A process for the fluorination of alkylsulfides and intermediates therefor

Abstract

The application discloses a fluoralkyl sulfuration method and intermediates. Specifically, the application provides a preparation method of a compound shown in formula I, which is selected from the following schemes: scheme 1: a compound shown in formula II and a compound shown in formula III are subjected to a reaction shown in the above formula in the presence of an additive in a solvent to obtain a compound shown in formula I; the additive is diphenyl phosphorus chloride or consists of an organic phosphorus reagent and an auxiliary; the auxiliary is a compound shown in formula H or K; scheme 2: a compound shown in formula II and a compound shown in formula III are subjected to a reaction shown in the above formula in an amide solvent to obtain a compound shown in formula I. The method has the advantages of wide substrate application range and high yield.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis and provides a method for fluoroalkyl sulfidation and its intermediates. Specifically, this invention provides a method for fluoroalkyl sulfidation starting from readily available fluoroalkyl 2-pyridyl sulfone, which can be used in the synthesis of various fluoroalkyl sulfides, including perfluoroalkyl sulfides, difluoromethyl sulfides, monofluoromethyl sulfides, functionalized difluoroalkyl sulfides, and functionalized monofluoroalkyl sulfides. The reagents and raw materials involved in this invention are inexpensive and readily available, the reaction conditions are mild, the operation is simple, the cost is low, it is easy to promote, and it is suitable for mass production. Background Technology

[0002] Due to the "extreme" properties of fluorine, such as its highest electronegativity, smallest atomic radius (excluding hydrogen), and ability to form the strongest carbon-participating single bond with carbon atoms, fluorine-containing organic molecules often exhibit unique physical, chemical, and biological properties. Therefore, they are widely used in various important economic and social fields, including materials, medicine, and pesticides, playing an irreplaceable role. Fluoroalkylthio groups are another important class of fluorine-containing groups besides fluoroalkyl groups. They can significantly improve the physicochemical properties and biological activity of organic compounds and have wide applications in drug and pesticide molecule design. For example, the trifluoromethylthio group (SCF3) has a high lipid-water partition coefficient of 1.44. Introducing it into molecules can significantly enhance lipid solubility, promote transmembrane absorption, and improve bioavailability, thereby reducing the effective dosage of drugs. The difluoromethylthio group (SCF2H), due to its moderate lipophilicity (between -CF3 and -CH3) and balanced electronegativity, can synergistically optimize drug-like properties such as lipid solubility and binding affinity. As a bioisosteric group, it exhibits stronger lipophilicity while retaining the hydrogen bond-donating ability of thiols, hydroxyl groups, and amines. In recent years, several drugs and pesticides containing fluorinated alkyl sulfide groups have successfully entered the market, including β-lactamase-resistant oxacillus antibiotic flomoxef sodium, topical anti-inflammatory drug fluticasone, veterinary anthelmintics Monepantel and Pyriprole, and herbicide SSH-108.

[0003] Traditional synthetic routes for fluoroalkyl sulfides mainly rely on the fluoroalkylation of thiophenols and thiols. While efficient, this method suffers from inherent limitations in substrate applicability due to the limited availability and compatibility of thiophenol and thiols precursors. In the past decade, strategies for directly introducing fluoroalkyl sulfide groups have gained significant attention due to their procedural economy and ease of operation. Against this backdrop, researchers have developed various fluoroalkyl sulfide reagents to achieve efficient and selective introduction of different fluoroalkyl sulfide groups (Acta Chimica Sinica 2017, 75, 744; Organic Chemistry 2020, 40, 1; Acc. Chem. Res. 2021, 54, 2946). These reagents can generally be divided into two categories: SR... f Type reagents and S(O) x R f Type reagents (x = 1, 2). Wherein, S(O) x R f The fluoroalkyl sulfonation of this type of reagent requires reductive elimination of the oxygen atom at the sulfur center (Asian J.Org.Chem.2019,8,627). It should be noted that currently, the fluoroalkyl moiety in all reagents must be pre-introduced as a complete structural unit. This design has three key limitations: firstly, the amount of sulfonated alkyl group that can be introduced... f First, the structural type is limited by the source of fluoroalkyl precursors; second, the existing reagent system lacks a universal activation mode, making it difficult to achieve unified activation; third, and most importantly, the system lacks the flexibility to modify the structure of introduced fluoroalkyl groups such as difluoromethyl and monofluoromethyl. This fundamental defect severely restricts the establishment and development of modular fluoroalkyl thiolation methodologies.

[0004] In summary, there is an urgent need in this field to develop a method suitable for modularly introducing fluoroalkyl sulfide groups into molecules to facilitate the synthesis of various fluoroalkyl sulfides, including perfluoroalkyl sulfides, difluoromethyl sulfides, monofluoromethyl sulfides, functionalized difluoroalkyl sulfides, and functionalized monofluoroalkyl sulfides. Summary of the Invention

[0005] The technical problem this invention aims to solve is that existing synthetic routes for fluoroalkyl sulfides are limited and have a narrow range of applicable substrates. Therefore, this invention provides a fluoroalkyl sulfidation method and its intermediate. This method has the advantages of a wide range of applicable substrates and high yield.

[0006] This invention provides a method for preparing a compound as shown in Formula I, wherein the compound is selected from the following schemes:

[0007]

[0008] Option 1: In a solvent, in the presence of an additive, the compound shown in Formula II and the compound shown in Formula III are reacted as shown above to obtain the compound shown in Formula I; the additive is diphenylphosphine chloride or is composed of an organophosphorus reagent and an auxiliary agent; the auxiliary agent is a compound shown in Formula H or K.

[0009] Option 2: In an amide solvent, the compound shown in Formula II and the compound shown in Formula III are reacted as shown in the above formula to obtain the compound shown in Formula I;

[0010] Where ring A is C 6-10 Aryl or 5-12 heteroaryl groups;

[0011] m is 1, 2, or 3;

[0012] R a Independent of H, halogen, C 1-6 Alkyl, -OC 1-6 Alkyl, -C(O)OC 1-6 Alkyl, C 6-10 aryl, 5-12 heteroaryl, with one or more R 1-1 Replacement C 1-6 Alkyl, with one or more R 1-1 Replacement -OC 1-6 Alkyl, with one or more R 1-1 Substituted -C(O)OC 1-6 Alkyl, with one or more R 1-1 Replacement C 6-10 aryl or aryl with one or more R 1-1 Substituted 5-12 heteroaryl groups;

[0013] R b For H, C 1-6 Alkyl, -OC 1-6 Alkyl, C 6-10 aryl, 5-12 heteroaryl, with one or more R 1-2 Replacement C 1-6 Alkyl, with one or more R 1-2 Replacement -OC 1-6 Alkyl, with one or more R 1-2 Replacement C 6-10 aryl or aryl with one or more R 1-2 Substituted 5-12 heteroaryl groups;

[0014] R 1-1 and R 1-2 Halogens are independent of each other;

[0015] R 1 H, halogen, C 1-6Alkyl, Halogenated C 1-6 Alkyl, -C(O)OC 1-6 alkyl or

[0016] R 2 H, halogen, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, -C(O)OC 1-6 alkyl or

[0017] R 1-3 Independently for C 1-6 Alkyl, C 6-10 aryl, 5-12 heteroaryl, with one or more R 1-2 Replacement C 6-10 aryl or aryl with one or more R 1-2 Substituted 5-12 heteroaryl groups;

[0018] R 3 for

[0019] R 1-4 Independently for C 1-6 alkyl;

[0020] Y - Independently - OTf or - BF4;

[0021] The heteroatoms in the 5-12 membered heteroaryl group are independently selected from one, two, or three of N, O, and S, and the number of heteroatoms is independently one, two, or three.

[0022]

[0023] R c and R d Independently for C 1-6 alkyl.

[0024] In one scheme, the compound shown in Formula II is

[0025] W independently for -NR a1 , O or S;

[0026] Or one of the R a R a1Together with the atoms attached thereto, it forms a 5-6 membered heterocycle; ring A1 is phenyl or a 5-6 membered heteroaryl, wherein the heteroatoms of the 5-6 membered heteroaryl are selected from one, two, or three of N, O, and S, and the number of the heteroatoms is one, two, or three; the 5-6 membered heterocycle optionally also includes one, two, or three heteroatoms selected from N, O, and S, and the number of the heteroatoms is one, two, or three.

[0027] R a1 The definition of R is as follows in any embodiment of this invention. a Definition;

[0028] Preferably, the compound shown in Formula II is

[0029] In one of the schemes, R a Independent of H, halogen, C 1-6 Alkyl, -OC 1-6 Alkyl, -C(O)OC 1-6 Alkyl, C 6-10 aryl, 5-12 heteroaryl, surrounded by one or more R 1-1 Replacement C 6-10 aryl or aryl with one or more R 1-1 Substituted 5-12 heteroaryl groups.

[0030] In one of the schemes, R a Independently, H, fluorine, chlorine, bromine, iodine, methyl, ethyl, tert-butyl, methoxy, phenyl,

[0031] In one of the schemes, R a1 For H, C 1-6 Alkyl or C 6-10 Aryl.

[0032] In one of the schemes, R a1 It can be H, methyl, ethyl, tert-butyl, or phenyl.

[0033] In one of the schemes, R b For H, C 1-6 Alkyl, -OC 1-6 Alkyl, C 6-10 aryl, 5-12 heteroaryl, with one or more R 1-2 Replacement C 6-10 aryl or aryl with one or more R 1-2 Substituted 5-12 heteroaryl groups.

[0034] In one of the schemes, R b H, methyl, ethyl, tert-butyl, methoxy, phenyl

[0035] In one of the schemes, R 1-1 and R 1-2 It is F.

[0036] In one embodiment, the compound represented by Formula II is any of the following compounds:

[0037]

[0038] In one of the schemes, R 1 It is H or a halogen, such as H or F.

[0039] In one of the schemes, R 1-3 C 1-6 Alkyl, C 6-10 aryl or aryl with one or more R 1-2 Replacement C 6-10 Aryl.

[0040] In one of the schemes, R 1-3 Methyl, phenyl or In one of the schemes, R 2 For H, F, CF3, methyl, ethyl, In one of the schemes, R 1-4 It is a methyl group.

[0041] In one embodiment, the compound represented by Formula III is any of the following compounds:

[0042]

[0043] In one embodiment, the compound represented by Formula I is any of the following compounds:

[0044]

[0045]

[0046] In one of the schemes, schemes 1 and 2, the reaction is carried out in an inert atmosphere, such as a nitrogen atmosphere.

[0047] In one embodiment, embodiment 1, the solvent is a nitrile solvent, an ether solvent, a benzene solvent, or an amide solvent, such as a nitrile solvent or a benzene solvent, or even a nitrile solvent.

[0048] In one embodiment, Scheme 1, the nitrile solvent is acetonitrile; the ether solvent is tetrahydrofuran; the benzene solvent is toluene; and the amide solvent is N,N-dimethylformamide or N-methylpyrrolidone.

[0049] In one embodiment, in embodiment 1, the ratio of the number of moles of the compound as shown in formula II to the volume of the solvent is (0.01-1) mmol:1 mL, for example (0.05-0.5) mmol:1 mL, or for example 0.15 mmol:1 mL, 0.17 mmol:1 mL or 0.2 mmol:1 mL.

[0050] In one embodiment, in embodiment 1, the molar ratio of the compound shown in formula III to the compound shown in formula II is (1-5):1, for example (1-3):1, or for example 1.5:1 or 2:1.

[0051] In one embodiment, the additive is diphenylphosphine chloride (Ph2PCl); preferably, the molar ratio of the diphenylphosphine chloride to the compound shown in Formula II is (1-10):1, for example (1-8):1, or even 4:1.

[0052] In one embodiment, the additive consists of an organophosphorus reagent and an auxiliary agent.

[0053] In one embodiment, the organophosphorus reagent is triphenylphosphine (Ph3P) or (R... z O)2P(O)H,R z Independently for C 1-4 Alkyl; preferably, the (R) z O)2P(O)H is dimethyl phosphite ((MeO)2P(O)H) or diethyl phosphite ((EtO)2P(O)H); more preferably, the organophosphite reagent is diethyl phosphite.

[0054] In one of the schemes, R c It is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, such as tert-butyl.

[0055] In one of the schemes, R d It is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, such as methyl.

[0056] In one embodiment, the auxiliary agent is trimethylchlorosilane (TMSCl) or tetrabutylammonium chloride (nBu4NCl).

[0057] In one embodiment, the molar ratio of the organophosphorus reagent to the compound shown in Formula II is (1-10):1, for example (2-8):1, or for example 3:1 or 4:1.

[0058] In one embodiment, the molar ratio of the adjuvant to the compound shown in Formula II is (1-10):1, for example (2-8):1, or for example 3:1 or 4:1.

[0059] In one embodiment, embodiment 1, the reaction temperature is 30-100°C, for example 40-90°C, or for example 40°C, 60°C, or 80°C.

[0060] In schemes 1 and 2, the reaction process is monitored using conventional methods in the art (e.g., TLC or LCMS), with the disappearance or cessation of reaction of the compound shown in Formula II as the endpoint. In one scheme, the reaction time is 5-10 hours, for example, 6 hours.

[0061] In Scheme 1, after the reaction is completed, it also includes post-processing steps that are conventional for such reactions in the art, such as extraction (e.g., ethyl acetate extraction), drying, filtration, and purification (e.g., column chromatography, with petroleum ether or petroleum ether / ethyl acetate as the eluent).

[0062] In one embodiment, embodiment 1, the components in the reaction system consist of the solvent, the additive, the compound as shown in formula II, and the compound as shown in formula III.

[0063] In one embodiment, embodiment 2, the amide solvent is N,N-dimethylformamide or N-methylpyrrolidone, for example, N,N-dimethylformamide.

[0064] In one embodiment, in embodiment 2, the ratio of the number of moles of the compound as shown in formula II to the volume of the amide solvent is (0.01-1) mmol:1 mL, for example (0.05-0.5) mmol:1 mL, or for example 0.15 mmol:1 mL, 0.17 mmol:1 mL or 0.2 mmol:1 mL.

[0065] In one embodiment, embodiment 2, the molar ratio of the compound shown in formula III to the compound shown in formula II is (1.5-5):1, for example (2-5):1, or for example 2:1 or 2.5:1.

[0066] In one embodiment, embodiment 2, the reaction temperature is 30-100°C, for example 40-90°C, or for example 40°C, 60°C, or 80°C.

[0067] In Scheme 2, after the reaction is completed, it also includes post-processing steps that are conventional for such reactions in the art, such as extraction (e.g., ethyl acetate extraction), drying, filtration, and purification (e.g., column chromatography, with petroleum ether or petroleum ether / ethyl acetate as the eluent).

[0068] In one embodiment, embodiment 2, the components of the reaction system consist of the solvent, the compound shown in formula II, and the compound shown in formula III.

[0069] This invention provides a method for preparing a compound as shown in Formula I-1, comprising the following steps:

[0070]

[0071] In an amide solvent, the compound shown in Formula II and the compound shown in Formula III are subjected to a sulfonation reaction as shown above to obtain the compound shown in Formula I-1;

[0072] The molar ratio of the compound shown in Formula III to the compound shown in Formula II is (0.1-1.5):1;

[0073] m, ring A, R a R b R 1 R 2 R 3 The definition is as described in any of the preceding embodiments; the operation and conditions of the sulfonation reaction are also as described in Scheme 2 of any embodiment of the present invention.

[0074] In one embodiment, the molar ratio of the compound shown in Formula III to the compound shown in Formula II is (0.5-1):1, for example, 1:1.

[0075] The sulfonation reaction is followed by post-processing steps that are conventional to such reactions in the art, such as extraction (e.g., ethyl acetate extraction), washing (e.g., washing with 5% lithium chloride aqueous solution), drying, filtration, and purification (e.g., column chromatography, with petroleum ether or petroleum ether / ethyl acetate as the eluent).

[0076] This invention provides a method for preparing a compound as shown in Formula I, comprising the following steps:

[0077] In a solvent, in the presence of a reducing agent, the compound shown in Formula I-1 is subjected to the reduction reaction shown in the following formula to obtain the compound shown in Formula I;

[0078]

[0079] m, ring A, R a R b R 1 and R 2 The definition is as described in the previous scheme.

[0080] In one embodiment, the reduction reaction is carried out in an inert atmosphere, such as a nitrogen atmosphere.

[0081] In one embodiment, the solvent in the reduction reaction is an amide solvent, such as N,N-dimethylformamide or N-methylpyrrolidone, such as N,N-dimethylformamide.

[0082] In one embodiment, the ratio of the molar number of the compound shown in Formula I-1 to the volume of the amide solvent in the reduction reaction is (0.01-1) mmol:1 mL, for example (0.05-0.5) mmol:1 mL, or for example 0.15 mmol:1 mL, 0.17 mmol:1 mL or 0.2 mmol:1 mL.

[0083] In one embodiment, the reducing agent in the reduction reaction is diphenylphosphine chloride (Ph2PCl), phosphorus trichloride (PCl3), oxalyl chloride ((COCl)2), or tripolymer phosgene (CO(OCCl3)2).

[0084] In one embodiment, the molar ratio of the reducing agent to the compound shown in Formula I-1 in the reduction reaction is (1-5):1, for example (1-3):1, or for example 1:1.

[0085] In one embodiment, the temperature of the reduction reaction is 10-40°C, for example, 20-25°C.

[0086] The reduction reaction is monitored using conventional methods in the art (e.g., TLC or LCMS), with the disappearance or cessation of reaction of the compound shown in Formula II as the endpoint. In one embodiment, the reaction time is 5-10 hours, for example, 6 hours.

[0087] In one embodiment, the components of the reduction reaction system consist of the solvent, the compound as shown in Formula I-1, and the reducing agent.

[0088] In one embodiment, the reduction reaction, the method for preparing the compound shown in Formula I, further includes the method for preparing the compound shown in Formula I-1 as described in any of the preceding embodiments.

[0089] This invention provides a compound as shown in Formula III-1.

[0090]

[0091] R 1 and R 2 The definition is as described in any of the previous schemes; for example

[0092] This invention provides a method for preparing a compound as shown in Formula III-1, comprising the following steps:

[0093]

[0094] In a solvent (e.g., acetonitrile), in the presence of trifluoroacetic acid and a urea-hydrogen peroxide complex, the compound shown in Formula IV-1 is reacted as shown above to give the compound shown in Formula III-1.

[0095] Unless otherwise specified, the terms used in this invention have the following meanings:

[0096] Those skilled in the art will understand that, according to conventions used in the art, the structural formulas of the groups described in this invention are... This refers to the fact that the corresponding group is connected to other fragments or groups in the compound through this site.

[0097] In this article, a single hyphen "-" can be added before the substituents used to indicate that the named substituent is connected to the parent part by a single bond.

[0098] The term "multiple" refers to 2, 3, 4 or 5, preferably 2 or 3.

[0099] When any variable (e.g., R) 1-1-1 When a variable appears multiple times in the definition of a compound, the definition at each position is independent of the definitions at the other positions; their meanings are independent and do not affect each other. Therefore, if a group is surrounded by one, two, or three R... 1-1-1 Group substitution, meaning that the group can be replaced by up to 3 R groups. 1-1-1 Replace, the position R 1-1-1 Definition and other positions R 1-1-1 The definitions are independent of each other. Furthermore, combinations of substituents and / or variables are only permitted if the combination produces a stable compound.

[0100] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0101] The term "alkyl" refers to a straight-chain or branched alkyl group having a specified number of carbon atoms. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and similar alkyl groups.

[0102] "Aryl" refers to a polycyclic group consisting of an all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) and possessing a conjugated π-electron system. "6-10-membered aryl" refers to an all-carbon aryl group containing 6-10 carbon atoms, such as phenyl and naphthyl; preferably phenyl. The aryl ring may be fused to a heteroaryl, heterocyclic alkyl, or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring.

[0103] "Heteroaryl" refers to a heteroaryl system containing 1 to 3 heteroatoms, wherein the heteroatoms include nitrogen, oxygen, or S. A 5-6 membered heteroaryl refers to a heteroaryl system containing 5-6 ring atoms, and a 5-12 membered heteroaryl refers to a heteroaryl system containing 5-12 ring atoms, preferably a 5-6 membered heteroaryl; more preferably a 5-6 membered heteroaryl containing 1 or 2 N atoms. Non-limiting embodiments include furanyl, thiophene, pyridinyl, pyrroleyl, N-alkylpyrroleyl, pyrimidinyl, pyrazinyl, pyrazole, imidazolyl, triazolyl, tetrazolyl, indoleyl, etc.; preferably indoleyl. The heteroaryl ring may be fused to an aryl, heterocyclic alkyl, or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring. Non-limiting embodiments include:

[0104] "Optional" means that the event or environment described below may but does not have to occur, and this description includes situations in which the event or environment may or may not occur. For example, "optionally alkyl-substituted heterocyclic alkyl groups" means that alkyl groups may but do not have to be present, and this description includes cases where heterocyclic alkyl groups are substituted with alkyl groups and cases where heterocyclic alkyl groups are not substituted with alkyl groups.

[0105] Based on common knowledge in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0106] The reagents and raw materials used in this invention are all commercially available.

[0107] The positive and progressive effects of this invention are as follows: This invention provides a method for fluoroalkyl sulfidation using difluoromethanesulfonylpyridinium salt or difluoromethanesulfonylpyridinium nitroxide compound, which has the advantages of a wide range of applicable substrates and high yield. Detailed Implementation

[0108] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0109] Example 1: Synthesis of 1-methyl-2-difluoromethanesulfonylpyridinium salt of trifluoromethanesulfonic acid

[0110]

[0111] Add difluoromethyl (2-pyridyl) sulfone to a 100 mL Schlenk tube. (9.65 g, 50 mmol, 1.0 equivalent) was added, and three vacuum / nitrogen cycles were performed to establish an inert atmosphere. Anhydrous dichloromethane (25 mL) was added, and the mixture was cooled to 0 °C. Methyl trifluoromethanesulfonate (MeOTf, 20.35 mL, 150 mmol, 3.0 equivalent) was added in one step, and the reaction system was then heated to room temperature and stirred for 18 hours. After the reaction was complete, the upper solvent layer was removed, and the lower liquid layer was washed with anhydrous dichloromethane (3 × 10 mL). The resulting oily liquid was further washed with cold diethyl ether (3 × 10 mL) and dried under high vacuum for 3–4 hours to give the target compound as a white solid (14.9 g, yield 84%).

[0112] The specific compound prepared in Example 1 is

[0113] 14.9 g of white solid was obtained, with a yield of 84%.

[0114] MPa: 55.7-57.4℃.

[0115] 1 H NMR (500MHz, CD3CN) δ9.10(d,J=6.0Hz,1H),8.86(t,J=7.2Hz,1H),8.79(d,J=6.3Hz,1H),8.44(t,J=6.9Hz,1H),7.04(t,J=51.9Hz,1H),4.63(s,3H).

[0116] 19 F NMR (471MHz, CD3CN) δ-78.07 (s, 3F), -120.04 (d, J = 52.0Hz, 2F).

[0117] 13 C NMR (126MHz, CD3CN) δ153.62, 149.38, 135.62, 134.90, 116.13 (t, J = 287.7Hz), 50.19.

[0118] HRMS(ESI,m / z):[M-OTf] + Calcd.for C7H8F2NO2S + :208.0238; Found:208.0240.

[0119] Example 2 Synthesis of 1-methyl-2-difluoromethanesulfonylpyridinium salt of tetrafluoroboronic acid

[0120]

[0121] Add difluoromethyl (2-pyridyl) sulfone to a 100 mL Schlenk tube. (1.93 g, 10 mmol, 1.0 equivalent) was added, and three vacuum / nitrogen cycles were performed. Anhydrous dichloromethane (10 mL) was added, and the mixture was cooled to 0 °C. Trimethyloxonium tetrafluoroborate (Me3OBF4, 2.96 g, 20 mmol, 2.0 equivalent) was added in a single batch, and the mixture was then brought to room temperature and stirred for 18 hours. After the reaction was complete, the reaction mixture was diluted with anhydrous acetonitrile (10 mL) and filtered through a 0.2 μm PTFE filter. Cold diethyl ether (20 mL) was then added to the filtrate, causing a white solid to precipitate. The precipitate was washed with cold diethyl ether (3 × 20 mL) and dried under high vacuum to give the target compound as a white solid (2.06 g, 70% yield).

[0122] The specific compound prepared in Example 2 is

[0123] 2.06 g of white solid was obtained, with a yield of 70%.

[0124] MPa: 127.6-128.5℃.

[0125] 1 H NMR (500MHz, CD3CN) δ9.04(d,J=6.0Hz,1H),8.85(t,J=8.7Hz,1H),8.78(d,J=7.9Hz,1H),8.43(t,J=7.0Hz,1H),6.98(t,J=52.0Hz,1H),4.62(s,3H).

[0126] 19 F NMR (471MHz, CD3CN) δ-119.88 (d, J = 52.0Hz, 2F), -147--154 (4F).

[0127] 13 C NMR (126MHz, CD3CN) δ153.50, 149.39, 145.06, 135.64, 134.90, 116.12 (t, J = 288.5Hz), 50.15.

[0128] HRMS(ESI,m / z):[M-BF4] + Calcd.for C7H8F2NO2S + :208.0238;Found:208.0238.

[0129] Example 3 Synthesis of 2-difluoromethanesulfonylpyridine N-oxide (1d)

[0130]

[0131] Add difluoromethyl (2-pyridyl) sulfone to a 500 mL flask Urea-hydrogen peroxide complex (73 g, 776.5 mmol, 1.0 equivalent) and trifluoroacetic acid (107 mL, d = 1.535, 776.5 mmol, 3.0 equivalent) were added to the flask in three portions at 0 °C, with the trifluoroacetic acid added at a rate of 45 mL / h, with each addition spaced one hour apart, and stirring continuously. The mixture was then stirred for 18 hours, during which time the temperature was gradually raised to room temperature. After the reaction was complete, excess sodium bicarbonate aqueous solution was slowly added for treatment, followed by extraction with dichloromethane, washing with saturated brine, and drying with anhydrous magnesium sulfate. After filtration and concentration, the residue was recrystallized from ethyl acetate / petroleum ether to give the target compound (35.5 g). Additional petroleum ether was then added to the mother liquor to precipitate the second portion of the target compound (7.4 g). The mother liquor was evaporated to dryness and then recrystallized a second time to give the third portion of the target compound (2.5 g). The final yield of the target compound was 84% ​​(45.4 g).

[0132] The specific compound prepared in Example 3 is

[0133] 45.4 g of white solid was obtained, with a yield of 84%.

[0134] MPa: 110.2-111.8℃.

[0135] 1 H NMR(500MHz,CD3CN)δ8.29(d,J=6.4Hz,1H),8.08(dd,J=8.1,2.0Hz,1H),7.71(d dd,J=8.4,6.4,2.1Hz,1H),7.58(td,J=7.9,1.1Hz,1H),7.19(t,J=54.6Hz,3H).

[0136] 19 F NMR (471MHz, CD3CN) δ-124.14 (d, J = 54.6Hz, 2F).

[0137] 13 C NMR (126MHz, CD3CN) δ144.26, 141.80, 133.01, 129.81, 127.65, 115.73 (t, J = 285.0Hz).

[0138] HRMS(ESI,m / z):[M+H] + Calcd.for C6H6F2NO3S + :210.0031;Found:210.0031.

[0139] Examples 4-32 illustrate typical procedures for difluoromethyl thiolation in acetonitrile using 1-methyl-2-difluoromethanesulfonylpyridinium trifluoromethanesulfonate.

[0140]

[0141] Add 1-methyl-2-difluoromethanesulfonylpyridinium salt to a 10 mL Schlenk tube. (354 mg, 1.0 mmol) and unsubstituted or substituted indole (0.50 mmol). Under a nitrogen atmosphere, (EtO)₂P(O)H (0.25 mL, 2.0 mmol, 4.0 equivalent), TMSCl (0.25 mL, 2.0 mmol, 4.0 equivalent), and anhydrous acetonitrile (3 mL) were added sequentially to a test tube via a syringe. The mixture was stirred at 80 °C for 6 hours. After the reaction was complete, the reaction mixture was separated into layers with ethyl acetate (20 mL) and water (20 mL). The aqueous phase was extracted with ethyl acetate (5 × 10 mL), and the combined organic phases were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate as eluent to give the target product.

[0142] Example 4

[0143] The specific compound prepared in Example 4 is Substrate is Elution with petroleum ether / ethyl acetate = 20 / 1 (v / v) yielded 74.3 mg of a yellow oily liquid, with a yield of 75%.

[0144] 1 H NMR (500MHz, CDCl3) δ8.39 (s, 1H), 7.83 (d, J = 6.8Hz, 1H), 7.44 (d, J = 2.7Hz, 1H), 7.43–7.39 (m, 1H), 7.34–7.26 (m, 2H), 6.70 (t, J = 57.5Hz, 1H).

[0145] 19 F NMR (471MHz, CDCl3) δ-91.94 (d, J = 58.1Hz, 2F).

[0146] 13C NMR (126MHz, CDCl3) δ136.19, 131.99, 129.81, 123.38, 121.15 (t, J = 275.7Hz), 121.44, 119.43, 111.74, 96.71 (t, J = 4.2Hz).

[0147] HRMS(ESI,m / z):[M+H] + Calcd.for C9H8F2NS + :200.0340; Found:200.0338.

[0148] Example 5

[0149] The specific compound prepared in Example 5 is Substrate is Elution with petroleum ether / ethyl acetate = 100 / 1 (v / v) yielded 85.2 mg of a yellow oily liquid, with a yield of 70%.

[0150] 1 H NMR (500MHz, CDCl3) δ7.82 (d, J = 7.9 Hz, 1H), 7.39-7.28 (m, 4H), 6.69 (t, J = 57.6 Hz, 1H), 3.81 (s, 3H).

[0151] 19 F NMR (471MHz, CDCl3) δ-92.15 (d, J = 57.2Hz, 2F).

[0152] 13 C NMR (126MHz, CDCl3) δ137.31, 136.24, 130.52, 122.85, 121.19 (t, J = 276.0Hz), 121.02, 119.48, 109.91, 94.19 (t, J = 3.9Hz), 33.27.

[0153] HRMS(ESI,m / z):[M+H] + Calcd.for C 10 H 10 F2NS + :214.0497; Found:214.0493.

[0154] Example 6

[0155] The specific compound prepared in Example 6 is Substrate is Eluting with petroleum ether yielded 108 mg of a yellow oily liquid, with a yield of 79%.

[0156] 1 H NMR (500MHz, CDCl3) δ7.92–7.84(m,1H),7.62(s,1H),7.60–7.54(m,3H),7.52(d ,J=7.0Hz,2H),7.45(t,J=7.2Hz,1H),7.37–7.29(m,2H),6.76(t,J=57.4Hz,1H).

[0157] 19 F NMR (471MHz, CDCl3) δ-92.36 (d, J = 57.2Hz, 2F).

[0158] 13 C NMR (126MHz, CDCl3) δ138.76,136.63,135.17,130.95,129.94,127.60,124.70 ,123.66,121.88,121.05(t,J=276.0Hz),119.81,111.14,97.54(t,J=3.9Hz).

[0159] HRMS(ESI,m / z):[M+H] + Calcd.for C 15 H 12 F2NS + :276.0653; Found:276.0652.

[0160] Example 7

[0161] The specific compound prepared in Example 7 is Substrate is Elution with petroleum ether / ethyl acetate = 20 / 1 (v / v) yielded 68.8 mg of a yellow oily liquid, with a yield of 64%.

[0162] 1 H NMR (500MHz, CDCl3) δ8.25(s,1H),7.71(dt,J=5.9,3.3Hz,1H),7.35–7.29(m,1H),7.26–7.17(m,2H),6.63(t,J=57.5Hz,1H),2.56(s,3H).

[0163] 19 F NMR (471MHz, CDCl3) δ-91.95 (d, J = 58.1Hz, 2F).

[0164] 13C NMR (126MHz, CDCl3) δ142.77, 135.20, 130.94, 122.53, 121.35 (t, J = 275.7Hz), 121.17, 118.77, 110.82, 93.60, 12.29.

[0165] HRMS(ESI,m / z):[M+H] + Calcd.for C 10 H 10 F2NS + :214.0497; Found:214.0496.

[0166] Example 8

[0167] The specific compound prepared in Example 8 is Substrate is Elution with petroleum ether / ethyl acetate = 20 / 1 (v / v) yielded 93.3 mg of a yellow oily liquid, with a yield of 82%.

[0168] 1 H NMR(500MHz, CDCl3)δ8.09(s,1H),7.66–7.60(m,1H),7.23–7.16(m,1H),7.15–7.08 (m,2H),6.52(td,J=57.5,1.5Hz,1H),2.85(q,J=7.6Hz,2H),1.19(t,J=7.6Hz,3H).

[0169] 19 F NMR (471MHz, CDCl3) δ-91.95 (d, J = 58.1Hz, 2F).

[0170] 13 C NMR (126MHz, CDCl3) δ148.23, 135.19, 130.89, 122.52, 121.36 (t, J = 276.0Hz), 121.15, 118.86, 110.98, 92.47, 19.68, 13.95.

[0171] HRMS(ESI,m / z):[M+H] + Calcd.for C 11 H 12 F2NS + :228.0653; Found:228.0652.

[0172] Example 9

[0173] The specific compound prepared in Example 9 is Substrate is Elution with petroleum ether / ethyl acetate = 20 / 1 (v / v) gave 118.3 mg of pink solid, yield 86%.

[0174] 1 H NMR (500MHz, CDCl3) δ8.46 (s, 1H), 7.88 (d, J = 9.2Hz, 1H), 7.79 (d, J = 7.8Hz, 2H), 7.52 (t, J = 7. 4Hz,2H),7.47(t,J=6.6Hz,1H),7.44–7.37(m,1H),7.36–7.27(m,1H),6.72(t,J=57.2Hz,2H).

[0175] 19 F NMR (471MHz, CDCl3) δ-91.30 (d, J = 57.2Hz, 2F).

[0176] 13 C NMR (126MHz, CDCl3) δ143.39,135.50,131.80,131.04,129.12,128.89,128.74 ,123.64,121.62,δ121.57(t,J=277.0Hz),119.81,111.33,93.73(t,J=3.8Hz).

[0177] HRMS(ESI,m / z):[M+H] + Calcd.for C 15 H 12 F2NS + :276.0653; Found:276.0648

[0178] Example 10

[0179] The specific compound prepared in Example 10 is as follows: Substrate is Eluting with petroleum ether / ethyl acetate = 20 / 1 (v / v) gave 122 mg of a brown solid, yield 83%.

[0180] MPa: 82.8-84.1℃

[0181] 1H NMR (500MHz, CDCl3) δ8.48(s,1H),7.85(d,J=8.5Hz,1H),7.76(ddt,J=9.1,5.0,2.7Hz,2H ),7.41(d,J=6.1Hz,1H),7.36–7.26(m,2H),7.20(t,J=8.7Hz,2H),6.72(t,J=57.1Hz,1H).

[0182] 19 F NMR (471MHz, CDCl3) δ-92.0 (d, J = 57.2Hz, 2F), -111.9--112.6 (m, 1F).

[0183] 13 C NMR (126MHz, CDCl3) δ164.21,162.22,142.54,135.48,131.69,130.63,127.19, 123.76,121.75,121.36(t,J=277.0Hz),119.82,116.12,115.94,111.33,93.78.

[0184] HRMS(ESI,m / z):[M+H] + Calcd.for C 15 H 11 F3NS + :294.0559;Found:294.0555.

[0185] Example 11

[0186] The specific compound prepared in Example 11 is Substrate is Elution with petroleum ether / ethyl acetate = 100 / 1 (v / v) yielded 83.2 mg of a reddish-brown oily liquid, with a yield of 73%.

[0187] 1 H NMR (500MHz, CDCl3) δ7.69 (d, J = 7.3Hz, 1H), 7.24 (s, 1H), 7.20 (p, J = 6.8Hz, 2H), 6.56 (t, J = 57.5Hz, 1H), 3.63 (s, 3H), 2.49 (s, 3H).

[0188] 19 F NMR (471MHz, CDCl3) δ-92.20 (d, J = 57.4Hz, 2F).

[0189] 13C NMR (126MHz, CDCl3) δ144.44, 136.89, 130.37, 122.04, δ121.45 (t, J = 275.9Hz), 120.88, 118.66, 109.24, 92.05 (d, J = 4.3Hz), 30.38, 10.99.

[0190] HRMS(ESI,m / z):[M+H] + Calcd.for C 11 H 12 F2NS + :228.0653; Found:228.0649.

[0191] Example 12

[0192] The specific compound prepared in Example 12 is as follows: Substrate is Eluting with petroleum ether / ethyl acetate = 100 / 1 (v / v) gave 103 mg of a yellow solid, yield 71%.

[0193] 1 H NMR(500MHz, CDCl3) δ7.86(d,J=7.9Hz,1H),7.59–7.50(m,1H),7.46(d,J=7.9Hz,1H),7.43(d,J =8.1Hz,1H),7.37(t,J=7.6Hz,0H),7.32(t,J=7.4Hz,1H),6.62(t,J=57.4Hz,1H),3.69(s,3H).

[0194] 19 F NMR (471MHz, CDCl3) δ-91.85 (d, J = 57.2Hz, 2F).

[0195] 13 C NMR (126MHz, CDCl3) δ147.27,137.28,131.05,130.53,130.21,129.16,128.45 ,123.12,121.46,121.36(t,J=276.5Hz),119.66,110.01,93.85,31.76,29.85.

[0196] HRMS(ESI,m / z):[M+H] + Calcd.for C 16 H 14 F2NS + :290.0810; Found:290.0805

[0197] Example 13

[0198] The specific compound prepared in Example 13 is as follows: Substrate is Eluting with petroleum ether / ethyl acetate = 20 / 1 (v / v) gave 129 mg of a yellow solid, yield 85%.

[0199] 1 H NMR(500MHz, CDCl3)δ7.89(d,J=7.9Hz,1H),7.60–7.49(m,3H),7.46(td,J=5.7,3.0Hz,3H),7.3 5(dt,J=22.6,6.4Hz,2H),6.62(t,J=57.4Hz,1H),4.14(q,J=7.2Hz,2H),1.32(t,J=7.2Hz,3H).

[0200] 19 F NMR (471MHz, CDCl3) δ-92.41 (d, J = 57.2Hz, 2F).

[0201] 13 C NMR (126MHz, CDCl3) δ146.96,136.03,130.89,130.74,130.56,129.19,128.48,122.99,121.33,119.76,110.23,94.16,39.67,15.48.

[0202] HRMS(ESI,m / z):[M+H] + Calcd.forC 17 H 16 F2NS + :304.0967; Found:304.0964.

[0203] Example 14

[0204] The specific compound prepared in Example 14 is: Substrate is Eluting with petroleum ether / ethyl acetate = 100 / 1 (v / v) yielded 90 mg of a yellow solid, with a yield of 65%.

[0205] 1H NMR (500MHz, CDCl3) δ7.74(d,J=7.3Hz,1H),7.34(d,J=8.9Hz,1H),7.23(qd,J=7.0,1.4Hz,2H),6.61(t,J=57.6 Hz, 1H), 4.13 (t, J = 7.5Hz, 2H), 2.57 (s, 3H), 1.77 (p, J = 7.7Hz, 2H), 1.41 (h, J = 7.4Hz, 2H), 0.98 (t, J = 7.3Hz, 3H).

[0206] 19 F NMR (471MHz, CDCl3) δ-92.76 (d, J = 58.1Hz, 2F).

[0207] 13 C NMR (126MHz, CDCl3) δ143.98, 136.27, 130.54, 121.97, 121.55 (t, J = 276.0Hz), 120.80, 118.77, 109.57, 92.32, 44.16, 32.18, 20.40, 11.02.

[0208] HRMS(ESI,m / z):[M+H] + Calcd.for C 14 H 18 F2NS + :270.1122;Found:270.1120.

[0209] Example 15

[0210] The specific compound prepared in Example 15 is as follows: Substrate is Elution with petroleum ether / ethyl acetate = 20 / 1 (v / v) yielded 66 mg of a yellow oily liquid, with a yield of 62%.

[0211] 1 H NMR(500MHz, CDCl3)δ8.08(s,1H),7.61(d,J=7.9Hz,1H),7.35(d,J=8.2Hz,1H),7 .30(t,J=6.9Hz,1H),7.18(t,J=7.5Hz,1H),6.71(t,J=57.0Hz,1H),2.45(s,3H).

[0212] 19 F NMR (471MHz, CDCl3) δ-91.41 (d, J = 57.2Hz, 2F).

[0213] 13 C NMR (126MHz, CDCl3) δ137.26, 128.25, 124.29, 122.07, 120.37 (t, J = 277.8Hz), 119.98, 119.80, 114.79, 111.07, 9.59.

[0214] HRMS(ESI,m / z):[M+H] + Calcd.for C 10 H 10 F2NS + :214.0496; Found:214.0495.

[0215] Example 16

[0216] The specific compound prepared in Example 16 is Substrate is Elution with petroleum ether / ethyl acetate = 20 / 1 (v / v) yielded 56 mg of a yellow oily liquid, with a yield of 53%.

[0217] 1 H NMR (500MHz, CDCl3) δ8.39(s,1H),7.65(d,J=8.1Hz,1H),7.48(d,J=2.7Hz,1H),7 .19(t,J=7.6Hz,1H),7.10(d,J=7.2Hz,1H),6.69(t,J=57.6Hz,1H),2.51(s,3H).

[0218] 19 F NMR (471MHz, CDCl3) δ-92.06 (d, J = 57.2Hz, 2F).

[0219] 13 C NMR (126MHz, CDCl3) δ135.78, 131.63, 123.90, 121.62, 121.14 (t, J = 276.0Hz), 120.93, 117.14, 97.26, 16.50.

[0220] HRMS(ESI,m / z):[M+H] + Calcd.for C 10 H 10 F2NS + :214.0497; Found:214.0492.

[0221] Example 17

[0222] The specific compound prepared in Example 17 is as follows: Substrate is Elution with petroleum ether / ethyl acetate = 20 / 1 (v / v) yielded 56 mg of a yellow oily liquid, with a yield of 49%.

[0223] 1 H NMR (500MHz, CDCl3) δ8.33(s,1H),7.66(d,J=8.7Hz,1H),7.33(d,J=2.7Hz,1H),6.9 3(dd,J=8.7,2.3Hz,1H),6.85(d,J=2.4Hz,1H),6.69(t,J=57.5Hz,1H),3.85(s,3H).

[0224] 19 F NMR (471MHz, CDCl3) δ-91.91 (d, J = 57.2Hz, 2F).

[0225] 13 C NMR (126MHz, CDCl3) δ157.43, 137.00, 130.74, 124.03, 121.20 (t, J = 275.7Hz), 120.16, 111.47, 96.77, 95.02, 55.86.

[0226] HRMS(ESI,m / z):[M+H] + Calcd.for C 10 H 10 F2NOS + :230.0446; Found:230.0444.

[0227] Example 18

[0228] The specific compound prepared in Example 18 is: Substrate is Elution with petroleum ether / ethyl acetate = 20 / 1 (v / v) yielded 82 mg of a yellow oily liquid, with a yield of 69%.

[0229] 1 H NMR (500MHz, CDCl3) δ7.57(d,J=7.9Hz,1H),7.33(s,1H),7.21–7.13(m,1H),7.01(d,J=7.0Hz ,1H),6.67(t,J=57.8Hz,1H),4.19(t,J=5.0Hz,2H),3.02(t,J=6.2Hz,3H),2.32–2.22(m,1H).

[0230] 19F NMR (471MHz, CDCl3) δ-92.85 (d, J = 58.1Hz, 2F).

[0231] 13 C NMR (126MHz, CDCl3) δ134.70,133.46,128.34,124.19–120.93(m),121.43,119.80,116.85,94.04,44.61,24.55,22.77.

[0232] HRMS(ESI,m / z):[M+H] + Calcd.for C 12 H 12 F2NS + :240.0653; Found:240.0652.

[0233] Example 19

[0234] The specific compound prepared in Example 19 is Substrate is Elution with petroleum ether / ethyl acetate = 20 / 1 (v / v) yielded 99 mg of a yellow oily liquid, with a yield of 86%.

[0235] MPa: 50.5-51.7℃

[0236] 1 H NMR (500MHz, CDCl3) δ7.68(dd,J=8.6,5.3Hz,1H),7.30(s,1H),7.06–6.97(m,2H),6.65(t,J=57.4Hz,1H),3.77(s,3H).

[0237] 19 F NMR (471MHz, CDCl3) δ-92.74 (d, J=57.2Hz, 2F), -119.88 (td, J=9.5, 5.2Hz, 1F).

[0238] 13 C NMR (126MHz, CDCl3) δ160.48 (d, J = 239.8Hz), 137.38 (d, J = 12.0Hz), 136.60, 126.99, 120.93 (t ,J=276.0Hz),120.64(d,J=9.9Hz),109.88(d,J=24.4Hz),96.42(d,J=26.5Hz),94.65,33.45.

[0239] HRMS(ESI,m / z):[M+H]+ Calcd.for C 10 H9F3NS + :232.0402;Found:232.0401.

[0240] Example 20

[0241] The specific compound prepared in Example 20 is as follows: Substrate is Elution with petroleum ether / ethyl acetate = 100 / 1 (v / v) yielded 85 mg of a yellow oily liquid, with a yield of 75%.

[0242] 1 H NMR (500MHz, CDCl3) δ7.57(s,1H),7.26(d,J=12.5Hz,2H),7.14(d,J=6.4Hz,1H),6.65(t,J=57.8Hz,1H),3.78(s,3H),2.51(s,3H).

[0243] 19 F NMR (471MHz, CDCl3) δ-92.81 (d, J = 57.2Hz, 2F).

[0244] 13 C NMR (126MHz, CDCl3) δ136.23, 135.73, 130.71, 130.54, 124.51, 121.31 (t, J = 275.7Hz), 119.02, 109.63, 93.46, 33.32, 21.60.

[0245] HRMS(ESI,m / z):[M+H] + Calcd.for C 11 H 12 F2NS + :228.0653; Found:228.0652.

[0246] Example 21

[0247] The specific compound prepared in Example 21 is Substrate is Elution with petroleum ether / ethyl acetate = 20 / 1 (v / v) yielded 75 mg of a yellow oily liquid, with a yield of 61%.

[0248] MPa: 69.7-71.3℃

[0249] 1H NMR (500MHz, CDCl3) δ7.73(s,1H),7.32(s,1H),7.24(s,2H),6.78–6.50(m,1H),3.79(s,3H).

[0250] 19 F NMR (471MHz, CDCl3) δ-92.81 (d, J = 57.2Hz, 2F).

[0251] 13 C NMR (126MHz, CDCl3) δ137.45, 135.73, 131.69, 127.17, 123.27, 121.81 (d, J = 275.7Hz), 119.03, 111.07, 93.85, 33.51.

[0252] HRMS(ESI,m / z):[M+H] + Calcd.for C 10 H9ClF2NS + :248.0107; Found:248.0108.

[0253] Example 22

[0254] The specific compound prepared in Example 22 is Substrate is Elution with petroleum ether / ethyl acetate = 20 / 1 (v / v) yielded 127 mg of a yellow oily liquid, with a yield of 75%.

[0255] MPa: 105.3-106.7℃

[0256] 1 H NMR (500MHz, CDCl3) δ8.07 (s, 1H), 7.53 (d, J = 8.7Hz, 1H), 7.25 (s, 1H), 7.10 (d, J = 8.5Hz, 1H), 6.62 (t, J = 57.4Hz, 1H), 3.77 (s, 3H).

[0257] 19 F NMR (471MHz, CDCl3) δ-92.86 (d, J = 58.1Hz, 2F).

[0258] 13 C NMR (126MHz, CDCl3) δ136.89, 136.47, 132.92, 131.29, 128.40, 120.64 (t, J = 276.2Hz), 111.91, 93.55, 84.99, 33.48.

[0259] HRMS(ESI,m / z):[M+H] + Calcd.for C 10 H9F2INS + :339.9463; Found:339.9461.

[0260] Example 23

[0261] The specific compound prepared in Example 23 is Substrate is Elution with petroleum ether / ethyl acetate = 20 / 1 (v / v) yielded 105 mg of a yellow oily liquid, with a yield of 91%.

[0262] MPa: 63.9-65.2℃

[0263] 1 H NMR (500MHz, CDCl3) δ7.25(s,1H),7.20(td,J=8.1,4.8Hz,1H),7.13(d,J=7.6Hz,1H),6.92–6.84(m,1H),6.73(d,J=57.7Hz,1H),3.79(s,3H).

[0264] 19 F NMR (471MHz, CDCl3) δ-94.88 (dd, J=58.1, 3.5Hz, 2F), -125.53 (dq, J=12.1, 4.3Hz, 1F).

[0265] 13 C NMR (126MHz, CDCl3) δ157.78, 155.80, 140.18 (d, J = 9.9Hz), 136.83, 123.37 (d ,J=7.8Hz),120.83(t,J=276.0Hz),118.47,106.77–106.04(m),92.03,33.62.

[0266] HRMS(ESI,m / z):[M+H] + Calcd.for C 10 H9F3NS + :232.0402;Found:232.0403。

[0267] Example 24

[0268] The specific compound prepared in Example 24 is Substrate is Eluting with petroleum ether / ethyl acetate = 20 / 1 (v / v) gave 95 mg of white solid, yield 77%.

[0269] MPa: 72.7-74.2℃

[0270] 1 H NMR (500MHz, CDCl3) δ7.34 (s, 1H), 7.26 (q, J = 4.5Hz, 1H), 7.23–7.15 (m, 2H), 6.80 (t, J = 58.2Hz, 1H), 3.80 (s, 3H).

[0271] 19 F NMR (471MHz, CDCl3) δ-95.68 (d, J = 58.1Hz, 2F).

[0272] 13 C NMR (126MHz, CDCl3) δ138.78, 138.33, 126.64, 125.67, 123.29, 122.36, 121.41 (t, J = 276.0Hz), 108.99, 94.29, 33.59.

[0273] HRMS(ESI,m / z):[M+H] + Calcd.for C 10 H9ClF2NS + :248.0107;Found:248.0106;

[0274] Example 25

[0275] The specific compound prepared in Example 25 is Substrate is Elution with petroleum ether / ethyl acetate = 10 / 1 (v / v) yielded 124 mg of a yellow oily liquid, with a yield of 85%.

[0276] 1 H NMR (500MHz, CDCl3) δ8.18 (s, 1H), 7.53 (d, J = 8.4Hz, 1H), 7.37 (d, J = 1.6Hz, 1H), 7.34–7.24 (m, 1H), 6.62 (t, J = 57.1Hz, 1H), 2.51 (d, J = 1.3Hz, 3H).

[0277] 19 F NMR (471MHz, CDCl3) δ-92.38 (d, J = 57.2Hz, 2F).

[0278] 13C NMR (126MHz, CDCl3) δ143.54, 135.88, 129.94, 124.38, 120.99 (t, J = 276.0Hz), 120.08, 115.73, 113.74, 93.80, 12.27.

[0279] HRMS(ESI,m / z):[M+H] + Calcd.for C 10 H9BrF2NS + :291.9602; Found:293.9602.

[0280] Example 26

[0281] The specific compound prepared in Example 26 is Substrate is Elution with petroleum ether / ethyl acetate = 10 / 1 (v / v) yielded 100 mg of a yellow oily liquid, with a yield of 81%.

[0282] 1 H NMR (500MHz, CDCl3) δ8.16 (s, 1H), 7.58 (d, J = 8.4Hz, 1H), 7.20 (s, 1H), 7.17 (dd, J = 8.4, 1.8Hz, 1H), 6.63 (t, J = 57.1Hz, 1H), 2.51 (s, 3H).

[0283] 19 F NMR (471MHz, CDCl3) δ-92.35 (d, J = 57.2Hz, 2F).

[0284] 13 C NMR (126MHz, CDCl3) δ143.61, 135.44, 129.59, 128.17, 121.76, 121.02 (t, J = 276.2Hz), 119.67, 110.80, 93.64, 12.23.

[0285] HRMS(ESI,m / z):[M+H] + Calcd.for C 10 H9ClF2NS + :248.0107; Found:248.0105.

[0286] Example 27

[0287] The specific compound prepared in Example 27 is Substrate is Eluting with petroleum ether / ethyl acetate = 15 / 1 (v / v) gave 64.7 mg of a yellow solid, yield 57%.

[0288] MPa: 95.2-96.8℃

[0289] 1 H NMR (500MHz, CDCl3) δ8.16(s,1H),7.48(s,1H),7.20(d,J=8.1Hz,1H),7.03(d,J=8.2Hz,1H),6.62(t,J=57.6Hz,1H),2.54(s,3H),2.48(s,3H).

[0290] 19 F NMR (471MHz, CDCl3) δ-92.54 (d, J = 57.2Hz, 2F).

[0291] 13 C NMR (126MHz, CDCl3) δ142.77, 133.45, 131.13, 130.63, 124.02, 121.46 (t, J = 276.0Hz), 118.46, 93.05, 21.64, 12.31.

[0292] HRMS(ESI,m / z):[M+H] + Calcd.for C 11 H 12 F2NS + :228.0653; Found:228.0651.

[0293] Example 28

[0294] The specific compound prepared in Example 28 is Substrate is Elution with petroleum ether / ethyl acetate = 20 / 1 (v / v) yielded 72.8 mg of a yellow oily liquid, with a yield of 60%.

[0295] 1 H NMR (500MHz, CDCl3) δ8.22(s,1H),7.20–7.14(m,2H),6.85(dd,J=8.7,2.6Hz,1H),6.62(t,J=57.4Hz,1H),3.90(s,3H),2.51(s,3H).

[0296] 19 F NMR (471MHz, CDCl3) δ-92.40 (d, J = 57.2Hz, 2F).

[0297] 13 C NMR (126MHz, CDCl3) δ155.28, 143.37, 131.74, 130.02, 121.42 (t, J = 276.0Hz), 112.40, 111.65, 100.61, 93.13, 55.95, 12.32.

[0298] HRMS(ESI,m / z):[M+H] + Calcd.for C 11 H 12 F2NOS + :244.0602;Found:244.0602.

[0299] Example 29

[0300] The specific compound prepared in Example 29 is Substrate is Eluting with petroleum ether / ethyl acetate = 100 / 1 (v / v) gave 119 mg of a yellow solid, yield 82%.

[0301] 1 H NMR (500MHz, CDCl3) δ8.29(s,1H),7.79(s,1H),7.27(dd,J=8.5,1.9Hz,2H),7.15(d,J=8.5Hz,2H),6.61(t,J=57.2Hz,2H),2.53(s,6H).

[0302] 19 F NMR (471MHz, CDCl3) δ-92.53 (d, J = 57.2Hz, 2F).

[0303] 13 C NMR (126MHz, CDCl3) δ144.13, 133.85, 132.83, 125.42, 121.47, 120.91 (t, J = 276.2Hz), 114.63, 112.27, 93.28, 12.35.

[0304] HRMS(ESI,m / z):[M+H] + Calcd.for C 10 H9BrF2NS + :291.9602;Found:291.9601.

[0305] Example 30

[0306] The specific compound prepared in Example 30 is as follows: Substrate is Eluting with petroleum ether / ethyl acetate = 10 / 1 (v / v) yielded 90 mg of a red oily liquid, with a yield of 78%.

[0307] 1 H NMR (500MHz, CDCl3) δ8.25(s,1H),7.34(d,J=9.5Hz,1H),7.22(dt,J=7.6,3.3Hz,1H),6.93(t,J=9.1Hz,1H),6.62(t,J=57.3Hz,1H),2.55(s,3H).

[0308] 19 F NMR (471MHz, CDCl3) δ-92.53 (d, J=57.2Hz, 1F), -123.19 (td, J=9.1, 4.3Hz, 2F).

[0309] 13 C NMR (126MHz, CDCl3) δ158.97 (d, J = 236.2Hz), 144.60, 131.96 (d, J = 9.9Hz), 131. 55,121.04(t,J=276.0Hz),111.53(d,J=9.4Hz),110.63,104.27,93.71,12.43.

[0310] HRMS(ESI,m / z):[M+H] + Calcd.for C 10 H9F3NS + :232.0402;Found:232.0401.

[0311] Example 31

[0312] The specific compound prepared in Example 31 is Substrate is Eluting with petroleum ether / ethyl acetate = 20 / 1 (v / v) gave 80.9 mg of a yellow solid, yield 70%.

[0313] 1 H NMR (500MHz, CDCl3) δ8.48 (s, 1H), 6.68–6.35 (m, 1H), 4.29 (q, J = 7.1Hz, 2H), 2.51 (s, 3H), 2.34 (s, 3H), 1.35 (t, J = 7.2Hz, 3H).

[0314] 19 F NMR (471MHz, CDCl3) δ-92.95 (d, J = 57.2Hz, 2F).

[0315] 13 C NMR (126MHz, CDCl3) δ165.58, 139.49, 132.19, 120.18 (t, J = 277.5Hz), 112.98, 105.70, 59.67, 14.45 (d, J = 26.0Hz), 12.25.

[0316] HRMS(ESI,m / z):[M+H] + Calcd.for C 10 H 14 F2NO2S + :250.0708;Found:250.0708.

[0317] Example 32

[0318] The specific compound prepared in Example 32 is Substrate is through 19 F NMR spectroscopy analysis determined the yield to be 36%.

[0319] 19 F NMR (471MHz, MeCN) δ-93.5 (d, J = 58.5Hz, 2F).

[0320] Example 33 Gram-scale operation of difluoromethylthiolation in acetonitrile with 1-methyl-2-difluoromethanesulfonylpyridinium salt of trifluoromethanesulfonate.

[0321]

[0322] Under a nitrogen atmosphere, a magnetic stir bar was added sequentially to a 250 mL reaction flask. (7.08g, 20mmol, 2.0 equivalents) (2.21 g, 10 mmol, 1.0 equivalent), (EtO)₂P(O)H (5.0 mL, 40 mmol, 4.0 equivalent), TMSCl (5.0 mL, 40 mmol, 4.0 equivalent), and anhydrous acetonitrile (50 mL). The mixture was stirred at 80 °C for 18 hours. After the reaction was complete, the reaction solution was partitioned with ethyl acetate (20 mL) and water (50 mL). The aqueous layer was extracted with ethyl acetate (5 × 20 mL), and the combined organic phases were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by silica gel column chromatography with petroleum ether / ethyl acetate (100:1 v / v) as the mobile phase to obtain the target product. 2.15g, yield 71%. Structural confirmation data are the same as in Example 13.

[0323] Examples 34-40: Typical procedure for difluoromethylthiolation in DMF using 1-methyl-2-difluoromethanesulfonylpyridinium salt of trifluoromethanesulfonate.

[0324]

[0325] Add 1-methyl-2-difluoromethanesulfonylpyridinium to a 10 mL Schlenk tube. (712mg, 2.0mmol) and (1.0 mmol). Anhydrous DMF (5 mL) was added under a nitrogen atmosphere. The mixture was stirred at 80 °C for 6 hours. After the reaction was complete, 25 μL of trifluorotoluene was added as an internal standard. 19 The yield was determined by 1F NMR spectroscopy. The post-processing steps were as follows: 5 ml of saturated ammonium chloride aqueous solution was added, followed by 50 ml of water, and then the mixture was extracted three times with EA (20*3). Dry column chromatography was used for separation, and petroleum ether and ethyl acetate were used for elution and purification.

[0326] Example 34

[0327] The specific compound prepared in Example 34 is Substrate is through 19 F NMR spectroscopy analysis showed a yield of 72%. Structural confirmation data were the same as in Example 4.

[0328] Example 35

[0329] The specific compound prepared in Example 35 is Substrate is through 19 FNMR spectroscopy analysis showed a yield of 76%. Structural confirmation data were the same as in Example 7.

[0330] Example 36

[0331] The specific compound prepared in Example 36 is Substrate is through 19 FNMR spectroscopy analysis showed a yield of 81%. Structural confirmation data were the same as in Example 9.

[0332] Example 37

[0333] The specific compound prepared in Example 37 is Substrate is through 19 FNMR spectroscopy analysis showed a yield of 84%. Structural confirmation data were the same as in Example 12.

[0334] Example 38

[0335] The specific compound prepared in Example 38 is Substrate is through 19 F NMR spectroscopy analysis showed a yield of 74%. Structural confirmation data were the same as in Example 28.

[0336] Example 39

[0337] The specific compound prepared in Example 39 is Substrate is through 19 FNMR spectroscopy analysis showed a yield of 81%. Structural confirmation data were the same as in Example 30.

[0338] Example 40

[0339] The specific compound prepared in Example 40 is as follows:

[0340] Substrate is through 19 F NMR spectroscopy analysis showed a yield of 69%.

[0341] Examples 41-43 and Control Example 1: Effects of different sulfone structures on the reaction

[0342]

[0343] Add the appropriate sulfone reagent to a 10 mL Schlenk tube. (0.6 mmol, 2.0 equivalent) and (0.30 mmol, 1.0 equivalent). Under a nitrogen atmosphere, (EtO)₂P(O)H (1.2 mmol, 4.0 equivalent), TMSCl (1.2 mmol, 4.0 equivalent), and anhydrous acetonitrile (2 mL) were added sequentially to a test tube using a syringe. The mixture was stirred at 80 °C for 6 hours.

[0344] Add 25 μL of trifluorotoluene as an internal standard, and then... 19 F NMR spectroscopy analysis The yield.

[0345]

[0346]

[0347] Effect of additives on the reaction in acetonitrile in Examples 44-48 and Comparative Examples 2-3

[0348]

[0349] Add sulfone reagent to a 10 mL Schlenk tube (0.6 mmol, 2.0 equivalent) and (0.30 mmol, 1.0 equivalent). Under a nitrogen atmosphere, the additive and anhydrous acetonitrile (2 mL) were added. The mixture was stirred at 80 °C for 6 hours. 25 μL of trifluorotoluene was added as an internal standard. 19 F NMR spectroscopy analysis The yield.

[0350]

[0351] Effects of solvent on the reaction when (EtO)₂P(O)H / TMSCl is used as an additive in Examples 49-50 and Control Examples 4-5

[0352]

[0353] Add sulfone reagent to a 10 mL Schlenk tube. (0.6 mmol, 2.0 equivalent) and (0.30 mmol, 1.0 equivalent). Under a nitrogen atmosphere, (EtO)₂P(O)H (1.2 mmol, 4.0 equivalent), TMSCl (1.2 mmol, 4.0 equivalent), and solvent (2 mL) were added sequentially to a test tube using a syringe. The mixture was stirred at 80 °C for 6 hours. 25 μL of trifluorotoluene was added as an internal standard. 19 F NMR spectroscopy analysis The yield.

[0354] Example solvent <![CDATA[ 19 F NMR spectral yield]]> Example 49 Acetonitrile 93％ Example 50 Toluene 84％ Compare with Example 4 Tetrahydrofuran 33％ Compare with Example 5 DMF 50％

[0355] Effect of temperature on the reaction when (EtO)2P(O)H / TMSCl is used as an additive in Examples 51-53

[0356]

[0357] Add sulfone reagent to a 10 mL Schlenk tube. (0.6 mmol, 2.0 equivalent) and (0.30 mmol, 1.0 equivalent). Under a nitrogen atmosphere, (EtO)₂P(O)H (1.2 mmol, 4.0 equivalent), TMSCl (1.2 mmol, 4.0 equivalent), and solvent (2 mL) were added sequentially to a test tube using a syringe. The mixture was stirred at 80°C, 60°C, or 40°C for 6 hours. 25 μL of trifluorotoluene was added as an internal standard. 19 F NMR spectroscopy analysis The yield.

[0358] Example temperature <![CDATA[ 19 F NMR spectral yield]]> Example 51 80℃ 93％ Example 52 60℃ 80％ Example 53 40℃ 50％

[0359] Example 54: Effect of reducing reagent dosage in acetonitrile on the reaction

[0360]

[0361] Add sulfone reagent to a 10 mL Schlenk tube. (0.45 mmol, 1.5 equivalents) and (0.30 mmol, 1.0 equivalent). Under a nitrogen atmosphere, (EtO)₂P(O)H (0.9 mmol, 3.0 equivalent), TMSCl (0.9 mmol, 3.0 equivalent), and solvent (2 mL) were added sequentially to a test tube using a syringe. The mixture was stirred at 80 °C for 6 hours. 25 μL of trifluorotoluene was added as an internal standard. 19 F NMR spectroscopy analysis The yield was 84%.

[0362] Effect of solvent on reaction in Examples 55-56 and Comparative Examples 6-9 without additives

[0363]

[0364] Add sulfone reagent to a 10 mL Schlenk tube. (0.6 mmol, 2.0 equivalent) and (0.30 mmol, 1.0 equivalent). Under a nitrogen atmosphere, add 2 mL of solvent to a test tube using a syringe. Stir the mixture at 80 °C for 6 hours. Add 25 μL of trifluorotoluene as an internal standard. 19 F NMR spectroscopy analysis The yield.

[0365] solvent <![CDATA[ 19 F NMR spectral yield]]> Example 55 DMF 72％ Example 56 NMP 67％ Compare with Example 6 DMSO 0％ Compare with Example 7 Acetonitrile 0％ Compare with Example 8 Tetrahydrofuran 0％ Compare with Example 9 Toluene 0％

[0366] Effect of reagent dosage on the reaction in DMF without additives in Examples 57 and 10-11 (Comparative Examples 10-11)

[0367]

[0368] Add the appropriate amount of sulfone reagent to a 10 mL Schlenk tube. (0.30 mmol, 1.0 equivalent). Under a nitrogen atmosphere, DMF (2 mL) was added to a test tube using a syringe. The mixture was stirred at 80 °C for 6 hours. Trifluorotoluene was added as an internal standard. 19 F NMR spectroscopy analysis The yield.

[0369]

[0370]

[0371] Examples 58-60: Typical procedures for preparing sulfoxides in DMF without additives

[0372]

[0373] Add to a 10 mL reaction tube (1.0 mmol, 1.0 equivalent) and

[0374] (1.0 mmol, 1.0 equivalent). DMF (5 mL) was added under a nitrogen atmosphere. The mixture was stirred at 80 °C for 6 hours. After the reaction was complete, the mixture was post-treated with water (50 mL). The aqueous layer was extracted with ethyl acetate (5 × 10 mL), and the combined organic phases were washed with 5% lithium chloride aqueous solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by silica gel column chromatography to obtain the target product.

[0375] Example 58

[0376] The specific compound prepared in Example 58 is Substrate is Eluting with petroleum ether / ethyl acetate = 2 / 1 (v / v) gave 198 mg of a yellow solid, yield 80%.

[0377] MPa: 157.2-158.9℃.

[0378] 1 H NMR (500MHz, CD3CN) δ10.08 (s, 1H), 7.52 (dd, J = 9.6, 2.7 Hz, 1H), 7.43 (dd, J = 8. 9,4.5Hz,1H),7.02(td,J=9.2,2.6Hz,1H),6.74(t,J=51.8Hz,1H),2.53(s,3H).

[0379] 19 F NMR (471MHz, CD3CN) δ-119.19 (dd, J=261.8, 54.6Hz, 1F), δ-122.76 (dd, J=207.24, 55.5Hz, 1F), -123.10 (td, J=9.5, 4.3Hz, 1F).

[0380] 13C NMR(126MHz,CD3CN)δ159.36(d,J=235.1Hz),145.78,133.39,126.73(d,J=10.9Hz),120.90(t, J=283.5Hz), 113.92 (d, J=9.9Hz), 111.91 (d, J=26.0Hz), 105.75, 105.42 (d, J=25.5Hz), 12.41.

[0381] HRMS(ESI,m / z):[M+H] + Calcd.for C 10 H9F3NOS + :248.0351; Found:248.0349.

[0382] Example 59

[0383] The specific compound prepared in Example 59 is Substrate is Add 25 μL of trifluorotoluene as an internal standard, and then... 19 F NMR spectroscopy analysis determined the yield to be 88%. Elution with petroleum ether / ethyl acetate = 2 / 1 (v / v) gave 153 mg of a yellow solid, yielding 71%.

[0384] Example 60

[0385] The specific compound prepared in Example 60 is as follows: Substrate is Add 25 μL of trifluorotoluene as an internal standard, and then... 19 F NMR spectroscopy analysis determined the yield to be 92%. Elution with petroleum ether / ethyl acetate = 4 / 1 (v / v) gave 254 mg of a yellow solid, yielding 83%.

[0386] Examples 61-64: Effect of subsequent addition of additives to DMF on the reaction

[0387]

[0388] Add to a 10 mL reaction tube (0.3 mmol, 1.0 equivalent) and (0.30 mmol, 1.0 equivalent). Under a nitrogen atmosphere, add DMF (2 mL). Stir the mixture at 80 °C for 6 hours. Cool the reaction system to -20 °C, add diphenylphosphine chloride (Ph₂PCl) (0.30 mmol, 1.0 equivalent), phosphorus trichloride (PCl₃) (0.30 mmol, 1.0 equivalent), trichlorophosphorus (CO(OCCl₃)₂) (0.30 mmol, 1.0 equivalent), or oxaloyl chloride (COCl)₂ (0.30 mmol, 1.0 equivalent), and slowly raise the temperature to room temperature while stirring. The reaction proceeds for 6 hours. Add 25 μL of trifluorotoluene as an internal standard. 19 F NMR spectroscopy analysis The yield. The structural confirmation data are the same as in Example 4.

[0389] additive <![CDATA[ 19 F NMR spectral yield]]> Example 61 <![CDATA[Ph₂PCl (0.30 mmol, 1.0 equivalent)]]> 70％ Example 62 <![CDATA[PCl3 (0.30 mmol, 1.0 equivalent)]]> 65％ Example 63 <![CDATA[CO(OCCl3)2 (0.30 mmol, 1.0 equivalent)]]> 62％ Example 64 <![CDATA[(COCl)2 (0.30 mmol, 1.0 equivalent)]]> 60％

[0390] Example 65: One-pot difluoromethyl sulfidation starting from 2-PySO2CF2H

[0391]

[0392] Difluoromethyl(2-pyridyl) sulfone was added to a 10 mL reaction tube. (193 mg, 1.0 mmol, 2.0 equivalents) was added, and three vacuum / nitrogen cycles were performed to establish an inert atmosphere. Anhydrous dichloromethane (1 mL) was added, and the mixture was cooled to 0 °C. Methyl trifluoromethanesulfonate (3.0 mmol, 6.0 equivalents) was added in one go, and the reaction system was then brought to room temperature and stirred for 18 hours. After the reaction was complete, the upper solvent layer was removed by pipetting, and the lower liquid layer was washed with anhydrous dichloromethane (3 × 0.5 mL). The resulting oily liquid was dried under high vacuum. Then, under a nitrogen atmosphere, [the following was added]... (0.5 mmol, 1.0 equivalent) and DMF (3 mL). The mixture was stirred at 80 °C for 6 hours. After the reaction was complete, 25 μL of trifluorotoluene was added as an internal standard, and the solution was analyzed. 19 F NMR spectroscopy analysis determined the yield to be 65%.

[0393] The structural verification data is the same as in Example 4.

[0394] Examples 66-69: Fluoroalkyl sulfidation of indole by various fluoroalkyl (2-pyridyl) sulfones

[0395]

[0396] A fluoroalkyl(2-pyridyl) sulfone was added to a 10 mL reaction tube. (1.0 mmol, 2.0 equivalents) was added, and three vacuum / nitrogen cycles were performed to establish an inert atmosphere. Anhydrous dichloromethane (1 mL) was added, and the mixture was cooled to 0 °C. Methyl trifluoromethanesulfonate (3.0 mmol, 6.0 equivalents) was added in one go, and the reaction system was then brought to room temperature and stirred for 18 hours. After the reaction was complete, the upper solvent layer was removed by pipetting, and the lower liquid layer was washed with anhydrous dichloromethane (3 × 0.5 mL). The resulting oily liquid was dried under high vacuum. Then, under a nitrogen atmosphere, [the following was added]... (0.5 mmol, 1.0 equivalent) and DMF (3 mL). The mixture was stirred at 80 °C for 6 hours. After the reaction was complete, 25 μL of trifluorotoluene was added as an internal standard, and the solution was analyzed. 19 F NMR spectroscopy was used to determine the yield of the target product.

[0397] Post-processing steps: Add 3 mL of saturated ammonium chloride aqueous solution and 30 mL of water, extract multiple times with EA (10*5), evaporate to dryness, and separate by column chromatography with PE / EA.

[0398] Example 66

[0399] The specific compound prepared in Example 66 is as follows: The reagent is Add 25 μL of trifluorotoluene as an internal standard, and then... 19 F NMR spectroscopy analysis determined the yield to be 75%. 19 F NMR (471MHz, DMF) δ-183.0 (t, J = 52.4Hz, 1F).

[0400] Example 67

[0401] The specific compound prepared in Example 67 is as follows: The reagent is Add 25 μL of trifluorotoluene as an internal standard, and then... 19 F NMR spectroscopy analysis determined the yield to be 68%. 19 F NMR(471MHz,DMF)δ-44.0(s,3F).

[0402] Example 68

[0403] The specific compound prepared in Example 68 is The reagent is Add 25 μL of trifluorotoluene as an internal standard, and then... 19 F NMR spectroscopy analysis determined the yield to be 63%. 19 F NMR (471MHz, DMF) δ -82.7 (t, J = 3.5Hz, 3F), -93.3 (q, J = 3.5Hz, 2F).

[0404] Example 69

[0405] The specific compound prepared in Example 69 is The reagent is Add 25 μL of trifluorotoluene as an internal standard, and then... 19 F NMR spectroscopy analysis determined the yield to be 70%. 19 F NMR(471MHz,DMF)δ-84.5(s,2F).

[0406] Examples 70-72: Typical Operations of Modular Sulfonation Modification of 2-PySO2CF2H

[0407]

[0408] Will 2.0 mmol (1.0 equivalent) and dithioether (RS)₂ (2.4 mmol, 1.2 equivalent) were dissolved in DMF (20 mL). tBuONa (5.0 mmol, 2.5 equivalent) was slowly added to the reaction system at room temperature. The reaction system was gently shaken while adding the base, and the reaction was complete upon addition. The reaction mixture was then poured into ice water, resulting in a white precipitate. After filtration and drying under vacuum, the obtained solid, acetonitrile (10 mL), dichloromethane (5 mL), and water (15 mL) were added to a reaction flask. The reaction mixture was then cooled to 0 °C in an ice-water bath, followed by the sequential addition of sodium periodate (9.2 mmol, 4.6 equivalent) and RuCl₃·xH₂O (5 mg). The mixture was slowly heated to room temperature and stirred for 18 hours. After the reaction was complete, water was added for dilution, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under vacuum. The resulting white solid was the target product.

[0409] Example 70

[0410] The specific compound prepared in Example 70 is as follows:

[0411] The disulfide used is 315 mg of white solid was obtained, with a yield of 58%.

[0412] Example 71

[0413] The specific compound prepared in Example 71 is

[0414] The disulfide used is 534 mg of white solid was obtained, with a yield of 81%.

[0415] Example 72

[0416] The specific compound prepared in Example 72 is

[0417] The disulfide used is 485 mg of white solid was obtained, with a yield of 69%.

[0418] Examples 73-75: Typical Operations of Indole Fluoroalkyl Sulfation with 2-PySO2CF2H Derivatives

[0419]

[0420] A derivative of 2-PySO2CF2H was added to a 10 mL reaction tube. (0.5 mmol, 2.0 equivalents) was added, and three vacuum / nitrogen cycles were performed to establish an inert atmosphere. Anhydrous dichloromethane (2 mL) was added, and the mixture was cooled to 0 °C. Methyl trifluoromethanesulfonate (1.5 mmol, 6.0 equivalents) was added in one go, and the reaction system was then brought to room temperature and stirred for 18 hours. After the reaction was complete, the upper solvent layer was removed by pipetting, and the residue was washed with anhydrous dichloromethane (3 × 1 mL). The resulting solid was dried under high vacuum. Then, under a nitrogen atmosphere, [the following was added]... (0.25 mmol, 1.0 equivalent) and DMF (1.5 mL). The mixture was stirred at 80 °C for 6 hours. After the reaction was complete, trifluorotoluene was added as an internal standard, and the mixture was subjected to... 19 F NMR spectroscopy was used to determine the yield of the target product.

[0421] Example 73

[0422] The specific compound prepared in Example 73 is The derivative of 2-PySO2CF2H used is Add 25 μL of trifluorotoluene as an internal standard, and then... 19 F NMR spectroscopy analysis determined the yield to be 66%. 19 FNMR(471MHz,DMF)δ-78.9(s,2F).

[0423] Example 74

[0424] The specific compound prepared in Example 74 is

[0425] The derivative of 2-PySO2CF2H used is Add 25 μL of trifluorotoluene as an internal standard, and then... 19 F NMR spectroscopy analysis determined the yield to be 61%. 19 F NMR(471MHz,DMF)δ-79.0(s,2F).

[0426] Example 75

[0427] The specific compound prepared in Example 75 is

[0428] The derivative of 2-PySO2CF2H used is Add 25 μL of trifluorotoluene as an internal standard, and then... 19 F NMR spectroscopy analysis determined the yield to be 63%. 19 F NMR(471MHz,DMF)δ-79.4(s,2F).

[0429] Examples 76-77: Typical Operations of Modular Functionalization Modification of 2-PySO2CF2H

[0430]

[0431] Will LiHMDS (10.0 mmol, 1.0 equivalent) and iodide (20 mmol, 2.0 equivalent) or diethyl carbonate were dissolved in THF (70 mL) and HMPA (7.7 mL). LiHMDS (22 mmol, 2.2 equivalent) was slowly added to the reaction system at -80 °C. The reaction system was gently shaken while adding the base, and the reaction was complete after the addition of the base. The reaction was then quenched with 8 mL of saturated ammonium chloride aqueous solution, followed by the addition of 80 mL of water and extraction with EA (20*3). After drying with MgSO4, the solution was filtered and rotary evaporated. The solution was then column-filtered with a specific eluent ratio and concentrated under vacuum to obtain the target product.

[0432] Example 76

[0433] The specific compound prepared in Example 76 is

[0434] The iodide used was iodomethane, yielding 1.68 g of a white solid, with a yield of 81%.

[0435] Example 77

[0436] The specific compound prepared in Example 77 is

[0437] The iodide used was iodomethane, yielding 1.1 g of a yellow solid, with a yield of 50%.

[0438] Examples 78-79: Typical operation of indole-fluoroalkyl sulfidation with 2-PySO2CF2H derivative.

[0439]

[0440] Example 78

[0441] The specific compound prepared in Example 78 is The derivative of 2-PySO2CF2H used is Add 25 μL of trifluorotoluene as an internal standard, and then... 19 F NMR spectroscopy analysis determined the yield to be 83%. 19 F NMR (471MHz, DMF) δ-67.0 (q, J = 16.5Hz, 2F).

[0442] Example 79

[0443] The specific compound prepared in Example 79 is

[0444] The derivative of 2-PySO2CF2H used is Add 25 μL of trifluorotoluene as an internal standard, and then... 19 F NMR spectroscopy analysis determined the yield to be 80%. 19 F NMR (471MHz, DMF) δ-75.8 (t, J=13.2Hz, 2F).

Claims

1. A method for preparing a compound as shown in Formula I, characterized in that, It is selected from the following options: Option 1: In a solvent, in the presence of an additive, the compound shown in Formula II and the compound shown in Formula III are reacted as shown above to obtain the compound shown in Formula I; the additive is diphenylphosphine chloride or is composed of an organophosphorus reagent and an auxiliary agent; the auxiliary agent is a compound shown in Formula H or K. Option 2: In an amide solvent, the compound shown in Formula II and the compound shown in Formula III are reacted as shown in the above formula to obtain the compound shown in Formula I; Where ring A is C 6-10 Aryl or 5-12 heteroaryl groups; m is 1, 2, or 3; R a Independent of H, halogen, C 1-6 Alkyl, -OC 1-6 Alkyl, -C(O)OC 1-6 Alkyl, C 6-10 aryl, 5-12 heteroaryl, with one or more R 1-1 Replacement C 1-6 Alkyl, with one or more R 1-1 Replacement -OC 1-6 Alkyl, with one or more R 1-1 Substituted -C(O)OC 1-6 Alkyl, with one or more R 1-1 Replacement C 6-10 aryl or aryl with one or more R 1-1 Substituted 5-12 heteroaryl groups; R b For H, C 1-6 Alkyl, -OC 1-6 Alkyl, C 6-10 aryl, 5-12 heteroaryl, with one or more R 1-2 Replacement C 1-6 Alkyl, with one or more R 1-2 Replacement -OC 1-6 Alkyl, with one or more R 1-2 Replacement C 6-10 aryl or aryl with one or more R 1-2 Substituted 5-12 heteroaryl groups; R 1-1 and R 1-2 Halogens are independent of each other; R 1 H, halogen, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, -C(O)OC 1-6 alkyl or R 2 H, halogen, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, -C(O)OC 1-6 alkyl or R 1-3 Independently for C 1-6 Alkyl, C 6-10 aryl, 5-12 heteroaryl, with one or more R 1-2 Replacement C 6-10 aryl or aryl with one or more R 1-2 Substituted 5-12 heteroaryl groups; R 3 for R 1-4 Independently for C 1-6 alkyl; Y - for - OTf or - BF4; The heteroatoms in the 5-12 membered heteroaryl group are independently selected from one, two, or three of N, O, and S, and the number of heteroatoms is independently one, two, or three. R c and R d Independently for C 1-6 alkyl.

2. The method for preparing the compound of formula I as described in claim 1, characterized in that, The compound shown in Formula II is W independently for -NR a1 , O or S; R a1 H, halogen, C 1-6 Alkyl, -OC 1-6 Alkyl, -C(O)OC 1-6 Alkyl, C 6-10 aryl, 5-12 heteroaryl, with one or more R 1-1 Replacement C 1-6 Alkyl, with one or more R 1-1 Replacement -OC 1-6 Alkyl, with one or more R 1-1 Substituted -C(O)OC 1-6 Alkyl, with one or more R 1-1 Replacement C 6-10 aryl or aryl with one or more R 1-1 The substituted 5-12-membered heteroaryl group; the heteroatoms in the 5-12-membered heteroaryl group are independently selected from one, two or three of N, O and S, and the number of heteroatoms is independently one, two or three; Or, one of the R a R a1 Together with the atoms attached thereto, it forms a 5-6 membered heterocycle; ring A1 is phenyl or a 5-6 membered heteroaryl, wherein the heteroatoms of the 5-6 membered heteroaryl are selected from one, two or three of N, O and S, and the number of the heteroatoms is one, two or three; the 5-6 membered heterocycle optionally also includes one, two or three heteroatoms selected from N, O and S, and the number of the heteroatoms is one, two or three.

3. The method for preparing the compound of formula I as described in claim 1 or 2, characterized in that, It meets one or more of the following conditions: (1)R a Independent of H, halogen, C 1-6 Alkyl, -OC 1-6 Alkyl, -C(O)OC 1-6 Alkyl, C 6-10 aryl, 5-12 heteroaryl, surrounded by one or more R 1-1 Replacement C 6-10 aryl or aryl with one or more R 1-1 Substituted 5-12 heteroaryl groups; for example, R a Independently, H, fluorine, chlorine, bromine, iodine, methyl, ethyl, tert-butyl, methoxy, phenyl, (2)R a1 For H, C 1-6 Alkyl or C 6-10 Aryl; for example, H, methyl, ethyl, tert-butyl, or phenyl; (3)R b For H, C 1-6 Alkyl, -OC 1-6 Alkyl, C 6-10 aryl, 5-12 heteroaryl, with one or more R 1-2 Replacement C 6-10 aryl or aryl with one or more R 1-2 Substituted 5-12 heteroaryl groups, such as H, methyl, ethyl, tert-butyl, methoxy, phenyl, (4)R 1-1 and R 1-2 For F; (5)R 1-3 C 1-6 Alkyl, C 6-10 aryl or aryl with one or more R 1-2 Replacement C 6-10 Aryl; for example, R 1-3 Methyl, phenyl or Better yet, R 2 For H, F, CF3, methyl, ethyl, (6)R 1-4 It is methyl; (7)R 1 It is H or a halogen, such as H or F.

4. The method for preparing the compound of formula I as described in claim 1, characterized in that, It meets one or more of the following conditions: (1) The compound shown in Formula II is any of the following compounds: (2) The compound shown in Formula III is any of the following compounds: Preferably, the compound shown in Formula I is any of the following compounds:

5. A method for preparing the compound of formula I as described in any one of claims 1, 2, or 4, characterized in that, It meets one or more of the following conditions: (1) In schemes 1 and 2, the reaction is carried out in an inert atmosphere, such as a nitrogen atmosphere; (2) In Scheme 1, the solvent is a nitrile solvent, an ether solvent, a benzene solvent or an amide solvent, for example, a nitrile solvent or a benzene solvent, or for example, a nitrile solvent; Preferably, the nitrile solvent is acetonitrile; the ether solvent is tetrahydrofuran; the benzene solvent is toluene; and the amide solvent is N,N-dimethylformamide or N-methylpyrrolidone. (3) In Scheme 1, the ratio of the number of moles of the compound shown in Formula II to the volume of the solvent is (0.01-1) mmol:1 mL, for example (0.05-0.5) mmol:1 mL, or for example 0.15 mmol:1 mL, 0.17 mmol:1 mL or 0.2 mmol:1 mL; (4) In Scheme 1, the molar ratio of the compound shown in Formula III to the compound shown in Formula II is (1-5):1, for example (1-3):1, or for example 1.5:1 or 2:1; (5) In Scheme 1, the additive is diphenylphosphine chloride; preferably, the molar ratio of the diphenylphosphine chloride to the compound shown in Formula II is (1-10):1, for example (1-8):1, or for example 4:1; (6) In Scheme 1, the additive consists of an organophosphorus reagent and an auxiliary agent; preferably, the organophosphorus reagent is triphenylphosphine or (R z O)2P(O)H,R z Independently for C 1-4 Alkyl; more preferably, the (R) z O)2P(O)H is dimethyl phosphite or diethyl phosphite; more preferably, the organophosphorus reagent is diethyl phosphite; (7) In Scheme 1, the auxiliary agent is trimethylchlorosilane or tetrabutylammonium chloride; (8) The molar ratio of the organophosphorus reagent to the compound shown in Formula II is (1-10):1, for example (2-8):1, or for example 3:1 or 4:1; (9) The molar ratio of the adjuvant to the compound shown in Formula II is (1-10):1, for example (2-8):1, or for example 3:1 or 4:1; (10) In Scheme 1, the temperature of the reaction is 30-100°C, for example 40-90°C, or for example 40°C, 60°C or 80°C; (11) In Scheme 1, after the reaction is completed, a post-processing step is also included, which includes extraction, drying, filtration and purification, such as column chromatography, with petroleum ether or petroleum ether / ethyl acetate as the eluent. (12) In Scheme 1, the components in the reaction system consist of the solvent, the additive, the compound as shown in Formula II and the compound as shown in Formula III; (13) In Scheme 2, the amide solvent is N,N-dimethylformamide or N-methylpyrrolidone, for example, N,N-dimethylformamide; (14) In Scheme 2, the ratio of the number of moles of the compound shown in Formula II to the volume of the amide solvent is (0.01-1) mmol:1 mL, for example (0.05-0.5) mmol:1 mL, or for example 0.15 mmol:1 mL, 0.17 mmol:1 mL or 0.2 mmol:1 mL; (15) In Scheme 2, the molar ratio of the compound shown in Formula III to the compound shown in Formula II is (1.5-5):1, for example (2-5):1, or for example 2:1 or 2.5:1; (16) In Scheme 2, the temperature of the reaction is 30-100°C, for example 40-90°C, or for example 40°C, 60°C or 80°C; (17) In Scheme 2, after the reaction is completed, a post-processing step is also included, which includes extraction, drying, filtration and purification, such as column chromatography, with petroleum ether or petroleum ether / ethyl acetate as the eluent; (18) In Scheme 2, the components in the reaction system consist of the solvent, the compound shown in Formula II and the compound shown in Formula III.

6. A method for preparing a compound as shown in Formula I-1, characterized in that, It includes the following steps: In an amide solvent, the compound shown in Formula II and the compound shown in Formula III are subjected to a sulfonation reaction as shown above to obtain the compound shown in Formula I-1; The molar ratio of the compound shown in Formula III to the compound shown in Formula II is (0.1-1.5):1; m, ring A, R a R b R 1 R 2 R 3 The definition is as described in any one of claims 1-4.

7. The method for preparing the compound as shown in Formula I-1 as described in claim 6, characterized in that, It meets one or more of the following conditions: (1) The reaction is carried out in an inert atmosphere, such as a nitrogen atmosphere; (2) The amide solvent is N,N-dimethylformamide or N-methylpyrrolidone, for example, N,N-dimethylformamide; (3) The ratio of the number of moles of the compound shown in Formula II to the volume of the amide solvent is (0.01-1) mmol:1 mL, for example (0.05-0.5) mmol:1 mL, or for example 0.15 mmol:1 mL, 0.17 mmol:1 mL or 0.2 mmol:1 mL; (4) The molar ratio of the compound shown in Formula III to the compound shown in Formula II is (0.5-1):1, for example 1:1; (5) The temperature of the sulfonation reaction is 30-100℃, for example 40-90℃, or for example 40℃, 60℃ or 80℃; (6) After the sulfonation reaction is completed, a post-processing step is also included, which includes extraction, drying, filtration and purification, such as column chromatography, with petroleum ether or petroleum ether / ethyl acetate as the eluent; (7) The components in the sulfonation reaction system consist of the solvent, the compound shown in Formula II and the compound shown in Formula III.

8. A method for preparing a compound as shown in Formula I, characterized in that, It includes the following steps: In a solvent, in the presence of a reducing agent, the compound shown in Formula I-1 is subjected to the reduction reaction shown in the following formula to obtain the compound shown in Formula I; m, ring A, R a R b R 1 and R 2 The definition is as described in any one of claims 1-4.

9. The method for preparing the compound as shown in Formula I according to claim 8, characterized in that, It meets one or more of the following conditions: (1) The reduction reaction is carried out in an inert atmosphere, such as a nitrogen atmosphere; (2) The solvent is an amide solvent, such as N,N-dimethylformamide or N-methylpyrrolidone, such as N,N-dimethylformamide; (3) The ratio of the number of moles of the compound shown in Formula I-1 to the volume of the amide solvent is (0.01-1) mmol:1 mL, for example (0.05-0.5) mmol:1 mL, or for example 0.15 mmol:1 mL, 0.17 mmol:1 mL or 0.2 mmol:1 mL; (4) The reducing agent is diphenylphosphine chloride, phosphorus trichloride, oxalyl chloride or triphosgene; (5) The molar ratio of the reducing agent to the compound shown in Formula I-1 is (1-5):1, for example (1-3):1, or for example 1:1; (6) The reaction temperature is 10-40℃, for example 20-25℃; (7) The components in the system of the reduction reaction consist of the solvent, the compound as shown in Formula I-1 and the reducing agent; (8) The method for preparing the compound as shown in Formula I further includes the method for preparing the compound as shown in Formula I-1 as described in claim 5.

10. A compound as shown in Formula III-1 R 1 and R 2 The definition is as described in any one of claims 1-4; for example

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