Method for enantioselective synthesis of NH-aziridine

Abstract

The invention discloses a method for enantioselective synthesis of NH-aziridine, which comprises the following steps: in the presence of a chiral phosphoric acid catalyst, reacting alpha-cyano heterocyclic conjugated olefin as shown in a formula (I) with N-acyloxyhydroxylamine in an organic solvent to obtain NH-aziridine as shown in a formula (II), according to the present invention, the method can be smoothly performed in the inert organic solvent at the temperature of-40-25 DEG C, the substrate can suitably cover pyridine, quinoline, benzimidazole, benzothiazole, benzoxazole and other N-heteroaromatic rings, the product yield is high, and the enantiomeric excess (ee) can be up to 99%. Inorganic additives (such as magnesium oxide) may be optionally added during the reaction to increase yield on individual substrates without affecting enantioselectivity. The method avoids the traditional multi-step sequence of nitrogen protection first and then deprotection, and has the advantages of economical steps, mild conditions, feasible amplification and the like.

Description

Technical Field

[0001] This invention belongs to the field of chiral organic catalysis and asymmetric synthesis technology, specifically relating to a method for the enantioselective construction of unprotected NH-azacyclopropanes from α-cyanoheterocyclic conjugated alkenes under chiral phosphoric acid catalysis. Background Technology

[0002] Azacyclic propane (also known as aziridine) is a three-membered nitrogen-containing small ring structure. Due to significant ring strain, it exhibits high reactivity and can form covalent bonds with macromolecules such as nucleic acids or proteins in the biological environment, thus holding important application value in antitumor and other drug molecules. Simultaneously, azircyclic propane is also a multifunctional synthetic equivalent in synthetic chemistry: it can participate in cycloaddition / ring-expansion transformations with substrates such as isocyanates to construct nitrogen-containing heterocyclic skeletons; it can also undergo stereoselective ring-opening under the action of nucleophiles to efficiently provide chiral amines and their derivatives. Therefore, developing methods for the enantioselective construction of azircyclic propane has ongoing research and industrial significance.

[0003] Existing publicly available technologies for the enantioselective conversion of olefins to the aziridine skeleton mainly include:

[0004] (1) Transition metal-catalyzed nitroene / related unit transfer route: This type of method can achieve aziridineation of a variety of substrates, but it often involves first constructing N-protected aziridine to improve the stability of the intermediate, and then deprotecting it, which leads to an increase in steps and limitations in atom economy and functional group tolerance; the applicability and selectivity to electron-deficient alkenes or nitrogen-containing heterocyclic α-alkenes are also unstable.

[0005] (2) Aza-Darzens type and multi-component tandem strategy: under certain conditions, enantioselective aziridine derivatives can be obtained, but the product forms are mostly protected structures such as carboxylic acid esters / carbamates. The system depends on specific oxidants / additives or customized conditions such as low temperature. The intermediate stability and separation and purification are difficult.

[0006] (3) Organic small molecule catalysis (e.g.) Acid / ion pair catalysis: Enantiotropic control can be achieved in some systems, but it is still rare to directly obtain unprotected (NH) azircyclic propanes, and they are easily affected by side reactions such as ring opening / rearrangement, resulting in racemization or decreased selectivity.

[0007] From a chemical perspective, unprotected (NH)-azacyclopropanes possess both small-ring strain and strong electrophilic / leaving characteristics, making them readily react with substrates or byproducts during construction.

[0008] Acid production can lead to side reactions, and the compounds are also prone to ring-opening or racemization during purification and storage. These problems are even more pronounced when the substrate is an electron-depleted olefin or a nitrogen-containing heterocyclic α-conjugated olefin, making the one-step, enantioselective direct acquisition of NH-azacyclopropane a long-standing challenge in publicly available technologies.

[0009] Existing asymmetric aziridine propanation methods mostly rely on a multi-step sequence of "N-protecting group introduction—cyclization—deprotection," and for α-cyanoheterocyclic conjugated olefin substrates, which present challenges in both electronic effects and steric hindrance, it is difficult to simultaneously achieve activation and stereocontrol. A universal and efficient solution remains to obtain unprotected (NH) chiral aziridine propane directly in a one-step, enantioselective manner under mild conditions.

[0010] In summary, while existing asymmetric aziridine propanation techniques have made progress, a universal and efficient solution remains lacking for the one-step, enantioselective direct acquisition of unprotected (NH) aziridine propanes under mild and scalable conditions, especially with substrates exhibiting challenging electronic properties and steric hindrance. Therefore, it is necessary to provide a novel asymmetric synthetic method capable of directly constructing NH-aziridine propanes without relying on protecting groups, while simultaneously considering substrate applicability, yield, and enantioselectivity. Summary of the Invention

[0011] To address the aforementioned technical problems in the prior art, the present invention aims to provide an enantioselective method for synthesizing NH-azacyclopropane.

[0012] The technical solution adopted in this invention is as follows:

[0013] An enantioselective synthesis method for NH-azacyclopropane involves reacting an α-cyanoheterocyclic conjugated olefin of formula (I) with an N-acyloxyhydroxylamine in an organic solvent in the presence of a chiral phosphoric acid catalyst to obtain NH-azacyclopropane of formula (II); the reaction formula is as follows:

[0014]

[0015] R in equation (I) 1 The N-heteroaromatic ring may be substituted or unsubstituted, and the N-heteroaromatic ring is selected from pyridine, quinoline, oxalool, benzimidazole, benzothiazole, benzoxazole, or pyrimidine. The substituents of the N-heteroaromatic ring are selected from C1-C6 alkyl, C1-C6 alkoxy, phenyl, halophenyl, halogen, trifluoromethyl, cyano, or nitro; R 2 It is cyano, ester, or trifluoromethyl, preferably cyano; R 3 Selected from one of the following: C1-C6 alkyl or alkoxy, C2-C6 alkenyl or alkynyl, aryl and its substitutes, nitrogen- or oxygen-containing five / six-membered heterocycles, ester or C1-C3 perfluoroalkyl.

[0016] Furthermore, the α-cyanoheterocyclic conjugated olefin represented by formula (I) is selected from one of the following:

[0017]

[0018] Further, the N-acyloxyhydroxylamine is selected from diphenylphosphonylhydroxylamine DPPH, p-nitrobenzoylhydroxylamine, p-trifluoromethylbenzoylhydroxylamine, p-trifluoromethylbenzenesulfonylhydroxylamine or per-2,4-dinitrobenzoylhydroxylamine; the molar ratio of N-acyloxyhydroxylamine to the compound of formula (I) is 1.0-5.0:1.0, preferably 2.0-2.5:1.0.

[0019] Furthermore, the chiral phosphoric acid catalyst is one of BINOL or 8H-BINOL derivatives, preferably one of the following:

[0020]

[0021] Further, the organic solvent is one or more of chlorobenzene, trifluorotoluene, toluene, xylene, dichloromethane, chloroform, acetonitrile, n-hexane, methyl tert-butyl ether (MTBE), and ethyl acetate, preferably chlorobenzene or trifluorotoluene.

[0022] Furthermore, the reaction temperature is -40 to 25°C.

[0023] Furthermore, when the N-acyloxyhydroxylamine is selected from diphenylphosphonohydroxylamine DPPH, the reaction temperature is 0-25℃, and the catalyst is selected from (R)-A1 to (R)-A10.

[0024] Furthermore, when the N-acyloxyhydroxylamine is selected from p-nitrobenzoylhydroxylamine, the reaction temperature is -40 to -20°C, and the catalyst is selected from (R)-A2, (R)-B2, and (R)-B3.

[0025] Furthermore, the concentration of compound (I) in the organic solvent is 0.10-0.20 M.

[0026] Furthermore, the molar amount of the chiral phosphoric acid catalyst is 3-5 mol% of the molar amount of the compound of formula (I).

[0027] Furthermore, an inorganic additive is added to the reaction system. The inorganic additive is selected from anhydrous magnesium sulfate or magnesium oxide and is used to control the effective water content of the system and / or suppress side reactions, thereby improving the yield on individual substrates.

[0028] The ratio of the inorganic additive to the compound of formula (I) is 0.3-2.4 g:1 mmol, preferably 1.0-1.5 g:1 mmol.

[0029] Furthermore, the following post-processing steps are included after the reaction: the solution is filtered through diatomaceous earth after the reaction, the filtrate is concentrated under reduced pressure and then purified by silica gel column chromatography, with the eluent being petroleum ether / ethyl acetate at a volume ratio of 3-10:1.

[0030] In a preferred embodiment of the present invention, a suitable chiral phosphate skeleton and solvent system can be selected based on the electronic and steric characteristics of the substrate, and inorganic additives (e.g., anhydrous magnesium sulfate or magnesium oxide) can be optionally added to improve the yield on individual substrates; the additives are not essential for the reaction to occur. Other specific parameters of the present invention (such as the range of substituents, catalyst type, feed ratio, temperature, and solvent selection) are detailed in the specific embodiments.

[0031] Compared with the disclosed technology, the present invention has the following beneficial effects:

[0032] (1) One-step direct access to NH-azacyclopropane: avoids the “protection-deprotection” sequence, improves step and atom economy, and reduces potential functional group incompatibility and scale-up costs.

[0033] (2) Balancing enantioselectivity and reaction efficiency: Enantioselective construction of three-membered rings was achieved under chiral phosphoric acid catalysis. Examples show that high enantiomeric excess can be obtained while maintaining good yield.

[0034] (3) Clear substrate applicability: It is applicable to a variety of nitrogen-containing heterocyclic α-cyanoconjugated olefin substrates (such as pyridine, quinoline, benzimidazole, benzothiazole, benzoxazole, pyrimidine, etc.), which verifies the universality of the method.

[0035] (4) Process-friendly and scalable: mild conditions and readily available components; optional inorganic additives for process optimization rather than essential elements, facilitating scale-up and green chemistry practices; the resulting NH-azacyclopropane can be further stereoselectively ring-opening / functionalized to obtain chiral amines and their drug-related derivatives. Detailed implementation method:

[0036] The following embodiments are used to further illustrate the technical solution of the present invention, enabling those skilled in the art to implement the present invention accordingly, but should not be construed as limiting the scope of protection of the present invention. Any non-substantial changes to the steps, conditions, or dosages made without departing from the spirit and substance of the present invention should be considered as falling within the scope of protection of the present invention.

[0037] I. Terminology Explanation

[0038] Unless otherwise specified: "Room temperature" means 20–30°C; "overnight" means 8–16 h. Temperature refers to the external bath temperature; amount of substance is expressed in mol; "equivalent," "mol%," etc., are based on substrate (I). "Optional / Optional" indicates that this element is not necessary for the reaction to occur and is used for process optimization.

[0039] II. General Analysis and Characterization Methods

[0040] 1. Melting point determination: The melting point was determined using a HyNeng MP430 video melting point apparatus to ensure purity and consistency.

[0041] 2. Nuclear Magnetic Resonance Spectroscopy (NMR): ¹H NMR and ¹³C NMR spectra were recorded using a Bruker 400MHz or 600MHz instrument. All ¹³C NMR spectra were obtained using broadband proton decoupling techniques to improve resolution. ¹H NMR chemical shifts are expressed in ppm and corrected for residual signal relative to the solvent.

[0042] 3. High-resolution mass spectrometry (HRMS): High-resolution mass spectrometry analysis was performed using an Agilent 6210TOF LC / MS with an ESI or EI ion source to ensure accurate mass determination.

[0043] 4. Polarimetry: The optical rotation is measured using an AUTOPOLV automatic polarimeter, typically at 20–25°C, to confirm the optical purity of the compound.

[0044] 5. High Performance Liquid Chromatography (HPLC): An Agilent 1100 HPLC system was used, equipped with Daicel Chiralpak IA, IB, IC, ID, IE, IF, IG, IJ columns or equivalent columns, to analyze enantiomeric excess values ​​(ee values) and ensure high-precision determination of enantioselectivity excess values.

[0045] The above brands / models are for illustrative purposes only and do not constitute a limitation; the key is that the parameters are reproducible and the standards are consistent.

[0046] III. Reagents, Catalysts and Additives

[0047] 3.1 Chiral phosphoric acid (CPA)

[0048] The chiral phosphoric acid used in the invention is BINOL or an 8H-BINOL derivative (such as TRIP type with a 3,3′-position bulky aryl substitution), which can be obtained commercially or prepared according to existing technology. Illustrative reference [1]: Akiyama et al., Org. Lett. 2009, 11, 2445–2447;

[0049] Reference [2]: Sewgobind et al., J.Org.Chem.2008,73,6405–6408;

[0050] Reference [3]: Akhani et al., J.Org.Chem.2014,79,2384–2396;

[0051] Reference [4]: ​​Saha et al., Chem. Eur. J. 2015, 21, 2348–2352;

[0052] Reference [5]: Jie Yang et al., ACS Catal. 2018, 8(2): 850–858.

[0053] Reference [6]: Ching-Nung et al., Angew. Chem. Int. Ed. 2021, 60(9): 4479-4484.

[0054] Reference [7]: Lei Yang et al., Chem. Sci. 2017, 8(2): 1344–1349.

[0055] Reference [8]: Nan Fajun et al., CN, 2020007342, 2020.01.09

[0056] Reference [9]: Scott et al., Chirality 2014, 26(7):344-355.

[0057] Reference

[10] : Michailidis et al., Chem. Eur. J. 2015, 21(14): 5561–5583.

[0058] 3.2 Nitrogen Sources and Additives

[0059] The nitrogen source is an N-acyloxyhydroxylamine (such as p-nitrobenzoylhydroxylamine, diphenylphosphohydroxylamine DPPH, etc.), which can be commercially available or prepared according to literature.

[0060] Optional additives: Anhydrous magnesium sulfate or magnesium oxide can improve yields on certain substrates; not essential for the reaction.

[0061] IV. General Operating Procedures

[0062] General Operating Procedure A (applicable to DPPH nitrogen source systems): In a 10 mL reaction tube, add the compound shown in formula (I) (0.2 mmol, 1.0 equiv), Binol phosphoric acid catalyst (R)-A7 (0.01 mmol, 0.05 equiv), and trifluorotoluene (2.0 mL, 0.1 M) sequentially. After stirring at 0 °C for ten minutes, add diphenylphosphohydroxylamine (DPPH) (0.48 mmol, 2.4 equiv) all at once, and continue the reaction at this temperature. Monitor the reaction progress by TLC. After the reaction is complete, filter the reaction solution through diatomaceous earth and concentrate it. The crude product is purified by column chromatography (eluting with petroleum ether / ethyl acetate).

[0063] General Procedure B (applicable to the p-nitrobenzoylhydroxylamine system): In a 10 mL reaction tube, add the compound shown in Formula (I) (0.2 mmol, 1.0 equiv), 8H-Binol phosphoric acid catalyst (R)-B3 (0.01 mmol, 0.05 equiv), and chlorobenzene (2.0 mL, 0.1 M) sequentially. After stirring at -40 °C for ten minutes, add p-nitrobenzoylhydroxylamine (0.48 mmol, 2.4 equiv) all at once, and continue the reaction at this temperature. Monitor the reaction progress by TLC. After the reaction is complete, filter the reaction solution through diatomaceous earth and concentrate it. The crude product is purified by column chromatography (eluting with petroleum ether / ethyl acetate). Optional process optimization: In General Procedure A or B, MgSO4 or MgO (1.0-1.5 g / mmol substrate) can be added all at once before adding the nitrogen source; only a few substrates showed yield increases, and ee was generally maintained.

[0064] V. Preparation and Sources of Catalysts

[0065] The chiral phosphoric acid catalysts (R)-A1~A10, (R)-B1~B3, (S)-C1~C2, etc. used in the embodiments of the present invention are all known or commercially available compounds in the prior art; for specific preparation, please refer to the common methods in the art and the above illustrative references.

[0066] VI. Post-processing and purification

[0067] The reaction solution is filtered through diatomaceous earth (or filter plate), and the filtrate is concentrated under reduced pressure; the crude product is purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3-10:1 (v / v), or adjusted according to polarity); recrystallization is performed if necessary.

[0068] VII. Representative Implementation Examples of Condition Optimization

[0069] Example 1: Screening and optimization of disubstituted reaction conditions

[0070] To determine the optimal reaction conditions for the method of this invention, the effects of factors such as catalyst, nitrogen source, solvent, and temperature on the reaction yield and enantioselectivity (ee value) were systematically investigated using the reaction of compound I-1 with a nitrogen source (target product II-1) with a chiral phosphoric acid catalyst of 5 mol%.

[0071] Procedure: In a 10 mL reaction tube, compound I-1 (45 mg, 0.2 mmol), Binol phosphoric acid catalyst (0.01 mmol, 0.05 equiv), and solvent (2.0 mL, 0.1 M) of formula (I) were added sequentially. After stirring at 0 °C or 25 °C for ten minutes, a nitrogen source (0.48 mmol, 2.4 equiv) was added all at once, and the reaction was continued at this temperature. The reaction progress was monitored by TLC. After the reaction was completed, the reaction solution was filtered through diatomaceous earth and concentrated. The crude product was purified by column chromatography.

[0072] 1.1 Screening of nitrogen sources for disubstituted substrates

[0073] The reaction of compound I-1 (45 mg, 0.2 mmol) with a nitrogen source (2.4 equivalents, 0.48 mmol) (target product II-1) was investigated under the following conditions: the dispersion concentration of compound I-1 in the solvent was 0.1 M, and the amount of chiral phosphoric acid catalyst was 5 mol% of the molar amount of compound I-1. The effects of different nitrogen sources on the reaction were investigated, and the results are shown in Table A.

[0074] Table A shows the effect of different nitrogen sources on the reaction.

[0075]

[0076] Conclusion: The screening results show that different nitrogen sources have a significant impact on the reaction. Among them, DPPH exhibits the best reaction performance in the reaction system.

[0077] 1.2 Screening of disubstituted substrate solvents

[0078] The reaction of compound I-1 (45 mg, 0.2 mmol) with DPPH (87 mg, 0.48 mmol) (target product II-1) was investigated under the following conditions: the dispersion concentration of compound I-1 in the solvent was 0.1 M, and the amount of chiral phosphoric acid catalyst was 5 mol% of the molar amount of compound I-1. The effects of different nitrogen sources on the reaction were examined, and the results are shown in Table B.

[0079] Table B shows the effect of different solvents on the reaction.

[0080]

[0081] Note: PhCl is chlorobenzene; DCM is dichloromethane; PhCF3 is trifluorotoluene; THF is tetrahydrofuran; EtOH is ethanol.

[0082] Conclusion: The screening results show that trifluorotoluene exhibits the best reaction performance in the reaction system.

[0083] 1.3 Screening of Disubstituted Substrate Catalysts

[0084] The reaction of compound I-1 (45 mg, 0.2 mmol) with DPPH (87 mg, 0.48 mmol) (target product II-1) was investigated under the following conditions: the dispersion concentration of compound I-1 in the solvent was 0.1 M, and the amount of chiral phosphoric acid catalyst was 5 mol% of the molar amount of compound I-1. The effects of different chiral phosphoric acid catalysts on the reaction were examined, and the results are shown in Table C.

[0085] Table C shows the effect of different chiral phosphoric acid catalysts on the reaction.

[0086]

[0087] Conclusion: The screening results show that different chiral phosphoric acid catalysts have a decisive influence on the reaction. Among them, (R)-A7 exhibits the best catalytic effect in the reaction system.

[0088] In summary, the optimization results show that the efficiency and selectivity of the method of this invention are highly dependent on the precise matching of the nitrogen source, solvent, and temperature. The optimal reaction temperature was determined to be 0°C using DPPH as the nitrogen source, (R)-A7 as the catalyst, and PhCF3 as the solvent.

[0089] Example 2: Screening and optimization of trisubstitution reaction conditions

[0090] To determine the optimal reaction conditions for the method of the present invention, the effects of catalyst, nitrogen source, solvent, temperature and other factors on the reaction yield and enantioselectivity (ee value) were systematically investigated using compound I-11 (56 mg, 0.2 mmol) and p-nitrobenzoylhydroxylamine (87 mg, 0.48 mmol) with a chiral phosphoric acid loading of 5 mol% (target product II-11) as a model.

[0091] Procedure: In a 10 mL reaction tube, I-11 (56 mg, 0.2 mmol), phosphoric acid catalyst (0.01 mmol, 0.05 equiv), and solvent (2.0 mL, 0.1 M) were added sequentially. After stirring at the appropriate temperature for ten minutes, p-nitrobenzoyl hydroxylamine (0.48 mmol, 2.4 equiv) was added all at once, and the reaction was continued at this temperature. The reaction progress was monitored by TLC. After the reaction was completed, the reaction solution was filtered through diatomaceous earth and concentrated. The crude product was purified by column chromatography (eluting with petroleum ether / ethyl acetate).

[0092] 2.1 Screening of trisubstituted substrate catalysts

[0093] The reaction of compound I-11 (56 mg, 0.2 mmol) with p-nitrobenzoyl hydroxylamine (87 mg, 0.48 mmol) was investigated under the following conditions: the dispersion concentration of compound I-11 in the solvent was 0.1 M, and the amount of chiral phosphoric acid catalyst was 5 mol% of the molar amount of compound I-11. The effects of different catalysts on the reaction were examined, and the results are shown in Table D.

[0094] Table D shows the effect of different chiral phosphoric acid catalysts on the reaction.

[0095]

[0096] Note: FPhCl is chlorobenzene.

[0097] Conclusion: The screening results show that different chiral phosphoric acid catalysts have a decisive influence on the reaction. Among them, (R)-B3 exhibits the best catalytic effect in the reaction system.

[0098] 2.2 Screening of trisubstituted substrate solvents and temperature

[0099] The reaction of compound I-11 (56 mg, 0.2 mmol) with p-nitrobenzoyl hydroxylamine (87 mg, 0.48 mmol) was investigated under the following conditions: the dispersion concentration of compound I-1 in the solvent was 0.1 M, and the amount of chiral phosphoric acid catalyst was 5 mol% of the molar amount of compound I-1. The effects of different solvents on the reaction were examined, and the results are shown in Table E.

[0100] Table E shows the effect of different solvents on the reaction.

[0101]

[0102] Note: PhCl is chlorobenzene; DCM is dichloromethane; PhCF3 is trifluorotoluene; THF is tetrahydrofuran; EtOH is ethanol.

[0103] Conclusion: The screening results show that the reaction effect is optimal when the solvent is PhCl and the temperature is -40℃.

[0104] In summary, the optimization results show that the efficiency and selectivity of the method of this invention are highly dependent on the precise matching of the nitrogen source, solvent, and temperature. The optimal reaction temperature was determined to be -40°C using p-nitrobenzoyl hydroxylamine as the nitrogen source, (R)-B3 as the catalyst, and PhCl as the solvent.

[0105] Example 3: Substrate universality study

[0106] 3.1 Substrate Expansion Based on General Operation Step A Following general operation step A, reactions were carried out using different disubstituted α-cyano heterocyclic conjugated alkenes (I-1 to I-10) as substrates. The results are shown in Table F:

[0107] Table F: Substrate Scope for Disubstituted Olefins

[0108]

[0109] 3.2 Substrate Expansion Based on General Operation Step B Following general operation step B, reactions were carried out using different trisubstituted α-cyano heterocyclic conjugated alkenes (I-11 to I-31) as substrates. The results are shown in Table H:

[0110] Table G: Substrate Scope of Trisubstituted Olefins

[0111]

[0112] Example 4: Product Derivative Study

[0113] After obtaining product II-1 under standard conditions, derivatization studies were conducted on product II-1. The procedures and results are as follows: II-1 (45 mg, 0.2 mmol) and THF (1.0 ml, 0.2 M) were added to a 4 ml reaction flask. 12N HCl was diluted to a concentration of 0.4 M with EtOAc, and 2.0 ml (0.8 mmol, 4.0 equiv.) was added to the reaction solution. The reaction was carried out at room temperature. The reaction progress was monitored by TLC, and the reaction ended in about 1.0 h. After the reaction, the product was extracted with EtOAc (3 ml × 3), dried over Na2SO4, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1-5:1, v / v). Product III-1 was obtained as a colorless oil. Characterization data are shown in "VIII. Characterization Data of Representative Products".

[0114]

[0115] VIII. Characterization data of representative products

[0116] Compound II-1:

[0117]

[0118] Compound II-1 is a white solid with a yield of 93% and an ee value of 94%. mp: 119.8–120.9 °C. 1 H NMR (400MHz, CDCl3) δ8.51(s,1H),7.88(dd,J=8.4,2.3Hz,1H),7.71(d,J=8.3Hz,1H),2.54(d,J=9.3Hz,0H),2.49(d,J=8.4Hz,1H),2.41(t,J=9.9Hz,1H). 13C NMR(101MHz, CDCl3)δ31.1,38.6,118.8,120.4,123.0,140.0,150.6,151.0.HRMS(ESI)m / z calcd.for C8H6BrN3[M+H] + :223.9834; found:223.9818.[α] D 20 =-110.1(c 1.0,CHCl3).ee: Chiralpak IE, n-hexane / EtOH=70:30, 1.0mL·min -1 , λ=220nm, t_R(major / minor)=9.215 / 8.116min.

[0119] Compound II-2:

[0120]

[0121] Compound II-2 is a colorless oily liquid with a yield of 64% and an ee value of 95%. 1 H NMR (400MHz, CDCl3) δ8.39 (s, 1H), 7.83 (d, J = 2.1Hz, 1H), 2.94 (s, 1H), 2.64 (s, 1H), 2.16 (s, 1H). 13 C NMR(100MHz, CDCl3)δ146.8,145.7,137.7,134.1,132.9,115.9,53.3,48.2.HRMS(ESI)m / z calcd.forC8H5Cl2N3[M+H] + :213.9933; found:213.9956.[α] D 20 =-272.4(c 1.0,CHCl3).ee: ChiralpakIB, n-hexane / EtOH=80:20, 1.0mL·min -1 , λ=220nm, t_R(major / minor)=16.188 / 15.010min.

[0122] Compound II-3:

[0123]

[0124] Compound II-3 is a yellow oily liquid with a yield of 95% and an ee value of 98%. 1H NMR (400MHz, CDCl3) δ1.3(t,J=7.1Hz,2H),2.4(s,1H),2.7(d,J=10.5Hz,1H),4.2(dq,J=7.1,10.7Hz,1 H),4.4(dq,J=7.1,10.7Hz,3H),7.2–7.4(m,2H),7.7–7.7(m,1H),7.8–7.8(m,1H),8.2(d,J=8.1Hz,1H). 13 C NMR(101MHz, CDCl3)δ-0.2,13.9,21.5,35.1,37.6,62.8,112.9,120.5,124.5,125. 4,128.0,129.7,132.3,134.6,141.1,145.8,149.3,170.8.HRMS(ESI)m / zcalcd.for C 19 H 19 N3O4S[M+H] + :386.1169; found:386.1169.[α] D 20 =-42.3(c 1.0,CHCl3).ee: Chiralpak IE, n-hexane / EtOH=70:30, 1.0mL·min -1 , λ=220nm, t_R(major / minor)=8.942 / 13.185min.

[0125] Compound II-11:

[0126]

[0127] Compound II-11 is a white solid with a yield of 95% and an ee value of 97%. The mp value is 93.4-95.8℃. 1 H NMR (400MHz, CDCl3) δ8.52 (d, J=2.3Hz, 1H), 7.89 (dd, J=8.4, 2.3Hz, 1H), 7.71 (d, J=8.4Hz,1H),4.33(d,J=6.0Hz,1H),3.52(s,3H),3.48(s,3H),2.88–2.76(m,2H). 13 C NMR(101MHz, CDCl3)δ151.0,149.9,123.1,120.7,117.3,104.2,55.3,54.7,34.4.HRMS(ESI)m / zcalcd.for C 11 H 12 BrN3O2[M+H]+ :298.0198; found:298.0186.[α] D 20 =-458.2(c 1.0,CHCl3).Chiralpak IE, n-hexane / EtOH=70:30, 1.0mL·min -1 , λ=254nm, t_R(major / minor)=9.680 / 10.428min.

[0128] Compound II-12:

[0129]

[0130] Compound II-12 is a white solid with a yield of 99% and an ee value of 95%. mp: 89.5-112.1℃. 1 H NMR (400MHz, CDCl3) δ8.19(d,J=8.5Hz,1H),8.03(s,1H),7.94(d,J=8.6Hz,1H),7.86 –7.76(m,2H),4.46(d,J=6.3Hz,1H),3.59(s,3H),3.53(s,3H),2.93(d,J=6.3Hz,1H). 13 C NMR (101MHz, CDCl3) δ151.8,145.9,136.9,134.1,130.5,129.8,128.9,121.2,119.7,117.6,104.02,54.8,49.8,34.8.HRMS(ESI)m / z calcd.for C 15 H 14 BrN3O2[M+H] + :348.0330; found:348.0342.[α] D 20 =-108.8(c 1.0,CHCl3).ee: Chiralpak IE, n-hexane / EtOH=70:30, 1.0mL·min -1 , λ=254nm, t_R(major / minor)=12.439 / 14.862min.

[0131] Compound II-13:

[0132]

[0133] Compound II-13 is a white solid with a yield of 99% and an ee value of 87%. mp: 137.0–160.9 °C.1 H NMR (400MHz, DMSO) δ7.84–7.77(m,1H),7.81–7.74(m,1H),7.46(pd,J=7.4,1.5Hz,2H),4.65(s,1H),4.25(s,1H),3.44(s,3H),3.42(s,3H). 13 C NMR(101MHz,DMSO)δ159.2,150.8,140.6,126.7,125.8120.5,116.2,111.7,103.9,54.7,54.4,46.1.HRMS(ESI)m / zcalcd.for C 13 H 13 N3O3[M+H] + :260.1022; found 260.1030.[α] D 20 =-111.7(c 1.0,CHCl3).ee: Chiralpak IH, n-hexane / EtOH=70:30, 1.0mL·min -1 , λ=254nm, t_R(major / minor)=11.339 / 13.294min.

[0134] Compound II-14:

[0135]

[0136] Compound II-14 is a white solid with a yield of 81% and an ee value of 92%. mp: 130.8–141.0 °C. 1 H NMR (400MHz, DMSO) δ8.13(d,J=8.0Hz,1H),8.05(d,J=7.6Hz,1H),7.57(t,J=7.0Hz,1H), 7.50(t,J=7.4Hz,1H),5.02(s,1H),4.46(s,1H),3.44(s,3H),3.42(s,3H),2.95(s,1H). 13 CNMR(101MHz, CDCl3)δ157.8,139.6,132.0,131.1,128.1,127.8,121.5,107.5,59.3,53.8,5.3.HRMS(ESI)m / z calcd.for C 13 H13N3O2S[M+H] + :276.0796; found:276.0801.[α] D 20=-430.2(c 1.0,CHCl3).ee: Chiralpak IE, n-hexane / EtOH=70:30, 1.0mL·min -1 , λ=254nm, t_R(major / minor)=14.729 / 17.217min.

[0137] Compound II-20:

[0138]

[0139] Compound II-20 is a yellow solid with a yield of 83% and an ee value of 90%. mp: 176.1-176.9℃. 1 H NMR (600MHz, CDCl3) δ8.52(d,J=2.1Hz,1H),7.88(dd,J=8.4,2.3Hz,1H),7.67(d,J=8.4Hz,1H),3. 69(t,J=6.0Hz,2H),2.57(t,J=6.4Hz,1H),1.87–1.74(m,2H),1.66(ttd,J=15.5,7.8,5.0Hz,4H). 13 C NMR(151MHz, CDCl3)δ151.1,150.9,140.1,122.8,120.3,118.1,62.6,49.3,37.0,32.2,31.2,23.3.HRMS(ESI)m / z calcd.for C 12 H 14 BrN3O[M+H] + :296.0393; found:296.0393.[α] D 20 =+80.8(c 1.0,CHCl3).ee: Chiralpak IE, n-hexane / EtOH=90:10, 1.0mL·min -1 , λ=254nm, t_R(major / minor)=37.392 / 40.510min.

[0140] Compound II-21:

[0141]

[0142] Compound II-21 is a colorless oily liquid with a yield of 73% and an ee value of 96%. 1H NMR (600MHz, CDCl3) δ8.53(s,1H),7.90(d,J=8.3Hz,1H),7.69(d,J=8.3Hz,1H),3.57(t,J=79.6Hz,2H),3.01(s,3H),2.78(s,2H),1.45(s,9H). 13 C NMR (151MHz, CDCl3) δ151.1,150.4,140.2,122.9,120.6,117.7,80.4,50.0,47.3,35.7,29.8,28.6,0.1.HRMS(ESI)m / z calcd.forC 15 H 19 BrN4O2[M+H] + :367.0768; found:367.0764.[α] D 20 =-62.4(c 1.0,CHCl3).ee: Chiralpak IE, n-hexane / EtOH=99:1, 1.0mL·min -1 , λ=254nm, t_R(major / minor)=29.821 / 28.282min.

[0143] Compound II-22:

[0144]

[0145] Compound II-22 is a colorless oily liquid with a yield of 87% and an ee value of 94%. 1 H NMR (600MHz, CDCl3) δ3.5(d,J=9.8Hz,1H),3.6(d,J=9.8Hz,1H),7.8(d,J=8.4Hz,1H),8.0(dd,J=2.3,8.4Hz,1H),8.6–8.7(m,1H). 13 C NMR(151MHz, CDCl3)δ37.2,59.4,95.1,115.2,121.7,123.5,140.7,148.5,151.2.HRMS(ESI)m / z calcd.for C9H5BrCl3N3[M+H] + :339.8805; found:339.8805.[α] D 20 =-458.2(c 1.0,CHCl3).ee: Chiralpak IE, n-hexane / EtOH=70:30, 1.0mL·min -1, λ=254nm, t_R(major / minor)=5.630 / 6.585min.

[0146] Compound II-23:

[0147]

[0148] Compound II-23 is a colorless, oily liquid in 82% yield with an ee value of 98%. mp: 175.3–181.8 °C. 1 HNMR (400MHz, CDCl3) δ2.8(d,J=9.7Hz,1H),2.9(dt,J=6.0,11.4Hz,1H),3.7(dd,J=6.7,10.9Hz,1H),3.9(dd,J=4.9,10 .9Hz,1H),4.6(d,J=1.6Hz,2H),7.3–7.4(m,5H),7.7(d,J=8.3Hz,1H),7.9(dd,J=2.3,8.4Hz,1H),8.5(d,J=2.2Hz,1H). 13 C NMR (101MHz, CDCl3) δ36.0,47.3,70.3,73.8,117.4,120.4,123.0,127.9,128.0,128.5,137.6,140.0,150.2,150.8.HRMS(ESI)m / z calcd.for C 16 H 14 BrN3O[M+H] + :344.0393; found:344.0393.[α] D 20 =-92.0(c 1.0,CHCl3).ee: Chiralpak IE, n-hexane / EtOH=70:30, 1.0mL·min -1 , λ=254nm, t_R(major / minor)=8.868 / 8.417min.

[0149] Compound III-1

[0150]

[0151] Compound III-1 is a colorless oily liquid with a yield of 66% and an ee value of 94%. 1 H NMR (400MHz, CDCl3)

[0152] δ8.72(d,J=2.3Hz,1H),7.96(dd,J=8.4,2.3Hz,1H),7.70(d,J=8.4Hz,1H),4.02(d,J=11.1Hz,1H),3.79(d,J=11.1Hz,1H),2.55(s,2H). 13 C NMR (151MHz, CDCl3) δ153.98,151.00,140.20,122.13,121.68,119.98,60.27,51.26.ee: Chiralpak IE, n-hexane / EtOH=70:30, 1.0mL·min -1 , λ=280nm, t_R(major / minor)=9.163 / 7.486min.

[0153] Through this series of embodiments, the present invention demonstrates its high efficiency and broad applicability to various structural substrates, while maintaining high yield and high stereoselectivity. The descriptions herein are merely examples of implementations of the inventive concept; the scope of protection of the present invention should not be limited to the specific forms described, but should include all variations, equivalents, or modifications within the spirit and scope of the invention.

Claims

1. A process for the enantioselective synthesis of NH-aziridines, characterized in that: The alpha-cyano heterocyclic conjugated ene represented by formula (I) is reacted with N-acyloxyhydroxylamine in an organic solvent in the presence of a chiral phosphoric acid catalyst to obtain NH-aziridine represented by formula (II); the reaction formula is as follows: R in formula (I) is selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6alkoxy, C2-C6alkenyl, C2-C6alkynyl, aryl, and substituted versions thereof, a nitrogen or oxygen containing five / six membered heterocycle, an ester group, or a C1-C3perfluoroalkyl group. 1 is a substituted or unsubstituted N-heteroaromatic ring, the N-heteroaromatic ring being selected from the group consisting of pyridine, quinoline, oxathin, benzimidazole, benzothiazole, benzoxazole, or pyrimidine, the substituents of the N-heteroaromatic ring being selected from the group consisting of C1-C6alkyl, C1-C6alkoxy, phenyl, halophenyl, halogen, trifluoromethyl, cyano, or nitro; R 2 is cyano, ester, or trifluoromethyl, preferably cyano; R 3 is selected from the group consisting of C1-C6alkyl or alkoxy, C2-C6alkenyl or alkynyl, aryl and substituted versions thereof, a nitrogen or oxygen containing five / six membered heterocycle, an ester group, or a C1-C3perfluoroalkyl group.

2. A process for the enantioselective synthesis of NH-aziridines according to claim 1, characterized by: The alpha-cyano heterocyclic conjugated ene represented by formula (I) is selected from one of the following:

3. A process for the enantioselective synthesis of NH-aziridines according to claim 1, characterized by: The N-acyloxyhydroxylamine is selected from diphenylphosphinyl hydroxylamine DPPH, p-nitrobenzoyl hydroxylamine, p-trifluoromethyl benzoyl hydroxylamine, p-trifluoromethyl phenylsulfonyl hydroxylamine or per-2,4-dinitrobenzoyl hydroxylamine; the molar ratio of N-acyloxyhydroxylamine to the compound of formula (I) is 1.0-5.0:1.0, preferably 2.0-2.5:1.

0.

4. A process for the enantioselective synthesis of NH-aziridines according to claim 1, characterized by: The chiral phosphoric acid catalyst is one of BINOL or 8H-BINOL derivatives, preferably one of the following:

5. A process for the enantioselective synthesis of NH-aziridines according to claim 1, characterized by: The organic solvent is one or more of chlorobenzene, trifluorotoluene, toluene, xylene, dichloromethane, chloroform, acetonitrile, n-hexane, methyl tert-butyl ether MTBE, ethyl acetate, preferably chlorobenzene or trifluorotoluene.

6. A process for the enantioselective synthesis of NH-aziridines as claimed in claim 1, wherein: The reaction temperature is -40-25℃.

7. A process for the enantioselective synthesis of NH-aziridines as claimed in claim 1, wherein: The concentration of the compound of formula (I) in the organic solvent is 0.10-0.20M.

8. A process for the enantioselective synthesis of NH-aziridines as claimed in claim 1, wherein: The molar amount of the chiral phosphoric acid catalyst is 3-5mol% of the molar amount of the compound of formula (I).

9. A process for the enantioselective synthesis of NH-aziridines as claimed in claim 1, wherein: An inorganic additive is further added in the reaction system, and the inorganic additive is selected from anhydrous magnesium sulfate or magnesium oxide, which is used to control the effective water content of the system and / or inhibit side reactions; The feeding ratio of the inorganic additive to the compound of formula (I) is 0.3-2.4g:1mmol, preferably 1.0-1.5g:1mmol.

10. A process for the enantioselective synthesis of NH-aziridines as claimed in claim 1, wherein: The following post-processing steps are further included after the reaction is completed: after the reaction is completed, the reaction mixture is filtered through diatomite, and the filtrate is concentrated under reduced pressure and then purified by silica gel column chromatography, and the eluent is a mixed solvent of petroleum ether / ethyl acetate=3-10:1 by volume.

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