A chiral catalyst based on the synergistic effect of double nitrogen heterocyclic carbene-nitrile oxide adduct, a preparation method and application thereof

Abstract

This invention belongs to the fields of organic catalysis and asymmetric catalysis, and relates to a bichiral synergistic nitrogen heterocyclic carbene-oxynitrile adduct catalyst, its preparation method, and its application. The catalyst is composed of a nitrogen heterocyclic carbene unit and an oxynitrile unit, wherein both the nitrogen heterocyclic carbene and oxynitrile moieties can incorporate chiral structural units, thereby constructing a synergistic chiral environment composed of two chiral sources within the overall catalyst structure. This structural design allows for a more refined stereoselectivity control during the catalytic reaction, thereby enhancing the catalyst's stereoinductive ability in asymmetric catalytic reactions. The catalyst is prepared through a modular synthesis process, which involves fewer steps and is safe and simple to operate, and the catalyst structure is easily modulated. Applying this catalyst to acyl rearrangement reactions enables effective control of the reaction's stereoselectivity, thereby efficiently synthesizing various indolones or benzofuranones containing a chiral quaternary carbon center at the C3 position.

Description

Technical Field

[0001] This invention belongs to the fields of organic catalysis and asymmetric catalysis, and relates to a biphasic synergistic nitrogen heterocyclic carbene-oxynitrile adduct catalyst, its preparation method, and its application. Background Technology

[0002] Acyl migration reactions are a class of highly practical organic reactions. Essentially, they involve the transfer of acyl groups within or between substrates to achieve skeletal rearrangement or functional group interconversion, making them an efficient method for synthesizing complex molecules. Acyl migration reactions exhibit diverse migration modes and broad substrate adaptability, and are widely used in the total synthesis of natural products, drug molecule modification, and molecular design (Burke HM, McSweeney L, Scanlan E M). Nat. Commun., 2017, 8 (15655.). In the development of asymmetric acyl transfer reactions, the activation of acyl donors using nucleophilic catalysts is an important and classic strategy. In 2003, Fu et al. reported planar chiral DMAP derivatives as chiral acyl transfer catalysts, achieving the construction of indolone structures with a chiral quaternary carbon center at the C3 position via acyl transfer reactions. (IDHills and GCFu, 15655.) Angew. Chem., Int. Ed., 2003, 42 (3921-3924). Between 2015 and 2019, Suga's group systematically studied the application of DMAP-type chiral catalysts in asymmetric acyl migration reactions. They constructed C3-functionalized DMAP catalysts via the Ugi multicomponent reaction and applied them to the acyl rearrangement reaction of indole carbonates, achieving a yield of 98% and an enantiomeric ratio of 99:1. Subsequently, they developed an axially chiral BINOL-DMAP catalyst, catalyzing the acyl migration of phenyl carbonate substrates at a catalyst dosage of 0.5 mol%, yielding hydroxyindole derivatives with an enantiomeric ratio greater than 98:2. This was further applied to the benzofuran carbonate system, achieving high regioselectivity (α:γ = 10:90) and an enantioselectivity of 95:5 (H. Suga and A. Kakehi, 3921-3924). Chem. Commune ,2015, 51 , 5932-5935;H. Suga and A. Kakehi, Org. Lett. ,2016, 18 , 3626–3629;H. Suga and A. Kakehi, J. Org. Chem. .,2019, 84(13540-13549). However, existing asymmetric catalytic systems for acyl migration reactions still have certain limitations, such as numerous catalyst synthesis steps, high raw material costs, and a limited range of applicable substrates. Furthermore, some reaction systems still require relatively harsh reaction conditions. Therefore, developing novel chiral catalysts with novel structures, easy preparation, and high efficiency in catalyzing acyl migration reactions to achieve efficient asymmetric synthesis of indolones and benzofuranones containing chiral quaternary carbon centers is of significant research importance and application value.

[0003] Nitrogen heterocyclic carbenes (NHCs), as important ligands and nucleophilic catalysts, have been widely studied and applied in fine organic synthesis. Nitriles, as typical 1,3-dipolar compounds, can combine with nitrogen heterocyclic carbenes to form nitrogen heterocyclic carbene-nitrile adducts (M. Temprado, S. Majumdar, CD Hoff, et al.). Structure Chem. 2013, 24 (2059). Although the potential applications of chiral nitrogen heterocyclic carbene oxidizing nitrile adducts in asymmetric organic synthesis have gradually attracted attention, research on synergistic stereoregulation through the introduction of multi-chiral elements remains relatively lacking. To address this deficiency, this invention discloses a nitrogen heterocyclic carbene-oxidizing nitrile adduct catalyst with bichiral synergistic effects, its preparation method, and its applications. Through the synergistic effect of intramolecular chiral nitrogen heterocyclic carbene and chiral oxidizing nitrile units, a highly efficient and novel catalytic system is provided for asymmetric synthesis. Summary of the Invention

[0004] This invention provides a method for preparing a chiral oxynitrile adduct catalyst based on bipolar synergy and its application in asymmetric acyl migration reactions. By introducing chiral oxynitrile structural units into the nitrogen heterocyclic carbene skeleton, a bipolar catalytic system is constructed, enabling the two chiral factors, nitrogen heterocyclic carbene and oxynitrile, to exert a synergistic stereoregulatory effect during the reaction, thereby effectively improving the stereoselectivity of the catalytic reaction. This catalytic system can be applied to the acyl migration reactions of substrates such as 2-indolyl carbonates and benzofuran carbonates, constructing indolones and benzofuranones containing chiral quaternary carbon centers with high yields and good enantioselectivity, demonstrating good catalytic efficiency and application potential.

[0005] The technical solution of the present invention: A bichiral nitrogen heterocyclic carbene-nitrile oxide adduct catalyst is proposed, consisting of two chiral structural units: a chiral nitrogen heterocyclic carbene unit and a chiral nitrile oxide unit. The general molecular formula of the nitrogen heterocyclic carbene-nitrile oxide adduct catalyst is shown below: Among them, R 1 It can be methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, benzyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, or tert-butoxy; R 2 It is (R)-1-methylethoxy, (S)-1-methylethoxy, (R)-1-methylpropoxy, (S)-1-methylpropoxy, (R)-1-methylbutoxy, (S)-1-methylbutoxy, (R)-2-methylbutoxy, (S)-2-methylbutoxy, (R)-1-phenylethoxy or (S)-1-phenylethoxy; R 3 It can be hydrogen, Br, Cl, F, methyl or methoxy.

[0006] By systematically modulating the structure of the nitric oxide moiety, a new chiral control unit is introduced into the existing chiral nitrogen heterocyclic carbene framework, thereby constructing a nitrogen heterocyclic carbene-nitric oxide adduct catalyst system with multiple chiral sources. This multi-chiral synergistic structure can form a more refined stereocontrol environment during catalysis, thus effectively improving the reactivity and enantioselectivity of asymmetric acyl rearrangement reactions.

[0007] A method for preparing a chiral nitrogen heterocyclic carbene-nitrile oxidizing adduct catalyst based on bichiral synergistic reaction involves the following steps: In an inert atmosphere, a chiral nitrogen heterocyclic carbene precursor salt is deprotonated by potassium bis(trimethylsilyl)amino to generate an active carbene, which then undergoes a coupling reaction with a chiral oxidizing nitrile. The reaction solution is filtered, concentrated, recrystallized in a solvent, and vacuum dried to obtain the nitrogen heterocyclic carbene-nitrile oxidizing adduct catalyst.

[0008] Furthermore, the inert atmosphere is argon or nitrogen.

[0009] Further, the solvent is one or a mixture of two or more of the following: tetrahydrofuran, toluene, n-hexane, cyclohexane, dichloromethane, 1,2-dichloroethane, ethylene glycol dimethyl ether, 1,4-dioxane, diethyl ether, and acetonitrile.

[0010] Furthermore, the molar ratio of the chiral nitrogen heterocyclic carbene precursor salt to potassium bis(trimethylsilyl)amino is 1:(0.8~1.2).

[0011] Furthermore, the deprotonation reaction temperature is 0~30℃, and the reaction time is 0.2~24 h.

[0012] The molar ratio of the chiral nitrogen heterocyclic carbene precursor salt to the chiral oxynitrile is 1: (0.5~1.5).

[0013] Furthermore, the coupling reaction is carried out at a temperature of 0–30 °C for 24–72 h.

[0014] Furthermore, the chiral nitrogen heterocyclic carbene precursor salt is: .

[0015] In the application of the above-mentioned nitrogen heterocyclic carbene-oxidizing nitrile adduct catalyst in the asymmetric acyl migration reaction of indole or furan, a molecular sieve is added to the asymmetric acyl migration reaction, and the mass ratio of nitrogen heterocyclic carbene-oxidizing nitrile adduct catalyst to molecular sieve is controlled to be 1: (5~10).

[0016] Furthermore, the molecular sieve is a 3Å molecular sieve, a 4Å molecular sieve, or a 5Å molecular sieve.

[0017] Furthermore, the reaction temperature is 0~30℃, and the reaction time is 12~72 h.

[0018] The beneficial effects of this invention are as follows: It provides a nitrogen-heterocyclic carbene-nitrile adduct catalyst containing a chiral nitrile oxide structure. This catalyst, by simultaneously introducing chiral nitrogen-heterocyclic carbene units and chiral nitrile oxide units into its molecular structure, forms a synergistic regulatory system with multiple chiral sources. The two chiral elements interact, jointly influencing the stereoinductive ability of the catalyst, thereby effectively improving the asymmetric catalytic activity and selectivity of the reaction. The catalyst can be synthesized using a modular strategy, with relatively simple preparation steps and easily adjustable structure. It demonstrates practical value in catalyzing reactions of indole carbonate and benzofuran substrates, and has potential applications in the asymmetric synthesis of pharmaceuticals and fine chemicals. Attached Figure Description

[0019] Figure 1 This is the 1H NMR spectrum of the chiral indole obtained in Example 4.

[0020] Figure 2 This is the carbon NMR spectrum of the chiral indole obtained in Example 4.

[0021] Figure 3 This is a high-performance liquid chromatogram of the racemic product corresponding to the chiral indole ketone obtained in Example 4.

[0022] The racemic product exhibits two chromatographic peaks with approximately equal areas, symmetrical shapes, and good baseline separation on a chiral column. As shown in the figure, the peak areas of peak 1 (retention time 13.357 min) and peak 2 (retention time 16.110 min) are 1193.50415 mAU·s and 1218.42017 mAU·s, respectively, with an area ratio of 49.4835:50.5165, which is close to the theoretical 1:1 ratio of the racemic mixture and can be used as a standard reference for subsequent chiral separation and quantitative analysis.

[0023] Figure 4 This is the high-performance liquid chromatogram of the chiral indole ketone obtained in Example 4.

[0024] The chiral product exhibited a single main peak on a chiral column, with symmetrical peak shape, good baseline separation, and no obvious co-eluting enantiomer peaks. Peak 1 (retention time 14.936 min) was the dominant peak, with a peak area of ​​18241.5 mAU·s (peak height 578.01459 mAU, peak area accounting for 95.6406%), and can be considered the main component of the target chiral enantiomer. Peak 2 (retention time 18.186 min) was a trace associated peak with a peak area of ​​831.46271 mAU·s (accounting for 4.3594%), representing the residue of another enantiomer. The overall chromatogram indicates that the chiral product has high enantioselectivity (ee value approximately 91.3%). Detailed Implementation

[0025] The specific embodiments of the present invention will be further described below with reference to the accompanying drawings and technical solutions.

[0026] Example 1 In an argon-protected glove box, a chiral nitrogen-heterocyclic carbene precursor salt (1 mmol) was added to a reaction flask of appropriate size, followed by the addition of potassium bis(trimethylsilyl)amino (KHMDS, 1 mol·L⁻¹). -1 THF solution (1 mmol) and anhydrous and oxygen-free THF (8 mL) were stirred at room temperature for 4 h to generate the corresponding nitrogen heterocyclic carbene active species. Then, chiral oxynitrile (1.1 mmol) (R) was added. 1 It is a methoxy group, R 2 For (S)-1-methylpropoxy, R 3 (To be hydrogen), the reaction was continued with stirring at room temperature for 12 h. After the reaction was completed, the reaction system was filtered through a sintered glass funnel, and the solvent was removed from the filtrate under reduced pressure. The crude product was purified by recrystallization using a mixed solvent of THF and n-hexane. Because the polarity and solubility of this product are very similar to those of the impurities, it cannot be separated by conventional column chromatography and can only be purified by recrystallization, resulting in a low purification yield.

[0027] Finally, the target product—a solid nitrogen heterocyclic carbene-oxidizing nitrile chiral catalyst, Al—was obtained by vacuum drying.

[0028] The structural characterization data of the product obtained in Example 1 are shown below: Pink solid, yield: 21%. 1 H NMR (400 MHz, CDCl3) d 8.26 (d, J = 9.0 Hz, 2H), 7.88– 7.71 (m, 4H), 7.50 (q, J= 7.1 Hz, 4H), 7.43 – 7.30 (m, 4H), 7.23 (d, J = 8.5Hz, 1H), 6.67 (d, J = 8.4 Hz, 1H), 6.54 (d, J = 8.0 Hz, 2H), 6.50 – 6.30 (m, 1H),3.81 (s, 1H), 3.75 (d, J = 6.2 Hz, 1H), 3.68 (s, 2H), 3.06 (s, 2H), 2.62 (d, J =8.3 Hz, 2H), 1.85 (d, J = 3.2 Hz, 2H), 1.58 (d, J = 6.8 Hz, 8H), 1.39 (d, J = 6.0Hz, 3H), 1.27 (d, J = 3.4 Hz, 5H), 1.13 (d, J = 6.0 Hz, 1H), 0.97 (t, J = 7.5 Hz,1H), 0.88 (t, J = 6.6 Hz, 3H), 0.67 (t, J = 7.4 Hz, 2H). 13 C NMR(101 MHz, CDCl3) d 157.19, 155.14, 131.80, 129.85, 127.12, 126.38, 124.83, 124.11, 124.08,122.84, 122.74, 122.65, 103.39, 101.43, 72.90, 65.98, 53.61, 50.14, 40.79,40.66, 29.61, 27.51, 26.92, 23.63, 20.68, 17.16, 17.11, 13.89, 13.56, 12.17,8.27.HRMS(ESI, m / z ): [M+H] + calcd for C 39 H 42 N3O3 + : 600.3221, found: 600.3228. Example 2 In an argon-protected glove box, a chiral nitrogen-heterocyclic carbene precursor salt (1 mmol) was added to a reaction flask of appropriate size, followed by the addition of potassium bis(trimethylsilyl)amino (KHMDS, 1 mol·L⁻¹). -1 THF solution (1 mmol) and anhydrous and oxygen-free THF (8 mL) were stirred at room temperature for 4 h to generate the corresponding nitrogen heterocyclic carbene active species. Then, chiral oxynitrile (1.1 mmol) (R) was added. 1 It is 1-methylpropoxy, R 2 For (S)-1-methylpropoxy, R 3 (For hydrogen), the reaction was continued with stirring at room temperature for 12 h. After the reaction was completed, the reaction system was filtered through a sintered glass funnel, and the solvent was removed from the filtrate under reduced pressure. The crude product was purified by recrystallization using a mixed solvent of THF and n-hexane, and finally dried under vacuum to obtain the target product—a nitrogen heterocyclic carbene-nitrile oxidizing cyanide chiral catalyst solid A2.

[0029] The structural characterization data of the product obtained in Example 2 are shown below: Brownish-red solid, yield: 29%. 1 H NMR (400 MHz, CDCl3) d 8.22 (d, J = 31.7 Hz, 2H), 7.98– 7.72 (m, 4H), 7.61 – 7.46 (m, 4H), 7.46 – 7.34 (m, 4H), 7.18 (t, J = 9.0 Hz,1H), 6.70 – 6.53 (m, 2H), 6.52 – 6.43 (m, 1H), 4.43 (d, J = 11.0 Hz, 1H), 4.34– 4.21 (m, 1H), 3.11 (d, J = 13.3 Hz, 2H), 2.88 – 2.37 (m, 2H), 1.77 – 1.50 (m,6H), 1.38 (dd, J = 6.1, 2.9 Hz, 2H), 1.26 (d, J = 6.9 Hz, 4H), 1.12 – 0.81 (m,7H), 0.78 (t, J = 7.4 Hz, 1H), 0.66 (dt, J = 11.1, 7.4 Hz, 2H). 13 C NMR (101 MHz, CDCl3) d 158.16, 157.98, 157.24, 134.91, 133.79, 133.75, 133.72, 131.97, 131.92, 129.03, 128.32, 128.29, 126.86, 126.82, 126.14, 126.10, 124.99, 124.68, 124.60, 104.71, 104.22, 74.82, 74.77, 74.74, 74.64, 74.50, 52.24, 52.14, 52.10, 42.76, 42.70, 31.60, 29.75, 29.69, 29.10, 28.81, 22.68, 19.78,19.37, 19.31, 19.17, 18.44, 16.16, 16.12, 16.05, 14.15, 10.34, 10.26, 9.91,9.75.HRMS(ESI, m / z ): [M+H] + calcd for C 42 H 48 N3O3 + : 642.3690, found: 642.3688. Example 3 In an argon-protected glove box, a chiral nitrogen-heterocyclic carbene precursor salt (1 mmol) was added to a reaction flask of appropriate size, followed by the addition of potassium bis(trimethylsilyl)amino (KHMDS, 1 mol·L⁻¹). -1 THF solution (1 mmol) and anhydrous and oxygen-free THF (8 mL) were stirred at room temperature for 4 h to generate the corresponding nitrogen heterocyclic carbene active species. Then, chiral oxynitrile (1.1 mmol) (R) was added. 1 It is methyl, R 2 For (S)-1-methylpropoxy, R 3 The reaction mixture was stirred at room temperature for 12 h (Br). After the reaction was complete, the reaction system was filtered through a sintered glass funnel, and the solvent was removed from the filtrate under reduced pressure. The crude product was purified by recrystallization using a mixed solvent of THF and n-hexane, and finally dried under vacuum to obtain the target product—a solid A3, a nitrogen heterocyclic carbene-nitrile oxidizing catalyst.

[0030] Brownish-red solid, yield: 52%.

[0031] Example 4 In an argon-protected glove box, a chiral nitrogen-heterocyclic carbene precursor salt (1 mmol) was added to a reaction flask of appropriate size, followed by the addition of potassium bis(trimethylsilyl)amino (KHMDS, 1 mol·L⁻¹). -1 THF solution (1 mmol) and anhydrous and oxygen-free THF (8 mL) were stirred at room temperature for 4 h to generate the corresponding nitrogen heterocyclic carbene active species. Then, chiral oxynitrile (1.1 mmol) (R) was added. 1 It is isopropyl, R 2 For (S)-1-methylpropoxy, R 3 (For hydrogen), the reaction was continued with stirring at room temperature for 12 h. After the reaction was completed, the reaction system was filtered through a sintered glass funnel, and the solvent was removed from the filtrate under reduced pressure. The crude product was purified by recrystallization using a mixed solvent of THF and n-hexane, and finally dried under vacuum to obtain the target product—a nitrogen heterocyclic carbene-nitrile oxidizing chiral catalyst solid B1.

[0032] The structural characterization data of the product obtained in Example 4 are shown below: Red solid, yield: 44%. 1 H NMR (400 MHz, CDCl3) d 8.20 (d, J = 27.2 Hz, 2H), 7.80 (dd, J = 15.2, 7.2 Hz, 4H), 7.49 (s, 4H), 7.38 (d, J = 7.5 Hz, 4H), 7.20 (d, J =10.4 Hz, 1H), 6.61 (dd, J = 13.8, 8.4 Hz, 1H), 6.56 – 6.38 (m, 1H), 4.74 – 4.16(m, 2H), 3.11 (d, J = 6.2 Hz, 2H), 2.67 (s, 2H), 1.60 (s, 6H), 1.38 (d, J = 5.9Hz, 2H), 1.25 (d, J = 10.9 Hz, 4H), 1.16 (d, J = 6.0 Hz, 1H), 1.01 (d, J = 5.9 Hz, 3H), 0.88 (t, J = 6.9 Hz, 3H), 0.65 (d, J = 7.8 Hz, 1H).13 C NMR (101 MHz, CDCl3) d 157.98, 157.30, 133.77, 131.93, 129.10, 129.07, 128.35, 126.93, 126.86, 126.12, 124.92, 124.74, 124.71, 124.68, 124.63, 104.80, 104.73, 104.30, 104.22, 74.79, 74.72, 69.81, 69.62, 52.18, 52.08, 42.77, 42.71, 31.62, 29.67, 28.71, 22.95, 22.68, 22.45, 21.81, 21.60, 19.30, 19.20, 16.14, 16.10, 14.17,10.27, 9.78.HRMS(ESI, m / z ): [M+H] + calcd for C 41 H 46 N3O3 + : 628.3534, found:628.3585. Example 5 In an argon-protected glove box, a chiral nitrogen-heterocyclic carbene precursor salt (1 mmol) was added to a reaction flask of appropriate size, followed by the addition of potassium bis(trimethylsilyl)amino (KHMDS, 1 mol·L⁻¹). -1 THF solution (1 mmol) and anhydrous and oxygen-free THF (8 mL) were stirred at room temperature for 4 h to generate the corresponding nitrogen heterocyclic carbene active species. Then, chiral oxynitrile (1.1 mmol) (R) was added. 1 It is methyl, R 2 For (S)-1-methylpropoxy, R 3 (For hydrogen), the reaction was continued with stirring at room temperature for 12 h. After the reaction was completed, the reaction system was filtered through a sintered glass funnel, and the solvent was removed from the filtrate under reduced pressure. The crude product was purified by recrystallization using a mixed solvent of THF and n-hexane, and finally dried under vacuum to obtain the target product—a nitrogen heterocyclic carbene-nitrile oxidizing cyanide chiral catalyst solid B2.

[0033] The structural characterization data of the product obtained in Example 5 are shown below: Dark red solid, yield: 64%.

[0034] Example 6 In an argon-protected glove box, a chiral nitrogen-heterocyclic carbene precursor salt (1 mmol) was added to a reaction flask of appropriate size, followed by the addition of potassium bis(trimethylsilyl)amino (KHMDS, 1 mol·L⁻¹). -1 THF solution (1 mmol) and anhydrous and oxygen-free THF (8 mL) were stirred at room temperature for 4 h to generate the corresponding nitrogen heterocyclic carbene active species. Then, chiral oxynitrile (1.1 mmol) (R) was added. 1 It is methyl, R 2 For (S)-1-methylpropoxy, R 3 The reaction mixture was stirred at room temperature for 12 h (Br). After the reaction was complete, the reaction system was filtered through a sintered glass funnel, and the solvent was removed from the filtrate under reduced pressure. The crude product was purified by recrystallization using a mixed solvent of THF and n-hexane, and finally dried under vacuum to obtain the target product—a nitrogen heterocyclic carbene-nitrile oxidizing cyanide chiral catalyst solid B3.

[0035] The structural characterization data of the product obtained in Example 6 are shown below: Pink solid, yield: 60%.

[0036] Application Example 1 Under anhydrous and oxygen-free conditions, 0.3 mmol of 2-indole carbonate substrate, 5 mL of ultra-dry solvent toluene, and 240 mg of 4 Å molecular sieve (powder) were added to a dry and clean strip flask. After stirring at room temperature for 1 h, a chiral nitrogen heterocyclic carbene nitrile oxidizing adduct catalyst A1 (0.03 mmol, 10 mol%) was added, and the mixture was stirred at -40°C. o The reaction was carried out at C for 24 hours. No further post-treatment was required. The solution could be directly filtered to remove the molecular sieve, concentrated, and then a certain amount of internal standard (trimethoxybenzene) was added. The reaction solution was then tested. 1 H NMR was used to calculate the yield to be 95%. The target product was obtained by column chromatography, and the product was tested by high performance liquid chromatography with an ee value of 91%.

[0037] The structural characterization data of the product obtained from Example 1 are shown below: 1 H NMR (500 MHz, CDCl3) d 7.78 (d, J = 8.0 Hz, 1H), 7.51 (dd, J = 7.4, 1.5Hz, 1H), 7.45 – 7.27 (m, 8H), 7.22 – 7.07 (m, 5H), 7.02 (d, J= 8.0 Hz, 2H), 6.97 – 6.89 (m, 2H), 3.78 (d, J = 13.4 Hz, 1H), 3.68 (d, J = 13.4 Hz, 1H). 13 C NMR (101 MHz, CDCl3) d 170.71, 166.73, 149.81, 149.53, 148.30, 139.31, 132.86,129.62, 129.44, 129.09, 129.03, 127.57, 126.92, 126.04, 125.97, 125.64,124.86, 123.12, 120.96, 120.71, 115.22, 61.18, 40.53.HRMS(ESI, m / z ): [M+Na] + Calculated for C 29 H 21 NO5Na + : 486.1318, found: 486.1310. Application Example 2 Under anhydrous and oxygen-free conditions, 0.3 mmol of 2-indole carbonate substrate, 5 mL of ultra-dry solvent toluene, and 240 mg of 4 Å molecular sieve (powder) were added to a dry and clean strip flask. After stirring at room temperature for 1 h, chiral nitrogen heterocyclic carbene nitrile oxidizing adduct catalyst A2 (0.03 mmol, 10 mol%) was added, and the mixture was stirred at -40°C. o The reaction was carried out at C for 24 hours. No further post-treatment was required. The solution could be directly filtered to remove the molecular sieve, concentrated, and then a certain amount of internal standard (trimethoxybenzene) was added. The reaction solution was then tested. 1 H NMR was used to calculate the yield to be 64%. The target product was obtained by column chromatography, and the product was tested by high performance liquid chromatography with an ee value of 89%.

[0038] The product obtained in Application Example 2 is the same as the product obtained in Application Example 1, and the characterization data are the same as those in Application Example 1.

[0039] Application Example 3 Under anhydrous and oxygen-free conditions, 0.3 mmol of 2-indole carbonate substrate, 5 mL of ultra-dry solvent toluene, and 240 mg of 4 Å molecular sieve (powder) were added to a dry and clean strip flask. After stirring at room temperature for 1 h, chiral nitrogen heterocyclic carbene nitrile oxidizing adduct catalyst B1 (0.03 mmol, 10 mol%) was added, and the mixture was stirred at -40°C.o The reaction was carried out at C for 24 hours. No further post-treatment was required. The solution could be directly filtered to remove the molecular sieve, concentrated, and then a certain amount of internal standard (trimethoxybenzene) was added. The reaction solution was then tested. 1 H NMR was used to calculate the yield to be 40%. The target product was obtained by column chromatography, and the product was tested by high performance liquid chromatography with an ee value of 95%.

[0040] The product obtained in Application Example 3 is the same as the product obtained in Application Example 1, and the characterization data are the same as those in Application Example 1.

[0041] Application Example 4 Under anhydrous and oxygen-free conditions, 0.3 mmol of carbonate-2-furan substrate, 7 mL of ultra-dry solvent toluene, and 240 mg of 4 Å molecular sieve (powder) were added to a dry and clean strip flask. After stirring at room temperature for 1 h, a chiral nitrogen heterocyclic carbene nitrile oxidizing adduct catalyst A1 (0.03 mmol, 10 mol%) was added, and the mixture was stirred at -40°C. o The reaction was carried out at C for 24 hours. No further post-treatment was required. The solution could be directly filtered to remove the molecular sieve, concentrated, and then a certain amount of internal standard (trimethoxybenzene) was added. The reaction solution was then tested. 1 H NMR was used to calculate the yield to be 88%. The target product was obtained by column chromatography, and the product was tested by high performance liquid chromatography with an ee value of 9%.

[0042] The structural characterization data of the product obtained from Example 4 are shown below: 1 H NMR (400 MHz, CDCl3) d 7.44 – 7.29 (m, 4H), 7.26 – 7.18 (m, 3H), 7.01 – 6.93 (m, 2H), 1.88 (s, 3H). 13 C NMR (101 MHz, CDCl3): d 173.8, 166.8, 153.4, 150.2, 130.3, 129.5, 128.2, 126.5, 124.9, 123.4, 121.0, 111.4, 54.0, 20.6. Application Example 5 Under anhydrous and oxygen-free conditions, 0.3 mmol of carbonate-2-furan substrate, 7 mL of ultra-dry solvent toluene, and 240 mg of 4 Å molecular sieve (powder) were added to a dry and clean strip flask. After stirring at room temperature for 1 h, a chiral nitrogen heterocyclic carbene nitrile oxidizing adduct catalyst A2 (0.03 mmol, 10 mol%) was added, and the mixture was stirred at -40°C. o The reaction was carried out at C for 24 hours. No further post-treatment was required. The solution could be directly filtered to remove the molecular sieve, concentrated, and then a certain amount of internal standard (trimethoxybenzene) was added. The reaction solution was then tested. 1 H NMR was used to calculate the yield to be 74%. The target product was obtained by column chromatography, and the product was tested by high performance liquid chromatography with an ee value of 1%.

[0043] The product obtained in Application Example 5 is the same as the product obtained in Application Example 4, and the characterization data are the same as those in Application Example 4.

[0044] Application Example 6 Under anhydrous and oxygen-free conditions, 0.3 mmol of carbonate-2-furan substrate, 7 mL of ultra-dry solvent toluene, and 240 mg of 4 Å molecular sieve (powder) were added to a dry and clean strip flask. After stirring at room temperature for 1 h, chiral nitrogen heterocyclic carbene nitrile oxidizing adduct catalyst B1 (0.03 mmol, 10 mol%) was added, and the mixture was stirred at -40°C. o The reaction was carried out at C for 24 hours. No further post-treatment was required. The solution could be directly filtered to remove the molecular sieve, concentrated, and then a certain amount of internal standard (trimethoxybenzene) was added. The reaction solution was then tested. 1 H NMR was used to calculate the yield to be 75%. The target product was obtained by column chromatography, and the product was tested by high performance liquid chromatography with an ee value of 11%.

[0045] The product obtained in Application Example 6 is the same as the product obtained in Application Example 4, and the characterization data are the same as those in Application Example 4.

[0046] The above embodiments are only used to illustrate the present invention. Any equivalent transformations and improvements made on the basis of the technical solutions of the present invention should not be excluded from the protection scope of the present invention.

Claims

1. A biphasic synergistic nitrogen heterocyclic carbene-nitrile oxide adduct catalyst, characterized in that, This nitrogen-heterocyclic carbene-nitrile oxide adduct catalyst consists of two chiral structural units: a chiral nitrogen-heterocyclic carbene unit and a chiral nitrile oxide unit. The general molecular formula of the nitrogen-heterocyclic carbene-nitrile oxide adduct catalyst is shown below: Among them, R 1 It can be methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, benzyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, or tert-butoxy; R 2 It is (R)-1-methylethoxy, (S)-1-methylethoxy, (R)-1-methylpropoxy, (S)-1-methylpropoxy, (R)-1-methylbutoxy, (S)-1-methylbutoxy, (R)-2-methylbutoxy, (S)-2-methylbutoxy, (R)-1-phenylethoxy or (S)-1-phenylethoxy; R 3 It can be hydrogen, Br, Cl, F, methyl or methoxy.

2. A method for preparing a biphasic synergistic nitrogen heterocyclic carbene-nitrile oxide adduct catalyst, characterized in that, In an inert atmosphere, a chiral nitrogen heterocyclic carbene precursor salt is deprotonated by potassium bis(trimethylsilyl)amino to generate an active carbene, which then undergoes a coupling reaction with a chiral nitric oxide. The reaction solution is filtered, concentrated, recrystallized in a solvent, and dried under vacuum to obtain the nitrogen heterocyclic carbene-nitric oxide adduct catalyst.

3. The preparation method according to claim 2, characterized in that, The inert atmosphere is argon or nitrogen.

4. The preparation method according to claim 2, characterized in that, The solvent is one or a mixture of two or more of the following: tetrahydrofuran, toluene, n-hexane, cyclohexane, dichloromethane, 1,2-dichloroethane, ethylene glycol dimethyl ether, 1,4-dioxane, diethyl ether, and acetonitrile.

5. The preparation method according to claim 2, characterized in that, The deprotonation reaction temperature is 0~30℃, and the reaction time is 0.2~24 h.

6. The preparation method according to claim 2, characterized in that, The molar ratio of the chiral nitrogen heterocyclic carbene precursor salt to the chiral oxynitrile is 1: (0.5~1.5).

7. The preparation method according to claim 2, characterized in that, The coupling reaction is carried out at a temperature of 0-30°C for 24-72 h.

8. The preparation method according to claim 2, characterized in that, The chiral nitrogen heterocyclic carbene precursor salt is: .

9. The application of the nitrogen heterocyclic carbene-oxidizing nitrile adduct catalyst according to claim 1 in the asymmetric acyl migration reaction of indole or furan, characterized in that, Molecular sieves are added to the asymmetric acyl migration reaction to control the mass ratio of nitrogen heterocyclic carbene-oxynitrile adduct catalyst to molecular sieve to be 1: (5~10).

10. The application according to claim 9, characterized in that, The molecular sieve is a 3Å molecular sieve, a 4Å molecular sieve, or a 5Å molecular sieve; The reaction temperature is -60~60℃, and the reaction time is 0.2~72 h.

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