Method for preparing chiral nitro compound

Abstract

The invention discloses a method for preparing a chiral nitro compound, and belongs to the technical field of organic synthesis and asymmetric catalysis. The method comprises the following step: in the presence of an N-heterocyclic carbene precursor, alkali and alcohol, in an organic solvent, enabling a 2-nitrobenzofuran compound as shown in a formula II to react with 5-chloromethylfurfural to obtain the chiral nitro compound as shown in a formula I. The N-heterocyclic carbene precursor is preferably a bifunctional hydrogen bond donor type precursor having a thiourea structure. The method is carried out at room temperature, does not need a metal catalyst, and has the advantages of mild conditions, simplicity and convenience in operation, wide substrate application range, high stereoselectivity, good yield and the like. The product prepared by the method is novel in structure, can be used as a chiral catalyst or a drug synthesis intermediate, and conforms to the concept of green chemistry and high-value utilization of biomass.

Description

A method for preparing chiral nitro compounds Technical Field

[0001] This invention relates to a method for preparing chiral nitro compounds, belonging to the fields of organic synthesis and asymmetric catalysis. Background Technology

[0002] The sustainable conversion of biomass resources into fuels and high-value-added chemicals is of great significance. Furfural derivatives (such as HMF, CMF, and AMF) are often considered important platform molecules connecting the biomass and chemical industries. However, research on using these platform molecules to catalyze asymmetric reactions to prepare high-value-added chiral compounds remains relatively limited. On the other hand, the dearomatization of aromatic compounds can directly convert planar aromatic raw materials into three-dimensional chiral frameworks. Existing research focuses more on electron-rich aromatic heterocyclic systems, while the development of catalytic asymmetric dearomatization of electron-deficient aromatic heterocyclic systems is relatively insufficient. There is an urgent need to develop new, efficient, universal, and stereoselective catalytic strategies. NHC catalysis can achieve various types of "polarity reversal" and diverse intermediate conversions via Breslow intermediates, and has been used in several asymmetric dearomatization reactions; however, there is still room for improvement in general methods targeting electron-deficient aromatic heterocyclic systems that also consider substrate availability and high stereoselectivity. Summary of the Invention

[0003] The purpose of this invention is to provide a method for preparing chiral nitro compounds by dearomatization, which has the advantages of being metal-free, having a wide substrate range, and being highly efficient. Furthermore, this method features mild reaction conditions, good stereoselectivity, and simple operation.

[0004] The method for preparing the chiral nitro compound of Formula I provided by the present invention includes the following steps:

[0005] The 2-nitrobenzene furan compound shown in Formula II is obtained by reacting it with 5-chloromethylfurfural in the presence of a nitrogen-containing heterocyclic carbene precursor, a base, and an alcohol in an organic solvent.

[0006]

[0007] Among them, R 1 R 2 R 3 R 4 They are independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy or C1-C6 alkylthio.

[0008] In the preparation method of this invention, the nitrogen-heterocyclic carbene precursor is a bifunctional hydrogen-bonding donor type nitrogen-heterocyclic carbene precursor with a thiourea structure; the nitrogen-heterocyclic carbene precursor is a compound having the structure shown in Formula III or its enantiomer: .

[0009] In the preparation method of the present invention, the alkali is an inorganic carbonate, selected from rubidium carbonate, cesium carbonate or potassium carbonate, preferably rubidium carbonate.

[0010] In the preparation method of this invention, the alcohol is a C1-C6 alcohol, preferably methanol or ethanol.

[0011] In the preparation method of this invention, the organic solvent is acetonitrile, tetrahydrofuran, 1,4-dioxane, toluene, dichloromethane, or a mixture thereof, preferably acetonitrile.

[0012] In the preparation method of the present invention, the molar ratio of the compound shown in Formula II to the 5-chloromethylfurfural is 1:1 to 1:3; and / or, the amount of the nitrogen heterocyclic carbene precursor is 0.05 to 0.5 equivalents of the molar amount of the compound shown in Formula II.

[0013] In the preparation method of this invention, the reaction is carried out at room temperature, and the reaction time is monitored by thin-layer chromatography until the 5-chloromethylfurfural raw material disappears.

[0014] Preferably, the present invention prepares compounds with the following structures:

[0015]

[0016]

[0017]

[0018] Compared with the prior art, the technical solution provided by the present invention has the following significant advantages: the products are novel and of high value: a series of chiral nitro compounds with novel structures have been successfully synthesized. These compounds have a three-dimensional chiral skeleton and can be used as catalysts for small organic molecules or key intermediates for drug synthesis, with broad application prospects.

[0019] The method is highly efficient and selective: Employing a bifunctional synergistic catalytic strategy of nitrogen-containing heterocyclic carbene / thiourea, this method achieves highly efficient and stereoselective dearomatization of electronically defective aromatic heterocycles (such as 2-nitrobenzofuran). Examples demonstrate that this method exhibits excellent yields (51%-79%), extremely high diastereoselectivity (dr>20:1), and good enantioselectivity (er up to 95:5).

[0020] The reaction conditions are mild and environmentally friendly: the entire reaction is carried out at room temperature, without the need for metal catalysts, thus avoiding heavy metal pollution; the reaction raw materials are readily available, and the operation is simple and safe.

[0021] Good substrate applicability: This method has good tolerance to a variety of substituents on nitroaromatic heterocycles (such as halogen, methoxy, methylthio, etc.), showing a wide range of substrate applicability.

[0022] In line with the concepts of green chemistry and biomass utilization: using 5-chloromethylfurfural, a biomass-derived platform molecule, as a key raw material, it is efficiently converted into high-value-added chiral chemicals, providing a new asymmetric synthesis route with atom economy for the high-value utilization of biomass resources. Attached Figure Description

[0023] Figure 1 shows the compound of formula I-1 prepared in Example 1 of this invention. 1 H-NMR spectrum.

[0024] Figure 2 shows the compound of formula I-1 prepared in Example 1 of this invention. 13 C-NMR spectrum.

[0025] Figure 3 is the HPLC chromatogram of the compound of formula I-1 prepared in Example 1 of this invention.

[0026] Figure 4 is an HPLC chromatogram of the racemic mixture of the compound shown in Formula I-1 prepared in Comparative Example 1 of this invention.

[0027] Figure 5 is a single-crystal structure diagram of the compound of formula I-10 prepared in Example 1 of the present invention. Detailed Implementation

[0028] Unless otherwise specified, the experimental methods used in the following examples are conventional methods.

[0029] Unless otherwise specified, all materials and reagents used in the following examples are commercially available.

[0030] This invention provides a series of chiral nitro compounds with the general formula I. These compounds are constructed using the biomass platform molecule 5-chloromethylfurfural (CMF) as the key structural unit through a catalytic asymmetric dearomatization reaction with a nitro aromatic heterocycle (such as 2-nitrobenzofuran), forming a chiral center with a three-dimensional structure. These compounds possess novel structures and can serve as high-value-added small-molecule organic catalysts or intermediates in drug synthesis.

[0031] The present invention is characterized by providing a method for preparing the above-mentioned chiral nitro compounds. This method employs a bifunctional synergistic catalytic system of nitrogen-containing heterocyclic carbene (NHC) and thiourea, achieving efficient catalytic asymmetric dearomatization of electronically defective aromatic heterocycles (such as 2-nitrobenzofuran) with 5-chloromethylfurfural under mild room temperature conditions and without metal involvement. Specifically, the reaction process is as follows: in the presence of a chiral carbene precursor, a base, and methanol, 5-chloromethylfurfural is reacted with the nitro aromatic heterocyclic compound shown in Formula II in acetonitrile solvent, yielding the target chiral product with high yield and high stereoselectivity.

[0032] This invention provides an efficient, green, and universal catalytic asymmetric synthesis method, which has significant theoretical implications and application prospects in the fields of organic synthetic chemistry, chiral drug development, and biomass conversion.

[0033] In the following examples, nuclear magnetic resonance (NMR) was measured using a Bruker NMR spectrometer, and high-performance liquid chromatography (HPLC) was performed using an Agilent 1100 series HPLC system.

[0034] In this invention, the absolute configuration of the chiral amine compounds was determined using a Bruker Smart APEXII CCD single-crystal diffractometer, and the single crystals were grown by slowly evaporating the compounds dissolved in a mixed solution of n-hexane and diethyl ether.

[0035] The synthetic routes for all the following embodiments of the present invention are as follows:

[0036] The meanings of each substituent are as described above.

[0037] However, those skilled in the art should understand that any catalyst suitable for this type of reaction is acceptable.

[0038] Example 1: A magnetic spool was added to a pre-dried 4 mL sample vial, followed by the addition of 2-nitrobenzuran II-1 (R 1 =H,R 2 =H,R 3 =H,R 4 =H)(0.1 mmol, 1 equivalent), 5-chloromethylfurfural (0.15 mmol, 1.5 equivalent), carbene precursor III (0.02 mmol, 0.2 equivalent), rubidium carbonate (0.12 mmol, 1.2 equivalent), were injected into 2 mL of acetonitrile, followed by the addition of methanol (8 μL, 2.0 equivalent). The mixture was stirred at room temperature until the alkenal disappeared as indicated by thin-layer chromatography. The reaction solution was then concentrated and purified by column chromatography to obtain the compound shown in I-1.

[0039]

[0040] The experimental data for I-1 are as follows: 1 H-NMR spectra and 13 The C-NMR spectra are shown in Figures 1 and 2, and the HPLC spectrum is shown in Figure 3: 23.8 mg, 79% yield, >20:1 dr, yellow oily liquid. [α]3 / 26 / 143118 D-44.6 (c0.37,CHCl3), 90:10 er, determined by HPLC [Daicel CHIRALPAK IC column, n-hexane / isopropanol = 80 / 20, 1.0 mL / min, λ = 254 nm, t(major) = 15.8 min, t(minor) = 20.1 min]; 1 H NMR(300MHz, CDCl3)δ 7.37-7.27 (m, 1H), 7.16 - 7.06 (m,2H), 7.06 - 6.99 (m, 2H), 6.40(d,J= 3.4 Hz,1H), 5.99 (d,J= 1.6 Hz, 1H), 4.15 (t,J= 7.6 Hz, 1H), 3.90 (s,3H), 3.14 (dd,J= 7.5, 3.4 Hz, 2H). 13 C NMR (126 MHz, CDCl3) δ158.9, 157.7,155.1, 144.3, 130.0, 125.2, 124.5, 123.5, 119.0, 110.9, 110.4, 109.1, 52.0,48.7, 33.0. IR(KBr)ν2907, 2852, 1757, 1732, 1220, 734. HRMS(ESI) m / z: [M+Na] + Theoretical value C 15 H 13 NNaO 6326.0635; measured value 326.0637.

[0041] Example 2: A magnetic spool was added to a pre-dried 4 mL sample vial, followed by the addition of 2-nitrobenzuran II-2 (R 1 =Cl,R 2 =H,R 3 =H,R 4=H)(0.1 mmol, 1 equivalent), 5-chloromethylfurfural (0.15 mmol, 1.5 equivalent), carbene precursor III (0.02 mmol, 0.2 equivalent), rubidium carbonate (0.12 mmol, 1.2 equivalent), were injected into 2 mL of acetonitrile, followed by the addition of methanol (8 μL, 2.0 equivalent). The mixture was stirred at room temperature until the alkenal disappeared as indicated by thin-layer chromatography. The reaction solution was then concentrated, and the compound shown in I-2 was obtained after separation and purification by column chromatography.

[0042]

[0043] The experimental data for I-2 are as follows: 21.7 mg, 64% yield, >20:1 dr, yellow oily liquid. [α]3 / 26 / 143120 D+16.7 (c0.48,CHCl3), 88:12 er, determined by HPLC [Daicel CHIRALPAK IC column, n-hexane / isopropanol = 80 / 20, 1.0 mL / min, λ = 254 nm, t (major) = 11.6 min, t (minor) = 14.5 min]; 1 HNMR(500 MHz, CDCl3) δ 7.28 – 7.22 (m, 1H), 7.10 (d,J= 3.4 Hz, 1H), 7.06 (dd,J= 8.1, 0.9 Hz, 1H), 6.98 (d,J= 8.1 Hz, 1H), 6.26 (d,J= 3.5 Hz, 1H), 6.10 (d,J= 1.5 Hz, 1H), 4.22 – 4.19 (m, 1H), 3.89 (s, 3H), 3.51 (dd,J= 15.8, 4.1 Hz,1H), 3.08 (dd,J= 15.7, 9.4 Hz, 1H). 13C NMR (126 MHz, CDCl3) δ 158.8, 158.6, 154.7, 144.5, 131.2, 130.5, 124.0, 123.8, 119.0, 110.3, 109.5, 108.5, 51.9, 48.9, 29.9. IR(KBr)v3020, 2922, 2851, 1727, 1648, 1614, 1593, 1569, 1522,1448, 1371, 1306, 1240, 1212, 1137, 1088, 1021, 988, 966, 910, 764, 669, 628,482.HRMS(ESI)m / z: [M+Na] + Theoretical value C 15 H 12 ClNNaO6360.0245; Measured value 360.0248. Example 3: Add a magnetic spool to a pre-dried 4mL sample vial, and add 2-nitrobenzenefuran II-3 (R 1 =Br,R 2 =H,R 3 =H,R 4 =H)(0.1 mmol, 1 equivalent), 5-chloromethylfurfural (0.15 mmol, 1.5 equivalent), carbene precursor III (0.02 mmol, 0.2 equivalent), rubidium carbonate (0.12 mmol, 1.2 equivalent), were injected into 2 mL of acetonitrile, followed by the addition of methanol (8 μL, 2.0 equivalent). The mixture was stirred at room temperature until the alkenal disappeared as indicated by thin-layer chromatography. The reaction solution was then concentrated and purified by column chromatography to obtain the compound shown in I-3.

[0044]

[0045] 24.9 mg, 65% yield, >20:1 dr, yellow oily liquid. [α]3 / 26 / 143125+34.4 (c0.49,CHCl3), 88:12 er, determined by HPLC [Daicel CHIRALPAK IC column, n-hexane / isopropanol = 80 / 20, 1.0 mL / min, λ = 254 nm, t (major) = 12.4 min, t (minor) = 15.4 min]; 1HNMR(500 MHz, CDCl3) δ 7.25 - 7.15 (m, 2H), 7.10 (d,J= 3.5 Hz, 1H), 7.01 (d,J=7.6 Hz, 1H), 6.25 (d,J= 3.4 Hz, 1H), 6.12 - 6.08 (m, 1H), 4.13 (dd,J= 9.5,3.9 Hz, 1H), 3.89 (s, 3H), 3.53 (dd,J= 15.8, 4.0 Hz, 1H), 3.10 (dd,J= 15.7,9.4 Hz, 1H). 13 C NMR(126 MHz, CDCl3) δ 158.8, 158.3, 154.7, 144.5, 131.4,126.9, 125.8, 118.9, 118.5, 110.2, 110.0, 108.2, 51.8, 50.1, 29.9. IR(KBr)v3583, 2926, 2361, 1728, 1568, 1522, 1443, 1370, 1306, 1239, 1206, 1137,1087, 1021, 987, 965, 926, 884, 800, 783, 762, 701, 654, 615, 527, 472. HRMS(ESI)m / z: [M+K] + Theoretical value C 15 H 12 BrKNO6419.9480; measured value 419.9480.

[0046] Example 4: A magnetic spool was added to a pre-dried 4 mL sample vial, followed by the addition of 2-nitrobenzuran II-4 (R 1 =H,R 2 =Ome, R 3 =H,R 4 =H)(0.1 mmol, 1 equivalent), 5-chloromethylfurfural (0.15 mmol, 1.5 equivalent), carbene precursor III (0.02 mmol, 0.2 equivalent), rubidium carbonate (0.12 mmol, 1.2 equivalent), were injected into 2 mL of acetonitrile, followed by the addition of methanol (8 μL, 2.0 equivalent). The mixture was stirred at room temperature until the alkenal disappeared as indicated by thin-layer chromatography. The reaction solution was then concentrated and purified by column chromatography to obtain the compound shown in I-4.

[0047]

[0048] 25.3 mg, 76% yield, >20:1 dr, yellow oily liquid. [α]3 / 26 / 143118 D-57.1 (c0.39,CHCl3), 89:11 er, determined by HPLC [Daicel CHIRALPAK IC column, n-hexane / isopropanol = 80 / 20, 1.0 mL / min, λ = 254 nm, t (major) = 23.5 min, t (minor) = 30.4 min]; 1 H NMR(500 MHz, CDCl3) δ 7.14 (d,J= 3.4 Hz, 1H), 6.99 (d,J= 8.7 Hz, 1H), 6.82 (dd,J= 8.7, 2.7 Hz, 1H), 6.58 (d,J= 2.6 Hz, 1H), 6.27 (d,J= 3.4 Hz, 1H), 5.96 (d,J= 1.3 Hz, 1H), 4.12 (t,J= 7.6 Hz, 1H), 3.91 (s, 3H), 3.74 (s, 3H), 3.20 -3.07 (m, 2H). 13 C NMR(126 MHz, CDCl3) δ 158.9, 156.1, 155.1, 151.6, 144.3,126.2, 119.0, 114.9, 111.1, 110.4, 110.3, 109.6, 55.9, 52.0, 49.1, 32.9. IR(KBr)v3566, 3022, 2254, 1717, 1651, 1540, 1521, 1456, 1374, 1230, 1036, 919,757, 667, 518. HRMS(ESI)m / z: [M+Na] + Theoretical value C 16 H 15 NNaO 7356.0741; Measured value 356.0742.

[0049] Example 5: A magnetic spool was added to a pre-dried 4 mL sample vial, followed by the addition of 2-nitrobenzuran II-5 (R 1 =H,R 2 =Cl,R 3 =H,R 4=H)(0.1 mmol, 1 equivalent), 5-chloromethylfurfural (0.15 mmol, 1.5 equivalent), carbene precursor III (0.02 mmol, 0.2 equivalent), rubidium carbonate (0.12 mmol, 1.2 equivalent), were injected into 2 mL of acetonitrile, followed by the addition of methanol (8 μL, 2.0 equivalent). The mixture was stirred at room temperature until the alkenal aldehyde disappeared as indicated by thin-layer chromatography. The reaction solution was then concentrated, and the compounds were purified by column chromatography to obtain the compounds shown in I-5.

[0050]

[0051] 24.7 mg, 73% yield, >20:1 dr, yellow oily liquid. [α]3 / 26 / 143120 D-58.7 (c0.46,CHCl3), 92:8 er, determined by HPLC [Daicel CHIRALPAK IC column, n-hexane / isopropanol = 80 / 20, 1.0 mL / min, λ = 254 nm, t (major) = 16.1 min, t (minor) = 21.5 min]; 1 HNMR(500 MHz, CDCl3) δ 7.28 (d,J= 2.3 Hz, 1H), 7.14 (d,J= 3.4 Hz, 1H), 7.04 –6.98 (m, 2H), 6.26 (d,J= 3.4 Hz, 1H), 6.01 (d,J= 1.6 Hz, 1H), 4.12 (t,J= 7.5Hz, 1H), 3.91 (s, 3H), 3.14 (h,J= 8.3 Hz, 2H). 13 C NMR(126 MHz, CDCl3) δ 158.8,156.4, 154.4, 144.5, 130.0, 128.6, 127.2, 124.7, 118.9, 110.5, 109.3, 52.0,48.7, 32.8. IR(KBr)v2921, 2851, 1726, 1649, 1568, 1522, 1473, 1437, 1370,1306, 1234, 1209, 1154, 1137, 1086, 1021, 989, 966, 925, 878, 816, 763, 681,512, 446. HRMS(ESI)m / z: [M+Na] + Theoretical value C 15 H 12ClNNaO6 360.0245; Measured value 360.0247.

[0052] Example 6: A magnetic spool was added to a pre-dried 4 mL sample vial, followed by the addition of 2-nitrobenzuran II-6 (R 1 =H,R 2 =Br,R 3 =H,R 4 =H)(0.1 mmol, 1 equivalent), 5-chloromethylfurfural (0.15 mmol, 1.5 equivalent), carbene precursor III (0.02 mmol, 0.2 equivalent), rubidium carbonate (0.12 mmol, 1.2 equivalent), were injected into 2 mL of acetonitrile, followed by the addition of methanol (8 μL, 2.0 equivalent). The mixture was stirred at room temperature until the alkenal disappeared as indicated by thin-layer chromatography. The reaction solution was then concentrated, and the compound shown in I-6 was obtained after separation and purification by column chromatography.

[0053]

[0054] 27.1 mg, 71% yield, >20:1 dr, yellow solid, melting point 93-95 °C. [α]3 / 26 / 143118 D -22.7 (c0.70, CHCl3), 91:9 er, determined by HPLC [Daicel CHIRALPAK IC column, n-hexane / isopropanol = 80 / 20, 1.0 mL / min, λ = 254 nm, t (major) = 16.4 min, t (minor) = 21.7 min]; 1 H NMR(500 MHz, CDCl3) δ 7.42 (dd,J= 8.5, 2.1 Hz, 1H), 7.19 - 7.10(m, 2H), 6.98 (d,J= 8.5 Hz, 1H), 6.26 (d,J= 3.5 Hz, 1H), 6.01 (d,J= 1.6 Hz,1H), 4.12 (t,J= 7.5 Hz, 1H), 3.91 (s, 3H), 3.20 - 3.08 (m, 2H). 13C NMR(126MHz, CDCl3) δ 158.9, 156.9, 154.4, 144.5, 132.9, 132.6, 127.64, 127.61,127.3, 118.9, 115.6, 112.5, 110.6, 109.1, 52.0, 48.6, 32.9. IR(KBr)v3022,2254, 1719, 1635, 1569, 1522, 1472, 1437, 1375, 1307, 1230, 1038, 920, 765,667, 517. HRMS(ESI)m / z: [MH] - Theoretical value C 15 H 11 O6NBr 379.9775; measured value 379.9757.

[0055] Example 7: A magnetic spool was added to a pre-dried 4 mL sample vial, followed by the addition of 2-nitrobenzuran II-7 (R 1 =H,R 2 =H,R 3 =Ome, R 4 =H)(0.1 mmol, 1 equivalent), 5-chloromethylfurfural (0.15 mmol, 1.5 equivalent), carbene precursor III (0.02 mmol, 0.2 equivalent), rubidium carbonate (0.12 mmol, 1.2 equivalent), were injected into 2 mL of acetonitrile, followed by the addition of methanol (8 μL, 2.0 equivalent). The mixture was stirred at room temperature until the alkenal disappeared as indicated by thin-layer chromatography. The reaction solution was then concentrated, and the compound shown in I-7 was obtained after separation and purification by column chromatography.

[0056]

[0057] 26.0 mg, 78% yield, >20:1 dr, yellow oily liquid. [α]3 / 26 / 143118 D -45.8 (c0.62,CHCl3), 95:5 er, determined by HPLC [Daicel CHIRALPAK IC column, n-hexane / isopropanol = 80 / 20, 1.0 mL / min, λ = 254 nm, t (major) = 24.6 min, t (minor) = 31.5 min]; 1HNMR(500 MHz, CDCl3) δ 7.13 (d,J= 3.4 Hz, 1H), 6.88 (d,J= 8.3 Hz, 1H), 6.66(s, 1H), 6.56 (dd,J= 8.3, 2.3 Hz, 1H), 6.24 (d,J= 3.4 Hz, 1H), 5.99 (d,J= 1.3Hz, 1H), 4.08 (t,J= 7.5 Hz, 1H), 3.90 (s, 3H), 3.80 (s, 3H), 3.13 - 3.07 (m,2H). 13 C NMR(126 MHz, CDCl3) δ 161.6, 159.04, 158.96, 155.3, 144.2, 124.6,119.0, 116.9, 110.3, 109.8, 109.4, 97.3, 55.7, 52.0, 48.3, 33.3. IR(KBr)v3566,3022, 2254, 1718, 1633, 1568, 1499, 1374, 1306, 1232, 1140, 1083, 920, 797,757, 667, 518. HRMS(ESI)m / z: [M+Na] + Theoretical value C 16 H 15 NNaO 7356.0741; Measured value 356.0741.

[0058] Example 8: A magnetic spool was added to a pre-dried 4 mL sample vial, followed by the addition of 2-nitrobenzuran II-8 (R 1 =H,R 2 =H,R 3 =SMe,R 4 =H)(0.1 mmol, 1 equivalent), 5-chloromethylfurfural (0.15 mmol, 1.5 equivalent), carbene precursor III (0.02 mmol, 0.2 equivalent), rubidium carbonate (0.12 mmol, 1.2 equivalent), were injected into 2 mL of acetonitrile, followed by the addition of methanol (8 μL, 2.0 equivalent). The mixture was stirred at room temperature until the alkenal aldehyde disappeared as indicated by thin-layer chromatography. The reaction solution was then concentrated and purified by column chromatography to obtain the compound shown in I-8.

[0059]

[0060] 24.8 mg, 71% yield, >20:1 dr, yellow solid, melting point 121-123 °C. [α]3 / 26 / 143118 D -68.3 (c0.50, CHCl3), 94:6 er, determined by HPLC [Daicel CHIRALPAK IC column, n-hexane / isopropanol = 80 / 20, 1.0 mL / min, λ = 254 nm, t (major) = 23.7 min, t (minor) = 31.0 min]; 1 H NMR(500 MHz, CDCl3) δ 7.13 (d,J= 3.4 Hz, 1H), 6.97 (s, 1H), 6.89(s, 2H), 6.24 (d,J= 3.4 Hz, 1H), 6.00 (d,J= 1.4 Hz, 1H), 4.12 - 4.07 (m, 1H), 3.91 (s, 3H), 3.12 (d,J= 7.5 Hz, 2H), 2.49 (s, 3H). 13 C NMR(126 MHz, CDCl3) δ158.9, 158.4, 155.0, 144.3, 141.5, 124.5, 121.8, 121.3, 119.0, 110.6, 109.3,108.4, 52.0, 48.5, 33.0, 15.7. IR(KBr)v3587, 3022, 2254, 1650, 1635, 1569,1540, 1521, 1507, 1436, 1420, 1375, 1231, 919, 796, 755, 668, 525. HRMS(ESI)m / z: [M+Na] + Theoretical value C 16 H 15 NNaO6S 372.0512; measured value 372.0515.

[0061] Example 9: A magnetic spool was added to a pre-dried 4 mL sample vial, followed by the addition of 2-nitrobenzuran II-9 (R 1 =H,R 2 =H,R 3 =Cl,R 4=H)(0.1 mmol, 1 equivalent), 5-chloromethylfurfural (0.15 mmol, 1.5 equivalent), carbene precursor III (0.02 mmol, 0.2 equivalent), rubidium carbonate (0.12 mmol, 1.2 equivalent), were injected into 2 mL of acetonitrile, followed by the addition of methanol (8 μL, 2.0 equivalent). The mixture was stirred at room temperature until the alkenal disappeared as indicated by thin-layer chromatography. The reaction solution was then concentrated, and the compound shown in I-9 was obtained after separation and purification by column chromatography.

[0062]

[0063] 17.1 mg, 51% yield, >20:1 dr, yellow oily liquid. [α]3 / 26 / 143118 D-44.8 (c0.63,CHCl3), 91:9 er, determined by HPLC [Daicel CHIRALPAK IC column, n-hexane / isopropanol = 80 / 20, 1.0 mL / min, λ = 254 nm, t (major) = 15.4 min, t (minor) = 20.2 min]; 1 HNMR(500 MHz, CDCl3) δ 7.15 - 7.08 (m, 1H), 7.02 (dd,J= 8.0, 1.8 Hz, 1H), 6.91(d,J= 8.0 Hz, 1H), 6.24 (d,J= 3.4 Hz, 1H), 6.02 (d,J= 1.7 Hz, 1H), 4.12 (t,J=7.5 Hz, 1H), 3.91 (s, 3H), 3.13 (d,J= 7.5 Hz, 2H). 13 C NMR (126 MHz, CDCl3) δ158.9, 158.4, 154.6, 144.4, 135.6, 125.1, 124.0, 123.8, 118.9, 111.8, 110.6,109.3, 52.0, 48.3, 32.9. IR(KBr)v3022, 2254, 1718, 1618, 1570, 1522, 1476,1437, 1420, 1374, 1308, 1228, 758, 667. HRMS(ESI)m / z: [MH] - Theoretical value C 15 H 11 O6NCl 336.0280; measured value 336.0263.

[0064] Example 10: A magnetic spool was added to a pre-dried 4 mL sample vial, followed by the addition of 2-nitrobenzuran II-10 (R). 1 = H, R 2 = H,R 3 = Br, R 4 = H)(0.1 mmol, 1 equivalent), 5-chloromethylfurfural (0.15 mmol, 1.5 equivalent), carbene precursor III (0.02 mmol, 0.2 equivalent), rubidium carbonate (0.12 mmol, 1.2 equivalent), were injected into 2 mL of acetonitrile, followed by the addition of methanol (8 μL, 2.0 equivalent). The mixture was stirred at room temperature until the alkenal aldehyde disappeared as indicated by thin-layer chromatography. The reaction solution was then concentrated, and the compound shown in I-10 was obtained after separation and purification by column chromatography.

[0065]

[0066] 25.2 mg, 66%, >20:1 dr, yellow solid, mp 137-138 °C. [α]3 / 26 / 143118 D -28.0 (c0.10, CHCl3), 90:10 er, determined by HPLC [Daicel CHIRALPAK IC column, n-hexane / isopropanol = 80 / 20, 1.0 mL / min, λ = 254 nm, t (major) = 15.0 min, t (minor) = 19.6 min]; 1 H NMR(500 MHz, CDCl3) δ 7.22 - 7.09 (m, 3H), 6.86 (d,J= 8.0 Hz, 1H), 6.24 (d,J= 3.4 Hz, 1H), 6.01 (d,J= 1.6 Hz, 1H), 4.10 (t,J= 7.5 Hz, 1H), 3.91(s, 3H), 3.13 (d,J= 7.5 Hz, 2H). 13C NMR(126 MHz, CDCl3) δ 158.9, 158.5, 154.5,144.4, 126.7, 125.5, 124.5, 123.1, 118.9, 114.7, 110.6, 109.2, 52.0, 48.3,32.8. IR(KBr)v3566, 3021, 2254, 1635, 1559, 1540, 1521, 1507, 1436, 1420, 1375, 1231, 1039, 919, 757, 667, 525. HRMS(ESI)m / z: [M+Na] + Theoretical value C 15 H 12 BrNNaO6403.9740; measured value 403.9741.

[0067] The single crystal structure diagram is shown in Figure 5. It can be seen that both chiral centers of the target product are in the R configuration.

[0068] Comparative Example 1: A pre-dried reaction tube was cooled to room temperature under vacuum, and 2-nitrobenzuran II-1 (R) was added under nitrogen protection. 1 = H, R 2 = H, R 3 = H, R 4 = H)(0.1 mmol, 1 equivalent), rac-III (0.02 mmol, 0.2 equivalents), cesium carbonate (0.12 mmol, 1.2 equivalents), 5-chloromethylfurfural (0.15 mmol, 1.5 equivalents), 2 mL of anhydrous acetonitrile was injected under air, followed by the addition of methanol (0.2 mmol, 2.0 equivalents). The mixture was stirred at room temperature until the 2-nitrobenzenefuran disappeared as a control by thin-layer chromatography (generally 8 hours). The reaction solution was concentrated, and the compound shown in rac-I-1 (which is a racemic mixture) was obtained after column chromatography separation and purification.

[0069]

[0070] The experimental data for rac-I-1 are as follows: 23.8 mg, 79% yield, yellow oily liquid. 1H NMR(300 MHz, CDCl3) δ 7.37 - 7.27 (m,1H), 7.16 - 7.06 (m, 2H), 7.06 - 6.99 (m, 2H), 6.40 (d,J= 3.4 Hz,1H), 5.99(d,J= 1.6 Hz, 1H), 4.15 (t,J= 7.6 Hz, 1H), 3.90 (s, 3H), 3.14 (dd,J= 7.5, 3.4Hz, 2H). 13 C NMR (126 MHz, CDCl3) δ158.9, 157.7, 155.1, 144.3, 130.0, 125.2, 124.5, 123.5, 119.0, 110.9, 110.4, 109.1, 52.0, 48.7, 33.0. IR(KBr)ν2907,2852, 1757, 1732, 1220, 734. HRMS(ESI) m / z: [M+Na] + Theoretical value C 15 H 13 NNaO 6326.0635; measured value 326.0637.

[0071] The HPLC chromatogram of the racemic mixture of the compound shown in Formula I-1 prepared in Comparative Example 1 is shown in Figure 4.

[0072] The chiral nitro compounds I-1 to I-10 prepared in this invention, due to the presence of multiple functional groups such as a chiral center, nitro group, ester group, furan ring, and potential formyl group in their structure, can participate in other asymmetric reactions as chiral ligands or organic catalysts. Preliminary tests show that compound I-1 exhibits certain catalytic activity (ee>80%) in a certain model of asymmetric Michael addition reaction. Furthermore, this type of structural framework is also commonly found in some biologically active molecules and can serve as a key intermediate in the synthesis of antibacterial, anti-inflammatory, and other drug active molecules.

[0073] The above description is merely a preferred embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any variations or substitutions that can be easily conceived by those skilled in the art within the technical scope disclosed in the present invention should be included within the scope of protection of the present invention. Therefore, the scope of protection of the present invention should be determined by the scope of the claims.

Claims

1. A method for preparing the chiral nitro compound shown in Formula I, comprising the following steps: in the presence of a nitrogen heterocyclic carbene precursor, a base and an alcohol, in an organic solvent, reacting the 2-nitrobenzofuran compound shown in Formula II with 5-chloromethylfurfural to obtain the compound; in, R 1 R 2 R 3 R 4 They are independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy or C1-C6 alkylthio.

2. The preparation method according to claim 1, characterized in that: The nitrogen heterocyclic carbene precursor is a bifunctional hydrogen bond donor type nitrogen heterocyclic carbene precursor with a thiourea structure.

3. The preparation method according to claim 2, characterized in that: The nitrogen-heterocyclic carbene precursor is a compound having the structure shown in Formula III or its enantiomer: 。 4. The preparation method according to any one of claims 1-3, characterized in that: The alkali is an inorganic carbonate, selected from rubidium carbonate, cesium carbonate, or potassium carbonate.

5. The preparation method according to any one of claims 1-4, characterized in that: The alcohol is a C1-C6 alcohol, preferably methanol or ethanol.

6. The preparation method according to any one of claims 1-5, characterized in that: The organic solvent is acetonitrile, tetrahydrofuran, 1,4-dioxane, toluene, dichloromethane, or a mixture thereof.

7. The preparation method according to any one of claims 1-6, characterized in that: The molar ratio of the compound shown in Formula II to the 5-chloromethylfurfural is 1:1 to 1:3; and / or, the amount of the nitrogen-heterocyclic carbene precursor is 0.05 to 0.5 equivalents of the molar amount of the compound shown in Formula II.

8. The preparation method according to any one of claims 1-7, characterized in that: The reaction was carried out at room temperature, and the reaction time was monitored by thin-layer chromatography until the 5-chloromethylfurfural raw material disappeared.

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