N-alkoxy quaternary ammonium salt chiral catalysts and their use in hydrogen atom transfer and alkylation reactions

Abstract

The application discloses a kind of N-alkoxy quaternary ammonium salt chiral catalyst, can be used as hydrogen atom transfer reagent and catalyst of radical reaction, mediate C-C bond coupling and alkylation reaction.The alkoxyl group is introduced on the chiral quaternary ammonium salt catalytic center nitrogen atom of binaphthyl skeleton, and a series of N-alkoxy quaternary ammonium salt chiral hydrogen atom transfer reagent is synthesized for the first time.Compared with the chiral phase transfer catalyst based on chiral binaphthyl skeleton (catalytic center nitrogen atom is connected with aliphatic carbon chain or aromatic carbon) developed by applicant earlier, the catalyst of the application introduces alkoxyl group on catalytic center N atom, so that N atom is directly connected with oxygen atom, changes the electronic effect and bond breaking mode of catalytic center, changes the traditional participation of quaternary ammonium salt chiral catalyst in ionic reaction into participation in radical reaction, realizes the C-C bond coupling difficult to complete under ionic reaction condition, and provides a feasible scheme for C-C bond construction and alkylation based on radical chemistry.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of organic small molecule catalysis and radical chemistry, and particularly relates to N-alkoxy quaternary ammonium salt chiral catalysts and their application in hydrogen atom transfer and alkylation reactions. BACKGROUND

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

[0003] In recent years, late-stage functionalization synthetic strategies have become a hot topic in the fields of organic synthesis and medicinal chemistry, and are used for selectively modifying existing molecules (especially complex molecules). In the late stage of complex organic molecule synthesis, specific functional group introduction, transformation or modification is carried out on molecules that already have a certain structural complexity, without significantly changing the overall structure of the molecule, so as to further optimize and functionalize the molecular structure, and adjust the properties of the compound, such as biological activity, physical property or reactivity, to obtain a target molecule with specific properties or biological activity.

[0004] Free radical reactions provide a powerful strategy 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, free radical reactions have good advantages in the later functionalization and structural modification of complex molecules: (1) Free radical reactions often have unique selectivity and can react at specific positions in complex molecules, which is very critical for the precise introduction of required functional groups in later stage structural modification. (2) Free radical reactions usually proceed under relatively mild conditions and do not require overly harsh reaction conditions such as high temperature, high pressure or strong acid and base. This is particularly important for complex molecules, because complex molecules may be more sensitive to severe reaction conditions and are prone to side reactions or molecular structure destruction. (3) In some cases, free radical reactions can provide unique stereochemical control, which is crucial for constructing complex molecules with specific spatial configurations. For example, free 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 find it difficult to achieve such precise stereochemical control due to the formation of ion pairs and the complexity of the reaction mechanism. (4) Free radical reactions have good compatibility with many functional groups, while ionic reactions often have strict requirements on the functional groups in the substrate. Complex molecules usually contain multiple functional groups, and free radical reactions can modify the structure of the target position without affecting other functional groups. For example, when multiple functional groups such as hydroxyl and carbonyl exist in a molecule at the same time, free radical reactions can selectively functionalize the carbon-hydrogen bond at a specific position without causing unnecessary side reactions with other functional groups. (5) Free radical reactions often have high atom economy, which can more effectively utilize the atoms in the reactants and reduce the generation of waste. This 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 CH activation and hydrogen abstraction based on free radical reactions have very strong application prospects in functionalization in the later stages of synthesis and have attracted much attention.

[0007] The chiral phase transfer catalyst based on the chiral binaphthyl skeleton developed by the applicant in the early stage has the catalytic center N atom connected with a fatty carbon chain or an aromatic carbon, and realizes the following based on ionic reactions: (1) construction of complex chiral alpha-amino acids through alpha-alkylation reaction; (2) asymmetric Michael addition reaction; (3) asymmetric aldol condensation reaction; (4) asymmetric Mannich reaction; (5) asymmetric Darzens reaction; (6) asymmetric Neber rearrangement reaction; (7) asymmetric epoxidation reaction; (8) asymmetric aziridination reaction; (9) asymmetric dihydroxylation reaction; (10) asymmetric fluorination reaction; (11) asymmetric Strecker reaction, and has good application prospect.

[0008] However, the quaternary ammonium salt chiral phase transfer catalyst (Maruoka catalyst) based on the chiral binaphthyl skeleton is currently only applicable to ionic reactions, and cannot be used in radical reactions, which limits its reaction and application.

[0009] In order to further expand the application of the quaternary ammonium salt catalyst and break through the limitation of the existing ionic reaction, the alkoxyl group is introduced to the catalytic center N atom of the quaternary ammonium salt catalyst based on the chiral binaphthyl skeleton in the application, so that the N atom is directly connected with the oxygen atom, the electronic effect and bond breaking mode of the catalytic center are changed, the traditional quaternary ammonium salt chiral catalyst participating in ionic reaction is changed to participating in radical reaction, so as to realize C-H activation and hydrogen abstraction based on radical reaction, and then realize the C-C bond coupling which is difficult to complete under ionic reaction conditions, provide a feasible scheme for C-C bond construction and alkylation based on radical chemistry, and provide a new strategy for post-modification of complex molecules. SUMMARY

[0010] The N atom of the chiral quaternary ammonium salt catalytic center in the simplified Maruoka catalyst developed by the applicant in the early stage is connected with a fatty carbon chain or an aromatic carbon, the weak interaction of the catalytic center is relatively single, which leads to the relatively single defects of the action mode and effect of the catalytic center, and the catalytic reaction type is limited, that is, it is only applicable to ionic reactions. The N-O bond connection can change the electronic effect, steric effect and bond breaking mode of the catalytic center, enrich the action mode of the active center of the catalyst, and further broaden the catalytic reaction type and catalytic activity.

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

[0012] To achieve the above object, the technical scheme adopted by the present application is:

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

[0016] Regarding the definition of the term: "substitution" means that the hydrogen atoms in the molecule are replaced by other different atoms or molecules. The minimum and maximum values of the carbon content in the carbon-hydrogen group are indicated by a prefix, 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 straight-chain or branched alkyl groups containing 1-4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, etc.

[0017] As a preferred technical scheme, R is H atom, phenyl, -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 scheme, 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 application also protects the application of the N-alkoxy quaternary ammonium salt chiral catalyst based on free radical reaction in hydrogen atom transfer, alkylation reaction, and C-C bond construction reaction.

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

[0023]

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

[0025]

[0026] The N atom of the catalyst active center is connected with a fatty carbon chain or an aromatic carbon, the weak interaction of the catalytic center is relatively single, which leads to the relatively single defects of the action mode and effect of the catalytic center, and the catalytic reaction type is limited, that is, it is only suitable for ionic reactions. However, when the N-O bond is connected, the action mode of the catalyst active center can be enriched by changing the electronic effect, steric hindrance effect, and bond breaking mode of the catalytic center, thereby widening the catalytic reaction type and catalytic activity. 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 the quaternary ammonium salt catalyst from ionic reaction to free radical reaction. The present application 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 succeeds. Application research shows that the introduction of the alkoxy group of the catalytic center changes the electronic effect, steric hindrance effect, and bond breaking mode (from heterolysis to homolysis) of the catalytic center of the catalyst, and successfully develops a quaternary ammonium salt phase transfer catalyst which is difficult to achieve hydrogen atom transfer in ionic reaction mode, that is, to selectively capture hydrogen atoms from aldehyde group-H and cyclic ether alpha-H, and to perform alkylation reaction with a vinyl phenyl sulfone to construct a C-C bond, which has less dosage and high yield than existing hydrogen capture catalysts. Under the same conditions, a chiral phase transfer catalyst with a similar binaphthyl skeleton cannot be realized based on ionic reaction type.

[0027] Compared with the prior art, the present application has the following beneficial effects:

[0028] This invention introduces an alkoxy group into the catalytic center of a chiral quaternary ammonium salt catalyst with a binaphthyl skeleton, thereby modifying the electronic effect, steric effect, and bond cleavage mechanism of the catalyst center. This chirality transforms the reaction type involved in these binaphthyl quaternary ammonium salt catalysts from ionic to free radical reactions. This series of catalysts selectively abstracts hydrogen atoms from the aldehyde group (-H) and the cyclic ether group (α-H), successfully reacting with vinyl phenyl sulfone to form a C-C bond. Under the same conditions, chiral phase transfer catalysts with similar binaphthyl skeletons cannot be achieved using ionic reactions. Compared to existing hydrogen-abstracting catalysts, these catalysts require less dosage and have higher yields, demonstrating promising application prospects. DETAILED DESCRIPTION

[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 embodiments described are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative efforts are within the scope of protection of the present invention.

[0030] Unless otherwise specified, the experimental methods used in the examples of the present invention are conventional methods; the materials and reagents used are commercially available reagents and materials unless otherwise specified.

[0031] 1. Synthesis method:

[0032] The synthesis of N-alkoxy quaternary ammonium salt chiral catalyst PTC-1 to -3 series compounds is shown below:

[0033]

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

[0035]

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

[0037] 1 H NMR (400 MHz, CDC13): 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 C NMR (100 MHz, CDC13): 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] (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), phenyl formate (6.5 mL, 60 mmol) were added sequentially into a 120 mL pressure tube under argon protection, 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 to separate the layers, then the lower organic phase was removed, the resulting mixture was diluted with ethyl acetate and poured into water, washed with brine, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product which was separated and purified by silica gel column chromatography (ethyl acetate: n-hexane = 1:10) to obtain white solid (S)-2 (1.78 g, 3.6 mmol, yield 60%).

[0041] 1 H NMR (400 MHz, CDC13): 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] 13C NMR (100 MHz, CDC13): 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] To a solution of (S)-2 (2.27 g, 4.6 mmol) in ethanol (143.5 mL) was added a 40% KOH solution (13.8 mL) at room temperature and the reaction mixture was heated to reflux with stirring for 24 h. After the end of the reaction, the system was cooled to room temperature and then the pH was adjusted to 1 with a 2 M HC1 solution. The resulting mixture was extracted with ethyl acetate and the organic phase was retained. The resulting organic phase was adjusted to pH 13 with a 1 M KOH solution, the phases were separated and the aqueous phase was retained. The aqueous phase was then adjusted to pH 1 and extracted with ethyl acetate. The 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 (S)-3 as a white solid (1.46 g, 4.28 mmol, 93% yield).

[0045] 1 H NMR (400 MHz, CDC13): 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 C NMR (100 MHz, CDC13): 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 mixture solution of tetrabutylammonium hydrogen sulfate (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, then (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 give (S)-4 (1.1 g, 2.58 mmol, yield 76%) as a white solid.

[0049] 1 H 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 C 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, super dry tetrahydrofuran (18 mL) was added to magnesium powder (438 mg, 18 mmol) and heated to reflux, then 1,2-dibromoethane (1.55 mL, 18 mmol) was slowly added dropwise to the system to obtain a MgBr2solution (off-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, then n-butyllithium (2.5 M dissolved in n-hexane, 6.1 mL, 15 mmol) was slowly added dropwise at 0°C, and after stirring at 0°C for 45 min, LiTMP (yellow clear solution) was obtained. After the MgBr2solution was cooled to 0°C, LiTMP was slowly added, and then stirring was continued at 0°C for 2 h to obtain a tetrahydrofuran solution of Mg(TMP)2(brown clear solution).

[0053] To the prepared Mg(TMP)2solution (0.31 M, 27.1 mL, 8.4 mmol) was added a solution of (S)-4 (899.5 mg, 2.1 mmol) in tetrahydrofuran (10 mL) at 0 °C under argon and stirred for 3 h at room temperature. Subsequently, the system was cooled to -78 °C and bromine (860 μL, 16.8 mmol) was added slowly and stirred for 1 h at room temperature. 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, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was separated and purified by silica gel column chromatography (dichloromethane: n-hexane = 1:1) to obtain a white solid (S)-5 (1.01 g, 1.73 mmol, yield 82%).

[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] To the reaction flask was added (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), N,N-dimethylformamide (14.8 mL) under argon, and then heated to 90 °C for 16 h. After the reaction was completed, the system was cooled to room temperature and poured into a saturated ammonium chloride solution, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which 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, yield 90%).

[0058] 1H NMR (400 MHz, CDC13): 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 C NMR (100 MHz, CDC13): 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] 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) at 0 °C, and the reaction mixture was stirred at room temperature for 5 h. After the reaction was completed, the mixture was quenched with water under an ice water bath, and then acidified with 1 M HC1 solution. The resulting mixture was extracted with dichloromethane, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude (S)-7 was used in the next reaction without purification.

[0062]

[0063] 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) at 0 °C, and the reaction was left to stir at room temperature for 1 h. After the end of the reaction, the system was poured into water, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product which was purified by column chromatography on silica gel (ethyl acetate: n-hexane = 1:20) to obtain (S)-8 as a white solid (1148 mg, 1.63 mmol, 96% yield over two steps).

[0064] 1 H NMR (400 MHz, CDC13): 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, CDC13): 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, and methoxybutylamine (3.0 mmol) was added, and stirred at room temperature for 24 h. After the end of the reaction, the mixture was quenched by pouring into water and extracted with dichloromethane, the organic phase was back-extracted with saturated brine and dried over anhydrous sodium sulfate, and the crude product was purified by column chromatography on silica gel (MeOH: DCM = 1:50) to obtain the target catalyst (S)-PTC-1.

[0068] 1H NMR (500 MHz, CDC13): 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, ethoxybutylamine (325 μL, 3.0 mmol) was added, and the mixture was stirred at room temperature for 24 h. After the reaction was completed, the mixture was quenched into water and extracted with dichloromethane. 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 H NMR (500 MHz, CDC13): 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 13C NMR (101 MHz, CD2Cl2) 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, and stirred at room temperature for 24 h. After the reaction was completed, the mixture was quenched by pouring into water and extracted with dichloromethane, and 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-3.

[0074] 1 H 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: Aldehyde-H grabbing and alkylation catalytic test

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

[0077]

[0078] Table 1. Comparison of the reaction of cyclohexyl aldehyde with acetyl phenyl sulfone catalyzed by N-alkoxy quaternary ammonium salt chiral catalysts of the present application and existing catalysts

[0079]

[0080] wherein trace represents trace amount, the amount of each catalyst in Table 1 is the same, and the structural formulae of (S)-PTC-4, HAT-i and 4CzIPN are as follows:

[0081]

[0082] The data are characterized as follows:

[0083]

[0084] 4CzIPN (7.9 mg, 0.01 mmol, 5 mol%), catalyst (2 mol%) and vinyl phenyl sulfone (33.6 mg, 0.2 mmol) were weighed into a 10 mL sealed tube equipped with a magnetic stir bar, acetonitrile (2 mL, 0.1 M) and cyclohexanecarboxaldehyde (524 μL, 4 mmol, 20 eq.) were added sequentially under an argon atmosphere, and the reaction system was diluted with ethyl acetate and concentrated under reduced pressure. The crude product was purified by column chromatography to obtain the target compound.

[0085] 1 H NMR (500 MHz, CDC13): 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, CDC13) 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: From Table 1, it can be seen that the classic Maruoka catalyst (S)-PTC-4 cannot catalyze the reaction of starting cyclohexyl aldehyde and vinyl phenyl sulfone (No. 7), indicating that the classic Maruoka catalyst based on the ionic reaction mechanism cannot catalyze the reaction. As a control example, in the presence of the commonly used hydrogen atom transfer reagent HAT-i, the conversion yield is trace (No. 5), and in the presence of HAT-i, further adding potassium carbonate, the yield is 39% (No. 6). In contrast, the presence of (S)-PTC-1 developed by the present application improves the reaction conversion, and the yield is 84% (No. 1). The methoxy group in the (S)-PTC-1 catalyst is converted into ethoxy group to obtain the catalyst (S)-PTC-2, and the yield is further improved to 96% (No. 2), and the ethoxy group is converted into butoxy group to synthesize (S)-PTC-3, and the yield is slightly decreased to 93% (No. 3). It is shown that the enantioselectivity of the product is not affected by the length of the flexible chain on N.

[0088] In order to investigate the effect of base on the catalytic system, further adding potassium carbonate on the basis of No. 2, the corresponding yield is decreased from 96% to 33% (No. 4), indicating that the presence of base can significantly reduce the yield and conversion of N-alkoxy quaternary ammonium salt catalyst.

[0089] The results of Table 1 show that the N-alkoxy quaternary ammonium salt catalyst designed by the present application starts the alkylation reaction of cyclohexyl aldehyde and vinyl phenyl sulfone by free radical reaction type to construct C-C bond. The reaction condition is mild, and the alkoxy group has good reactivity, conversion and yield.

[0090] Application example 2: capture of cyclic ether-α-H and alkylation catalytic test

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

[0092]

[0093] Table 2 Comparison of N-alkoxy quaternary ammonium salt chiral catalyst of the present application and existing catalyst in catalyzing the reaction of tetrahydrofuran and acetyl phenyl sulfone

[0094]

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

[0096]

[0097] Data characterization is as follows:

[0098]

[0099] To a 10 mL vial equipped with a magnetic stir bar, 4CzIPN (7.9 mg, 0.01 mmol, 5 mol%), catalyst, vinylbenzene sulfone (33.6 mg, 0.2 mmol, 1 eq.) were weighed under argon atmosphere, acetonitrile (2 mL, 0.1 M) and tetrahydrofuran (325 μL, 4 mmol, 20 eq.) were added sequentially, the reaction mixture was diluted with ethyl acetate and concentrated under reduced pressure. The crude product was purified by column chromatography to obtain the target compound.

[0100] 1 H NMR (400 MHz, CDC13): 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, CDC13) 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 classic Maruoka catalyst (S)-PTC-4 cannot catalyze the initiation of the reaction of tetrahydrofuran with vinyl phenyl sulfone (shown in No. 8), indicating that the classic Maruoka catalyst based on the ionic reaction mechanism cannot catalyze the initiation of the reaction. As a control example, in the presence of the commonly used hydrogen atom transfer reagent HAT-i (20%) and HAT-R (20%), the yield is low, being 44% and 18% respectively (see No. 1 and 3), and when the amount of catalyst is reduced to 2%, the conversion rate and conversion yield are trace amounts (No. 2 and 4). In contrast, the presence of (S)-PTC-1 developed by the present application (only 2% of the loading amount) significantly improves the reaction conversion, and the yield is 44% (No. 5). The conversion of the methoxy group in the (S)-PTC-1 catalyst to an ethoxy group to obtain the catalyst (S)-PTC-2 further improves the yield to 68% (No. 6), and further reducing the loading amount of the catalyst (S)-PTC-3 to 0.5% slightly reduces the yield, but the reduction is not large (53%, No. 7).

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

[0105] Obviously, the above embodiments of the present application are only examples for clearly illustrating the technical solutions of the present application, and are not intended to limit the specific embodiments of the present application. Any modification, equivalent replacement and improvement made within the spirit and principle of the present application should be included in the protection scope of the claims of the present application.

Claims

1. An N-alkoxy quaternary ammonium salt chiral catalyst, 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 hydrogen atom, a phenyl group, a 3,4,5-trifluorophenyl group or a 3,5-bis(trifluoromethyl)phenyl group; n is an integer from 0 to 6; and X is bromine.

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

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

4. The N-alkoxy quaternary ammonium salt chiral catalyst according to claim 3, characterized in that R is 3,4,5-trifluorophenyl.

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 use of the N-alkoxy quaternary ammonium salt chiral catalyst according to claim 1 in an alkylation reaction based on a C-C bond, characterized in that: The N-alkoxy quaternary ammonium salt chiral catalyst is applied to the alkylation reaction based on C-C bond construction as follows: 。 7. The use of the N-alkoxy quaternary ammonium salt chiral catalyst according to claim 1 in an alkylation reaction based on a C-C bond, characterized in that: The N-alkoxy quaternary ammonium salt chiral catalyst is applied to the alkylation reaction based on C-C bond construction as follows: 。

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