Propargylated 3, 3-disubstituted indoline-2-ketone compound containing continuous chiral center and synthesis method thereof

文档序号：574163 发布日期：2021-05-21 浏览：15次中文

阅读说明：本技术 一种炔丙基化含连续手性中心的3,3-二取代吲哚啉-2-酮类化合物及其合成方法 (Propargylated 3, 3-disubstituted indoline-2-ketone compound containing continuous chiral center and synthesis method thereof ) 是由胡向平夏金涛于 2019-11-21 设计创作，主要内容包括：本发明涉及一种炔丙基化含连续手性中心的3,3-二取代吲哚啉-2-酮类化合物及其合成方法。采用的手性铜催化剂是由铜盐与手性三齿P,N,N-配体(L2或L3)或手性三齿N,N,N-配体(L1)在各种极性和非极性溶剂中原位生成。本发明可以方便地制备各种炔丙基化含连续手性中心的3,3-二取代吲哚啉-2-酮类化合物,其非对映体过量比高达99:1,对映体过量百分数高达99％。本发明具有操作步骤简单、原料易制备、底物适用范围广、产率优秀、非对映及对映选择性高等特点。(The invention relates to a propargylated 3, 3-disubstituted indoline-2-ketone compound containing a continuous chiral center and a synthesis method thereof. The chiral copper catalyst is prepared from copper salt and chiral tridentate P, N, N-ligand (L2 or L3) or chiral tridentate N, N, N-ligand (L1) in situ in various polar and nonpolar solvents. The invention can conveniently prepare various propargylated 3, 3-disubstituted indoline-2-ketone compounds containing continuous chiral centers, the diastereomer excess ratio is up to 99:1, and the enantiomeric excess percentage is up to 99%. The method has the characteristics of simple operation steps, easy preparation of raw materials, wide application range of the substrate, excellent yield, high diastereo-selectivity and enantioselectivity and the like.)

1. A propargylated 3, 3-disubstituted indoline-2-ketone compound containing a continuous chiral center is characterized in that: the propargylated 3, 3-disubstituted indoline-2-ketone compound containing a continuous chiral center has one of the following structures:

i and II are enantiomers, III and IV are enantiomers, I and III or IV are diastereomers, and II and III or IV are diastereomers;

in the formula: r¹,R²，R³，R⁴Is C1-C40 alkyl, C3-C12 cycloalkyl or C3-C12 cycloalkyl with substituent, phenyl and substituted phenyl, benzyl and substituted benzyl, five-membered or six-membered heterocyclic aromatic group containing one or more than two oxygen, sulfur and nitrogen atoms, ester group;

the substituent on the C3-C12 naphthenic base, the substituent on the phenyl and the substituent on the benzyl are respectively one or more than two of C1-C40 alkyl, C1-C40 alkoxy, halogen, nitro, ester group or cyano, and the number of the substituents is 1-5.

2. A method for synthesizing propargylated 3, 3-disubstituted indolin-2-ones containing a continuous chiral center according to claim 1, characterized in that: in the presence of an alkaline additive, a chiral copper catalyst catalyzes a nucleophilic substitution reaction between 3-substituted indoline-2-ketone and propargyl acetate in a reaction medium to prepare a propargylated 3, 3-disubstituted indoline-2-ketone compound containing a continuous chiral center.

3. The method for synthesizing propargylated 3, 3-disubstituted indoline-2-one compounds containing continuous chiral centers according to claim 2, wherein the method comprises the following steps: the method comprises the following specific steps:

(1) preparation of chiral copper catalyst: under the protection of nitrogen, stirring copper salt and chiral tridentate ligand in a molar ratio of 1: 0.1-10 in a reaction medium for 30 minutes to prepare a chiral copper catalyst;

the chiral tridentate ligand is a chiral tridentate P, N, N-ligand (L-2 or L-3) or a chiral tridentate N, N, N-ligand (L-1);

(2) preparation of propargylated 3, 3-disubstituted indoline-2-ones containing a continuous chiral center: dissolving 3-substituted indoline-2-ketone, propargyl acetate and an alkaline additive in a reaction medium, then adding the solution into the solution of the chiral copper catalyst stirred in the step (1) under the protection of nitrogen for catalytic reaction, and stirring for reaction at a certain temperature for not less than 10 hours; after the reaction is finished, concentrating under reduced pressure until no solvent exists basically, separating by silica gel column chromatography, concentrating under reduced pressure, and drying in vacuum to obtain a target product;

the molar ratio of the chiral copper catalyst to the 3-substituted indoline-2-ketone compound is 0.01-100% to 1;

the molar ratio of the alkaline additive to the propargyl acetate compound is 0.5-10: 1;

the molar ratio of the 3-substituted indoline-2-ketone compound to the propargyl acetate compound is 1: 1 to 4.

4. The method for synthesizing propargylated 3, 3-disubstituted indolin-2-ones containing a continuous chiral center according to claim 2 or 3, wherein the method comprises the following steps: the reaction medium is at least one of methanol, ethanol, isopropanol, isobutanol, toluene, dichloromethane, diethyl ether, tetrahydrofuran, dimethyl sulfoxide or N, N-dimethylformamide.

5. The method for synthesizing propargylated 3, 3-disubstituted indolin-2-ones containing a continuous chiral center according to claim 2 or 3, wherein the method comprises the following steps: the 3-substituted indoline-2-ketone compound has the following structure:

6. The method for synthesizing propargylated 3, 3-disubstituted indolin-2-ones containing a continuous chiral center according to claim 2 or 3, wherein the method comprises the following steps: the propargyl acetate compound has the following structure:

in the formula: r¹Is one or more than two of C1-C10 alkyl, phenyl, substituted phenyl, naphthyl, substituted naphthyl, C5-C10 sulfur-containing heterocycle and C5-C10 oxygen-containing heterocycle; the substituent on the substituted phenyl, the substituted naphthyl, the sulfur-containing heterocycle of C5-C10 and the oxygen-containing heterocycle of C5-C10 is one or more of C1-C40 alkyl, alkoxy of C1-C40, halogen, nitro, ester group or cyano, and the number of the substituent is 1-5.

7. Propargyl according to claim 3The synthetic method of the 3, 3-disubstituted indoline-2-ketone compound containing the continuous chiral center is characterized in that: the copper salt is Cu (OAc)₂·H₂O、Cu(OAc)₂、Cu(OTf)₂、CuCl₂、CuOAc、CuCl、CuI、CuClO₄、CuOTf·0.5C₆H₆、Cu(CH₃CN)₄BF₄、Cu(CH₃CN)₄ClO₄Or Cu (CH)₃CN)₄PF₆One or more than two of them.

8. The method for synthesizing propargylated 3, 3-disubstituted indolin-2-ones containing a continuous chiral center according to claim 3, wherein the method comprises the following steps: the chiral tridentate P, N, N-ligand (L-2 or L-3) or the chiral tridentate N, N, N-ligand (L-1) has the following structural features:

in the formula: r⁴，R⁵H, alkyl in C1-C10, cycloalkyl in C3-C8, phenyl and substituted phenyl, benzyl and substituted benzyl; the substituent on the substituted phenyl or the substituted benzyl is one or more than two of C1-C4 alkyl, C1-C40 alkoxy, halogen, nitro, ester group or cyano, and the number of the substituent is 1-5;

R⁶，R⁷is H, halogen, alkyl and cycloalkyl, phenyl and substituted phenyl, alkoxy, phenoxy, acyl or nitro;

R⁸is C1-C40 alkyl, C3-C12 cycloalkyl, phenyl and substituted phenyl, naphthyl and substituted naphthyl, and contains one or more than two five-membered or six-membered heterocyclic aromatic groups of oxygen, sulfur and nitrogen atoms; the substituent on the substituted phenyl or the substituted naphthyl is one or more than two of C1-C40 alkyl, C1-C40 alkoxy, halogen, nitro, ester group or cyano, and the number of the substituent is 1-5.

9. The method for synthesizing propargylated 3, 3-disubstituted indoline-2-one compounds containing continuous chiral centers according to claim 2, wherein the method comprises the following steps: the alkaline additive isⁱPr₂NEt、NEt₃、ⁱPrNMe₂、ⁱBu₃N、CyNMe₂、Cy₂NMe、^tBuOK、KOH、K₂CO₃、K₃PO₄、NaOH、Na₂CO₃、NaHCO₃Or Cs₂CO₃One or more than two of them.

10. The method for synthesizing propargylated 3, 3-disubstituted indolin-2-ones containing a continuous chiral center according to claim 2 or 3, wherein the method comprises the following steps: the catalytic reaction conditions are as follows:

temperature: -40 ℃ to 0 ℃;

reaction medium: a protic solvent;

pressure: normal pressure;

time: >0.5 hours.

Technical Field

The invention belongs to the field of organic synthesis, and particularly relates to a propargylated 3, 3-disubstituted indoline-2-ketone compound containing a continuous chiral center and a synthesis method thereof.

Background

Chiral 3, 3-disubstituted indoline-2-ketone compounds are widely used as an important structural unit in various natural products with biological activity and a series of active drug molecules. 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At present, the synthesis method of chiral 3, 3-disubstituted indoline-2-ketone compounds mainly comprises the steps of [ (a) Trost, B.M ]; frederiksen, M.U.Angew.chem., int.Ed.2005,44,308.(b)Luan,X.；Wu,L.；Drinkel,E.；Mariz,R.；Gatti,M.；Dorta,R.Org.Lett.2010,12,1912.(c)V.；Cuthbertson,J.D.；Pickworth,M.；Pugh,D.S.；Taylor,R.J.K.Org.Lett.2011,13,4264.(d)Trost,B.M.；Masters,J.T.；Burns,A.C.Angew.Chem.,Int.Ed.2013,52,2260.(e)Ren,L.；Lian,X.-L.；Gong,L.-Z.Chem.-Eur.J.2013,19,3315.(f)Shimizu,S.；Tsubogo,T.；Xu,P.；Kobayashi,S.Org.Lett.2015,17,2006.(g)Cao,Z.-Y.；Wang,Y.-H.；Zeng,X.-P.；Zhou,J.Tetrahedron Lett.2014,55,2571.(h)Trost,B.M.；Chan,W.H.；Malhotra,S.Chem.-Eur.J.2017,23,4405.(i)Yamamoto,K.；Qureshi,Z.；Tsoung,J.；Pisella,G.；Lautens,M.Org.Lett.2016,18,4954.(j)Li,Y.；Wang,K.；Ping,Y.；Wang,Y.；Kong,W.Org.Lett 2018,20,921.(k)Wang,K.；Ding,Z.；Zhou,Z.；Kong,W.J.Am.Chem.Soc.2018,140,12364.(l)Ma,T.；Chen,Y.；Li,Y.；Ping,Y.；Kong,W.ACS.Catal.2019,9,9127.(m)Ping,Y.；Li,Y.；Zhu,J.；Kong,W.Angew.Chem.,Int.Ed.2019,58,1562.；(n)Xu,S.；Wang,K.；Kong,W.Org.Lett.2019,21,7498.(o)Che,J.；Reddy,A.G.K.；Niu,L.；Xing,D.；Hu,W.Org.Lett.2019,21,4571.]and organocatalysis [ (a) You, y; wu, z. -j.; wang, z. -h.; xu, x. -y.; zhang, x. -m.; yuan, w. — c.j.org.chem.2015,80,8470.(b) Zhu, l.; chen, q.; shen, d.; zhang, w.; shen, c.; zeng, x.; zhong, g.org.lett.2016,18,2387.(c) Dalpozzo, r.; bartoli, g.; benvivini, g.chem.soc.rev.2012,41,7247.(d) Cheng, d.; ishihara, y.; tan, b.; barbas, c.f.; ACS cata.2014, 4,743 (e) Xia, x.; zhu, q.; wang, j.; chen, j.; cao, w.; zhu, Bo.; wu, x.j.org.chem.2018,83,14617.(f) Zhao, j.; li, Ya.; chen L. -Y.; ren, x.j.org.chem.2019,84,5099.]And (4) carrying out two aspects. These methods include the nucleophilic addition to isatin [ (a) g.luppi, Cozzi, p.g.; monari, m.; kaptein, b.; broxterman, q.b.; tomasini, c.j.org.chem.2005,70,7418.; (b) shintani, r.; inoue, m.; hayaashi, t.angelw.chem.2006, 118, 3431; angew.chem.int.ed.2006,45,3353; (c) toulec, p.y.r.b.; c.; de Vries, J.G.; fernga, b.l.; minnaard, a.j.org.lett.2006,8,2715; (d) nakamura, s.; hara, n.; nakashima, H.；Kubo,K.；Shibata,N.；Toru,T.Chem.Eur.J.2008,14,8079.；(e)Alcaide,B.；Almendros,P.Angew.Chem.2008,120,4710.；Angew.Chem.Int.Ed.2008,47,4632.；(f)Cheng,X.；Vellalath,S.；Goddard,R.；List,B.J.Am.Chem.Soc.2008,130,15786.；(g)Itoh,T.；Ishikawa,H.；Hayashi,Y.Org.Lett.2009,11,3854.；(h)Tomita,D.；Yamatsugu,K.；Kanai,M.；Shibasaki,M.J.Am.Chem.Soc.2009,131,6946.；(i)Itoh,J.；Han,S.B.；Krische,M.J.Angew.Chem.2009,121,6431.；Angew.Chem.Int.Ed.2009,48,6313.；(j)Hanhan,V.；Sahin,A.H.；Chang,T.W.；Fettinger,J.C.；Franz,A.K.Angew.Chem.2010,122,756.；Angew.Chem.Int.Ed.2010,49,744.]By alkylation or arylation of [ (a) Trost, b.m.; frederiksen, M.U.Angew.chem.2005,117, 312; angew.chem.int.ed.2005,44,308; (b) trost, b.m.; zhang, y.j.am.chem.soc.2006,128, 4590; (c) trost, b.m.; zhang, y.j.am.chem.soc.2007,129, 14548; (d) trost, b.m.; zhang, y.chem.eur.j.2010,16,296; (e) xiao, z. -k.; yin, h. -y.; shao, l. -x.org.lett.2013,15,1254.]Fluorinated [ (a) Hamashima, y.; suzuki, t.; takano, h.; shimura, y.; sodeoka, m.j.am.chem.soc.2005,127, 10164; (b) shibata, n.; kohno, j.; takai, k.; ishimaru, t.; nakamura, s.; toru, t.; kanemasa, s.angelw.chem.2005, 117, 4276; angew.chem.int.ed.2005,44,4204; (c) ishimaru, t.; shibata, n.; horikawa, t.; yasuda, n.; nakamura, s.; toru, t.; shiro, m.angelw.chem.2008, 120, 4225; angew. chem.int.ed.2008,47,4157.]Hydroxylated [ (a) Ishimaru, t.; shibata, n.; nagai, j.; nakamura, s.; toru, t.; kanemasa, s.j.am.chem.soc.2006,128, 16488; (b) sano, d.; nagata, k.; itoh, t.org.lett.2008,10,1593.]And aldol condensation reaction [ (a) Ogawa, s.; shibata, n.; inagaki, j.; nakamura, s.; toru, t.; shiro, m.angelw.chem.2007, 119, 8820; angew.chem.int.ed.2007,46,8666; (b) shen, k.; liu, x.; zheng, k.; li, W.; hu, x.; lin, l.; feng, x.chem.eur.j.2010,16,3736.]Mannich reaction [ (a) Tian, X; jiang, k.; peng, j.; du, w.; chen, y. -c.org.lett.2008,10,3583.; (b) he, r.; ding, c.; maruoka, k.angelw.chem.2009, 121, 4629.; angew.chem.int.ed.2009,48,4559.]Michael addition reaction [ (a) galzeano, p.; benivenni, g.; pesciaioli, f.; mazzani, a.; giannichi,B.；Sambri,L.；Bartoli,G.；Melchiorre,P.；Chem.Eur.J.2009,15,7846.；(b)Bui,T.；Syed,S.；Barbas III,C.F.J.Am.Chem.Soc.2009,131,8758.；(c)Kato,Y.；Furutachi,M.；Chen,Z.；Mitsunuma,H.；Matsunaga,S.；Shibasaki,M.J.Am.Chem.Soc.2009,131,9168.；(d)He,R.；Shirakawa,S.；Maruoka,K.J.Am.Chem.Soc.2009,131,16620.]Amination [ (a) Cheng, l.; liu, l.; wang, d.; chen, y. -j.org.lett.2009,11,3874.; (b) qian, z. -q.; zhou, f.; du, t. -p.; wang, B. -L.; ding, m.; zhao, x. -l.; zhou, j.chem.commun.2009, 6753; (c) mouri, s.; chen, z.; mitsunuma, h.; furutachi, m.; matsunaga, s.; shibasaki, m.j.am.chem.soc.2010,132,1255.]And arylation reactions [ Taylor, a.m.; altman, r.a.; buchwald, s.l.j.am.chem.soc.2009,131,9900.]Direct functionalization of 3-substituted indole 2-ones. However, according to our knowledge, the direct asymmetric propargyl substitution of 3-substituted indole 2-ones in these processes has hardly been reported correspondingly. The propargyl-substituted molecule is used as a multifunctional unit, so that subsequent diversity derivatization of the molecule can be realized, such as various reactions including click reaction, Sonogashira coupling, hydrogenation and the like, and a plurality of convenient ways are provided for the construction of some drug molecules. The invention realizes a synthetic method of propargylated 3, 3-disubstituted indoline-2-ketone compounds containing continuous chiral centers through copper-catalyzed asymmetric propargyl substitution reaction, and has important research significance for further enriching the synthesis and application of chiral 3, 3-disubstituted indoline-2-ketone compounds.

Disclosure of Invention

The invention aims to provide a propargylated 3, 3-disubstituted indoline-2-ketone compound containing a continuous chiral center and a synthesis method thereof, and the synthesis method is used for preparing the propargylated 3, 3-disubstituted indoline-2-ketone compound containing the continuous chiral center through a nucleophilic substitution reaction between a copper-catalyzed 3-substituted indoline-2-ketone compound and propargyl acetate. The method has the characteristics of simple operation steps, easy preparation of raw materials, mild reaction conditions, wide substrate application range, excellent reaction yield, high diastereoselectivity and enantioselectivity and the like.

A propargylated 3, 3-disubstituted indolin-2-one compound containing a continuous chiral center, the propargylated 3, 3-disubstituted indolin-2-one compound containing a continuous chiral center having one of the following structures:

i and II are enantiomers, III and IV are enantiomers, I and III or IV are diastereomers, and II and III or IV are diastereomers;

The invention provides a method for synthesizing propargylated 3, 3-disubstituted indoline-2-ketone compounds containing continuous chiral centers, which synthesizes propargylated 3, 3-disubstituted indoline-2-ketone compounds containing continuous chiral centers by catalyzing nucleophilic substitution reaction between 3-substituted indoline-2-ketone compounds and propargyl acetate by using a chiral copper catalyst in the presence of an alkaline additive.

The method comprises the following specific steps:

(1) preparation of chiral copper catalyst: under the protection of nitrogen, copper salt and chiral P, N, N-ligand are stirred in a reaction medium for 1-2 hours according to the molar ratio of 1: 0.1-10 to prepare a chiral copper catalyst; the chiral tridentate ligand is a chiral tridentate P, N, N-ligand (L-2 or L-3) or a chiral tridentate N, N, N-ligand (L-1);

(2) preparation of propargylated 3, 3-disubstituted indoline-2-ones containing a continuous chiral center: dissolving a 3-substituted indoline-2-ketone compound, propargyl acetate and an alkaline additive in a reaction medium, and then adding the solution into the stirred solution of the chiral copper catalyst under the protection of nitrogen, and stirring and reacting at-40-0 ℃ for not less than 10 hours; after the reaction is finished, concentrating under reduced pressure until no solvent exists basically, separating by silica gel column chromatography, concentrating under reduced pressure, and drying in vacuum to obtain a target product;

the molar ratio of the chiral copper catalyst to the 3-substituted indoline-2-ketone compound is 0.01-100% to 1;

the molar ratio of the alkaline additive to the propargyl acetate compound is 0.5-10: 1;

the molar ratio of the 3-substituted indoline-2-ketone compound to the propargyl acetate compound is 1: 1 to 4.

The reaction medium is at least one of methanol, ethanol, isopropanol, isobutanol, toluene, dichloromethane, diethyl ether, tetrahydrofuran, dimethyl sulfoxide or N, N-dimethylformamide.

The propargylated 3, 3-disubstituted indoline-2-ketone compound containing a continuous chiral center has one of the following structures:

i and II are enantiomers of each other, III and IV are enantiomers of each other, I and III or IV are diastereomers of each other, and II and III or IV are diastereomers of each other. In the formula: r¹,R²，R³，R⁴Is C1-C40 alkyl, C3-C12 cycloalkyl or C3-C12 cycloalkyl with substituent, phenyl and substituted phenyl, benzyl and substituted benzyl, five-membered or six-membered heterocyclic aromatic group containing one or more than two oxygen, sulfur and nitrogen atoms and ester group. The substituents on the C3-C12 naphthenic base, the substituents on the phenyl and the substituents on the benzyl are respectively one or more than two of C1-C40 alkyl, C1-C40 alkoxy, halogen, nitro, ester group or cyano, and the number of the substituents is 1-5.

The 3-substituted indoline-2-ketone compound has the following structure:

in the formula: r²，R³，R⁴Is one or more than two of C1-C40 alkyl, C3-C12 cycloalkyl or C3-C12 cycloalkyl with substituent, phenyl and substituted phenyl, benzyl and substituted benzyl, five-membered or six-membered heterocyclic aromatic group containing one or more than two oxygen, sulfur and nitrogen atoms and ester group; the substituents on the C3-C12 naphthenic base, the substituents on the phenyl and the substituents on the benzyl are respectively one or more than two of C1-C40 alkyl, C1-C40 alkoxy, halogen, nitro, ester group or cyano, and the number of the substituents is 1-5.

The propargyl acetate compound has the following structure:

The copper salt is Cu (OAc)₂·H₂O、Cu(OAc)₂、Cu(OTf)₂、CuCl₂、CuOAc、CuCl、CuI、CuClO₄、CuOTf·0.5C₆H₆、Cu(CH₃CN)₄BF₄、Cu(CH₃CN)₄ClO₄Or Cu (CH)₃CN)₄PF₆One or more than two of them.

The chiral P, N, N-ligand or chiral tridentate N, N, N-ligand has one of the following structural features:

in the formula: r⁴，R⁵H, alkyl in C1-C10, cycloalkyl in C3-C8, phenyl and substituted phenyl, benzyl and substituted benzyl; the substituent on the substituted phenyl or the substituted benzyl is one or more than two of C1-C40 alkyl, C1-C40 alkoxy, halogen, nitro, ester group or cyano, and the number of the substituent is 1-5;

R⁶，R⁷is H, halogen, alkyl and cycloalkyl, phenyl and substituted phenyl, alkoxy, phenoxy, acyl or nitro;

The alkaline additive is various inorganic bases or organic bases:ⁱPr₂NEt、NEt₃、ⁱPrNMe₂、ⁱBu₃N、CyNMe₂、Cy₂NMe、^tBuOK、KOH、K₂CO₃、K₃PO₄、NaOH、Na₂CO₃、NaHCO₃or Cs₂CO₃One or more than two of them. Preference is given toⁱPr₂NEt、Et₃N、Cs₂CO₃Or K₂CO₃。

The catalytic reaction conditions are preferably as follows:

temperature: -40 ℃ -0 ℃;

reaction medium: protic solvents, preferably methanol;

pressure: normal pressure;

time: >0.5 hours, preferably 10 hours.

The molar ratio of the chiral copper catalyst to the 3-substituted indoline-2-ketone compound is 0.01-100% to 1;

the molar ratio of the alkaline additive to the propargyl acetate compound is 0.5-10: 1;

the molar ratio of the 3-substituted indoline-2-ketone compound to the propargyl acetate compound is 1: 1-4;

the reaction equation of the invention is as follows:

the invention has the following advantages:

1. high reaction yield, good stereoselectivity and mild reaction conditions.

2. The starting materials are easy to prepare.

3. The chiral ligand is simple and convenient to synthesize, the catalyst is easy to prepare, and the catalyst loading capacity is low.

4. Compared with the traditional method, the method can efficiently synthesize various propargylated 3, 3-disubstituted indoline-2-ketone compounds containing continuous chiral centers.

Drawings

In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings needed to be used in the embodiments will be briefly described below, it should be understood that the following drawings only illustrate some embodiments of the present invention and therefore should not be considered as limiting the scope, and for those skilled in the art, other related drawings can be obtained according to the drawings without inventive efforts.

FIG. 1 is a NMR spectrum of 1-methyl-3-phenyl-3- (1-phenylprop-2-yn-1-yl) indolin-2-one I-1 prepared in example 1;

FIG. 2 is a NMR carbon spectrum of 1-methyl-3-phenyl-3- (1-phenylprop-2-yn-1-yl) indolin-2-one I-1 prepared in example 1;

FIG. 3 is a NMR spectrum of 1-methyl-3-p-methylphenyl-3- (phenylprop-2-yn-1-yl) indolin-2-one I-2 prepared in example 11;

FIG. 4 is a NMR carbon spectrum of 1-methyl-3-p-methylphenyl-3- (phenylprop-2-yn-1-yl) indolin-2-one I-2 prepared in example 11;

FIG. 5 is a NMR spectrum of 1, 3-dimethyl-3- (1-phenylprop-2-yn-1-yl) indolin-2-one I-3 prepared in example 12;

FIG. 6 is a NMR carbon spectrum of 1, 3-dimethyl-3- (1-phenylprop-2-yn-1-yl) indolin-2-one I-3 prepared in example 12;

FIG. 7 is a NMR spectrum of 1-methyl-3-phenyl-3- (1-p-methylphenylprop-2-yn-1-yl) indolin-2-one I-4 prepared in example 13;

FIG. 8 is a NMR carbon spectrum of 1-methyl-3-phenyl-3- (1-p-methylphenylprop-2-yn-1-yl) indolin-2-one I-4 prepared in example 13;

FIG. 9 is a NMR spectrum of 1-phenyl-3- (1-phenylprop-2-yn-1-yl) indolin-2-one I-5 prepared in example 14;

FIG. 10 is a NMR carbon spectrum of 1-phenyl-3- (1-phenylprop-2-yn-1-yl) indolin-2-one I-5 prepared in example 14;

FIG. 11 is a NMR spectrum of 6-chloro-1-methyl-3-phenyl-3- (1-phenylprop-2-yn-1-yl) indolin-2-one I-6 prepared in example 15;

FIG. 12 is a NMR carbon spectrum of 6-chloro-1-methyl-3-phenyl-3- (1-phenylprop-2-yn-1-yl) indolin-2-one I-6 prepared in example 15;

Detailed Description

The following examples further illustrate the invention but are not intended to limit the invention thereto. Melting points were determined by a melting point apparatus, High Performance Liquid Chromatography (HPLC) by Agilent 1100 series HPLC, optical rotation by JASCO P-1020 polarimeter, nuclear magnetic resonance by Bruker nuclear magnetic resonance apparatus, and molecular weights by liquid chromatography High Resolution Mass Spectrometry (HRMS) MicroMass.

Example 1

Cu(CH₃CN)₄PF₆And L-2-1 as a catalystReacting to generate propargylated 1-methyl-3-phenyl-3- (1-phenylprop-2-alkyne-1-yl) indoline-2-ketone I-1 containing two continuous chiral centers.

The metal precursor Cu (CH) is added into a reaction bottle₃CN)₄PF₆(0.015mmol, 5 mol%) and chiral ligand L-2-1(0.0165mmol, 5.5 mol%), adding 1.0mL of anhydrous methanol under the protection of nitrogen, and stirring at room temperature for 0.5 h. Then the reaction tube was transferred to a constant temperature reaction freezer at-40 ℃ to mix 1-methyl-3-phenylindolin-2-one V-1 (0.3mmol, 1.0equiv), 1-phenylpropargyl acetate VI-1 (0.36mmol, 1.2equiv) and Cs₂CO₃(0.36mmol, 1.2equiv) was dissolved in 2.0mL of anhydrous methanol, and the solution was added to the stirred solution of the catalyst under nitrogen protection and stirred at-40 ℃ for 10 h. After the reaction is finished, concentrating under reduced pressure until no solvent exists basically, separating by silica gel column chromatography, concentrating under reduced pressure, drying in vacuum to obtain white foamy solid with 99 percent yield,>20/1d.r.,>99% ee. The hydrogen and carbon nuclear magnetic resonance spectra of the product I-1 are shown in FIGS. 1 and 2: m.p. 150 ℃ and 152 ℃.>99％ee was determined by chiral HPLC(Daicel Chiralcel OD-H,0.46cm×25cm,n-hexane/i-PrOH＝98/2,1.0ml/min,254nm,40℃):t_R(major enantiomer)＝11.2min,t_R(minor enantiomer)＝19.0min.[α]_D ²⁵＝331(c 0.55,CH₂Cl₂).¹H NMR analysis of crude products indicated d.r.>20:1.¹H NMR(400MHz,CDCl₃)δ7.90(d,J＝7.1Hz,1H),7.60(d,J＝7.2Hz,2H),7.46–7.21(m,4H),7.16(t,J＝7.2Hz,1H),7.11–6.84(m,5H),6.51(d,J＝7.5Hz,1H),4.96(s,1H),2.74(s,3H),2.21(s,1H).¹³C NMR(101MHz,CDCl₃)δ176.0,144.1,137.8,135.2,129.2,128.9,128.5,128.3,128.1,127.7,127.4,127.3,126.9,122.1,108.0,82.9,73.4,60.7,45.1,26.0.HRMS(ESI)calc.for C₂₄H₂₀NO[M+H]⁺:338.1539,found:338.1540.

The structural formula of V-1, VI-1, I-1, L-2-1 is as follows:

example 2

L-1-1 is used as ligand to react to generate a product I-1

The ligand L-2-1 in example 1 is replaced by the ligand L-1-1, the temperature is 0 ℃, the alkali additive is diisopropylethylamine, and the reaction is stirred for 10 hours, and the rest is the same as example 1. The reaction gave compound I-1 in 92% yield, 54/46dr, 90% ee.

The structural formula of L-1-1 is as follows:

example 3

L-3-1 is used as ligand to react to generate a product I-1

The ligand L-2-1 in example 1 was replaced with ligand L-3-1 at 0 deg.C and the base additive was diisopropylethylamine, and the reaction was stirred for 10h, the remainder being the same as in example 1. The reaction gave compound I-1 in 92% yield, 65/35dr, 95% ee.

The structural formula of L-3-1 is as follows:

example 4

Cu(OTf)₂Catalytically reacting with L-2-1 to produce a product I-1

Cu (CH) in example 1₃CN)₄PF₆With Cu (OTf)₂Instead, the rest is the same as example 1. Compound I-1 was obtained in 36% yield, 94/6dr, 98% ee.

Example 5

Cu(CH₃CN)₄BF₄Catalytically reacting with L-2-1 to produce a product I-1

Cu (CH) in example 1₃CN)₄PF₆With Cu (CH)₃CN)₄BF₄Instead, the rest is the same as example 1. Compound I-1 was obtained in 78% yield, 94/6dr, 99% ee.

Example 6

Cu(CH₃CN)₄ClO₄Catalytically reacting with L-2-1 to produce a product I-1

Cu (CH) in example 1₃CN)₄PF₆With Cu (CH)₃CN)₄ClO₄Instead, the rest is the same as example 1. Compound i-1 was obtained in 82% yield, 98/2dr,>99％ee。

example 7

TEA as base additive to produce the product I-1

Cs in example 1₂CO₃The TEA was replaced, as in example 1. Compound i-1 was obtained in 43% yield, 73/27dr,>99％ee。

example 8

K₃PO₄As an alkali additive to produce the product I-1

Cs in example 1₂CO₃Is replaced by K₃PO₄Otherwise, the same procedure as in example 1 was repeated. Compound i-1 was obtained in 63% yield, 98/2dr,>99％ee。

example 9

KO^tBu is used as an alkali additive to react to generate a product I-1

Cs in example 1₂CO₃Replacement is with KO^tBu, otherwise as in example 1. Compound i-1 was obtained in 79% yield, 97/3dr,>99％ee。

example 10

K₂CO₃As an alkali additive to produce the product I-1

Cs in example 1₂CO₃Is replaced by K₂CO₃Otherwise, the same procedure as in example 1 was repeated. Compound i-1 was obtained in 79% yield, 97/3dr,>99％ee。

example 11

The V-2 is used as a substrate to react to generate 1-methyl-3-p-methylphenyl-3- (phenylpropane-2-alkyne-1-yl) indoline-2-ketone I-2

The 1-methyl-3-phenylindolin-2-one V-1 in example 1 was replaced with 1-methyl-3-p-methylphenylindolin-2-one V-2, and the rest was performedExample 1 gave compound I-2 in 90% yield, 13.3/dr, 97% ee. The hydrogen and carbon nuclear magnetic resonance spectra of the product I-2 are shown in FIGS. 3 and 4: m.p. 162-.>99％ee was determined by chiral HPLC(Daicel Chiralcel OD-H,2×0.46cm×25cm,n-hexane/i-PrOH＝98/2,1.0ml/min,254nm,40℃):t_R(major enantiomer)＝22.4min,t_R(minor enantiomer)＝41.3min.[α]_D ²⁰＝+274.52(c 0.68,CH₂Cl₂).¹H NMR analysis of crude products indicated d.r.>20:1.¹H NMR(400MHz,CDCl₃)δ7.89(d,J＝7.4Hz,1H),7.47(d,J＝8.1Hz,2H),7.26(t,J＝7.7Hz,1H),7.16(d,J＝7.7Hz,3H),7.07–6.95(m,5H),6.50(d,J＝7.8Hz,1H),4.94(d,J＝2.4Hz,1H),2.72(s,3H),2.32(s,3H),2.22(d,J＝2.3Hz,1H).¹³C NMR(101MHz,CDCl₃)δ176.1,144.1,137.4,135.3,134.8,129.2,129.2,128.8,128.5,127.9,127.4,127.3,126.9,122.1,107.9,83.0,73.4,60.5,45.0,26.0,21.1.HRMS(ESI)calc.for C₂₅H₂₂NO[M+H]⁺:352.1696,found:352.1692.

The structural formula of V-2 and I-2 is as follows:

example 12

V-3 is used as a substrate to react to generate 1, 3-dimethyl-3- (1-phenylpropane-2-alkyne-1-yl) indoline-2-keto I-3

Example 1 was followed by substituting 1-methyl-3-phenylindolin-2-one V-1 in example 1 with 1, 3-dimethylindolin-2-one V-3. Compound i-3 was obtained in 76% yield, 99/1dr,>99% ee. The hydrogen and carbon nuclear magnetic resonance spectra of the product I-3 are shown in FIGS. 5 and 6:>99％ee was determined by chiral HPLC(Daicel Chiralcel AD-H,0.46cm×25cm,n-hexane/i-PrOH＝95/5,1.0ml/min,254nm,40℃):t_R(major enantiomer)＝6.5min,t_R(minor enantiomer)＝7.1min.[α]_D ²⁵＝54.4(c 0.40,CH₂Cl₂).¹H NMR analysis of crude products indicated d.r.>99:1.¹H NMR(400MHz,CDCl₃)δ7.74(d,J＝7.3Hz,1H),7.19(t,J＝7.7Hz,1H),7.08(t,J＝7.5Hz,1H),7.02(d,J＝7.1Hz,1H),6.97(t,J＝7.4Hz,2H),6.90(d,J＝7.5Hz,2H),6.47(d,J＝7.7Hz,1H),4.18(d,J＝2.2Hz,1H),2.77(s,3H),2.47(d,J＝2.4Hz,1H),1.69(s,3H).¹³C NMR(101MHz,CDCl₃)δ178.3,143.1,135.7,130.6,128.5,128.3,127.3(overlapping),124.3,122.1,107.6,82.9,73.4,52.3,45.4,25.7,21.6.HRMS(ESI)calc.for C₁₉H₁₈NO[M+H]⁺:276.1383,found:276.1384.

the structural formula of V-3 and I-3 is as follows:

example 13

V-4 is used as a substrate to react to generate 1-methyl-3-phenyl-3- (1-p-methylphenyl prop-2-alkyne-1-yl) indoline-2-ketone I-4

The procedure of example 1 was repeated except that 1-phenylpropargyl acetate VI-1 in example 1 was replaced with 1-p-methylphenylpargyl acetate VI-2. Compound I-4 was obtained in 66% yield, 19/1dr, 99% ee. The hydrogen and carbon nuclear magnetic resonance spectra of the product I-4 are shown in FIGS. 7 and 8:>99％ee was determined by chiral HPLC(Daicel Chiralcel OJ-H,2×0.46cm×25cm,n-hexane/i-PrOH＝95/5,0.8ml/min,254nm,40℃):t_R(major enantiomer)＝44.9min,t_R(minor enantiomer)＝31.1min.[α]_D ²⁵＝260(c 0.86,CH₂Cl₂).¹H NMR analysis of crude products indicated d.r.＝19:1.¹H NMR(400MHz,CDCl₃)δ7.83(d,J＝6.9Hz,1H),7.57–7.47(m,2H),7.27(t,J＝7.3Hz,2H),7.24–7.17(m,2H),7.09(td,J＝7.6,0.8Hz,1H),6.84(d,J＝8.1Hz,2H),6.73(d,J＝8.0Hz,2H),6.46(d,J＝7.7Hz,1H),4.84(d,J＝2.5Hz,1H),2.69(s,3H),2.12(d,J＝2.6Hz,1H),2.10(s,3H).¹³C NMR(101MHz,CDCl₃)δ176.1,144.2,137.9,137.0,132.2,129.4,129.0,128.8,128.4,128.0,127.7,126.9,126.6,122.1,108.0,83.2,73.2,60.7,44.7,26.0,21.0.HRMS(ESI)calc.for C₂₅H₂₂NO[M+H]⁺:352.1696,found:352.1692.

the structural formula of V-4 and I-4 is as follows:

example 14

V-5 is used as a substrate to react to generate 1-phenyl-3- (1-phenylpropane-2-alkyne-1-yl) indoline-2-ketone I-5

Example 1 was followed by substituting 1-methyl-3-phenylindolin-2-one V-1 in example 1 with 1-phenyl-3-phenylindolin-2-one V-5. Compound i-5 was obtained in 66% yield, 8/1dr,>99% ee. The hydrogen and carbon nuclear magnetic resonance spectra of the product I-5 are shown in FIGS. 9 and 10:>99％ee was determined by chiral HPLC(Daicel Chiralcel OD-H,0.46cm×25cm,n-hexane/i-PrOH＝95/5,1.0ml/min,254nm,40℃):t_R(major enantiomer)＝10.4min,t_R(minor enantiomer)＝9.3min.[α]_D ²⁵＝228(c 0.85,CH₂Cl₂).¹H NMR analysis of crude products indicated d.r.＝8:1.NMR for the major product:¹H NMR(400MHz,CDCl₃)δ8.07–7.93(m,1H),7.69(d,J＝7.9Hz,2H),7.40(t,J＝7.6Hz,2H),7.36–7.26(m,4H),7.21(dd,J＝5.6,3.4Hz,2H),7.18–7.12(m,1H),7.12–7.04(m,4H),6.72(d,J＝7.5Hz,2H),6.52–6.39(m,1H),5.02(d,J＝2.4Hz,1H),2.26(d,J＝2.3Hz,1H).¹³C NMR(101MHz,CDCl₃)δ175.4,144.4,137.8,135.5,134.1,129.9,129.6,129.4,128.8,128.6,128.4,128.2,128.1,127.8,127.7,127.3,126.8,126.7,122.6,109.3,82.9,73.5,60.6,45.5.HRMS(ESI)calc.for C₂₉H₂₂NO[M+H]⁺:400.1696,found:400.1700.

the structural formula of V-5 and I-5 is as follows:

example 15

V-6 is used as a substrate to react to generate 6-chloro-1-methyl-3-phenyl-3- (1-phenylpropane-2-alkyne-1-yl) indoline-2-keto I-6

Example 1 was followed by substituting 1-methyl-3-phenylindolin-2-one V-1 in example 1 with 6-chloro-1-methyl-3-phenylindolin-2-one V-6. Compound i-6 was obtained in 77% yield, 19/1dr,>99% ee. The hydrogen and carbon nuclear magnetic resonance spectra of the product I-6 are shown in FIGS. 11 and 12:>99％ee was determined by chiral HPLC(Daicel Chiralcel OD-H,0.46cm×25cm,n-hexane/i-PrOH＝95/5,1.0ml/min,254nm,40℃):t_R(major enantiomer)＝9.0min,t_R(minor enantiomer)＝12.2min.[α]_D ²⁵＝248.4(c 0.37,CH₂Cl₂).¹H NMR analysis of crude products indicated d.r.＝19:1.¹H NMR(400MHz,CDCl₃)δ7.82(d,J＝8.0Hz,1H),7.60–7.53(m,2H),7.41–7.29(m,3H),7.16(dd,J＝8.0,1.9Hz,1H),7.10–7.03(m,4H),6.54(d,J＝1.9Hz,1H),4.94(d,J＝2.6Hz,1H),2.74(s,3H),2.24(d,J＝2.6Hz,1H).¹³C NMR(101MHz,CDCl₃)δ175.9,145.3,137.3,134.8,134.7,129.1,128.5,127.9,127.9,127.8,127.6,127.5,126.7,122.0,108.6,82.6,73.6,60.5,45.0,26.1.HRMS(ESI)calc.for C₂₄H₁₉ClNO[M+H]⁺:372.1150,found:372.1150.

the structural formula of V-6 and I-6 is as follows:

examples 16 to 43

Reaction substrate suitability

The invention has wide substrate applicability, a plurality of substrates can participate in the reaction, and the 3, 3-disubstituted oxindole compound can be obtained with high yield and high stereoselectivity. See table 1:

TABLE 1

entry	Ⅴ(R²,R³,R⁴)	Ⅵ(R¹)	yield(％)	dr	ee(％)
						16	R²＝C₆H₅,R³＝H,R⁴＝Me	R¹＝2-FC₆H₄	54	>20:1	99
17	R²＝C₆H₅,R³＝H,R⁴＝Me	R¹＝3-ClC₆H₄	93	19:1	>99
						18	R²＝C₆H₅,R³＝H,R⁴＝Me	R¹＝4-ClC₆H₄	93	19:1	>99
19	R²＝C₆H₅,R³＝H,R⁴＝Me	R¹＝4-FC₆H₄	62	19:1	>99
						20	R²＝C₆H₅,R³＝H,R⁴＝Me	R¹＝4-BrC₆H₄	95	>20:1	98
21	R²＝C₆H₅,R³＝H,R⁴＝Me	R¹＝4-OMeC₆H₄	92	>20:1	>99
						22	R²＝C₆H₅,R³＝H,R⁴＝Me	R¹＝4-CF₃C₆H₄	70	>20:1	95
23	R²＝C₆H₅,R³＝H,R⁴＝Me	R¹＝2-naphthyl	43	>20:1	>99
						24	R²＝C₆H₅,R³＝H,R⁴＝Me	R¹＝2-thienyl	89	>20:1	99
25	R²＝C₆H₅,R³＝H,R⁴＝Me	R¹＝H	-	-	-
						26	R²＝C₆H₅,R³＝H,R⁴＝Me	R¹＝Me	-	-	-
27	R²＝4-OMeC₆H₄,R³＝H,R⁴＝Me	R¹＝C₆H₅	84	>20:1	>99
						28	R²＝3-MeC₆H₄,R³＝H,R⁴＝Me	R¹＝C₆H₅	79	13:1	>99
29	R²＝3-OMeC₆H₄,R³＝H,R⁴＝Me	R¹＝C₆H₅	91	>20:1	>99
						30	R²＝3-CF₃C₆H₄,R³＝H,R⁴＝Me	R¹＝C₆H₅	93	7:1	>99
31	R²＝2-MeC₆H₄,R³＝H,R⁴＝Me	R¹＝C₆H₅	66	>20:1	>99
						32	R²＝2-OHC₆H₄,R³＝H,R⁴＝Me	R¹＝C₆H₅	88	>20:1	>99
33	R²＝2-naphthyl,R³＝H,R⁴＝Me	R¹＝C₆H₅	89	12:1	>99
						34	R²＝2-thienyl,R³＝H,R⁴＝Me	R¹＝C₆H₅	75	>20:1	99
35	R²＝3-methyl-2-thienyl,R³＝H,R⁴＝Me	R¹＝C₆H₅	89	>20:1	>99
						36	R²＝1-pyrrolyl,R³＝H,R⁴＝Me	R¹＝C₆H₅	81	>20:1	>99
37	R²＝C₆H₅,R³＝4-Cl,R⁴＝Me	R¹＝C₆H₅	-	-	-
						38	R²＝C₆H₅,R³＝5-F,R⁴＝Me	R¹＝C₆H₅	95	12:1	>99
39	R²＝C₆H₅,R³＝5-OMe,R⁴＝Me	R¹＝C₆H₅	90	5:1	>99
						40	R²＝C₆H₅,R³＝7-CF₃,R⁴＝Me	R¹＝C₆H₅	39	>20:1	95
41	R²＝C₆H₅,R³＝H,R⁴＝Bn	R¹＝C₆H₅	78	9:1	99
						42	R²＝C₆H₅,R³＝H,R⁴＝Boc	R¹＝C₆H₅	79	19:1	>99
43	R²＝C₆H₅,R³＝H,R⁴＝H	R¹＝C₆H₅	-	-	-

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Propargylated 3, 3-disubstituted indoline-2-ketone compound containing continuous chiral center and synthesis method thereof

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