CN114874126B - Synthetic method of 3-bromoindole compound - Google Patents

Synthetic method of 3-bromoindole compound Download PDF

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CN114874126B
CN114874126B CN202210505444.5A CN202210505444A CN114874126B CN 114874126 B CN114874126 B CN 114874126B CN 202210505444 A CN202210505444 A CN 202210505444A CN 114874126 B CN114874126 B CN 114874126B
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substituted aniline
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bromoindole
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CN114874126A (en
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伍婉卿
方松佳
江焕峰
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South China University of Technology SCUT
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract

The invention discloses a synthetic method of 3-bromoindole compounds. The synthesis method comprises the following steps: adding N-substituted aniline compound, alkyne-bromide compound, palladium salt catalyst, ligand, oxidant, alkali and solvent into a reactor, stirring the mixture at 100 to 110 ℃ for reaction, and separating and purifying the reaction liquid to obtain the 3-bromoindole compound. The method develops the oxidation cyclization reaction of the N-substituted aniline and alkyne halogen, and constructs a series of highly functionalized 3-bromoindole compounds. In addition, the method has the main characteristics of simple and easily obtained raw materials, safe operation, mild conditions, good reaction selectivity and wide substrate universality.

Description

Synthetic method of 3-bromoindole compound
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to a synthesis method of a 3-bromoindole compound.
Background
Indole compounds, particularly C3 functionalized indole compounds, are important heterocyclic compounds and have biological and pharmacological activities such as anticancer, antibacterial, antihypertensive and the like. The special chemical property and biological activity make the heterocyclic compound have great interest in the fields of food, pesticide, dye, medicine, material, etc., so that the synthesis and modification of the heterocyclic compound are important in organic chemistry. In recent years, with the vigorous development of transition metal catalyzed cross-coupling reactions, the construction of functionalized indole derivatives based on carbon-to-bromine bond conversion in 3-haloindoles has gained favor from organic chemists. In order to promote the development of the field, the synthesis of the 3-bromoindole compound has important significance.
Because the electron cloud density of the 3-position carbon of the indole is higher, the construction of a carbon-bromine bond can be realized by receiving the attack of bromine positive ions, and in the past decades, the synthesis reaction of the 3-bromoindole compound is concentrated on the direct bromination of an indole ring carbon-hydrogen bond. In these reported synthetic methods for 3-bromoindoles (L.Yang, Z.Lu, S.S.Stahl.Chem.Commun.2009, 6460;P.P.Singh,T.Thatikonda,K.A.A.Kumar,S.D.Sawant,B.Singh,A.K.Sharma,P.R.Sharma,D.Singh,R.A.Vishwakarma.J.Org.Chem.2012, 77,5823; l.shi, d.zhang, r.lin, c.zhang, x.li, n.jiao. Tetrahedron lett.2014,55,2243;L.Sun,X.Zhang,C.Wang,H.Teng,J.Ma,Z.Li,H.Chen,H.Jiang.Green Chem.2019,21,2732.), indole is used directly as a substrate, limiting the diversity of the product, and in addition, either dangerous bromine water or N-bromosuccinimide is used as a bromine source, the atomic economy is poor; or the electrochemical participation is needed, and the operation is complicated. Therefore, the development of a novel green, efficient and high-selectivity method for synthesizing the 3-bromoindole compound is significant.
Alkynes as important structural motifs in organic chemistry and material chemistry are superior reaction precursors that participate in a variety of transformations, and cyclization reactions based on alkynes and amine derivatives are efficient, straightforward methods for synthesizing indoles (J.S.S.Neto, G.Zeni.Org.Chem.Front. 2020,7,155.). Among these, the direct C-H bond-activated cyclization reaction of aromatic amines and internal alkynes catalyzed by transition metals is a route to indole products with higher atom economy and raw material availability (Z.Shi, C.Zhang, S.Li, D.Pan, S.Ding, Y.Cui, N.Jiao.Angew.Chem., int.Ed.2009,48,4572;X.Chen,X.Li,N.Wang,J.Jin,P.Lu,Y. Wang, eur. J. Org. Chem.2012,4380; D.Shen, J.Han, J.Chen, H.Deng, M.Shao, H.Zhang, W.Cao.Org.Lett.2015,17,3283.). However, unlike common internal alkyne compounds, alkyne bromine compounds have active carbon-bromine single bonds at the same time of having carbon-carbon triple bonds, bromine atoms of alkyne bromine are difficult to be reserved under the catalysis of transition metal, so that reaction selectivity becomes difficult to control, and thus, the synthesis of bromoindole compounds by using alkyne bromine and aniline as substrates has not been reported so far. In conclusion, the reaction for realizing the 3-bromoindole compound based on the high-selectivity conversion synthesis of the alkyne bromocarbon-carbon triple bond is expected to have application prospect besides the methodological novelty.
Disclosure of Invention
The invention aims at overcoming the defects and shortcomings of the prior art and provides a synthetic method of 3-bromoindole compounds. The method takes simple and easily obtained N-substituted aniline and alkyne bromine as raw materials, common palladium salt as a catalyst, amino acid as a ligand, lithium salt as alkali, benzoquinone as an oxidant, acetonitrile and N, N-dimethylformamide as solvents, adopts an oxidation cyclization strategy, selectively constructs indole derivatives with bromine reserved, has the advantages of high atom economy, single selectivity, simple and safe operation, wide substrate applicability and the like, and has good application prospects in practical production and research.
The aim of the invention is achieved by the following technical scheme.
A synthetic method of 3-bromoindole compounds comprises the following steps:
adding a substrate N-substituted aniline compound, an alkyne bromine compound, a palladium salt catalyst, a ligand, an oxidant, alkali and a solvent into a reactor, stirring the mixture at 100 to 110 ℃ for reaction, cooling the mixture to room temperature after the reaction is finished, and separating and purifying the product to obtain the 3-bromoindole compound.
Further, the chemical reaction equation of the synthesis process is as follows:
wherein R is 1 More than one of methyl, ethyl, isopropyl, butyl, cyclohexyl and benzyl;
R 2 is hydrogen, 4-methyl, 2-methoxy, 2, 4-dimethyl, wherein the number preceding the group indicates the position of the group on the benzene ring;
R 3 phenyl, n-hexyl, 3-thienyl, 1-naphthyl.
Further, the palladium salt catalyst is tetraphenylphosphine palladium, and the molar ratio of the addition amount of the palladium salt catalyst to the N-substituted aniline compound is 0.1-0.14:1.
Further, the ligand is DL-pyroglutamic acid, and the molar ratio of the adding amount of the ligand to the N-substituted aniline compound is 0.2-0.28:1.
Further, the molar ratio of the addition of the alkyne bromine compound to the N-substituted aniline compound is 2.0-3.0:1.
Further, the oxidant is benzoquinone, and the molar ratio of the addition amount of the oxidant to the N-substituted aniline compound is 1.5-2.0:1.
Further, the alkali is lithium hydroxide monohydrate, and the molar ratio of the addition amount of the alkali to the N-substituted aniline compound is 1.5-2.0:1.
Further, the solvent is a mixed solvent of acetonitrile and N, N-dimethylformamide according to a volume ratio of 7:1.
Further, the stirring reaction time is 12 to 24 hours, preferably 20 to 24 hours.
Further, the separation and purification operations are as follows: extracting the reaction liquid with ethyl acetate, combining organic phases, drying the organic phases by using anhydrous magnesium sulfate, filtering, evaporating the organic solvent under reduced pressure to obtain a crude product, and purifying the crude product by column chromatography to obtain the 3-bromoindole compound.
Furthermore, the eluent of the column chromatography is petroleum ether or a mixed solvent of petroleum ether and ethyl acetate according to the volume ratio of 20-150:1, preferably a mixed solvent of petroleum ether or petroleum ether and ethyl acetate according to the volume ratio of 30-100:1.
The reaction principle of the synthesis method is that under the promotion of alkali, N-substituted aniline, divalent palladium and ligand are coordinated to form nitrogen palladium species, then alkyne bromocarbon-carbon triple bond is subjected to migration insertion, then C-H activation and reduction elimination are carried out, 3-bromoindole compounds and zero-valent palladium are obtained, and the zero-valent palladium can participate in catalytic circulation again after being oxidized by benzoquinone and regenerated into divalent palladium.
Compared with the prior art, the invention has the following advantages:
(1) The invention develops a synthetic method for constructing 3-bromoindole compounds by the oxidative cyclization reaction of N-substituted aniline and alkyne bromine under palladium catalysis, and most of the basic raw material N-substituted aniline can be directly purchased, and the method has the characteristics of simple and easily obtained raw materials, safe and simple operation, mild conditions, high atom economy and wide substrate applicability;
(2) The synthesis method is novel and efficient, and has good tolerance to functional groups, so that the synthesis method is expected to be applied to actual industrial production and further derivatization.
Drawings
FIG. 1 is a hydrogen spectrum of the target product obtained in example 1;
FIG. 2 is a carbon spectrum of the target product obtained in example 1;
FIG. 3 is a hydrogen spectrum of the target product obtained in example 2;
FIG. 4 is a carbon spectrum of the target product obtained in example 2;
FIG. 5 is a hydrogen spectrum of the target product obtained in example 3;
FIG. 6 is a carbon spectrum of the target product obtained in example 3;
FIG. 7 is a hydrogen spectrum of the target product obtained in example 4;
FIG. 8 is a carbon spectrum of the target product obtained in example 4;
FIG. 9 is a hydrogen spectrum of the target product obtained in example 5;
FIG. 10 is a carbon spectrum of the target product obtained in example 5;
FIG. 11 is a hydrogen spectrum of the target product obtained in example 6;
FIG. 12 is a carbon spectrum of the target product obtained in example 6;
FIG. 13 is a hydrogen spectrum of the target product obtained in example 7;
FIG. 14 is a carbon spectrum of the target product obtained in example 7;
FIG. 15 is a hydrogen spectrum of the target product obtained in example 8;
FIG. 16 is a carbon spectrum of the target product obtained in example 8;
FIG. 17 is a hydrogen spectrum of the target product obtained in example 9;
FIG. 18 is a carbon spectrum of the target product obtained in example 9;
FIG. 19 is a hydrogen spectrum of the target product obtained in example 10;
FIG. 20 is a carbon spectrum of the target product obtained in example 10;
FIG. 21 is a hydrogen spectrum of the target product obtained in example 11;
FIG. 22 is a carbon spectrum of the target product obtained in example 11;
FIG. 23 is a hydrogen spectrum of the target product obtained in example 12;
FIG. 24 is a carbon spectrum of the target product obtained in example 12.
Detailed Description
The technical scheme of the present invention is described in further detail below with reference to specific examples and drawings, but the scope and embodiments of the present invention are not limited thereto.
Example 1
To the reaction tube were added 0.1 mmol of N-methylaniline, 0.01 mmol of tetra-triphenylphosphine palladium, 0.02 mmol of DL-pyroglutamic acid, 0.2 mmol of lithium hydroxide monohydrate, 0.15 mmol of benzoquinone, 0.3 mmol of phenyl bromoacetylene, 1.0 ml of acetonitrile: the mixed solvent of N, N-dimethylformamide (7:1, v/v) is stirred and reacted for 24 hours at the rotating speed of 700rpm at the temperature of 100 ℃; stirring was stopped, 5mL of water was added, extraction was performed 3 times with ethyl acetate, the organic phases were combined and dried over 0.5g of anhydrous magnesium sulfate, filtration, concentration under reduced pressure, and separation and purification by column chromatography using petroleum ether as the eluent to give the objective product in 66% yield.
The hydrogen spectrogram and the carbon spectrogram of the obtained target product are respectively shown in fig. 1 and 2, and the structural characterization data are shown as follows:
1 H NMR(400MHz,CDCl 3 )δ7.63-7.60(m,1H),7.54-7.43(m,5H), 7.36-7.34(m,1H),7.32-7.28(m,1H),7.25-7.21(m,1H),3.66(s,3H)；
13 C NMR(100MHz,CDCl 3 )δ138.0,136.8,130.9,130.4,128.7, 128.4,127.2,122.8,120.5,119.3,109.7,90.1,31.6；
IR:ν max (KBr)＝3052,2928,2839,1465,1330,1219,1104,1013, 940,794,740,695,492cm -1 ；
HRMS(ESI)m/z:calcd for C 15 H 13 BrN[M+H] + ,286.0226；found 286.0225.
the structure of the target product is deduced from the above data as follows:
example 2
To the reaction tube were added 0.1 mmol of N-ethylaniline, 0.014 mmol of tetra-triphenylphosphine palladium, 0.028 mmol of DL-pyroglutamic acid, 0.2 mmol of lithium hydroxide monohydrate, 0.15 mmol of benzoquinone, 0.3 mmol of phenyl bromoacetylene, 1.0 ml of acetonitrile: the mixed solvent of N, N-dimethylformamide (7:1, v/v) is stirred and reacted for 24 hours at the rotating speed of 700rpm at the temperature of 100 ℃; stirring was stopped, 5mL of water was added, extraction was performed 3 times with ethyl acetate, the organic phases were combined and dried over 0.5g of anhydrous magnesium sulfate, filtration, concentration under reduced pressure, and separation and purification by column chromatography using petroleum ether as the eluent to give the objective product in 81% yield.
The hydrogen spectrogram and the carbon spectrogram of the obtained target product are respectively shown in fig. 3 and 4, and the structural characterization data are shown as follows:
1 H NMR(400MHz,CDCl 3 )δ7.63-7.61(m,1H),7.53-7.44(m,5H), 7.38-7.36(m,1H),7.31-7.27(m,1H),7.24-7.20(m,1H),4.11(q,J＝7.2Hz,2H),1.22(t,J＝7.0Hz,3H)；
13 C NMR(100MHz,CDCl 3 )δ137.6,135.6,130.7,130.5,128.7, 128.5,127.4,122.7,120.4,109.9,90.5,39.5,15.3；
IR:ν max (KBr)＝3057,2980,2928,1459,1338,1195,1110,1021, 929,742,698,612,490cm -1 ；
HRMS(ESI)m/z:calcd for C 16 H 15 BrN[M+H] + ,300.0382；found 300.0380.
the structure of the target product is deduced from the above data as follows:
example 3
To the reaction tube were added 0.1 mmol of N-isopropylaniline, 0.014 mmol of tetra-triphenylphosphine palladium, 0.028 mmol of DL-pyroglutamic acid, 0.15 mmol of lithium hydroxide monohydrate, 0.15 mmol of benzoquinone, 0.3 mmol of phenyl bromoacetylene, 1.0 ml of acetonitrile: the mixed solvent of N, N-dimethylformamide (7:1, v/v) is stirred and reacted for 24 hours at the rotating speed of 700rpm at the temperature of 100 ℃; stirring was stopped, 5mL of water was added, extraction was performed 3 times with ethyl acetate, the organic phases were combined and dried over 0.5g of anhydrous magnesium sulfate, filtration, concentration under reduced pressure, and separation and purification by column chromatography using petroleum ether as the eluent to give the objective product in 61% yield.
The hydrogen spectrogram and the carbon spectrogram of the obtained target product are respectively shown in fig. 5 and 6, and the structural characterization data are shown as follows:
1 H NMR(400MHz,CDCl 3 )δ7.63-7.57(m,2H),7.54-7.47(m,3H), 7.46-7.43(m,2H),7.27-7.18(m,2H),4.54(hept,J＝7.0Hz,1H),1.56(d, J＝6.8Hz,6H)；
13 C NMR(100MHz,CDCl 3 )δ137.9,134.1,131.4,130.7,128.7, 128.5,128.1,122.2,120.1,119.6,112.3,90.6,49.0,21.6；
IR:ν max (KBr)＝3044,2981,2928,1451,1321,1180,1114,1021, 938,736,489cm -1 ；
HRMS(ESI)m/z:calcd for C 17 H 17 BrN[M+H] + ,314.0539；found 314.0536.
the structure of the target product is deduced from the above data as follows:
example 4
To the reaction tube were added 0.1 mmol of N-butylaniline, 0.014 mmol of tetra-triphenylphosphine palladium, 0.028 mmol of DL-pyroglutamic acid, 0.2 mmol of lithium hydroxide monohydrate, 0.2 mmol of benzoquinone, 0.3 mmol of phenyl bromoacetylene, 1.0 ml of acetonitrile: the mixed solvent of N, N-dimethylformamide (7:1, v/v) is stirred and reacted for 24 hours at the rotating speed of 700rpm at the temperature of 100 ℃; stirring was stopped, 5mL of water was added, extraction was performed 3 times with ethyl acetate, the organic phases were combined and dried over 0.5g of anhydrous magnesium sulfate, filtration, concentration under reduced pressure, and separation and purification by column chromatography using petroleum ether as the eluent to obtain the objective product in 70% yield.
The hydrogen spectrogram and the carbon spectrogram of the obtained target product are respectively shown in fig. 7 and 8, and the structural characterization data are shown as follows:
1 H NMR(400MHz,CDCl 3 )δ7.61(d,J＝7.6Hz,1H),7.53-7.43 (m,5H),7.38-7.36(m,1H),7.30-7.26(m,1H),7.23-7.20(m,1H),4.07(t, J＝7.6Hz,2H),1.59(p,J＝7.6Hz,2H),1.13(h,J＝7.4Hz,2H),0.75(t,J＝7.4Hz,3H)；
13 C NMR(100MHz,CDCl 3 )δ137.9,135.9,130.8,130.6,128.7, 128.4,127.3,122.6,120.4,119.4,110.1,90.5,44.4,32.0,19.9,13.5；
IR:ν max (KBr)＝3057,2953,2867,1458,1344,1239,1181,1020, 932,741,698,615,490cm -1 ；
HRMS(ESI)m/z:calcd for C 18 H 19 BrN[M+H] + ,328.0695；found 328.0693.
the structure of the target product is deduced from the above data as follows:
example 5
To the reaction tube were added 0.1 mmol of N-cyclohexylaniline, 0.014 mmol of tetrakis triphenylphosphine palladium, 0.028 mmol of DL-pyroglutamic acid, 0.2 mmol of lithium hydroxide monohydrate, 0.15 mmol of benzoquinone, 0.3 mmol of phenyl bromoacetylene, 1.0 ml of acetonitrile: the mixed solvent of N, N-dimethylformamide (7:1, v/v) is stirred and reacted for 24 hours at the rotating speed of 700rpm at the temperature of 100 ℃; stirring was stopped, 5mL of water was added, extraction was performed 3 times with ethyl acetate, the organic phases were combined and dried over 0.5g of anhydrous magnesium sulfate, filtration, concentration under reduced pressure, and separation and purification by column chromatography using petroleum ether as the eluent to give the objective product in 46% yield.
The hydrogen spectrogram and the carbon spectrogram of the obtained target product are respectively shown in fig. 9 and 10, and the structural characterization data are shown as follows:
1 H NMR(400MHz,CDCl 3 )δ7.64-7.60(m,2H),7.54-7.47(m,3H), 7.44-7.41(m,2H),7.25-7.17(m,2H),4.07(tt,J＝12.4,3.7Hz,1H),2.32-2.24(m,2H),1.89-1.84(m,4H),1.69-1.67(m,1H),1.27-1.20(m, 3H)；
13 C NMR(100MHz,CDCl 3 )δ138.0,134.5,131.5,130.6,128.7, 128.4,127.9,122.1,120.0,119.6,112.60,90.6,57.5,31.6,26.2,25.4；
IR:ν max (KBr)＝3055,2928,2854,1450,1332,1176,1073,1022, 947,895,824,742,697,498cm -1 ；
HRMS(ESI)m/z:calcd for C 20 H 21 BrN[M+H] + ,354.0852；found 354.0849.
the structure of the target product is deduced from the above data as follows:
example 6
To the reaction tube were added 0.1 mmol of N-benzylaniline, 0.014 mmol of tetrakis triphenylphosphine palladium, 0.028 mmol of DL-pyroglutamic acid, 0.2 mmol of lithium hydroxide monohydrate, 0.15 mmol of benzoquinone, 0.3 mmol of phenyl bromoacetylene, 1.0 ml of acetonitrile: the mixed solvent of N, N-dimethylformamide (7:1, v/v) is stirred and reacted for 24 hours at the speed of 700rpm at the temperature of 110 ℃; stirring was stopped, 5mL of water was added, extraction was performed 3 times with ethyl acetate, the organic phases were combined and dried over 0.5g of anhydrous magnesium sulfate, filtration, concentration under reduced pressure, and separation and purification by column chromatography using petroleum ether as the eluent to give the objective product in 33% yield.
The hydrogen spectrogram and the carbon spectrogram of the obtained target product are respectively shown in fig. 11 and 12, and the structural characterization data are shown as follows:
1 H NMR(400MHz,CDCl 3 )δ7.66-7.63(m,1H),7.42(s,5H), 7.26-7.20(m,6H),6.94(d,J＝6.8Hz,2H),5.27(s,2H)；
13 C NMR(100MHz,CDCl 3 )δ138.2,137.6,136.4,130.6,130.3, 128.8,128.7,128.5,127.5,127.3,126.0,123.1,120.8,119.4,110.6,91.0, 48.3；
IR:ν max (KBr)＝3055,2921,2852,1452,1342,1171,1072,1023, 939,740,697,562,450cm -1 ；
HRMS(ESI)m/z:calcd for C 21 H 17 BrN[M+H] + ,362.0539；found 362.0537
the structure of the target product is deduced from the above data as follows:
example 7
To the reaction tube were added 0.1 mmol of N-ethyl-4-methylaniline, 0.014 mmol of tetra-triphenylphosphine palladium, 0.028 mmol of DL-pyroglutamic acid, 0.2 mmol of lithium hydroxide monohydrate, 0.15 mmol of benzoquinone, 0.2 mmol of phenyl bromoacetylene, 1.0 ml of acetonitrile: the mixed solvent of N, N-dimethylformamide (7:1, v/v) is stirred and reacted for 24 hours at the rotating speed of 700rpm at the temperature of 100 ℃; stirring was stopped, 5mL of water was added, extraction was performed 3 times with ethyl acetate, the organic phases were combined and dried over 0.5g of anhydrous magnesium sulfate, filtration, concentration under reduced pressure, and separation and purification by column chromatography using petroleum ether as the eluent to give the objective product in 76% yield.
The hydrogen spectrogram and the carbon spectrogram of the obtained target product are respectively shown in fig. 13 and 14, and the structural characterization data are shown as follows:
1 H NMR(400MHz,CDCl 3 )δ7.52-7.43(m,5H),7.40(s,1H),7.26 (d,J＝8.4Hz,1H),7.12-7.09(m,1H),4.08(q,J＝7.2Hz,2H),2.50(s,3H),1.21(t,J＝7.0Hz,3H)；
13 C NMR(100MHz,CDCl 3 )δ137.6,134.0,130.9,130.5,129.9, 128.6,128.4,127.6,124.3,119.0,109.7,89.9,39.5,21.4,15.3；
IR:ν max (KBr)＝3039,2982,2921,1464,1345,1194,1079,1024, 864,793,704,596,432cm -1 ；
HRMS(ESI)m/z:calcd for C 17 H 17 BrN[M+H] + ,314.0539；found 314.0537.
the structure of the target product is deduced from the above data as follows:
example 8
To the reaction tube were added 0.1 mmol of N-ethyl-4-methoxyaniline, 0.014 mmol of tetra-triphenylphosphine palladium, 0.028 mmol of DL-pyroglutamic acid, 0.2 mmol of lithium hydroxide monohydrate, 0.15 mmol of benzoquinone, 0.3 mmol of phenyl bromoacetylene, 1.0 ml of acetonitrile: the mixed solvent of N, N-dimethylformamide (7:1, v/v) is stirred and reacted for 24 hours at the rotating speed of 700rpm at the temperature of 100 ℃; stirring was stopped, 5mL of water was added, extraction was performed 3 times with ethyl acetate, the organic phases were combined and dried over 0.5g of anhydrous magnesium sulfate, filtration, concentration under reduced pressure, and separation and purification by column chromatography using petroleum ether: ethyl acetate in a volume ratio of 30:1 as the column chromatography eluent to give the objective product in 65% yield.
The hydrogen spectrogram and the carbon spectrogram of the obtained target product are respectively shown in fig. 15 and fig. 16, and the structural characterization data are shown as follows:
1 H NMR(400MHz,CDCl 3 )δ7.52-7.43(m,5H),7.26(d,J＝8.8 Hz,1H),7.04(d,J＝2.4Hz,1H),6.93(dd,J＝8.8,2.4Hz,1H),4.07(q, J＝7.2Hz,2H),3.90(s,3H),1.20(t,J＝7.2Hz,3H)；
13 C NMR(100MHz,CDCl 3 )δ154.9,138.0,130.8,130.7,130.5, 128.6,128.5,127.8,113.3,110.9,100.6,90.0,55.9,39.6,15.4；
IR:ν max (KBr)＝3060,2982,2833,1617,1469,1344,1286,1207, 1031,955,861,702,612,503,438cm -1 ；
HRMS(ESI)m/z:calcd for C 17 H 17 BrNO[M+H] + ,330.0488；found 330.0486.
the structure of the target product is deduced from the above data as follows:
example 9
To the reaction tube were added 0.1 mmol of N-ethyl-2, 4-dimethylaniline, 0.014 mmol of tetra-triphenylphosphine palladium, 0.028 mmol of DL-pyroglutamic acid, 0.2 mmol of lithium hydroxide monohydrate, 0.15 mmol of benzoquinone, 0.3 mmol of phenyl bromoacetylene, 1.0 ml of acetonitrile: the mixed solvent of N, N-dimethylformamide (7:1, v/v) is stirred and reacted for 20 hours at the rotating speed of 700rpm at the temperature of 100 ℃; stirring was stopped, 5mL of water was added, extraction was performed 3 times with ethyl acetate, the organic phases were combined and dried over 0.5g of anhydrous magnesium sulfate, filtration, concentration under reduced pressure, and separation and purification by column chromatography using petroleum ether as the eluent to give the objective product in 56% yield.
The hydrogen spectrogram and the carbon spectrogram of the obtained target product are respectively shown in fig. 17 and 18, and the structural characterization data are shown as follows:
1 H NMR(400MHz,CDCl 3 )δ7.52-7.42(m,5H),7.01(s,1H),6.76 (s,1H),4.01(q,J＝7.1Hz,2H),2.81(s,3H),2.45(s,3H),1.19(t,J＝ 7.0Hz,3H)；
13 C NMR(100MHz,CDCl 3 )δ137.1,136.0,132.3,131.3,130.8, 130.7,128.6,128.4,124.0,122.5,107.8,89.4,39.4,21.7,19.6,15.2；
IR:ν max (KBr)＝3061,2973,2923,2859,1612,1458,1365,1238, 1181,1076,1029,970,827,749,699,595,499cm -1 ；
HRMS(ESI)m/z:calcd for C 18 H 19 BrN[M+H] + ,328.0695；found 328.0693.
the structure of the target product is deduced from the above data as follows:
example 10
To the reaction tube were added 0.1 mmol of N-ethylaniline, 0.014 mmol of tetrakis triphenylphosphine palladium, 0.028 mmol of DL-pyroglutamic acid, 0.2 mmol of lithium hydroxide monohydrate, 0.15 mmol of benzoquinone, 0.3 mmol of 1-bromo-octyne, 1.0 ml of acetonitrile: the mixed solvent of N, N-dimethylformamide (7:1, v/v) is stirred and reacted for 24 hours at the rotating speed of 700rpm at the temperature of 100 ℃; stirring was stopped, 5mL of water was added, extraction was performed 3 times with ethyl acetate, the organic phases were combined and dried over 0.5g of anhydrous magnesium sulfate, filtration, concentration under reduced pressure, and separation and purification by column chromatography using petroleum ether as the eluent to give the objective product in 25% yield.
The hydrogen spectrogram and the carbon spectrogram of the obtained target product are respectively shown in fig. 19 and 20, and the structural characterization data are shown as follows:
1 H NMR(400MHz,CDCl 3 )δ7.51-7.49(m,1H),7.29-7.27(m,1H), 7.211-7.17(m,1H),7.14-7.12(m,1H),4.17(q,J＝7.2Hz,2H),2.81(t,J ＝7.2Hz,2H),1.63(p,J＝7.7Hz,2H),1.46-1.39(m,2H),1.39-1.30(m,7H),0.90(t,J＝7.0Hz,3H)；
13 C NMR(100MHz,CDCl 3 )δ137.6,135.0,127.1,121.6,119.9, 118.6,109.2,89.3,38.6,31.6,29.4,29.1,25.2,22.6,15.5,14.1；
IR:ν max (KBr)＝3055,2928,2859,1542,1460,1340,1224,1161, 1109,1015,929,788,738,565cm -1 ；
HRMS(ESI)m/z:calcd for C 16 H 23 BrN[M+H] + ,308.1008；found 308.1005.
the structure of the target product is deduced from the above data as follows:
example 11
To the reaction tube were added 0.1 mmol of N-ethylaniline, 0.014 mmol of tetraphenylphosphine palladium, 0.028 mmol of DL-pyroglutamic acid, 0.2 mmol of lithium hydroxide monohydrate, 0.15 mmol of benzoquinone, 0.3 mmol of 3- (bromoethynyl) thiophene, 1.0 ml of acetonitrile: the mixed solvent of N, N-dimethylformamide (7:1, v/v) is stirred and reacted for 24 hours at the rotating speed of 700rpm at the temperature of 100 ℃; stirring was stopped, 5mL of water was added, extraction was performed 3 times with ethyl acetate, the organic phases were combined and dried over 0.5g of anhydrous magnesium sulfate, filtration, concentration under reduced pressure, and separation and purification by column chromatography using petroleum ether as the eluent to give the objective product in 43% yield.
The hydrogen spectrogram and the carbon spectrogram of the obtained target product are respectively shown in fig. 21 and 22, and the structural characterization data are shown as follows:
1 H NMR(400MHz,CDCl 3 )δ7.59(d,J＝7.8Hz,1H),7.52-7.51 (m,1H),7.49-7.47(m,1H),7.37-7.35(m,1H),7.30-7.24(m,2H) 7.23-7.19(m,1H),4.17(q,J＝7.2Hz,2H),1.29(t,J＝7.2Hz,3H)；
13 C NMR(100MHz,CDCl 3 )δ135.6,132.8,130.6,128.7,127.4, 126.4,125.8,122.8,120.4,119.4,109.8,90.8,39.5,15.4；
IR:ν max (KBr)＝2979,2924,2851,1647,1457,1334,1170,1105, 924,868,741,644,586cm -1 ；
HRMS(ESI)m/z:calcd for C 14 H 13 BrNS[M+H] + ,305.9947；found 305.9944.
the structure of the target product is deduced from the above data as follows:
example 12
To the reaction tube were added 0.1 mmol of N-ethylaniline, 0.014 mmol of tetraphenylphosphine palladium, 0.028 mmol of DL-pyroglutamic acid, 0.2 mmol of lithium hydroxide monohydrate, 0.15 mmol of benzoquinone, 0.3 mmol of 1- (bromoethynyl) naphthalene, 1.0 ml of acetonitrile: the mixed solvent of N, N-dimethylformamide (7:1, v/v) is stirred and reacted for 24 hours at the rotating speed of 700rpm at the temperature of 100 ℃; stirring was stopped, 5mL of water was added, extraction was performed 3 times with ethyl acetate, the organic phases were combined and dried over 0.5g of anhydrous magnesium sulfate, filtration, concentration under reduced pressure, and separation and purification by column chromatography using petroleum ether: ethyl acetate in a volume ratio of 100:1 as the column chromatography eluent to give the objective product in 55% yield.
The hydrogen spectrogram and the carbon spectrogram of the obtained target product are respectively shown in fig. 23 and 24, and the structural characterization data are shown as follows:
1 H NMR(400MHz,CDCl 3 )δ7.99(d,J＝8.0Hz,1H),7.94(d,J＝ 8.0Hz,1H),7.68(d,J＝7.6Hz,1H),7.62-7.58(m,1H),7.56-7.49(m,3H),7.44-7.41(m,2H),7.35-7.31(m,1H),7.27(t,J＝7.2Hz,1H), 4.07-3.78(m,2H),1.09(t,J＝7.2Hz,3H)；
13 C NMR(100MHz,CDCl 3 )δ136.0,135.5,133.6,132.6,129.7, 129.6,128.4,128.4,127.4,126.8,126.3,125.7,125.2,122.6,120.4,119.4,109.9,92.0,39.6,15.5；
IR:ν max (KBr)＝3051,2986,2931,1455,1337,1209,1161,1111, 1011,927,787,739,653,520cm -1 ；
HRMS(ESI)m/z:calcd for C 20 H 17 BrN[M+H] + ,350.0539；found 350.0537.
the structure of the target product is deduced from the above data as follows:
the above examples are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above examples, and any other changes, modifications, substitutions, combinations, and simplifications that do not depart from the spirit and principle of the present invention should be made in the equivalent manner, and the embodiments are included in the protection scope of the present invention.

Claims (9)

1. The synthesis method of the 3-bromoindole compound is characterized by comprising the following steps:
adding a substrate N-substituted aniline compound, an alkyne bromine compound, a palladium salt catalyst, a ligand, an oxidant, alkali and a solvent into a reactor, stirring the mixture at 100 to 110 ℃ for reaction, cooling the mixture to room temperature after the reaction is finished, and separating and purifying the product to obtain the 3-bromoindole compound. Wherein the palladium salt catalyst is tetraphenylphosphine palladium; the ligand is DL-pyroglutamic acid; the oxidant is benzoquinone; the base is lithium hydroxide monohydrate;
the chemical reaction equation for the synthesis process is shown below:
wherein R is 1 More than one of methyl, ethyl, isopropyl, butyl, cyclohexyl and benzyl;
R 2 is hydrogen, 4-methyl, 2-methoxy or 2, 4-dimethyl, wherein the numbers preceding the groups represent the position of the groups on the benzene ring；
R 3 Is phenyl, n-hexyl, 3-thienyl or 1-naphthyl.
2. The synthesis method according to claim 1, wherein the molar ratio of the addition amount of the palladium salt catalyst to the N-substituted aniline compound is 0.1-0.14:1.
3. The method according to claim 1, wherein the molar ratio of the ligand to the N-substituted aniline compound is 0.2 to 0.28:1.
4. The method according to claim 1, wherein the molar ratio of the added amount of the alkyne-bromine compound to the N-substituted aniline compound is 2.0 to 3.0:1.
5. The synthesis method according to claim 1, wherein the molar ratio of the addition amount of the oxidizing agent to the N-substituted aniline compound is 1.5-2.0:1.
6. The synthesis method according to claim 1, wherein the molar ratio of the addition amount of the base to the N-substituted aniline compound is 1.5-2.0:1.
7. The synthesis method according to claim 1, wherein the solvent is a mixed solvent of acetonitrile and N, N-dimethylformamide in a volume ratio of 5-8:1.
8. The method of claim 1, wherein the stirring reaction is carried out for a period of 20 to 24 hours.
9. The synthetic method of claim 1 wherein the separation and purification is performed by: extracting the reaction liquid with ethyl acetate, combining organic phases, drying the organic phases by using anhydrous magnesium sulfate, filtering, evaporating the organic solvent under reduced pressure to obtain a crude product, and purifying the crude product by column chromatography to obtain the 3-bromoindole compound.
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CN108383769A (en) * 2018-03-20 2018-08-10 韩邦森 A kind of synthetic method of medicine intermediate acyl indol class compound
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CN108383769A (en) * 2018-03-20 2018-08-10 韩邦森 A kind of synthetic method of medicine intermediate acyl indol class compound
CN108864164A (en) * 2018-06-30 2018-11-23 华南理工大学 A kind of synthetic method of the 2- alkynyl Benzazole compounds of level-one amine guiding

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