CN108864164B - A kind of synthetic method of primary amine-directed 2-alkynyl indole compounds - Google Patents
A kind of synthetic method of primary amine-directed 2-alkynyl indole compounds Download PDFInfo
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Abstract
本发明公开了一种一级胺导向的2‑炔基吲哚类化合物的合成方法。该合成方法为：在反应器中，加入2‑(1H‑吲哚‑1‑基)苯胺类化合物、炔卤、钯盐催化剂、碱、溶剂，于80~110℃下搅拌反应，反应液经分离纯化，得到2‑炔基吲哚类化合物。本发明方法发展了2‑(1H‑吲哚‑1‑基)苯胺与炔卤的交叉偶联反应，构建了一系列高度官能化的2‑炔基吲哚类化合物，反应以水为溶剂，符合绿色有机化学的发展需要。此外，原料简单易得、操作安全、区域选择性好以及底物普适性广是反应的主要特点。
The invention discloses a method for synthesizing primary amine-oriented 2-alkynyl indole compounds. The synthesis method comprises the following steps: adding 2-(1 H -indol-1-yl)aniline compound, alkyne halide, palladium salt catalyst, alkali and solvent into a reactor, stirring and reacting at 80-110 DEG C, and the reaction solution After separation and purification, 2-alkynyl indole compounds were obtained. The method of the invention develops the cross-coupling reaction of 2-(1 H -indol-1-yl)aniline and alkyne halide, constructs a series of highly functionalized 2-alkynyl indole compounds, and the reaction uses water as a solvent , in line with the development needs of green organic chemistry. In addition, the simple and easy availability of starting materials, safe operation, good regioselectivity and broad substrate universality are the main characteristics of the reaction.
Description
Technical Field
The invention belongs to the field of 2-alkynyl indole compounds, and particularly relates to a synthesis method of a primary amine-guided 2-alkynyl indole compound.
Background
Indole compounds are widely used as an important heterocyclic compound in the nature, and special chemical properties and biological activities of the indole compounds are paid attention to the fields of medicines, dyes, foods and the like, so that the synthesis and modification of the heterocyclic compound are very important in organic chemistry. The traditional approach to the construction of functionalized indole derivatives is to carry out C-H halogenation of the indole followed by the classical cross-coupling reaction. In recent years, with the vigorous development of C-H bond activation, a method of functionalizing indole with a direct C-H bond has been more and more favored by organic chemists. Alkynes are important structural elements in material chemistry and synthetic chemistry and are excellent reaction precursors participating in various types of conversion, so that the direct alkynylation reaction of the inactivated C-H bond of the indole catalyzed by the transition metal has important significance.
Generally, the indole compound has an electron cloud density at the 3-position carbon higher than that at the 2-position carbon, so that the 3-position carbon is easy to be metallized compared with the 2-position carbon. How to realize the alkynylation reaction of the 2-carbon of the indole with high selectivity still has the challenge. In the reported methods for the transition metal-catalyzed direct alkynylation synthesis of 2-alkynylindoles (l.yang, l.zhao, c. -J Li, chem.comm.2010, 46,4184; g.l.tolnai, s.ganss, j.p.branch, Waser j.org.lett.2013,15,112; z. -z.zhang, b.liu, c. -y.wang, b. -F, shi.org.lett.2015,17,4094; t.li, z.wang, w. -b.qin, t.b.wen, chemcat chem.2016,8,2146; z.ruan, n.sauermann, e.oni, l.ackerman, angew.chem.chem.int.7, 129, 0. 201n, n.sauerman, e.oni, l.ackerman, angew.chem.chem.7, 129, 0. economical, 0. nun., using bulky substrates, bulky and/or low-valent iodinated starting materials, and/or low cost, multiple-cost substrates. Therefore, the development of a green, efficient and high-selectivity method for synthesizing the 2-alkynyl indole compound is significant.
The diversity of directing groups has led to a tremendous growth in C-H functionalization strategies as an important tool for organic synthesis over the past decade. In recent years, the activation of the C-H bond and hence the cross-coupled product via a primary amine as a targeting group has attracted the interest of researchers (Z.Liang, R.Feng, H.Yin, Y.Zhang.org.Lett.2013,15,4544; C.Suzuki, K.Morimoto, K.Hirano, T.Satoh, M.Miura.Adv.Synth.Cat.2014, 356,152; G.Jiang, W.Hu, J.Li, C.Zhu, W.Wu, H.Jiang.Chem.Commun.2018,54,1746.). In addition to direct cross-coupling reactions, cyclization reactions can also occur with naked amino groups as targeting groups, and backbones of some alkaloids, drugs can be directly constructed in this way (p.bai, x. -f.huang, g. -d.xu, z. -z.huang.org.lett.2016,18,3058; t.u.thikekar, c. -m.sun.adv.synth.catal.2017,359,3388.), but the use of primary amines as targeting groups for the alkynylation of indoles has not been reported. In conclusion, the primary amine is used as a guiding group to realize the 2-position alkynylation reaction of the indole compound, and the application prospect of the method is expected besides the methodological novelty.
Disclosure of Invention
The invention aims to provide a synthetic method of a primary amine-guided 2-alkynyl indole compound aiming at the defects of the prior art. The method selectively constructs the 2-site alkynylated indole derivative by taking simple and easily-obtained 2- (1H-indole-1-yl) aniline and alkyne halide as raw materials, common palladium salt as a catalyst, cesium salt as alkali, water as a solvent and primary amine as a guide group, has the advantages of high atom economy, single selectivity, simple and safe operation, wide substrate applicability and the like, and has good application prospect in practical production and research.
The purpose of the invention is realized by the following technical scheme.
A synthetic method of a primary amine-oriented 2-alkynyl indole compound comprises the following steps:
adding a substrate 2- (1H-indole-1-yl) aniline compound, alkyne halide, a palladium salt catalyst, alkali and a solvent into a reactor, stirring and reacting at 80-110 ℃, cooling to room temperature after the reaction is finished, and separating and purifying a product to obtain the 2-alkynyl indole compound.
Further, the chemical reaction equation of the synthesis process is as follows:
in the formula, R1Is a substituent on indole, R1At least one selected from the group consisting of hydrogen, 3-methyl, 4-fluoro, 4-methoxy, 5-chloro, 5-methyl, 5-cyano, 6-fluoro, 7-chloro, and 5, 6-dichloro;
R2is a substituent on aniline and is hydrogen, 4-methyl or 4, 6-dimethyl;
R3is a substituent on alkyne halide and is triisopropyl silicon base;
x is chlorine, bromine or iodine.
Further, the 2- (1H-indol-1-yl) aniline compound is 2- (1H-indol-1-yl) aniline; the alkyne halide is (2-bromoethynyl) triisopropylsilane.
Further, the palladium salt catalyst is one or more than two of palladium chloride, palladium acetate and palladium tetranitrile tetrafluoroborate.
Furthermore, the molar ratio of the added amount of the palladium salt catalyst to the 2- (1H-indol-1-yl) aniline compound is 0.03-0.1: 1.
Furthermore, the molar ratio of the added alkyne halide to the 2- (1H-indole-1-yl) aniline compound is 1.6-3.0: 1.
Further, the alkali is one or more than two of cesium pivalate, potassium acetate, cesium fluoride, sodium bicarbonate and potassium bicarbonate.
Furthermore, the molar ratio of the added alkali to the 2- (1H-indole-1-yl) aniline compound is 2.0-4.0: 1.
Further, the solvent is water, toluene, 1, 2-dichloroethane or a mixed solvent of water and toluene in a volume ratio of 2: 1.
Further, the stirring reaction time is 12-24 hours, preferably 20-24 hours.
Further, the separation and purification operations are as follows: extracting the reaction liquid with ethyl acetate, combining organic phases, drying with anhydrous magnesium sulfate, filtering, decompressing, steaming and removing the organic solvent to obtain a crude product, and purifying by column chromatography to obtain the 2-alkynyl indole compound.
Furthermore, the eluent for column chromatography is a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 20-150: 1, preferably a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 30-100: 1.
The reaction principle of the synthetic method is that under the promotion of alkali, 2- (1H-indole-1-yl) aniline and palladium salt catalyst are coordinated to form a six-membered ring palladium intermediate when amino is used as a guide group, then alkyne halide is subjected to oxidation addition with the intermediate, and reduction elimination is carried out to obtain the 2-alkynyl indole compound.
Compared with the prior art, the invention has the following advantages and beneficial effects:
(1) the invention develops a synthetic method for constructing the 2-alkynyl indole compound by the cross-coupling reaction of 2- (1H-indole-1-yl) aniline and alkyne halide under the guidance of amino, wherein the 2- (1H-indole-1-yl) aniline serving as a basic raw material can be synthesized by cheap o-iodoaniline and indole, and the synthetic 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 synthetic method is convenient to operate, can use water as a solvent, is green and environment-friendly, and has good tolerance on functional groups, so that the synthetic method is expected to be applied to actual industrial production and further derivatization.
Drawings
FIGS. 1 and 2 are a hydrogen spectrum and a carbon spectrum of the objective product obtained in example 1, respectively;
FIGS. 3 and 4 are a hydrogen spectrum and a carbon spectrum of the objective product obtained in example 2, respectively;
FIGS. 5 and 6 are a hydrogen spectrum and a carbon spectrum of the objective product obtained in example 3, respectively;
FIGS. 7 and 8 are a hydrogen spectrum and a carbon spectrum, respectively, of the objective product obtained in example 4;
FIGS. 9 and 10 are a hydrogen spectrum and a carbon spectrum, respectively, of the objective product obtained in example 5;
FIGS. 11 and 12 are a hydrogen spectrum and a carbon spectrum, respectively, of the objective product obtained in example 6;
FIGS. 13 and 14 are a hydrogen spectrum and a carbon spectrum, respectively, of the objective product obtained in example 7;
FIGS. 15 and 16 are a hydrogen spectrum and a carbon spectrum, respectively, of the objective product obtained in example 8;
FIGS. 17 and 18 are a hydrogen spectrum and a carbon spectrum, respectively, of the objective product obtained in example 9;
FIGS. 19 and 20 are a hydrogen spectrum and a carbon spectrum, respectively, of the objective product obtained in example 10;
FIGS. 21 and 22 are a hydrogen spectrum and a carbon spectrum, respectively, of the objective product obtained in example 11;
FIGS. 23 and 24 are a hydrogen spectrum and a carbon spectrum, respectively, of the objective product obtained in example 12;
FIGS. 25 and 26 are a hydrogen spectrum and a carbon spectrum, respectively, of the objective product obtained in example 13;
FIGS. 27 and 28 are a hydrogen spectrum and a carbon spectrum, respectively, of the objective product obtained in example 14;
fig. 29 and 30 are a hydrogen spectrum and a carbon spectrum of the objective product obtained in example 15, respectively.
Detailed Description
The technical solutions of the present invention are further described in detail below with reference to specific examples and drawings, but the scope and implementation of the present invention are not limited thereto.
Example 1
Adding 0.2 mmol of 2- (1H-indol-1-yl) aniline, 0.006 mmol of tetranitrile palladium tetrafluoroborate, 0.4 mmol of cesium pivalate, 0.32 mmol of triisopropylsilylpropargyl bromide and 1.5 ml of water as a solvent into a reaction tube, and stirring at 100 ℃ and 700rpm for 24 hours; stopping stirring, adding 5mL of water, extracting for 3 times by using ethyl acetate, combining organic phases, drying by using 0.5g of anhydrous magnesium sulfate, filtering, concentrating under reduced pressure, and separating and purifying by column chromatography, wherein the eluent of the column chromatography is a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 100:1, so that the target product is obtained, and the yield is 80%.
The obtained hydrogen spectrogram and carbon spectrogram of the target product are respectively shown in fig. 1 and fig. 2, and the structural characterization data are shown as follows:
1H NMR(400MHz,CDCl3)δ＝7.54(d,J＝7.6Hz,1H),7.16-7.04(m,4H),6.93-6.91(d,J＝8.0Hz,1H),6.86(s,1H),6.71-6.76(m,2H),3.03(s,2H),0.89(s,21H)；
13C NMR(100MHz,CDCl3)δ＝144.1,137.2,130.0,129.6,127.3,123.6,123.1,122.5,121.0,120.8,118.4,116.1,110.7,109.0,97.7,97.4,18.4,11.1；
IR(KBr)νmax 3870,3380,3049,2942,2865,2151,1615,1456,1311,1227,1002,799,713cm-1；
HRMS(ESI)Calcd for C25H33N2Si[M+H]+:389.2408,Found 389.2412。
the structure of the target product is deduced from the above data as follows:
example 2
Adding 0.2 mmol of 2- (3-methyl-1H-indol-1-yl) aniline, 0.006 mmol of tetranitrile palladium tetrafluoroborate, 0.4 mmol of cesium pivalate, 0.32 mmol of triisopropylsilylpropargyl bromide and 1.5 ml of water as a solvent into a reaction tube, and stirring at 100 ℃ and 700rpm for 24 hours; stopping stirring, adding 5mL of water, extracting for 3 times with ethyl acetate, combining the organic phases, drying with 0.5g of anhydrous magnesium sulfate, filtering, concentrating under reduced pressure, and purifying by column chromatography using a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 100:1 as eluent to obtain the target product with a yield of 86%.
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:
1H NMR(400MHz,CDCl3)δ＝7.58(d,J＝7.7Hz,1H),7.22-7.11(m,4H),6.99(d,J＝8.0Hz,1H),6.82-6.77(m,2H),3.28(s,2H),2.47(s,3H),0.98(s,21H)；
13C NMR(100MHz,CDCl3)δ＝144.0,136.9,130.0,129.3,127.6,123.8,123.4,120.7,120.1,119.3,118.7,118.4,116.1,110.6,99.6,97.3,18.5,11.1,9.9；
IR(KBr)νmax 3679,3052,2945,2865,2148,1697,1597,1505,1454,1308,1225,797,718cm-1；
HRMS(ESI)Calcd for C26H35N2Si[M+H]+:403.2564,Found 403.2569。
the structure of the target product is deduced from the above data as follows:
example 3
Adding 0.2 mmol of 2- (4-methyl-1H-indol-1-yl) aniline, 0.006 mmol of tetranitrile palladium tetrafluoroborate, 0.4 mmol of cesium pivalate, 0.32 mmol of triisopropylsilylpropargyl bromide and 1.5 ml of water as a solvent into a reaction tube, and stirring at 100 ℃ and 700rpm for 24 hours; stopping stirring, adding 5mL of water, extracting for 3 times with ethyl acetate, combining the organic phases, drying with 0.5g of anhydrous magnesium sulfate, filtering, concentrating under reduced pressure, and purifying by column chromatography using a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 100:1 as eluent to obtain the target product with a yield of 67%.
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:
1H NMR(400MHz,CDCl3)δ＝7.25-7.21(m,1H),7.17(dd,J＝7.7Hz,1H),7.14-7.10(t,J＝7.8Hz,1H),7.00(s,1H),6.97(d,J＝7.2Hz,1H),6.87-6.80(m,3H),3.50(s,2H),2.58(s,3H),0.98(s,21H)；
13C NMR(100MHz,CDCl3)δ＝144.0,137.0,130.6,130.0,129.6,127.2,123.8,123.3,121.9,120.9,118.4,116.1,108.4,107.6,97.8,97.2,18.6,18.4,11.1；
IR(KBr)νmax 3732,3671,2941,2862,2150,1620,1504,1308,1228,796,713cm-1；
HRMS(ESI)Calcd for C26H35N2Si[M+H]+:403.2564,Found 403.2566。
the structure of the target product is deduced from the above data as follows:
example 4
Adding 0.2 mmol of 2- (4-fluoro-1H-indol-1-yl) aniline, 0.006 mmol of tetranitrile palladium tetrafluoroborate, 0.4 mmol of cesium pivalate, 0.32 mmol of triisopropylsilylpropargyl bromide and 1.5 ml of water as a solvent into a reaction tube, and stirring at 100 ℃ and 700rpm for 24 hours; stopping stirring, adding 5mL of water, extracting for 3 times with ethyl acetate, combining the organic phases, drying with 0.5g of anhydrous magnesium sulfate, filtering, concentrating under reduced pressure, and purifying by column chromatography using a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 100:1 as eluent to obtain the target product with a yield of 74%.
The hydrogen spectrogram and the carbon spectrogram of the obtained target product are respectively shown in fig. 7 and fig. 8, and the structural characterization data are shown as follows:
1H NMR(400MHz,CDCl3)δ＝7.25-7.21(m,1H),7.17-7.15(m,1H),7.12-7.07(m,1H),7.01(s,1H),6.85-6.77(m,4H),3.34(s,2H),0.96(d,J＝2.4Hz,21H)；
13C NMR(100MHz,CDCl3)δ＝156.1(d,J＝248.8Hz),143.9,139.4(d,J＝10.5Hz),129.9(d,J＝4.7Hz),124.1(d,J＝7.7Hz),122.8,122.6,118.6,116.6(d,J＝22.8Hz),116.3,106.8(d,J＝3.8Hz),105.5,105.3,104.8,97.9,97.0,18.4,11.1.
IR(KBr)νmax 3388,2945,2154,1687,1488,1313,1234,788,675cm-1；
HRMS(ESI)Calcd for C25H32FN2Si[M+H]+:407.2313,Found 407.2319。
the structure of the target product is deduced from the above data as follows:
example 5
Adding 0.2 mmol of 2- (4-chloro-1H-indol-1-yl) aniline, 0.006 mmol of tetranitrile palladium tetrafluoroborate, 0.4 mmol of cesium pivalate, 0.32 mmol of triisopropylsilylpropargyl bromide and 1.5 ml of water as a solvent into a reaction tube, and stirring at 100 ℃ and 700rpm for 20 hours; stopping stirring, adding 5mL of water, extracting for 3 times by using ethyl acetate, combining organic phases, drying by using 0.5g of anhydrous magnesium sulfate, filtering, concentrating under reduced pressure, and separating and purifying by column chromatography, wherein the eluent of the column chromatography is a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 100:1, so that the target product is obtained, and the yield is 82%.
The obtained hydrogen spectrogram and carbon spectrogram of the target product are respectively shown in fig. 9 and fig. 10, and the structural characterization data are shown as follows:
1H NMR(400MHz,CDCl3)δ＝7.24-7.20(m,1H),7.15-7.12(m,2H),7.08(t,J＝7.8Hz,1H),7.04(s,1H),6.89(d,J＝8.0Hz,1H),6.83-6.78(m,2H),3.44(s,2H),0.96(d,J＝2.3Hz,21H)；
13C NMR(100MHz,CDCl3)δ＝143.9,137.8,129.9,129.8,126.2,126.1,124.1,123.2,122.6,120.5,118.5,116.2,109.4,107.3,98.3,97.0,18.4,11.1.
IR(KBr)νmax 2946,2154,1613,1503,1309,1228,796,713cm-1；
HRMS(ESI)Calcd for C25H32ClN2Si[M+H]+,423.2018,found 423.2024。
the structure of the target product is deduced from the above data as follows:
example 6
Adding 0.2 mmol of 2- (4-methoxy-1H-indol-1-yl) aniline, 0.006 mmol of tetranitrile palladium tetrafluoroborate, 0.4 mmol of cesium pivalate, 0.32 mmol of triisopropylsilylpropargyl bromide and 1.5 ml of water as a solvent into a reaction tube, and stirring at 100 ℃ and 700rpm for 24 hours; stopping stirring, adding 5mL of water, extracting for 3 times with ethyl acetate, combining the organic phases, drying with 0.5g of anhydrous magnesium sulfate, filtering, concentrating under reduced pressure, and purifying by column chromatography, wherein the eluent of the column chromatography is a mixed solvent of petroleum ether and ethyl acetate with the volume ratio of 60:1, so as to obtain the target product with the yield of 56%.
The hydrogen spectrogram and the carbon spectrogram of the obtained target product are respectively shown in fig. 11 and fig. 12, and the structural characterization data are shown as follows:
1H NMR(400MHz,CDCl3)δ＝7.23-7.19(m,1H),7.16(d,J＝7.7Hz,1H),7.11(t,J＝8.0Hz,1H),7.05(s,1H),6.83-6.78(m,2H),6.62(d,J＝8.4Hz,1H),6.53(d,J＝7.6Hz,1H),3.96(s,3H),3.49(s,2H),0.96(s,21H)；
13C NMR(100MHz,CDCl3)δ＝153.4,144.0,138.5,129.9,129.56,124.6,123.2,121.1,118.4,118.2,116.1,106.6,104.0 100.4,97.8,96.8,55.4,18.4,11.1；
IR(KBr)νmax 3378,2940,2149,1610,1494,1313,1250,798,675cm-1；
HRMS(ESI)Calcd for C26H35N2OSi[M+H]+:419.2513,Found 419.2514。
the structure of the target product is deduced from the above data as follows:
example 7
Adding 0.2 mmol of 2- (5-chloro-1H-indol-1-yl) aniline, 0.006 mmol of tetranitrile palladium tetrafluoroborate, 0.4 mmol of cesium pivalate, 0.32 mmol of triisopropylsilylpropargyl bromide and 1.5 ml of water as a solvent into a reaction tube, and stirring at 100 ℃ and 700rpm for 24 hours; stopping stirring, adding 5mL of water, extracting for 3 times with ethyl acetate, combining the organic phases, drying with 0.5g of anhydrous magnesium sulfate, filtering, concentrating under reduced pressure, and purifying by column chromatography using a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 100:1 as eluent to obtain the target product with a yield of 78%.
The obtained hydrogen spectrogram and carbon spectrogram of the target product are respectively shown in fig. 13 and fig. 14, and the structural characterization data are shown as follows:
1H NMR(400MHz,CDCl3)δ＝7.58(d,J＝2.0Hz,1H),7.24-7.20(m,1H),7.14-7.11(m,2H),6.91(d,J＝8.4Hz,1H),6.86(s,1H),6.83-6.78(m,2H),3.45(s,2H),0.95(d,J＝2.0Hz,21H)；
13C NMR(001MHz,CDCl3)δ＝143.9,135.5,129.9,129.8,128.2,126.5,123.9,123.8,122.6,120.2,118.5,116.2,111.8,108.3,98.3,97.0,18.4,11.1；
IR(KBr)νmax 3379,2941,2152,1616,1451,1311,1228,796,717cm-1；
HRMS(ESI)Calcd for C25H32ClN2Si[M+H]+:423.2018,Found 423.2012。
the structure of the target product is deduced from the above data as follows:
example 8
Adding 0.2 mmol of 2- (5-methyl-1H-indol-1-yl) aniline, 0.006 mmol of tetranitrile palladium tetrafluoroborate, 0.4 mmol of cesium pivalate, 0.32 mmol of triisopropylsilylpropargyl bromide and 1.5 ml of water as a solvent into a reaction tube, and stirring at 100 ℃ and 700rpm for 24 hours; stopping stirring, adding 5mL of water, extracting for 3 times with ethyl acetate, combining the organic phases, drying with 0.5g of anhydrous magnesium sulfate, filtering, concentrating under reduced pressure, and purifying by column chromatography using a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 100:1 as eluent to obtain the target product with a yield of 76%.
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:
1H NMR(400MHz,CDCl3)δ＝7.39(s,1H),7.22-7.17(m,1H),7.16-7.14(m,1H),7.03-7.00(m,1H),6.89(d,J＝8.4Hz,1H),6.85(s,1H),6.81-6.77(m,2H),3.46(s,2H),2.43(s,3H),0.96(s,21H)；
13C NMR(100MHz,CDCl3)δ＝144.1,135.6,130.1,130.0,129.5,127.5,125.4,123.2,122.4,120.5,118.4,116.1,110.4,108.5,97.8,97.1,21.4,18.4,11.1；
IR(KBr)νmax 2945,2150,1615,1458,1308,1228,797,716cm-1；
HRMS(ESI)Calcd for C26H35N2Si[M+H]+:403.2564,Found 403.2568。
the structure of the target product is deduced from the above data as follows:
example 9
Adding 0.2 mmol of 2- (5-cyano-1H-indol-1-yl) aniline, 0.006 mmol of tetranitrile palladium tetrafluoroborate, 0.4 mmol of cesium pivalate, 0.32 mmol of triisopropylsilylpropargyl bromide and 1.5 ml of water as a solvent into a reaction tube, and stirring at 100 ℃ and 700rpm for 24 hours; stopping stirring, adding 5mL of water, extracting for 3 times with ethyl acetate, combining the organic phases, drying with 0.5g of anhydrous magnesium sulfate, filtering, concentrating under reduced pressure, and purifying by column chromatography using a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 50:1 as eluent to obtain the target product with a yield of 71%.
The obtained hydrogen spectrogram and carbon spectrogram of the target product are respectively shown in fig. 17 and fig. 18, and the structural characterization data are shown as follows:
1H NMR(400MHz,CDCl3)δ＝7.97(d,J＝0.6,1H),7.39-7.39(m,1H),7.29-7.22(m,1H),7.16–7.11(m,1H),7.05(d,J＝8.6Hz,1H),6.98(s,1H),6.88–6.80(m,2H),3.33(s,2H),0.96(d,J＝3.0Hz,21H).
13C NMR(100MHz,CDCl3)δ＝143.8,138.6,130.3,129.6,127.0,126.4,126.2,125.0,121.8,120.2,118.6,116.4,111.6,109.0,104.0,99.7,96.2,18.3,11.0；
IR(KBr)νmax 3373,2942,2222,1615,1460,1312,1230,797,719cm-1；
HRMS(ESI)Calcd for C26H32N3Si[M+H]+:414.2360,Found 414.2361。
the structure of the target product is deduced from the above data as follows:
example 10
Adding 0.2 mmol of 2- (6-fluoro-1H-indol-1-yl) aniline, 0.006 mmol of tetranitrile palladium tetrafluoroborate, 0.4 mmol of cesium pivalate, 0.32 mmol of triisopropylsilylpropargyl bromide and 1.5 ml of water as a solvent into a reaction tube, and stirring at 100 ℃ and 700rpm for 24 hours; stopping stirring, adding 5mL of water, extracting for 3 times by using ethyl acetate, combining organic phases, drying by using 0.5g of anhydrous magnesium sulfate, filtering, concentrating under reduced pressure, and separating and purifying by column chromatography, wherein the eluent of the column chromatography is a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 100:1, so that the target product is obtained, and the yield is 85%.
The hydrogen spectrogram and the carbon spectrogram of the obtained target product are respectively shown in fig. 19 and fig. 20, and the structural characterization data are shown as follows:
1H NMR(400MHz,CDCl3)δ＝7.54-7.50(m,1H),7.24-7.20(m,1H),7.15-7.13(m,1H),6.93-6.87(m,2H),6.83-6.78(m,2H),6.70-6.67(m,1H),3.48(s,2H),0.96(s,21H).
13C NMR(100MHz,CDCl3)δ＝161.2(d,J＝240.7Hz),143.9,137.4(d,J＝12.3Hz),129.81(d,J＝8.1Hz),123.6,123.1(d,J＝4.1Hz),122.6,121.8(d,J＝10.0Hz),118.5,116.2,109.8(d,J＝24.9Hz),108.9,97.6,97.3,92,2,97.0,18.4,11.1；
IR(KBr)νmax 2944,2150,1612,1496,1307,1230,799,716cm-1；
HRMS(ESI)Calcd for C25H32FN2Si[M+H]+:407.2313,Found 407.2318。
the structure of the target product is deduced from the above data as follows:
example 11
Adding 0.2 mmol of 2- (7-chloro-1H-indol-1-yl) aniline, 0.006 mmol of tetranitrile palladium tetrafluoroborate, 0.4 mmol of cesium pivalate, 0.32 mmol of triisopropylsilylpropargyl bromide and 1.5 ml of water as a solvent into a reaction tube, and stirring at 100 ℃ and 700rpm for 24 hours; stopping stirring, adding 5mL of water, extracting for 3 times with ethyl acetate, combining the organic phases, drying with 0.5g of anhydrous magnesium sulfate, filtering, concentrating under reduced pressure, and purifying by column chromatography using a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 100:1 as eluent to obtain the target product with a yield of 70%.
The obtained hydrogen spectrogram and carbon spectrogram of the target product are respectively shown in fig. 21 and 22, and the structural characterization data are shown as follows:
1H NMR(400MHz,CDCl3)δ＝7.51(d,J＝7.6,1H),7.20(t,J＝7.6Hz,1H),7.12-7.17(m,2H),7.03(t,J＝7.8Hz,1H),6.93(s,1H),6.77(t,J＝7.8Hz,2H),3.43(s,2H),0.95(s,21H)；
13C NMR(100MHz,CDCl3)δ＝145.0,132.4,130.5,130.0,129.8,125.0,124.6,124.5,121.3,119.7,117.9,117.1,115.5,109.2,98.3,96.8,18.4,11.0；
IR(KBr)νmax 2945,2154,1693,1606,1308,1226,796,713cm-1；
HRMS(ESI)Calcd for C25H32ClN2Si[M+H]+,423.2018,Found 423.2021。
the structure of the target product is deduced from the above data as follows:
example 12
Adding 0.2 mmol of 2- (5, 6-dichloro-1H-indol-1-yl) aniline, 0.006 mmol of tetranitrile palladium tetrafluoroborate, 0.4 mmol of cesium pivalate, 0.32 mmol of triisopropylsilylpropargyl bromide and 1.5 ml of water as a solvent into a reaction tube, and stirring at 100 ℃ and 700rpm for 24 hours; stopping stirring, adding 5mL of water, extracting for 3 times with ethyl acetate, combining the organic phases, drying with 0.5g of anhydrous magnesium sulfate, filtering, concentrating under reduced pressure, and purifying by column chromatography using a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 100:1 as eluent to obtain the target product with a yield of 71%.
The obtained hydrogen spectrogram and carbon spectrogram of the target product are respectively shown in fig. 23 and 24, and the structural characterization data are shown as follows:
1H NMR(400MHz,CDCl3)δ＝7.68(s,1H),7.26-7.22(m,1H),7.13-7.10(m,2H),6.84-6.79(m,3H),3.47(s,2H),0.95(d,J＝2.4Hz,21H).
13C NMR(100MHz,CDCl3)δ＝143.9,135.9,130.1,129.7,127.7,126.7,125.0,124.5,122.1,121.7,118.6,116.3,112.2,108.0,99.0,96.6,18.4,11.0；
IR(KBr)νmax 2950,1612,1306,1227,795,716cm-1；
HRMS(ESI)Calcd for C25H31Cl2N2Si[M+H]+,457.1628,Found 457.1621。
the structure of the target product is deduced from the above data as follows:
example 13
Adding 0.2 mmol of 2- (-1H-indol-1-yl) -4-methylaniline, 0.006 mmol of tetranitrile palladium tetrafluoroborate, 0.4 mmol of cesium pivalate, 0.32 mmol of triisopropylsilylpropargyl bromide and 1.5 ml of water as a solvent into a reaction tube, and stirring at 100 ℃ and 700rpm for 24 hours; stopping stirring, adding 5mL of water, extracting for 3 times by using ethyl acetate, combining organic phases, drying by using 0.5g of anhydrous magnesium sulfate, filtering, concentrating under reduced pressure, and separating and purifying by column chromatography, wherein the eluent of the column chromatography is a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 100:1, so that the target product is obtained, and the yield is 60%.
The hydrogen spectrum and the carbon spectrum of the obtained target product are respectively shown in fig. 25 and 26, and the structural characterization data are shown as follows:
1H NMR(400MHz,CDCl3)δ＝7.61(d,J＝7.8,1H),7.19(t,J＝7.5Hz,1H),7.13(t,J＝7.3Hz,1H),7.03-6.98(m,3H),6.92(s,1H),6.74(d,J＝8.4Hz,1H),3.07(s,2H),2.24(s,3H),0.97(s,21H).
13C NMR(100MHz,CDCl3)δ＝141.4,137.1,130.2,127.8,127.2,123.6,123.1,122.5,121.0,120.7,116.3,110.8,108.9,97.8,97.3,20.2,18.4,11.1；
IR(KBr)νmax 3673,1695,1306,1226,796,715cm-1；
HRMS(ESI)Calcd for C26H35N2Si[M+H]+,403.2564,found 403.2569。
the structure of the target product is deduced from the above data as follows:
example 14
Adding 0.2 mmol of 2- (-1H-indol-1-yl) -4, 6-dimethylaniline, 0.006 mmol of tetranitrile palladium tetrafluoroborate, 0.4 mmol of cesium pivalate, 0.32 mmol of triisopropylsilylpropargyl bromide and 1.5 ml of water as a solvent into a reaction tube, and stirring at 100 ℃ and 700rpm for reaction for 24 hours; stopping stirring, adding 5mL of water, extracting with ethyl acetate for 3 times, combining the organic phases, drying with 0.5g of anhydrous magnesium sulfate, filtering, concentrating under reduced pressure, and purifying by column chromatography using a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 100:1 as eluent to obtain the target product with a yield of 73%.
The hydrogen spectrum and the carbon spectrum of the obtained target product are respectively shown in fig. 27 and 28, and the structural characterization data are shown as follows:
1H NMR(400MHz,CDCl3)δ＝7.61(d,J＝8.0,1H),7.19-7.10(m,2H),6.99(d,J＝8.0,1H),6.93(d,J＝8.0,2H),6.85(s,1H),3.04(s,2H),2.22(s,3H),2.17(s,3H),0.95(s,21H)；
13C NMR(100MHz,CDCl3)δ＝139.8,137.4,131.4,127.7,127.2,127.0,123.5,123.4,122.9,122.6,120.9,120.7,110.8,108.7,97.9,97.1,20.2,18.4,17.5,11.1；
IR(KBr)νmax 3385,2941,2151,1694,1599,1312,1228,797,717cm-1；
HRMS(ESI)Calcd for C27H37N2Si[M+H]+,417.2721,Found 417.2727。
the structure of the target product is deduced from the above data as follows:
example 15
Adding 0.2 mmol of 2- (-1H-pyrrole-1-yl) -aniline, 0.006 mmol of tetranitrile palladium tetrafluoroborate, 0.8 mmol of cesium pivalate, 0.6 mmol of triisopropylsilylpropargyl bromide and 1.5 ml of water as a solvent into a reaction tube, and stirring at 100 ℃ and 700rpm for 24 hours; stopping stirring, adding 5mL of water, extracting for 3 times with ethyl acetate, combining the organic phases, drying with 0.5g of anhydrous magnesium sulfate, filtering, concentrating under reduced pressure, and purifying by column chromatography using a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 100:1 as eluent to obtain the target product with a yield of 33%.
The obtained hydrogen spectrum and carbon spectrum of the target product are respectively shown in fig. 29 and fig. 30, and the structural characterization data are shown as follows:
1H NMR(400MHz,CDCl3)δ＝7.13-7.08(m,2H),6.73-6.69(m,2H),6.49(s,2H),3.50(s,2H),0.92(s,42H)；
13C NMR(100MHz,CDCl3)δ＝143.8,129.6,129.5,124.3,118.1,118.0,116.0,115.0,97.5,94.8,18.4,11.1；
IR(KBr)νmax 2944,2145,1460,1306,1229,794,716cm-1；
HRMS(ESI)Calcd for C35H51N2Si2[M+H]+,519.3585,found 519.3591。
the structure of the target product is deduced from the above data as follows:
the above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.
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| Palladium-catalyzed primary amine-directed regioselective mono- and di-alkynylation of biaryl-2-amines;Guangbin Jiang等,;《Chem. Commun.》;20180122;1746-1749页 * |
| Palladium-Catalyzed Regioselective Alkynylation of Pyrroles and Azoles under Mild Conditions: Application to the Synthesis of a Dopamine D-4 Receptor Agonist;Etienne Brachet等;《J. Org. Chem.》;20150815;7519-7529页 * |
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