CN108864164B - Synthesis method of primary amine-guided 2-alkynyl indole compound - Google Patents
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- SIKJAQJRHWYJAI-UHFFFAOYSA-N benzopyrrole Natural products C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 title claims abstract description 28
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 title claims abstract description 22
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 title claims abstract description 22
- 238000001308 synthesis method Methods 0.000 title claims abstract description 7
- -1 aniline compound Chemical class 0.000 claims abstract description 48
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 37
- 238000003756 stirring Methods 0.000 claims abstract description 35
- 238000006243 chemical reaction Methods 0.000 claims abstract description 25
- 239000002904 solvent Substances 0.000 claims abstract description 23
- 238000000034 method Methods 0.000 claims abstract description 12
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N N-phenyl amine Natural products NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims abstract description 11
- 239000003054 catalyst Substances 0.000 claims abstract description 9
- 150000002940 palladium Chemical class 0.000 claims abstract description 9
- 238000010189 synthetic method Methods 0.000 claims abstract description 9
- 239000003513 alkali Substances 0.000 claims abstract description 8
- 239000000758 substrate Substances 0.000 claims abstract description 7
- 239000012295 chemical reaction liquid Substances 0.000 claims abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 102
- 239000000047 product Substances 0.000 claims description 63
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical group [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 36
- 229910052739 hydrogen Inorganic materials 0.000 claims description 34
- 239000001257 hydrogen Substances 0.000 claims description 34
- 238000004440 column chromatography Methods 0.000 claims description 23
- 239000012046 mixed solvent Substances 0.000 claims description 19
- 229910052763 palladium Inorganic materials 0.000 claims description 18
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 17
- LGVUAXNPXVXCCW-UHFFFAOYSA-M cesium;2,2-dimethylpropanoate Chemical compound [Cs+].CC(C)(C)C([O-])=O LGVUAXNPXVXCCW-UHFFFAOYSA-M 0.000 claims description 17
- 238000001035 drying Methods 0.000 claims description 17
- 238000001914 filtration Methods 0.000 claims description 17
- 239000012074 organic phase Substances 0.000 claims description 17
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- 238000003786 synthesis reaction Methods 0.000 claims description 7
- 230000015572 biosynthetic process Effects 0.000 claims description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 4
- XJHCXCQVJFPJIK-UHFFFAOYSA-M caesium fluoride Chemical compound [F-].[Cs+] XJHCXCQVJFPJIK-UHFFFAOYSA-M 0.000 claims description 4
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 3
- VMJNTFXCTXAXTC-UHFFFAOYSA-N 2,2-difluoro-1,3-benzodioxole-5-carbonitrile Chemical group C1=C(C#N)C=C2OC(F)(F)OC2=C1 VMJNTFXCTXAXTC-UHFFFAOYSA-N 0.000 claims description 2
- HNNUBQWDWJNURV-UHFFFAOYSA-N 2-bromoethynyl-tri(propan-2-yl)silane Chemical group CC(C)[Si](C(C)C)(C(C)C)C#CBr HNNUBQWDWJNURV-UHFFFAOYSA-N 0.000 claims description 2
- CVICEEPAFUYBJG-UHFFFAOYSA-N 5-chloro-2,2-difluoro-1,3-benzodioxole Chemical group C1=C(Cl)C=C2OC(F)(F)OC2=C1 CVICEEPAFUYBJG-UHFFFAOYSA-N 0.000 claims description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- 239000002585 base Substances 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 238000001816 cooling Methods 0.000 claims description 2
- 239000012043 crude product Substances 0.000 claims description 2
- 239000011630 iodine Chemical group 0.000 claims description 2
- 229910052740 iodine Chemical group 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims description 2
- 235000011056 potassium acetate Nutrition 0.000 claims description 2
- 239000011736 potassium bicarbonate Substances 0.000 claims description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 2
- 230000008569 process Effects 0.000 claims description 2
- 238000011403 purification operation Methods 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 238000000926 separation method Methods 0.000 claims description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 2
- 238000010025 steaming Methods 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 2
- 150000001448 anilines Chemical class 0.000 claims 1
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 claims 1
- 238000006880 cross-coupling reaction Methods 0.000 abstract description 4
- 239000002994 raw material Substances 0.000 abstract description 4
- 238000011161 development Methods 0.000 abstract description 3
- 238000002360 preparation method Methods 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 60
- 238000001228 spectrum Methods 0.000 description 36
- 229910052799 carbon Inorganic materials 0.000 description 35
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 34
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 34
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 30
- 239000003208 petroleum Substances 0.000 description 17
- 239000003480 eluent Substances 0.000 description 16
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 15
- 238000005160 1H NMR spectroscopy Methods 0.000 description 15
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 15
- 238000012512 characterization method Methods 0.000 description 15
- HMPYMEWXRJVKLL-UHFFFAOYSA-N 2-indol-1-ylaniline Chemical compound NC1=CC=CC=C1N1C2=CC=CC=C2C=C1 HMPYMEWXRJVKLL-UHFFFAOYSA-N 0.000 description 6
- 238000005905 alkynylation reaction Methods 0.000 description 5
- 150000002475 indoles Chemical class 0.000 description 5
- 150000003141 primary amines Chemical class 0.000 description 4
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- 230000008685 targeting Effects 0.000 description 3
- 230000004913 activation Effects 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 150000002391 heterocyclic compounds Chemical class 0.000 description 2
- 150000002431 hydrogen Chemical class 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- NVAUTFORCOFBFJ-UHFFFAOYSA-N 1-(2-aminophenyl)indole-5-carbonitrile Chemical compound NC1=CC=CC=C1N1C2=CC=C(C#N)C=C2C=C1 NVAUTFORCOFBFJ-UHFFFAOYSA-N 0.000 description 1
- QJUUPKRWPDGHDZ-UHFFFAOYSA-N 2-(3-methylindol-1-yl)aniline Chemical compound C12=CC=CC=C2C(C)=CN1C1=CC=CC=C1N QJUUPKRWPDGHDZ-UHFFFAOYSA-N 0.000 description 1
- MEBGFZAAOKIDIW-UHFFFAOYSA-N 2-(4-chloroindol-1-yl)aniline Chemical compound ClC1=C2C=CN(C2=CC=C1)C1=C(N)C=CC=C1 MEBGFZAAOKIDIW-UHFFFAOYSA-N 0.000 description 1
- NGJRCKPFXMPVHD-UHFFFAOYSA-N 2-(4-fluoroindol-1-yl)aniline Chemical compound FC1=C2C=CN(C2=CC=C1)C1=C(N)C=CC=C1 NGJRCKPFXMPVHD-UHFFFAOYSA-N 0.000 description 1
- KXZOMDAEMJEFED-UHFFFAOYSA-N 2-(4-methoxyindol-1-yl)aniline Chemical compound COC1=C2C=CN(C2=CC=C1)C1=C(N)C=CC=C1 KXZOMDAEMJEFED-UHFFFAOYSA-N 0.000 description 1
- HFENVTPHPFPMEK-UHFFFAOYSA-N 2-(4-methylindol-1-yl)aniline Chemical compound C1=CC=2C(C)=CC=CC=2N1C1=CC=CC=C1N HFENVTPHPFPMEK-UHFFFAOYSA-N 0.000 description 1
- INNZKWKCSMLFFF-UHFFFAOYSA-N 2-indol-1-yl-4-methylaniline Chemical compound N1(C=CC2=CC=CC=C12)C1=C(N)C=CC(=C1)C INNZKWKCSMLFFF-UHFFFAOYSA-N 0.000 description 1
- UBPDKIDWEADHPP-UHFFFAOYSA-N 2-iodoaniline Chemical compound NC1=CC=CC=C1I UBPDKIDWEADHPP-UHFFFAOYSA-N 0.000 description 1
- GDMZHPUPLWQIBD-UHFFFAOYSA-N 2-pyrrol-1-ylaniline Chemical compound NC1=CC=CC=C1N1C=CC=C1 GDMZHPUPLWQIBD-UHFFFAOYSA-N 0.000 description 1
- 238000010499 C–H functionalization reaction Methods 0.000 description 1
- 241001384048 Paraorygmatobothrium bai Species 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 150000001345 alkine derivatives Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 229940054051 antipsychotic indole derivative Drugs 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- TVFDJXOCXUVLDH-UHFFFAOYSA-N caesium atom Chemical class [Cs] TVFDJXOCXUVLDH-UHFFFAOYSA-N 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 230000026030 halogenation Effects 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- ZGYICYBLPGRURT-UHFFFAOYSA-N tri(propan-2-yl)silicon Chemical compound CC(C)[Si](C(C)C)C(C)C ZGYICYBLPGRURT-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/0803—Compounds with Si-C or Si-Si linkages
- C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
- C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/0803—Compounds with Si-C or Si-Si linkages
- C07F7/0825—Preparations of compounds not comprising Si-Si or Si-cyano linkages
- C07F7/0827—Syntheses with formation of a Si-C bond
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- Organic Chemistry (AREA)
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Abstract
The invention discloses a synthetic method of a primary amine-guided 2-alkynyl indole compound. The synthesis method comprises the following steps: in the reactor, 2- (1) is addedHThe preparation method comprises the following steps of (1) reacting an-indole-1-yl) aniline compound, alkyne halide, a palladium salt catalyst, alkali and a solvent at 80-110 ℃ under stirring, and separating and purifying reaction liquid to obtain the 2-alkynyl indole compound. The method of the invention develops 2- (1)HThe cross coupling reaction of-indole-1-yl) aniline and alkyne halide constructs a series of highly functionalized 2-alkynyl indole compounds, and the reaction takes water as a solvent, thereby meeting the development requirements of green organic chemistry. In addition, the main characteristics of the reaction are simple and easily available raw materials, safe operation, good regioselectivity and wide substrate universality.
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.
Claims (8)
1. A synthetic method of a primary amine-oriented 2-alkynyl indole compound is characterized by comprising the following steps:
in the reactor, the substrate 2- (1) is addedH-indole-1-yl) aniline compounds, alkyne halide, a palladium salt catalyst, alkali and a solvent, stirring and reacting at 80-110 ℃, cooling to room temperature after the reaction is finished, and separating and purifying the product to obtain the 2-alkynyl indole compounds; the palladium salt catalyst is palladium tetrafluoborate; the alkali is one or more than two of cesium pivalate, potassium acetate, cesium fluoride, sodium bicarbonate and potassium bicarbonate; the chemical reaction equation of the synthesis process is as follows:
in the formula, R1One 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 hydrogen, 4-methyl or 4, 6-dimethyl;
R3is triisopropylsilyl;
x is chlorine, bromine or iodine.
2. The method of synthesis according to claim 1, wherein the 2- (1)HThe (E) -indol-1-yl) aniline compound is 2- (1)H-indol-1-yl) aniline; the alkyne halide is (2-bromoethynyl) triisopropylsilane.
3. The method of synthesis according to claim 1, characterized in thatThen, the amount of the palladium salt catalyst added is equal to 2- (1)HThe mol ratio of the (E) -indole-1-yl) aniline compound is 0.03-0.1: 1.
4. The method of claim 1, wherein the alkyne halide is added in an amount corresponding to 2- (1)HThe mol ratio of the (E) -indol-1-yl) aniline compound is 1.6-3.0: 1.
5. The method of claim 1, wherein the base is added in an amount corresponding to 2- (1)HThe mol ratio of the (E) -indol-1-yl) aniline compound is 2.0-4.0: 1.
6. The synthesis method according to claim 1, wherein the solvent is water, toluene or a mixed solvent of water and toluene.
7. The synthesis method according to claim 1, wherein the stirring reaction time is 20 to 24 hours.
8. The synthesis method according to claim 1, characterized in that the separation and purification operations are: 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.
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| CN106279236A (en) * | 2016-08-11 | 2017-01-04 | 南京理工大学 | A kind of method of synthesis 2 triisopropylsilyl acetylene Benzazole compounds |
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| C2-Selective Direct Alkynylation of Indoles;Gergely L. Tolnai等,;《Org. Lett.》;20121218;112-115页 * |
| Palladium-catalyzed primary amine-directed regioselective mono- and di-alkynylation of biaryl-2-amines;Guangbin Jiang等,;《Chem. Commun.》;20180122;1746-1749页 * |
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