Method for synthesizing indoline derivative by palladium-catalyzed asymmetric hydrogenation

Abstract

The invention discloses a method for synthesizing indoline derivatives through palladium-catalyzed asymmetric hydrogenation, and belongs to the technical field of organic synthesis. According to the method, an indole derivative is used as a reaction substrate, a chiral diphosphine complex of palladium is used as a catalyst, Bronsted acid is used as an additive, the indoline derivative is synthesized through asymmetric hydrogenation, a chiral diphosphine ligand is one of (S)-MeO-Biphep, (S)-SynPhos, (S)-SegPhos, (S)-BINAP and (S)-JosiPhos, a metal precursor of palladium is palladium trifluoroacetate, and the chiral diphosphine ligand is one of (S)-MeO-Biphep, (S)-SynPhos, (S)-SegPhos, (S)-BINAP and (S)-JosiPhos. The Bronsted acid is methanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, D-camphorsulfonic acid or L-camphorsulfonic acid. A specific indole derivative is hydrogenated to obtain a corresponding chiral indoline derivative, and the enantiomeric excess of the chiral indoline derivative can reach 97%. The method is simple, convenient and practical to operate, high in enantioselectivity and good in yield, and the reaction has green atom economy and is environment-friendly.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and particularly relates to a method for synthesizing indoline derivatives by catalytically hydrogenating indole derivatives with high enantioselectivity in a homogeneous system using palladium. Technical Background

[0002] Chiral indoline is the core structure of many bioactive molecules, pharmaceutical intermediates and natural products. Therefore, the synthesis and biological activity research of this type of compound has attracted extensive attention from organic chemists and the pharmaceutical community. The following formula is the structural unit of the drug active molecule containing chiral indoline:

[0003]

[0004] In view of the importance of chiral indolines and their derivatives in the fields of medicine and synthetic chemistry, chemists have developed some methods to synthesize such compounds, usually by direct asymmetric hydrogenation of indole or tandem indole synthesis and asymmetric hydrogenation. Some of the indoline derivatives with one chiral center and two chiral centers that have been developed by asymmetric hydrogenation strategies are synthesized, 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-GuiZhou.An Enantioselective Approach to 2,3-Disubstituted Indolines throughConsecutive Bronsted Acid / Pd-Complex-Promoted TandemReactions.Chem.Eur.J.2011,17,7193-7197. However, so far, there are still few reports on the synthesis of indoline derivatives containing three chiral centers. Therefore, the synthesis of indoline derivatives with multiple chiral centers is very meaningful in the research of medicine and pesticides.

[0005] Asymmetric hydrogenation has the advantages of good atom economy, high catalyst activity, fast reaction speed, convenient product separation, and few side reactions. Currently, many chiral catalytic hydrogenation systems have been applied in industry. Summary of the invention

[0006] In view of this, the purpose of the present invention is to provide a method for synthesizing indoline derivatives by palladium-catalyzed asymmetric hydrogenation. The method is simple and practical to operate, the raw materials are readily available, the enantioselectivity is high, the yield is good, and the reaction has the advantages of green atom economy and environmental friendliness.

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

[0008] The present invention provides a method for synthesizing a chiral indoline derivative, wherein an indole derivative I is used as a reaction substrate, a chiral bisphosphine complex of palladium is used as a catalyst, and a Bronsted acid is used as an additive, and an indoline derivative II is synthesized by asymmetric hydrogenation, and the reaction formula is as follows:

[0009]

[0010] Where:

[0011] Ar is phenyl or phenyl containing a substituent, wherein the substituent is halogen, C1-C 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 solution, 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 solution, preferably, the metal precursor of palladium is palladium trifluoroacetate, palladium acetate, or palladium chloride.

[0014] Based on the above technical solution, preferably, the Bronsted 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 comprises the following steps:

[0016] (1) adding a palladium metal precursor and a chiral diphosphine ligand into a reaction container, adding acetone after inert gas replacement, stirring for 0.5 to 5 hours, and removing the acetone to obtain a catalyst;

[0017] (2) Under an inert gas atmosphere, an organic solvent is added to a reaction vessel containing the catalyst, and the mixture is transferred to an ampoule containing the indole derivative I, and Bronsted acid is added. The mixture is placed in a reaction vessel, and hydrogen is introduced to a pressure of 500-900 psi. The mixture is reacted at 60-90° C. for 4-48 hours to obtain a chiral indoline derivative.

[0018] Based on the above technical solution, preferably, the organic solvent described in step (2) includes DCM, TFE and HFIP.

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

[0020] Based on the above technical scheme, preferably, the chiral bisphosphine ligand is (S)-MeO-BIPHEP, the organic solvent is TFE, the reaction temperature is 80°C, the hydrogen pressure is 750psi, and the enantiomeric excess is more than 97%.

[0021] Based on the above technical solution, preferably, the inert gas described 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 and enantioselectivity, complete reaction, specific product generation, and very few side reactions detected by nuclear magnetic resonance hydrogen spectrum, so that separation is convenient and a pure product with high enantiomeric excess can be obtained.

[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 the amount of catalyst used is small.

[0026] 4. The chiral indoline derivatives obtained by the present invention can be further N-Ts transformed to obtain chiral indoline derivatives with more diverse structures. DETAILED DESCRIPTION

[0027] The present invention is described in detail below by way of examples, but the present invention is not limited to the following examples. The synthesis of the reaction substrates in the examples is referenced to: 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 chiral ligand (0.0066 mmol) were added to the reaction flask, 1 ml of acetone was added after nitrogen replacement, stirred at room temperature for 1 hour, and then concentrated in vacuo. 3 ml of organic solvent was added under nitrogen, and the solution was transferred to an ampoule containing substrate 1a (58.0 mg, 0.20 mmol) in advance, and Brønsted acid was added. A magnetic bar was added, and after stirring evenly, the solution was placed in a reactor and hydrogen was introduced to 750 psi. The reaction was carried out at 80°C for 24 hours. Hydrogen was slowly released, and the reaction solution was extracted with saturated sodium bicarbonate solution and dichloromethane. The organic phase was collected and dried over anhydrous sodium sulfate, and then directly separated by column chromatography to obtain a pure product. The types of organic solvent and chiral bisphosphine ligand, the type of Brønsted acid, the pressure of hydrogen, and the temperature of the reaction were changed. The specific parameters are shown in 1, and 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, elute: Hexanes / i-PrOH=90 / 10, detector: 230 nm, flow rate: 0.9 mL / min, 30°C, t1=34.7 min (maj), t2=43.2 min.

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

[0034]

[0035]

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

[0037] Examples 14-19

[0038] Synthesis of Chiral Indoline Derivatives 2 by Palladium-Catalyzed Asymmetric Hydrogenation

[0039] Palladium trifluoroacetate (2.0 mg, 0.006 mmol) and (S)-MeO-BiPhep (3.9 mg, 0.0066 mmol) were placed in a reaction flask, and 1 ml of acetone was added after nitrogen replacement. The mixture was stirred at room temperature for 1 hour. The mixture was then concentrated in vacuo, and 3 ml of 2,2,2-trifluoroethanol was added under nitrogen. The solution was transferred to an ampoule containing substrate 1 (0.30 mmol) in advance, placed in a reactor, and hydrogen was introduced to 750 psi. The reaction was carried out at 80°C for 24 hours, and hydrogen was slowly released. The reaction solution was extracted with saturated sodium bicarbonate solution and dichloromethane. The organic phase was collected and dried over anhydrous sodium sulfate, and then separated by column chromatography to obtain a pure product. The type of reaction substrate was changed, and the reaction formula was 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] Embodiment 20

[0049] 2a (224 mg, 0.81 mmol) was added to the reaction flask, and pyridine (154.2 mg, 1.95 mmol) and 3 ml of dichloromethane were added after nitrogen replacement, and the mixture was cooled in an ice-water bath. TsCl (185.9 mg, 0.98 mmol) was weighed separately, and 2 ml of dichloromethane was added to prepare a solution, which was slowly added dropwise to the reaction flask. After the addition, the mixture was heated to room temperature and reacted for 24 hours. Saturated sodium bicarbonate solution was added to quench, and dichloromethane was extracted. The organic phase was collected and dried over anhydrous sodium sulfate, and then separated by column chromatography to obtain a pure product. This conversion provides an efficient and concise way to synthesize other abundant chiral indolines with N-Ts protection. The reaction formula is as follows:

[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 a chiral indoline derivative, characterized in that: Indole derivative I is used as a reaction substrate, a chiral bisphosphine complex of palladium is used as a catalyst, and Bronsted acid is used as an additive to synthesize indoleline derivative II by asymmetric hydrogenation. The reaction formula is as follows: Where: Ar is phenyl or phenyl containing a substituent, wherein the substituent is halogen, C1-C 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.

2. The method according to claim 1, characterized in that The chiral diphosphine ligand is one of (S)-MeO-Biphep, (S)-SynPhos, (S)-SegPhos, (S)-BINAP and (S)-JosiPhos.

3. The method according to claim 1, characterized in that The metal precursor of palladium is palladium trifluoroacetate, palladium acetate, and palladium chloride.

4. The method according to claim 1, characterized in that The Bronsted acid is methanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, D-camphorsulfonic acid or L-camphorsulfonic acid.

5. The method according to any one of claims 1 to 4, characterized in that: The method comprises the following steps: (1) adding a palladium metal precursor and a chiral diphosphine ligand into a reaction container, adding acetone after inert gas replacement, stirring for 0.5 to 5 hours, and removing the acetone to obtain a catalyst; (2) Under an inert gas atmosphere, an organic solvent is added to a reaction vessel containing the catalyst, and the mixture is transferred to an ampoule containing indole derivative I, and Bronsted acid is added. The mixture is placed in a reaction vessel, and hydrogen is introduced to a pressure of 500-900 psi. The mixture is reacted at 60-90° C. for 4-48 hours to obtain a chiral indole derivative.

6. The method according to claim 5, characterized in that The organic solvent described in step (2) includes DCM, TFE and HFIP.

7. The method according to claim 5, characterized in that The molar ratio of the palladium metal precursor, the chiral diphosphine ligand, the Bronsted acid and the indole derivative I is 1:1-1.2:40-80:20-100.

8. The method according to claim 5, characterized in that The chiral bisphosphine ligand is (S)-MeO-BIPHEP, the organic solvent is TFE, the reaction temperature is 80°C, the hydrogen pressure is 750 psi, and the enantiomeric excess is more than 97%.

9. The method according to claim 5, characterized in that The inert gas described in step (2) is nitrogen, argon or helium.

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