A difluoromethyl reagent, its preparation method and application

Abstract

The application discloses a difluoromethyl reagent, a preparation method and application thereof, relates to the design and invention of a difluoromethyl reagent and the technical field of compound preparation. The difluoromethyl reagent has the following general structure: wherein X is BF4, OTf or PF6; and R is alkoxy, halogen, NO2, CN or CF3. The reagent is a kind of stable and wide-spectrum difluoromethyl reagent, is convenient to use and operate, and can efficiently perform various difluoromethyl conversion reactions.

Description

Technical Field

[0001] This invention relates to the field of design and invention of difluoromethyl reagents and compound preparation technology, and particularly to a difluoromethyl reagent, its preparation method and application. Background Technology

[0002] The introduction of fluorine atoms into small organic molecules often results in unique physical, chemical, and biological properties. Therefore, fluorine-containing functional molecules have found wide application in medicine, pesticides, materials, and other fields, playing a particularly important role in drug development. Fluorine-containing drugs have become a hot topic in new drug research, and currently, fluorine modification of bioactive molecules and lead compounds has become a routine strategy in new drug design and development.

[0003] Difluoroalkyl groups are important structural building blocks, commonly found in pharmaceuticals, pesticides, and functional materials, playing a particularly important role in drug design and discovery, and are widely used in drug development. Difluoromethyl (CF₂H) is a bioisostere of groups such as hydroxyl (OH) and thiol (SH). Furthermore, hydrogen bonding between drug molecules and target proteins is a crucial factor influencing drug pharmacological activity and target affinity. As a hydrogen bond donor, difluoromethyl (CF₂H) exhibits better lipophilicity than hydroxyl (OH) and amino (NH) groups, which can improve the lipophilicity, membrane permeability, bioavailability, and other pharmacokinetic properties of drug molecules. Therefore, developing stable, practical, and efficient difluoromethyl reagents and their corresponding green and efficient difluoromethyl reactions can selectively introduce difluoromethyl building blocks into bioactive molecules and drug molecules, facilitating the study of the relationship between drug structure and properties, the discovery of new lead compounds or candidate drug molecules with special properties, and ultimately accelerating new drug development. Therefore, the development of difluoromethyl reagents and the development of new difluoromethyl reaction methods and strategies have been an important research direction and hot topic in organofluorine chemistry and medicinal chemistry for the past 20 years.

[0004] Electrophilic difluoromethyl reagents are a crucial strategy and approach for the selective and direct introduction of difluoromethyl groups into organic molecules, particularly in the later stages of total synthesis of drug molecules. They can be synthesized via electrophilic, difluorocarbene, and difluoromethyl radical pathways, playing a vital role in organofluorine chemistry and drug design and development. However, due to inherent limitations, the development and application of electrophilic difluoromethyl reagents have lagged behind, with very few reported examples. This is primarily due to the strong acidity of the proton in the +CF₂H group, the high electronegativity of the +CF₂H center, and the relatively hard nature of the reagents. These reagents are often sensitive to light, heat, and alkalis, exhibiting poor stability, complex and difficult synthesis, or low reactivity and efficiency. Consequently, they are suitable for a limited range of reactions and have significant application limitations. Currently, only a few reagents have been reported, including thionium salt type (Prakash reagent Org. Lett. 2007, 9, 1863 [1] and Liu reagent Org. Lett. 2018, 20, 6925 [2]), sulfoxide imine type (Hu reagent Org. Lett. 2009, 11, 2109 [3]), [7] thionylide type (Shen reagent Angew. Chem. Int. Ed. 2016, 55, 9050 [4]). However, these reagents also have problems such as poor stability, low reactivity, or limited application range. In summary, the electrophilic difluoromethyl reagents currently under development all have problems such as instability, complex synthesis, low reactivity and efficiency, limited reaction types, narrow application range, and low atom economy. Therefore, the development of a multi-purpose electrophilic difluoromethyl reagent that is convenient to synthesize, stable and efficient, highly universal, and widely applicable is an important issue that urgently needs to be addressed. Summary of the Invention

[0005] To solve the above-mentioned technical problems, the objective of this invention is achieved through the following technical solutions.

[0006] The difluoromethyl reagent of the present invention has the following structural formula:

[0007]

[0008] Where X is BF4, OTf, PF6, etc., and R is alkoxy, halogen, NO2, CN or CF3, etc.

[0009] The preparation method of the above-mentioned difluoromethyl reagent is as follows: 1-((difluoromethyl)sulfoxide)-2-phenoxybenzene or its analogues are cyclized in the presence of trifluoromethanesulfonic anhydride, and then exchanged with the corresponding anion to obtain the difluoromethyl reagent.

[0010] Furthermore, the difluoromethyl reagent is a compound of formula 1a or formula 1b:

[0011]

[0012] Preferably, 1-((difluoromethyl)sulfoxide)-2-phenoxybenzene is cyclized in the presence of trifluoromethanesulfonic anhydride, followed by anion exchange with a tetrafluoroborate solution to obtain the electrophilic difluoromethyl reagent S-(difluoromethyl)phenoxthiatetrafluoroborate of formula 1a. Specifically, 1-((difluoromethyl)sulfoxide)-2-phenoxybenzene (1.0 equivalent) is added to diethyl ether, and trifluoromethanesulfonic anhydride (1 equivalent) is added dropwise at 0°C. After the reaction is complete, the diethyl ether is removed, and the reactants are dissolved in dichloromethane. Then, anion exchange is performed with sodium tetrafluoroborate (1M). Finally, the dichloromethane phase is distilled under reduced pressure until viscous, and diethyl ether is added dropwise at -10°C. Recrystallization yields the product S-(difluoromethyl)phenoxthiatetrafluoroborate.

[0013] Furthermore, the 1-((difluoromethyl)sulfoxide)-2-phenoxybenzene is synthesized by coupling 1-((difluoromethyl)sulfoxide)-2-bromobenzene with phenol. Specifically, 1-((difluoromethyl)sulfoxide)-2-bromobenzene (1.0 equivalent) is added to phenol (2.0 equivalent), cuprous iodide (1.0 equivalent), and n-butylimidazole (1.0 equivalent), placed in a glove box, toluene is added, the box is sealed, and the mixture is removed and reacted at 150°C. After the reaction is complete, the reaction solution is extracted with dichloromethane, the dichloromethane phase is collected, the solvent is removed by vacuum distillation, and the crude product is purified by silica gel column chromatography to obtain 1-((difluoromethyl)sulfoxide)-2-phenoxybenzene.

[0014] Preferably, 1-(2-((difluoromethyl)sulfoxide)phenoxy)-3,5-dimethoxybenzene is cyclized in the presence of trifluoromethanesulfonic anhydride, followed by anion exchange with tetrafluoroborate solution to obtain the electrophilic difluoromethyl reagent 10-(difluoromethyl)-1,3-dimethoxy-10H-phenoxane-10-tetrafluoroborate thionium salt of formula 1b. Specifically, 1-(2-((difluoromethyl)sulfoxide)phenoxy)-3,5-dimethoxybenzene (1.0 equivalent) is added to diethyl ether, and trifluoromethanesulfonic anhydride (1 equivalent) is added dropwise at 0°C. After the reaction is complete, the diethyl ether is removed, and the reactants are dissolved in dichloromethane. Then, anion exchange is performed with sodium tetrafluoroborate (1M). Finally, the dichloromethane phase is distilled under reduced pressure until viscous, and diethyl ether is added dropwise at -10°C. Recrystallization yields the product S-(difluoromethyl)phenoxane tetrafluoroborate.

[0015] Furthermore, the 1-(2-((difluoromethyl)sulfoxide)phenoxy)-3,5-dimethoxybenzene is synthesized by coupling 1-((difluoromethyl)sulfoxide)-2-bromobenzene with 2,4-dimethoxyphenol. Specifically, 1-((difluoromethyl)sulfoxide)-2-bromobenzene (1.0 equivalent) is added to 2,4-dimethoxyphenol (2.0 equivalent), cuprous iodide (1.0 equivalent), and n-butylimidazolium (1.0 equivalent), placed in a glove box, toluene is added, the box is sealed, and the mixture is removed and reacted at 150°C. After the reaction is complete, the reaction solution is extracted with dichloromethane, the dichloromethane phase is collected, the solvent is removed by vacuum distillation, and the crude product is purified by silica gel column chromatography to obtain 1-(2-((difluoromethyl)sulfoxide)phenoxy)-3,5-dimethoxybenzene.

[0016] Preferably, the 1-((difluoromethyl)sulfoxide)-2-bromobenzene is synthesized by reacting 2-bromo-difluoromethylphenyl sulfide with m-chloroperoxybenzoic acid. Specifically, 1.0 equivalent of 2-bromo-difluoromethylphenyl sulfide is added to dichloromethane, and m-chloroperoxybenzoic acid (1.0 equivalent) is slowly added under zero-degree conditions. The reaction is allowed to proceed overnight. After the reaction is complete, the mixture is extracted with a saturated sodium carbonate aqueous solution, and the dichloromethane phase is collected. The solvent is removed by vacuum distillation, and the crude product is purified by silica gel column chromatography to obtain 1-((difluoromethyl)sulfoxide)-2-bromobenzene.

[0017] Preferably, 2-bromo-difluoromethylphenyl sulfide is synthesized by reacting 2-bromothiophenol with diethyl bromodifluoromethyl phosphate. Specifically, 2-bromothiophenol (1.0 equivalent) is added to purified water and acetonitrile. After adding a stir bar, sodium hydroxide (3.0 equivalent) is added at zero degrees Celsius, followed by dropwise addition of diethyl bromodifluoromethyl phosphate (2.0 equivalent). The reaction is allowed to proceed overnight. After the reaction is complete, the mixture is extracted with petroleum ether, the petroleum ether is collected, the solvent is removed by vacuum distillation, and the crude product is purified by silica gel column chromatography to obtain 2-bromo-difluoromethylphenyl sulfide.

[0018] It should be noted that, compared to previous reagents, the atom economy of the reagent designed in this invention can be greatly improved by the reuse of the fine chemical phenoxathia. Phenoxathia is widely used in the pharmaceutical industry and materials science; moreover, it can be used directly as an important raw material in the synthesis of alkyl, aryl radical reagents, and other reagents.

[0019] One application of the above-mentioned difluoromethyl reagent is for the hydrogen / difluoromethyl bifunctionalization reaction of alkenes to synthesize compounds having the structure of Formula 3:

[0020]

[0021] Among them, R 1 For H; R 2H, alkyl, or aryl, etc.; EWG is an ester, ketone, sulfone, or other electron-withdrawing group.

[0022] Specifically, compounds of formula 3 are synthesized using 2,6-dimethyl-3,5-diethyl-1,4-dihydropyridine as a hydrogen donor and phenyl acrylate or non-activated olefins with the difluoromethyl reagent.

[0023] Furthermore, the above-mentioned difluoromethyl reagent can be used to synthesize the following compounds:

[0024]

[0025] Another application of the above-mentioned difluoromethyl reagent in this invention is for the difluoromethyl functionalization reaction of tetrahydroisoquinoline C(sp3)-H to synthesize compounds having the structure of Formula 5:

[0026]

[0027] Among them, R 1 H is an electron-withdrawing or electron-donating substituent; R 2 H is an electron-withdrawing or electron-donating substituent.

[0028] Specifically, compounds having the structure of Formula 5 are synthesized by using 2-phenyl-1,2,3,4-tetrahydroisoquinoline or its derivatives with the difluoromethyl reagent.

[0029] Furthermore, the above-mentioned difluoromethyl reagent can be used to synthesize the following compounds:

[0030]

[0031] This invention designs and prepares a broad-spectrum, stable electrophilic difluoromethyl reagent, namely "(difluoromethyl)phenoxathia sulfonium salt". This reagent is simple to synthesize, the raw materials are readily available, and it can be synthesized in large quantities. The reagent is stable, is a stable solid that can be stored, and is convenient to use. The reagent has high efficiency and diverse reactivity, and can carry out various difluoromethyl conversion reactions via three pathways: difluoromethyl free radical (·CF2H), difluoromethyl cation (+CF2H), and difluorocarbene (:CF2).

[0032] This reagent is a stable, widely applicable difluoromethyl reagent that is easy to use and can efficiently perform various difluoromethyl conversion reactions. It provides a powerful difluoromethyl reagent platform for the convenient introduction of difluoromethyl building blocks into organic molecules, bioactive molecules, and drugs. It has broad application prospects in the fields of pharmaceuticals, pesticides, and functional materials. Attached Figure Description

[0033] To more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings used in the following description of the embodiments will be briefly introduced. Obviously, the drawings described below are some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0034] Figure 1 This invention relates to the design of an electrophilic difluoromethyl reagent.

[0035] Figure 2 This is the synthesis reaction formula for the electrophilic difluoromethyl reagent 1a of the present invention.

[0036] Figure 3 This is the synthetic route for the electrophilic difluoromethyl reagent 1a of the present invention.

[0037] Figure 4 This is the synthetic route for the electrophilic difluoromethyl reagent 1b of the present invention. Detailed Implementation

[0038] The technical solution of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0039] It should be understood that, when used in this specification and the appended claims, the terms "comprising" and "including" indicate the presence of the described features, integrals, steps, operations, elements and / or components, but do not exclude the presence or addition of one or more other features, integrals, steps, operations, elements, components and / or collections thereof.

[0040] I. Reagent Design

[0041] To address the inherent limitation of insufficient thermodynamic stability in electrophilic difluoromethyl reagents, and based on an analysis of past failures, this study considers the thermodynamic stability of reagents at the molecular level, designing and developing thermodynamically stable electrophilic difluoromethyl reagents. For example... Figure 1As shown in Figure A, as early as 2007, Professor Prakash's group, a renowned international organofluorine chemist, attempted to synthesize a difluoromethyl reagent in the form of a dibenzothiophene thionium salt. However, the synthesis was highly unstable, decomposing in situ into dibenzothiophene and trifluoromethanesulfonate, failing to yield the desired difluoromethyl reagent. Only a small amount of thionium salt 19F NMR signal was detected at -80°C. Based on this failed approach, we analyzed that the relatively high ring strain of the three coplanar rings of the dibenzothiophene five-membered ring might cause the S-CF2H bond to have a low dissociation enthalpy, resulting in extreme thermodynamic instability and rapid reagent decomposition. Therefore, we proposed expanding the ring to a six-membered ring using a phenoxathiophene or thiaanthracene skeleton, such as... Figure 1 As shown in B. Therefore, firstly, the six-membered heterocyclic rings of phenoxathia or thiathracene have relatively low ring strain and are thermodynamically relatively stable; secondly, the abundant π electrons on the aromatic ring can disperse the positive charge of the sulfonium salt through p-π and d-π interactions, maximizing the stabilizing effect of the reagent; thirdly, the abundant outer electrons on the oxygen or sulfur atoms at the para position can interact with the electron-deficient S atom at the center of the sulfonium salt, further delocalizing the positive charge of the sulfonium salt and lowering the molecular energy, thereby improving the thermodynamic stability of the reagent (according to X-ray single-crystal diffraction measurements, the distance between O and S is...). The sum of Pandehua radii less than 0 and S (This confirms the existence of a force between two atoms).

[0042] II. Synthesis of Reagents

[0043] like Figure 2 The synthesis reaction of the electrophilic difluoromethyl reagent shown is as follows: o-phenoxyphenyl difluoromethyl sulfoxide is synthesized by coupling o-bromophenyl difluoromethyl sulfoxide with phenol, followed by cyclization to S-(difluoromethyl)phenoxathia trifluoromethanesulfonate under the action of trifluoromethanesulfonic anhydride (Tf2O). Anion exchange with sodium tetrafluoroborate solution (NaBF4) yields the target electrophilic difluoromethyl reagent, S-(difluoromethyl)phenoxathia tetrafluoroborate. The obtained reagent is a stable crystalline powder, and its structure was confirmed by X-ray single-crystal diffraction studies.

[0044] The specific synthetic route of the electrophilic difluoromethyl reagent S-(difluoromethyl)phenoxathiatetrafluoroborate of the present invention is as follows: Figure 3 As shown. The specific implementation process is as follows.

[0045] Step 1: Take a dry 500mL round-bottom flask, add 2-bromobenzylthiophenol (5.7g, 30.0 mmol, 1.0 equivalent), then add 100mL of purified water and 100mL of acetonitrile. After adding a stir bar of appropriate size, add sodium hydroxide (3.6g, 90.0 mmol, 3.0 equivalent) at 0°C. After 10 minutes, add diethyl bromodifluoromethyl phosphate (16.0g, 60.0 mmol, 2.0 equivalent) dropwise. Let the reaction proceed overnight. After the reaction is complete, extract twice with 100mL of petroleum ether and the reaction solution. Collect the petroleum ether, remove the solvent by vacuum distillation, and purify the crude product by silica gel column chromatography to obtain 2-bromo-difluoromethyl phenyl sulfide.

[0046] Spectral data characterization of the product:

[0047] The following compound was prepared using the method described above:

[0048] 2-Bromo-difluoromethylphenyl sulfide

[0049] (2-bromophenyl)(difluoromethyl)sulfane

[0050]

[0051] White liquid; Rf = 0.8 (petroleum ether); 6.57 g, 92% separation yield; 1 H-NMR (CDCl3): 6.87 (t, 1H, JH-F=57.50Hz), 7.20-7.26 (m, 1H), 7.28-7.34 (m, 1H), 7.60-7.68 (m, 2H). 13 C-NMR (CDCl3): 120.6 (t, J=277Hz), 128.50, 128.52, 129.3, 131.2, 134.0, 136.6 19 F-NMR (CDCl3): -92.65 (d, J=57.50Hz).

[0052] Step 2: Take a dry 250mL round-bottom flask, add 2-bromo-difluoromethylphenyl sulfide (7.17 g, 30.0 mmol, 1.0 equivalent), then add 100mL of dichloromethane. Under zero-degree conditions, slowly add m-chloroperoxybenzoic acid (5.2 g, 30.0 mmol, 1.0 equivalent). React overnight. After the reaction is complete, extract twice with 100mL of saturated sodium carbonate aqueous solution and collect the dichloromethane phase. Remove the solvent by vacuum distillation. The crude product is purified by silica gel column chromatography to obtain 1-((difluoromethyl)sulfoxide)-2-bromobenzene.

[0053] The following compound was prepared using the method described above:

[0054] 1-((difluoromethyl)sulfoxide)-2-bromobenzene

[0055] 1-((difluoromethyl)sulfinyl)-2-phenoxybenzen

[0056]

[0057] White solid; Rf = 0.4 (petroleum ether: ethyl acetate = 10:1); 6.71 g, 88% separation yield; 1 H NMR (400MHz, CDCl3) NMR (400MHz, =7.9, 1.6Hz, 1H), 7.72-7.62 (m, 2H), 7.52 (dd, J=7.6, 1.6Hz, 1H), 6.36 (s, 1H). 19 F NMR (377MHz, CDCl3) NMR (377MHz, CDC19, 1.6

[0058] Step 3: Take a dry 100mL reaction flask, add 1-((difluoromethyl)sulfoxide)-2-bromobenzene (7.6g, 30.0 mmol, 1.0 equivalent), then add phenol (5.6g, 60.0 mmol, 2.0 equivalent), cuprous iodide (5.7g, 30.0 mmol, 1.0 equivalent) and n-butylimidazolium (3.7g, 30.0 mmol, 1.0 equivalent), place in a glove box, add 30mL of toluene, seal, remove, and react at 150℃ for 12 hours. After the reaction is complete, extract the reaction solution twice with 50mL of dichloromethane, collect the dichloromethane phase, remove the solvent by vacuum distillation, and purify the crude product by silica gel column chromatography to obtain 1-((difluoromethyl)sulfoxide)-2-phenoxybenzene.

[0059] The following compound was prepared using the method described above:

[0060] 1-((difluoromethyl)sulfoxide)-2-phenoxybenzene

[0061] 1-((difluoromethyl)sulfinyl)-2-phenoxybenzen

[0062]

[0063] Pale yellow liquid; Rf = 0.3 (petroleum ether: ethyl acetate = 10:1); 6.67 g, 83% separation yield; 1¹H NMR (500 MHz, CDCl₃) NMR (500 MHz, CDCl₃ / ethyl acetate = 10:1); 6.67 g, 83% separation yield; mmol, 2.0 equivalent), cuprous iodide (5.7 g, 30.0 mmol, 1.0 equivalent) and n-butylimidazolium (3.7 g, 30.0 mmol, 1.0 equivalent) were placed in a glove box, 30 mL of toluene was added, the box was sealed, and the mixture was removed and reacted at 150 °C for 12 h. After the reaction was completed, the reaction solution was extracted twice with 50 mL of dichloromethane, the dichloromethane phase was collected, the solvent was removed by vacuum distillation, and the crude product was purified by silica gel column chromatography to obtain 1-((tz, 1H). 13 C10 NMR (151 MHz, CDCl3) NMR (151 MHz, CDCl3 ethyl acetate = 10:1); 6.67 g, 83% separation yield; mmol, 2.0 equivalent), cuprous iodide (5.7 g, 30.0 mmol, 1.0 equivalent) and n-butylimidazole (3.7 g, 30.0 mmol, 1.0 equivalent), release 19 FNMR (471 MHz, CDCl3) NMR (471 MHz, CDCl3 ethyl acetate = 10:1); 6.67 g, 83% separation yield; mmol, 2.0 equivalent), cuprous iodide (5.7 g, 30.0 mmol, 1.0 equivalent) and n-butylimidazole (3.7 g, 3269.0403, found 269.0440).

[0064] Step 4: Take a dry 250mL round-bottom reaction flask, add 1-((difluoromethyl)sulfoxide)-2-phenoxybenzene (24.1 g, 90.0 mmol, 1.0 equivalent), then add 90mL of diethyl ether. At 0℃, add trifluoromethanesulfonic anhydride (25.6 g, 90.0 mmol, 1 equivalent) dropwise. After 15 minutes, confirm the reaction is complete by thin-layer chromatography with silica gel. After the reaction is complete, remove the diethyl ether, add 100mL of dichloromethane to dissolve the reactants, and then perform negative ion exchange four times with 100mL of sodium tetrafluoroborate (1M). Finally, distill the dichloromethane phase under reduced pressure until viscous, add diethyl ether dropwise at -10℃, and recrystallize to obtain the product S-(difluoromethyl)phenoxathiatetrafluoroborate.

[0065] The following compound was prepared using the method described above:

[0066] S-(difluoromethyl)phenoxathiotetrafluoroborate

[0067] Difluoromethyl Phenoxathiinium Tetrafluoroborate

[0068]

[0069] Light brown solid; 25.25 g, 84% recrystallization yield; 1 H NMR (500MHz, CDCl₂) 3 NMR (500 MHz, CDClxathiinium Tetrafluoroborate) was performed with diethyl ether, 100 mL of dichloromethane was added to dissolve the reactants, and then 100 mL of tetrafluoroborate was added to 6 (m, 4H), 7.56-7.34 (t, 1H). 19 F NMR (471 MHz, CDCl3) NMR (471 MHz, CDCl3) xathiinium Tetrafluoroborate diethyl ether, added 100 13 C NMR (101 MHz, CDCl3) NMR (101 MHz, CDCl3) ⇌ xathiinium Tetrafluoroborate. The reactants were dissolved in 100 mL of dichloromethane, then precipitated with 100 mL of tetrafluoroborate (m, 4H). The precipitate was 7.56–7.34 (t, 1H). In a glove box, 30 mL of methyl ether was added. The precipitate was 251.0337, and the precipitate was 251.0335. Melting point: 97–99 °C.

[0070] The specific synthetic route of the electrophilic difluoromethyl reagent 10-(difluoromethyl)-1,3-dimethoxy-10H-phenoxane-10-tetrafluoroboronic acid thioonium salt of the present invention is as follows: Figure 4 As shown. The specific implementation process is as follows.

[0071] Step 1: Take a dry 100mL reaction flask, add 1-((difluoromethyl)sulfoxide)-2-bromobenzene (7.6g, 30.0 mmol, 1.0 equivalent), then add 2,4-dimethoxyphenol (5.6g, 60.0 mmol, 2.0 equivalent), cuprous iodide (5.7g, 30.0 mmol, 1.0 equivalent), and n-butylimidazolium (3.7g, 30.0 mmol, 1.0 equivalent). Place the flask in a glove box, add 30mL of toluene, seal, and remove. React at 150℃ for 12 hours. After the reaction is complete, extract the reaction solution twice with 50mL of dichloromethane, collect the dichloromethane phase, remove the solvent by vacuum distillation, and purify the crude product by silica gel column chromatography to obtain 1-(2-((difluoromethyl)sulfoxide)phenoxy)-3,5-dimethoxybenzene.

[0072] The following compound was prepared using the method described above:

[0073] 1-(2-((difluoromethyl)sulfoxide)phenoxy)-3,5-di-methoxybenzene

[0074] 1-(2-((difluoromethyl)sulfinyl)phenoxy)-3,5-dimethoxybenzene

[0075]

[0076] Pale yellow liquid; Rf = 0.3 (petroleum ether: ethyl acetate = 10:1); 6.67 g, 73% separation yield; 1 HNMR (400MHz, CDCl3) NMR (400MHzJ=7.8, 1.7Hz, 1H), 7.48 (ddd, J=8.6, 7.5, 1.7Hz, 1H), 7.32 (td, J=7.6, 1.0Hz, 1H), 6.95 (dd, J=8.3, 1.0Hz, 1H), 6.40 (t, J=55.1, 0.9Hz, 1H), 6.31 (t, J=2.3Hz, 1H), 6.20 (d, J=2.3Hz, 2H), 3.74 (s, 6H). 19 F NMR (377MHz, CDCl3) NMR (377--135.97(m). 13 C NMR (101MHz, CDCl3) δ161.88, 161.43, 156.65, 155.49, 154.53, 133.79, 126.75, 124.28, 123. 15(t, J=295.1Hz), 117.38, 110.70, 98.19, 96.61, 55.56, 55.41.HRMS (ESI): m / z[M+H]+calcd for C15H15F2O4S+329.0659, found 329.0452.

[0077] Step 2: Take a dry 250mL round-bottom reaction flask, add 1-(2-((difluoromethyl)sulfoxide)phenoxy)-3,5-dimethoxybenzene (24.1 g, 90.0 mmol, 1.0 equivalent), then add 90mL of diethyl ether. At 0℃, add trifluoromethanesulfonic anhydride (25.6 g, 90.0 mmol, 1 equivalent) dropwise. After 15 minutes, confirm the reaction is complete by thin-layer chromatography with silica gel. After the reaction is complete, remove the diethyl ether, add 100mL of dichloromethane to dissolve the reactants, and then perform negative ion exchange four times with 100mL of sodium tetrafluoroborate (1M). Finally, distill the dichloromethane phase under reduced pressure until viscous, add diethyl ether dropwise at -10℃, and recrystallize to obtain the product 10-(difluoromethyl)-1,3-dimethoxy-10H-phenoxane-10-tetrafluoroborate thionium salt.

[0078] The following compound was prepared using the method described above:

[0079] 10-(difluoromethyl)-1,3-dimethoxy-10H-phenoxane-10-tetrafluoroboronic acid thionium salt

[0080] 10-(difluoromethyl)-1,3-dimethoxy-10H-phenoxathiin-10-iumTetrafluoroborate

[0081]

[0082] Pale yellow solid; 27.15 g, 76% recrystallization yield; 1 H NMR (500MHz, CDCl3) NMR (500M, J=8.1, 1.5Hz, 1H), 7.88 (ddd, J=8.7, 7.4, 1.6Hz, 1H), 7.58 (ddd, J=8.4, 7.5, 1.2Hz, 1H), 7 .54 (d, J=1.2Hz, 1H), 7.42 (t, J=54.5, 4.0Hz, 1H), 6.66 (d, J=2.2Hz, 1H), 6.56 (d, J=2.2Hz, 1H), 4.09 (s, 3H), 3.99 (s, 3H). 19 F NMR (377MHz, CDCl3) NMR (377MHz, CDClHz, 1H), 6.56 (d, J=2.2Hz, 13 C NMR (101MHz, CDCl3) δ168.35, 160.87, 154.99, 152.23, 139.15, 137.64, 133.59, 127.34, 1 19.89, 114.29 (t, J=297.8Hz), 97.06, 96.45, 57.74, 56.64.HRMS (ESI): m / z[M-BF4]+calcd for C15H13F2O3S+311.0548, found 311.0362.Melting point: 95-100℃.

[0083] III. Application of Reagents

[0084] (1) Hydrogen / difluoromethyl bifunctionalization of alkenes

[0085] Implementation process:

[0086] Optimization of reaction conditions and parameters: Using phenyl acrylate as the template substrate, reagent 1 is a difluoromethyl reagent, and 2,6-dimethyl-3,5-diethyl-1,4-dihydropyridine as the hydrogen donor, the amount of 2,6-dimethyl-3,5-diethyl-1,4-dihydropyridine used in the reaction is 1.5 equivalents, 2.0 equivalents, and 2.5 equivalents of the template substrate, preferably 2.5 equivalents; the amount of difluoromethyl reagent used in the reaction is 1 equivalent, 1.5 equivalents, and 2.0 equivalents, preferably 2.0 equivalents; the solvent used in the reaction is MeCN, EA, DCM, or THF, preferably MeCN; the reaction time is 4 hours, 8 hours, and 12 hours, preferably 12 hours; the wavelength of light used is between 350 nm and 550 nm, preferably blue light with a wavelength of 450 nm; the reaction temperature is between -30℃ and 80℃, preferably 0℃ to 50℃, preferably room temperature. After the reaction was complete (monitored by TLC), the light and stirring were stopped, the solvent was removed by vacuum distillation, and the crude product was purified by silica gel column chromatography to obtain pure hydrogen / difluoromethylated phenyl acrylate (3a).

[0087] Take a dry 10 mL Schlenk tube and add substrate X (e.g., phenyl acrylate or activated electron-deficient olefin, 0.2 mmol, 1.0 equivalence), difluoromethyl reagent 1 (137.6 mg, 0.4 mmol, 2.0 equivalence), and 2,6-dimethyl-3,5-diethyl-1,4-dihydropyridine (142.1 mg, 0.5 mmol, 2.5 equivalence). Place the reaction tube in a glove box, then add 2 mL of acetonitrile as solvent, seal the tube, and stir the reaction solution under 12 W LED blue light for 12 hours. After the reaction is complete, remove the solvent by vacuum distillation, and purify the crude product by silica gel column chromatography to obtain hydrogen / difluoromethylated phenyl acrylate 3a.

[0088] Implementation process of optimal conditions for hydrogen / difluoromethyl bifunctionalization of olefins:

[0089]

[0090] Among them, R 1 For H; R 2 H, alkyl, aryl, etc.; EWG is ester, ketone, sulfone or other electron-withdrawing group.

[0091] Following the optimal conditions described above, the following hydrogen / difluoromethyl bifunctionalized products of olefins were obtained:

[0092]

[0093] The spectral data of the product are characterized as follows.

[0094] The following compound was prepared according to the aforementioned general formula method:

[0095] 4,4-Difluorobutyrate phenyl ester

[0096] Phenyl 4,4-difluorobutanoate

[0097]

[0098] White liquid; Rf = 0.3 (petroleum ether / ethyl acetate = 20:1); 43.5 mg, 88% separation yield; 1 ¹H NMR (400MHz, CDCl₃) NMR (400MHz, ethyl CDCl₃ = 20:1, 7.26–7.21 (m, 1H), 7.09 (dq, J = 6.9, 1.0 Hz, 2H), 6.01 (tt, J = 56.5, 4.1 Hz, 1H), 2.78 (t, J = 7.4 Hz, 2H), 2.29 (ttd, J = 17.5, 7.4, 4.1 Hz, 2H).

[0099] 19 F NMR (377MHz, CDCl3) NMR (377MHz, CDCl3 ethyl ester = 2)

[0100] The following compound was prepared according to the aforementioned general formula method:

[0101] 4,4-Difluorobutyric acid 4-ethylphenyl ester

[0102] 4-ethylphenyl 4,4-difluorobutanoate

[0103]

[0104] Colorless transparent liquid; Rf = 0.3 (petroleum ether / ethyl acetate = 20:1); 36.5 mg, 80% separation yield; 1 ¹H NMR (400MHz, CDCl₃) NMR (400MHz, CDCl / ethyl acetate = 20:1); 36.5-7.21 (m, 1H), 7.09 (dq, J = 6.9, 1.0 Hz, 2H), 6.01 (tt, J = 56.5, 4.1 Hz, 1H), 2.78 (t, J = 7.6 Hz, 2H), 2.33-2.21 (m, 2H), 1.23 (t, J = 7.6 Hz, 3H). 13 C NMR (151 MHz, CDCl3) NMR (151 MHz, CDCl / ethyl acetate = 20:1); 36.5-7.21 (m, 1H), 7.09 (dq, J = 6.9, 1.0 Hz, 2H), 6.01 (tt, J = 56.5, 4.1 Hz, 1H), 2.78 (t, J = 7. 19F NMR (377MHz, CDCl3) NMR (377MHz, CDCl / B 6.5, 17.4Hz).

[0105] HRMS(ESI): m / z[M+Na]+calcd for C12H14F2O2Na+250.9951, found 251.0856.

[0106] The following compound was prepared according to the aforementioned general formula method:

[0107] p-Methoxyphenyl 4-((6-((4,4-difluorobutyryl)oxy)hexyl)oxy)benzoic acid

[0108] 4-methoxyphenyl 4-((6-((4,4-difluorobutanoyl)oxy)hexyl)oxy)benzoate

[0109]

[0110] White solid; Rf = 0.3 (petroleum ether / ethyl acetate = 10:1); 81.8 mg, 87% separation yield; 1 ¹H NMR (400 MHz, CDCl₃) NMR (400 MHz, CDCl₃ ethyl ester = 10:1); 81.8 mg, 87% separation yield; γ(hexyl)oxy)benzoate 251.0856., 2H), 6.01 (tt, J = 56.5, 4.1 Hz, 1H), 2.78 (t, J = 7. Hz, 2H), 2.33-2.21 (m, 2H), 1.23 (t, J = 7.6 Hz, 3H). for 2.17 (dddt, J = 20.5, 13.1, 7.4, 3.7 Hz, 2H), 1.83 (dt, J = 8.1, 6.5 Hz, 2H), 1.69 (p, J = 6.8 Hz, 2H), 1.58-1.39 (m, 4H). 13 C NMR (151 MHz, CDCl3) NMR (151 MHz, CDCl3 ethyl ester = 10:1); 81.8 mg, 87% separation yield; y)hexyl)oxy)benzoate 251.0856., 2H), 6.01 (t, J = 56.5, 4.1 Hz 68.05, 64.87, 55.64, 29.74, 29.35 (t, J = 22.3 Hz), 29.01, 28.52, 26.84 (t, J = 6.0 Hz), 25.71. 19F NMR (377MHz, CDCl3) NMR (377MHz, CDCl3 ethyl ester = 10:1); 81.8 mg HRMS (ESI): m / z [M+Na]+ calcd for C24H28F2O6Na+ 473.0843, found 473.1751.

[0111] The following compound was prepared according to the aforementioned general formula method:

[0112] 2-([1,1′-biphenyl]-2-oxy)4,4-difluorobutyrate ethyl ester

[0113] 2-([1,1′-biphenyl]-2-yloxy)ethyl 4,4-difluorobutanoate

[0114]

[0115] White solid; Rf = 0.3 (petroleum ether / ethyl acetate = 20:1); 58.9 mg, 92% separation yield; 1 ¹H NMR (400 MHz, CDCl₃) NMR (400 MHz, ethyl CDCl₃ = 20:1); 58.9 mg, 92% separation yield; tenoate. 0843, found 473.13H), 7.09–7.04 (m, 1H), 6.97 (d, J = 8.1 Hz, 1H), 5.85 (tt, J = 56.6, 4.2 Hz, 1H), 4.37–4.34 (m, 2H), 4.16–4.13 (m, 2H), 2.42 (t, J = 7.5 Hz, 2H), 2.07 (dddd, J = 17.4, 10.0, 7.5, 3.7 Hz, 2H). 13 C NMR (101 MHz, CDCl3) NMR (101 MHz, ethyl CDCl3 = 20:1); 58.9 nm, 131.14, 129.57, 128.65, 127.93, 126.97, 121.84, 118.23-114.26 (m), 113.29, 66.53, 63.00, 29.23 (t, J = 22.2 Hz), 26.67 (t, J = 6.0 Hz). 19 F NMR (377MHz, CDCl3) NMR (377MHz, CDCl3 ethyl ester = 20:1); 58.9 nm, 131.14, 129.57, 128.65, 127.93, 126.97, 121.84, 118.23-11, found 343.1118.

[0116] The following compound was prepared according to the aforementioned general formula method:

[0117] Tetradecyl 4,4-difluorobutyrate

[0118] Tetradecyl 4,4-difluorobutanoate

[0119]

[0120] White solid; Rf = 0.3 (petroleum ether / ethyl acetate = 20:1); 57.0 mg, 89% separation yield; 1 ¹H NMR (400 MHz, CDCl₃) NMR (400 MHz, ethyl CDCl₃ = 20:1); 57.0 mg, 89% separation yield; .57, 128.65, 127.93, 126.97, 121.84, 118.23-11, found 343.1118.66.53, 63.00, 29.23 (t, J = 22.2 Hz), 26.67 (t, J = 6.0 Hz). 2H), 4 13 C10 NMR (126 MHz, CDCl3) NMR (126 MHz, ethyl CDCl3 = 20:1); 57.0 mg, 89% separation yield; .57, 12.69, 29.67, 29.65, 29.64, 29.57, 29.54, 29.51, 29.36, 29.23, 29.19, 28.56, 26.85 (t, J = 6.0 Hz), 25.88, 22.69, 14.12. 19 F NMR (377MHz, CDCl3) NMR (377MHz, ethyl CDCl3 = 20:1); 57.0 mg, 89% separation yield; .57, 12.69, 29.67, 29.65, 29.64, 29.57, 2343.1516, found 343.2420.

[0121] The following compound was prepared according to the aforementioned general formula method:

[0122] 4,4-Difluoro-2-methylbutyrate phenyl ester

[0123] Phenyl 4,4-difluoro-2-methylbutanoate

[0124]

[0125] Colorless transparent liquid; Rf = 0.3 (petroleum ether / ethyl acetate = 20:1); 23.5 mg, 55% separation yield; 1¹H NMR (400 MHz, CDCl₃) NMR (400 MHz, CDCl / ethyl acetate = 20:1); 23.589% separation yield; .57, 12.69, 29.67, 29.65, 29.2H), 6.00 (tt, J = 56.5, 4.5 Hz, 1H), 2.97 (h, J = 7.2 Hz, 1H), 2.49–2.36 (m, 1H), 2.10–1.98 (m, 1H), 1.42 (d, J = 7.2 Hz, 3H). 13 C NMR (151 MHz, CDCl3) NMR (151 MHz, CDCl / ethyl acetate = 20:1); 23.5 89% separation yield; .57, 12.69, 29.67, 29.65, 29.2H), 6.00 (tt, J = 56.5 (t, J = 5.4 Hz), 17.66. 19 F NMR (377MHz, CDCl3) NMR (377MHz, CDCl / ethyl acetate = 20:1); 23.589% separation yield; .57, 12.69, 29.67, 29.65, 29.2H), 6.00 (tt, J = 56.5 (t)

[0126] The following compound was prepared according to the aforementioned general formula method:

[0127] Diethyl 2-(difluoromethyl)succinate

[0128] Diethyl 2-(difluoromethyl)succinate

[0129]

[0130] Colorless transparent liquid; Rf = 0.3 (petroleum ether / ethyl acetate = 10:1); 25.5 mg, 57% separation yield; 1 ¹H NMR (400 MHz, CDCl₃) NMR (400 MHz, CDCl / ethyl acetate = 10:1); 25.589% separation yield; .57, 12.69, 29.67, 29.65, 29.2H), 6.00 (t, J = 56.5 (t, J = 5.4 Hz), 17.66 (t, J = 7.2 Hz, 1H), 2.49–2.36 (m, 1H), 2.10–1.98 (m, 1H), 1.4 (q, J = 7.3 Hz, 6H). 13C10 NMR (151 MHz, CDCl3) NMR (151 MHz, CDCl / ethyl acetate = 10:1); 25.5 89% separation yield; .57, 12.69, 29.67, 29.65, 29.2 H), 6.00 (tt, J = 56.5 (t, J = 5.4) 19 F NMR (471 MHz, CDCl3) NMR (471 MHz, CDCl / ethyl acetate = 10:1); 25.589% separation yield; .57, 12.69, for C9H14F2O4Na+ 246.9849, found 247.0754.

[0131] The following compound was prepared according to the aforementioned general formula method:

[0132] Ethyl 4,4-difluoro-2-(naphth-1-yl)butyrate

[0133] ethyl 4,4-difluoro-2-(naphthalen-1-y1)butanoate

[0134]

[0135] White solid; Rf = 0.3 (petroleum ether / ethyl acetate = 20:1); 23.4 mg, 42% separation yield; 1 HNMR (400MHz, CDCl3) NMR (400MHz, CDCl acid Hz, 1H), 7.89 (d, J=8.0Hz, 1H), 7.81 (d, J=7.8Hz, 1H), 7.60-7.56 (m, 1H), 7.52 (t, J=7.5Hz, 1H), 7.4 8-7.40 (m, 2H), 5.82 (tt, J=56.6, 4.6Hz, 1H), 4.70-4.55 (m, 1H), 3.67 (s, 3H), 2.87 (dtdd, J=19.2, 13.6, 8.8, 4.6Hz, 1H), 2.47-2.28 (m, 1H). 13 C NMR (151MHz, CDCl3) NMR (151MHz, CDCl acid Hz, 1H), 7.89 (d, J=8.0Hz, 1H), 7.81 (d, J=7.8 Hz, 1H), 7.60-7.56 (m, 1H), 7.52 (t, J=7.5Hz, 1H), 7.48-7.40 (m, 2H), 5.82 (tt, J=56. 19F NMR (377MHz, CDCl3) NMR (377MHz, CDCl acid Hz, 1H), 7.89(: m / z[M+Na]+calcd for C15H14F2O2Na+286.9951, found 287.0852.

[0136] The following compound was prepared according to the aforementioned general formula method:

[0137] ((3,3-difluoropropyl)sulfonyl)benzene

[0138] ((3,3-difluoropropyl)sulfonyl)benzene

[0139]

[0140] White solid; Rf = 0.3 (petroleum ether / ethyl acetate = 3:1); 41.8 mg, 95% separation yield; 1 H NMR (400MHz, CDCl3) NMR (400M.85 (m, 2H), 7.70 (t, J = 7.5Hz, 1H), 7.61 (t, J = 7.7Hz, 2H) , 6.00 (tt, J=56.0, 3.9Hz, 1H), 3.31-3.21 (m, 2H), 2.31 (dtt, J=20.8, 11.8, 4.2Hz, 2H). 19 F NMR (377MHz, CDCl3) NMR (377MHz, CDCl2H), 7.70 (t, J

[0141] The following compound was prepared according to the aforementioned general formula method:

[0142] 4,4-Difluoro-1-phenyl-1-butanone

[0143] 4,4-difluoro-1-phenylbutan-1-one

[0144]

[0145] Colorless transparent liquid; Rf = 0.3 (petroleum ether / ethyl acetate = 20:1); 27.7 mg, 77% separation yield; 1¹H NMR (400 MHz, CDCl₃) NMR (400 MHz, CDCl₃ / ethyl acetate = 20:1); 27.7 mg, 77% separation yield; 7.61 (t, J = 7.7 Hz, 2H), 6.00 (tt, J = 56.0, 3.9 Hz, 1H), 3.31 (ttd, J = 7.2 Hz, 2H), 2.31 (ttd, J = 18.0, 7.2, 4.2 Hz, 2H). 19 F NMR (377MHz, CDCl3) ethyl ester = 20:1); 27.7 mg, 77% separation yield; 7.61 (

[0146] (2) Difluoromethyl functionalization of tetrahydroisoquinoline C(sp3)-H

[0147] Implementation process:

[0148] Optimization process of reaction conditions and parameters:

[0149] Using 2-phenyl-1,2,3,4-tetrahydroisoquinoline 4aa as the template substrate, and difluoromethyl reagent 1, the reaction conditions were as follows: whether to use photocatalysts Ir[(ppy)2dtbpy]PF6 or Ir(ppy)3, preferably using photocatalyst Ir[(ppy)2dtbpy]PF6; the base used in the reaction was NaHCO3, Na2CO3, or K2CO3, preferably NaHCO3; the solvent used in the reaction was MeCN, EA, DCM, or THF, preferably MeCN; the wavelength of light used was between 350 nm and 550 nm, preferably blue light with a wavelength of 450 nm; the reaction temperature was between -30℃ and 80℃, preferably 0℃ to 50℃, preferably room temperature; the reaction time was overnight; after the reaction was completed (monitored by TLC), the light and stirring were stopped, the solvent was removed by vacuum distillation, and the crude product was purified by silica gel column chromatography to obtain pure 1-(difluoromethyl)-2-phenyl-1,2,3,4-tetrahydroisoquinoline.

[0150] Take a dry 10 mL Schlenk tube and add substrate 4 (e.g., 2-phenyl-1,2,3,4-tetrahydroisoquinoline or its derivatives, 0.2 mmol, 1.0 equivalence), difluoromethyl reagent 1 (137.6 mg, 0.4 mmol, 2.0 equivalence), Ir[(ppy)2dtbpy]PF6 (2.0 mg, 0.004 mmol, 2% equivalence), and NaHCO3 (48.2 mg, 0.6 mmol, 3.0 equivalence). Place the reaction tube in a glove box, then add 2 mL of acetonitrile as solvent, seal and remove the tube. Stir the reaction solution overnight under 12 W LED blue light. After the reaction is complete, remove the solvent by vacuum distillation. The crude product is purified by silica gel column chromatography to obtain 1-(difluoromethyl)-2-phenyl-1,2,3,4-tetrahydroisoquinoline.

[0151] Implementation process of optimal conditions for difluoromethyl functionalization of tetrahydroisoquinoline C(sp3)-H:

[0152]

[0153] R 1 H is an electron-withdrawing or electron-donating substituent; R 2 H is an electron-withdrawing or electron-donating substituent.

[0154] Following the optimal conditions described above, the following difluoromethyl functionalized product of tetrahydroisoquinoline C(sp3)-H was obtained:

[0155]

[0156] The data for each product are characterized as follows.

[0157] The following compound was prepared according to the aforementioned general formula method:

[0158] 1-(difluoromethyl)-2-phenyl-1,2,3,4-tetrahydroisoquinoline

[0159] 1-(difluoromethyl)-2-phenyl-1,2,3,4-tetrahydroisoquinoline

[0160]

[0161] Pale yellow solid; Rf = 0.3 (petroleum ether / ethyl acetate = 50:1); 47.1 mg, 91% separation yield; 1 ¹H NMR (400 MHz, CDCl₃) 400 MHz, CDCl₃ (petroleum ether / ethyl acetate = 50:1); 47.1 mg, 91% separation yield; reaction was carried out overnight under LED blue light with stirring. After the reaction was complete, the solvent was removed by vacuum distillation. The crude product was purified by silica gel column chromatography to obtain 1-( , 7.2, 4.2 (td, J = 7.2, 3.6 Hz, 1H), 3.54-3.41 (m, 1H), 2.99 (ddd, J = 15.2, 7.0, 5.1 Hz, 2H). 13 C NMR (101 MHz, CDCl3) 101 MHz, CDCl (petroleum ether / ethyl acetate = 50:1); 47.1 mg, 91% separation yield; reaction was stirred overnight under LED blue light irradiation, and the solvent was removed by vacuum distillation after the reaction was complete (J = 250.9 Hz), 114.09, 61.17 (t, J = 23.6 Hz), 43.53, 27.80.19 F NMR (377MHz, CDCl3)377MHz, CDCl.53, 27.80.7HRMS (ESI): m / z[M+H] + calcd for C16H16F2N + 260.1206, found 260.1244.

[0162] The following compound was prepared according to the aforementioned general formula method:

[0163] 1-(difluoromethyl)-2-(p-tolyl)-1,2,3,4-tetrahydroisoquinoline

[0164] 1-(difluoromethyl)-2-(p-tolyl)-1,2,3,4-tetrahydroisoquinoline

[0165] Pale yellow solid; Rf = 0.3 (petroleum ether / ethyl acetate = 50:1); 40.9 mg, 75% separation yield; 1 ¹H NMR (400 MHz, CDCl₃) 400 MHz, CDCl₃ (petroleum ether / ethyl acetate = 50:1); 40.9 mg, 75% separation yield; oisoquinoline was stirred overnight under blue light irradiation. After the reaction was complete, the solvent was removed by vacuum distillation. The crude product was purified by silica gel column chromatography to obtain 1-(…). After the reaction was complete (TLC monitoring), the light and stirring were stopped, the solvent was removed by vacuum distillation, and the crude product was purified by silica gel column chromatography… Purification yielded pure product 1-(7.2, 4.2 (td, J = 7.2, 3.6 Hz, 1H), 3.54-3.41 Hz, 1H), 3.84 (d, J = 2.1 Hz, 3H), 3.73 (dt, J = 11.7, 5.8 Hz, 1H), 3.50 (ddd, J = 12.1, 7.3, 5.5 Hz, 1H), 3.02 (td, J = 5.7, 5.2, 3.2 Hz, 2H). 13 C NMR (101 MHz, CDCl3) 101 MHz, CDCl (petroleum ether / ethyl acetate = 50:1); 40.9 mg, 75% separation yield; reaction was stirred overnight under blue light irradiation with oisoquinoline, and the solvent was removed by vacuum distillation after the reaction was complete (J = 249.5 Hz), 114.68, 61.35 (t, J = 23.3 Hz), 43.77, 27.67, 20.31. 19 F NMR (377MHz, CDCl3)377MHz, CDC1.77, 27.67, HRMS (ESI): m / z[M+H] + calcd for SCl7H18F2N+ 274.1363, found 274.1399.

[0166] The following compound was prepared according to the aforementioned general formula method:

[0167] 1-(difluoromethyl)-2-(4-isopropylphenyl)-1,2,3,4-tetrahydroisoquinoline

[0168] 1-(difluoromethyl)-2-(4-isopropylphenyl)-1,2,3,4-tetrahydroisoquinoline

[0169]

[0170] Pale yellow solid; Rf = 0.3 (petroleum ether / ethyl acetate = 50:1); 50.5 mg, 76% separation yield; 1 ¹H NMR (400 MHz, CDCl₃) 400 MHz, CDCl₃ (petroleum ether / ethyl acetate = 50:1); 50.5 mg, 76% separation yield; reaction was carried out overnight with stirring under blue light irradiation with oisoquinoline. After the reaction was completed, the solvent was removed by vacuum distillation. The crude product was subjected to silica gel chromatography at 6.94 (d, J = 8.4 Hz, 2H), 6.01 (d, J = 3.2 Hz, 1H), 4.96 (ddd, J = 17.4, 9.2, 3.2 Hz, 1H), 3.73 (ddd, J = 11.8, 6.8, 5.0 Hz, 1H), 3.50 (ddd, J = 12.2, 7.4, 5.2 Hz, 1H), 3.08-2.94 (m, 2H), 2.89 (p, J = 6.9 Hz, 1H), and 1.26 (d, J = 6.9 Hz, 6H). 13 C NMR (101 MHz, CDCl3) 101 MHz, CDCl (petroleum ether / ethyl acetate = 50:1); 50.5 mg, 76% separation yield; reaction was carried out overnight under blue light with stirring. After the reaction was completed, the solvent was removed by vacuum distillation (J = 252.1 Hz), 114.37, 61.38 (t, J = 23.2 Hz), 43.74, 33.13, 27.78, 24.21. 19 F NMR (377MHz, CDCl3)377MHz, CDCl.74, 33.13, HRMS (ESI): m / z[M+H] + calcd for C19H22F2N + 302.1676, found 302.1712.

[0171] Following the aforementioned general formula method, the following compound was prepared: 1-(difluoromethyl)-2-(3,4-dimethylphenyl)-1,2,3,4-tetrahydroisoquinoline

[0172] 1-(difluoromethyl)-2-(3,4-dimethylphenyl)-1,2,3,4-tetrahydroisoquinoline

[0173]

[0174] Pale yellow solid; Rf = 0.3 (petroleum ether / ethyl acetate = 50:1); 44.8 mg, 78% separation yield; 1 ¹H NMR (400 MHz, CDCl₃) 400 MHz, CDCl₃ (petroleum ether / ethyl acetate = 50:1); 44.8 mg, 78% separation yield; e-tetrahydroisoquinoline, after the reaction was complete, the solvent was removed by vacuum distillation, crude Hz, 1H), 6.70 (dd, J = 8.3, 2.8 Hz, 1H), 5.96 (td, J = 56.4, 3.2 Hz, 1H), 4.91 (ddd, J = 17.7, 9.2, 3.2 Hz, 1H), 3.67 (ddd, J = 12.0, 7.0, 4.9 Hz, 1H), 3.47 (ddd, J = 12.0, 6.8, 5.1 Hz, 1H), 3.04-2.88 (m, 2H), 2.25 (s, 3H), 2.18 (s, 3H). 13 C NMR (101MHz, CDCl3) 101MHz, CDCldd, J=8.3, 2.8Hz, 1H), 5.96 (td, J=56.4, 3.2Hz, 1H), 4.91 ( ddd, J=17.7, 9.2, 3.2J=248.6Hz), 112.13, 61.27 (t, J=23.2Hz), 43.71, 27.71, 20.41, 18.68. 19 F NMR (377MHz, CDCl3)377MHz, CDCl.71, 27.71,

[0175] Following the aforementioned general formula method, the following compound was prepared: 1-(difluoromethyl)-2-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline

[0176] 1-(difluoromethyl)-2-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline

[0177]

[0178] Pale yellow solid; Rf = 0.3 (petroleum ether / ethyl acetate = 50:1); 48.8 mg, 88% separation yield; 1 ¹H NMR (400 MHz, CDCl₃) 400 MHz, CDCl₃ (petroleum ether / ethyl acetate = 50:1); 48.8 mg, 88% separation yield; trahydroisoquinoline ¹H), 4.91 (ddd, J = 17.7, 9.2, 3.2 Hz, ¹H), 3.67 (ddd, J = 12.0, 7.0, 4.9 Hz, ¹H), 3.47 (ddd, J = 12.0, 6.8, 5.1 Hz, ¹H), 3.04–2.88 (m, ¹H), 2.99 (ddd, J = 15.2, 7.0, 5.1 Hz, 2H). 13 C NMR (101 MHz, CDCl3) 101 MHz, CDCl (petroleum ether / ethyl acetate = 50:1); 48.8 mg, 88% separation yield; trahydroisoquinoline 1H), 4.91 (ddd, JJ = 241.4 Hz), 115.88 (t, J = 23.5 Hz), 61.76 (t, J = 23.2 Hz), 44.32, 27.46. 19 F NMR (377MHz, CDCl3) δ-116.09--124.25 (m), -125.92 (dq, J=8.4, 4.3Hz). HRMS (ESI): m / z[M+H] + calcd for C16H15F3N + 278.1112, found 278.1149.

[0179] The following compound was prepared according to the aforementioned general formula method:

[0180] 2-(4-Bromophenyl)-1-(difluoromethyl)-1,2,3,4-tetrahydroisoquinoline

[0181] 2-(4-bromophenyl)-1-(difluoromethyl)-1,2,3,4-tetrahydroisoquinoline

[0182]

[0183] Pale yellow solid; Rf = 0.3 (petroleum ether / ethyl acetate = 50:1); 57.5 mg, 85% separation yield; 1¹H NMR (400 MHz, CDCl₃) 400 MHz, CDCl₃ (petroleum ether / ethyl acetate = 50:1); 57.5 mg, 85% separation yield; rahydroisoquinolinee 1H), 4.91 (ddd, J = 17.7, 9.2, 3.2 Hz, 1H), 3.67 (ddd, J = 12.0, 7.0, 4.9 Hz, 1H), 3.47 Hz, 1H), 3.71 (dt, J = 11.6, 5.7 Hz, 1H), 3.46 (ddd, J = 12.2, 7.3, 5.6 Hz, 1H), 3.02 (td, J = 5.9, 2.7 Hz, 2H). 13 C NMR (101 MHz, CDCl3) 101 MHz, CDCl (petroleum ether / ethyl acetate = 50:1); 57.5 mg, 85% separation yield; rahydroisoquinolinee 1H), 4.91 J = 245.6 Hz), 115.62, 110.72, 61.19 (t, J = 26.4 Hz), 43.69, 27.71. 19 F NMR (377MHz, CDCl3)377MHz, CDCl.69, 27.71.7HRMS (ESI): m / z[M+Na] + calcd for C17H15BrF2Na + 359.0224, found 359.0220.

[0184] The following compound was prepared according to the aforementioned general formula method:

[0185] 2-(4-Chlorophenyl)-1-(difluoromethyl)-1,2,3,4-tetrahydroisoquinoline

[0186] 2-(4-chlorophenyl)-1-(difluoromethyl)-1,2,3,4-tetrahydroisoquinoline

[0187]

[0188] Pale yellow solid; Rf = 0.3 (petroleum ether / ethyl acetate = 50:1); 48.1 mg, 82% separation yield; 1¹H NMR (400 MHz, CDCl₃) 400 MHz, CDCl₃ (petroleum ether / ethyl acetate = 50:1); 48.1 mg, 82% separation yield; rahydroisoquinolinee 1H), 4.91 (ddd, J = 17.7, 9.2, 3.2 Hz, 1H), 3.67 (ddd, J = 12. (dt, J = 11.3, 5.5 Hz, 1H), 3.54 (dt, J = 11.8, 6.8 Hz, 1H), 3.08 (t, J = 6.2 Hz, 2H). 13 C NMR (101 MHz, CDCl3) 101 MHz, CDCl (petroleum ether / ethyl acetate = 50:1); 48.1 mg, 82% separation yield; rahydroisoquinolinee 1H), 4.91 (ddd, JJ = 254.4 Hz), 115.26, 61.30 (t, J = 23.5 Hz), 43.80, 27.72. 19 F NMR (377MHz, CDCl3)377MHz, CDCl.80, 27.72.0HRMS (ESI): m / z[M+H] + calcd for C16H15C1F2N + 294.0816, found 294.0854.

[0189] The following compound was prepared according to the aforementioned general formula method:

[0190] 1-(difluoromethyl)-2-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline

[0191] 1-(difluoromethyl)-2-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline

[0192]

[0193] Pale yellow solid; Rf = 0.3 (petroleum ether / ethyl acetate = 50:1); 51.0 mg, 78% separation yield; 1¹H NMR (400 MHz, CDCl₃) 400 MHz, CDCl₃ (petroleum ether / ethyl acetate = 50:1); 51.0 mg, 78% separation yield; -1,2,3,4-tetrahydroisoqu, 4.91 (ddd, J = 17.7, 9.2, 3.2 Hz, 1H), 3.67 (ddd, J = 12. (dt, J = 11.3, 5.5 Hz, 1H), 3.54 (dt, J = 11.8, 6.8 Hz, 1H), 3.08 (t, J = 6.2 Hz, 2H). 13 C NMR (101 MHz, CDCl3) 101 MHz, CDCl (petroleum ether / ethyl acetate = 50:1); 51.0 mg, 78% separation yield; -1,2,3,4-tetrahydroisoqu, 4.91 (ddd, J = J = 64.2, 32.1 Hz), 115.74 (t, J = 246.1 Hz), 112.67, 60.86 (t, J = 23.8 Hz), 43.57, 27.91. 19 F NMR (377MHz, CDCl3)377MHz, CDCl.57, 27.91.6 (t, 1.0HRMS (ESI): m / z[M+H] + calcd for C17H15F5N + 328.1080.found 328.1117.

[0194] The following compound was prepared according to the aforementioned general formula method:

[0195] 1-(difluoromethyl)-6-methoxy-2-phenyl-1,2,3,4-tetrahydroisoquinoline

[0196] 1-(difluoromethyl)-6-methoxy-2-phenyl-1,2,3,4-tetrahydroisoquinolin

[0197]

[0198] Pale yellow solid; Rf = 0.3 (petroleum ether / ethyl acetate = 50:1); 39.3 mg, 68% separation yield; 1¹H NMR (400 MHz, CDCl₃) 400 MHz, CDCl₃ (petroleum ether / ethyl acetate = 50:1); 39.3 mg, 68% separation yield; -1,2,3,4-tetrahydroisoqu, 4.91 (ddd, J = 17.7, 9.2, 3.2 Hz, 1H), 3.67 (ddd, J = 12.), 6.75 (d, J = 12.) 2.7Hz, 1H), 5.94 (td, J=56.4, 3.4Hz, 1H), 4.90 (ddd, J=17.3, 8.9, 3.4Hz, 1H), 3.81 ( s, 3H), 3.69 (dt, J=11.8, 5.8Hz, 1H), 3.46 (dt, J=12.2, 6.3Hz, 1H), 2.99J=12.), 6.75 13 CNMR (101MHz, CDCl3) δ101MHz, CDCl17.3, 8.9, 3.4.85, 129.41, 118.67, 116.80 (t, J=252. 3, 250.3Hz), 115.21, 114.08, 113.35, 112.20, 60.64 (t, J=23.6Hz), 55.29, 43.42, 28.10. 19 FNMR (377MHz, CDCl3)377MHz, CDCl.29, 43.42, HRMS (ESI): m / z[M+H] + calcd for C17H18F2NO + 290.1312, found 290.1348.

[0199] The following compound was prepared according to the aforementioned general formula method:

[0200] 2-([1,1′-biphenyl]-4-yl)-1-(difluoromethyl)-1,2,3,4-tetrahydroisoquinoline

[0201] 2-([1,1′-biphenyl]-4-y1)-1-(difluoromethyl)-1,2,3,4-tetrahydroisoquinoline

[0202]

[0203] Pale yellow solid; Rf = 0.3 (petroleum ether / ethyl acetate = 50:1); 52.3 mg, 81% separation yield; 1HNMR (400MHz, CDCl3) 1H NMR (400MHz, Chloroform-d) δ7.55 (td, J=5.8, 3.1Hz, 4H), 7.40 (t, J=7.7Hz, 2H), 7.28 (ddd, J=12.3, 5.3, 2.2Hz, 3H), 7.25-7.18 (m, 2H), 7.05-6.98 (m, 2H ), 5.99 (td, J=56.2, 3.4Hz, 1H), 5.00 (ddd, J=16.6, 9.3, 3.4Hz, 1H), 3.75 (dt , J=11.6, 5.7Hz, 1H), 3.52 (ddd, J=12.2, 7.4, 5.5Hz, 1H), 3.08-2.94 (m, 2H). 13 C NMR (101MHz, CDCl3) 101MHz, CDClHz, Chloroform-d) δ7.55 (td, J=5.8, 3.1Hz, 4H), 7.40 (t, J= 7.7Hz, 2H), 7.28 (ddd, J=12.3, 5.3, J=249.5Hz), 114.17, 61.16 (t, J=23.6Hz), 43.62, 27.89. 19 F NMR (377MHz, CDCl3)377MHz, CDCl.62, 27.89.6HRMS (ESI): m / z[M+H] + calcd for C22H20F2N + 336.1519, found 336.1555.

[0204] The following compound was prepared according to the aforementioned general formula method:

[0205] 1-(difluoromethyl)-2-(3-methoxyphenyl)-1,2,3,4-tetrahydroisoquinoline

[0206] 1-(difluoromethyl)-2-(3-methoxyphenyl)-1,2,3,4-tetrahydroisoquinoline

[0207]

[0208] Pale yellow solid; Rf = 0.3 (petroleum ether / ethyl acetate = 50:1); 43.9 mg, 76% separation yield; 1H NMR (400 MHz, CDCl3) 400 MHz, CDCl (petroleum ether / ethyl acetate = 50:1); 43.9 mg, 76% separation yield; etrahydroisoquinoli 7.40 (t, J = 7.7 Hz, 2H), 7.28 (ddd, J = 12.3, 5.3, 2.2 Hz, 3H), 7.25–7.18 (m, 2.97 (td, J = 7.7 Hz, 2H), ... J=56.3, 3.3Hz, 1H), 4.95 (ddd, J=17.3, 9.1, 3.3Hz, 1H), 3.81 (d, J=2.1Hz, 3H), 3.70 (dt, J=11.7, 5.8Hz, 1H), 3.47 (ddd, J=12.1, 7.3, 5.5Hz, 1H), 2.99 (td, J=5.7, 5.2, 3.2Hz, 2H). 13 C NMR (101MHz, CDCl3) 101MHz, CDCl (petroleum ether / ethyl acetate = 50130.12, 128.75, 128.49, 128.25, 128.1Z9, 126.37, 115.99 (t, J = 243.8Hz), 106.91, 103.18, 100.89, 61.19 (t, J = 23.5Hz), 55.27, 43.59, 27.87, 27.86. 19 F NMR (377MHz, CDCl3)377MHz, CDCl.27, 43.59, HRMS (ESI): m / z[M+H] + calcd for C17H18F2NO + 290.1312, found 290.1348.

[0209] The following compound was prepared according to the aforementioned general formula method:

[0210] 2-(3-Chlorophenyl)-1-(difluoromethyl)-1,2,3,4-tetrahydroisoquinoline

[0211] 2-(3-chlorophenyl)-1-(difluoromethyl)-1,2,3,4-tetrahydroisoquinoline

[0212]

[0213] Pale yellow solid; Rf = 0.3 (petroleum ether / ethyl acetate = 50:1); 47.5 mg, 81% separation yield; 1HNMR(400MHz, CDCl3) 400MHz, C.26(m, 2H), 7.23(s, 1H), 7.21 - 7.16(m, 2H), 6.91(q, J = 3.2, 2.8Hz, 1H), 6.81(td, J = 8.5, 7.9, 2.2Hz, 2H), 5.94(td, J = 56.1, 3.6Hz, 1H), 4.92(ddd, J = 15.7, 9.6, 3.6Hz, 1H), 3.69(dt, J = 11.5, 5.7Hz, 1H), 3.44(dt, J = 12.2, 6.3Hz, 1H), 3.06 - 2.94(m, 2H). 13 C NMR(101MHz, CDCl3) 101MHz, CDCl(m, 2H), 7.23(s, 1H), 7.21 - 7.16(m, 2H), 6.91(q, J = 3.2, 2.8Hz, 1H), 6.81J = 244.8Hz), 113.80, 111.87, 61.08(t, J = 23.6Hz), 43.60, 27.79. 19 F NMR(377MHz, CDCl3) 377MHz, CDCl.60, 27.79.8HRMS(ESI): m / z[M + H] + calcd for C16H14ClF2N + 294.0816, found 294.0853.

[0214] References:

[0215] 【1】Prakash, G.K.S.; Weber, C.; Chacko, S.; Olah, G.A., New electrophilic difluoromethylating reagent. Org. Lett. 2007, 9(10), 1863 - 1866.

[0216] 【2】Lu, S.L; Li, X.; Qin, W.B.; Liu, J.J.; Huang, Y.Y.; Wong, H.N.C.; Liu, G.K., Air - and Light - Stable S-(Difluoromethyl)sulfonium Salts: C - Selective E1ectrophilic Difluoromethylation of beta - Ketoesters and Malonates. Org. Lett. 2018, 20(21), 6925 - 6929.

[0217] 【3】Zhang, W.; Wang, F.; Hu, J., N-Tosyl-S-difluoromethyl-S-phenylsulfoximine: A New Difluoromethylation Reagent for S-, N-, and C-Nucleophiles.Org.Lett.2009, 11(10), 2109-2112.

[0218] 【4】Zhu, J.; Liu, Y.; Shen, Q., Direct Difluoromethylation of Alcohols withan Electrophilic Difluoromethylated Sulfonium Ylide. Angew. Chem. Int., Ed. 2016, 55(31), 9050-9054.

[0219] 【5】W.-B.Qin, W.Xiong, X.Li, J.-Y.Chen, L.-T.Lin, Henry NCWong, G.-K.Liu, J.Org.Chem.2020, 85, 10479-10487.

[0220] The above description is merely a specific embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any person skilled in the art can easily conceive of various equivalent modifications or substitutions within the technical scope disclosed in the present invention, and these modifications or substitutions should all be covered within the scope of protection of the present invention. Therefore, the scope of protection of the present invention should be determined by the scope of the claims.

Claims

1. A difluoromethyl reagent, characterized in that, Compounds of formula 1a or 1b:

2. The method for preparing the difluoromethyl reagent according to claim 1, characterized in that, The difluoromethyl reagent is obtained by cyclizing 1-((difluoromethyl)sulfoxide)-2-phenoxybenzene or its analogues in the presence of trifluoromethanesulfonic anhydride, followed by corresponding anion exchange.

3. The method for preparing the difluoromethyl reagent according to claim 2, characterized in that, The electrophilic difluoromethyl reagent is obtained by cyclizing 1-((difluoromethyl)sulfoxide)-2-phenoxybenzene or 1-((difluoromethyl)sulfoxide)-2-phenoxy-3,5-dimethoxybenzene in the presence of trifluoromethanesulfonic anhydride, followed by anion exchange with sodium tetrafluoroborate solution.

4. The application of the difluoromethyl reagent as described in claim 1, characterized in that, For the hydrogen / difluoromethyl bifunctionalization reaction of alkenes, compounds with the following structure (Formula 3) are synthesized: Among them, R 1 For H; R 2 H, alkyl, or aryl; EWG is an ester, ketone, sulfone, or other electron-withdrawing group.

5. The application according to claim 4, characterized in that, Compounds of formula 3 were synthesized using 2,6-dimethyl-3,5-diethyl-1,4-dihydropyridine as a hydrogen donor and phenyl acrylate or non-activated olefins with the difluoromethyl reagent.

6. The application of the difluoromethyl reagent as described in claim 1, characterized in that, For the difluoromethyl functionalization reaction of tetrahydroisoquinoline C(sp3)-H, compounds with the following structure (Formula 5) were synthesized: Among them, R 1 H is an electron-withdrawing or electron-donating substituent; R 2 H is an electron-withdrawing or electron-donating substituent.

7. The application according to claim 6, characterized in that, Compounds having the structure of Formula 5 were synthesized by using 2-phenyl-1,2,3,4-tetrahydroisoquinoline or its derivatives with the difluoromethyl reagent.

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