Polyfluoroalkoxy aryl substituted triazole N-heterocyclic carbene catalyst and application thereof

Abstract

The invention discloses a triazole N-heterocyclic carbene catalyst containing a polyfluoroalkoxy aryl substituent and an application of the triazole N-heterocyclic carbene catalyst containing the polyfluoroalkoxy aryl substituent. According to the invention, trifluoroethoxy or hexafluoroisopropoxy is introduced into an N-phenyl site of a triazole skeleton, 11 kinds of triazole N-heterocyclic carbene catalysts containing polyfluoroalkoxy aryl substitutions are successfully synthesized, and the catalytic performance of the catalysts is explored. Compared with the existing other triazole NHC, the polyfluoroalkoxy aryl substituted triazole N-heterocyclic carbene catalyst disclosed by the invention shows optimal enantioselectivity and reactivity: under the condition that the dosage of the catalyst is 10 mol%, a target product can be obtained at the yield of 90% and the ratio of 98: 2 er. Meanwhile, the polyfluoroalkoxy aryl substituted triazole N-heterocyclic carbene catalyst is also suitable for model reactions of photocatalysis and electro-catalysis. Excellent reactivity and selectivity are shown in a three-component free radical cascade reaction in which aldehyde, styrene and a Togni I reagent participate.

Description

Technical Field

[0001] This invention relates to the field of organic chemistry, and more specifically, to a class of triazole nitrogen heterocyclic carbene catalysts containing polyfluoroalkoxy aryl substituted groups and their applications. Background Technology

[0002] Triazole-based nitrogen-containing heterocyclic carbenes (NHCs) are a class of organocatalysts widely used in organic synthesis. The substituents on the nitrogen atom largely determine their reactivity and stereoselectivity; therefore, selecting aromatic substituents with specific electronic and steric properties is often crucial and requires design for different reactions. For example, in the asymmetric benzoin condensation reaction (Org. Lett., 2007, 9, 2713-2716) and the Stetter reaction (Chem. Lett., 2008, 37, 2-7), electron-deficient aromatic N-substituents, such as pentafluorophenyl, are typically required. Conversely, in lactone or lactamation reactions, N-trimethyltriazole NHCs exhibit significantly better reactivity than their N-phenyl counterparts. Meanwhile, N-(2,6-dimethoxyphenyl)-substituted triazole NHC catalysts demonstrate unique activity in the hydroacylation of cyclopropylene.

[0003] Polyfluoroalkoxy groups exhibit properties distinct from traditional alkoxy groups due to the unique properties of fluorine (such as strong electronegativity, small atomic radius, and high CF bond energy). A typical example is the Still-Gennari olefination reaction: replacing the ethoxy group in the Horner-Wadsworth-Emmons reagent with a trifluoroethoxy or hexafluoroisopropoxy group completely reverses the Z / E stereoselectivity, making the Z-olefin the major product. Furthermore, polyfluorools also exhibit unique properties when used as solvents or additives in various transformation reactions.

[0004] While the N-pentafluorophenyl-substituted chiral triazole NHCs used by Li Junlong's research group can catalyze radical trifluoroacetylation reactions, the enantioselectivity is only 56:44 er. Crame's research group reported a chiral thiazole NHC with a large sterically hindered chiral side chain and a 12-membered ring skeleton, which can give the target product in 76% yield and with an enantioselectivity of 96:4 er. However, the synthesis of macrocyclic skeletons is relatively difficult; in contrast, commercially available 7-membered ring skeleton catalysts only provide poor enantioselectivity (60:40 er). Summary of the Invention

[0005] The purpose of this invention is to overcome the shortcomings of the prior art and provide a class of triazole nitrogen heterocyclic carbene catalysts containing polyfluoroalkoxyaryl substituted poly(fluoroalkoxy) carbene catalysts that can significantly improve the enantioselectivity of catalysts.

[0006] To achieve the above objectives, the present invention adopts the following technical solution: A class of triazole nitrogen heterocyclic carbene catalysts containing polyfluoroalkoxy aryl substitutions, named NHC1-11, has the structural formula shown in Formula I, II, or III:

[0007] Compared with the prior art, the present invention has the following beneficial effects: This invention develops a novel family of NHCs containing polyfluoroalkoxy-aryl substituted groups. Specifically, we introduced trifluoroethoxy or hexafluoroisopropoxy into the N-phenyl site of the triazole skeleton, successfully synthesizing 11 triazole-based nitrogen-heterocyclic carbene catalysts containing polyfluoroalkoxy-aryl substituted groups, and investigated their catalytic performance. Compared with other existing triazole-based NHCs, the triazole-based nitrogen-heterocyclic carbene catalysts of this invention exhibit the best enantioselectivity and reactivity: at a catalyst dosage of 10 mol% , the target product can be obtained in 90% yield and 98:2 er. Furthermore, this invention found that the newly synthesized triazole-based nitrogen-heterocyclic carbene catalysts containing polyfluoroalkoxy-aryl substituted groups are also suitable for photocatalytic and electrocatalytic model reactions. The triazole-based nitrogen-heterocyclic carbene catalysts containing polyfluoroalkoxy-aryl substituted groups synthesized in this invention exhibit excellent reactivity and selectivity in the three-component radical cascade reaction involving aldehydes, styrene, and Togni I reagent. Detailed Implementation

[0008] Example 1: Synthesis of intermediates TL-S13 and TL-S23 Compounds S1 (2,6-difluoronitrobenzene) and S2 (1,3,5-trifluoro-2-nitrobenzene) are commercially available reagents and can be purchased and used directly.

[0009] (1) Synthesis of TL-S11 and TL-S21:

[0010] Sodium hydride (6 g, 150 mmol, 3 equivalents, 60% mineral oil dispersion) was added to a 1000 mL round-bottom flask dried in a drying oven and equipped with a magnetic stirrer. The sodium hydride was washed three times with petroleum ether (50 mL × 3), removing the supernatant each time using a syringe with a long syringe. Anhydrous toluene (500 mL) was added, and the mixture was cooled to 0°C in an ice bath. 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP, 11.8 mL, 110 mmol, 2.2 equivalents) was added dropwise to the mixture with stirring, and the mixture was stirred at 0°C for 30 minutes. Subsequently, 2,6-difluoronitrobenzene (S1, 8.0 g, 50 mmol, 1 equivalent) or 1,3,5-trifluoro-2-nitrobenzene (S2, 8.9 g, 50 mmol, 1 equivalent) was added to an ice bath, and the reaction mixture was stirred and heated under reflux for 48 hours. After the reaction was complete, the mixture was cooled to room temperature, and the product was separated from the reaction solution by filtration. The filtrate was concentrated by rotary evaporation under reduced pressure. Then, it was diluted with dichloromethane and water. The aqueous phase was separated and extracted with dichloromethane. The organic phases were combined, washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, concentrated by rotary evaporation under reduced pressure, and finally purified by column chromatography (eluent: petroleum ether / ethyl acetate = 10:1) to give brown solid products TL-S11 (22 g, 97% yield) or TL-S21 (23 g, 98% yield).

[0011] (2) Synthesis of TL-S12 and TL-S22:

[0012] Add TL-S11 (22.8 g, 50 mmol, 1 equivalent) or TL-S21 (23.6 g, 50 mmol, 1 equivalent) dissolved in ethanol (100 mL) and water (75 mL) to a 250 mL three-necked round-bottom flask that has been dried in a drying oven. Then, add iron powder (14 g, 250 mmol, 5 equivalent) to the reaction solution in small batches. Adjust the pH of the solution to 5 with concentrated hydrochloric acid and heat the mixture under reflux for 12 hours with mechanical stirring.

[0013] After the reaction was complete, the mixture was cooled to room temperature, and the product was separated from the reaction solution by filtration. The filtrate was then concentrated by rotary evaporation under reduced pressure. Subsequently, it was diluted with dichloromethane and water. The aqueous phase was separated and extracted with dichloromethane. The organic phases were combined, washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, concentrated by rotary evaporation under reduced pressure, and finally purified by column chromatography (eluent: petroleum ether / ethyl acetate = 20:1) to give either the yellow solid product TL-S12 (18.3 g, 86% yield) or TL-S22 (18.8 g, 85% yield).

[0014] (3) Synthesis of TL-S13 and TL-S23:

[0015] To a 250 mL round-bottom flask dried in a drying oven and equipped with a magnetic stirrer, add either TL-S12 (1 equivalent, 21.3 g, 50 mmol) or TL-S22 (1 equivalent, 22.2 g, 50 mmol) dissolved in glacial acetic acid (22 mL), followed by 12 mL of concentrated sulfuric acid. Cool the mixture to -5 °C to 0 °C in an ice bath. Then, add dropwise an 8 mL solution of sodium nitrite (1.09 equivalent, 3.8 g, 54.5 mmol) in water at 0 °C, stirring the reaction mixture at this temperature for 1 hour. Next, add dropwise a 28 mL solution of stannous chloride (2 equivalent, 19.0 g, 100 mmol) in concentrated hydrochloric acid, stirring the mixture at room temperature for 5 hours. Dilute the reaction solution with dichloromethane and then neutralize with saturated sodium hydroxide solution in an ice bath at 0 °C. Separate the product from the reaction solution by filtration, and concentrate the filtrate by rotary evaporation under reduced pressure. The aqueous phase was then separated and extracted with dichloromethane. The organic phases were combined, washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, concentrated by rotary evaporation under reduced pressure, and finally purified by column chromatography (eluent: petroleum ether / ethyl acetate = 20:1) to give either TL-S13 (13.6 g, 62% yield) or TL-S23 (14.9 g, 65% yield) as a yellow solid.

[0016] Example 2: Synthesis of NHC1 (5aR,10bS)-2-(4-fluoro-2,6-bis(1,1,1,3,3,3-hexafluoroisopropoxy)phenyl)-5a,10b-dihydro-4H,6H-indolo[2,1-b][1,2,4]triazolo[4,3-d][1,4]oxazine-2-onium tetrafluoroborate (NHCl)

[0017] Add lactam (5 mmol, 1.0 equivalent) to a 100 mL round-bottom flask equipped with a magnetic stirrer. Then add dichloromethane (20 mL) and trimethoxytetrafluoroborate (5.5 mmol, 1.1 equivalent). Stir the heterogeneous mixture at room temperature until the reaction mixture becomes homogeneous. Add TL-S23 (5 mmol, 1.0 equivalent) and continue stirring for 12 hours. Reduce the solvent by rotary evaporation, then add chlorobenzene (50 mL) and triethyl orthoformate (12.5 mmol, 2.5 equivalent). Heat to reflux in an oil bath at 135 °C and stir open for 24 hours. Then add triethyl orthoformate again (12.5 mmol, 2.5 equivalent) and continue stirring for 24 hours. After cooling to room temperature, add toluene (30 mL) and stir with a magnetic stirrer. Filter the resulting slurry. The filter cake was washed with toluene (20 mL) and n-hexane (20 mL), and then rinsed with dichloromethane in a 15 mL ice bath through a glass dropper, finally yielding 1.5 g of white solid product, with a yield of 42%, which is NHC1. Its structural formula and NMR data are shown below.

[0018] 1 H NMR (600 MHz, Methanol- d 4): δ = 7.51-7.35 (m, 5H), 7.34-7.27 (m,1H), 6.41-6.28 (m, 2H), 6.15 (d, J = 4.2 Hz, 1H), 5.28-5.21 (m, 1H), 5.17 -5.06(m, 2H), 3.48 (dd, J = 17.1, 5.0 Hz, 1H), 3.27 (d, J = 17.1, 1H). 13 C NMR (151 MHz, Methanol-d 4 ):δ = 167.0 (d, J = 255.8 Hz), 155.2 (d, J =13.7 Hz), 152.1, 141.9, 136.3, 131.0, 128.6, 126.9, 124.3, 125.5-117.9 (m),113.1, 100.4 (d, J = 29.2 Hz), 78.8, 75.2 (p, J =34.1 Hz), 63.8, 60.8, 38.1. 19F NMR (565 MHz , Methanol-d 4 ): δ = -74.73 (m), -74.87 – -75.11 (m), -98.79 (t, J = 9.6 Hz), -154.41 (m). HRMS (ESI): calc. for [C 24 H 16 F 12 [N3O3] ([M] + ): 640.09003, found in: 640.08820.

[0019] Example 3: Synthesis of NHC2 (5aR,10bS)-2-(4-fluoro-2,6-bis(1,1,1,3,3,3-hexafluoroisopropoxy)phenyl)-5a,10b-dihydro-4H,6H-indolo[2,1-b][1,2,4]triazolo[4,3-d][1,4]oxazine-2-onium tetrafluoroborate (NHC2)

[0020] Add lactam (5 mmol, 1.0 equivalent) to a 100 mL round-bottom flask equipped with a magnetic stirrer. Then add dichloromethane (20 mL) and trimethoxytetrafluoroborate (5.5 mmol, 1.1 equivalent). Stir the heterogeneous mixture at room temperature until the reaction mixture becomes homogeneous. Add TL-S23 (5 mmol, 1.0 equivalent) and continue stirring for 12 hours. Reduce the solvent by rotary evaporation, then add chlorobenzene (50 mL) and triethyl orthoformate (12.5 mmol, 2.5 equivalent). Heat to reflux in an oil bath at 135 °C and stir open for 24 hours. Then add triethyl orthoformate again (12.5 mmol, 2.5 equivalent) and continue stirring for 24 hours. After cooling to room temperature, add toluene (30 mL) and stir with a magnetic stirrer. Filter the resulting slurry. The filter cake was washed with toluene (20 mL) and n-hexane (20 mL), and then rinsed with dichloromethane in a 15 mL ice bath through a glass dropper, finally yielding 1.2 g of white solid product, with a yield of 32%, namely NHC2, whose structural formula and NMR data are shown below.

[0021] 1 H NMR (600 MHz, Methanol- d4): δ = 7.51-7.35 (m, 5H), 7.34-7.27 (m,1H), 6.41-6.28 (m, 2H), 6.15 (d, J = 4.2 Hz, 1H), 5.28-5.21 (m, 1H), 5.17 -5.06(m, 2H), 3.48 (dd, J = 17.1, 5.0 Hz, 1H), 3.27 (d, J = 17.1, 1H). 13 C NMR (151 MHz, Methanol-d 4 ):δ = 167.0 (d, J = 255.8 Hz), 155.2 (d, J =13.7 Hz), 152.1, 141.9, 136.3, 131.0, 128.6, 126.9, 124.3, 125.5-117.9 (m),113.1, 100.4 (d, J = 29.2 Hz), 78.8, 75.2 (p, J =34.1 Hz), 63.8, 60.8, 38.1. 19 F NMR (565 MHz , Methanol-d 4 ): δ = -74.73 (m), -74.87 – -75.11 (m), -98.79 (t, J = 9.6 Hz), -154.41 (m). HRMS (ESI): calc. for [C 24 H 16 F 12 [N3O3] ([M] + ): 640.09003, found in: 640.08820.

[0022] Example 4: Synthesis of NHC3 (5aR,10bS)-2-(2,6-bis(1,1,1,3,3,3-hexafluoroisopropoxy)phenyl)-9-bromo-5a,10b-dihydro-4H,6H-indolo[2,1-b][1,2,4]triazolo[4,3-d][1,4]oxazine-2-onium tetrafluoroborate (NHC3)

[0023] Add lactam (5 mmol, 1.0 equivalent) to a 100 mL round-bottom flask equipped with a magnetic stirrer. Then add dichloromethane (20 mL) and trimethoxytetrafluoroborate (5.5 mmol, 1.1 equivalent). Stir the heterogeneous mixture at room temperature until the reaction mixture becomes homogeneous. Add TL-S13 (5 mmol, 1.0 equivalent) and continue stirring for 12 hours. Reduce the solvent by rotary evaporation, then add chlorobenzene (50 mL) and triethyl orthoformate (12.5 mmol, 2.5 equivalent). Heat to reflux in an oil bath at 135 °C and stir open for 24 hours. Then add triethyl orthoformate again (12.5 mmol, 2.5 equivalent) and continue stirring for 24 hours. After cooling to room temperature, add toluene (30 mL) and stir with a magnetic stirrer. Filter the resulting slurry. The filter cake was washed with toluene (20 mL) and n-hexane (20 mL), and then rinsed with dichloromethane in a 15 mL ice bath through a glass dropper to finally obtain 1.0 g of white solid product, with a yield of 24%, namely NHC3, whose structural formula and NMR data are shown below.

[0024] 1 H NMR (400 MHz, Methanol- d 4): δ = 7.90 (t, J = 8.8 Hz, 1H), 7.60 (d, J =1.9 Hz, 1H), 7.58 (dd, J = 8.0, 1.8 Hz, 1H), 7.47 (d, J = 8.8 Hz, 2H), 7.35 (d, J =8.0 Hz, 1H), 6.34 (p, J = 5.7 Hz, 2H), 6.18 (d, J = 4.2 Hz, 1H), 5.28 (d, J = 16.4Hz, 1H), 5.16-5.04 (m, 2H), 3.42 (dd, J = 17.4, 5.0 Hz, 1H), 3.25 (d, J = 17.3Hz, 1H). 13 C NMR (151 MHz, Methanol-d 4):δ = 154.1, 152.0, 141.3, 138.7, 136.3,134.3, 128.7, 127.7, 122.2 (d, J = 282.8 Hz), 122.1, 116.7, 111.9, 78.9, 75.4(dt, J = 68.2, 34.0 Hz), 63.3, 60.9, 37.7. 19 F NMR (565 MHz , Methanol-d 4 ): δ = δ -74.6, -74.7, -74.7, -74.7, -75.0, -75.0, -75.1, -75.1, -154.3, -154.3. HRMS (ESI): calc. for [C 24 H 15 BrF 12 [N3O3] ([M] + ): 700.0100, found in:700.0080.

[0025] Example 5: Synthesis of NHC4 (5aR,10bS)-9-bromo-2-(4-fluoro-2,6-bis(1,1,1,3,3,3-hexafluoroisopropoxy)phenyl)-5a,10b-dihydro-4H,6H-indolo[2,1-b][1,2,4]triazolo[4,3-d][1,4]oxazine-2-onium tetrafluoroborate (NHC4)

[0026] Add lactam (5 mmol, 1.0 equivalent) to a 100 mL round-bottom flask equipped with a magnetic stirrer. Then add dichloromethane (20 mL) and trimethoxytetrafluoroborate (5.5 mmol, 1.1 equivalent). Stir the heterogeneous mixture at room temperature until the reaction mixture becomes homogeneous. Add TL-S23 (5 mmol, 1.0 equivalent) and continue stirring for 12 hours. Reduce the solvent by rotary evaporation, then add chlorobenzene (50 mL) and triethyl orthoformate (12.5 mmol, 2.5 equivalent). Heat to reflux in an oil bath at 135 °C and stir open for 24 hours. Then add triethyl orthoformate again (12.5 mmol, 2.5 equivalent) and continue stirring for 24 hours. After cooling to room temperature, add toluene (30 mL) and stir with a magnetic stirrer. Filter the resulting slurry. The filter cake was washed with toluene (20 mL) and n-hexane (20 mL), and then rinsed with dichloromethane in a 15 mL ice bath through a glass dropper, finally yielding 1.9 g of white solid product, with a yield of 46%, namely NHC4, whose structural formula and NMR data are shown below.

[0027] 1 H NMR (400 MHz, Methanol- d 4): δ = 7.64 – 7.52 (m, 2H), 7.40 (d, J = 9.6Hz, 2H), 7.34 (d, J = 8.0 Hz, 1H), 6.32 (hept, J = 5.6 Hz, 2H), 6.18 (d, J = 4.1Hz, 1H), 5.26 (d, J = 16.4 Hz, 1H), 5.18 – 5.06 (m, 2H), 3.42 (dd, J = 17.3, 5.0Hz, 1H), 3.24 (d, J = 17.3 Hz, 1H). 13 C NMR (151 MHz, Methanol-d 4 ):δ = 165.7 (d, J = 255.8 Hz), 153.8 (d, J =13.7 Hz), 150.7, 139.9, 137.3, 132.9, 126.8 (d, J = 157.4 Hz), 120.7, 120.6 (q, J= 282.4 Hz), 111.7 (d, J = 4.2 Hz), 99.1 (d, J = 29.0 Hz), 77.5, 73.9 (p, J = 34.3Hz), 62.0, 59.5, 36.3. 19 F NMR (565 MHz , Methanol-d 4 ): δ = -74.6, -74.6, -74.6, -74.6, -74.6,-74.9, -74.9, -75.0, -75.0, -75.0, -98.7, -98.7, -98.7, -154.3, -154.4, -154.4, -154.4, -154.4. HRMS (ESI): calc. for [C 24 H 14 BrF 13 [N3O3] ([M] + ): 718.0005, found in:717.9986.

[0028] Example 6: Synthesis of NHC5 (5aR,10bS)-9-iodo-2-(4-fluoro-2,6-bis(1,1,1,3,3,3-hexafluoroisopropoxy)phenyl)-5a,10b-dihydro-4H,6H-indolo[2,1-b][1,2,4]triazolo[4,3-d][1,4]oxazine-2-onium tetrafluoroborate (NHC5)

[0029] Add lactam (5 mmol, 1.0 equivalent) to a 100 mL round-bottom flask equipped with a magnetic stirrer. Then add dichloromethane (20 mL) and trimethoxytetrafluoroborate (5.5 mmol, 1.1 equivalent). Stir the heterogeneous mixture at room temperature until the reaction mixture becomes homogeneous. Add TL-S23 (5 mmol, 1.0 equivalent) and continue stirring for 12 hours. Reduce the solvent by rotary evaporation, then add chlorobenzene (50 mL) and triethyl orthoformate (12.5 mmol, 2.5 equivalent). Heat to reflux in an oil bath at 135 °C and stir open for 24 hours. Then add triethyl orthoformate again (12.5 mmol, 2.5 equivalent) and continue stirring for 24 hours. After cooling to room temperature, add toluene (30 mL) and stir with a magnetic stirrer. Filter the resulting slurry. The filter cake was washed with toluene (20 mL) and n-hexane (20 mL), and then rinsed with dichloromethane in a 15 mL ice bath through a glass dropper, finally yielding 0.7 g of a white solid product with a yield of 16%, namely NHC5, whose structural formula and NMR data are shown below.

[0030] 1 H NMR (400 MHz, Chloroform- d ): δ = 7.78 (d, J = 8.4 Hz, 2H), 7.41 (d, J = 9.6 Hz, 2H), 7.22 (d, J = 7.9 Hz, 1H), 6.35 (hept, J = 5.6 Hz, 2H), 6.16 (d, J =4.2 Hz, 1H), 5.27 (d, J = 16.4 Hz, 1H), 5.11 (d, J = 16.5 Hz, 1H), 5.05 (t, J = 4.6Hz, 1H), 3.42 (dd, J = 17.4, 5.0 Hz, 1H), 3.24 (d, J = 17.3 Hz, 1H). 13 C NMR (151 MHz, Methanol-d 4 ):δ =167.1 (d, J = 255.9 Hz), 155.3 (d, J=13.8 Hz), 152.2, 141.9, 140.5, 138.8, 133.5, 128.9, 131.0 – 110.8 (m), 100.5(d, J = 29.0 Hz), 92.5, 78.7, 77.1, 75.4 (p, J = 68.4, 34.4 Hz), 63.2, 60.9,37.7. 19 F NMR (377 MHz , Methanol-d 4 ): δ =-74.5, -74.5, -74.5, -74.6, -74.9,-74.9, -75.0, -75.0, -98.7, -98.7, -98.7, -154.3, -154.3. HRMS (ESI): calc. for [C 24 H 14 F 13 IN3O3] ([M] + ): 765.9867, found in:765.9841.

[0031] Example 7: Synthesis of NHC6 (5aR,10bS)-9-nitro-2-(4-fluoro-2,6-bis(1,1,1,3,3,3-hexafluoroisopropoxy)phenyl)-5a,10b-dihydro-4H,6H-indolo[2,1-b][1,2,4]triazolo[4,3-d][1,4]oxazine-2-onium tetrafluoroborate (NHC6)

[0032] Add lactam (5 mmol, 1.0 equivalent) to a 100 mL round-bottom flask equipped with a magnetic stirrer. Then add dichloromethane (20 mL) and trimethoxytetrafluoroborate (5.5 mmol, 1.1 equivalent). Stir the heterogeneous mixture at room temperature until the reaction mixture becomes homogeneous. Add TL-S23 (5 mmol, 1.0 equivalent) and continue stirring for 12 hours. Reduce the solvent by rotary evaporation, then add chlorobenzene (50 mL) and triethyl orthoformate (12.5 mmol, 2.5 equivalent). Heat to reflux in an oil bath at 135 °C and stir open for 24 hours. Then add triethyl orthoformate again (12.5 mmol, 2.5 equivalent) and continue stirring for 24 hours. After cooling to room temperature, add toluene (30 mL) and stir with a magnetic stirrer. Filter the resulting slurry. The filter cake was washed with toluene (20 mL) and n-hexane (20 mL), and then rinsed with dichloromethane in a 15 mL ice bath through a glass dropper, finally yielding 0.4 g of a white solid product, with a yield of 11%, namely NHC6, whose structural formula and NMR data are shown below.

[0033] 1 H NMR (400 MHz, Methanol- d 4): δ = 8.37-8.26 (m, 2H), 7.67 (d, J = 8.3Hz, 1H), 7.40 (d, J = 9.6 Hz, 2H), 6.29 (dq, J = 8.9, 5.6, 4.5 Hz, 3H), 5.27 (d, J = 16.4 Hz, 1H), 5.20 (t, J = 4.5 Hz, 1H), 5.15 (d, J = 16.4 Hz, 1H), 3.59 (dd, J =18.1, 5.0 Hz, 1H), 3.45-3.32 (m, 1H). 13 C NMR (151 MHz, Methanol-d 4 ):δ = 165.7 (d, J = 256.0 Hz), 153.9 (d, J =13.8 Hz), 150.8, 148.4, 148.1, 137.0, 125.9 (d, J = 250.7 Hz), 120.6 (q, J=281.6 Hz), 118.6, 111.8 (d, J = 4.3 Hz), 99.2 (d, J = 28.9 Hz), 77.6, 74.0 (p, J =34.3 Hz), 61.8, 59.6, 36.9. 19 F NMR (565 MHz , Methanol-d 4 ): δ = -74.9, -74.9, -74.9, -74.9, -75.0,-98.6, -98.6, -98.6, -154.4, -154.5, -154.5, -154.6. HRMS (ESI): calc. for [C 24 H 14 F 13 [N4O5] ([M] + ): 685.0751, found in: 685.0733.

[0034] Example 8: Synthesis of NHC7 (5aR,10bS)-9-phenyl-2-(4-fluoro-2,6-bis(1,1,1,3,3,3-hexafluoroisopropoxy)phenyl)-5a,10b-dihydro-4H,6H-indolo[2,1-b][1,2,4]triazolo[4,3-d][1,4]oxazine-2-onium tetrafluoroborate (NHC7)

[0035] Add lactam (5 mmol, 1.0 equivalent) to a 100 mL round-bottom flask equipped with a magnetic stirrer. Then add dichloromethane (20 mL) and trimethoxytetrafluoroborate (5.5 mmol, 1.1 equivalent). Stir the heterogeneous mixture at room temperature until the reaction mixture becomes homogeneous. Add TL-S23 (5 mmol, 1.0 equivalent) and continue stirring for 12 hours. Reduce the solvent by rotary evaporation, then add chlorobenzene (50 mL) and triethyl orthoformate (12.5 mmol, 2.5 equivalent). Heat to reflux in an oil bath at 135 °C and stir open for 24 hours. Then add triethyl orthoformate again (12.5 mmol, 2.5 equivalent) and continue stirring for 24 hours. After cooling to room temperature, add toluene (30 mL) and stir with a magnetic stirrer. Filter the resulting slurry. The filter cake was washed with toluene (20 mL) and n-hexane (20 mL), and then rinsed with dichloromethane in a 15 mL ice bath through a glass dropper to finally obtain 1.0 g of white solid product, with a yield of 25%, namely NHC7, whose structural formula and NMR data are shown below.

[0036] 1 H NMR (600 MHz, Methanol- d 4): δ = 7.72 – 7.62 (m, 2H), 7.57 (d, J = 7.5Hz, 2H), 7.49 (dd, J = 7.9, 3.9 Hz, 1H), 7.45 – 7.35 (m, 4H), 7.32 (t, J = 7.4Hz, 1H), 6.26 (h, J = 5.4, 4.4 Hz, 2H), 6.22 (d, J = 4.3 Hz, 1H), 5.27 (ddd, J =16.3, 5.5, 2.8 Hz, 1H), 5.18 – 5.07 (m, 2H), 3.50 (dd, J = 17.1, 5.2 Hz, 1H), 3.33 (dd, J = 17.5, 3.9 Hz, 1H). 13 C NMR (151 MHz, Methanol-d 4 ):δ = 167.0 (d, J = 255.5 Hz), 155.3 (d, J=13.9 Hz), 152.3, 143.0, 141.7, 140.8, 137.0, 130.2, 129.0 (d, J = 229.2 Hz),128.6, 127.2, 123.1, 125.4-118.6 (m), 113.2 (d, J = 4.5 Hz), 100.5 (d, J = 29.0Hz), 78.9, 75.3 (p, J = 34.0 Hz), 63.8, 60.8, 37.6. 19 F NMR (565 MHz , Methanol-d 4 ): δ = -74.9, -74.9, -74.9, -75.0, -98.7,-98.7, -98.7, -154.1, -154.2, -154.2, -154.3, -154.3, -154.3, -154.3, -154.4,-154.4, -154.4, -154.4, -154.5, -154.5, -154.5, -154.6. HRMS (ESI): calc. for [C 30 H 19 BrF 13 [N3O3] ([M] + ): 716.1213, found in:716.1188.

[0037] Example 9: Synthesis of NHC8 (5aR,10bS)-9-(3,5-di-tert-butylphenyl)-2-(4-fluoro-2,6-bis(1,1,1,3,3,3-hexafluoroisopropoxy)phenyl)-5a,10b-dihydro-4H,6H-indolo[2,1-b][1,2,4]triazolo[4,3-d][1,4]oxazine-2-onium tetrafluoroborate (NHC8)

[0038] Add lactam (5 mmol, 1.0 equivalent) to a 100 mL round-bottom flask equipped with a magnetic stirrer. Then add dichloromethane (20 mL) and trimethoxytetrafluoroborate (5.5 mmol, 1.1 equivalent). Stir the heterogeneous mixture at room temperature until the reaction mixture becomes homogeneous. Add TL-S23 (5 mmol, 1.0 equivalent) and continue stirring for 12 hours. Reduce the solvent by rotary evaporation, then add chlorobenzene (50 mL) and triethyl orthoformate (12.5 mmol, 2.5 equivalent). Heat to reflux in an oil bath at 135 °C and stir open for 24 hours. Then add triethyl orthoformate again (12.5 mmol, 2.5 equivalent) and continue stirring for 24 hours. After cooling to room temperature, add toluene (30 mL) and stir with a magnetic stirrer. Filter the resulting slurry. The filter cake was washed with toluene (20 mL) and n-hexane (20 mL), and then rinsed with dichloromethane in a 15 mL ice bath through a glass dropper, finally yielding 0.7 g of a white solid product, with a yield of 17%, namely NHC8, whose structural formula and NMR data are shown below.

[0039] 1 H NMR (400 MHz, Chloroform- d ): δ = 10.62 (s, 1H), 7.64 – 7.51 (m, 2H), 7.45 – 7.36 (m, 2H), 7.33 (d, J = 1.8 Hz, 2H), 6.88 (d, J = 8.8 Hz, 2H), 6.23 (s, 1H), 5.14 (d, J = 16.4 Hz, 1H), 5.08 (q, J = 5.3 Hz, 3H), 4.99 (d, J =16.4 Hz, 1H), 3.43 (dd, J = 17.3, 4.6 Hz, 1H), 3.33 (d, J = 17.0 Hz, 1H), 1.63(s, 2H), 1.33 (s, 18H). 13 C NMR (151 MHz, Methanol-d 4 ):δ = 167.0 (d, J = 255.8 Hz), 155.3 (d, J=13.7 Hz), 152.2, 145.0, 141.9, 140.5, 136.6, 130.9, 127.0, 123.6, 122.9,122.6, 120.9, 113.1 (d, J = 4.4 Hz), 100.4 (d, J = 29.1 Hz), 78.9, 77.3 – 72.7(m), 63.8, 60.5, 37.4, 35.7, 31.9. 19 F NMR (565 MHz , Methanol-d 4 ): δ = -74.9, -74.9, -74.9, -74.9, -75.0,-75.0, -98.7, -98.7, -98.7, -154.2, -154.3, -154.5. HRMS (ESI): calc. for [C 38 H 35 F 13 [N3O3] ([M] + ): 828.2465, found in:828.2440.

[0040] Example 10: Synthesis of NHC9 (S)-2-(4-fluoro-2,6-bis(1,1,1,3,3,3-hexafluoroisopropoxy)phenyl)-5-isopropyl-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazine-2-onium tetrafluoroborate (NHC9)

[0041] Add lactam (5 mmol, 1.0 equivalent) to a 100 mL round-bottom flask equipped with a magnetic stirrer. Then add dichloromethane (20 mL) and trimethoxytetrafluoroborate (5.5 mmol, 1.1 equivalent). Stir the heterogeneous mixture at room temperature until the reaction mixture becomes homogeneous. Add TL-S23 (5 mmol, 1.0 equivalent) and continue stirring for 12 hours. Reduce the solvent by rotary evaporation, then add chlorobenzene (50 mL) and triethyl orthoformate (12.5 mmol, 2.5 equivalent). Heat to reflux in an oil bath at 135 °C and stir open for 24 hours. Then add triethyl orthoformate again (12.5 mmol, 2.5 equivalent) and continue stirring for 24 hours. After cooling to room temperature, add toluene (30 mL) and stir with a magnetic stirrer. Filter the resulting slurry. The filter cake was washed with toluene (20 mL) and n-hexane (20 mL), and then rinsed with dichloromethane in a 15 mL ice bath through a glass dropper, finally yielding 0.5 g of a white solid product with a yield of 16%, namely NHC9, whose structural formula and NMR data are shown below.

[0042] 1 H NMR (600 MHz, Methanol- d 4): δ = 7.40 (d, J = 9.6 Hz, 2H), 6.38 (p, J =5.6 Hz, 2H), 5.25 (d, J = 16.6 Hz, 1H), 5.07 (d, J = 16.6 Hz, 1H), 4.68 (q, J = 4.1Hz, 1H), 4.35 (dd, J = 13.1, 3.6 Hz, 1H), 4.21 (dd, J = 13.1, 4.1 Hz, 1H), 2.47 –2.37 (m, 1H), 1.11 (d, J = 6.9 Hz, 3H), 1.01 (d, J = 6.9 Hz, 3H). 13 C NMR (151 MHz, Methanol-d 4 ):δ = 165.6 (d, J = 255.6 Hz), 153.8 (d, J =13.8 Hz), 151.4, 119.7 (q, J= 281.8 Hz), 111.6, 98.8 (d, J = 29.2 Hz), 73.8 (p, J = 34.1 Hz), 63.8, 61.4, 61.1, 53.3, 31.6, 17.2, 16.1. 19 F NMR (377MHz , Methanol-d 4 ): δ = -74.8, -74.9, -74.9, -74.9, -75.0,-75.0, -98.8, -154.8, -154.8. HRMS (ESI): calc. for [C 20 H 17 F 13 [N3O3] ([M] + ): 594.1057, found in:594.1040.

[0043] Example 11: Synthesis of NHC10 (S)-5-Isobutyl-2-(4-fluoro-2,6-bis(1,1,1,3,3,3-hexafluoroisopropoxy)phenyl)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazine-2-onium tetrafluoroborate (NHC10)

[0044] Add lactam (5 mmol, 1.0 equivalent) to a 100 mL round-bottom flask equipped with a magnetic stirrer. Then add dichloromethane (20 mL) and trimethoxytetrafluoroborate (5.5 mmol, 1.1 equivalent). Stir the heterogeneous mixture at room temperature until the reaction mixture becomes homogeneous. Add TL-S23 (5 mmol, 1.0 equivalent) and continue stirring for 12 hours. Reduce the solvent by rotary evaporation, then add chlorobenzene (50 mL) and triethyl orthoformate (12.5 mmol, 2.5 equivalent). Heat to reflux in an oil bath at 135 °C and stir open for 24 hours. Then add triethyl orthoformate again (12.5 mmol, 2.5 equivalent) and continue stirring for 24 hours. After cooling to room temperature, add toluene (30 mL) and stir with a magnetic stirrer. Filter the resulting slurry. The filter cake was washed with toluene (20 mL) and n-hexane (20 mL), and then rinsed with dichloromethane in a 15 mL ice bath through a glass dropper, finally yielding 1.3 g of white solid product, with a yield of 38%, namely NHC10, whose structural formula and NMR data are shown below.

[0045] 1 H NMR (600 MHz, Methanol- d 4): δ = 7.41 – 7.35 (m, 2H), 6.34 (dtt, J =11.3, 8.6, 3.9 Hz, 2H), 5.24 (d, J = 16.6 Hz, 1H), 5.10 (dd, J = 16.6, 2.0 Hz,1H), 4.94 – 4.87 (m, 1H), 4.81 – 4.76 (m, 3H), 4.30 (dd, J = 12.9, 3.8 Hz, 1H),4.16 (dd, J = 12.9, 4.0 Hz, 1H), 1.87 (ddt, J = 21.3, 13.9, 7.2 Hz, 2H), 1.76(dq, J = 13.5, 6.7 Hz, 1H), 1.04 (dd, J = 6.6, 3.6 Hz, 6H). 13 C NMR (151 MHz, Methanol-d 4 ):δ = 167.0 (d, J = 255.6 Hz), 155.1 (d, J =13.9 Hz), 152.2, 121.1 (q, J = 282.0 Hz), 113.2, 100.4 (d, J = 29.1 Hz), 75.2 (p, J = 34.0 Hz), 67.7, 62.8, 57.1, 43.1, 25.6, 22.9, 22.1. 19 F NMR (565MHz , Methanol-d 4): δ = -74.8, -74.8, -74.8, -74.9, -74.9,-75.0, -75.0, -75.0, -75.0, -98.9, -98.9, -98.9, -99.0, -154.3, -154.4, -154.4, -154.4, -154.4, -154.5, -154.5, -154.6, -154.6, -154.7, -154.7. HRMS (ESI): calc. for [C 21 H 19 F 13 [N3O3] ([M] + ): 608.1213, found in: 608.1194.

[0046] Example 12: Synthesis of NHC11 (S)-5-phenyl-2-(4-fluoro-2,6-bis(1,1,1,3,3,3-hexafluoroisopropoxy)phenyl)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazine-2-onium tetrafluoroborate (NHC11)

[0047] Add lactam (5 mmol, 1.0 equivalent) to a 100 mL round-bottom flask equipped with a magnetic stirrer. Then add dichloromethane (20 mL) and trimethoxytetrafluoroborate (5.5 mmol, 1.1 equivalent). Stir the heterogeneous mixture at room temperature until the reaction mixture becomes homogeneous. Add TL-S23 (5 mmol, 1.0 equivalent) and continue stirring for 12 hours. Reduce the solvent by rotary evaporation, then add chlorobenzene (50 mL) and triethyl orthoformate (12.5 mmol, 2.5 equivalent). Heat to reflux in an oil bath at 135 °C and stir open for 24 hours. Then add triethyl orthoformate again (12.5 mmol, 2.5 equivalent) and continue stirring for 24 hours. After cooling to room temperature, add toluene (30 mL) and stir with a magnetic stirrer. Filter the resulting slurry. The filter cake was washed with toluene (20 mL) and n-hexane (20 mL), and then rinsed with dichloromethane in a 15 mL ice bath through a glass dropper, finally yielding 1.1 g of white solid product, with a yield of 32%, namely NHC11, whose structural formula and NMR data are shown below.

[0048] 1 H NMR (600 MHz, Methanol- d4): δ = 7.53 – 7.45 (m, 3H), 7.45 – 7.39(m, 2H), 7.34 (d, J = 9.6 Hz, 2H), 6.31 (ddt, J = 9.3, 6.0, 3.8 Hz, 2H), 5.99(dd, J = 7.1, 4.7 Hz, 1H), 5.37 (d, J = 16.6 Hz, 1H), 5.29 (d, J = 16.6 Hz, 1H),4.53 (dd, J = 12.8, 4.7 Hz, 1H), 4.28 (dd, J = 12.8, 7.1 Hz, 1H). 13 C NMR (151 MHz, Methanol-d 4 ):δ = 167.0 (d, J = 255.5 Hz), 155.1 (d, J =13.8 Hz), 152.8, 135.5 (d, J = 3.3 Hz), 131.4, 129.7 (d, J = 327.1 Hz), 125.7-118.2 (m), 112.9, 100.2 (d, J = 29.0 Hz), 75.9-73.9 (m), 70.3, 62.8, 61.9 (d, J =2.5 Hz). 19 F NMR (565MHz , Methanol-d 4 ): δ = -74.8, -74.8, -74.8, -74.8, -74.8,-74.9, -74.9, -74.9, -74.9, -74.9, -98.9, -98.9, -98.9, -154.4, -154.5, -154.5, -154.5, -154.6, -154.6, -154.6, -154.6. HRMS (ESI): calc. for [C 23 H 15 F 13 N3O3] ([M] +): 628.0900, found in:628.0881.

[0049] Example 13: Application of triazole nitrogen-containing heterocyclic carbene catalysts with polyfluoroalkoxy aryl substitution in the preparation of 4,4,4-trifluoro-1,2-diphenylbut-1-one Togni-CF3 reagent (0.15 mmol), NHC1 (0.02 mmol) from Example 2, and Cs2CO3 (0.02 mmol) were sequentially added to a 5 mL Shrek pressure-resistant tube. Nitrogen gas was purged three times using a double-row tube. Styrene (0.1 mmol) and benzaldehyde (0.15 mmol) were dissolved in dichloromethane and methyl tert-butyl ether (volume ratio 1:3), and this solution was added to the pressure-resistant tube using a 2.5 mL syringe. The reaction was carried out in an oil bath at 60 °C for 12 h. After the reaction was complete, the solution was concentrated under reduced pressure using a rotary evaporator to obtain the crude product. Purification by column chromatography yielded 4,4,4-trifluoro-1,2-diphenylbut-1-one, a colorless liquid.

[0050] 1 H NMR (400 MHz, Chloroform- d ):δ = 8.1 – 8.0 (m, 2H), 7.5 – 7.5 (m,1H), 7.4 (dd, J = 8.4, 6.9 Hz, 2H), 7.4 – 7.3 (m, 4H), 7.2 (s, 1H), 5.1 (dd, J =7.9, 2.5 Hz, 1H), 4.3 (dd, J = 14.9, 7.9 Hz, 1H), 3.0 (dd, J = 14.9, 2.5 Hz, 1H). UPCC: Enantiomer excess (62% ee) was determined by ultra-high performance coherence chromatography (chiral column: Chiralpak AD-3, mobile phase: CO2 / CH3OH = 50 / 50, flow rate: 0.5 mL / min, detection wavelength: 254 nm). Retention time t of the major enantiomer. R = 4.2 min, retention time t of minor enantiomers R = 4.4 min.

[0051]

[0052] Example 14: Application of triazole nitrogen-containing heterocyclic carbene catalysts with polyfluoroalkoxy aryl substitution in the preparation of (S)-1,2-diphenylprop-1-one To a 4 mL vial, N-benzoylimidazolium (0.1 mmol), Hantzsch ester (0.15 mmol), Cs₂CO₃ (0.015 mmol), NHC₂ (0.015 mmol) from Example 3, and 4-CzIPN (0.001 mmol) were added sequentially, followed by 2 mL of acetonitrile. The mixture was reacted under a 450 nm UV lamp for 16 h. After the reaction was complete, the product was concentrated under reduced pressure using a rotary evaporator to obtain the crude product. Purification by column chromatography yielded (S)-1,2-diphenylprop-1-one, a white solid.

[0053] 1 H NMR (400 MHz, Chloroform- d ):δ = 8.0 (d, J = 7.6 Hz, 2H), 7.5 (t, J =7.5 Hz, 1H), 7.4 (t, J = 7.6 Hz, 2H), 7.3 (d, J = 4.3 Hz, 4H), 7.2 (p, J = 4.4 Hz, 1H), 4.7 (q, J = 7.0 Hz, 1H), 1.5 (d, J = 6.9 Hz, 3H). UPCC: Enantiomer excess (15% ee) was determined by ultra-high performance coherence chromatography (chiral column: Chiralpak AD-3, mobile phase: CO2 / CH3OH = 50 / 50, flow rate: 0.5 mL / min, detection wavelength: 254 nm). Retention time t of the major enantiomer. R = 7.6 min, retention time t of minor enantiomers R = 8.1min.

[0054]

[0055] Example 15: Application of triazole nitrogen-containing heterocyclic carbene catalysts with polyfluoroalkoxy aryl substitution in the preparation of (S)-methyl(3-oxo-1,3-dihydroisobenzofuran-1-yl) terephthalate To an electrochemical Schleck tube equipped with a magnetic stirrer, 0.1 mmol of 3-hydroxyisobenzofuran-1(3H)-one, 0.01 mmol or 0.02 mmol of NHC7 from Example 8, 0.1 mmol of tetrabutylammonium iodide, 0.18 mmol of methyl terephthalate, and 3 mL of THF solvent were added sequentially. A platinum anode and cathode were then attached to the cap and assembled into the Schleck tube. The electrolysis reaction was carried out at room temperature using a constant current of 1.0 mA for 6 hours. After the reaction, the reaction solution was directly concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target product, (S)-methyl(3-oxo-1,3-dihydroisobenzofuran-1-yl) terephthalate, as a white solid. When the amount of NHC7 used in Example 8 was 0.02 mmol, the yield was 92%; when the amount of NHC7 used in Example 8 was 0.01 mmol, the yield was 90%.

[0056] 1 H NMR (400 MHz, Chloroform- d ):δ = 8.1 (s, 4H), 8.0 (d, J = 6.3 Hz, 1H), 7.8 (t, J = 7.5 Hz, 1H), 7.7 – 7.7 (m, 3H), 4.0 (s, 3H). UPCC: Enantiomer excess (96% ee) was determined by ultra-high performance coherence chromatography (chiral column: Chiralpak AD-3, mobile phase: CO2 / CH3OH = 50 / 50, flow rate: 0.5 mL / min, detection wavelength: 254 nm). Retention time t of the major enantiomer. R = 6.4 min, retention time t of minor enantiomers R = 12.4 min.

[0057]

[0058] Example 16: Performance differences in photochemical and electrochemical reactions compared to other existing catalysts In this invention, NHC4 from the embodiments was selected as a comparative object. We chose the NHC-catalyzed photoredox radical cross-coupling reaction, specifically the reaction of N-benzoylimidazolium with Hantzsch ester, as a template. Encouragingly, as a hexafluoroisopropyl (HFIP) substituted derivative of NHC-E, NHC-4 successfully improved the enantioselectivity from 54:46 er to 57.5:42.5 er. In the electroredox reaction, we used the dynamic kinetic resolution reaction of 3-hydroxyisobenzofuran-1(3H)-one with an aldehyde catalyzed by NHC as a template. Compared with other triazole NHCs, the NHC4 catalyst containing polyfluoroalkoxy substituents of this invention exhibited optimal enantioselectivity and reactivity: at a catalyst dosage of 10 mol% , the target product was obtained in 90% yield and at a 98:2 er.

[0059] .

Claims

1. A class of triazole nitrogen heterocyclic carbene catalysts containing polyfluoroalkoxy aryl substituted groups, named NHC1-11, with structural formulas as shown in Formula I, II, or III: 。 2. The application of the triazole nitrogen heterocyclic carbene catalyst containing polyfluoroalkoxy aryl substituted groups as described in claim 1 in a three-component free radical cascade reaction involving aldehydes, styrene, and Togni I reagent.

Images