Chiral indoline compound and synthesis method thereof

Abstract

The application belongs to the technical field of chiral synthesis, and particularly relates to a chiral indoline compound and a synthesis method thereof. A commercially available palladium catalyst and a chiral biphosphine ligand are used to perform asymmetric hydrogenation on a racemic 2-substituted indole compound substrate, so that a series of chiral indoline compounds containing continuous chiral centers outside the ring are obtained. Through the method, the chiral indoline compound can be simply and efficiently synthesized. The method has the advantages of high yield, low cost, mild conditions, green and environmentally-friendly process, high enantioselectivity and high diastereoselectivity.

Description

Technical Field

[0001] This invention belongs to the field of chiral synthesis technology, specifically relating to a chiral indoline compound and its synthesis method. Background Technology

[0002] Chiral indoline compounds form the core framework of many natural alkaloids or bioactive molecules, and for this reason, their synthesis has attracted widespread attention. Among numerous methods, the asymmetric hydrogenation of N-heterocyclic aromatic hydrocarbons has become a very simple and practical method for preparing chiral indoline compounds.

[0003] In 2000, Yoshihiko Ito reported the asymmetric hydrogenation of chiral indoline compounds using rhodium as a catalyst and acetyl-protected 2-position substituted indoles as substrates (J. Am. Chem. Soc. 2000, 122, 7614-7615). While this route achieved asymmetric hydrogenation of indoles with relatively good enantioselectivity, it required the preparation of substrates with protecting groups (see reaction formula I below).

[0004]

[0005] Compared to the methods mentioned above, the direct asymmetric hydrogenation of nitrogen-unprotected indoles presents certain challenges. In 2018, Zhang Xumu's research group reported the asymmetric hydrogenation of 2-substituted indoles under the action of transition metal rhodium and chiral bisphosphine ligand ZhaoPhos (see reaction formula II below).

[0006]

[0007] In summary, the reported synthesis of chiral indoline compounds via asymmetric hydrogenation often requires the prior preparation of indole compounds with protecting groups. Furthermore, most of the synthesized chiral indoline compounds contain only one chiral center.

[0008] Compared to preparing chiral indoline compounds with a single chiral center, synthesizing chiral indoline compounds with two unprotected chiral centers presents a significant challenge. The synthesis of indoline compounds with two consecutive chiral centers is difficult and rarely reported. In the reported methods for synthesizing indoline compounds with two chiral centers, the substrate is always 2,3-disubstituted indole, resulting in two chiral centers located within the ring, which has considerable limitations.

[0009] Therefore, existing technologies still need to be improved and developed. Summary of the Invention

[0010] In view of the shortcomings of the prior art, the purpose of this invention is to provide a chiral indoline compound and a method for synthesizing the same, in order to solve the problems of the difficulty in synthesizing indoline compounds containing two consecutive chiral centers, and the fact that both chiral centers are located within the compound ring.

[0011] The technical solution of the present invention is as follows:

[0012] A first aspect of the present invention provides a method for synthesizing chiral indoline compounds, comprising the steps of:

[0013] Under an inert atmosphere, palladium catalyst, acid, chiral bisphosphine ligand and solvent are mixed and stirred to obtain a first mixture;

[0014] A 2-substituted indole compound was added to the first mixture to obtain a second mixture;

[0015] The second mixture was reacted under a hydrogen atmosphere to obtain chiral indoline compounds;

[0016] The reaction formula for obtaining chiral indoline compounds from the 2-substituted indole compounds is shown below:

[0017]

[0018] In the formula: R 1 R is an alkyl, cycloalkyl, substituted aryl, or heterocyclic aryl group. 2 R is alkyl, benzyl, or substituted aryl. 3 It can be alkyl, aryl, heterocyclic aryl, alkoxy, or halogen, etc.

[0019] Optionally, the stirring conditions are: stirring at room temperature for 40 to 80 minutes.

[0020] Optionally, the acid is one of trifluoroacetic acid, acetic acid, p-toluenesulfonic acid, L-camphorsulfonic acid, trifluoromethanesulfonic acid, and sulfuric acid.

[0021] Optionally, the molar ratio of the palladium catalyst to the 2-substituted indole compound ranges from 0.01 mol% to 10 mol%, the molar ratio of the chiral bisphosphine ligand to the 2-substituted indole compound ranges from 0.02 mol% to 20 mol%, and the molar ratio of the acid to the 2-substituted indole compound ranges from 4.0 to 10.0 equivalents.

[0022] Optionally, the chiral bisphosphine ligand has one of the following structural formulas:

[0023]

[0024] Optionally, the solvent is one or more of dichloromethane, tetrahydrofuran, and toluene.

[0025] Optionally, the reaction temperature is 25-100℃, and the reaction time is 12-72h.

[0026] Optionally, the pressure of the hydrogen gas is 20-80 bar.

[0027] In a second aspect, the present invention provides a chiral indoline compound, wherein it is synthesized using the synthetic method described in the present invention;

[0028] Alternatively, the structural formula of the chiral indoline compound is shown below:

[0029]

[0030] Where: R 1 R is an alkyl, cycloalkyl, substituted aryl, or heterocyclic aryl group. 2 R is alkyl, benzyl, or substituted aryl. 3 It can be alkyl, aryl, heterocyclic aryl, alkoxy, or halogen.

[0031] Optionally, the chiral indoline compound has one of the following structural formulas:

[0032]

[0033] Beneficial Effects: This invention provides a chiral indoline compound and its synthetic method. The invention utilizes a commercially available palladium catalyst and chiral bisphosphine ligands to asymmetricly hydrogenate racemic 2-substituted indoline substrates, yielding a series of chiral indoline compounds containing continuous chiral centers outside the ring. This method provides a simple and efficient way to synthesize chiral indoline compounds. Furthermore, this method offers advantages such as high yield, low cost, mild conditions, environmentally friendly process, high enantioselectivity, and high diastereoselectivity. Attached Figure Description

[0034] Figure 1 This is a schematic diagram of the single-crystal structure of compound 2a synthesized in Example 1. Detailed Implementation

[0035] This invention provides a chiral indoline compound and its synthetic method. To make the objectives, technical solutions, and effects of this invention clearer and more explicit, the invention is further described in detail below. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the invention.

[0036] It should be noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of exemplary embodiments according to the invention. As used herein, the singular form is intended to include the plural form as well, unless the context clearly indicates otherwise. Furthermore, it should be understood that when the terms "comprising" and / or "including" are used in this specification, they indicate the presence of features, steps, operations, devices, components, and / or combinations thereof.

[0037] Most chiral indolines synthesized in the prior art contain only one chiral center, and the synthesis of indoline compounds with two consecutive chiral centers is difficult and rarely reported. In the reported methods for synthesizing indoline compounds with two chiral centers, the substrate is always 2,3-disubstituted indole, and the two chiral centers are located inside the ring, which has significant limitations.

[0038] Based on this, embodiments of the present invention provide a method for synthesizing chiral indoline compounds, comprising the following steps:

[0039] Under an inert atmosphere, a palladium catalyst (such as Pd(CF3CO2)2), an acid, a chiral bisphosphine ligand, and a solvent are mixed and stirred to obtain a first mixture.

[0040] A 2-substituted indole compound was added to the first mixture to obtain a second mixture;

[0041] The second mixture was reacted under a hydrogen atmosphere to obtain chiral indoline compounds;

[0042] The reaction formula for obtaining chiral indoline compounds from the 2-substituted indole compounds is shown below:

[0043]

[0044] In the formula: R 1 R is an alkyl, cycloalkyl, substituted aryl, or heterocyclic aryl group. 2 R is alkyl, benzyl, or substituted aryl. 3 It can be alkyl, aryl, heterocyclic aryl, alkoxy, or halogen, etc.

[0045] This invention provides a method for synthesizing chiral indoline compounds. Using readily available racemic 2-substituted indoles as substrates, palladium as a catalyst, and chiral bisphosphine as a ligand, this method synthesizes a series of novel chiral indoline compounds with continuous chiral centers outside the ring and potential pharmaceutical value through dynamic kinetic asymmetric hydrogenation. The method features mild reaction conditions, utilizes hydrogen as an inexpensive and readily available hydrogen source, has good substrate versatility, and can obtain the target products with excellent yields, enantioselectivity, and diastereoselectivity. Even at gram-scale, the reaction still exhibits good conversion and excellent enantioselectivity, demonstrating strong practicality.

[0046] It should be noted that direct asymmetric hydrogenation of nitrogen-containing aromatic hydrocarbons is one of the most direct methods for preparing chiral nitrogen-containing heterocycles with significant application value. Previous methods were limited to substrates that were monosubstituted indoles at the 2 or 3 position, or 2,3-disubstituted indoles. In this invention, racemic indoles containing a chiral carbon center at the 2-position were used as substrates. These readily available raw materials were utilized, along with commercially available palladium catalysts and chiral bisphosphine ligands, and inexpensive, environmentally friendly hydrogen gas as a reducing agent. Through a dynamic kinetic asymmetric hydrogenation strategy, a series of novel chiral indoline compounds without protecting groups on the nitrogen atom and containing continuous chiral centers were synthesized. Under the action of strong acid, the unprotected indoles first undergo protonation to obtain highly reactive indoline imine ion intermediates, which are then reduced. Therefore, the indole substrates involved in this invention do not require protection.

[0047] In some embodiments, the acid is one of trifluoroacetic acid (TFA), acetic acid (HOAc), p-toluenesulfonic acid (TsOH), L-camphorsulfonic acid (L-CSA), trifluoromethanesulfonic acid (HOTf), and sulfuric acid (H2SO4).

[0048] In some embodiments, the molar ratio of the palladium catalyst to the 2-substituted indole compound ranges from 0.01 mol% to 10 mol%, the molar ratio of the chiral bisphosphine ligand to the 2-substituted indole compound ranges from 0.02 mol% to 20 mol%, and the molar ratio of the acid to the 2-substituted indole compound ranges from 4.0 to 10.0 equivalents.

[0049] In some embodiments, the chiral bisphosphine ligand has one of the following structural formulas:

[0050]

[0051] In some embodiments, the solvent is one or more of dichloromethane (DCM), tetrahydrofuran (THF), and toluene.

[0052] In some embodiments, the stirring conditions are: stirring at room temperature for 40 to 80 minutes.

[0053] In some embodiments, the reaction temperature is 25-100°C, such as 25°C, 30°C, 40°C, 60°C, 80°C, 90°C, or 100°C, and the reaction time is 12-72 hours, such as 12 hours, 22 hours, 30 hours, 40 hours, 52 hours, 65 hours, or 72 hours.

[0054] In some embodiments, the pressure of the hydrogen gas is 20-80 bar, such as 20 bar, 30 bar, 40 bar, 50 bar, 60 bar, 70 bar, or 80 bar.

[0055] This invention also provides a chiral indoline compound synthesized by the synthetic method described above.

[0056] This invention also provides a chiral indoline compound, the structural formula of which is shown below:

[0057]

[0058] Where: R 1 R is an alkyl, cycloalkyl, substituted aryl, or heterocyclic aryl group. 2 R is alkyl, benzyl, or substituted aryl. 3 It can be alkyl, aryl, heterocyclic aryl, alkoxy, or halogen (such as chlorine or bromine).

[0059] In some embodiments, the chiral indoline compound has one of the following structural formulas:

[0060]

[0061] The present invention will be further described below through specific embodiments.

[0062] Example 1

[0063] Synthesis of chiral indoline compound 2a

[0064]

[0065] Under an argon atmosphere, Pd(CF3CO2)2 (0.7 mg, 2 mol%), L5 (1.8 mg, 2.4 mol%), and 1 mL of anhydrous dichloromethane were added to a hydrogenation flask. After stirring at room temperature for 60 minutes, starter 1a (34.1 mg, 0.1 mmol) and trifluoroacetic acid (68.4 mg, 0.6 mmol) were added sequentially. After reacting at 60 bar under a hydrogen atmosphere for 24 hours, all the starter was converted to product. Subsequently, hydrogen was slowly released, a saturated sodium bicarbonate solution was added, and the mixture was extracted with dichloromethane. The collected organic phase was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Then, column chromatography was performed to obtain product 2a.

[0066] Product 2a: The product was a white solid, 30.5 mg, yield 89%, dr > 20:1 (dr refers to diastereomer excess), 94% ee (ee refers to enantiomer excess), [α] 25 D = +27.5 (c 1.0, CHCl3);

[0067] 1 H NMR (400MHz, CDCl3): δ7.39-7.33(m,4H),7.35-7.31(m,4H),7.27-7.25(m,2H),7.07(d,J= 7.2Hz,1H),6.98(td,J1=7.6Hz,J2=1.2Hz,1H),6.69(td,J1=7.6Hz,J2=1.2Hz,1H),6.48(d ,J=7.6Hz,1H),5.19(AB,J=12.4Hz,1H),5.11(AB,J=12.4Hz,1H),4.52-4.46(m,1H),3.78( d, J=9.6Hz, 1H), 3.28 (dd, J1=15.6Hz, J2=8.4Hz, 1H), 2.81 (dd, J1=15.6Hz, J2=8.4Hz, 1H);

[0068] 13 C NMR (101MHz, CDCl3) δ172.3,150.1,136.5,135.8,129.1,128.9,128.7,128.4,128.1, 127.9,127.6,125.0,118.8,109.1,66.7,61.9,57.3,35.1.HRMS(ESI):calculatedfor C 23 H 21 NO2[M + H + ]344.1645, found 344.1637.

[0069] HPLC conditions: Phenomenex Chiral NX(2) column, n-hexane / isopropanol = 97 / 3, flow rate: 0.9 mL / min, 254 nm, t R1 = 8.726 min, t R2 = 11.107min (major).

[0070] The single crystal structure of product 2a is shown in [reference needed]. Figure 1 As shown.

[0071] Example 2

[0072] The synthesis conditions of the chiral indoline compound 2a in Example 1 were optimized through single-factor experiments. The experimental results are shown in Table 1 below.

[0073] Table 1

[0074]

[0075]

[0076] Example 3

[0077] The synthesis methods for chiral indoline compounds 2b to 2r are the same as those for chiral indoline compound 2a, the only difference being the different starting materials.

[0078] Product 2b: The product is a yellow oil, 31.7 mg, yield 88%, dr > 20:1, 93% ee, [α] 25 D = +49.8 (c 1.0, CHCl3);

[0079] 1 H NMR (400MHz, CDCl3): δ7.38-7.35(m,4H),7.34-7.30(m,4H),7.26-7.23(m,2H),6.78(dd ,J1=8.4Hz,J2=2.8Hz,1H),6.66(td,J1=8.8Hz,J2=2.4Hz,1H),6.36(dd,J1=8.8Hz,J2=4 .4Hz,1H),5.18(AB,J=12.4Hz,1H),5.10(AB,J=12.4Hz,1H),4.52-4.45(m,1H),3.76(d, J=9.6Hz, 1H), 3.24 (dd, J1=16.0Hz, J2=8.8Hz, 1H), 2.76 (dd, J1=16.0Hz, J2=7.6Hz, 1H);

[0080] 13C NMR (101MHz, CDCl3) δ 172.2, 157.0 (d, J = 234.0Hz), 146.2, 136.4, 135.8, 129.6 (d, J = 8.0Hz), 129.1, 128.8, 128.7, 128. 19F NMR(376MHz,CDCl3):δ-126.4.HRMS(ESI):calculated for C 23 H 20 FNO2[M + H + ]362.1551,found362.1552.

[0081] HPLC conditions: Phenomenex Chiral NX(2) column, n-hexane / isopropanol = 97 / 3, flow rate: 0.9 mL / min, 254 nm, t R1 = 8.463min, t R2 = 10.956min (major).

[0082] Product 2c: The product is a yellow oily liquid, 33.6 mg, yield 90%, dr > 20:1, 91% ee, [α] 25 D = +43.9 (c 1.0, CHCl3);

[0083] 1 H NMR (400MHz, CDCl3): δ7.37-7.35(m,4H),7.34-7.30(m,4H),7.26-7.25(m,2H),6. 70(s,1H),6.55(dd,J1=8.4Hz,J2=2.4Hz,1H),6.41(d,J=8.0Hz,1H),5.18(AB,J=1 2.4Hz,1H),5.10(AB,J=12.4Hz,1H),4.49-4.42(m,1H),3.77(d,J=10Hz,1H),3.73 (s,3H),3.24(dd,J1=15.6Hz,J2=8.4Hz,1H),2.78(dd,J1=15.6Hz,J2=7.2Hz,1H);

[0084] 13C NMR (101MHz, CDCl3) δ172.4,153.6,144.0,136.6,135.9,129.6,129.1,128.9,128.7,128. 4,128.1,128.0,112.5,112.0,109.6,66.7,62.4,57.3,56.1,35.6.HRMS(ESI):calculated for C 24 H 23 NO3[M + H + ]374.1751,found 374.1751.

[0085] HPLC conditions: Daicel Chiralpak OD-H column, hexane / isopropanol = 90 / 10, flow rate: 1.0 mL / min, 254 nm, t R1 =11.963min,t R2 = 15.628min (major).

[0086] Product 2d: The product was a yellow oily liquid, 33.9 mg, yield 90%, dr > 20:1, 93% ee, [α] 25 D = +56.2 (c 1.0, CHCl3);

[0087] 1 H NMR (400MHz, CDCl3): δ7.37-7.32(m,8H),7.27-7.24(m,2H),6.89(t,J=8.0Hz,1H),6.63(d,J=8.0Hz,1H),6.32(d,J=8.0Hz,1H),5.21(AB,J=12.4H z,1H),5.11(AB,J=12.4Hz,1H),4.56-4.49(m,1H),3.77(d,J=9.6Hz,1H),3.32(dd,J1=16.4Hz,J2=8.8Hz,1H),2.83(dd,J1=16.4Hz,J2=8.8Hz,1H);

[0088] 13 C NMR (101MHz, CDCl3) δ172.1,151.5,136.1,135.7,130.9,129.1,129.0,128.9,128.7,12 8.4,128.2,128.1,126.2,118.6,107.0,66.9,61.3,57.4,34.3.HRMS(ESI):calculated for C 23 H20 ClNO2[M+H + ]378.1255,found 378.1249.

[0089] HPLC conditions: Phenomenex Chiral NX(2) column, n-hexane / isopropanol = 97 / 3, flow rate: 0.9 mL / min, 254 nm, t R1 =6.921min,t R2 = 7.644min (major).

[0090] Product 2e: The product is a yellow liquid, 33.6 mg, yield 91%, dr > 20:1, 88% ee, [α] 25 D = +74.0 (c 1.0, CHCl3);

[0091] 1 H NMR (400MHz, CDCl3): δ7.40-7.36(m,4H),7.35-7.31(m,4H),7.27-7.25(m,2H ),6.97(t,J1=8.0Hz,1H),6.28(d,J=8.0Hz,1H),6.16(d,J=8.0Hz,1H),5.18( AB,J=12.4Hz,1H),5.11(AB,J=12.4Hz,1H),4.56-4.49(m,1H),3.91-3.78(m, 4H), 3.28 (dd, J1=16.0Hz, J2=8.8Hz, 1H), 2.79 (dd, J1=15.6Hz, J2=7.2Hz, 1H);

[0092] 13 C NMR (101MHz, CDCl3) δ172.3,156.6,151.8,136.5,135.8,129.1,128.9,128.9,128.6,128. 3,128.0,128.0,114.2,102.8,101.7,66.7,61.9,57.5,55.4,32.2.HRMS(ESI):calculated for C 24 H 23 NO3[M+H + ]374.1751,found 374.1747.

[0093] HPLC conditions: Phenomenex Chiral NX(2) column, n-hexane / isopropanol = 97 / 3, flow rate: 0.9 mL / min, 254 nm, t R1 =11.716min,tR2 = 13.529min (major).

[0094] Product 2f: The product is a yellow solid, 0.1 mmol in volume, 38.7 mg, yield 92%, dr > 20:1, 87% ee, [α] 25 D = +85.8 (c 1.0, CHCl3);

[0095] 1 H NMR (400MHz, CDCl3): δ7.39-7.35(m,5H),7.34-7.31(m,3H),7.26-7.24(m,2H),6 .88(d,J=7.6Hz,1H),6.77(dd,J1=8.0Hz,J2=2.0Hz,1H),6.57(d,J=2.0Hz,1H),5. 18(AB,J=12.4Hz,1H),5.10(AB,J=12.4Hz,1H),4.52-4.46(m,1H),3.74(d,J=9.6 Hz, 1H), 3.20 (dd, J1=16.0Hz, J2=8.8Hz, 1H), 2.72 (dd, J1=16.0Hz, J2=8.8Hz, 1H);

[0096] 13 C NMR (101MHz, CDCl3) δ172.1,151.5,136.1,135.7,130.9,129.1,129.0,128.9,128.7,1 28.4,128.2,128.1,126.2,118.6,107.0,66.9,61.3,57.4,34.3HRMS(ESI):calculated for C 23 H 20 BrNO2[M+H + ]422.0750,found 422.0749.

[0097] HPLC conditions: Phenomenex Chiral NX(2) column, n-hexane / isopropanol = 97 / 3, flow rate: 0.9 mL / min, 254 nm, t R1 =12.133min,t R2 = 16.143min (major).

[0098] Product 2g: The product was a yellow solid, 32.8mg, yield 92%, dr>20:1, 92% ee, [α] 25 D = +52.5 (c1.0, CHCl3);

[0099] 1 H NMR (400MHz, CDCl3): δ7.40-7.36(m,4H),7.35-7.31(m,4H),7.27-7.24(m,2H) ,6.95(d,J=7.2Hz,1H),6.51(d,J=7.6Hz,1H),6.32(s,1H),5.19(AB,J=12.4Hz, 1H),5.11(AB,J=12.8Hz,1H),4.49-4.46(m,1H),3.77(d,J=10.0Hz,1H),3.24(d d, J1=15.6Hz, J2=8.4Hz, 1H), 2.72 (dd, J1=16.0Hz, J2=7.2Hz, 1H), 2.23 (s, 3H);

[0100] 13 C NMR (101MHz, CDCl3) δ172.4,150.3,137.4,136.5,135.9,129.1,128.9,128.6,128.3,128.0 ,128.01,124.9,124.6,119.5,110.0,66.7,62.0,57.3,34.7,21.6.HRMS(ESI):calculated for C 24 H 23 NO2[M+H + ]358.1802,found 358.1798.

[0101] HPLC conditions: Phenomenex Chiral NX(2) column, n-hexane / isopropanol = 97 / 3, flow rate: 0.9 mL / min, 254 nm, t R1 =10.405min,t R2 = 11.786min (major).

[0102] Product 2h: The product is a yellow oily liquid, 33.6 mg, yield 94%, dr > 20:1, 99% ee, [α] 25 D = +56.2 (c 1.0, CHCl3);

[0103] 1H NMR (400MHz, CDCl3): δ7.38-7.35(m,4H),7.35-7.31(m,4H),7.24-7.22(m,2H),7 .04(t,J=7.6Hz,1H),6.28(d,J=7.6Hz,1H),6.16(d,J=7.6Hz,1H),5.20(AB,J=12. 0Hz,1H),5.13(AB,J=12.0Hz,1H),4.68-4.61(m,1H),4.08(d,J=9.6Hz,1H),3.29 (dd, J1=16.0Hz, J2=8.0Hz, 1H), 2.89 (dd, J1=16.0Hz, J2=8.0Hz, 1H), 2.22 (s, 3H);

[0104] 13 C NMR (101MHz, CDCl3) δ171.5,150.1,141.9,135.5,135.3,134.8,130.2,129.4,128.7,128. 7,128.5,128.2,128.2,126.0,112.2,67.2,62.2,55.3,33.6,18.8.HRMS(ESI):calculated for C 24 H 23 NO2[M+H + ]358.1802,found 358.1798.

[0105] HPLC conditions: Phenomenex Chiral NX(2) column, n-hexane / isopropanol = 97 / 3, flow rate: 0.9 mL / min, 254 nm, t R1 =11.716min,t R2 = 13.529min (major).

[0106] Gram-scale reaction results: 0.98 g of product was obtained in 2 h at a scale of 3 mmol, with a yield of 92%, dr > 20:1, and 98% ee.

[0107] Product 2i: The product was an oily liquid, 33.6 mg, yield 90%, dr > 20:1, 94% ee, [α] 25 D = +61.6 (c1.0, CHCl3);

[0108] 1H NMR (400MHz, CDCl3): δ7.35-7.32 (m, 4H), 7.30-7.28 (m, 3H), 7.06 (dd, J1=7.2Hz, J2=1.2Hz, 1H), 6.99(td,J1=7.6Hz,J2=1.2Hz,1H),6.92-7.28(m,2H),6.69(td,J1=7.6Hz,J2=1.2Hz,1H),6.48(d ,J=7.6Hz,1H),5.19(AB,J=12.4Hz,1H),5.11(AB,J=12.4Hz,1H),4.48-4.42(m,1H),3.83(s,3H) ,3.72(d,J=9.6Hz,1H),3.26(dd,J1=15.6Hz,J2=8.4Hz,1H),2.79(dd,J1=15.6Hz,J2=7.2Hz,1H);

[0109] 13 C NMR (101MHz, CDCl3) δ172.6,159.4,150.1,135.9,129.9,128.7,128.5,128.3,128.1,127. 9,127.5,125.0,118.8,114.5,109.1,66.7,61.9,56.4,55.4,35.0.HRMS(ESI):calculated for C 24 H 23 NO2[M+H + ]374.1751,found 374.1745.

[0110] HPLC conditions: Phenomenex Chiral NX(2) column, n-hexane / isopropanol = 90 / 10, flow rate: 1.0 mL / min, 254 nm, t R1 =12.270min,t R2 =24.344min (major).

[0111] Product 2j: The product is a yellow oily liquid, 33.9 mg, yield 90%, dr > 20:1, 93% ee, [α] 25 D = +11.0 (c 1.0, CHCl3);

[0112] 1H NMR (400MHz, CDCl3): δ7.41-7.34(m,4H),7.33-7.27(m,5H),7.06(dd,J1=7.2Hz,J2=1.2 Hz,1H),7.00(td,J1=7.6Hz,J2=1.2Hz,1H),6.70(td,J1=7.2Hz,J2=0.8Hz,1H),6.50(d,J =7.6Hz,1H),5.21(AB,J=12.0Hz,1H),5.13(AB,J=12.4Hz,1H),4.50-4.43(m,1H),3.76(d ,J=9.6Hz,1H),3.27(dd,J1=15.6Hz,J2=8.4Hz,1H),2.79(dd,J1=15.6Hz,J2=7.6Hz,1H);

[0113] 13 C NMR (101MHz, CDCl3) δ171.8,150.0,138.4,135.6,134.9,130.3,129.0,128.7,128.5,128.3,12 8.2,127.7,127.6,127.2,124.9,118.9,109.2,67.0,61.8,57.1,35.0.HRMS(ESI):calculated for C 23 H2ClNO2[M+H + ]378.1255,found 378.1252.

[0114] HPLC conditions: Phenomenex Chiral NX(2) column, n-hexane / isopropanol = 90 / 10, flow rate: 1.0 mL / min, 254 nm, t R1 =7.909min,t R2 = 9.508min (major).

[0115] Product 2k: The product is a white solid, 35.0 mg, yield 89%, dr > 20:1, 95% ee, [α] 25 D = +54.9 (c 1.0, CHCl3);

[0116] 1H NMR (400MHz, CDCl3): δ7.87-7.82(m,4H),7.55-7.50(m,3H),7.32-7.25(m,5H),7.08(d,J =7.2Hz,1H),6.98(t,J=7.6Hz,1H),6.69(t,J=7.2Hz,1H),6.45(d,J=7.6Hz,1H),5.22(d,J =12.4Hz,1H),5.11(d,J=12.4Hz,1H),4.63-4.56(m,1H),3.95(dd,J1=9.6Hz,J2=2.8Hz,1 H),3.62(s,1H),3.33(dd,J1=16.0Hz,J2=8.4Hz,1H),2.86(dd,J1=15.6Hz,J2=7.2Hz,1H);

[0117] 13 C NMR (101MHz, CDCl3) δ172.3,150.1,135.8,134.0,133.6,133.1,128.9,128.7,128.4,128.2,128.1,128.07,1 27.9,127.8,127.6,126.6,126.4,126.3,125.0,118.8,109.1,66.8,61.9,57.5,35.2.HRMS(ESI):calculated for C 27 H 23 NO2[M+H + ]394.1802,found 394.1802.

[0118] HPLC conditions: Phenomenex Chiral NX(2) column, n-hexane / isopropanol = 97 / 3, flow rate: 0.9 mL / min, 254 nm, t R1 =14.065min,t R2 = 20.136min (major).

[0119] Product 2L: The product is a yellow oily liquid, 34.4 mg, yield 89%, dr > 20:1, 94% ee, [α] 25 D = +70.4 (c 1.0, CHCl3);

[0120] 1H NMR (400MHz, CDCl3): δ7.35-7.32(m,3H),7.29-7.27(m,3H),7.05(dd,J1=7.2Hz,J2=1.2Hz,1H),6.98 (td, J1=7.6Hz, J2=1.2Hz, 1H), 6.92 (d, J=2.0Hz, 1H), 6.83-6.78 (m, 2H), 6.68 (td, J1=7.2Hz, J2=0.8Hz ,1H),6.49(d,J=8.0Hz,1H),5.97(s,2H),5.19(d,J=12.4Hz,1H),5.11(d,J=12.4Hz,1H),4.44-4.38(m ,1H),3.68(d,J=9.6Hz,1H),3.24(dd,J1=16.0Hz,J2=8.4Hz,1H),2.76(dd,J1=15.6Hz,J2=7.2Hz,1H);

[0121] 13 C NMR (101MHz, CDCl3) δ172.4,125.1,148.3,147.5,135.8,130.1,128.7,128.4,128.1,127.9,127.6 ,125.0,122.4,118.8,109.1,108.9,108.7,101.3,66.8,61.9,56.8,34.9.HRMS(ESI):calculated for C 24 H 21 NO4[M+H + ]388.1543, found 388.1537.

[0122] HPLC conditions: Phenomenex Chiral NX(2) column, n-hexane / isopropanol = 97 / 3, flow rate: 0.9 mL / min, 254 nm, t R1 =12.270min,t R2 =24.344min (major).

[0123] Product 2m: The product is a yellow oily liquid, 26.8 mg, yield 91%, dr > 20:1, 98% ee, [α] 25 D = +22.4 (c 1.0, CHCl3);

[0124] 1H NMR (400MHz, CDCl3): δ7.29-7.25(m,2H),7.22-7.18(m,3H),7.07(dd,J1=7.2Hz,J 2=2.0Hz,1H),7.02(td,J1=7.6Hz,J2=1.2Hz,1H),6.70(td,J1=7.2Hz,J2=0.8Hz,1 H),6.61(d,J=7.6Hz,1H),4.17-4.11(m,1H),4.04-3.93(m,2H),3.18(dd,J1=15.6 Hz,J2=8.8Hz,1H),2.98(d,J=6.8Hz,2H),2.93-2.86(m,1H),1.07(t,J=7.2Hz,1H);

[0125] 13 C NMR (101MHz, CDCl3): δ174.0,150.7,139.0,129.0,128.6,128.1,127.6,126.6,12 4.7,118.9,109.2,60.8,60.6,53.5,35.3,34.2,14.2.HRMS(ESI):calculatedfor C 19 H 21 NO2[M+H + ]296.1645,found 296.1637.

[0126] HPLC conditions: Phenomenex Chiral NX(2) column, n-hexane / isopropanol = 97 / 3, flow rate: 0.9 mL / min, 254 nm, t R1 =8.744min,t R2 = 10.717min (major).

[0127] Product 2n: The product is a yellow oily liquid, 33.6 mg, yield 90%, dr > 20:1, 94% ee, [α] 25 D = +24.7 (c 1.0, CHCl3);

[0128] 1H NMR (400MHz, CDCl3): δ7.53(d,J=7.6Hz,1H),7.22-7.17(m,2H),7.11-7.07(m,2H),7.02(t,J=7.6Hz,1H),6.69(t,J=7.6Hz,1H),6.62 (d,J=7.6Hz,1H),4.22-4.16(m,1H),4.01-3.94(m,2H),3.20(dd,J1=16.0Hz,J2=9.2Hz,1H),3.14-2.01(m,4H),1.06(t,J=7.2Hz,1H);

[0129] 13 C NMR (101MHz, CDCl3): δ174.0,150.8,138.5,133.0,131.3,128.4,128.0,127.6,127.5, 124.8,124.7,118.8,109.1,60.8,60.6,50.8,35.0,33.9,14.2.HRMS(ESI):calculated for C 19 H 21 BrNO2[M+H + ]374.0750, found 374.0752.

[0130] HPLC conditions: Phenomenex Chiral MD(2) column, n-hexane / isopropanol = 97 / 3, flow rate: 0.9 mL / min, 254 nm, t R1 =6.952min,t R2 = 20.724min (major).

[0131] Product 2o: The product is a yellow oily liquid, 17.3 mg, yield 79%, dr > 20:1, 88% ee, [α] 25 D = +10.2 (c 1.0, CHCl3);

[0132] 1 H NMR (400MHz, CDCl3): δ7.06(t,J=6.8Hz,1H),7.00(t,J=8.0Hz,1H),6.68(td,J1=7.6Hz,J2=1.2Hz,1H),6.59(d,J=7.2Hz ,1H),4.22-4.13(m,2H),4.10-3.99(m,1H),3.18-3.12(m,1H),2.87-2.70(m,1H),2.65-2.60(m,1H),1.28-1.22(m,6H);

[0133] 13 C NMR (101MHz, CDCl3): δ175.5,150.9,128.3,127.5,124.7,118.7,109.1,60.9,60.6,45.0,34.2,14.3,12.1.HRMS(ESI): calculated for C 13 H 17 NO2[M+H + ]220.1332,found220.1333.

[0134] HPLC conditions: Phenomenex Chiral MD(2), n-hexane / isopropanol = 97 / 3, flow rate: 0.9 mL / min, 254 nm, t R1 =6.952min,t R2 = 20.724min (major).

[0135] Product 2p: The product is a yellow oily liquid, 20.7 mg, yield 89%, dr > 20:1, 88% ee, [α] 25 D = +17.3 (c 1.0, CHCl3);

[0136] 1 H NMR (400MHz, CDCl3): δ7.05(d,J=7.2Hz,1H),7.00(t,J=7.6Hz,1H),6.68(t,J =7.2Hz,1H),6.59(d,J=7.6Hz,1H),4.19-4.12(m,2H),4.06(q,J=7.6Hz,1H),3 .18(dd,J1=15.6Hz,J2=8.8Hz,1H),2.87(dd,J1=15.6Hz,J2=8.0Hz,1H),2.51 -2.46(m,1H),1.74-1.66(m,2H),1.26(t,J=7.2Hz,3H),0.95(t,J=7.2Hz,3H);

[0137] 13 C NMR (101MHz, CDCl3): δ174.6,150.7,128.3,127.5,124.7,118.8,109.1,60.7,60.5,53.3,34.4,22.3,14.4,11.9.HRMS(ESI): calculated for C 14 H 19 NO2[M+H +]234.1489,found 234.1451.

[0138] HPLC conditions: Phenomenex Chiral MD(2) column, n-hexane / isopropanol = 97 / 3, flow rate: 0.7 mL / min, 254 nm, t R1 =6.162min,t R2 = 14.603min (major).

[0139] Product 2q: The product is a yellow oily liquid, 26.2 mg, yield 87%, dr > 20:1, 92% ee, [α] 25 D = +18.7 (c 1.0, CHCl3);

[0140] 1 H NMR (400MHz, CDCl3): δ7.04 (dd, J1=7.6Hz, J2=1.6Hz, 1H), 6.99 (dd, J1=7.6Hz, J2=1.2Hz, 1H), 6.67(td,J1=7.6Hz,J2=1.2Hz,1H),6.59(d,J=8.0Hz,1H),4.09-4.01(m,2H),4.06-3.06(m,1H) ,3.09(dd,J1=16.0Hz,J2=9.2Hz,1H),2.88(dd,J1=16.0Hz,J2=8.4Hz,1H),2.69-2.64(m,1H), 1.87-1.82(m,1H),1.71-1.62(m,5H),1.43-1.36(m,1H),1.19-1.11(m,7H),0.99-0.82(m,2H);

[0141] 13 C NMR (101MHz, CDCl3): δ175.0,150.7,128.3,127.5,124.7,118.7,109.1,61.5,60.5,4 8.9,36.8,36.1,34.3,34.1,32.6,26.6,26.4,26.3,14.4.HRMS(ESI):calculatedfor C 19 H 17 NO2[M+H + ]302.2115, found 302.2118.

[0142] HPLC conditions: Phenomenex Chiral NX column, n-hexane / isopropanol = 97 / 3, flow rate: 0.9 mL / min, t R1=5.963min,t R2 = 7.972min (major).

[0143] Product 2r: The product is a yellow oily liquid, 22.3 mg, yield 86%, dr>20:1, 88% ee, [α] 25 D = +23.7 (c 1.0, CHCl3);

[0144] 1 H NMR (400MHz, CDCl3): δ7.04 (dd, J1=7.2Hz, J2=1.2Hz, 1H), 6.99 (dd, J1=7.6Hz, J2=1. 2Hz,1H),6.67(td,J1=7.2Hz,J2=1.2Hz,1H),6.58(d,J=7.6Hz,1H),4.15-4.00(m,3H ),3.93(s,1H),3.06(dd,J1=15.6Hz,J2=8.8Hz,1H),2.88(dd,J1=15.6Hz,J2=8.0Hz, 1H),2.74-2.67(m,1H),2.63-2.59(m,1H),2.10-2.05(m,5H),1.23(t,J=7.2Hz,3H);

[0145] 13 C NMR (101MHz, CDCl3): δ173.5,150.8,128.1,127.4,124.7,118.7,109.0,60.6,60.4,56.9,36.0,34.1,28.6,26.9,19.0,14.5.HRMS(ESI): calculated for C 16 H 21 NO2[M+H + ]260.1645, found 260.1648.

[0146] HPLC analysis: Phenomenex Chiral NX(2) column, hexane / isopropanol = 95 / 5, flow rate: 0.7 mL / min, T = 25℃, 254 nm, t R1 =8.779min,t R2 = 9.710min (major).

[0147] In summary, this invention provides a method for synthesizing chiral indoline compounds via asymmetric hydrogenation. Starting from readily available and simple raw materials, this method allows for the rapid and simple preparation of chiral indoline compounds with continuous chiral centers, novel structures, and potential pharmaceutical value. Furthermore, the method utilizes mild reaction conditions, with hydrogen being an inexpensive and readily available hydrogen source. It exhibits good substrate versatility, achieving excellent yields, enantioselectivity, and diastereoselectivity of the target product. Even at gram-scale, the reaction maintains good conversion and excellent enantioselectivity, demonstrating strong practicality.

[0148] It should be understood that the application of the present invention is not limited to the examples above. Those skilled in the art can make improvements or modifications based on the above description, and all such improvements and modifications should fall within the protection scope of the appended claims.

Claims

1. A method for synthesizing chiral indoline compounds, characterized in that, Including the following steps: Under an inert atmosphere, palladium catalyst, acid, chiral bisphosphine ligand and solvent are mixed and stirred to obtain a first mixture; A 2-substituted indole compound was added to the first mixture to obtain a second mixture; The second mixture was reacted under a hydrogen atmosphere to obtain chiral indoline compounds; The reaction formula for obtaining chiral indoline compounds from the 2-substituted indole compounds is shown below: The acid is trifluoroacetic acid; The chiral bisphosphine ligand has one of the following structural formulas: ； The solvent is dichloromethane; The palladium catalyst is Pd(CF3CO2)2; The reaction temperature is 25-100℃; The chiral indoline compound has one of the following structural formulas: 。 2. The method for synthesizing chiral indoline compounds according to claim 1, characterized in that, The stirring conditions are: stirring at room temperature for 40 to 80 minutes.

3. The method for synthesizing chiral indoline compounds according to claim 1, characterized in that, The molar ratio of the palladium catalyst to the 2-substituted indole compound ranges from 0.01 mol% to 10 mol%, the molar ratio of the chiral bisphosphine ligand to the 2-substituted indole compound ranges from 0.02 mol% to 20 mol%, and the molar ratio of the acid to the 2-substituted indole compound ranges from 4.0 to 10.0 equivalents.

4. The method for synthesizing chiral indoline compounds according to claim 1, characterized in that, The reaction time is 12-72 h.

5. The method for synthesizing chiral indoline compounds according to claim 1, characterized in that, The pressure of the hydrogen gas is 20-80 bar.

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