A method for the synthesis of indoline derivatives by palladium-catalyzed asymmetric hydrogenation

Abstract

The application discloses a method for synthesizing indoline derivatives through palladium-catalyzed asymmetric hydrogenation, and belongs to the technical field of organic synthesis. The method uses indole derivatives as reaction substrates, uses a chiral diphosphine palladium complex as a catalyst, and uses a Bronsted acid as an additive to synthesize indoline derivatives through asymmetric hydrogenation. The chiral diphosphine ligand is one of (S)-MeO-Biphep, (S)-SynPhos, (S)-SegPhos, (S)-BINAP and (S)-JosiPhos; the metal precursor of palladium is palladium trifluoroacetate; and the Bronsted acid is methyl sulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, D-camphorsulfonic acid or L-camphorsulfonic acid. The hydrogenation of specific indole derivatives can obtain corresponding chiral indoline derivatives, and the enantiomeric excess of the chiral indoline derivatives can reach 97%. The method is simple and practical, has high enantioselectivity, has good yield, and has green atom economy and environmental friendliness.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a method for synthesizing indole derivatives by catalytic hydrogenation of indole derivatives using a homogeneous palladium system with high enantioselectivity. Technical Background

[0002] Chiral indoline is the core framework of many bioactive molecules, pharmaceutical intermediates, and natural products. Therefore, the synthesis and bioactivity studies of these compounds have attracted widespread attention from organic chemists and the pharmaceutical community. The following formula represents the structural unit of a pharmaceutically active molecule containing a chiral indoline:

[0003]

[0004] Given the importance of chiral indolines and their derivatives in pharmaceutical and synthetic chemistry, chemists have developed several methods to synthesize these compounds, typically through direct asymmetric hydrogenation of indole or tandem indole synthesis with asymmetric hydrogenation. Several asymmetric hydrogenation strategies have been developed to synthesize indoline derivatives with one or two chiral centers, for example: (a) Ying Duan, Lu Li, Mu-Wang Chen, Chang-Bin Yu, Hong-Jun Fan* and Yong-Gui Zhou. Homogenous Pd-Catalyzed Asymmetric Hydrogenation of Unprotected Indoles: Scope and Mechanistic Studies. J. Am. Chem. Soc. 2014, 136, 7688-7700.; (b) Chang-Bin Yu, Jie Wang and Yong-Gui Zhou. Facile Synthesis of Chiral Indolines through Asymmetric Hydrogenation of in situ Generated Indoles. Org. Chem. Front. 2018, 5, 2805-2809.;(c) Ying Duan, Mu-Wang Chen, Zhi-Shi Ye, Duo-Sheng Wang, Qing-An Chen, and Yong-Gui Zhou. An Enantioselective Approach to 2,3-Disubstituted Indolines through Consecutive Bronsted Acid / Pd-Complex-Promoted Tandem Reactions. Chem. Eur. J. 2011, 17, 7193-7197. However, to date, there are few reports on the synthesis of indoline derivatives containing three chiral centers. Therefore, the synthesis of indoline derivatives with multiple chiral centers is of great significance in pharmaceutical and pesticide research.

[0005] Asymmetric hydrogenation offers advantages such as good atom economy, high catalyst activity, fast reaction rate, convenient product separation, and fewer side reactions. Currently, many chiral catalytic hydrogenation systems have been applied industrially. Summary of the Invention

[0006] Therefore, the purpose of this invention is to provide a method for the asymmetric hydrogenation synthesis of indoline derivatives catalyzed by palladium. This invention is simple and practical to operate, uses readily available raw materials, has high enantioselectivity, good yield, and the reaction has the advantages of being green, atom-economical, and environmentally friendly.

[0007] To achieve the above objectives, the technical solution of the present invention is as follows:

[0008] This invention provides a method for synthesizing chiral indoline derivatives, using indole derivative I as a reaction substrate, a chiral bisphosphine complex of palladium as a catalyst, and Brønsted acid as an additive, to synthesize indoline derivative II via asymmetric hydrogenation, as shown in the following reaction formula:

[0009]

[0010] In the formula:

[0011] Ar is a phenyl group or a phenyl group containing a substituent, wherein the substituent is a halogen or a C1-C2 phenyl group. 20 Alkyl or C1-C 20 At least one of the alkoxy groups; R is C1-C 20 Alkyl or aryl; PP* is a chiral bisphosphine ligand.

[0012] Based on the above technical solutions, preferably, the chiral bisphosphine ligand is one of (S)-MeO-Biphep, (S)-SynPhos, (S)-SegPhos, (S)-BINAP, and (S)-JosiPhos.

[0013] Based on the above technical solutions, preferably, the palladium metal precursor is palladium trifluoroacetate, palladium acetate, or palladium chloride.

[0014] Based on the above technical solutions, preferably, the Brønsted acid is methanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, D-camphorsulfonic acid, or L-camphorsulfonic acid.

[0015] Based on the above technical solution, preferably, the method includes the following steps:

[0016] (1) Add palladium metal precursor and chiral bisphosphine ligand to the reaction vessel, replace with inert gas and add acetone, stir for 0.5-5 h, remove acetone and obtain catalyst;

[0017] (2) Under an inert gas atmosphere, add an organic solvent to the reaction vessel containing the catalyst, transfer it to an ampoule containing indole derivative I, add Brønsted acid, place it in a reaction vessel, introduce hydrogen gas to 500-900 psi, and react at 60-90°C for 4-48 h to obtain a chiral indoleline derivative.

[0018] Based on the above technical solutions, preferably, the organic solvents mentioned in step (2) include DCM, TFE and HFIP.

[0019] Based on the above technical solution, preferably, the molar ratio of the palladium metal precursor, chiral bisphosphine ligand, Brønsted acid and indole derivative I is 1:1 to 1.2:40 to 80:20 to 100.

[0020] Based on the above technical solutions, the preferred chiral bisphosphine ligand is (S)-MeO-BIPHEP, the organic solvent is TFE, the reaction temperature is 80℃, the hydrogen pressure is 750psi, and the enantiomeric excess is over 97%.

[0021] Based on the above technical solutions, preferably, the inert gas mentioned in step (2) is nitrogen, argon or helium.

[0022] Compared with the prior art, the present invention has the following beneficial effects:

[0023] 1. The method of the present invention has high reactivity, high enantioselectivity, complete reaction, specific product, and very few side reactions detected by 1H NMR spectroscopy, which makes separation convenient and can obtain high enantiomeric excess purity.

[0024] 2. The catalyst of the present invention is easy to prepare and the reaction operation is simple and practical.

[0025] 3. The hydrogenation reaction conditions of the present invention are mild and require a small amount of catalyst.

[0026] 4. The chiral indoline derivatives obtained in this invention can be further N-Ts transformed to obtain chiral indoline derivatives with more varied structures. Detailed Implementation

[0027] The present invention is described in detail below through examples, but the present invention is not limited to the following examples. The synthesis of the reaction substrates in the examples is referenced in: Qing, Y.; Wang, S.-G.; You, S.-L. Org. Lett. 2013, 15, 2688.

[0028] Examples 1-13

[0029] Optimization of conditions

[0030] Palladium trifluoroacetate (0.006 mmol, 2.0 mg) and a chiral ligand (0.0066 mmol) were added to a reaction flask. After purging with nitrogen, 1 mL of acetone was added, and the mixture was stirred at room temperature for 1 hour. The mixture was then concentrated under vacuum, and 3 mL of organic solvent was added under nitrogen. This solution was transferred to an ampoule pre-filled with substrate 1a (58.0 mg, 0.20 mmol). Brønsted acid was added, a magnetic stir bar was added, and the mixture was stirred thoroughly. The mixture was then placed in a reaction vessel, and hydrogen gas was introduced to 750 psi. The reaction was carried out at 80 °C for 24 hours. Hydrogen gas was slowly released, and the reaction solution was extracted with saturated sodium bicarbonate solution and dichloromethane. The organic phase was collected, dried over anhydrous sodium sulfate, and then directly separated by column chromatography to obtain the pure product. The specific parameters, including the type of organic solvent and chiral bisphosphine ligand, the type of Brønsted acid, the hydrogen pressure, and the reaction temperature, were varied as shown in Figure 1. The reaction formula and ligand structure are as follows:

[0031]

[0032] The enantiomeric excess of the product was determined by chiral liquid chromatography. HPLC: IA, eluent: Hexanes / i-PrOH=90 / 10, detector: 230nm, flow rate: 0.9mL / min, 30℃, t1=34.7min(maj), t2=43.2min.

[0033] Table 1. Asymmetric hydrogenation of indole derivative 1a

[0034]

[0035]

[0036] The yield was determined by NMR, and the enantiomeric excess of the product was determined by chiral liquid chromatography.

[0037] Examples 14-19

[0038] Palladium-catalyzed asymmetric hydrogenation synthesis of chiral indoline derivatives 2

[0039] Palladium trifluoroacetate (2.0 mg, 0.006 mmol) and (S)-MeO-BiPhep (3.9 mg, 0.0066 mmol) were added to a reaction flask, purged with nitrogen, and 1 mL of acetone was added. The mixture was stirred at room temperature for 1 hour. The mixture was then concentrated under vacuum, and 3 mL of 2,2,2-trifluoroethanol was added under nitrogen. This solution was transferred to an ampoule pre-filled with substrate 1 (0.30 mmol), placed in a reaction vessel, and purged with hydrogen to 750 psi. The reaction was carried out at 80°C for 24 hours, during which hydrogen was slowly released. The reaction mixture was extracted with saturated sodium bicarbonate solution and dichloromethane. The organic phase was collected, dried over anhydrous sodium sulfate, and separated by column chromatography to obtain the pure product. The reaction equation is as follows:

[0040]

[0041] The characterization data of the above compounds are as follows:

[0042] 7,8,8a,13,13a,13b-Hexahydro-5H-benzo[1,2]indolizino[8,7-b]indol-5-one(2a):85mg,98%yield,white solid,R f =0.4(hexanes / ethyl acetate=1 / 1),97%ee, 1 HNMR(400MHz, CDCl3)δ7.89(d,J=7.5Hz,1H),7.67-7.40(m,3H),7.08(d,J=7.3Hz,1 H),6.95(t,J=7.6Hz,1H),6.69(t,J=7.4Hz,1H),6.37(d,J=7.8Hz,1H),4.78(d,J=3. 1Hz, 1H), 4.56 (d, J = 8.4Hz, 1H), 3.86 (ddd, J = 12.9, 8.4, 4.4Hz, 1H), 3.63 (dd, J = 14. 3,6.3Hz,1H),3.43-3.29(m,1H),3.11(s,1H),2.24-2.10(m,1H),1.86-1.69(m,1H); 13 C NMR (100MHz, CDCl3) δ168.1,149.61,143.0,134.2,131.2,131.1,128.6,128.1,124.0,123.8,121.5,119 .0,109.5,59.9,57.9,39.2,37.3,27.5.HPLC(IA,elute:Hexanes / i-PrOH=90 / 10,detector:230nm,flow rate:0.9mL / min, 30℃, t1=34.7min(maj), t2=43.2min.

[0043] 9-Methyl-7,8,8a,13,13a,13b-hexahydro-5H-benzo[1,2]indolizino[8,7-b]indol-5-one(2b):79mg,91%yield,pale solid,128-129℃,R f =0.57(hexanes / ethylacetate=1 / 1),94%ee;[α] 20 D=-262.39(c0.79,CHCl3); 1 H NMR(400MHz,CDCl3)δ7.89(d,J=7.5Hz,1H),7.64–7.52(m,1H),7.48(dd,J=16.2,7.6Hz,2H),6.86(t,J=7.7Hz,1H),6.52(d,J=7.6Hz,1H),6.26(d,J=7.7Hz,1H),4.75(d,J=3.2Hz,1H),4.40(dd,J=7.1,3.3Hz,1H),4.11(dt,J=13.1,5.0Hz,1H),3.48(dd,J=14.9,6.9Hz,1H),3.23(ddd,J=13.3,10.1,3.4Hz,1H),3.13(s,1H),2.27(s,3H),2.09–2.02(m,1H),1.66–1.54(m,1H). 13 CNMR(100MHz,CDCl3)δ167.6,149.3,143.0,134.0,133.4,131.3,130.6,128.6,127.8,124.2,121.4,120.7,107.5,60.5,58.3,38.3,37.6,26.2,18.1.HPLC(OD-H,elute:Hexanes / i-PrOH=90 / 10,detector:230nm,flow rate:1.0mL / min),30℃,t1=34.3min,t2=35.7(maj);HRMS(ESI)m / z Calculated for C 19 H 18 N2O[M+H] + 291.1492,found 291.1503.

[0044] 10-Methyl-7,8,8a,13,13a,13b-hexahydro-5H-benzo[1,2]indolizino[8,7-b]indol-5-one(2c):86mg,95%yield,white solid,R f =0.57(hexanes / ethyl acetate=1 / 1), 1H NMR(400MHz,CDCl3)δ7.88(d,J=7.5Hz,1H),7.63-7.42(m,3H),6.89(s,1H),6.75(d,J=7.8Hz,1H),6.29(d,J=7.9Hz,1H),4.76(d,J=3.2Hz,1H),4.51(dd,J=8.2,3.3Hz,1H),3.89(ddd,J=12.7,8.0,4.5Hz,1H),3.56(dd,J=14.0,6.8Hz,1H),3.39-3.26(m,1H),3.01(s,1H),2.22(s,3H),2.18-2.07(m,1H),1.74(dtd,J=11.8,7.4,4.5Hz,1H). 13 C NMR(100 MHz,CDCl3)δ168.0,147.3,143.0,134.2,131.6,131.2,128.5,128.4,128.3,124.5,124.0,121.5,109.5,77.4,77.1,76.8,60.2,58.1,39.3,37.3,27.6,20.8.HPLC(AD-H,elute:Hexanes / i-PrOH=90 / 10,detector:230nm,flow rate:0.9mL / min,30℃,t1=30.1min,t2=32.4min(maj).HRMS(ESI)m / z Calculated for C 19 H 18 F3N2O[M+H] + 291.1492,found 291.1502.

[0045] 11-Methyl-7,8,8a,13,13a,13b-hexahydro-5H-benzo[1,2]indolizino[8,7-b]indol-5-one(2d):80mg,91%yield,white solid,77-78℃,R f =0.57(hexanes / ethylacetate=1 / 1),98%ee,[α] 20 D =-339.23(c0.80,CHCl3); 1H NMR(400MHz,CDCl3)δ7.90(d,J=7.5Hz,1H),7.59(t,J=7.0Hz,1H),7.51(dd,J=13.0,7.4Hz,2H),6.94(d,J=7.3Hz,1H),6.80(d,J=7.5Hz,1H),6.64(t,J=7.4Hz,1H),4.79(d,J=3.1Hz,1H),4.56(dd,J=8.5,3.0Hz,1H),3.83(ddd,J=13.0,8.6,4.4Hz,1H),3.67(dd,J=14.5,6.1Hz,1H),3.46-3.28(m,1H),2.86(s,1H),2.26-2.12(m,1H),1.84(s,3H),1.79(ddd,J=13.6,6.6,2.2Hz,1H) 13 C NMR(100MHz,CDCl3)δ168.1,148.3,143.0,134.2,131.2,130.4,129.0,128.6,124.0,121.6,121.3,119.1,118.9,59.7,58.0,39.5,37.3,27.4,16.6.HPLC(IC,elute:Hexanes / i-PrOH=80 / 20,detector:230nm,flow rate:1.0mL / min),30℃,t1=46.5min(maj),t2=58.2min;HRMS(ESI)m / z Calculated for C 19 H 18 N2O[M+H]+291.1492,found291.1495.

[0046] 12-Methyl-7,8,8a,13,13a,13b-hexahydro-5H-benzo[1,2]indolizino[8,7-b]indol-5-one(2e):72mg,83%yield,white solid,220-221℃,R f =0.58(hexanes / ethylacetate=1 / 1),96%ee,[α] 20 D =-313.03(c0.72,CHCl3), 1H NMR(400MHz,CDCl3)δ7.90(d,J=7.5Hz,1H),7.65-7.39(m,3H),6.71(d,J=2.5Hz,1H),6.53(dd,J=8.4,2.6Hz,1H),6.33(d,J=8.4Hz,1H),4.77(d,J=3.3Hz,1H),4.52(dd,J=8.1,3.3Hz,1H),4.00-3.87(m,1H),3.73(s,3H),3.60-3.50(m,1H),3.39-3.24(m,1H),2.91(s,1H),2.13(dddd,J=13.6,7.6,5.8,4.0Hz,1H),1.78-1.70(m,1H). 13 C NMR(100MHz,CDCl3)δ168.0,153.6,143.4,143.0,134.1,133.0,131.2,128.6,124.1,121.5,112.7,110.8,110.2,60.5,58.1,56.0,39.8,37.3,27.6.HPLC(AD-H,elute:Hexanes / i-PrOH=85 / 15,detector:230nm,flow rate:1.0mL / min),30℃,t1=14.0min(maj),t2=18.1min;HRMS(ESI)m / z Calculated forC 19 H 18 N2O[M+H]+291.1492,found 291.1505.

[0047] 10-Methoxy-7,8,8a,13,13a,13b-hexahydro-5H-benzo[1,2]indolizino[8,7-b]indol-5-one(2f):68mg,74%yield,white solid,203-204℃,R f =0.34(hexanes / ethylacetate=1 / 1),95%ee,[α] 20 D =-317.48(c 0.68,CHCl3); 1H NMR(400MHz, CDCl3) δ7.90(d,J=7.5Hz,1H),7.65-7.39(m,3H),6.71(d,J=2.5Hz,1 H),6.53(dd,J=8.4,2.6Hz,1H),6.33(d,J=8.4Hz,1H),4.77(d,J=3.3Hz,1H),4.52( dd,J=8.1,3.3Hz,1H),4.00-3.87(m,1H),3.73(s,3H),3.60-3.50(m,1H),3.39-3.2 4(m,1H),2.91(s,1H),2.13(dddd,J=13.6,7.6,5.8,4.0Hz,1H),1.78-1.70(m,1H). 13 C NMR (100MHz, CDCl3) δ168.0,153.6,143.4,143.0,134.1,133.0,131.20,128.55,124.1,121.5,112.7,110.8,11 0.2,60.5,58.11,56.0,39.75,37.30,27.60.HPLC(AD-H,elute:Hexanes / i-PrOH=85 / 15,detector:230nm,flow rate:1.0mL / min),30℃,t1=24.3min,t2=28.4min(maj); HRMS(ESI)m / z Calculatedfor C 19 H 18 N2O2[M+H]+307.1441,found 307.1450.

[0048] Example 20

[0049] Add 2a (224 mg, 0.81 mmol) to the reaction flask, purge with nitrogen, then add pyridine (154.2 mg, 1.95 mmol) and 3 mL of dichloromethane, and cool thoroughly in an ice-water bath. Separately, weigh 185.9 mg of TsCl (0.98 mmol), add 2 mL of dichloromethane to prepare a solution, and slowly add it dropwise to the reaction flask. After the addition is complete, bring the temperature to room temperature and react for 24 hours. Quench with saturated sodium bicarbonate solution, extract with dichloromethane, collect the organic phase, dry with anhydrous sodium sulfate, and separate by column chromatography to obtain the pure product. This provides an efficient and concise route for the synthesis of other abundant N-Ts protected chiral indolines, as shown in the following reaction formula:

[0050]

[0051] The characterization data of the above compounds are as follows:

[0052] 13-Tosyl-7,8,8a,13,13a,13b-hexahydro-5H-benzo[1,2]indolizino[8,7-b]indol-5-one(3):270mg,77%yield,white solid,264-265℃,R f =0.10(hexanes / ethylacetate=1 / 1),>99%ee,[α] 20 D =-370.97(c1.0,CHCl3); 1 H NMR(400MHz,CDCl3)δ7.88(d,J=7.7Hz,1H),7.74(d,J=7.6Hz,1H),7.60(dd,J=10.9,4.2Hz,1H),7.46(t,J=7.5Hz,1H),7.23(d,J=8.3Hz,2H),7.14-7.00(m,5H),6.96(d,J=7.4Hz,1H),5.24(dd,J=9.6,4.8Hz,1H),4.86(d,J=4.8Hz,1H),3.49-3.32(m,2H),3.25(td,J=13.0,5.7Hz,1H),2.37-2.29(m,3H),2.30-2.24(m,1H),2.24-2.13(m,1H) 13 C NMR(100MHz,CDCl3)δ168.1,144.1,142.7,141.5,134.3,133.7,133.2,130.7,129.4,128.3,127.3,125.9,125.7,123.7,122.7,118.9,63.3,57.62,38.2,35.6,21.6,21.5.HPLC(AD-H,elute:Hexanes / i-PrOH=80 / 20detector:230nm,flow rate:1.0mL / min),30℃,t1=26.3min(maj);HRMS(ESI)m / zCalculated for C 25 H 22 N2O3S[M+H]+431.1424,found 431.1423。

Claims

1. A method for synthesizing chiral indoline derivatives, characterized in that, Using indole derivative I as the substrate, a chiral bisphosphine complex of palladium as the catalyst, and Brønsted acid as an additive, indoleline derivative II was synthesized by asymmetric hydrogenation, as shown in the following reaction formula: In the formula: Ar is a phenyl group or a phenyl group containing a substituent, wherein the substituent is a halogen or a C1-C2 phenyl group. 20 Alkyl or C1-C 20 At least one of the alkoxy groups; PP It is a chiral bisphosphine ligand; The chiral bisphosphine ligand is ( S )-MeO-Biphep、( S )-SynPhos、( S )-SegPhos、( S )-BINAP、( S One of the JosiPhos; The palladium metal precursor is palladium trifluoroacetate, palladium acetate, or palladium chloride. The Brønsted acid is methanesulfonic acid, p-toluenesulfonic acid, or trifluoroacetic acid. D - Camphor sulfonic acid or L - Camphor sulfonic acid; The method includes the following steps: (1) Add palladium metal precursor and chiral bisphosphine ligand to the reaction vessel, replace with inert gas and add acetone, stir for 0.5~5h, remove acetone and obtain catalyst; (2) Under an inert gas atmosphere, add an organic solvent to the reaction vessel containing the catalyst, transfer it to an ampoule pre-filled with indole derivative I, add Brønsted acid, place it in a reaction vessel, purge with hydrogen gas to 500-900 psi, and maintain the temperature at 60-90°C. o The chiral indoline derivative was obtained by reacting at C for 4-48 h. The molar ratio of the palladium metal precursor, the chiral bisphosphine ligand, the Brønsted acid, and the indole derivative I is 1:1~1.2:40~80:20~100.

2. The method according to claim 1, characterized in that, The organic solvent mentioned in step (2) is dichloromethane, 2,2,2-trifluoroethanol or 1,1,1,3,3,3-hexafluoro-2-propanol.

3. The method according to claim 1, characterized in that, The chiral bisphosphine ligand is ( S )-MeO-BIPHEP, with 2,2,2-trifluoroethanol as the organic solvent, and a reaction temperature of 80°C. o C, hydrogen pressure is 750 psi, enantiomeric excess is over 97%.

4. The method according to claim 1, characterized in that, The inert gas mentioned in step (2) is nitrogen, argon or helium.

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