.74(s,3H),2.41(s,3H) 19 F NMR(376MHz, Methanol-d4)δ-80.10,-94.43,-100.83.

[0282] Example 86

[0283] Under nitrogen protection, III (0.170 g, 0.5 mmol, 1.0 equiv.) was added to a mixed solution of 2 mL trifluoroacetic acid and 0.2 mL trifluoromethanesulfonic acid. (0.090 g, 0.5 mmol, 1.0 equiv.), stirred at room temperature overnight. The solvent was removed and recrystallized from MeOH / Et2O to obtain the product. 0.148 g of white solid, yield 54%. 1 H NMR (400MHz, Methanol-d4) δ8.75(s,1H),8.10(s,1H),2.75(s,4H),2.41(s,4H).

[0284] Example 87

[0285] Under nitrogen protection, III (0.170 g, 0.5 mmol, 1.0 equiv.) was added to a mixed solution of 2 mL trifluoroacetic acid and 0.2 mL trifluoromethanesulfonic acid. (0.073 g, 0.5 mmol, 1.0 equiv.), stirred at room temperature overnight. The solvent was removed and recrystallized from MeOH / Et2O to obtain the product. White solid 0.243 g, yield 94%. 1 HNMR(400MHz, Methanol-d4)δ8.49(d,J=2.3Hz,1H),8.30–8.27(m,1H),7.96(d,J= 9.7Hz,1H),7.46(d,J=8.9Hz,1H),6.56(d,J=9.7Hz,1H),2.77(s,1H),2.40(s,1H).

[0286] Example 88

[0287] Under nitrogen protection, III (0.170 g, 0.5 mmol, 1.0 equiv.) was added to a mixed solution of 3 mL trifluoroacetic acid and 0.3 mL trifluoromethanesulfonic acid. (0.115 g, 0.5 mmol, 1.0 equiv.), stirred at room temperature overnight. The solvent was removed and recrystallized from MeOH / Et2O to obtain the product. 0.243 g of white solid, yield 81%. 1 HNMR (400MHz, Methanol-d4) δ8.61–8.59(m,1H),8.48(d,J=2.3Hz,1H),3.93(s,3H),2.75(s,3H),2.39(s,3H). 19 F NMR(376MHz,Methanol-d4)δ-76.17.

[0288] Application of iodized salt

[0289] Application 1:

[0290]

[0291] Under nitrogen protection, 0.164 g (0.3 mmol, 1.0 equiv.) was added to 3.0 mL of toluene, and then 0.117 g of cesium carbonate (0.36 mmol, 1.2 equiv.) was added. (38 mg, 0.36 mmol, 1.2 equiv.). Heat to 130 ° C and stir for 4 hours. Stop heating and remove toluene. Pass through the column with petroleum ether: dichloromethane in a ratio of 9:1 to obtain The product was a colorless oily liquid (72.6 mg) with a yield of 93%. No isoxazole was isolated from the product, indicating that the coupling method was highly selective and almost completely produced the biphenyl substituted product. 1 H NMR(400MHz,Chloroform-d)δ7.62–7.54(m,4H),7.45(dd,J=8.5,6.9Hz,2H),7.38–7.3 2(m,1H),7.21–7.15(m,2H),7.07(d,J=8.7Hz,2H),7.00(d,J=8.5Hz,2H),2.37(s,3H).

[0292] Compound data:

[0293]

[0294] Colorless oily liquid, 49.0 mg, yield 70%. 1H NMR(400MHz,Chloroform-d)δ7.85–7.80(m,2H),7.71–7.67(m,1H),7.42(dddd,J=21.0,8.1, 6.8,1.4Hz,2H),7.31–7.23(m,2H),7.19(d,J=8.2Hz,2H),7.00(d,J=8.5Hz,2H),2.38(s,3H).

[0295]

[0296] Colorless oily liquid, 48.6 mg, yield 72%. 1 H NMR (400MHz, Chloroform-d) δ7.15(dd,J=18.2,8.3Hz,4H),6.92(dd,J=8.6,3.0Hz,4H),2.90(p,J=6.9Hz,1H),2.33(s,6H),1.25(d,J=6.9Hz,1H).

[0297]

[0298] Colorless oily liquid, 62.8 mg, yield 91%. 1 H NMR (400MHz, Chloroform-d) δ7.90 (dd, J=8.2, 1.7Hz, 1H), 7.44 (ddd, J=8.7, 7. 3,1.7Hz,1H),7.18–7.10(m,3H),6.94(td,J=7.6,6.8,1.7Hz,3H),2.33(s,3H).

[0299]

[0300] Colorless oily liquid, 62.1 mg, yield 95%. 1 H NMR (400MHz, Chloroform-d) δ7.23 (d, J=9.0Hz, 2H), 7.17–7.08 (m, 2H), 6.89 (dd, J=8.7, 1.5Hz, 4H), 2.32 (s, 3H).

[0301]

[0302] Colorless oily liquid, 41.6 mg, yield 65%. 1H NMR (400MHz, Chloroform-d) δ7.09 (d, J = 8.1 Hz, 2H), 6.95 (d, J = 9.1 Hz, 2H), 6.89–6.82 (m, 4H), 3.79 (s, 3H), 2.31 (s, 3H).

[0303]

[0304] Colorless oily liquid, 62.1 mg, yield 95%. 1 H NMR (400MHz, Chloroform-d) δ7.93(d,J=8.4Hz,2H),7.19(d,J=8.0Hz,2H),7.00–6.95(m,4H),2.57(s,3H),2.36(s,3H).

[0305] Application 2:

[0306]

[0307] Under nitrogen protection, (0.330 g, 0.5 mmol, 1.0 equiv.) was added to 5.0 mL of toluene, followed by PhONa (58.0 mg, 0.5 mmol, 1.0 equiv.) and CF3SO3Na (86.0 mg, 0.5 mmol, 1.0 equiv.). Heat to 120°C and stir for 4 hours. Stop heating and remove the toluene. Pass the mixture through a column with petroleum ether and dichloromethane in a ratio of 9:1 to obtain 194.3 mg of colorless oily liquid, yield 83%. 1 H NMR(400MHz,Chloroform-d)δ7.33(t,J=8.6Hz,2H),7.24(t,J=9.0,3H),7.14–7.04(m,3H),7.02–6.94 (m,4H),6.90(m,5H),4.42(s,2H),4.01(q,J=6.9Hz,2H),3.39(s,2H),1.27(s,6H),1.24(t,J=7.0,3H).

[0308]

[0309] Colorless oily liquid, 0.5 mmol scale, 110.4 mg, yield 84%. 1 H NMR (400MHz, Chloroform-d) δ7.34 (ddd, J=8.6, 7.4, 0.9Hz, 1H), 7.09 (td, J=7.4, 1.0Hz, 1H), 7.04–6.97 (m, 2H).

[0310] Application three:

[0311]

[0312] Under nitrogen protection, 0.156 g (0.30 mmol, 1.0 equiv.) was added to 3.0 mL of N, N-dimethylformamide, and then added (40.5 mg, 0.36 mmol, 1.2 equiv.), CF3SO3Na (62 mg, 0.36 mmol, 1.0 equiv.). Heat to 130°C and stir for 5 hours. Stop heating and extract with ethyl acetate (10 mL*3). Combine the organic phases and dry them over anhydrous magnesium sulfate and filter. Pass the column with petroleum ether: dichloromethane in a ratio of 85:15 to obtain Colorless oily liquid, 76.9 mg, yield 89%. 1 H NMR(400MHz,Chloroform-d)δ7.78(d,J=9.0Hz,2H),7.70(dd,J=8.2,1.2Hz,1H),7.58( d,J=2.3Hz,1H),7.51–7.41(m,2H),7.37–7.30(m,2H),7.01–6.92(m,3H),3.93(s,3H).

[0313] No isoxazole substituted products were isolated from the above experimental products, indicating that the coupling method has good selectivity and almost completely produces naphthyl substituted products.

[0314] Application 4:

[0315]

[0316] Under nitrogen protection, 0.156 g (0.30 mmol, 1.0 equiv.) was added to 3.0 mL of N, N-dimethylformamide, and then added (60.9 mg, 0.36 mmol, 1.2 equiv.), CF3SO3Na (62 mg, 0.36 mmol, 1.0 equiv.). Heat to 130°C and stir for 5 hours. Stop heating and extract with ethyl acetate (10 mL*3). Combine the organic phases and dry them over anhydrous magnesium sulfate and filter. Pass the column with petroleum ether: dichloromethane in a ratio of 85:15 to obtain Colorless oily liquid, 34.5 mg, yield 75%. 1H NMR(400MHz,Chloroform-d)δ7.57(d,J=7.7Hz,2H),7.52(d,J=8.4Hz,2H),7.41(t,J=7.7Hz,2H) ,7.38–7.34(m,1H),7.29(t,J=7.4Hz,1H),7.23–7.18(m,2H),6.89(d,J=4.5Hz,3H),3.89(s,3H).

[0317] Application 5:

[0318]

[0319] Under nitrogen protection, (0.321 g, 0.50 mmol, 1.0 equiv.) was added with 3.0 mL of N,N-dimethylformamide, and then added (63 mg, 0.5 mmol, 1.0 equiv.), CF3SO3Na (86 mg, 0.5 mmol, 1.0 equiv.). Heat to 130 ° C and stir for 5 hours. Stop heating and extract with ethyl acetate (10 mL * 3). Combine the organic phases and dry them over anhydrous magnesium sulfate and filter. Pass the column with petroleum ether: dichloromethane = 85:15 ratio to obtain White solid, 0.5mmol scale, 133.2mg, yield 75%. 1 H NMR(400MHz,Chloroform-d)δ7.03–6.98(m,2H),6.96(s,1H),6.68–6.63(m,3H),3 .93(s,2H),2.26(s,3H),2.19(s,3H),2.16(s,3H),1.83–1.73(m,4H),1.27(s,6H).

[0320]

[0321] Brown oily liquid, 0.5 mmol scale, 166.0 mg, yield 69%. 1H NMR(400MHz,Chloroform-d)δ7.37–7.29(m,3H),7.26(d,J=15.7Hz,2H),7.10(t,J=7.6Hz,1H),7.05(s,3H),7.03–6.98(m,3H),6.94(t,J=2.0Hz ,1H),6.90(dd,J=8.1,2.5Hz,1H),6.78(s,2H),4.45(s,2H),4.07(q,J=7 .0Hz,2H),3.40(s,2H),2.30(s,3H),1.43(t,J=7.0Hz,3H),1.28(s,6H).

[0322] Application six:

[0323]

[0324] Under nitrogen protection, (0.640 g, 1.0 mmol, 1.0 equiv.) was added with 8.0 mL of trifluoroethanol and then added (119 mg, 1.0 mmol, 1.0 equiv.), CF3SO3Na (172 mg, 1.0 mmol, 1.0 equiv.). Heat to 130°C and stir for 5 hours. Stop heating and extract with ethyl acetate (10 mL*3). Combine the organic phases and dry them over anhydrous magnesium sulfate and filter. Pass the column with petroleum ether: dichloromethane in a ratio of 85:15 to obtain Colorless oily liquid, 281.1 mg, yield 77%. 1 H NMR(400MHz,Chloroform-d)δ7.42(d,J=8.9Hz,2H),7.22(d,J=9.0Hz,2H),7.18(d,J=7.3Hz,1H),7.11–7.05(m,2 H),7.02(d,J=8.9Hz,2H),6.88(d,J=8.9Hz,2H),6.75(t,J=6.9,1H),3.94(t,J=8.4Hz,2H),3.14(t,J=8.4Hz,2H).

[0325]

[0326] Yellow oily liquid, 0.5 mmol scale, 192.4 mg, yield 78% 1H NMR(400MHz,Chloroform-d)δ7.47(t,J=2.4Hz,1H),7.38-7.32(m,2H),7.27(dt,J=8.1, 3.9Hz,1H),7.13(dt,J=14.2,5.2Hz,3H),7.01(dd,J=22.5,6.8Hz,5H),6.94-6.88(m,2H) ,6.73-6.64(m,1H),δ6.55(d,J=5.6Hz,1H).,4.50-4.48(s,2H),4.14-4.03(q,J=7.0Hz,2 H), 3.97 (s, 2H), 3.45 (s, 2H), 3.17 (t, J = 8.7Hz, 2H), δ1.39 (t, J = 5.9Hz, 3H), 1.33 (s, 6H).

[0327] Application seven:

[0328]

[0329] Under nitrogen protection, 10.8 mg of NaH was added to 1.0 mL of N,N-dimethylformamide and then added at 0°C. (0.156 g, 0.30 mmol, 1.0 equiv.), ten minutes later, add (62 mg, 0.36 mmol, 1.2 equiv.) and 2.0 mL of N,N-dimethylformamide. Warm to room temperature and stir for 24 hours. Stop the reaction, add 5 mL of water, extract with ethyl acetate (10 mL*3), combine the organic phases, dry over anhydrous magnesium sulfate, and filter. Pass through a column with petroleum ether: ethyl acetate = 95:5 ratio to obtain a colorless oily liquid product. 78.3 mg, yield 87%. 1 H NMR(400MHz,Chloroform-d)δ7.81(dd,J=8.7,2.8Hz,4H),7.52(dd,J=8.7,2.0Hz,1H ),7.47(dd,J=6.4,3.1Hz,2H),4.29–4.21(m,4H),1.98(s,1H),1.26(t,J=7.1Hz,6H).

[0330] No isoxazole substituted products were isolated from the above experimental products, indicating that the coupling method has good selectivity and almost completely produces naphthyl substituted products.

[0331] Other similar compounds can be prepared in the same way.

[0332]

[0333] Colorless oily liquid, 38.5 mg, yield 70%. 1 H NMR (400MHz, Chloroform-d) δ7.61–7.52(m,4H),7.46–7.38(m,4H),7.35–7.29(m,1H),4.24(tdd,J=7.6,6.8,1.7Hz,4H),1.89(s,3H),1.28–1.24(m,6H).

[0334]

[0335] Colorless oily liquid, 0.5mmol scale, 233.0mg, yield 85% 1 H NMR(400MHz,Chloroform-d)δ7.35–7.30(m,2H),7.26(s,1H),7.22(dd,J=8.6 ,2.4Hz,1H),7.12–7.05(m,2H),7.03–6.96(m,3H),6.95–6.87(m,2H),6.77(d ,J=8.5Hz,1H),4.43(s,2H),4.24–4.19(m,4H),3.98(q,J=7.0Hz,2H),3.38(s ,2H),1.79(s,3H),1.34(t,J=6.9Hz,3H),1.29(s,6H),1.24(t,J=7.1Hz,6H).

[0336] Application 8:

[0337]

[0338] Under nitrogen protection, 0.328g (0.6mmol, 2.0equiv.) was added to 3.0mL of toluene, followed by 0.046g of cesium carbonate (0.3mmol, 1.0equiv.). Heat to 120°C and stir for 2 hours. Stop heating and remove the toluene. Pass the mixture through a column with petroleum ether: dichloromethane in a ratio of 9:1 to obtain 49.0 mg of colorless oily liquid, yield 94%.

[0339] Compound data:

[0340] 1 H NMR (400MHz, Chloroform-d) δ7.56(dd,J=6.2,2.6Hz,4H),7.45(t,J=7.5Hz,2H),7.36(t,J=7.2Hz,1H),7.14(t,J=8.6Hz,2H).

[0341] Other similar compounds can be prepared in the same way.

[0342]

[0343] (Known compound) Colorless oily liquid, 62.1 mg, yield 95%. 1 H NMR (400MHz, Chloroform-d) δ7.62(d,J=8.8Hz,1H),7.39–7.31(m,2H),7.15–7.10(m,1H),7.06–6.96(m,4H),6.78(d,J=8.8Hz,1H).

[0344] Application nine:

[0345]

[0346] Under nitrogen protection, Add 1,2-dichloroethane (0.330 g, 0.5 mmol, 1.0 equiv.) to 5.0 mL of 1,2-dichloroethane, followed by KSCN (48.6 mg, 0.5 mmol, 1.0 equiv.). Heat to 80°C and stir for 2 hours. Remove from heat and remove toluene. Pass through a column with petroleum ether:dichloromethane in a ratio of 9:1 to obtain 205.7 mg of a colorless oil (94% yield).

[0347]

[0348] Yellow oily liquid, 0.5mmol scale, 205.7mg. 1 H NMR(400MHz,Chloroform-d)δ7.53(d,J=2.3Hz,1H),7.38–7.29(m,3H),7.27(d,J=8.3Hz,1H),7.11(s,1H),7.06–6.97(m,3H),6 .91(d,J=5.1Hz,2H),6.81(d,J=8.6Hz,1H),4.46(s,2H),4.10(q,J=7.0Hz,2H),3.42(s,2H),1.45(t,J=7.0Hz,3H),1.32(s,6H).

[0349] Application 10:

[0350]

[0351] Under nitrogen protection, (0.280 g, 0.5 mmol, 1.0 equiv.) was added to 5.0 mL of toluene, followed by 0.487 g of cesium carbonate (1.5 mmol, 3.0 equiv.) and 0.295 g of nonafluoro-tert-butanol (1.25 mmol, 2.5 equiv.). Heat to 120°C and stir for 2 hours. Stop heating and remove the toluene. Pass the mixture through a column with petroleum ether: dichloromethane in a ratio of 2:1 to obtain 30.1 mg of white solid, yield 15%.

[0352] Compound data:

[0353] White solid, yield 15%. mp: 54-56 ℃. 1 H NMR(400MHz,Chloroform-d)δ6.08(s,2H),3.79(s,3H),3.79(s,6H). 19 F NMR(376MHz,Chloroform-d)δ-69.69.

[0354] Application 11:

[0355]

[0356] Under nitrogen protection, (0.320 g, 0.5 mmol, 1.0 equiv.) was added to 3.0 mL of toluene, followed by 0.652 g of cesium carbonate (2.0 mmol, 2.0 equiv.) and 0.200 g of trifluoroethanol (2.0 mmol, 2.0 equiv.). Heat to 120°C and stir for 4 hours. Stop heating and remove the toluene. Pass the mixture through a column with petroleum ether and dichloromethane in a ratio of 2:1 to obtain 222.7 mg of white solid, yield 64%. 1 H NMR (400MHz, Chloroform-d) δ7.41 (d, J = 8.7Hz, 2H), 6.96 (q, J = 9.1Hz, 4H), 6.83 (d, J = 8.8Hz, 2H), 4.34 (q, J = 8.1Hz, 2H). 19 F NMR (376MHz, Chloroform-d) δ-74.03 (t, J=8.2Hz).

[0357]

[0358] Colorless oil, 0.5 mmol scale, 154.2 mg, yield: 65%. 1H NMR(400MHz,Chloroform-d)δ7.35(t,J=8.0Hz,2H),7.28(t,J=7.9Hz,1H),7.12(t,J=7.9Hz,1H),7.08–6.97(m,5H),6.92(d,J=13.8Hz ,2H),6.84(d,J=8.4Hz,1H),4.46(s,2H),4.39(q,J=8.6Hz,2H),4.06(q,J=7.0Hz,2H),3.42(s,2H),1.44(t,J=7.0Hz,3H),1.31(s,6H). 19 F NMR (376MHz, Chloroform-d) δ-74.32 (t, J = 17.0Hz).

[0359] Application 12:

[0360]

[0361] Under nitrogen protection, (0.307 g, 0.5 mmol, 1.0 equiv.) was added to 5.0 mL of toluene, followed by 0.256 g of potassium diphenylphosphite (0.5 mmol, 1.0 equiv.). Et3N (50 mg, 0.5 mmol, 1.0 equiv.) was heated to 120°C and stirred for 12 hours. The heating was stopped and the toluene was removed by vortexing. The product was passed through a column with methanol:dichloromethane in a ratio of 40:1 to obtain

[0362] 162 mg of white solid, 0.5 mmol scale, yield 74%. 1 H NMR(400MHz,Chloroform-d)δ7.87(dd,J=12.4,7.7Hz,4H),7.56(t,J=7.4Hz,2H),7.48(dd,J=7.2,3.4Hz,4H),6. 51(s,2H),5.12(s,1H),4.93(dd,J=8.7,5.2Hz,1H),4.06(m,2H),3.74(t,J=8.8Hz,1H),3.58(m,1H),1.98(s,6H).

[0363]

[0364] White solid 161.9 mg, 0.5 mmol scale, yield 74%. 1H NMR(400MHz,Chloroform-d)δ7.90–7.84(m,4H),7.56–7.51(m,2H),7.48–7.42(m,4H),6.96(s ,1H),6.53(s,1H),3.85(t,J=5.7Hz,2H),2.20(s,3H),2.04(s,3H),1.70(m,4H),1.22(s,6H).

[0365]

[0366] Colorless oily liquid, 0.5mmol scale, 183.4mg, yield 62.1%. 1 H NMR(400MHz,Chloroform-d)δ7.99–7.91(m,4H),7.47(d,J=7.6Hz,2H),7.41(dd,J=6.2,3.7,4H),7.37–7.31(m,3H),7.25(m,1H),7.12–7.07(m ,1H),7.04–6.94(m,4H),6.88(s,2H),6.72(d,J=8.6Hz,1H),4.35(s,2H ),3.96(q,J=7.0,2H),3.32(s,2H),1.39(t,J=6.9Hz,3H),1.20(s,6H).

[0367] Application 13:

[0368]

[0369] Under nitrogen protection, (0.307g, 0.5mmol, 1.0equiv.) was added to 5.0mL of toluene, followed by 0.082g of sodium benzenesulfinate (0.55mmol, 1.0equiv.). CF3SO3Na (86.0mg, 0.5mmol, 1.0equiv.) was heated to 120°C and stirred for 12 hours. The heating was stopped and the toluene was removed by vortexing. The product was passed through a column with methanol:dichloromethane in a ratio of 40:1 to obtain 148 mg of white solid, yield 82%. 1 H NMR(400MHz,Chloroform-d)δ7.76(d,J=8.0Hz,2H),7.52(t,J=7.3Hz,1H),7.46(t,J=7.5Hz, 2H), 6.65 (s, 2H), 4.97 (m, 1H), 4.16 (m, 2H), 3.79 (t, J = 8.7Hz, 1H), 3.56 (m, 1H), 2.58 (s, 6H).

[0370] Other similar compounds can be prepared in the same way.

[0371]

[0372] Colorless oily liquid, 0.5mmol scale, 203.8mg, yield 79%. 1 H NMR(400MHz,Chloroform-d)δ8.18(d,J=2.5Hz,1H),7.95(d,J=7.7Hz,2H),7.57–7.38(m,4H),7.35–7.24(m,3H),7.11(dd,J=7.4,1.1Hz,1H), 7.03–6.96(m,3H),6.94–6.87(m,2H),6.75(d,J=8.7Hz,1H),4.47(s,2H ),3.93(q,J=7.0Hz,2H),3.46(s,2H),1.35(s,6H),1.26(t,J=6.2,3H).

[0373]

[0374] (Known compound) Colorless oily liquid, 254.2 mg, yield 82%. 1 H NMR (400MHz, Chloroform-d) δ7.97–7.79(m,4H),7.57–7.44(m,3H),7.41–7.32(m,2H),7.20(t,J=7.4Hz,1H),7.05–6.94(m,4H).

[0375]

[0376] Yellow solid 71.0 mg, yield 46%. 1 HNMR(400MHz,Chloroform-d)δ7.94(d,J=8.1Hz,2H),7.53–7.47(m,1H),7.47-7.41(m,2H),6.06(s,2H),3.81(s,3H),3.75(s,6H).

[0377] Application 14:

[0378]

[0379] Under nitrogen protection, (0.641 g, 1.0 mmol, 1.0 equiv.) was added to 5.0 mL of toluene, followed by 0.118 g of sodium methanesulfinate (1.0 mmol, 1.0 equiv.). CF3SO3Na (172 mg, 1.0 mmol, 1.0 equiv.) was heated to 120°C and stirred for 12 hours. The heating was stopped and the toluene was removed by vortexing. The product was passed through a column with methanol:dichloromethane in a ratio of 40:1 to obtain 125.5 mg of yellow solid, yield 77%. 1 H NMR (400MHz, Chloroform-d) δ7.89 (d, J = 8.8 Hz, 2H), 7.52 (d, J = 8.8 Hz, 2H), 7.08 (d, J = 8.8 Hz, 2H), 6.96 (d, J = 8.8 Hz, 2H), 3.05 (s, 2H).

[0380]

[0381] Colorless oily liquid, 0.5 mmol scale, 181.6 mg, 80% yield. 1 H NMR (400MHz, DMSO-d6) δ7.74(s,1H),7.61(d,J=8.7,1H),7.36(t,J=7.7Hz,2H),7.29(s,1H),7.15–7.09(m,2H),6.97(d,J=7.8Hz,3H ), 6.86 (d, J = 8.1, 1H), 6.82 (s, 1H), 4.41 (s, 2H), 4.15 (q, J = 7.0Hz, 2H), 3.38 (s, 2H), 3.20 (s, 3H), 1.34 (t, J = 7.0Hz, 3H), 1.22 (s, 6H).

[0382] Application 15:

[0383]

[0384] Under nitrogen protection, 0.373g (0.5mmol, 1.0equiv.) was added to 3.0mL of toluene, followed by 0.160g of potassium benzoate (1.0mmol, 2.0equiv.) and CF3SO3Na (86mg, 0.5mmol, 1.0equiv.). The mixture was heated to 120°C and stirred for 12 hours. The heating was stopped and the toluene was removed by vortexing. The product was passed through a column with petroleum ether and ethyl acetate in a ratio of 2:1 to obtain 148 mg of white solid, yield 82%. 1H NMR(400MHz,Chloroform-d)δ8.22(d,J=7.4Hz,2H),7.69(t,J=7.4Hz,1H),7.55(t,J=7.7Hz,2H),5.58(s,1H),4.09(s, 3H), 4.03 (s, 3H), 3.68 (s, 3H), 2.97 (d, J = 16.1Hz, 1H), 2.90 (m, 1H), 2.48 (dd, J = 16.2, 4.4Hz, 1H), 0.99 (d, J = 6.4Hz, 3H).

[0385] Other similar compounds can be prepared in the same way.

[0386]

[0387] Colorless oily liquid, 0.5mmol scale, 187.4mg, yield 75.5%. 1 H NMR(400MHz,Chloroform-d)δ8.22(d,J=6.6Hz,2H),7.62(d,J=7.5Hz,1H),7.54–7.46(m,2H),7.35–7.30(m,2H),7.26(d,J=2.0Hz,1H),7.20(m,1H),7.1 5(m,1H),7.12–7.07(m,1H),7.01(d,J=6.4Hz,3H),6.96–6.88(m,3H),4.45( s,2H),4.03(q,J=7.0,2H),3.42(s,2H),1.32(s,6H),1.28(t,J=7.0Hz,3H).

[0388]

[0389] (Known compound) white solid, 118.9 mg, yield 82%. 1 H NMR(400MHz,Chloroform-d)δ8.21(dd,J=8.2,1.6Hz,2H),7.68–7.59(m,1H),7.52(t,J=7.7Hz ,2H),7.40–7.29(m,2H),7.19(d,J=8.8Hz,2H),7.12(td,J=7.3,1.1Hz,1H),7.09–7.02(m,4H).

[0390] Application 16:

[0391]

[0392] Under nitrogen protection, (0.330 g, 0.5 mmol, 1.0 equiv.) was added to 5.0 mL of toluene, followed by TsONa (97.0 mg, 0.5 mmol, 1.0 equiv.) and CF3SO3Na (86.0 mg, 0.5 mmol, 1.0 equiv.). Heat to 120°C and stir for 4 hours. Stop heating and remove the toluene. Use petroleum ether: dichloromethane = 9:1 to obtain Colorless oily liquid, 181.6 mg, yield 80%. 1 H NMR(400MHz,Chloroform-d)δ7.73(d,J=8.1Hz,2H),7.39–7.29(m,4H),7.20(d,J=9.0Hz,2H),7.14(t,J=7.4,1H),7.07–6.98(m,3H), 6.91(d,J=8.9,1H),6.82–6.75(m,3H),4.30(s,2H),3.99(q,J=7.0,2H),3.28(s,2H),2.44(s,3H),1.39(t,J=7.0Hz,3H),1.24(s,6H).

[0393] Recovery of 1,3-dimethyl 4-iodoisoxazole XII

[0394] Under nitrogen protection, 0.176 g (0.3 mmol, 1.0 equiv.) was added to 3.0 mL of toluene, and then 0.117 g of cesium carbonate (0.36 mmol, 1.2 equiv.) was added. 38 μl (0.36 mmol, 1.2 equiv.). Heat to 130°C and stir for 4 hours. Stop heating and remove toluene. After isolating the coupling product, the residue is column-filtered with petroleum ether:dichloromethane in a ratio of 7:3 to obtain 46.7 mg of compound XII as a white solid (70% yield). The latter is used in a cyclic reaction to prepare the hypervalent iodine reagent of the present invention. 1 H NMR(400MHz,Chloroform-d)δ2.43(s,3H),2.25(s,3H).

[0395] All documents mentioned in this application are incorporated herein by reference, just as if each document were incorporated herein by reference individually. It should also be understood that after reading the above teachings of the present invention, those skilled in the art may make various changes or modifications to the present invention, and that such equivalents also fall within the scope of the claims appended hereto.

Claims

1. A hypervalent iodine reagent, characterized in that The reagent comprises an effective amount of a compound having the structure of the following formula I: In the formula, R is a group selected from the following groups: substituted or unsubstituted C6-C30 aryl, substituted or unsubstituted 5-30 membered heteroaryl; The substituted group is substituted by one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, C1-C4 haloalkyl, C1-C4 haloalkoxy, C6-C10 aryl, 5-12 membered heteroaryl, C6-C10 aryloxy, 5-12 membered heteroaryloxy, benzyloxy, CN, NO2, C(O)R 1 、O(CH2) p R 1 、C(O)OR 1 ; Among them, R 1 Selected from the group consisting of hydrogen, C1-C4 alkyl, C6-C10 aryl, 5-12 membered heteroaryl, C3-C8 cycloalkyl, 5-12 membered heterocyclyl; The above-mentioned alkyl, alkoxy, aryl, heteroaryl, cycloalkyl, heterocyclyl, aryloxy, heteroaryloxy or benzyloxy is optionally substituted by one or more substituents selected from the group consisting of: =O, halogen, COOH, C1-C4 alkyl, C1-C4 alkoxy, -CH(Ph)2, p is selected from the group consisting of 0, 1, 2, 3, or 4; And when R is phenyl, A is not 2. The hypervalent iodine reagent according to claim 1, wherein The aryl group is selected from the following group: phenyl, naphthyl; the heteroaryl group is selected from the following group: pyrrolyl, pyridyl, furyl.

3. A hypervalent iodine reagent, characterized in that The reagent comprises an effective amount of a compound having the structure of the following formula I: And the compound of formula I is selected from the following group:

4. The method for preparing a hypervalent iodine reagent according to any one of claims 1 to 3, wherein: The method comprises the steps of: In an inert solvent, in the presence of compounds IV and V, a compound of formula II is reacted with a compound of formula III to obtain a hypervalent iodine reagent I; wherein R is as described in claim 1 or 3.

5. The method according to claim 4, wherein The inert solvent is selected from the group consisting of DCM, DCE, or a combination thereof.

6. The method according to claim 4, wherein The method comprises: reacting at -30 to -10°C for a period of time, and then heating to 20 to 40°C and reacting for a period of time.

7. The method according to claim 4, wherein The method includes: (a) preparing a hypervalent iodine reagent by the method according to claim 4; and (b) Cooling the system to -30 to -10°C, then sequentially adding the compound of formula III and the compound of formula IV to the solution of formula II, and finally adding the compound of formula V to perform ion exchange to obtain a hypervalent iodine reagent.

8. The method according to claim 4, wherein The method further comprises the steps of extracting the prepared hypervalent iodine reagent with dichloromethane, and separating the organic phase to obtain the hypervalent iodine reagent.

9. The method for preparing a hypervalent iodine reagent according to any one of claims 1 to 3, wherein: The method comprises the steps of: In an inert solvent, a compound of formula VI is reacted with a compound of formula VII to obtain a hypervalent iodine reagent I; wherein R is as described in any one of claims 1 or 3.

10. The method according to claim 9, wherein The inert solvent is selected from the group consisting of TFE, DCM, HFIP, or a combination thereof.

11. The method for preparing a hypervalent iodine reagent according to any one of claims 1 to 3, wherein: The method comprises the steps of: In an inert solvent, a compound of formula VI is reacted with a compound of formula III to obtain a hypervalent iodine reagent I; wherein R is as described in claim 1 or 3; and the solvent is selected from the group consisting of trifluoroacetic acid, trifluoromethanesulfonic acid, or a combination thereof.

12. A coupling reaction method, characterized in that: The method comprises the steps of: In an inert solvent, a compound of formula I and R a XM reaction to obtain formula RXR a Compounds; Wherein, R and A are as defined in claim 1 or 3; M is Na or K; X is selected from the following group: O, S; R a is a group selected from the group consisting of a substituted or unsubstituted C1-C10 alkyl group, a substituted or unsubstituted C6-C30 aryl group, a substituted or unsubstituted 5-20 membered heteroaryl group, and a substituted or unsubstituted 8-20 membered heterocyclyl group; Wherein, the 5-20 membered heteroaryl is selected from the following group: pyrrolyl, pyridyl, furyl; the 8-20 membered heterocyclic group is tetrahydrofuranyl; The substituted group is substituted by one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, C1-C4 haloalkyl, C1-C4 haloalkoxy, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C10 aryl, 5-12 membered heteroaryl, C6-C10 aryloxy, 5-12 membered heteroaryloxy, benzyloxy, CN, NO2, SR 1 NR 1 R 2 、C(O)R 1 、O(CH2) p R 1 、C(O)OR 1 、C(O)NR 1 R 2 NR 1 C(O)R 2 , or S(O)2R 1 ; Among them, R 1 and R 2 Each is independently selected from the following group: C1-C4 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C10 aryl, 5-12 membered heteroaryl, C3-C8 cycloalkyl, 5-12 membered heterocyclyl; and the aryl, heteroaryl, cycloalkyl or heterocyclyl is optionally substituted by one or more substituents selected from the following group: =O, halogen, C1-C4 alkyl, C1-C4 alkoxy, C6-C10 aryloxy, 5-12 membered heteroaryloxy, benzyloxy; p is selected from the following group: 0, 1, 2, 3, 4, 5, 6, 7 or 8.

13. A fluorination reaction method, characterized in that: The method comprises the steps of: In an inert solvent, reacting a compound of formula I with CsF to obtain a compound of formula RF; wherein R and A are as defined in claim 1 or 3.

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