N-alkoxy quaternary ammonium salt chiral catalyst and application thereof in hydrogen atom transfer and alkylation reaction

Abstract

The invention discloses an N-alkoxy quaternary ammonium salt chiral catalyst which can be used as a hydrogen atom transfer reagent and a catalyst for free radical reaction to mediate C-C bond coupling and alkylation reaction. A series of N-alkoxy quaternary ammonium salt chiral hydrogen atom transfer reagents are synthesized for the first time by introducing alkoxy on a chiral quaternary ammonium salt catalytic central nitrogen atom of a binaphthalene skeleton. Compared with a chiral binaphthalene skeleton-based chiral phase transfer catalyst (a catalytic center nitrogen atom is connected with an aliphatic carbon chain or aromatic carbon) developed by an applicant in an earlier stage, the catalyst provided by the invention has the advantages that alkoxy is introduced to the catalytic center N atom, so that the N atom is directly connected with an oxygen atom, and the electronic effect and bond breaking mode of the catalytic center are changed; a quaternary ammonium salt chiral catalyst participates in a free radical reaction instead of participating in an ionic reaction traditionally, C-C bond coupling which is difficult to complete under the ionic reaction condition is achieved, and a feasible scheme is provided for C-C bond construction and alkylation based on free radical chemistry.

Description

Technical Field

[0001] The present invention belongs to the fields of organocatalysis and radical chemistry, and particularly relates to N-alkoxy quaternary ammonium salts chiral catalysts and their applications in hydrogen atom transfer and alkylation reactions. Background Art

[0002] Radical reactions and ionic reactions are two important types of reactions in organic chemistry and play important roles in the construction and creation of functional molecules.

[0003] In recent years, the late-stage functionalization synthetic strategy has become a hot topic in the fields of organic synthesis and medicinal chemistry and is used for selectively modifying existing molecules (especially complex molecules). In the late stage of the synthesis of complex organic molecules, without significantly changing the overall structure of the molecule, specific functional groups are introduced, transformed or modified to the molecule with a certain structural complexity, so as to further optimize and functionalize the molecular structure, adjust the properties of the compound, such as biological activity, physical properties or reactivity, to obtain target molecules with specific properties or biological activities.

[0004] Radical reactions provide powerful strategies for organic synthesis. Due to the unique properties of reactive open-shell species, bond cleavage that cannot be achieved through ionic reactions becomes possible. Therefore, compared with traditional ionic reactions, radical reactions have significant advantages in the late-stage functionalization and structural modification of complex molecules: (1) Radical reactions often exhibit unique selectivity and can react at specific positions in complex molecules, which is crucial for precisely introducing the desired functional groups in the later-stage structural modification. (2) Radical reactions usually occur under relatively mild conditions and do not require overly harsh reaction conditions such as high temperature, high pressure, or strong acids and bases. This is particularly important for complex molecules because they may be sensitive to severe reaction conditions and prone to side reactions or molecular structure destruction. (3) In some cases, radical reactions can provide unique stereochemical control, which is essential for constructing complex molecules with specific spatial configurations. For example, radical cyclization reactions can effectively control the stereochemistry of the product by controlling the reaction conditions and substrate structure, generating cyclic compounds with specific configurations. In similar cases, ionic reactions may be difficult to achieve such precise stereochemical control due to the formation of ion pairs and the complexity of the reaction mechanism. (4) Radical reactions have good compatibility with many functional groups, while ionic reactions often have strict requirements for the functional groups in the substrate. Complex molecules usually contain multiple functional groups, and radical reactions can modify the structure at the target position without affecting other functional groups. For example, when there are multiple functional groups such as hydroxyl and carbonyl groups in a molecule, radical reactions can selectively functionalize a specific carbon-hydrogen bond at a certain position without unnecessary side reactions with other functional groups. (5) Radical reactions often have high atom economy, can utilize the atoms in the reactants more effectively, and reduce the generation of waste, which is an important consideration in green chemistry and the synthesis of complex molecules.

[0005] Therefore, late-stage functionalization based on radical chemistry is widely used to optimize the properties of drug candidates and rapidly modify the structure of lead compounds to improve their potency, selectivity, solubility, and metabolic stability.

[0006] Currently, selective catalytic C-H activation and hydrogen atom abstraction based on radical reactions have very strong application prospects in the late-stage functionalization of synthesis and have attracted much attention.

[0007] Previously, the applicant developed a chiral phase-transfer catalyst based on a chiral binaphthyl skeleton. The catalytic center N atom is connected to an aliphatic carbon chain or an aromatic carbon. Based on ionic reactions, the following have been achieved: (1) constructing complex chiral α-amino acids through α-alkylation reactions; (2) asymmetric Michael addition reactions; (3) asymmetric aldol reactions; (4) asymmetric Mannich reactions; (5) asymmetric Darzens reactions; (6) asymmetric Neber rearrangements; (7) asymmetric epoxidation reactions; (8) asymmetric aziridination reactions; (9) asymmetric dihydroxylation reactions; (10) asymmetric fluorination reactions; (11) asymmetric Strecker reactions; and it has good application prospects.

[0008] However, this type of quaternary ammonium salt chiral phase-transfer catalyst (Maruoka catalyst) based on a chiral binaphthyl skeleton is currently only applicable to ionic reaction types and cannot function in free radical reaction types, restricting its reactions and applications.

[0009] In order to further expand the application of this type of quaternary ammonium salt catalyst and break through the existing ionic reaction limitations, in the present invention, an alkoxy group is introduced onto the catalytic center N atom of the quaternary ammonium salt catalyst with a chiral binaphthyl skeleton, directly connecting the N atom and the oxygen atom, changing the electronic effect and bond-breaking mode of the catalytic center, and transforming the traditional participation of the quaternary ammonium salt chiral catalyst in ionic reactions into participation in free radical reactions, so as to achieve C-H activation and hydrogen abstraction based on free radical reactions, and further achieve C-C bond coupling that is difficult to complete under ionic reaction conditions, providing a feasible solution for the construction and alkylation of C-C bonds based on free radical chemistry, and providing a new strategy for the late-stage modification of complex molecules. Summary of the Invention

[0010] Regarding the simplified Maruoka catalyst previously developed by the applicant, the N atom of the chiral quaternary ammonium salt catalytic center is connected to an aliphatic carbon chain or an aromatic carbon, and the weak interactions at the catalytic center are relatively single, resulting in the relatively single defect of the action mode and effect of the catalytic center, as well as the limitation of the catalytic reaction types, that is, it is only applicable to ionic reactions. However, when connected by an N-O bond, the action mode of the active center of the catalyst can be enriched by changing the electronic effect, steric effect, bond-breaking mode, etc. of the catalytic center, thereby broadening the catalytic reaction types and catalytic activities.

[0011] Therefore, the primary object of the present invention is to develop and expand the catalytic reaction types of such quaternary ammonium salt catalysts by introducing alkoxy groups into the catalytic center and changing the electronic effect, steric hindrance effect, and bond-breaking mode (from heterolytic cleavage to homolytic cleavage) of the catalytic center of the catalyst. The present invention provides the design and synthesis of a series of N-alkoxy quaternary ammonium salt chiral phase transfer catalysts, as well as their applications in hydrogen atom transfer, alkylation reactions, and C-C bond construction reactions based on radical reactions. This series of catalysts was evaluated through alkylation reactions based on C-C bond construction. In particular, it was found that the catalyst with R being 3,4,5-F3-C6H2 had excellent enantioselectivity, and the enantioselectivity of the product was not affected by the length of the flexible chain on the N of the catalyst.

[0012] To achieve the above object, the technical solution adopted by the present invention is as follows:

[0013] An N-alkoxy quaternary ammonium salt chiral catalyst, the structural formula of which is shown in formula (i) or formula (ii):

[0014]

[0015] Wherein, R is a hydrogen atom, a phenyl group, -3,4,5-F3-C6H2-, -3,5-CF3-C6H3-, or a naphthyl group; n is any natural number from 1 to 21; X is chlorine or bromine; wherein the hydrogen atom in -(CH2) n - can be substituted by one or more saturated alkyl groups; the saturated alkyl group is a saturated alkyl group of C1 to C3;

[0016] Regarding the definition of terms: "substituted" means that the hydrogen atom in a molecule is replaced by other different atoms or molecules. The minimum and maximum carbon atom contents in a hydrocarbon group are indicated by prefixes. For example, the prefix Ca~Cb alkyl indicates any alkyl group containing "a" to "b" carbon atoms. Therefore, for example, C1~C4 alkyl refers to a straight-chain or branched-chain alkyl group containing 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, and so on.

[0017] As a preferred technical solution, R is a hydrogen atom, a phenyl group, -3,4,5-F3-C6H2-, or -3,5-CF3-C6H3-; n is any integer from 0 to 6; X is bromine.

[0018] As a more preferred technical solution, n in formula (i) and (ii) is 0, 1, 2, or 3.

[0019] More specifically, the structural formula of the N-alkoxy quaternary ammonium salt chiral catalyst is as follows:

[0020]

[0021] The present invention simultaneously protects the application of the N-alkoxy quaternary ammonium salt chiral catalyst in hydrogen atom transfer, alkylation reaction, and C-C bond construction reaction based on free radical reaction. The reaction formula is as follows (under the condition of a wavelength of 456 nm):

[0022] Alkylation reaction 1 based on C-C bond construction:

[0023]

[0024] Alkylation reaction 2 based on C-C bond construction:

[0025]

[0026] The active center N of the catalyst is connected to the aliphatic carbon chain or aromatic carbon, and the weak interaction of the catalytic center is relatively single, resulting in the defects that the action mode and effect of the catalytic center are relatively single, and the types of catalytic reactions are limited, that is, it is only applicable to ionic reactions. When connected by an N-O bond, the action mode of the active center of the catalyst can be enriched by changing the electronic effect, steric effect, bond-breaking mode, etc. of the catalytic center, thereby broadening the types of catalytic reactions and catalytic activities. However, the introduction of N-alkoxy often makes the quaternary ammonium salt unstable, and it is difficult and challenging to change the reaction type of this type of quaternary ammonium salt catalyst from ionic reaction to free radical reaction. The present invention first attempts to introduce an alkoxy group on the N atom of the chiral quaternary ammonium salt phase transfer catalyst with a binaphthyl skeleton and achieves success. The application research shows that: the introduction of the alkoxy group at the catalytic center successfully develops the hydrogen atom transfer that is difficult to achieve in the ionic reaction mode by changing the electronic effect, steric hindrance effect, bond-breaking mode (from heterolytic cleavage to homolytic cleavage), etc. of the catalytic center of the catalyst, that is, selectively extracts hydrogen atoms from aldehyde group-H and cyclic ether α-H, and conducts an alkylation reaction with vinyl phenyl sulfone to construct a C-C bond, with less catalyst consumption and higher yield than the existing hydrogen abstraction catalysts. Under the same conditions, the chiral phase transfer catalyst with a similar binaphthyl skeleton cannot be achieved based on the ionic reaction type.

[0027] Compared with the prior art, the beneficial effects of the present invention are:

[0028] By introducing an alkoxy group into the catalytic center of a chiral quaternary ammonium salt catalyst with a binaphthyl skeleton, the present invention changes the electronic effect, steric hindrance effect, bond-breaking mode, etc. of the catalytic center of the catalyst, and designs and synthesizes a series of N-alkoxy quaternary ammonium salt chiral catalysts, realizing the transformation of the reaction type participated by the quaternary ammonium salt catalyst with such a binaphthyl skeleton from an ionic reaction to a radical reaction type. This series of catalysts selectively extracts hydrogen atoms from aldehyde-H and cyclic ether α-H, and successfully undergoes an alkylation reaction with vinyl phenyl sulfone to construct a C-C bond. Under the same conditions, a chiral phase transfer catalyst with a similar binaphthyl skeleton cannot achieve this based on the ionic reaction type. It has less catalyst consumption and higher yield than existing hydrogen abstraction catalysts, and has strong application prospects. Detailed implementation manners

[0029] The following will clearly and completely describe the technical solutions of the present invention in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all embodiments. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts shall fall within the protection scope of the present invention.

[0030] The test methods used in the embodiments of the present invention are all conventional methods unless otherwise specified; the materials, reagents, etc. used are reagents and materials that can be obtained from commercial channels unless otherwise specified.

[0031] I. Synthesis method:

[0032] The synthesis of the N-alkoxy quaternary ammonium salt chiral catalyst PTC-1~-3 series of compounds is shown as follows:

[0033]

[0034] The specific synthesis and characterization are as follows:

[0035]

[0036] Under the conditions of -78°C and argon protection, trifluoromethanesulfonic anhydride (14.3 mL, 85 mmol) was slowly added dropwise to a dichloromethane (85 mL) solution of (S)-binaphthol (10.02 g, 35 mmol) and triethylamine (13.90 mL, 100 mmol). Subsequently, the mixture was stirred at room temperature for 2 h. After the reaction was completed, the obtained mixture was slowly poured into a 1N HCl solution in an ice-water bath, extracted with n-hexane, the organic phase was washed with saturated sodium bicarbonate and then with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (ethyl acetate:n-hexane = 1:20) to obtain a white solid (S)-1 (17.9 g, 32.6 mmol, yield 93%).

[0037] 1 1H NMR (400 MHz, CDCl3): δ 8.14 - 8.12 (d, J = 9.2 Hz, 2H), 8.01 - 7.99 (d, J = 8.3 Hz, 2H), 7.63 - 7.61 (d, J = 9.2 Hz, 2H), 7.60 - 7.56 (ddd, J = 8.3, 6.8, 1.2 Hz, 2H), 7.42 - 7.38 (ddd, J = 8.3, 6.8, 1.2 Hz, 2H), 7.26 - 7.24 (d, J = 8.3 Hz, 2H).

[0038] 13 13C NMR (100 MHz, CDCl3): δ 145.6, 133.4, 132.6, 132.2, 128.6, 128.2, 127.6, 127.0, 123.7, 119.6, 118.4 (q, J C-F = 318.2 Hz).

[0039]

[0040] Under argon protection, (S)-1 (3.3 g, 6.0 mmol), palladium acetate (135 mg, 10 mol%), 1,3-bis(diphenylphosphino)propane (371 mg, 15 mol%), diisopropylethylamine (12 mL, 72 mmol), and phenyl formate (6.5 mL, 60 mmol) were successively added to a 120 mL high-pressure resistant reaction flask. The mixture was heated to 120 °C and stirred overnight. After the reaction was completed, the resulting mixture was cooled to room temperature and allowed to stand for phase separation. Then, the lower organic phase was separated by liquid separation. The obtained mixture was diluted with ethyl acetate and poured into water for washing, followed by washing with brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (ethyl acetate: n-hexane = 1:10) to obtain a white solid (S)-2 (1.78 g, 3.6 mmol, yield 60%).

[0041] 1 1H NMR (400 MHz, CDCl3): δ 8.31 (d, J = 8.8 Hz, 2H), 8.04 (d, J = 8.8 Hz, 2H), 7.96 (d, J = 8.4 Hz, 2H), δ 7.56 (ddd, J = 8.0, 6.8, 1.2 Hz, 2H), 7.31 (ddd, J = 8.8, 6.8, 1.2 Hz, 2H), 7.24 - 7.17 (m, 6H), δ 7.08 (dt, J = 8.4 Hz, 2H), 6.66 - 6.63 (m, 4H).

[0042] 1313C NMR (100 MHz, CDCl3): δ 165.6, 150.7, 140.6, 135.3, 133.1, 129.3, 128.4, 128.2, 127.5, 127.2, 127.1, 126.3, 125.7, 121.4.

[0043]

[0044] At room temperature, 40% KOH solution (13.8 mL) was added to an ethanol solution (143.5 mL) of (S)-2 (2.27 g, 4.6 mmol). The reaction mixture was heated to reflux and stirred for 24 h. After the reaction was completed, the system was cooled to room temperature, and then the pH value of the system was adjusted to 1 with 2 M HCl solution. The resulting mixture was extracted with ethyl acetate and separated, and the organic phase was retained. The pH value of the resulting organic phase was adjusted to 13 with 1 M KOH solution, and the aqueous phase was retained after separation. Then the pH of the aqueous phase was adjusted to 1 and extracted with ethyl acetate. The resulting organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was recrystallized (ethyl acetate / n-hexane) to obtain a white solid (S)-3 (1.46 g, 4.28 mmol, yield 93%).

[0045] 1 1H NMR (400 MHz, CDCl3): δ 8.09 (d, J = 8.8 Hz, 2H), 7.93 (d, J = 8.8 Hz, 2H), 7.89 (d, J = 8.0 Hz, 2H), δ 7.46 (ddd, J = 8.0, 7.2, 0.8 Hz, 2H), 7.12 (ddd, J = 8.0, 7.2, 0.8 Hz, 2H), 6.87 (d, J = 8.4, 6H).

[0046] 13 13C NMR (100 MHz, CDCl3): δ 172.2, 141.8, 135.3, 132.8, 128.0, 127.9, 127.8, 127.4, 126.6, 126.5, 125.5.

[0047]

[0048] A mixed solution of tetrabutylammonium hydrogensulfate (238 mg, 0.7 mmol) and potassium fluoride dihydrate (3.2 g, 34 mmol) in tetrahydrofuran (34 mL) was stirred at room temperature for 1 h. Subsequently, (S)-3 (1.17 g, 3.4 mmol) and 2-bromopropane (3.1 mL, 34 mmol) were added, and the mixture was heated to reflux and stirred for 24 h. After the reaction was completed, the system was poured into water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (ethyl acetate: n-hexane = 1:5) to obtain a white solid (S)-4 (1.1 g, 2.58 mmol, yield 76%).

[0049] 1 1H NMR (400 MHz, CDCl3): δ 8.17 (d, J = 8.4 Hz, 2H), 8.01 (d, J = 8.4 Hz, 2H), 7.92 (d, J = 8.0 Hz, 2H), 7.50 (ddd, J = 8.0, 6.8, 1.2 Hz, 2H), 7.24 (ddd, J = 8.4, 6.8, 1.2 Hz, 2H), 7.13 (d, J = 8.4 Hz, 2H), 4.75 (m, 2H), 0.76 (d, J = 6.2 Hz, 6H), 0.44 (d, J = 6.2 Hz, 6H).

[0050] 13 13C NMR (100 MHz, CDCl3): δ 166.8, 139.7, 134.8, 133.2, 128.4, 127.7, 127.7, 127.6, 127.5, 126.6, 126.2, 67.7, 21.1, 20.7.

[0051]

[0052] Under argon protection, ultradry tetrahydrofuran (18 mL) was added to magnesium powder (438 mg, 18 mmol) and heated to reflux. Subsequently, 1,2-dibromoethane (1.55 mL, 18 mmol) was slowly added dropwise to the system to obtain a MgBr2 solution (grayish-white suspension). Under argon protection, distilled 2,2,6,6-tetramethylpiperidine (6.1 mL, 36 mmol) and tetrahydrofuran (18 mL) were added to another flask. Subsequently, n-butyllithium (2.5 M dissolved in n-hexane, 6.1 mL, 15 mmol) was slowly added dropwise at 0 °C, and the mixture was continuously stirred at 0 °C for 45 min to obtain LiTMP (yellow clear solution). After the MgBr2 solution was cooled to 0 °C, LiTMP was slowly added, and then the mixture was continuously stirred at 0 °C for 2 h to obtain a tetrahydrofuran solution of Mg(TMP)2 (brown clear solution).

[0053] Under the protection of argon at 0 °C, a tetrahydrofuran solution (10 mL) of (S)-4 (899.5 mg, 2.1 mmol) was added to the prepared Mg(TMP)2 solution (0.31 M, 27.1 mL, 8.4 mmol), and the mixture was stirred at room temperature for 3 h. Subsequently, the system was cooled to -78 °C, and bromine (860 μL, 16.8 mmol) was slowly added, followed by continued stirring at room temperature for 1 h. After the reaction was completed, the mixture was poured into a 1 M HCl solution in an ice-water bath, washed with saturated sodium sulfite, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (methylene chloride: n-hexane = 1:1) to obtain a white solid (S)-5 (1.01 g, 1.73 mmol, 82% yield).

[0054] 1 H NMR (400 MHz, CDCl3): δ 8.24 (s, 2H), 7.82 (d, J = 8.4 Hz, 2H), 7.52 (t, J = 7.6 Hz, 2H), 7.34 (t, J = 7.6 Hz, 2H), 7.19 (d, J = 8.4 Hz, 2H), 4.78 (m, 2H), 0.79 (d, J = 6.2 Hz, 6H), 0.67 (d, J = 6.2 Hz, 6H).

[0055] 13 C NMR (100 MHz, CDCl3): δ 165.5, 134.2, 134.2, 133.9, 132.2, 131.5, 128.1, 127.7, 127.3, 126.9, 115.9, 69.0, 21.0, 20.7.

[0056]

[0057] Under the protection of argon, (S)-5 (866 mg, 1.48 mmol), 3,4,5-trifluorophenylboronic acid (1041.3 mg, 5.92 mmol), palladium acetate (16.8 mg, 5 mol%), triphenylphosphine (60.4 mg, 15 mol%), potassium carbonate (615 mg, 4.45 mmol), and N,N-dimethylformamide (14.8 mL) were successively added to the reaction flask, and then heated to 90 °C for reaction for 16 h. After the reaction was completed, the system was cooled to room temperature and poured into saturated ammonium chloride solution for washing, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (ethyl acetate: n-hexane = 1:20) to obtain a white solid (S)-6 (915 mg, 1.33 mmol, 90% yield).

[0058] 11H NMR (400 MHz, CDCl3): δ 7.94 (s, 2H), 7.94 (d, J = 8.0 Hz, 2H), 7.56 (ddd, J = 8.0, 6.8, 1.2 Hz, 2H), 7.38 (ddd, J = 8.8, 6.8, 1.2 Hz, 2H), 7.31 (d, J = 8.4 Hz, 2H), 7.20 - 7.13 (m, 4H), 4.62 - 4.52 (m, 4H), 0.62 (d, J = 6.2 Hz, 6H), 0.55 (d, J = 6.2 Hz, 6H).

[0059] 13 13C NMR (100 MHz, CDCl3): δ 166.9, 151.0 (ddd, J C-F = 248.9, 9.9, 4.1 Hz), 139.5 (ddd, J C-F = 250.6, 15.2, 15.1 Hz), 137.0 (ddd, J C-F = 8.1, 7.8, 4.8 Hz), 134.8, 134.4, 133.0, 132.4, 132.2, 129.5, 128.1, 128.0, 127.6, 113.1 (dd, J C-F = 15.8, 5.9 Hz), 68.6, 20.8, 20.6.

[0060]

[0061] At 0 °C, a solution of (S)-6 (1158 mg, 1.7 mmol) in tetrahydrofuran (5.0 mL) was slowly added dropwise to a solution of lithium aluminum hydride (356.8 mg, 8.5 mmol) in tetrahydrofuran (5.0 mL). The reaction mixture was stirred at room temperature for 5 h. After the reaction was completed, the mixture was quenched with water in an ice-water bath and then acidified with 1 M HCl solution. The resulting mixture was extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product (S)-7 could be used in the next step without purification.

[0062]

[0063] At 0 °C, phosphorus tribromide (240 μL, 2.55 mmol) was slowly added dropwise to a solution of (S)-7 (988.2 mg, 1.7 mmol) in tetrahydrofuran (5.0 mL), and the reaction was stirred at room temperature for 1 h. After the reaction was completed, the reaction system was poured into water, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (ethyl acetate: n-hexane = 1:20) to obtain a white solid (S)-8 (1148 mg, 1.63 mmol, the yield of the two-step reaction was 96%).

[0064] 1 H NMR (400 MHz, CDCl3): δ 7.93 (d, J = 8.2 Hz, 2H), 7.89 (s, 2H), 7.56 (ddd, J = 8.0, 6.9, 1.0 Hz, 2H), 7.34 (ddd, J = 8.4, 7.0, 1.1 Hz, 2H), 7.29 - 7.25 (m, 4H), 7.13 (d, J = 8.5 Hz, 2H), 4.18 (s, 4H).

[0065] 13 C NMR (100 MHz, CDCl3): δ 150.9 (ddd, J C-F = 253.8, 9.8, 4.3 Hz), 139.6 (d, J C-F = 250.9 Hz), 137.9, 136.4, 136.1, 133.0, 132.1, 131.7, 130.7, 128.1, 127.8, 127.4, 127.2, 114.1 (dd, J C-F = 16.1, 5.8 Hz), 31.1.

[0066]

[0067] (S)-8 (200 mg, 0.28 mmol) was dissolved in 1 mL of acetonitrile, methoxybutylamine (3.0 mmol) was added, and the mixture was stirred at room temperature for 24 h. After the reaction was completed, the mixture was poured into water to quench the reaction, extracted with dichloromethane, the organic phase was back-extracted with saturated brine, dried over anhydrous sodium sulfate, and the crude product was separated and purified by silica gel column (MeOH:DCM = 1:50) to obtain the target catalyst (S)-PTC-1.

[0068] 11H NMR (500 MHz, CDCl3): δ 8.09 - 8.03 (m, 4H), 7.72 - 7.65 (m, 2H), 7.49 - 7.35 (m, 5H), 7.29 - 7.21 (m, 2H), 7.03 - 6.89 (m, 1H), 5.91 (d, J = 15.5 Hz, 1H), 4.92 (d, J = 13.1 Hz, 1H), 4.61 - 4.55 (m, 1H), 4.15 (d, J = 15.5 Hz, 1H), 3.97 (d, J = 15.5 Hz, 1H), 3.37 (s, 3H), 3.12 - 3.02 (m, 1H), 1.11 - 1.03 (m, 2H), 0.95 - 0.92 (m, 1H), 0.89 - 0.86 (m, 1H), 0.78 (t, J = 7.1 Hz, 3H), 0.78 (t, J = 7.2 Hz, 3H). MS (ESI): calcd. for C 39 H 30 F6N + [M - Br] + 641.65, found 642.07.

[0069]

[0070] (S)-8 (200 mg, 0.28 mmol) was dissolved in 1 mL of acetonitrile, and ethoxybutylamine (325 μL, 3.0 mmol) was added. The mixture was stirred at room temperature for 24 h. After the reaction was completed, the mixture was poured into water to quench the reaction, and dichloromethane was added for extraction. The organic phase was back - extracted with saturated brine and dried over anhydrous sodium sulfate. The crude product was separated and purified by silica gel column (MeOH:DCM = 1:50) to obtain the target catalyst (S)-PTC - 2 (80 mg, 0.11 mmol, yield 39%).

[0071] 1 1H NMR (500 MHz, CDCl3): δ 8.08 - 8.03 (m, 4H), 7.70 - 7.64 (m, 2H), 7.46 - 7.39 (m, 2H), 7.37 - 7.34 (m, 2H), 7.27 - 7.21 (m, 2H), 7.14 - 7.0 (m, 1H), 4.93 (d, J = 13.0 Hz, 1H), 4.20 (d, J = 13.0 Hz, 1H), 4.04 (d, J = 15.4 Hz, 1H), 3.23 - 2.95 (m, 2H), 1.32 - 1.21 (m, 4H), 1.19 - 1.02 (m, 2H), 0.97 (t, J = 6.8 Hz, 3H), 0.78 (t, J = 7.2 Hz, 3H). 1313C NMR (101 MHz, CD2Cl2) δ 152.26, 150.32, 141.07, 139.10, 138.94, 138.07, 137.75, 136.30, 134.97, 134.70, 134.03, 133.78, 131.87, 131.57, 131.28, 130.84, 129.28, 128.83, 128.76, 128.70, 128.56, 128.03, 127.70, 127.51, 124.11, 122.53, 114.64, 65.67, 60.08, 59.79, 58.95, 29.77, 24.30, 18.90, 13.60, 11.99.

[0072]

[0073] (S)-8 (200 mg, 0.28 mmol) was dissolved in 1 mL of acetonitrile, and butoxybutylamine (3.0 mmol) was added. The mixture was stirred at room temperature for 24 h. After the reaction was completed, the mixture was poured into water to quench the reaction, and dichloromethane was added for extraction. The organic phase was back-extracted with saturated brine and dried over anhydrous sodium sulfate. The crude product was separated and purified by silica gel column chromatography (MeOH:DCM = 1:50) to obtain the target catalyst (S)-PTC-3.

[0074] 1 1H NMR (500 MHz, CDCl3): δ 8.05 - 8.02 (m, 4H), 7.70 - 7.66 (m, 2H), 7.45 - 7.33 (m, 5H), 7.26 - 7.25 (m, 2H), 7.07 - 6.93 (m, 1H), 5.79 (d, J = 15.0 Hz, 1H), 4.91 (d, J = 13.1 Hz, 1H), 4.69 - 4.63 (m, 1H), 4.30 (d, J = 15.0 Hz, 1H), 4.03 (d, J = 13.0 Hz, 1H), 3.71 - 3.66 (m, 1H), 3.05 - 2.98 (m, 2H), 1.32 - 1.05 (m, 8H), 0.85 (t, J = 6.8 Hz, 3H), 0.78 (t, J = 7.1 Hz, 3H), 0.78 (t, J = 7.1 Hz, 3H).

[0075] Application Example 1: Extraction of Aldehyde-H and Its Alkylation Catalytic Test

[0076] Cyclohexyl aldehyde was subjected to an alkylation reaction with acetylphenyl sulfone under the catalysis of 2 mol% of N-alkoxy quaternary ammonium salt chiral catalyst. The results are shown in Table 1, and the reaction formula is as follows (under irradiation at a wavelength of 456 nm):

[0077]

[0078] Table 1. Comparison of the reaction of cyclohexyl aldehyde and acetylphenyl sulfone catalyzed by the N-alkoxy quaternary ammonium salt chiral catalyst of the present invention and the existing catalysts

[0079]

[0080] Among them, trace represents trace amount. The dosages of each catalyst in Table 1 are the same. Among them, the structural formulas of (S)-PTC-4, HAT-i and 4CzlPN are as follows:

[0081]

[0082] The data characterization is as follows:

[0083]

[0084] Weigh 4CzIPN (7.9 mg, 0.01 mmol, 5 mol%), catalyst (2 mol%) and vinylphenyl sulfone (33.6 mg, 0.2 mmol) into a 10 mL sealed tube equipped with a magnetic stir bar. Under an argon atmosphere, successively add acetonitrile (2 mL, 0.1 M) and cyclohexanecarbaldehyde (524 μL, 4 mmol, 20 eq.). The reaction system dilutes the mixture with ethyl acetate and then concentrates it under reduced pressure. The crude product is purified by column chromatography to obtain the target compound.

[0085] 1 H NMR (500 MHz, CDCl3): δ 7.90 - 7.88 (m, 2H), 7.67 - 7.64 (m, 1H), 7.58 - 7.55 (m, 2H), 3.35 (dd, J = 8.3 Hz, J = 6.8 Hz, 2H), 2.94 (dd, J = 8.3 Hz, J = 6.8 Hz, 2H), 2.33 (ddt, J = 11.2 Hz, J = 7.2 Hz, J = 3.4 Hz, 1H), 1.81 - 1.73 (m, 4H), 1.66 - 1.50 (m, 3H), 1.32 - 1.14 (m, 7H).

[0086] 13 C NMR (101 MHz, CDCl3) δ 209.24, 139.12, 133.89, 129.39, 127.97, 50.82, 50.65, 32.86, 28.40, 25.68, 25.49.

[0087] Results and Discussion: As can be seen from Table 1, the classic Maruoka catalyst (S)-PTC-4 cannot catalyze the initiation of the reaction between cyclohexyl aldehyde and vinyl phenyl sulfone (shown in Entry 7), indicating that the classic Maruoka catalyst based on an ionic reaction mechanism cannot catalyze the initiation of this reaction. As a control example, in the presence of the commonly used hydrogen atom transfer reagent HAT-i, the conversion yield is trace (shown in Entry 5). In the presence of HAT-i, potassium carbonate is further added, and the yield is 39% (shown in Entry 6). In contrast, the presence of (S)-PTC-1 developed in the present invention increases the reaction conversion, and the yield is 84% (shown in Entry 1). The methoxy group in the (S)-PTC-1 catalyst is converted to an ethoxy group to obtain the catalyst (S)-PTC-2, and the yield is further increased to 96% (shown in Entry 2). While converting the ethoxy group to a butoxy group to synthesize (S)-PTC-3, the yield slightly decreases to 93% (shown in Entry 3). It shows that the enantioselectivity of the product is not affected by the length of the flexible chain on the catalyst N.

[0088] To explore the influence of the base on this catalytic system, potassium carbonate is further added on the basis of Entry 2, and the corresponding yield decreases from 96% to 33% (shown in Entry 4), indicating that the presence of the base will cause a significant decrease in the corresponding yield and conversion of the N-alkoxy quaternary ammonium salt catalyst.

[0089] The results in Table 1 show that the N-alkoxy quaternary ammonium salt catalyst designed in the present invention initiates the alkylation reaction between cyclohexyl aldehyde and vinyl phenyl sulfone through a radical reaction type to construct a C-C bond. The reaction conditions are mild, and the alkoxy group has good reaction activity, conversion, and yield.

[0090] Application Example 2: Extraction of Cyclic Ether-α-H and Its Alkylation Catalytic Test

[0091] Tetrahydrofuran undergoes an alkylation reaction with acetyl phenyl sulfone under the catalysis of a 2 mol% N-alkoxy quaternary ammonium salt chiral catalyst. The results are shown in Table 1, and the reaction formula is as follows (under irradiation at a wavelength of 456 nm):

[0092]

[0093] Table 2 Comparison of the Reactions of Tetrahydrofuran with Acetyl Phenyl Sulfone Catalyzed by the N-alkoxy Quaternary Ammonium Salt Chiral Catalyst of the Present Invention and Existing Catalysts

[0094]

[0095] Among them, the structural formula of HAT-R is as follows:

[0096]

[0097] The data characterization is as follows:

[0098]

[0099] 4CzIPN (7.9 mg, 0.01 mmol, 5 mol%) and the catalyst were weighed into a 10 mL sealed tube equipped with a magnetic stir bar. Under an argon atmosphere, acetonitrile (2 mL, 0.1 M) and tetrahydrofuran (325 μL, 4 mmol, 20 eq.) were successively added. The reaction system was diluted with ethyl acetate and then concentrated under reduced pressure. The crude product was purified by column chromatography to obtain the target compound.

[0100] 1 H NMR (400 MHz, CDCl3): δ 7.92 (d, J = 7.2 Hz, 2H), 7.66 (t, J = 7.4 Hz, 1H), 7.57 (t, J = 7.6 Hz, 2H), 3.87 - 3.82 (m, 1H), 3.82 - 3.76 (m, 1H), 3.70 - 3.64 (m, 1H), 3.30 (ddd, J = 14.0 Hz, J = 11.5 Hz, J = 5.0 Hz, 1H), 3.14 (ddd, J = 14.0 Hz, J = 11.3 Hz, J = 4.9 Hz, 1H), 2.03 - 1.92 (m, 2H), 1.89 - 1.82 (m, 3H), 1.50 - 1.42 (m, 1H).

[0101] 13 C NMR (101 MHz, CDCl3) δ 139.20, 133.66, 129.28, 128.04, 67.86, 53.61, 31.22, 28.51, 25.60.

[0102] Results and Discussion:

[0103] As can be seen from Table 2, the classical Maruoka catalyst (S)-PTC-4 cannot catalyze the initiation of the reaction of tetrahydrofuran with vinyl phenyl sulfone (shown in Entry 8), indicating that the classical Maruoka catalyst based on the ionic reaction mechanism cannot catalyze the initiation of this reaction. As a control example, in the presence of the commonly used hydrogen atom transfer reagents HAT-i (20%) and HAT-R (20%), the yields are relatively low, 44% and 18% respectively (see Entries 1 and 3), while when the amount of the catalyst is reduced to 2%, the reaction conversion rate and the conversion yield are trace amounts (Entries 2 and 4). In contrast, the presence of (S)-PTC-1 developed in the present invention (only with a 2% loading amount) significantly improves the reaction conversion, and the yield is 44% (Entry 5). When the methoxy group in the (S)-PTC-1 catalyst is converted to an ethoxy group to obtain the catalyst (S)-PTC-2, the yield is further increased to 68% (Entry 6). Further reducing the loading amount of the catalyst (S)-PTC-3 to 0.5%, the yield slightly decreases, but the decrease is not significant (53%, Entry 7).

[0104] The results in Table 2 show that the N-alkoxy quaternary ammonium salt catalyst designed in the present invention initiates the reaction of tetrahydrofuran with vinyl phenyl sulfone through a free radical reaction type, and the alkoxy group has good reaction activity, conversion rate and yield.

[0105] Obviously, the above-mentioned embodiments of the present invention are merely examples for clearly illustrating the technical solutions of the present invention, rather than limitations on the specific implementation manners of the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principle of the claims of the present invention shall be included within the protection scope of the claims of the present invention.

Claims

1. A chiral catalyst of N-alkoxy quaternary ammonium salts, characterized in that, The structural formula of the N-alkoxy quaternary ammonium salt chiral catalyst is shown in Formula (i) or Formula (ii): Wherein, R is a H atom, a phenyl group, -3,4,5-F3-C6H2- or -3,5-CF3-C6H3-; n is any integer from 0 to 6; X is bromine.

2. The N-alkoxy quaternary ammonium salt chiral catalyst according to claim 1, wherein n is 0, 1, 2, 3, 5.

3. The N-alkoxy quaternary ammonium salt chiral catalyst according to claim 1, wherein n is 0, 1, 2 or 3.

4. The N-alkoxy quaternary ammonium salt chiral catalyst according to claim 3, wherein R is -3,4,5-F3-C6H2-.

5. The N-alkoxy quaternary ammonium salt chiral catalyst according to claim 1 or 4, characterized in that, The structural formula of the N-alkoxy quaternary ammonium salt chiral catalyst is any one of the following structures:

6. The application of the N-alkoxy quaternary ammonium salt chiral catalyst according to claim 1 in radical chemical reactions and as a hydrogen atom transfer reagent.

7. The application according to claim 6, wherein The N-alkoxy quaternary ammonium salt chiral catalyst is used for C-C bond construction and alkylation reactions.

8. The application according to claim 7, wherein The application of the N-alkoxy quaternary ammonium salt chiral catalyst in the alkylation reaction based on C-C bond construction is as follows:

9. The application according to claim 7, characterized in that The application of the N-alkoxy quaternary ammonium salt chiral catalyst in the alkylation reaction based on C-C bond construction is as follows:

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