CN115010565A - Synthesis method of spiro chiral indolinone containing indole skeleton - Google Patents

Synthesis method of spiro chiral indolinone containing indole skeleton Download PDF

Info

Publication number
CN115010565A
CN115010565A CN202110247252.4A CN202110247252A CN115010565A CN 115010565 A CN115010565 A CN 115010565A CN 202110247252 A CN202110247252 A CN 202110247252A CN 115010565 A CN115010565 A CN 115010565A
Authority
CN
China
Prior art keywords
chiral
phosphoric acid
indole
reaction
isatin
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN202110247252.4A
Other languages
Chinese (zh)
Inventor
周永贵
王新维
李翔
陈木旺
吴波
孙蕾
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Dalian Institute of Chemical Physics of CAS
Original Assignee
Dalian Institute of Chemical Physics of CAS
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Dalian Institute of Chemical Physics of CAS filed Critical Dalian Institute of Chemical Physics of CAS
Priority to CN202110247252.4A priority Critical patent/CN115010565A/en
Publication of CN115010565A publication Critical patent/CN115010565A/en
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B53/00—Asymmetric syntheses
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
    • B01J31/0234—Nitrogen-, phosphorus-, arsenic- or antimony-containing compounds
    • B01J31/0255—Phosphorus containing compounds
    • B01J31/0257—Phosphorus acids or phosphorus acid esters
    • B01J31/0258—Phosphoric acid mono-, di- or triesters ((RO)(R'O)2P=O), i.e. R= C, R'= C, H
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/20—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/584—Recycling of catalysts

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Materials Engineering (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Indole Compounds (AREA)

Abstract

The invention provides a synthesis method of spiro chiral indolinone containing indole skeleton, wherein the catalyst used in the synthesis method is chiral phosphoric acid. The method can obtain spiro indolinone containing indole skeleton (enantiomeric excess can reach more than 99%). The method has the advantages of simple and easy operation, commercial availability of the catalyst, good enantioselectivity and yield and potential application value.

Description

Synthesis method of spiro-chiral indolinone containing indole skeleton
Technical Field
The invention belongs to the field of asymmetric catalytic synthesis, and relates to a method for asymmetrically synthesizing spiro indolinone containing an indole skeleton by using isatin and 2- (2-indole) aniline derivatives as reaction substrates and chiral phosphoric acid as a catalyst.
Technical Field
Indole alkaloids have attractive chemical structure and broad spectrum of biological activity. Asymmetric catalysis of asymmetric Pictet-Spengler reactions provides a simple and efficient method for the synthesis of such enantiomerically pure compounds. Currently, the literature reports that the construction of the stereocenter by functionalization of the C-3 position of indoles is achieved by the Pictet-Spengler reaction using indoleethylamine and derivatives thereof. In contrast, relatively few reports have been made of the functionalization of the C-2 position of indoles by the Pictet-Spengler reaction. While the high enantioselectivity of such reactions for the construction of stereocenters for quaternary carbons has been only one successful report for the synthesis of chiral seven-membered ring benzazepindoles (Li, X.; Chen, D.; Gu, H.; Lin, X.Chem.Commun.2014,50,7538.). Jacobsen and You report such reactions, but with relatively low ee values (1Lee, y.; Klausen, r.s.; Jacobsen, e.n.org.lett.2011,13,5564; Wang, s. -g.; Zhang, w.; You, s. -l.org.lett.2013,15,1488.).
Disclosure of Invention
The invention aims to provide a method for asymmetrically synthesizing spiro-indolinone containing an indole skeleton by using isatin and 2- (2-indole) aniline derivatives as reaction substrates and chiral phosphoric acid as a catalyst.
The method has the advantages of easily obtained raw materials, simple and practical operation, high enantioselectivity, good yield, friendly reaction environment and the like.
In order to achieve the purpose, the technical scheme of the invention is as follows:
the invention provides a method for synthesizing spiro chiral indolinone containing an indole skeleton, which is characterized in that isatin and a 2- (2-indole) aniline derivative are used as reaction substrates in the reaction, chiral phosphoric acid is used as a catalyst, and the spiro chiral indolinone containing the indole skeleton is asymmetrically synthesized, wherein the reaction formula is as follows:
Figure BDA0002964530990000011
in the formula:
Ar 1 ,Ar 2 ,Ar 3 is a benzene ring with a substituent on the phenyl group, orThe substituent is halogen, alkoxy or C 1 -C 20 At least one of alkyl groups of (a);
r is alkyl or arylmethyl, including benzyl, naphthylmethyl, 4-methylbenzyl, 4-methoxybenzyl, benzhydryl and the like, preferably 4-methylbenzyl;
temperature: -20-30 ℃;
time: 1-120 hours;
CPA is chiral phosphoric acid.
Based on the technical scheme, preferably, the reaction steps of the method are as follows:
under the protection of nitrogen, mixing a 2- (2-indole) aniline derivative, isatin, catalyst chiral phosphoric acid and an organic solvent, stirring and reacting for 1-120h at-20-30 ℃, directly spin-drying the solvent, and carrying out column chromatography to obtain a corresponding chiral ketal amine compound; the molar ratio of the 2- (2-indole) aniline derivative to the isatin to the catalyst is (0.01-0.1): (1-2): 1-2, preferably (1-2): 1:0.05, more preferably (1-1.5): 1:0.05, and further preferably 1:1.5: 0.05.
Based on the technical scheme, the ratio of the catalyst, the isatin, the 2- (2-indole) aniline derivative and the organic solvent is preferably 0.01-0.1 mmol/1-2 mmol/1-50 ml, and preferably 0.05 mmol/1 mmol/1.5 mmol/10 ml.
Based on the technical scheme, preferably, a molecular sieve or anhydrous sodium sulfate can be added in the reaction, and the ratio of the molecular sieve or the anhydrous sodium sulfate to the isatin is 0.1-2 g:1mmol, anhydrous sodium sulfate is used to remove water from the reaction, and 0.5g:1mmol is preferred.
Based on the technical scheme, the organic solvent is preferably an aromatic hydrocarbon solvent, or dichloromethane, diethyl ether, ethyl acetate, dioxane, acetonitrile, chloroform and the like.
More preferably, the aromatic hydrocarbon solvent is toluene, xylene, benzene, trimethylbenzene, chlorobenzene, or the like.
Based on the technical scheme, preferably, the chiral phosphoric acid is a chiral phosphoric acid with a binaphthyl skeleton, and the structural formula is as follows:
Figure BDA0002964530990000021
in the formula:
Ar 4 is phenyl or benzene ring containing substituent, anthryl or phenanthryl, wherein the substituent is methyl, trifluoromethyl or isopropyl; further preferably, the chiral phosphoric acid is (R) -TRIP, and Ar is 2,4, 6-triisopropylphenyl.
The reaction is that isatin and 2- (2-indole) aniline derivatives are used as reaction substrates to synthesize chiral ketal amine compound, Ar 1 ,Ar 2 ,Ar 3 Is a benzene ring with phenyl containing substituent groups, wherein the substituent groups are halogen, alkoxy or C 1 -C 20 At least one of alkyl groups of (a); r is alkyl or arylmethyl; chiral phosphoric acid (R) -TRIP as catalyst, o-xylene as solvent at-20 deg.c and in the presence of anhydrous sodium sulfate and in the enantiomeric excess of>99％。
The invention has the following advantages:
1. the raw materials are simple and easy to obtain, and the synthesis is convenient.
2. The reaction has high enantioselectivity (the enantiomeric excess can reach more than 99 percent), high yield and convenient separation, can obtain high-purity products, and has potential application value.
3. The catalyst synthesis route is mature and commercially available.
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 29
Optimization of conditions
Under the protection of nitrogen, adding 2- (2-indole) aniline derivative (0.1 mmol), chiral phosphoric acid (0.005 mmol) and a solvent (1 ml) into a 25 ml Schelenk tube, adding isatin (0.11 mmol), reacting at 30 ℃ for 8-48h, directly spin-drying the solvent, and adding an internal standard to measure nuclear magnetic yield; the conditions of the solvent, the catalyst chiral phosphoric acid, the temperature, the charge ratio and the like in the reaction are changed, and the reaction formula and the chiral phosphoric acid have the following structures as shown in a table (table 1):
Figure BDA0002964530990000031
TABLE 1 Condition optimization a
Figure BDA0002964530990000032
Figure BDA0002964530990000041
a Reaction conditions 1a (0.10 mmol), 2a (0.10 mmol), toluene (1.0 ml), chiral phosphoric acid (0.005 mmol); b yield by nuclear magnetic assay. c Yield by hplc. d 50 mg of
Figure BDA0002964530990000042
Molecular sieves are used. e The reaction is carried out at 0 ℃. f Reaction at-20 ℃. g 50 mg of anhydrous sodium sulfate was used. h 1a (0.10 mmol), 2a (0.13 mmol). i 1a (0.15 mmol), 2a (0.10 mmol). f Chiral phosphoric acid (0.010 mmol.) examples 30-47
Chiral indolinone substrate expansion for chiral phosphoric acid catalyzed synthesis of spiro ring and containing indole structure
Under the protection of nitrogen, adding isatin (0.2 mmol), chiral phosphoric acid (R) -4g (0.01 mmol, 7.6 mg), o-xylene toluene (2 ml) and anhydrous sodium sulfate (100 mg) into a 25 ml Schelenk tube, stirring at-20 ℃ for 10 minutes, adding 2- (2-indole) aniline derivative (0.3 mmol) into the tube, reacting at-20 ℃ for 48-120 hours, adding saturated sodium bicarbonate solution, quenching the reaction, extracting, and separating by column chromatography to obtain a pure product. The yield was isolated and the enantiomeric excess of the product was determined by chiral liquid chromatography. Reaction formula and substrate Scale a The structure of (A) is as follows:
Figure BDA0002964530990000051
a reaction conditions 1(0.30 mmol), 2(0.20 mmol), o-xylene toluene (2.0 ml), chiral phosphoric acid (R) -4g (0.01 mmol), reaction at-20 ℃ for 120 hours; b for 48 hours. c Chiral phosphoric acid (R) -4g (0.02 mmol) and reaction at-10 deg.C for 120 hours.
(R)-11'-Benzyl-1-(4-methylbenzyl)-5',11'-dihydrospiro[indoline-3,6'-indolo[3,2-c]quinolin]-2-one(3aa):104mg,98％yield,light yellow solid,m.p.＝133-134℃,new compound,R f ＝0.40(hexanes/ethyl acetate 5:1),90％ee,[α] 20 D ＝+45.67(c 1.04,CH 2 Cl 2 )； 1 H NMR(400MHz,CDCl 3 )δ7.52(d,J＝7.4Hz,1H),7.46–7.30(m,9H),7.25–7.15(m,3H),7.15–7.04(m,3H),6.94(d,J＝7.8Hz,1H),6.88–6.79(m,1H),6.78–6.65(m,2H),6.37(d,J＝7.9Hz,1H),5.79(d,J＝17.9Hz,1H),5.66(d,J＝17.9Hz,1H),5.12(d,J＝15.4Hz,1H),4.78(d,J＝15.4Hz,1H),4.47(brs,1H),2.39(s,3H). 13 C NMR(100MHz,CDCl 3 )δ176.5,143.3,142.5,139.7,137.5,137.5,133.9,132.7,132.3,130.0,129.6,129.1,128.5,127.8,127.5,126.1,126.1,123.9,123.5,122.7,122.4,120.4,119.0,118.5,114.7,114.5,109.8,109.5,108.6,63.7,49.2,43.9,21.2.Enantiomeric excess was determined by HPLC(IC column,elute:n-Hexane/i-PrOH＝70/30,detector:254nm,flow rate:0.7mL/min,30℃),retention time 9.9min and 10.9min(major).HRMS(ESI)m/z Calculated for C 37 H 30 N 3 O[M+H] + 532.2383,found 532.2386.
(+)-11'-Methyl-1-(4-methylbenzyl)-5',11'-dihydrospiro[indoline-3,6'-indolo[3,2-c]quinolin]-2-one(3ba):28mg,31％yield,red oil,new compound,R f ＝0.50(hexanes/ethyl acetate 5:1),62％ee,[α] 20 D ＝+29.64(c 0.56,CH 2 Cl 2 )； 1 H NMR(400MHz,CDCl 3 )δ7.81(d,J＝7.7Hz,1H),7.48(d,J＝7.0Hz,1H),7.36–7.30(m,2H),7.25(d,J＝7.9Hz,2H),7.20–7.03(m,5H),6.96–6.83(t,J＝8.3Hz,2H),6.82–6.64(m,2H),6.23(d,J＝8.0Hz,1H),5.09(d,J＝15.3Hz,1H),4.69(d,J＝15.3Hz,1H),4.43(brs,1H),4.13(s,3H),2.36(s,3H). 13 C NMR(100MHz,CDCl 3 )δ176.6,143.4,142.6,139.4,137.5,133.6,132.7,132.3,129.9,129.5,128.4,127.7,126.1,123.5,123.4,122.8,122.0,119.8,118.8,118.3,115.3,114.6,109.4,109.3,107.8,63.6,43.8,33.1,21.2.Enantiomeric excess was determined by HPLC(AD-H column,elute:n-Hexane/i-PrOH＝70/30,detector:254nm,flow rate:0.7mL/min,30℃),retention time 17.5min and 24.9 min(major).HRMS(ESI)m/z Calculated for C 31 H 26 N 3 O[M+H] + 456.2070,found 456.2071.
(+)-11'-Benzyl-1-methyl-5',11'-dihydrospiro[indoline-3,6'-indolo[3,2-c]quinolin]-2-one(3ab):88mg,99％yield,yellow oil,new compound,R f ＝0.35(hexanes/ethyl acetate 3:1),87％ee,[α] 20 D ＝+75.11(c 0.88,CH 2 Cl 2 )； 1 H NMR(400MHz,CDCl 3 )δ7.53–7.30(m,8H),7.22(d,J＝8.3Hz,1H),7.16–7.02(m,4H),6.91(t,J＝7.5Hz,1H),6.79–6.62(m,2H),6.46(d,J＝8.0Hz,1H),5.82–5.60(m,2H),4.48(brs,1H),3.32(s,3H). 13 C NMR(100MHz,CDCl 3 )δ176.5,143.5,143.1,139.6,137.5,133.8,132.3,130.1,129.1,128.5,127.5,126.1,125.9,123.8,123.6,122.7,122.4,120.5,119.0,118.2,114.8,114.7,109.9,108.5,108.4,63.7,49.0,26.4.Enantiomeric excess was determined by HPLC(IA column,elute:n-Hexane/i-PrOH＝70/30,detector:254nm,flow rate:0.7mL/min,30℃),retention time 9.4min(major)and 12.0min.HRMS(ESI)m/z Calculated for C 30 H 24 N 3 O[M+H] + 442.1914,found 442.1919.
(+)-1,11'-Dibenzyl-5',11'-dihydrospiro[indoline-3,6'-indolo[3,2-c]quinolin]-2-one(3ac):100mg,96％yield,light yellow oil,new compound,R f ＝0.40(hexanes/ethyl acetate 5:1),87％ee,[α] 20 D ＝+33.80(c 1.00,CH 2 Cl 2 )； 1 H NMR(400 MHz,CDCl 3 )δ7.49(d,J＝7.3Hz,1H),7.41–7.36(m,5H),7.35–7.27(m,7H),7.18(d,J＝8.3Hz,1H),7.09–7.02(m,3H),6.89(d,J＝7.8Hz,1H),6.79(t,J＝7.5Hz,1H),6.71–6.64(m,2H),6.31(d,J＝8.0Hz,1H),5.75(d,J＝17.7Hz,1H),5.62(d,J＝17.9Hz,1H),5.12(d,J＝15.4Hz,1H),4.78(d,J＝15.4Hz,1H),4.44(brs,1H). 13 C NMR(100MHz,CDCl 3 )δ171.7,138.6,137.7,135.0,132.7,131.0,129.1,127.5,125.2,124.4,124.1,123.8,123.1,122.7,121.4,121.3,119.1,118.8,117.9,117.7,115.6,114.2,113.7,110.0,109.8,105.1,104.7,103.8,59.0,44.4,39.4.Enantiomeric excess was determined by HPLC(IA column,elute:n-Hexane/i-PrOH＝70/30,detector:254nm,flow rate:0.7mL/min,30℃),retention time 12.7min(major)and 17.0min.HRMS(ESI)m/z Calculated for C 36 H 28 N 3 O[M+H] + 518.2227,found 518.2223.
(+)-11'-Benzyl-1-(4-methoxybenzyl)-5',11'-dihydrospiro[indoline-3,6'-indolo[3,2-c]quinolin]-2-one(3ad):50mg,45％yield,yellow oil,new compound,R f ＝0.35(hexanes/ethyl acetate 5:1),85％ee,[α] 20 D ＝+31.10(c 1.00,CH 2 Cl 2 )； 1 H NMR(400MHz,CDCl 3 )δ7.50(d,J＝7.3Hz,1H),7.44–7.30(m,9H),7.20(d,J＝8.2Hz,1H),7.12–7.01(m,3H),6.94(d,J＝7.8Hz,1H),6.87(d,J＝8.6Hz,2H),6.80(t,J＝7.5Hz,1H),6.75–6.62(m,2H),6.31(d,J＝8.0Hz,1H),5.77(d,J＝17.9Hz,1H),5.65(d,J＝17.9Hz,1H),5.08(d,J＝15.2Hz,1H),4.74(d,J＝15.2Hz,1H),4.44(brs,1H),3.82(s,3H). 13 C NMR(100MHz,CDCl 3 )δ176.4,159.2,143.3,142.4,139.7,137.4,133.8,132.3,129.9,129.2,129.1,128.5,127.8,127.5,126.1,123.8,123.5,122.6,122.4,120.3,118.9,118.4,114.7,114.5,114.2,109.8,109.5,108.5,63.7,55.3,49.1,43.6.Enantiomeric excess was determined by HPLC(IA column,elute:n-Hexane/i-PrOH＝70/30,detector:254nm,flow rate:0.7mL/min,30℃),retention time 17.5min(major)and 18.8min.HRMS(ESI)m/z Calculated for C 37 H 30 N 3 O 2 [M+H] + 548.2333,found 548.2329.
(-)-11'-Benzyl-1-(naphthalen-1-ylmethyl)-5',11'-dihydrospiro[indoline-3,6'-indolo[3,2-c]quinolin]-2-one(3ae):101mg,89％yield,yellow solid,new compound,m.p.＝166-168℃,R f ＝0.25(hexanes/ethyl acetate 5:1),90％ee,[α] 20 D ＝-9.60(c 1.01,CH 2 Cl 2 )； 1 H NMR(400MHz,CDCl 3 )δ8.16(d,J＝8.1Hz,1H),7.99–7.89(m,1H),7.85(d,J＝8.2Hz,1H),7.59–7.47(m,4H),7.42(t,J＝7.1Hz,4H),7.37–7.31(m,3H),7.30–7.20(m,2H),7.15–7.00(m,3H),6.93–6.68(m,4H),6.34(d,J＝7.9Hz,1H),5.80(d,J＝17.9Hz,1H),5.67(d,J＝17.9Hz,1H),5.51(d,J＝16.0Hz,1H),5.40(d,J＝16.0Hz,1H),4.48(brs,1H). 13 C NMR(100MHz,CDCl 3 )δ176.5,143.3,142.9,139.7,137.4,134.0,133.9,132.1,131.2,130.6,130.0,129.1,129.0,128.5,128.5,127.5,126.7,126.1,126.1,125.6,125.3,123.8,123.5,123.1,122.7,122.4,120.4,119.1,118.5,114.9,114.6,110.0,109.8,108.4,63.6,49.1,42.3.Enantiomeric excess was determined by HPLC(IA column,elute:n-Hexane/i-PrOH＝70/30,detector:254nm,flow rate:0.7mL/min,30℃),retention time 12.0min(major)and 17.9min.HRMS(ESI)m/z Calculated for C 40 H 30 N 3 O[M+H] + 568.2383,found 568.2383.
(+)-1-Benzhydryl-11'-benzyl-5',11'-dihydrospiro[indoline-3,6'-indolo[3,2-c]quinolin]-2-one(3af):108mg,91％yield,yellow oil,new compound,R f ＝0.40(hexanes/ethyl acetate 10:1),89％ee,[α] 20 D ＝+0.93(c 1.08,CH 2 Cl 2 )； 1 H NMR(400MHz,CDCl 3 )δ7.54(d,J＝6.9Hz,1H),7.50–7.30(m,16H),7.24–7.15(m,2H),7.14–7.01(m,4H),6.83(t,J＝7.5Hz,1H),6.76–6.63(m,3H),6.30(d,J＝8.0Hz,1H),5.78(d,J＝17.8Hz,1H),5.65(d,J＝17.9Hz,1H),4.46(s,1H). 13 C NMR(100MHz,CDCl 3 )δ176.5,143.3,142.2,139.7,137.8,137.7,137.4,134.0,132.3,129.5,129.1,128.8,128.7,128.7,128.6,128.5,127.9,127.9,127.5,126.1,126.1,123.9,123.2,122.7,122.4,120.3,119.0,118.6,114.8,114.7,112.3,109.8,108.8,63.3,58.6,49.1.Enantiomeric excess was determined by HPLC(IA column,elute:n-Hexane/i-PrOH＝70/30,detector:254nm,flow rate:0.7mL/min,30℃),retention time 12.9min and 22.4min(major).HRMS(ESI)m/z Calculated for C 42 H 32 N 3 O[M+H] + 594.2540,found 594.2542.
(+)-11'-Benzyl-5-bromo-1-(4-methylbenzyl)-5',11'-dihydrospiro[indoline-3,6'-indolo[3,2-c]quinolin]-2-one(3ag):50mg,41％yield,yellow oil,new compound,R f ＝0.45(hexanes/ethyl acetate 5:1),93％ee,[α] 20 D ＝+34.70(c 1.00,CH 2 Cl 2 )； 1 H NMR(400MHz,CDCl 3 )δ7.61(d,J＝1.8Hz,1H),7.48–7.38(m,4H),7.38–7.31(m,3H),7.30–7.20(m,3H),7.20–7.04(m,4H),6.86(t,J＝7.5Hz,1H),6.79(d,J＝8.3Hz,1H),6.76–6.66(m,2H),6.41(d,J＝8.0Hz,1H),5.78(d,J＝17.9Hz,1H),5.67(d,J＝17.9Hz,1H),5.10(d,J＝15.3Hz,1H),4.74(d,J＝15.4Hz,1H),4.44(brs,1H),2.38(s,3H). 13 C NMR(100MHz,CDCl 3 )δ176.0,142.9,141.4,139.7,137.8,137.3,134.4,133.8,132.8,132.2,129.6,129.2,128.6,127.8,127.5,126.1,123.6,122.7,122.6,120.6,119.2,118.3,116.3,114.5,114.3,111.0,109.9,107.7,63.9,49.2,44.0,21.2.Enantiomeric excess was determined by HPLC(IA column,elute:n-Hexane/i-PrOH＝70/30,detector:254nm,flow rate:0.7mL/min,30℃),retention time 14.4min(major)and 20.2min.HRMS(ESI)m/z Calculated for C 37 H 29 BrN 3 O[M+H] + 610.1489( 79 Br)and 612.1475( 81 Br),found 610.1484( 79 Br)and 612.1465( 81 Br).
(+)-11'-Benzyl-5-methyl-1-(4-methylbenzyl)-5',11'-dihydrospiro[indoline-3,6'-indolo[3,2-c]quinolin]-2-one(3ah):43mg,39％yield,yellow oil,new compound,R f ＝0.35(hexanes/ethyl acetate 5:1),92％ee,[α] 20 D ＝+35.46(c 0.86,CH 2 Cl 2 )； 1 H NMR(400MHz,CDCl 3 )δ7.46–7.39(m,3H),7.38–7.29(m,6H),7.25–7.05(m,6H),6.88–6.80(m,2H),6.77–6.66(m,2H),6.41(d,J＝8.0Hz,1H),5.79(d,J＝17.9Hz,1H),5.67(d,J＝17.9Hz,1H),5.10(d,J＝15.3Hz,1H),4.75(d,J＝15.3Hz,1H),4.45(brs,1H),2.39(s,3H),2.28(s,3H). 13 C NMR(100MHz,CDCl 3 )δ176.5,143.4,140.0,139.7,137.5,133.8,133.1,132.8,132.4,130.2,129.5,129.1,128.5,127.9,127.5,126.7,126.1,123.9,122.6,122.4,120.4,118.9,118.6,114.6,114.5,109.8,109.3,108.6,63.9,49.2,43.9,21.2,21.1.Enantiomeric excess was determined by HPLC(IA column,elute:n-Hexane/i-PrOH＝60/40,detector:254nm,flow rate:0.6mL/min,30℃),retention time 13.3min(major)and 20.6min.HRMS(ESI)m/z Calculated for C 38 H 32 N 3 O[M+H] + 546.2540,found 546.2543.
(+)-11'-Benzyl-6-bromo-1-(4-methylbenzyl)-5',11'-dihydrospiro[indoline-3,6'-indolo[3,2-c]quinolin]-2-one(3ai):117mg,96％yield,yellow solid,new compound,m.p.＝150-151℃,R f ＝0.25(hexanes/ethyl acetate 5:1),83％ee,[α] 20 D ＝+18.12(c 1.17,CH 2 Cl 2 )； 1 H NMR(400MHz,CDCl 3 )δ7.49–7.40(m,3H),7.39–7.27(m,6H),7.27–7.18(m,4H),7.17–7.03(m,3H),6.91(t,J＝7.4Hz,1H),6.79–6.61(m,2H),6.43(d,J＝7.9Hz,1H),5.78(d,J＝17.9Hz,1H),5.66(d,J＝17.9Hz,1H),5.09(d,J＝15.4Hz,1H),4.70(d,J＝15.4Hz,1H),4.49(brs,1H),2.42(s,3H). 13 C NMR(100MHz,CDCl 3 )δ176.3,143.8,143.1,139.7,137.8,137.4,133.9,132.1,131.3,129.8,129.2,128.7,127.8,127.6,127.4,126.5,126.1,123.7,123.6,122.7,122.6,120.6,119.2,118.3,114.6,114.6,112.9,110.0,107.8,63.5,49.2,44.0,21.3.Enantiomeric excess was determined by HPLC(IA column,elute:n-Hexane/i-PrOH＝60/40,the detector:254nm,flow rate:0.6mL/min,30℃),retention time 13.3min(major)and 16.8min.HRMS(ESI)m/z Calculated for C 37 H 29 BrN 3 O[M+H] + 610.1489( 79 Br)and 612.1475( 81 Br),found 610.1491( 79 Br)and 612.1478( 81 Br).
(+)-11'-Benzyl-7-bromo-1-(4-methylbenzyl)-5',11'-dihydrospiro[indoline-3,6'-indolo[3,2-c]quinolin]-2-one(3aj):87mg,71％yield,yellow oil,new compound,R f ＝0.20(hexanes/ethyl acetate 10:1),83％ee,[α] 20 D ＝+1.06(c 0.85,CH 2 Cl 2 )； 1 H NMR(400MHz,CDCl 3 )δ7.54(d,J＝8.1Hz,1H),7.49(d,J＝6.9Hz,1H),7.46–7.20(m,9H),7.18–7.04(m,4H),6.99–6.89(m,2H),6.77–6.66(m,2H),6.50(d,J＝8.0Hz,1H),5.77(d,J＝17.9Hz,1H),5.66(d,J＝17.9Hz,1H),5.53–5.38(m,2H),4.46(brs,1H),2.38(s,3H). 13 C NMR(100MHz,CDCl 3 )δ177.2,143.0,140.1,139.7,137.4,136.9,135.9,135.7,134.3,134.0,129.3,129.2,128.6,127.6,127.1,126.1,125.5,124.9,123.6,122.7,122.6,120.6,119.3,118.4,114.7,110.0,108.2,102.7,63.1,49.1,44.4,21.2.Enantiomeric excess was determined by HPLC(IAcolumn,elute:n-Hexane/i-PrOH＝70/30,detector:254nm,flow rate:0.7mL/min,30℃),retention time18.3min(major)and 20.4min.HRMS(ESI)m/z Calculated for C 37 H 29 BrN 3 O[M+H] + 610.1489( 79 Br)and 612.1475( 81 Br),found 610.1488( 79 Br)and 612.1475( 81 Br).
(+)-11'-Benzyl-8'-methoxy-1-(4-methylbenzyl)-5',11'-dihydrospiro[indoline-3,6'-indolo[3,2-c]quinolin]-2-one(3ca):75mg,67％yield,light yellow solid,new compound,R f ＝0.30(hexanes/ethyl acetate5:1),75％ee,[α] 20 D ＝+41.86(c 0.75,CH 2 Cl 2 )； 1 H NMR(400MHz,CDCl 3 )δ7.58(d,J＝7.2Hz,1H),7.48–7.25(m,9H),7.20–7.03(m,5H),6.92(d,J＝7.8Hz,1H),6.82–6.64(m,3H),5.75(d,J＝17.8Hz,1H),5.65(d,J＝2.0Hz,1H),5.59(d,J＝17.8Hz,1H),5.17(d,J＝15.4Hz,1H),4.66(d,J＝15.4Hz,1H),4.52(brs,1H),3.29(s,3H),2.37(s,3H). 13 C NMR(100MHz,CDCl 3 )δ176.5,154.3,143.5,142.9,137.6,137.5,134.9,134.3,132.7,132.2,129.9,129.6,129.1,128.5,127.7,127.5,126.4,126.1,124.1,123.5,122.6,119.0,114.9,114.6,112.5,110.6,109.4,108.2,99.7,63.7,54.9,49.2,43.8,21.2.Enantiomeric excess was determined by HPLC(IA column,elute:n-Hexane/i-PrOH＝60/40,detector:254nm,flow rate:0.6mL/min,30℃),retention time 14.5min(major)and 22.5min.HRMS(ESI)m/zCalculated for C 38 H 32 N 3 O 2 [M+H] + 562.2489,found 562.2486.
(+)-11'-Benzyl-8'-chloro-1-(4-methylbenzyl)-5',11'-dihydrospiro[indoline-3,6'-indolo[3,2-c]quinolin]-2-one(3da):108mg,96％yield,light yellow solid,new compound,R f ＝0.50(hexanes/ethyl acetate5:1),94％ee,[α] 20 D ＝+48.52(c 1.08,CH 2 Cl 2 )； 1 H NMR(400MHz,CDCl 3 )δ7.49(d,J＝7.1Hz,1H),7.46–7.26(m,9H),7.20(d,J＝7.9Hz,2H),7.15–7.00(m,4H),6.94(d,J＝7.8Hz,1H),6.78–6.62(m,2H),6.30(d,J＝1.7Hz,1H),5.74(d,J＝17.9Hz,1H),5.62(d,J＝17.9Hz,1H),5.15(d,J＝15.4Hz,1H),4.73(d,J＝15.4Hz,1H),4.48(brs,1H),2.39(s,3H). 13 C NMR(100MHz,CDCl 3 )δ176.3,143.5,142.4,138.0,137.6,137.0,135.1,132.5,131.8,130.3,129.8,129.2,129.0,127.7,127.6,126.1,126.0,125.9,124.8,123.7,122.8,122.6,119.0,117.8,114.7,114.2,110.9,109.8,108.0,63.5,49.2,43.9,21.3.Enantiomeric excess was determined by HPLC(IA column,elute:n-Hexane/i-PrOH＝60/40,detector:254nm,flow rate:0.6mL/min,30℃),retention time 14.3min(major)and 17.1min.HRMS(ESI)m/z Calculated for C 37 H 29 ClN 3 O[M+H] + 566.1994( 35 Cl)and 568.1984( 37 Cl),found 566.1997( 35 Cl)and 568.1976( 37 Cl).
(+)-11'-Benzyl-9'-chloro-1-(4-methylbenzyl)-5',11'-dihydrospiro[indoline-3,6'-indolo[3,2-c]quinolin]-2-one(3ea):111mg,98％yield,yellow oil,new compound,R f ＝0.40(hexanes/ethyl acetate 5:1),81％ee,[α] 20 D ＝+41.80(c 1.11,CH 2 Cl 2 )； 1 H NMR(400MHz,CDCl 3 )δ7.45–7.16(m,10H),7.08(d,J＝7.2Hz,2H),7.04–6.92(m,3H),6.86(d,J＝7.5Hz,1H),6.69–6.52(m,3H),6.25–6.02(m,2H),5.88(d,J＝17.9Hz,1H),5.03(d,J＝15.3Hz,1H),4.65(d,J＝15.3Hz,1H),4.39(brs,1H),2.30(s,3H). 13 C NMR(100MHz,CDCl 3 )δ176.2,143.6,142.4,139.4,137.7,136.4,135.0,132.6,131.9,130.2,129.6,129.0,128.9,127.9,127.2,127.1,126.2,126.0,124.5,123.6,123.4,121.1,119.2,117.2,117.1,114.8,114.1,109.7,109.4,63.4,50.4,43.9,21.3.Enantiomeric excess was determined by HPLC(IC column,elute:n-Hexane/i-PrOH＝70/30,detector:254nm,flow rate:0.7mL/min,30℃),retention time 8.0 min and 9.1min(major).HRMS(ESI)m/z Calculated for C 37 H 29 ClN 3 O[M+H] + 566.1994( 35 Cl)and 568.1989( 37 Cl),found 566.1991( 35 Cl)and 568.1977( 37 Cl).
(+)-11'-Benzyl-10'-chloro-1-(4-methylbenzyl)-5',11'-dihydrospiro[indoline-3,6'-indolo[3,2-c]quinolin]-2-one(3fa):112mg,99％yield,yellow oil,new compound,R f ＝0.40(hexanes/ethyl acetate 5:1),>99％ee,[α] 20 D ＝+50.98(c 1.12,CH 2 Cl 2 )； 1 H NMR(400MHz,CDCl 3 )δ7.45–7.16(m,10H),7.13(s,1H),7.09(d,J＝7.7Hz,2H),6.99(dd,J＝12.7,7.2Hz,2H),6.85(d,J＝7.8Hz,1H),6.74–6.54(m,3H),6.12(d,J＝8.5Hz,1H),5.64(d,J＝17.9Hz,1H),5.51(d,J＝17.9Hz,1H),5.04(d,J＝15.3Hz,1H),4.61(d,J＝15.3Hz,1H),4.41(brs,1H),2.30(s,3H). 13 C NMR(100MHz,CDCl 3 )δ176.3,143.4,142.4,140.1,137.7,136.9,134.7,132.6,132.0,130.2,129.6,129.3,128.9,128.3,127.8,127.7,126.0,123.6,122.7,122.4,121.1,119.2,119.1,114.7,114.3,109.9,109.7,108.5,63.6,49.2,43.9,21.3.Enantiomeric excess was determined by HPLC(IA column,elute:n-Hexane/i-PrOH＝70/30,detector:254nm,flow rate:0.7mL/min,30℃),retention time 13.9min(major).HRMS(ESI)m/z Calculated for C 37 H 29 ClN 3 O[M+H] + 566.1994( 35 Cl)and 568.1989( 37 Cl),found 566.1994( 35 Cl)and 568.1979( 37 Cl).
(+)-11'-Benzyl-3'-methyl-1-(4-methylbenzyl)-5',11'-dihydrospiro[indoline-3,6'-indolo[3,2-c]quinolin]-2-one(3ga):96mg,88％yield,light yellow solid,new compound,m.p.＝200-201℃,R f ＝0.25(hexanes/ethyl acetate 5:1),12％ee,[α] 20 D ＝+4.37(c 0.96,CH 2 Cl 2 )； 1 H NMR(400MHz,CDCl 3 )δ7.56(d,J＝7.2Hz,1H),7.49–7.30(m,9H),7.27–7.17(m,3H),7.11(t,J＝7.5Hz,2H),6.97(d,J＝7.8Hz,1H),6.86(t,J＝7.5Hz,1H),6.67–7.51(m,2H),6.37(d,J＝8.0Hz,1H),5.79(d,J＝17.9Hz,1H),5.67(d,J＝17.9Hz,1H),5.15(d,J＝15.4Hz,1H),4.79(d,J＝15.4Hz,1H),4.45(brs,1H),2.42(s,3H),2.29(s,3H). 13 C NMR(100MHz,CDCl 3 )δ176.7,143.4,142.6,139.6,138.7,137.6,137.5,134.2,132.7,132.4,130.0,129.6,129.1,127.8,127.5,126.2,124.0,123.5,122.6,122.2,120.3,120.0,118.3,115.3,112.2,109.8,109.6,107.8,63.8,49.1,43.9,21.5,21.3.Enantiomeric excess was determined by HPLC(IA column,elute:n-Hexane/i-PrOH＝60/40,detector:254nm,flow rate:0.6mL/min,30℃),retention time 12.0min(major)and 20.6min.HRMS(ESI)m/z Calculated for C 38 H 32 N 3 O[M+H] + 546.2540,found 546.2540.
(+)-11'-Benzyl-5-bromo-8'-chloro-3'-methyl-1-(4-methylbenzyl)-5',11'-dihydrospiro[indoline-3,6'-indolo[3,2-c]quinolin]-2-one(3dg):121mg,94％yield,light yellow solid,new compound,m.p.＝150-152℃,R f ＝0.35(hexanes/ethyl acetate 5:1),95％ee,[α] 20 D ＝+62.31(c1.21,CH 2 Cl 2 )； 1 H NMR(400MHz,CDCl 3 )δ7.61(d,J＝1.9Hz,1H),7.51–7.26(m,9H),7.22(d,J＝7.9Hz,2H),7.18–7.03(m,3H),6.82(d,J＝8.4Hz,1H),6.76–6.64(m,2H),6.41(d,J＝1.7Hz,1H),5.75(d,J＝17.9Hz,1H),5.64(d,J＝17.9Hz,1H),5.16(d,J＝15.4Hz,1H),4.69(d,J＝15.4Hz,1H),4.50(brs,1H),2.40(s,3H). 13 C NMR(100MHz,CDCl 3 )δ175.9,143.0,141.2,138.1,137.9,136.8,135.0,134.0,133.1,132.0,129.9,129.3,129.1,129.0,127.7,127.7,126.4,126.0,124.5,122.9,122.8,119.2,117.5,116.4,114.7,113.8,111.3,111.0,107.1,63.7,49.3,44.1,21.3.Enantiomeric excess was determined by HPLC(IA column,elute:n-Hexane/i-PrOH＝60/40,detector:254nm,flow rate:0.6mL/min,30℃),retention time 13.4min(major)and 19.1min.HRMS(ESI)m/z Calculated for C 37 H 28 BrClN 3 O 2 [M+H] + 644.1099( 35 Cl+ 79 Br)and 646.1081( 35 Cl+ 81 Br),found 644.1097( 35 Cl+ 79 Br)and 646.1084( 35 Cl+ 81 Br).
(+)-11'-Benzyl-8'-chloro-3',5-dimethyl-1-(4-methylbenzyl)-5',11'-dihydrospiro[indoline-3,6'-indolo[3,2-c]quinolin]-2-one(3dh):111mg,96％yield,yellow oil,new compound,R f ＝0.30(hexanes/ethyl acetate 5:1),91％ee,[α] 20 D ＝+50.18(c 1.11,CH 2 Cl 2 )； 1 H NMR(400MHz,CDCl 3 )δ7.48–7.39(m,3H),7.39–7.26(m,6H),7.26–7.00(m,6H),6.85(d,J＝7.9Hz,1H),6.78–6.64(m,2H),6.39(s,1H),5.75(d,J＝17.9Hz,1H),5.64(d,J＝17.9Hz,1H),5.16(d,J＝15.3Hz,1H),4.71(d,J＝15.4Hz,1H),4.51(brs,1H),2.40(s,3H),2.30(s,3H). 13 C NMR(100MHz,CDCl 3 )δ176.4,143.5,139.9,138.1,137.6,137.0,135.1,133.4,132.7,132.0,130.6,129.8,129.2,129.0,127.7,126.6,126.2,126.0,124.8,122.8,122.6,118.9,117.9,114.7,114.0,110.9,109.6,108.1,63.7,49.2,44.0,21.3,21.1.Enantiomeric excess was determined by HPLC(IA column,elute:n-Hexane/i-PrOH＝60/40,detector:254nm,flow rate:0.6mL/min,30℃),retention time 13.0min(major)and 20.8min.HRMS(ESI)m/z Calculated for C 38 H 31 ClN 3 O[M+H] + 580.2150( 35 Cl)and 582.2141( 37 Cl),found 580.2146( 35 Cl)and 582.2136( 37 Cl).
Examples 48 to 50
Chiral indolinone substrate development for synthesizing spiro containing pyrrole structure under catalysis of chiral phosphoric acid
Isatin (0.2 mmol), chiral phosphoric acid (R) -4g (0.01 mmol), o-xylene (2 ml) and anhydrous sodium sulfate (100 mg) were added to a 25 ml Schelenk tube under nitrogen protection, and after stirring at-20 ℃ for 10 minutes, the 2- (2-pyrrole) aniline derivative (0.3 mmol) was added thereto and reacted at-20 ℃ for 120 hours, and then a saturated sodium bicarbonate solution was added to quench the reaction, followed by extraction and column chromatography to obtain a pure product. The yield was isolated and the enantiomeric excess of the product was determined by chiral liquid chromatography. The reaction formula and the structure of the product are as follows:
Figure BDA0002964530990000161
a reaction conditions 1(0.30 mmol), 2(0.20 mmol), o-xylene (2.0 mmol)Ml), chiral phosphoric acid (R) -4g (0.01 mmol), reaction at-20 ℃ for 120 hours; b chiral phosphoric acid (R) -4g (0.02 mmol) and reaction at-10 deg.C for 120 hours.
(-)-1'-Benzyl-2'-methyl-1-(4-methylbenzyl)-1',5'-dihydrospiro[indoline-3,4'-pyrrolo[3,2-c]quinolin]-2-one(3ha):82mg,83％yield,light yellow oil,new compound,R f ＝0.10(hexanes/ethyl acetate10:1),88％ee,[α] 20 D ＝-17.32(c 0.82,CH 2 Cl 2 )； 1 H NMR(400MHz,CDCl 3 )δ7.46–7.37(m,3H),7.35–7.14(m,9H),7.05(t,J＝7.4Hz,1H),6.93(t,J＝7.4Hz,1H),6.81(d,J＝7.8Hz,1H),6.69–6.58(m,2H),5.52–5.37(m,3H),5.05(d,J＝15.5Hz,1H),4.77(d,J＝15.5Hz,1H),4.28(brs,1H),2.38(s,3H),2.14(s,3H). 13 C NMR(100MHz,CDCl 3 )δ177.4,141.7,141.4,137.7,137.4,133.7,133.0,132.3,129.5,129.4,129.1,127.6,127.3,126.1,126.0,125.9,125.1,123.3,120.0,118.9,117.4,116.3,114.4,109.3,103.0,63.8,48.9,43.7,21.2,12.4.Enantiomeric excess was determined by HPLC(IA column,elute:n-Hexane/i-PrOH＝70/30,detector:254nm,flow rate:0.7mL/min,30℃),retention time 13.4min(major)and 18.2min.HRMS(ESI)m/z Calculated for C 34 H 30 N 3 O[M+H] + 496.2383,found 496.2382.
(-)-1'-Benzyl-5-bromo-2'-methyl-1-(4-methylbenzyl)-1',5'-dihydrospiro[indoline-3,4'-pyrrolo[3,2-c]quinolin]-2-one(3hg):93mg,81％yield,yellow oil,new compound,R f ＝0.40(hexanes/ethyl acetate 5:1),86％ee,[α] 20 D ＝-46.52(c 0.46,CH 2 Cl 2 )； 1 H NMR(400MHz,CDCl 3 )δ7.53(s,1H),7.44–7.11(m,11H),6.93(t,J＝7.4Hz,1H),6.73–6.56(m,3H),5.54–5.34(m,3H),5.01(d,J＝15.6Hz,1H),4.73(d,J＝15.6Hz,1H),4.24(brs,1H),2.37(s,3H),2.14(s,3H). 13 C NMR(100MHz,CDCl 3 )δ176.9,140.9,140.7,137.6,137.5,135.7,132.5,132.5,132.2,129.6,129.1,128.4,127.5,127.4,126.1,126.1,125.8,120.0,119.1,116.5,116.0,115.9,114.4,110.9,103.0,63.9,48.9,43.7,21.2,12.4.Enantiomeric excess was determined by HPLC(IA column,elute:n-Hexane/i-PrOH＝60/40,detector:254nm,flow rate:0.6mL/min,30℃),retention time 14.4min(major)and 16.4min.HRMS(ESI)m/z Calculated for C 34 H 29 BrN 3 O[M+H] + 574.1489( 79 Br)and 576.1474( 81 Br),found 574.1486( 79 Br)and 576.1477( 81 Br).
(-)-1'-Benzyl-2',5-dimethyl-1-(4-methylbenzyl)-1',5'-dihydrospiro[indoline-3,4'-pyrrolo[3,2-c]quinolin]-2-one(3hh):92mg,90％yield,yellow oil,new compound,R f ＝0.45(hexanes/ethyl acetate 5:1),76％ee,[α] 20 D ＝-19.42(c 0.87,CH 2 Cl 2 )； 1 H NMR(400MHz,CDCl 3 )δ7.41(t,J＝7.5Hz,2H),7.37–7.26(m,4H),7.25–7.15(m,5H),7.05(d,J＝8.6Hz,1H),6.93(t,J＝7.3Hz,1H),6.76–6.57(m,3H),5.57–5.35(m,3H),5.03(d,J＝16.0Hz,1H),4.76(d,J＝15.9Hz,1H),4.27(brs,1H),2.38(s,3H),2.30(s,3H),2.15(s,3H). 13 C NMR(100MHz,CDCl 3 )δ177.4,141.5,139.3,137.7,137.3,133.8,133.1,132.9,132.3,129.7,129.5,129.1,127.6,127.3,126.0,126.0,125.9,125.8,119.9,118.8,117.4,116.2,114.3,109.1,103.1,63.9,48.9,43.7,21.2,21.1,12.5.Enantiomeric excess was determined by HPLC(IA column,elute:n-Hexane/i-PrOH＝60/40,detector:254nm,flow rate:0.6mL/min,30℃),retention time 12.7min(major)and 17.6min.HRMS(ESI)m/z Calculated for C 35 H 32 N 3 O 2 [M+H] + 510.2540,found 510.2539.

Claims (10)

1. A synthetic method of spiro-chiral indolinone containing an indole skeleton is characterized in that isatin and 2- (2-indole) aniline derivatives are used as reaction substrates, chiral phosphoric acid is used as a catalyst, and the spiro-chiral indolinone containing the indole skeleton is asymmetrically synthesized by the following reaction formula:
Figure FDA0002964530980000011
in the formula:
Ar 1 ,Ar 2 ,Ar 3 is phenyl or benzene ring containing substituent, and the substituent is halogen, alkoxy or C 1 -C 20 At least one of alkyl groups of (a);
r is alkyl or arylmethyl.
2. The method according to claim 1, wherein the method comprises the following specific reaction steps:
under the protection of nitrogen, mixing a catalyst, isatin, a 2- (2-indole) aniline derivative and an organic solvent, stirring at-20-30 ℃ for reaction for 1-120h, then, spin-drying the solvent, and performing column chromatography separation to obtain spiro indolinone;
the molar ratio of the catalyst to the isatin to the 2- (2-indole) aniline derivative is 0.01-0.1: 1-2.
3. The method according to claim 2, wherein the ratio of the catalyst, isatin, 2- (2-indole) aniline derivative and organic solvent is 0.01-0.1mmol: 1-2 mmol:1-50 ml.
4. The method according to claim 2, wherein the organic solvent is an aromatic hydrocarbon solvent.
5. The method according to claim 2, wherein the organic solvent is at least one of dichloromethane, diethyl ether, ethyl acetate, dioxane, acetonitrile, chloroform.
6. The method according to claim 1 or 2, wherein the chiral phosphoric acid is a chiral phosphoric acid of a binaphthyl skeleton.
7. The method of claim 6, wherein the chiral phosphoric acid has the following structural formula:
Figure FDA0002964530980000012
in the formula:
Ar 4 is phenyl or benzene ring containing substituent, anthryl or phenanthryl, wherein the substituent is methyl, trifluoromethyl or isopropyl.
8. The method according to claim 4, wherein the aromatic hydrocarbon solvent is at least one of toluene, xylene, benzene, chlorobenzene, and trimethylbenzene.
9. The method of claim 7, wherein the chiral phosphoric acid is (R) -TRIP.
10. The method according to claim 1 or 2, wherein a molecular sieve or anhydrous sodium sulfate is further added to the reaction, and the ratio of the molecular sieve or anhydrous sodium sulfate to the isatin is 0.1-2 g:1 mmol.
CN202110247252.4A 2021-03-05 2021-03-05 Synthesis method of spiro chiral indolinone containing indole skeleton Pending CN115010565A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202110247252.4A CN115010565A (en) 2021-03-05 2021-03-05 Synthesis method of spiro chiral indolinone containing indole skeleton

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202110247252.4A CN115010565A (en) 2021-03-05 2021-03-05 Synthesis method of spiro chiral indolinone containing indole skeleton

Publications (1)

Publication Number Publication Date
CN115010565A true CN115010565A (en) 2022-09-06

Family

ID=83064692

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202110247252.4A Pending CN115010565A (en) 2021-03-05 2021-03-05 Synthesis method of spiro chiral indolinone containing indole skeleton

Country Status (1)

Country Link
CN (1) CN115010565A (en)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102627650A (en) * 2012-03-08 2012-08-08 徐州师范大学 Chiral spiro(pyrrolidine-3, 2'-oxindole)compound and synthesis method thereof
CN107602577A (en) * 2017-09-06 2018-01-19 苏州大学 Chiral bridge ring skeleton hydroxyindole spiro piperidines and its synthetic method
CN108409746A (en) * 2018-05-15 2018-08-17 中山大学 A kind of chiral oxo spiro indole class compound and its raceme and preparation method containing pyrroles or indoles and azacycloalkyl structure
CN111848623A (en) * 2019-04-25 2020-10-30 中国科学院大连化学物理研究所 Method for synthesizing fluorine-containing chiral ketal amine by catalysis of chiral phosphoric acid

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102627650A (en) * 2012-03-08 2012-08-08 徐州师范大学 Chiral spiro(pyrrolidine-3, 2'-oxindole)compound and synthesis method thereof
CN107602577A (en) * 2017-09-06 2018-01-19 苏州大学 Chiral bridge ring skeleton hydroxyindole spiro piperidines and its synthetic method
CN108409746A (en) * 2018-05-15 2018-08-17 中山大学 A kind of chiral oxo spiro indole class compound and its raceme and preparation method containing pyrroles or indoles and azacycloalkyl structure
CN111848623A (en) * 2019-04-25 2020-10-30 中国科学院大连化学物理研究所 Method for synthesizing fluorine-containing chiral ketal amine by catalysis of chiral phosphoric acid

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
XIN-WEI WANG等: "Chiral phosphoric acid-catalyzed regioselective synthesis of spiro aminals with quaternary stereocenters", 《TETRAHEDRON LETTERS》 *

Similar Documents

Publication Publication Date Title
CN111675712B (en) Synthesis method of pyrazolone benzodiazepine compound
CN107602577A (en) Chiral bridge ring skeleton hydroxyindole spiro piperidines and its synthetic method
CN114920775B (en) Axial chiral bisindole catalyst and synthetic method and application thereof
Lautens et al. Ring-opening reactions of an oxabicyclic compound with cuprates
CN112812097B (en) Method for synthesizing 3- (2-pyridine) substituted pyrrole compound by visible light catalysis
CN111517964B (en) Method for splitting chiral compound
CN111848322B (en) Axial chiral oxindole-substituted styrene compound and resolution method and application thereof
CN111848623B (en) Method for synthesizing fluorine-containing chiral ketal amine by catalysis of chiral phosphoric acid
CN115010565A (en) Synthesis method of spiro chiral indolinone containing indole skeleton
CN114874139B (en) Synthesis method of 1-benzyl or allyl 3, 4-dihydroisoquinoline
CN114014865A (en) Asymmetric trimeric indole compound and preparation method thereof
Chen et al. Synthetic Studies on d-Biotin, Part 9. An Improved Asymmetric Synthetic Route to d-Biotin via Hoffmann–Roche Lactone–Thiolactone Approach
CN109851599B (en) Preparation method of 2-aminobenzofuran compound
CN112209947A (en) Chiral indoxazinone compound and synthesis method thereof
Shumaila et al. Diastereoselective synthesis of 1, 1, 4-trisubstituted-2, 3, 4, 9-tetrahydrospiro-β-carbolines via glacial acetic acid catalyzed Pictet-Spengler reaction
CN116178371A (en) Method for synthesizing spiro chiral indolinone through indole C6-position Pictet-Spengler reaction
CN114213410B (en) Synthesis method of aromatic ring [ a ] carbazole compound and aromatic ring [ g ] pyridine indole compound
CN114605273B (en) Method for synthesizing arylaminophenol compound by palladium-catalyzed CO-participated 1, 4-eneyne aromatization reaction
CN115057848B (en) Axis chiral isopyranone-indole derivative and synthesis method thereof
CN110563658A (en) synthesis method of 1, 5-benzodiazepine compound
CN111808045B (en) Method for synthesizing chiral seven-element cyclic sulfonamide through organic catalysis
CN113735867B (en) Chiral indolo oxa seven-membered ring compound and synthesis method thereof
CN117820316B (en) Chiral indolo-dihydropyridoindole compound and synthesis method thereof
CN112341444B (en) 3- (2, 3-dihydropyrrole) indole compound and preparation method thereof
CN114075234B (en) Intermediate for preparing L-erythro biopterin compounds and preparation method thereof

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
RJ01 Rejection of invention patent application after publication

Application publication date: 20220906

RJ01 Rejection of invention patent application after publication