CN109912488B

CN109912488B - Method for synthesizing 3-alkyl indoline by alkylation of non-activated olefin under catalysis of copper

Info

Publication number: CN109912488B
Application number: CN201910136346.7A
Authority: CN
Inventors: 梁德强; 霍波洁; 王宝玲; 李维莉; 马银海
Original assignee: Kunming University
Current assignee: Kunming University
Priority date: 2019-02-25
Filing date: 2019-02-25
Publication date: 2022-05-10
Anticipated expiration: 2039-02-25
Also published as: CN109912488A

Abstract

The invention provides a method for synthesizing 3-alkyl indoline by alkylating non-activated olefin under the catalysis of copper, which uses a composite catalyst formed by copper halide and DTBP to react simple alkane with the DTBPN-allylaniline derivative generationexoThe 2-unsubstituted 3-alkyl indoline is obtained by selective alkylation/cyclization cascade reaction, and the method is simple, the substrate adaptability is wide, and the process operability is strong.

Description

Method for synthesizing 3-alkyl indoline by alkylation of non-activated olefin under catalysis of copper

Technical Field

The invention belongs to the technical field of organic synthesis, and particularly relates to a method for synthesizing 3-alkylindoline by alkylation of non-activated olefin under catalysis of copper.

Background

Alkanes are the main components of fossil fuels such as petroleum, natural gas and coal, and are first-grade products of the petrochemical industry. Therefore, the conversion of this bulk chemical into a more valuable compound is one of the core tasks of sustainable chemistry in the future. Direct C-H bond functionalization is an ideal reaction with atom and step economy, and inert alkane C-H bond direct functionalization has been a great challenge in this field due to extremely weak acidity and high dissociation energy. Indolines are very important nitrogen-containing heterocyclic compounds and have great application in the dye industry, the synthesis of perfumes and organic intermediates, the synthesis of medicines and pesticides. Due to the diverse biological activity and clinical application of compounds taking indoline as a parent nucleus structure, scientists are required to synthesize more indoline derivatives with diverse structures as drug lead molecules. The method for directly synthesizing high-value alkyl indoline from cheap simple alkane by utilizing C-H bond functionalization reaction is attractive, but the high-value compounds such as alkyl indoline obtained by the reaction of the simple alkane and non-activated alkene are rarely reported, which is probably caused by the problem of mismatch of the polarities of the reaction. Unactivated alkyl groups have weak nucleophilicity, they tend to react with electron deficient species, whereas the dehydrogenation coupling of simple alkanes with non-activated alkenes (nucleophiles) in the absence of suitable catalysts is difficult to perform.

Disclosure of Invention

In order to solve the problems in the prior art, the invention aims to provide a method for synthesizing 3-alkylindoline by alkylating non-activated olefin under the catalysis of copper, which directly uses simple alkane and N-allylaniline derivative to carry out exo selective alkylation/cyclization cascade reaction under the catalysis of copper to obtain 2-site unsubstituted 3-alkylindoline.

The purpose of the invention is realized as follows:

a method for synthesizing 3-alkyl indoline by alkylation of non-activated olefin under catalysis of copper is characterized in that the reaction route is as follows:

wherein:

a is C or N;

R¹is hydrogen, halogen, C_1-6Alkyl or phenyl;

R²is hydrogen or C_1-6An alkyl group;

R³is COR⁴Or SO₂R⁵；

R⁴Is C_1-17Alkyl or-O-C_1-6An alkyl group;

R⁵is C_1-6Alkyl, N-dimethyl or

R⁶Is hydrogen, halogen, hydroxy, C_1-6Alkyl or-O-C_1-6An alkyl group;

the catalyst comprises a catalyst 1 and a catalyst 2, wherein the catalyst 1 is selected from copper halide, and the catalyst 2 is selected from DTBP.

The term "halogen" as used herein refers to fluorine, chlorine, bromine or iodine. The term "C" as used herein_1-6Alkyl "means a saturated straight or branched chain hydrocarbon group having 1 to 6 carbon atoms, e.g. methylEthyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl and the like, preferably methyl, ethyl, propyl, isopropyl, tert-butyl or isobutyl. The term "C" as used herein_1-17Alkyl "means a saturated, straight-chain or branched-chain hydrocarbon group having from 1 to 17 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, n-C₇H₁₅、n-C₉H₁₉、n-C₁₁H₂₃、n-C₁₇H₃₅. The term "-O-C" as used in the present invention_1-6Alkyl "means a saturated straight or branched chain alkoxy group having 1 to 6 carbon atoms, such as methoxy, ethoxy, t-butoxy, and the like. The term "alkyl" as used herein is an alkyl group, preferably C_1-17Alkyl or cycloalkyl.

The term "copper halide" used in the present invention is preferably copper chloride, copper bromide or copper iodide, more preferably copper iodide. Further, the amount of copper iodide used in the present invention is 5 to 10 mol%. The DTBP of the invention is used in an amount of 3-3.5 equivalents. The reaction temperature of the method is preferably 140-160 ℃.

Further, in the present invention, R¹Selected from hydrogen, methyl, chlorine, bromine or phenyl; r²Selected from hydrogen or methyl; r³Is COR⁴Or SO₂R⁵；R⁴Selected from methyl, ethyl, n-C₇H₁₅、n-C₉H₁₉、n-C₁₁H₂₃、n-C₁₇H₃₅t-Bu or tert-butoxy; r⁵Selected from methyl, ethyl, N-dimethyl; alkyl is selected from cyclopentyl, cyclohexyl, cycloheptyl.

In the compounds of formula I and formula II herein, R¹Can be independently ortho-position, meta-position or para-position, can be simultaneously substituted by the ortho-position, the meta-position or/and the para-position, and can also be independently substituted; r⁶Can be independently ortho-position, meta-position or para-position, can be simultaneously substituted by the ortho-position, the meta-position or/and the para-position, and can also be independently substituted.

The compound of formula II of the present invention is selected from the group consisting of compounds 2a1-4e, as shown in Table 1 below.

TABLE 12 a1-4c Compounds

Advantageous effects

Without intending to be bound by any theory, it is believed that although the synthesis of high value alkylindolines by reacting simple alkanes with non-activated alkenes is very attractive, the non-activated alkyls have a weak nucleophilicity, they tend to react with electron deficient species, and the dehydrocoupling of simple alkanes with non-activated alkenes in the absence of a suitable catalyst is difficult to achieve. The present inventors have conducted experiments on alkylation/cyclization reactions of N-allylaniline derivatives with simple alkanes, and have surprisingly found that the use of a composite catalyst formed from copper halide and DTBP allows the exo-selective alkylation/cyclization cascade reaction of simple alkanes with N-allylaniline derivatives to obtain 2-unsubstituted 3-alkylindolines, and that the process is simple, substrate adaptability is broad, and process operability is strong.

Detailed Description

In order to make the objects and technical solutions of the present invention clearer, preferred embodiments of the present invention are described in detail below. It is to be noted that: the following examples are intended to illustrate the invention further and are not to be construed as limiting the scope of the invention. The invention is not limited to the embodiments described above, but rather, many modifications and variations may be made by one skilled in the art without departing from the scope of the invention.

The compound of formula I as a raw material of the present invention can be prepared by reference to literature references (literature reference 1: D.Liang, Q.Dong, P.Xu, Y.Dong, W.Li, Y.Ma, J.Org.Chem.2018,83, 11978-11986; literature reference 2: S.O' Sullivan, E.Doni, T.Tuttle, J.A.Murphy.Angew.Chem.int.Ed.2014,53, 474-478; Angew.Chem.2014,126, 484-488; literature reference 3: Z.Wu, S.Li, H.Xu.Angew.Chem.int.Ed.2018,57, 14070-14074; Angew.Chem.2018,130, 14266-14270.; 4: CN 201811634880.2).

Example 1

Alkylation of N-allylaniline derivatives to alkyl indolines (as an example for the synthesis of 2a 1) is carried out as follows:

the method comprises the following operation steps: to a Schlenk tube equipped with a magnetic stirrer were added N-allylamine derivative 1a1(57mg, 0.3mmol), DTBP (154mg, 1.05mmol), CuI (3mg, 0.015mmol), and cyclohexane (3.0mL) in that order. The mixture was stirred at 140 ℃ under sealed heating for 6h, then saturated Na was added₂S₂O₃Aqueous solution (2mL) and water (10.0 mL). The mixture was extracted 3 more times with dichloromethane (10.0mL) and the organic phases were combined. The organic solvent was evaporated using a rotary evaporator and the resulting residue was subjected to column chromatography using 300-400 mesh silica gel as the stationary phase and petroleum ether and ethyl acetate as the eluent to give the 3-alkylindoline product 2a 1.

The effect of the catalyst and temperature on the reaction was examined with reference to example 1, and the details are shown in Table 2.

Table 2 shows the influence of the catalyst and temperature on the reaction^[a]

^[a]Reaction conditions are as follows: 1a1(0.3mmol), cyclohexane (3.0mL), 140 deg.C, 6 h.

^[b]5.0-6.0mol/L decane solution.

The inventors began the present study on the alkylation/cyclization reaction of N- (2-methylallyl) acetanilide 1a1 (Table 2). Satisfactorily, 1a1 was reacted with cyclohexane at 140 ℃ in the presence of 10 mol% CuI and 3.5 equivalents of di-tert-butyl peroxide (DTBP) to give 3- (cyclohexylmethyl) indoline 2a1 (sequence No. 1) in 81% yield. Control experiments showed that the yield was low without the copper catalyst (number 2). CuBr (No. 3) and CuCl (No. 4) are also usable catalysts, and Cu (OAc)₂(No. 5) MnCl₂(No. 8) CoCl₂(No. 9) or tetrabutylammonium iodide (TBAI, No. 10) showed almost no advantageous effect. Using FeCl₃(number 6) or AgNO₃(No. 7), the yield was lower than that of the cuprous-catalyzed reaction. Next, the inventors tested a series of oxidants against DTBP. The yield decreased to some extent when dicumyl peroxide (DCP, No. 11) or anhydrous tert-butyl hydroperoxide (TBHP, No. 12) was used, while dibenzoyl peroxide (BPO, No. 13), tert-butyl perbenzoate (TBPB, No. 14), m-chloroperoxybenzoic acid (mCPBA, No. 15), K₂S₂O₈Both (No. 16) and Oxone (No. 17) are ineffective oxidants for this reaction. Under otherwise optimal conditions, when the reaction is carried out at 120 ℃ the yield of the 2-position unsubstituted 3-alkylindoline 2a1 is only 11% (No. 18), while a decrease in the amount of DTBP also decreases the yield (No. 19). Finally, the inventors found that using 5% CuI was sufficient to obtain a satisfactory yield (No. 20).

After obtaining the optimal reaction conditions, the inventors further investigated the applicable range of the substrate (see table 3 below for details). N-allylated acetanilides bearing bromine or chlorine atoms in the para-position of the N-aryl group can be reacted smoothly with cyclohexane and yield in high yields of the corresponding 3-alkylindolines 2a3,4, whereas methyl and phenyl substituents are unfavorable, 5-methyl or 5-phenylindolines 2a2,5 being produced only in moderate yields. It is noted that 3-alkyl-2, 3-dihydropyrrolo [3,2-c ] pyridines 2b can also be synthesized from the corresponding allylated 4-aminopyridines. The reaction involving propionyl-protected N-allylaniline gives indolines 2c1,2 in 61-71% yield, which are sensitive to steric effects, and the yields of 3-alkylindolines 2d1,2 and 2e1,2 protected by long chain acyl groups (such as octanoyl, dodecanoyl and stearoyl) are relatively reduced, whereas the corresponding indolines 2e3 can only be obtained in very low yields when using more sterically hindered pivaloyl substrates. The substrate having a t-butoxy substituent on the nitrogen atom was reacted with the solvent cyclohexane to produce the product 2f in 62% yield. This alkylation/cyclization cascade can also be extended to N-allylated sulfonamide substrates. Overall, the yield of N-methanesulfonyl or N-ethanesulfonylindoline, 2g, h, was higher than the yield of o-toluenesulfonyl or dimethylsulfamoyl product, 2i, j. Allylated N-o-toluenesulfonyl para-chloroaniline is a challenging substrate and its reaction needs to be carried out at 160 ℃. Allylated 3, 5-dichloroaniline is also a highly reactive substrate and corresponds to 4, 6-dichloroindoline 2k produced in 70% yield. Other alkane solvents may also participate in the reaction to produce the corresponding cyclopentylmethyl, cycloheptylmethyl, or cyclooctylmethylindoline 2l-n in moderate to high yields.

TABLE 3 Synthesis of 3-alkylindolines from N-allylaniline

^[a]Reaction conditions are as follows: 1(0.3mmol), DTBP (1.05mmol), CuI (0.015mmol), alkane solvent (3.0mL), 140 ℃,6 h.

^[b]The reaction was carried out at 160 ℃.

The 6-endo-trig cyclization process may also occur in the present reaction according to the Bowden temperature rule. In the early days, the inventors all used N- (2-methallyl) substrates and after the above reactions all achieved exo selectivity, the inventors attempted to extend the reaction to simple N-allylaniline derivatives. It is surprising that the reaction without a methyl-branched substrate also exhibits a high exo selectivity, although the corresponding 3-monosubstituted indolines 4a-c are produced in only moderate yields, as specified below.

Alkylation/cyclization of unbranched N-allylic amides

In conclusion, the inventor develops a copper-catalyzed exo-selective N-allylaniline alkylation/cyclization cascade reaction, the reaction directly synthesizes 2-position unsubstituted 3-alkyl indoline by using non-activated olefin and simple alkane, and the reaction has simple operation and wide substrate range. This is a simple alkane with an inactive alkene C (sp)³) Rare examples of-H bond functionalization reactions.

Nuclear magnetic data of target product

2a1, 1- (3-methyl-3- (cyclohexylmethyl) indolin-1-yl) -1-ethanone, an inseparable rotamer mixture of 2:9 (derived from hindered rotation of the N- (CO) bond in the amide group), pale yellow oil.¹H NMR(400MHz,CDCl₃)δ＝0.83-1.65(m,16H),2.22(s,3H),3.70(d,J＝10.2Hz,1H),3.90(d,J＝10.2Hz,1H),7.03(ddd,J＝0.8,7.4,7.4Hz,1H),7.10(dd,J＝0.8,7.4Hz,1H),7.17-7.21(m,1H),8.18(d,J＝8.1Hz,1H)；¹³C NMR(100MHz,CDCl₃)δ＝168.66,141.82,140.09,127.70,123.69,122.36,116.91,61.91,48.60,43.69,35.48,34.73,34.62,27.84,26.37,26.30,26.13,24.33；HRMS(ESI-TOF)Calcd for C₁₈H₂₆NO⁺([M+H]⁺)272.2009.Found 272.2010.

2a2, 1- (3, 5-dimethyl-3- (cyclohexylmethyl) indolin-1-yl) -1-ethanone, a non-separable rotameric mixture of 1:4, a light brown oil.¹H NMR(400MHz,CDCl₃)δ＝0.83-1.65(m,16H),2.21(s,3H),2.31(s,3H),3.68(d,J＝10.2Hz,1H),3.89(d,J＝10.2Hz,1H),6.89(s,1H),6.99(d,J＝7.4Hz,1H),8.05(d,J＝8.2Hz,1H)；¹³C NMR(100MHz,CDCl₃)δ＝168.31,140.31,139.50,133.25,128.17,122.92,116.62,62.04,48.56,43.64,35.48,34.72,34.65,27.71,26.37,26.31,26.14,24.22,21.17；HRMS(ESI-TOF)Calcd for C₁₉H₂₈NO⁺([M+H]⁺)286.2165.Found 286.2176.

2a3, 1- (3-methyl-3- (cyclohexylmethyl) -5-bromoindolin-1-yl) 1-ethanone, 1:9 rotamer mixture, yellowish oil.¹H NMR(400MHz,CDCl₃)δ＝0.84-1.67(m,16H),2.21(s,3H),3.71(d,J＝10.2Hz,1H),3.91(d,J＝10.2Hz,1H),7.19(d,J＝1.5Hz,1H),7.29(dd,J＝1.6,8.6Hz,1H),8.07(d,J＝8.6Hz,1H)；¹³C NMR(100MHz,CDCl₃)δ＝168.72,142.56,140.90,130.56,125.59,118.37,116.09,61.87,48.43,43.79,35.39,34.67,34.62,27.79,26.32,26.27,26.07,24.22；HRMS(ESI-TOF)Calcd for C₁₈H₂₅BrNO⁺([M+H]⁺)350.1114.Found 350.1112.

2a4, 1- (3-methyl-3- (cyclohexylmethyl) -5-chloroindolin-1-yl) -1-ethanone, 1:9 rotameric mixture, light yellow oil.¹H NMR(400MHz,CDCl₃)δ＝0.84-1.67(m,16H),2.21(s,3H),3.72(d,J＝10.2Hz,1H),3.92(d,J＝10.2Hz,1H),7.04(d,J＝2.0Hz,1H),7.15(dd,J＝2.2,8.6Hz,1H),8.12(d,J＝8.6Hz,1H)；¹³C NMR(100MHz,CDCl₃)δ＝168.66,142.16,140.43,128.54,127.63,122.68,117.89,61.92,48.42,43.79,35.39,34.67,34.61,27.81,26.32,26.26,26.07,24.18；HRMS(ESI-TOF)Calcd for C₁₈H₂₅ClNO⁺([M+H]⁺)306.1619.Found 306.1606.

2a5, 1- (3-methyl-3- (cyclohexylmethyl) -5-phenylindolin-1-yl) -1-ethanone, 1:6 rotameric mixture, light yellow oil.¹H NMR(400MHz,CDCl₃)δ＝0.83-1.69(m,16H),2.25(s,3H),3.75(d,J＝10.2Hz,1H),3.96(d,J＝10.2Hz,1H),7.30-7.33(m,2H),7.40-7.45(m,3H),7.57(d,J＝7.4Hz,2H),8.24(d,J＝8.4Hz,1H)；¹³C NMR(100MHz,CDCl₃)δ＝168.62,141.27,141.15,140.79,136.85,128.73,126.90,126.73,121.06,117.04,62.16,48.61,43.78,35.49,34.76,34.67,27.87,26.37,26.30,26.11,24.28；HRMS(ESI-TOF)Calcd for C₂₄H₃₀NO⁺([M+H]⁺)348.2322.Found 348.2325.

2b, 1- (3-methyl-3- (cyclohexylmethyl) -2, 3-dihydro-1H-pyrrolo [3, 2-c)]Pyridin-1-yl) -1-ethanone, a 2:15 rotamer mixture, a light brown oil.¹H NMR(400MHz,CDCl₃)δ＝0.83-1.68(m,16H),2.25(s,3H),3.73(d,J＝10.1Hz,1H),3.93(d,J＝10.0Hz,1H),8.00(d,J＝5.2Hz,1H),8.32(s,1H),8.40(d,J＝5.5Hz,1H)；¹³C NMR(100MHz,CDCl₃)δ＝169.76,149.72,148.39,144.44,135.22,111.32,62.08,48.51,43.12,35.36,34.72,34.66,28.08,26.31,26.25,26.03,24.33；HRMS(ESI-TOF)Calcd for C₁₇H₂₅N₂O⁺([M+H]⁺)273.1961.Found 273.1976.

2c1, 1- (3, 5-dimethyl-3- (cyclohexylmethyl) indolin-1-yl) -1-propanone, rotameric mixture of 2:11, yellowish oil.¹H NMR(400MHz,CDCl₃)δ＝0.83-1.66(m,19H),2.31(s,3H),2.43(q,J＝7.4Hz,2H),3.67(d,J＝10.2Hz,1H),3.88(d,J＝10.2Hz,1H),6.89(s,1H),6.99(d,J＝8.0Hz,1H),8.09(d,J＝8.2Hz,1H)；¹³C NMR(100MHz,CDCl₃)δ＝171.67,140.19,139.73,133.08,128.19,122.89,116.57,61.05,48.56,43.64,35.50,34.73,34.64,29.16,27.70,26.37,26.32,26.14,21.16,8.81；HRMS(ESI-TOF)Calcd for C₂₀H₃₀NO⁺([M+H]⁺)300.2322.Found 300.2326.

2c2, 1- (3-methyl-3- (cyclohexylmethyl) -5-bromoindolin-1-yl) -1-propanone, as a yellowish solid mp 100-.¹H NMR(400MHz,CDCl₃)δ＝0.84-1.64(m,19H),2.43(q,J＝7.3Hz,2H),3.69(d,J＝10.2Hz,1H),3.90(d,J＝10.2Hz,1H),7.19(d,J＝1.5Hz,1H),7.29(dd,J＝2.0,8.6Hz,1H),8.11(d,J＝8.6Hz,1H)；¹³C NMR(100MHz,CDCl₃)δ＝172.08,142.44,141.14,130.57,125.56,118.30,115.91,60.90,48.44,43.79,35.41,34.68,34.62,29.20,27.79,26.33,26.27,26.07,8.68；HRMS(ESI-TOF)Calcd for C₁₉H₂₇BrNO⁺([M+H]⁺)364.1271.Found 364.1273.

2d1, 1- (3, 5-dimethyl-3- (cyclohexylmethyl) indolin-1-yl) -1-octanone, 1:6 rotamer mixture, yellowish oil.¹H NMR(400MHz,CDCl₃)δ＝0.83-1.64(m,27H),1.69-1.77(m,2H),2.31(s,3H),2.39(t,J＝7.7Hz,2H),3.68(d,J＝10.2Hz,1H),3.89(d,J＝10.2Hz,1H),6.89(s,1H),6.99(d,J＝8.2Hz,1H),8.09(d,J＝8.2Hz,1H)；¹³C NMR(100MHz,CDCl₃)δ＝171.15,140.22,139.75,133.08,128.17,122.87,116.66,61.22,48.59,43.60,36.01,35.51,34.74,34.64,31.75,29.42,29.19,27.68,26.38,26.33,26.15,24.74,22.66,21.16,14.10；HRMS(ESI-TOF)Calcd for C₂₅H₄₀NO⁺([M+H]⁺)370.3104.Found 370.3104.

2d2, 1- (3-methyl-3- (cyclohexylmethyl) -5-bromoindolin-1-yl) -1-octanone, as a yellowish solid mp 84-85 ℃.¹H NMR(400MHz,CDCl₃)δ＝0.84-1.76(m,29H),2.39(t,J＝7.6Hz,2H),3.70(d,J＝10.2Hz,1H),3.91(d,J＝10.2Hz,1H),7.18(d,J＝1.6Hz,1H),7.29(dd,J＝2.0,8.6Hz,1H),8.10(d,J＝8.6Hz,1H)；¹³C NMR(100MHz,CDCl₃)δ＝171.56,142.47,141.15,130.54,125.54,118.40,115.92,61.06,48.48,43.75,35.99,35.42,34.69,34.61,31.72,29.35,29.17,27.78,26.33,26.28,26.07,24.60,22.65,14.10；HRMS(ESI-TOF)Calcd for C₂₄H₃₇BrNO⁺([M+H]⁺)434.2053.Found 434.2049.

2e1, 1- (3-methyl-3- (cyclohexylmethyl) -5-bromoindolin-1-yl) -1-decadione, yellowish oil.¹H NMR(400MHz,CDCl₃)δ＝0.83-1.76(m,37H),2.39(t,J＝7.6Hz,2H),3.70(d,J＝10.2Hz,1H),3.91(d,J＝10.2Hz,1H),7.18(d,J＝1.6Hz,1H),7.29(dd,J＝2.0,8.6Hz,1H),8.10(d,J＝8.6Hz,1H)；¹³C NMR(100MHz,CDCl₃)δ＝171.58,142.46,141.15,130.56,125.54,118.40,115.93,61.07,48.48,43.75,36.00,35.43,34.69,34.61,31.92,29.65,29.63,29.53,29.51,29.40,29.35,27.78,26.33,26.28,26.07,24.60,22.70,14.13；HRMS(ESI-TOF)Calcd for C₂₈H₄₅BrNO⁺([M+H]⁺)490.2679.Found 490.2680.

2e2, 1- (3-methyl-3- (cyclohexylmethyl) -5-bromoindolin-1-yl) -1-octadecanone, yellowish oil.¹H NMR(400MHz,CDCl₃)δ＝0.81-1.76(m,49H),2.39(t,J＝7.6Hz,2H),3.70(d,J＝10.2Hz,1H),3.91(d,J＝10.2Hz,1H),7.18(d,J＝1.7Hz,1H),7.29(dd,J＝2.0,8.6Hz,1H),8.10(d,J＝8.6Hz,1H)；¹³C NMR(100MHz,CDCl₃)δ＝171.58,142.46,141.15,130.56,125.54,118.40,115.93,61.07,48.48,43.75,36.00,35.43,34.69,34.61,31.94,29.71,29.69,29.67,29.65,29.53,29.51,29.40,29.38,27.78,26.33,26.28,26.07,24.60,22.71,14.14；HRMS(ESI-TOF)Calcd for C₃₄H₅₇BrNO⁺([M+H]⁺)574.3618.Found 574.3619.

2e3, 2, 2-dimethyl-1- (3-methyl-3- (cyclohexylmethyl) -5-bromoindolin-1-yl) -1-propanone, light yellow oil.¹H NMR(400MHz,CDCl₃)δ＝0.84-1.68(m,25H),3.89(d,J＝10.1Hz,1H),4.08(d,J＝10.1Hz,1H),7.19(d,J＝2.1Hz,1H),7.29(dd,J＝2.1,8.7Hz,1H),8.10(d,J＝8.7Hz,1H)；¹³C NMR(100MHz,CDCl₃)δ＝176.48,142.73,142.15,130.34,125.21,119.84,116.14,62.26,47.66,44.41,40.21,35.57,34.66,34.53,27.64,26.34,26.26,26.07；HRMS(ESI-TOF)Calcd for C₂₁H₃₁BrNO⁺([M+H]⁺)392.1584.Found 392.1582.

Tert-butyl 2f, 3-methyl-3- (cyclohexylmethyl) -5-chloroindoline-1-carboxylate, rotamer mixture of 2:3, yellowish solid mp 101-.¹H NMR(400MHz,CDCl₃)δ＝0.82-1.66(m,25H),3.64(brs,1H,unexchangeable),3.84(brs,1H,unexchangeable),7.01(d,J＝2.2Hz,1H),7.10(d,J＝8.4Hz,1H),7.32(brs,0.38H(1H minor),unexchangeable),7.76(brs,0.57H(1H major),unexchangeable)；¹³C NMR(100MHz,CDCl₃)δ＝151.42,141.89(br,major or minor),140.80(bs,major and minor),139.56(br,major or minor),126.36,126.13,121.77(bs,major and minor),114.58,80.54(br,minor),79.72(br,major),59.55(bs,major and minor),47.46,42.06(bs,major),41.55(bs,minor),34.37,33.62,33.52,27.43,26.80,25.35,25.28,25.11；HRMS(ESI-TOF)Calcd for C₂₁H₃₁ClNO₂ ⁺([M+H]⁺)364.2038.Found 364.2038.

2g1, 3-methyl-3- (cyclohexylmethyl) -1- (methylsulfonyl) -5-bromoindoline, a light brown oil.¹H NMR(400MHz,CDCl₃)δ＝0.86-1.68(m,16H),2.89(s,3H),3.66(d,J＝10.1Hz,1H),3.83(d,J＝10.1Hz,1H),7.22(d,J＝1.8Hz,1H),7.26(d,J＝8.7Hz,1H),7.29-7.32(m,1H)；¹³C NMR(100MHz,CDCl₃)δ＝142.62,139.96,130.96,126.52,116.22,114.68,62.64,47.89,43.85,35.42,34.62,34.61,34.59,27.04,26.33,26.28,26.05；HRMS(ESI-TOF)Calcd for C₁₇H₂₅BrNO₂S⁺([M+H]⁺)386.0784.Found 386.0785.

2g2, 3-methyl-3- (cyclohexylmethyl) -5-phenyl-1- (methylsulfonyl) indoline, a slightly brown oil.¹H NMR(400MHz,CDCl₃)δ＝0.83-1.72(m,16H),2.93(s,3H),3.70(d,J＝10.0Hz,1H),3.87(d,J＝10.0Hz,1H),7.31-7.35(m,2H),7.41-7.45(m,4H),7.53-7.55(m,2H)；¹³C NMR(100MHz,CDCl₃)δ＝140.87,140.79,140.21,137.02,128.82,127.15,127.12,126.90,122.03,113.34,62.88,48.07,43.83,35.52,34.73,34.66,34.54,27.15,26.40,26.33,26.10；HRMS(ESI-TOF)Calcd for C₂₃H₃₀NO₂S⁺([M+H]⁺)384.1992.Found 384.2003.

2h1, 3-methyl-3- (cyclohexylmethyl) -1- (ethylsulfonyl) -5-bromoindoline, brown oil.¹H NMR(400MHz,CDCl₃)δ＝0.85-1.65(m,19H),3.11(q,J＝7.4Hz,2H),3.71(d,J＝10.1Hz,1H),3.89(d,J＝10.1Hz,1H),7.20(d,J＝1.6Hz,1H),7.22(d,J＝8.7Hz,1H),7.27(dd,J＝1.8,8.5Hz,1H)；¹³C NMR(100MHz,CDCl₃)δ＝142.34,140.24,130.79,126.45,115.64,114.50,62.59,47.89,44.23,43.89,35.43,34.60,27.14,26.34,26.28,26.05,7.81；HRMS(ESI-TOF)Calcd for C₁₈H₂₇BrNO₂S⁺([M+H]⁺)400.0940.Found 400.0938.

2h2, 3-methyl-3- (cyclohexylmethyl) -1- (ethylsulfonyl) -5-chloroindoline, brown oil.¹H NMR(400MHz,CDCl₃)δ＝0.85-1.68(m,19H),3.11(q,J＝7.4Hz,2H),3.72(d,J＝10.1Hz,1H),3.90(d,J＝10.1Hz,1H),7.06(d,J＝2.1Hz,1H),7.12(dd,J＝2.2,8.6Hz,1H),7.27(d,J＝8.6Hz,1H)；¹³C NMR(100MHz,CDCl₃)δ＝141.95,139.72,128.27,127.89,123.56,114.01,62.64,47.88,44.19,43.90,35.44,34.61,34.58,27.15,26.34,26.28,26.05,7.80；HRMS(ESI-TOF)Calcd for C₁₈H₂₇ClNO₂S⁺([M+H]⁺)356.1446.Found 356.1433.

2h3, 3-methyl-3- (cyclohexylmethyl) -5-phenyl-1- (ethylsulfonyl) indoline, a slightly brown oil.¹H NMR(400MHz,CDCl₃)δ＝0.83-1.71(m,19H),3.16(q,J＝7.4Hz,2H),3.77(d,J＝10.0Hz,1H),3.94(d,J＝10.0Hz,1H),7.31-7.34(m,2H),7.40-7.44(m,4H),7.53-7.55(m,2H)；¹³C NMR(100MHz,CDCl₃)δ＝140.88,140.61,140.46,136.52,128.80,127.03,126.99,126.87,122.00,113.15,62.83,48.07,44.09,43.87,35.53,34.71,34.67,27.26,26.40,26.34,26.11,7.86；HRMS(ESI-TOF)Calcd for C₂₄H₃₂NO₂S⁺([M+H]⁺)398.2148.Found 398.2145.

2i, 3-methyl-3- (cyclohexylmethyl) -1- (o-tolylsulfonyl) -5-chloroindoline, a slightly brown oil.¹H NMR(400MHz,CDCl₃)δ＝0.73-0.93(m,2H),1.01-1.29(m,8H),1.34-1.63(m,6H),2.59(s,3H),3.64(d,J＝10.2Hz,1H),3.81(d,J＝10.2Hz,1H),7.00(d,J＝2.1Hz,1H),7.09(dd,J＝2.2,8.6Hz,1H),7.29-7.32(m,2H),7.34(d,J＝8.6Hz,1H),7.46(ddd,J＝1.3,7.5,7.5Hz,1H),7.93(dd,J＝1.1,8.0Hz,1H)；¹³C NMR(100MHz,CDCl₃)δ＝142.00,140.14,138.12,137.16,133.12,132.99,129.40,128.35,127.72,126.30,123.36,115.07,61.66,47.78,43.90,35.34,34.46,34.42,26.97,26.26,26.21,26.03,20.94；HRMS(ESI-TOF)Calcd for C₂₃H₂₉ClNO₂S⁺([M+H]⁺)418.1602.Found 418.1617.

2j1, N, 3-trimethyl-3- (cyclohexylmethyl) -5-bromoindoline-1-sulfonamide, dark brown oil.¹H NMR(400MHz,CDCl₃)δ＝0.84-1.68(m,16H),2.89(s,6H),3.67(d,J＝9.8Hz,1H),3.86(d,J＝9.9Hz,1H),7.17(s,1H),7.18(d,J＝8.6Hz,1H),7.25(dd,J＝2.0,8.7Hz,1H)；¹³C NMR(100MHz,CDCl₃)δ＝141.94,141.01,130.60,126.07,115.12,114.83,62.91,47.95,43.86,38.28,35.48,34.60,34.57,27.14,26.36,26.31,26.07；HRMS(ESI-TOF)Calcd for C₁₈H₂₈BrN₂O₂S⁺([M+H]⁺)415.1049.Found 415.1044.

2j2, N, N, 3-trimethyl-3- (cyclohexylmethyl) -5-phenylindoline-1-sulfonylAmine, slightly brown oil.¹H NMR(400MHz,CDCl₃)δ＝0.83-1.69(m,16H),2.92(s,6H),3.73(d,J＝9.8Hz,1H),3.92(d,J＝9.9Hz,1H),7.29-7.33(m,2H),7.36(d,J＝8.2Hz,1H),7.38(d,J＝1.8Hz,1H),7.40-7.45(m,2H),7.53-7.55(m,2H)；¹³C NMR(100MHz,CDCl₃)δ＝141.28,141.06,140.19,136.01,128.76,126.88,126.86,126.81,121.66,113.43,63.16,48.11,43.83,38.32,35.58,34.71,34.64,27.24,26.42,26.36,26.13；HRMS(ESI-TOF)Calcd for C₂₄H₃₃N₂O₂S⁺([M+H]⁺)413.2257.Found 413.2259.

2k, 1- (3-methyl-3- (cyclohexylmethyl) -4, 6-dichloroindolin-1-yl) -1-octanone, as a yellowish oil.¹H NMR(400MHz,CDCl₃)δ＝0.84-1.75(m,28H),1.95(dd,J＝5.8,15.5Hz,1H),2.38(d,J＝7.4Hz,2H),3.70(d,J＝10.4Hz,1H),3.99(d,J＝10.4Hz,1H),6.97(d,J＝1.9Hz,1H),8.29(s,1H)；¹³C NMR(100MHz,CDCl₃)δ＝171.80,144.98,134.05,133.30,130.51,124.68,115.94,61.65,45.85,44.98,36.12,35.19,34.83,34.20,31.71,29.29,29.16,26.95,26.32,26.21,26.10,24.48,22.64,14.09；HRMS(ESI-TOF)Calcd for C₂₄H₃₆Cl₂NO⁺([M+H]⁺)424.2168.Found 424.2164.

2l1, 1- (3-methyl-3- (cyclopentylmethyl) -5-bromoindolin-1-yl) -1-octanone, as a yellowish oil.¹H NMR(400MHz,CDCl₃)δ＝0.87-1.81(m,27H),2.39(t,J＝7.6Hz,2H),3.69(d,J＝10.2Hz,1H),3.95(d,J＝10.2Hz,1H),7.18(d,J＝1.9Hz,1H),7.29(dd,J＝2.1,8.6Hz,1H),8.10(d,J＝8.6Hz,1H)；¹³C NMR(100MHz,CDCl₃)δ＝171.53,142.14,141.40,130.57,125.64,118.38,115.92,60.87,47.70,43.98,36.99,35.98,34.70,34.18,31.73,29.35,29.16,27.84,25.13,24.74,24.55,22.64,14.10；HRMS(ESI-TOF)Calcd for C₂₃H₃₅BrNO⁺([M+H]⁺)420.1897.Found 420.1898.

2l2, 2, 2-dimethyl-1- (3-methyl-3- (cyclopentylmethyl) -5-bromoindolin-1-yl) -1-propanone, brown oil.¹H NMR(400MHz,CDCl₃)δ＝0.92-1.83(m,23H),3.87(d,J＝10.1Hz,1H),4.11(d,J＝10.1Hz,1H),7.19(d,J＝2.1Hz,1H),7.29(dd,J＝2.1,8.7Hz,1H),8.10(d,J＝8.7Hz,1H)；¹³C NMR(100MHz,CDCl₃)δ＝176.50,142.85,142.02,130.37,125.31,119.87,116.14,62.25,46.51,44.68,40.20,36.94,34.88,34.17,27.64,26.15,25.31,24.73；HRMS(ESI-TOF)Calcd for C₂₀H₂₉BrNO⁺([M+H]⁺)378.1427.Found 378.1428.

2m, 1- (3-methyl-3- (cycloheptylmethyl) -5-bromoindolin-1-yl) -1-octanone, as a yellowish oil.¹H NMR(400MHz,CDCl₃)δ＝0.89(t,J＝7.0Hz,3H),1.09-1.62(m,26H),1.72(tt,J＝7.3,7.3Hz,2H),2.39(t,J＝7.6Hz,2H),3.69(d,J＝10.2Hz,1H),3.91(d,J＝10.2Hz,1H),7.19(d,J＝1.9Hz,1H),7.29(dd,J＝2.1,8.6Hz,1H),8.10(d,J＝8.6Hz,1H)；¹³C NMR(100MHz,CDCl₃)δ＝171.52,142.25,141.24,130.55,125.58,118.41,115.91,61.03,49.19,44.03,36.90,36.32,36.10,35.99,31.72,29.36,29.16,28.46,28.20,27.30,26.12,26.07,24.61,22.64,14.10；HRMS(ESI-TOF)Calcd for C₂₅H₃₉BrNO⁺([M+H]⁺)448.2210.Found 448.2208.

2n, 1- (3-methyl-3- (cyclooctylmethyl) -5-bromoindolin-1-yl) -1-octanone, as a yellowish oil.¹H NMR(400MHz,CDCl₃)δ＝0.89(t,J＝7.0Hz,3H),1.14-1.60(m,28H),1.72(tt,J＝7.3,7.3Hz,2H),2.39(t,J＝7.6Hz,2H),3.69(d,J＝10.2Hz,1H),3.92(d,J＝10.2Hz,1H),7.19(d,J＝1.9Hz,1H),7.29(dd,J＝2.1,8.6Hz,1H),8.11(d,J＝8.6Hz,1H)；¹³C NMR(100MHz,CDCl₃)δ＝171.50,142.17,141.30,130.55,125.63,118.43,115.91,60.96,49.22,44.02,36.00,34.42,33.86,33.62,31.72,29.36,29.16,27.42,27.24,27.21,26.26,25.15,24.96,24.61,22.65,14.10；HRMS(ESI-TOF)Calcd for C₂₆H₄₁BrNO⁺([M+H]⁺)462.2366.Found 462.2378.

4a, 1- (3- (cyclohexylmethyl) indolin-1-yl) -1-octanone, 1:8 rotamer mixture, light yellow oil.¹H NMR(400MHz,CDCl₃)δ＝0.87-1.84(m,26H),2.42(t,J＝7.6Hz,2H),3.43-3.50(m,1H),3.64(dd,J＝6.2,10.1Hz,1H),4.14(dd,J＝9.7,9.7Hz,1H),7.01(dd,J＝7.4,7.4Hz,1H),7.13(d,J＝7.3Hz,1H),7.19(dd,J＝7.7,7.7Hz,1H),8.23(d,J＝8.1Hz,1H)；¹³C NMR(100MHz,CDCl₃)δ＝171.50,142.78,135.67,127.70,123.66,123.43,116.97,54.77,43.71,37.36,36.04,35.55,34.13,32.72,31.75,29.40,29.19,26.54,26.31,26.22,24.63,22.66,14.11；HRMS(ESI-TOF)Calcd for C₂₃H₃₆NO⁺([M+H]⁺)342.2791.Found 342.2778.

4b, 1- (5-methyl-3- (cyclohexylmethyl) indolin-1-yl) -1-octanone, 1:6 rotamer mixture, light brown oil.¹H NMR(400MHz,CDCl₃)δ＝0.87-1.85(m,26H),2.31(s,3H),2.40(t,J＝7.7Hz,2H),3.39-3.46(m,1H),3.62(dd,J＝6.2,10.2Hz,1H),4.13(dd,J＝9.7,9.7Hz,1H),6.94(s,1H),6.99(d,J＝8.0Hz,1H),8.10(d,J＝8.2Hz,1H)；¹³C NMR(100MHz,CDCl₃)δ＝171.15,140.48,135.80,132.99,128.13,124.26,116.67,54.86,43.70,37.34,35.93,35.61,34.21,32.65,31.76,29.41,29.20,26.55,26.32,26.21,24.66,22.66,21.08,14.11；HRMS(ESI-TOF)Calcd for C₂₄H₃₈NO⁺([M+H]⁺)356.2948.Found 356.2951.

4c, 1- (3- (cyclohexylmethyl) -5-bromoindolin-1-yl) -1-octanone, yellowish semi-solid.¹H NMR(400MHz,CDCl₃)δ＝0.89-1.84(m,26H),2.41(t,J＝7.6Hz,2H),3.42-3.49(m,1H),3.64(dd,J＝6.4,10.2Hz,1H),4.15(dd,J＝9.8,9.8Hz,1H),7.23(s,1H),7.29(ddd,J＝0.5,2.0,8.6Hz,1H),8.10(d,J＝8.6Hz,1H)；¹³C NMR(100MHz,CDCl₃)δ＝171.58,141.90,138.05,130.52,126.77,118.30,115.81,54.76,43.50,37.23,35.94,35.49,34.15,32.55,31.74,29.36,29.18,26.47,26.26,26.14,24.51,22.66,14.12；HRMS(ESI-TOF)Calcd for C₂₃H₃₅BrNO⁺([M+H]⁺)420.1897.Found 420.1898.

Claims

1. A method for synthesizing 3-alkyl indoline by alkylation of non-activated olefin under catalysis of copper is characterized in that the reaction route is as follows:

wherein:

a is C or N;

R¹is hydrogen, halogen, C_1-6Alkyl or phenyl;

R²is hydrogen or C_1-6An alkyl group;

R³is COR⁴Or SO₂R⁵；

R⁴Is C_1-17Alkyl or-O-C_1-6An alkyl group;

R⁵is C_1-6Alkyl, N-dimethyl or

R⁶Is hydrogen, halogen, hydroxy, C_1-6Alkyl or-O-C_1-6An alkyl group;

the catalyst comprises a catalyst 1 and a catalyst 2, wherein the catalyst 1 is selected from copper halide, and the catalyst 2 is selected from DTBP; the copper halide is selected from CuBr, CuCl or CuI; the reaction temperature is 140-160 ℃.

2. The method of claim 1, wherein: the copper halide is selected from copper iodide.

3. The method of claim 2, wherein: the dosage of the copper iodide is 5-10 mol%.

4. The method of claim 1, wherein: the amount of the DTBP is 3-3.5 equivalents.

5. The method of any one of claims 1-4, wherein: the halogen refers to fluorine, chlorine, bromine or iodine; said C is_1-6Alkyl means a saturated straight or branched chain hydrocarbon group having 1 to 6 carbon atoms; said C is_1-17Alkyl means a saturated straight or branched chain hydrocarbon group having 1 to 17 carbon atoms; said-O-C_1-6Alkyl means a saturated straight or branched chain alkoxy group having 1 to 6 carbon atoms.

6. The method of any one of claims 1-4, wherein: said C is_1-6The alkyl group is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl or isohexyl; said C is_1-17The alkyl group is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, n-C₇H₁₅、n-C₉H₁₉、n-C₁₁H₂₃Or n-C₁₇H₃₅(ii) a said-O-C_1-6The alkyl group is selected from methoxy, ethoxy or tert-butoxy.

7. The method of any one of claims 1-4, wherein: r¹Selected from hydrogen, methyl, chlorine, bromine or phenyl; r²Selected from hydrogen or methyl; r³Is COR⁴Or SO₂R⁵；R⁴Selected from methyl, ethyl, n-C₇H₁₅、n-C₉H₁₉、n-C₁₁H₂₃、n-C₁₇H₃₅t-Bu or tert-butoxy; r⁵Selected from methyl, ethyl, N-dimethyl; alkyl is selected from cyclopentyl, cyclohexyl, cycloheptyl.

8. The method of any one of claims 1-4, wherein: the compound of formula II is selected from

1- (3-methyl-3- (cyclohexylmethyl) indolin-1-yl) -1-ethanone;

1- (3, 5-dimethyl-3- (cyclohexylmethyl) indolin-1-yl) -1-ethanone;

1- (3-methyl-3- (cyclohexylmethyl) -5-bromoindolin-1-yl) -1-ethanone;

1- (3-methyl-3- (cyclohexylmethyl) -5-chloroindolin-1-yl) -1-ethanone;

1- (3-methyl-3- (cyclohexylmethyl) -5-phenylindolin-1-yl) -1-ethanone;

1- (3-methyl-3- (cyclohexylmethyl) -2, 3-dihydro-1H-pyrrolo [3,2-c ] pyridin-1-yl) -1-ethanone;

1- (3, 5-dimethyl-3- (cyclohexylmethyl) indolin-1-yl) -1-propanone;

1- (3-methyl-3- (cyclohexylmethyl) -5-bromoindolin-1-yl) -1-propanone;

1- (3, 5-dimethyl-3- (cyclohexylmethyl) indolin-1-yl) -1-octanone;

1- (3-methyl-3- (cyclohexylmethyl) -5-bromoindolin-1-yl) -1-octanone;

1- (3-methyl-3- (cyclohexylmethyl) -5-bromoindolin-1-yl) -1-decadione;

1- (3-methyl-3- (cyclohexylmethyl) -5-bromoindolin-1-yl) -1-octadecanone;

2, 2-dimethyl-1- (3-methyl-3- (cyclohexylmethyl) -5-bromoindolin-1-yl) -1-propanone;

3-methyl-3- (cyclohexylmethyl) -5-chloroindoline-1-carboxylic acid tert-butyl ester;

3-methyl-3- (cyclohexylmethyl) -1- (methylsulfonyl) -5-bromoindoline;

3-methyl-3- (cyclohexylmethyl) -5-phenyl-1- (methylsulfonyl) indoline;

3-methyl-3- (cyclohexylmethyl) -1- (ethylsulfonyl) -5-bromoindoline;

3-methyl-3- (cyclohexylmethyl) -1- (ethylsulfonyl) -5-chloroindoline;

3-methyl-3- (cyclohexylmethyl) -5-phenyl-1- (ethylsulfonyl) indoline;

3-methyl-3- (cyclohexylmethyl) -1- (o-tolylsulfonyl) -5-chloroindoline;

n, 3-trimethyl-3- (cyclohexylmethyl) -5-bromoindoline-1-sulfonamide;

n, 3-trimethyl-3- (cyclohexylmethyl) -5-phenylindoline-1-sulfonamide;

1- (3-methyl-3- (cyclohexylmethyl) -4, 6-dichloroindolin-1-yl) -1-octanone;

1- (3-methyl-3- (cyclopentylmethyl) -5-bromoindolin-1-yl) -1-octanone;

2, 2-dimethyl-1- (3-methyl-3- (cyclopentylmethyl) -5-bromoindolin-1-yl) -1-propanone;

1- (3-methyl-3- (cycloheptylmethyl) -5-bromoindolin-1-yl) -1-octanone;

1- (3-methyl-3- (cyclooctylmethyl) -5-bromoindolin-1-yl) -1-octanone;

1- (3- (cyclohexylmethyl) indolin-1-yl) -1-octanone;

1- (5-methyl-3- (cyclohexylmethyl) indolin-1-yl) -1-octanone;

1- (3- (cyclohexylmethyl) -5-bromoindolin-1-yl) -1-octanone.