CN110790694A - Method for synthesizing chiral indoline by using indole generated in situ by asymmetric hydrogenation under catalysis of palladium - Google Patents
Method for synthesizing chiral indoline by using indole generated in situ by asymmetric hydrogenation under catalysis of palladium Download PDFInfo
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- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/24—Phosphines, i.e. phosphorus bonded to only carbon atoms, or to both carbon and hydrogen atoms, including e.g. sp2-hybridised phosphorus compounds such as phosphabenzene, phosphole or anionic phospholide ligands
- B01J31/2495—Ligands comprising a phosphine-P atom and one or more further complexing phosphorus atoms covered by groups B01J31/1845 - B01J31/1885, e.g. phosphine/phosphinate or phospholyl/phosphonate ligands
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Abstract
A method for synthesizing chiral indoline by using indole generated in situ by palladium-catalyzed asymmetric hydrogenation. 1-5 mol% of palladium catalyst is adopted, 1-2.0equiv. acid is added, and the indole compound generated in situ is subjected to asymmetric hydrogenation to obtain a corresponding chiral indoline compound, wherein the enantiomeric excess of the chiral indoline compound can reach 96% at most. The method has the advantages of simple, convenient, practical and feasible operation, high yield, environment friendliness, commercial availability of the catalyst, mild reaction conditions and potential practical application value.
Description
Technical Field
The invention relates to a method for synthesizing chiral indoline by using indole generated in situ by highly enantioselective catalytic hydrogenation of a homogeneous system of palladium, belonging to the field of asymmetric catalytic synthesis.
Background
The chiral indoline compound is widely existed in natural products and bioactive molecules, has broad-spectrum physiological activity, and can be used as medicaments, insecticides, herbicides and the like. (references I.W. Southon and J.Buckingham, Dictionary of Alkaloids, Chapman and Hall, New York, 1989; (b) D.Zhang, H.Song and Y.Qin, Acc.chem.Res.,2011,44, 447.For some oligomers, see (c) W.G.Kim, J.P.Kim, H.Koshino, K.shin-Ya, H.Setoand I.D.Yoo, Tetrahedron,1997,53, 4309; (d) R.M.Jones, S.Han and J.V.Moody, Patent Appl.WO 2009151626,2009). Based on this, the asymmetric synthesis of chiral indolines and derivatives thereof has received extensive attention from researchers. The synthesis of the compound by asymmetric hydrogenation of indole derivatives is a simple, direct and efficient method. (references two are (a) D.S. Wang, Q.A. Chen, S.M.Lu and Y.G.Zhou, chem.Rev.,2012, 112,2557, (b) Y.M.He, F.T.Song and Q.H.Fan, Top.Curr.chem.,2013, 343,145, (c) R.Kuwano, heterocyles, 2008,76,909, (d) F.Glorius, org.biomol.chem., 2005,3,4171, (e) S.M.Lu, X.W.Hanand Y.G.Zhou, Chin.J.org.chem., 2012, 2005,25,634, (g) J.Xie and Q.Zhou, acta.Siwa, 70, 7). Kuwano and Ito et al developed Rh, Ru and Ir catalytic systems for the hydrogenation of N-Ac, Ts, Boc protected indoles since 2000 to synthesize a series of N-protected chiral indoline derivatives (ref. three (a) Kuwano, R.; Sato, K.; Kurokawa, T.; Karube, D.; Ito, Y.J.am.Chem.Soc.2000,122,7614.(b) Kuwano, R.; Kaneda, K.; Ito, T.; Sato, K.; Kurokawa, T.; Cheto, Y.Org.Lett.2004,6,2213.(c) Kuwano, R.; Kashiwabara, M.org.Lett.2006,8,2653.(d) Kuwano, R.; Kashibara, M.W.2006, Sawato, Kawary, R.; Bayt Baytz. J.52. Ito, Eupatz. A.52. A.; Bayt et. J.. In 2010, the week group first reported the palladium-catalyzed asymmetric hydrogenation of simple indoles to chiral indolines. (references four (a) D.S. Wang, Q.A.Chen, W.Li, C.B.Yu, Y.G.ZHou and X.Zhang, J.Am.chem.Soc., 2010,132,8909 (b) Y.Duan, M.W.Chen, Z.S.Ye, D.S.Wang, Q.A.Chen and Y.ZHou, chem.Eur.J.,2011,17,7193 (c) Y.Duan, M.W.Chen, Q.A.Chen, C.B.Yu and Y.G.ZHou, org.mol.Chen.2012, 10,1235 (d) C.Li, J.Chen, G.683, D.Liu, Y.Lihang, Fuhang, 69, 3, 9, 3.3, 69, 9). To date, although asymmetric hydrogenation of indoles has progressed. However, the above strategies also face limitations such as difficult and relatively unstable synthesis of indole. Therefore, the development of a highly efficient and more universal route for synthesizing chiral indoline derivative is of great significance and is a challenging direction.
Disclosure of Invention
The invention aims to provide a method for synthesizing chiral indoline by using indole generated in situ by palladium-catalyzed asymmetric hydrogenation. In order to achieve the purpose, the technical scheme adopted by the invention is as follows:
the invention uses chiral diphosphine P-P of palladium*The complex is used as a catalyst to realize the asymmetric hydrogenation of in-situ generated indole, and the reaction formula and the conditions are as follows:
in the formula:
r is C1-12Alkyl or aryl of (a);
the aryl is phenyl or an aromatic ring connected with different groups capable of attracting electrons or supplying electrons, and the groups are one or more than two of methyl, ethyl, methoxy, trifluoromethyl and halogen.
Ar is phenyl and aromatic ring connected with different groups R 'capable of attracting electrons or supplying electrons, wherein R' is one or more than two of methyl, ethyl, methoxy, trifluoromethyl and halogen
The hydrogenation reaction comprises two stages of catalyst preparation and substrate hydrogenation:
(1) preparing a catalyst: adding a palladium metal precursor and a chiral diphosphine ligand into an organic solvent acetone, stirring for 0.5-2.0 hours at room temperature, and then carrying out vacuum concentration to remove the acetone to obtain a catalyst;
(2) hydrogenation reaction: adding the catalyst, the organic solvent and the additive into a reaction substrate, and introducing hydrogen for reaction to obtain a hydrogenated product. Releasing hydrogen, removing additives added in the reaction by using sodium bicarbonate solution, extracting by using dichloromethane (30mL) for three times, drying by using anhydrous sodium sulfate, removing the solvent by decompression, and then directly carrying out column chromatography separation to obtain a pure product.
The additive is trifluorosulfonic acid, methanesulfonic acid, ethylsulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, camphoric acid or benzoic acid.
In the preparation of the catalyst and the hydrogenation reaction, the organic solvent used in the reaction is one or two of trifluoroethanol, hexafluoroisopropanol, dichloromethane, 1, 2-dichloroethane and toluene, preferably trifluoroethanol, wherein the dichloromethane and the toluene have slightly poor effects.
The palladium metal precursor is selected from palladium acetate or palladium trifluoroacetate. The ligand is selected from (R) -DTBM-SegPhos or (R) -MeO-Biphep or (R) -BTFM-GarPhos or (S) -SynPhos or (R) -BINAP or (R) -H8-BINAPax,S,S)-C3-TunePhos or (R) -DifluorPhos, preferred bisphosphine ligands being: (R) -SegPhos or (R) -MeO-Biphep or (S) -SynPhos.
The metal precursor of palladium and the bisphosphine ligand are both commercially available and do not require any treatment.
The reaction feeding comprises the following steps: the molar ratio of the metal precursor of palladium, the chiral diphosphine ligand, the additive and the substrate is as follows: 0.01-0.05:0.011-0.055:1.0-2.0:1.
In the asymmetric hydrogenation reaction, the hydrogen reaction pressure is 10-1000psi, preferably 200-500 psi, the reaction temperature is 0-80 deg.C, preferably 30-60 deg.C, and the reactant concentration is 0.025-0.5 mmol/mL.
The invention has the beneficial effects that:
1. the reaction activity and the enantioselectivity are high, and a high enantiomeric excess pure product can be obtained;
2. the catalyst is convenient to prepare, and the reaction operation is simple, convenient and practical;
3. the hydrogenation reaction condition is mild.
Detailed Description
The present invention will be described in more detail by way of examples, but the present invention is not limited to the following examples.
Examples 1 to 16:
optimization of hydrogenation reaction conditions
Adding a palladium precursor (1-5 mol% of the amount of a substrate) and a chiral diphosphine ligand (1.1-5.5 mol% of the amount of the substrate) into a reaction bottle under the nitrogen atmosphere, adding acetone (1.0-2.0 mL), stirring at room temperature for 1h, removing the acetone under reduced pressure, then taking the catalyst into a glove box, dissolving the catalyst by using an organic solvent for hydrogenation reaction, transferring the catalyst into a reaction bottle containing an additive (1.0-2.0 equiv of the amount of the substrate) and 0.2mmol of the substrate, then putting the reaction bottle into a reaction kettle, introducing hydrogen (10-1000 psi), and reacting at 0-80 ℃ for 12-48 hours; releasing hydrogen, removing the solvent under reduced pressure, adding sodium bicarbonate aqueous solution, extracting with DCM, combining the organic layers, removing the solvent under reduced pressure, and separating by column chromatography to obtain the pure product. The types of organic solvents, additives and chiral diphosphine ligands in the reaction process are changed to obtain 16 different examples, the changed types are shown in table 1, and the reaction formula and the ligand structure are as follows:
the yield was the conversion, the enantiomeric excess of the product was determined by chiral liquid chromatography and is detailed in table 1.
TABLE 1 in situ optimization of conditions for palladium catalyzed asymmetric hydrogenation of generated indolesa
Examples 17 to 30
Synthesis of chiral indoline 2 from indole generated in situ by palladium-catalyzed asymmetric hydrogenation
Adding a palladium precursor (1-5 mol% of the amount of a substrate) and a chiral diphosphine ligand (1.1-5.5 mol% of the amount of the substrate) into a reaction bottle under the nitrogen atmosphere, adding acetone (1.0-2.0 mL), stirring at room temperature for 1h, removing the acetone under reduced pressure, then taking the catalyst into a glove box, dissolving the catalyst by using a solvent for hydrogenation reaction, transferring the catalyst into a reaction bottle containing an additive (1.0-2.0 equiv. of the amount of the substrate) and 0.25mmol of the substrate, then putting the reaction bottle into a reaction kettle, introducing hydrogen (10-1000 psi), and reacting at 0-80 ℃ for 12-48 hours; releasing hydrogen, removing the solvent under reduced pressure, adding an aqueous solution of sodium bicarbonate, extracting with DCM, combining the organic layers, removing the solvent under reduced pressure, separating by column chromatography to obtain a pure product, and changing the type of a substrate in the reaction process to obtain 14 different examples, wherein the specific changed types are shown in the reaction formula and the ligand structure of Table 2 as follows:
the yields were isolated and the enantiomeric excesses of the products were determined by chiral liquid chromatography, as shown in table 2. Watch (A)
2. Chiral indoline synthesized from indole generated in situ by palladium-catalyzed asymmetric hydrogenationa
(+)-(R)-2-Benzylindoline(3a):51mg,98％yield,colorless oil,knowncompound,Rf＝ 0.65(hexanes/ethyl acetate 10/1),95％ee,[α]20 D＝+95.09(c1.02,CHCl3),[lit.[4]:[α]RT D＝
CDCl3)δ150.6,139.1,129.2,128.7,128.4,127.4,126.5,124.8,118.6,109.1,61.0,42.7,36.0.HPLC(OD-H,elute:n-hexane/i-PrOH＝99/1,detector:254nm,30℃,flow rate:1.0mL/min),t1＝14.8min(maj),t2＝16.6min.
(+)-(R)-2-(2-Methylbenzyl)indoline(3b):51mg,91％yield,colorless oil,known compound,Rf＝0.60(hexanes/ethyl acetate 20/1),94％ee,[α]20 D＝+90.49(c1.00,CHCl3),
[lit.[4]:[α]RT D＝+74.8(c 1.50,CHCl3)for 94％ee]；1HNMR(400MHz,CDCl3)δ7.19-7.12 (m,4H),7.08(d,J＝7.2Hz,1H),7.00(t,J＝7.6Hz,1H),6.71-6.67(m,1H),6.54(d,J＝ 7.7Hz,1H),4.14-4.01(m,1H),3.54(brs,1H),3.13(dd,J＝15.5,8.4Hz,1H),2.93-2.75(m, 3H),2.32(s,3H)；13C NMR(100MHz,CDCl3)δ150.6,137.3,136.6,130.6,129.8,128.4, 127.4,126.6,126.1,124.9,118.6,109.2,59.7,39.7,36.1,19.7.HPLC(OD-H,elute: n-hexane/i-PrOH＝99/1,detector:254nm,30℃,flow rate:1.0mL/min),t1＝13.8 min(maj),t2＝15.7min.
(+)-(R)-2-(3-Methylbenzyl)indoline(3c):50mg,90％yield,colorless oil,known compound,Rf＝0.55(hexanes/ethyl acetate 20/1).95％ee,[α]20 D＝+86.69(c1.00,CHCl3),
150.6,139.1,138.3,130.0,128.6,128.5,127.4,127.2,126.2,124.9,118.6,109.2,61.0,42.7, 36.0,21.5.HPLC(OD-H,elute:n-hexane/i-PrOH＝99/1,detector:254nm,30℃,flow rate: 1.0mL/min),t1＝11.6min(maj),t2＝12.9min.
(+)-(R)-2-(4-Methylbenzyl)indoline(3d):52mg,93％yield,colorless oil,known compound,Rf＝0.50(hexanes/ethyl acetate 20/1).95％ee,[α]20 D＝+87.95(c0.98,CHCl3),
42.3,35.9,21.1.HPLC(OD-H,elute:n-hexane/i-PrOH＝99/1,detector:254nm,30℃,flow rate:1.0mL/min),t1＝11.6min(maj),t2＝12.9min.
(+)-(R)-2-Methylindoline(3e):32mg,96％yield,colorless oil,knowncompound,Rf＝ 0.75(hexanes/ethyl acetate 10/1).90％ee,[α]20 D＝+3.98(c0.56,benzene),[lit.[4]:[α]RT D＝
1.27(d,J＝6.2Hz,3H)；13C NMR(100 MHz,CDCl3)δ151.0,128.9,127.3,124.7,118.6,109.2,55.2,37.8,22.3.HPLC(OD-H,elute:n-hexane/i-PrOH＝97/3,detector:254nm,30℃,flow rate:0.8mL/min),t1＝11.0min(maj),t2＝12.5min.
(+)-(R)-2-Ethylindoline(3f):30mg,82％yield,colorless oil,knowncompound,Rf＝0.60 (hexanes/ethyl acetate 20/1).94％ee,[α]20 D＝+5.88(c0.34,CHCl3),[lit.[5]:[α]22 D＝-5.5(c
1.68-1.56(m,2H),0.96(t,J＝7.4Hz,3H)；13C NMR(100MHz,CDCl3)δ151.0,128.9, 127.2,124.7,118.4,109.1,61.5,35.8,29.6,10.7.HPLC(OD-H,elute:n-hexane/i-PrOH＝ 95/5,detector:254nm,30℃,flow rate:1.0mL/min),t1＝8.0min(maj),t2＝9.0min.
(+)-(R)-2-Propylindoline(3g):34mg,84％yield,colorless oil,knowncompound,Rf＝ 0.60(hexanes/ethyl acetate 20/1).94％ee,[α]20 D＝+11.50(c0.40,CHCl3),[lit.[6]:[α]25 D＝+9.3(c 0.3,CHCl3)for 96％e.e.]；1H NMR(400MHz,CDCl3)δ7.06(d,J＝7.2Hz,1H), 6.99(t,J＝7.6Hz,1H),6.67(t,J＝7.3Hz,1H),6.59(d,J＝7.7Hz,1H),3.91-3.79(m,1H), 3.47-3.05(m,1H；brs,1H),2.71-2.62(m,1H),1.65-1.51(m,2H),1.47-1.34(m,2H),0.96(t, J＝7.3Hz,3H)；13C NMR(100MHz,CDCl3)δ151.0,128.9,127.2,124.7,118.5,109.1, 59.8,39.1,36.2,19.8,14.2.HPLC(OD-H,elute:n-hexane/i-PrOH＝95/5,detector:254nm, 30℃,flow rate:1.0mL/min),t1＝7.7min(maj),t2＝9.2min.
(+)-(S)-2-Isopropylindoline(3h):38mg,94％yield,colorless oil,knowncompound,[7]Rf＝0.80(hexanes/ethyl acetate 10/1).96％ee,[α]20 D＝-12.86(c0.70,CHCl3),1H NMR(400
(d,J＝6.7Hz,3H)；13C NMR(100MHz,CDCl3)δ151.4,129.2,127.2,124.5,118.3,108.8,66.6,34.2,34.0,19.6,19.1.HPLC(OD-H,elute:n-hexane/i-PrOH＝99/1,detector:254nm, 30℃,flow rate:1.0mL/min),t1＝10.7min(maj),t2＝17.5min.
(+)-(R)-2-Butylindoline(3i):43mg,98％yield,colorless oil,knowncompound,Rf＝0.85(hexanes/ethyl acetate 10/1).94％ee,[α]20 D＝+16.28(c0.86,CHCl3),
(m,1H),2.70-2.62(m,1H),1.66-1.54(m,2H),1.41-1.30(m,4H),0.92(t,J＝6.9Hz,3H)；13CNMR(100MHz,CDCl3)δ151.0,128.9,127.2,124.7,118.4,109.1,60.1,36.6,36.2, 28.8,22.8,14.1.HPLC(OD-H,elute:n-hexane/i-PrOH＝99/1,detector:254nm,30℃, flowrate:1.0mL/min),t1＝9.5min(maj),t2＝13.1min.
(+)-(R)-2-Pentylindoline(3j):46mg,97％yield,colorless oil,knowncompound,Rf＝0.85(hexanes/ethyl acetate 10/1).93％ee,[α]20 D＝+15.87(c0.92,CHCl3),[lit.[4]:[α]RT D＝
6H),0.90(t,J＝6.9Hz,3H)；13C NMR(100MHz,CDCl3)δ151.0,128.9,127.2,124.6, 118.4,109.1,60.1,36.8,36.2,31.9,26.3,22.7,14.0.HPLC(OD-H,elute:n-hexane/i-PrOH ＝99/1,detector:254nm,30℃,flow rate:1.0mL/min),t1＝9.6min(maj),t2＝12.4min.
(+)-(R)-2,7-Dimethylindoline(3k):35mg,94％yield,colorless oil,knowncompound,Rf＝0.65(hexanes/ethyl acetate 10/1).96％ee,[α]20 D＝+8.12(c0.48,CHCl3),1H NMR(400
118.6,55.2,38.1,22.5,16.9.HPLC(OD-H,elute:n-hexane/i-PrOH＝99/1,detector:254nm,30℃,flow rate:1.0mL/min),t1＝11.1min,t2＝12.4nin(maj).
(+)-(R)-7-Methoxy-2-methylindoline(3l):37mg,91％yield,colorless oil,new compound,Rf＝0.40(hexanes/ethyl acetate 20/1).80％ee,[α]20 D＝+8.09(c0.68,CHCl3),
129.9,119.1,117.3,109.2,55.7,55.3,38.4,22.3.HPLC(OD-H,elute:n-hexane/i-PrOH＝99/1,detector:254nm,30℃,flow rate:1.0mL/min),t1＝13.9min,t2＝16.6min(maj).HRMS Calculated for C10H14NO[M+H]+164.1070,found:164.1072.
(+)-(R)-5-Methoxy-2-methylindoline(3m):33mg,81％yield,yellow oil,newcompound,Rf＝0.20(hexanes/ethyl acetate 20/1).84％ee,[α]20 D＝+7.00(c0.60,CHCl3),3H)；13C NMR(100MHz,CDCl3)δ153.5,144.7,130.8,112.1,111.7,109.9,56.0,55.7, 38.3,22.2.HPLC(OD-H,elute:n-hexane/i-PrOH＝95/5,detector:254nm,30℃,flow rate:1.0mL/min),t1＝9.2min(maj),t2＝18.4min.
(+)-(R)-2,5,7-Trimethylindoline(3n):36mg,90％yield,colorless oil,newcompound, Rf＝0.70(hexanes/ethyl acetate 10/1).94％ee,[α]20 D＝+10.48(c0.42,
CDCl3)δ147.2,128.8,128.7,128.2,122.9,118.6,55.4,38.2,22.4,20.8,16.8.HPLC(OD-H, elute:n-hexane/i-PrOH＝99/1,detector:254nm,30℃,flow rate:1.0mL/min),t1＝7.3 min,t2＝8.1min(maj).HRMS Calculated for C11H16N[M+H]+162.1277,found:162.1282。
Claims (8)
1. Method for synthesizing chiral indoline by asymmetric hydrogenationCharacterized in that: the chiral indoline is chiral diphosphine P-P of palladium*The coordination compound catalyzes the preparation of indole generated in situ.
In the formula:
r is C1-12Alkyl or aryl of (a);
the aryl is phenyl or an aromatic ring connected with different groups capable of attracting electrons or supplying electrons, and the groups are one or more than two of methyl, ethyl, methoxy, trifluoromethyl and halogen.
Ar is phenyl and an aromatic ring connected with different groups R 'for electron withdrawing or electron supplying, wherein R' is one or more than two of methyl, ethyl, methoxy, trifluoromethyl and halogen.
2. The process for asymmetric hydrogenation synthesis according to claim 1, characterized by comprising two stages of catalyst preparation and substrate hydrogenation:
(1) preparing a catalyst: stirring a palladium metal precursor and a chiral diphosphine ligand in acetone at room temperature for 0.5-2.0 hours, and then carrying out vacuum concentration to remove acetone to obtain a catalyst;
(2) hydrogenation reaction: adding the catalyst, the organic solvent and the additive into a reaction substrate, introducing hydrogen to react to obtain a hydrogenated product, and purifying to obtain a pure product;
the additive is trifluorosulfonic acid, methanesulfonic acid, ethylsulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, camphoric acid or benzoic acid.
3. The method of asymmetric hydrogenation synthesis according to claim 2, characterized in that: the purification steps are as follows: releasing hydrogen, removing additive in the reaction by sodium bicarbonate solution, extracting three times by dichloromethane, drying by anhydrous sodium sulfate, removing solvent by decompression, and directly carrying out column chromatography separation to obtain a pure product.
4. The method of asymmetric hydrogenation synthesis according to claim 2, characterized in that: the organic solvent is one or two of trifluoroethanol, hexafluoroisopropanol, dichloromethane, 1, 2-dichloroethane and toluene.
5. The method of asymmetric hydrogenation synthesis according to any one of claims 1-2, characterized in that: the palladium metal precursor is selected from palladium acetate or palladium trifluoroacetate.
6. The method of asymmetric hydrogenation synthesis according to any one of claims 1-2, characterized in that: the chiral diphosphine ligand is selected from (R) -DTBM-SegPhos, (R) -MeO-Biphep, (R) -BTFM-GarPhos, (S) -SynPhos, (R) -BINAP, (R) H8)ax,S,S)-C3-TunePhos or (R) -DifluorPhos.
7. The synthesis process of asymmetric hydrogenation according to any one of claims 1-2, characterized in that: the molar ratio of the metal precursor of palladium, the chiral diphosphine ligand, the additive and the substrate is as follows: 0.01-0.05:0.022-0.11:1.0-2.0:1.
8. The method of asymmetric hydrogenation synthesis according to claim 2, characterized in that: in the step (2), the reaction pressure of hydrogen is 10-1000psi, the reaction temperature is 0-80 ℃, and the reactant concentration is 0.025-0.5 mmol/mL.
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| US20130274283A1 (en) * | 2010-08-11 | 2013-10-17 | The Regents Of The University Of California | Premature-termination-codons readthrough compounds |
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| US20130274283A1 (en) * | 2010-08-11 | 2013-10-17 | The Regents Of The University Of California | Premature-termination-codons readthrough compounds |
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