CN103755621A - Method for preparing polysubstituted indole from aryl hydrazine and alkyne - Google Patents
Method for preparing polysubstituted indole from aryl hydrazine and alkyne Download PDFInfo
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- CN103755621A CN103755621A CN201410031322.2A CN201410031322A CN103755621A CN 103755621 A CN103755621 A CN 103755621A CN 201410031322 A CN201410031322 A CN 201410031322A CN 103755621 A CN103755621 A CN 103755621A
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- C—CHEMISTRY; METALLURGY
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- 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
- C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
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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
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
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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
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/12—Radicals substituted by oxygen atoms
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Abstract
The invention discloses a method for preparing polysubstituted indole. The method comprises the following step: carrying out alkyne cyclization reaction based on hydrocarbon chain activation on aryl hydrazine hydrochloride disclosed as Formula II, alkyne disclosed as Formula III, catalyst, alkali and additives to obtain the compound disclosed as Formula I. The accessible raw materials are subjected to on-pot reaction to generate orientating group in situ in the reaction without presetting the orientating group on the substrate. After the cyclization reaction, the orientating group is automatically removed, and the obtained NH indole can be conveniently derived to obtain the N-substituted indole and has favorable compatibility with multiple substituent groups; no additional oxidizer and strong acid or strong alkali are needed in the reaction; the atomic economical efficiency is high; and although the catalyst is not cheap, the addition amount is small.
Description
Technical field
The invention belongs to fine chemical product and catalyze and synthesize field, relate to a kind of method of being prepared polysubstituted indoles by aryl hydrazines and alkynes.
Background technology
Indoles is a nitrogenous aromatic heterocycle, and its derivative is extensively present in occurring in nature [(a) Joule, J.A.; Mills, K., Heterocyclic Chemistry, 5th ed.; Wiley-Blackwell:West Sussex, United Kingdom, 2010. (b) Eicher, T.; Hauptmann, S.; Speicher, A.The Chemistry of Heterocycles:Structure, Reactions, Syntheses, and Applications, 2nd ed.; Wiley-VCH GmbH & Co.KGaA:Weinheim, Germany, 2003.].Tryptophane containing indole ring is mammiferous a kind of indispensable amino acid, and indolylacetic acid (growth hormone) is one of most important endogenous hormones of plant.In organism, tryptophane can transform into the serotonin (5-HT containing indole ring, thrombotonin), it is a kind of neurotransmitter and vaso-active substance that central nervous system is unified in surrounding tissue that be extensively present in, in nervous system regulation and cardiovascular function, and the many-side such as breathing, sleep, appetite plays a significant role.Many have in unique bioactive complex biological alkali also contain indole ring, if vincaleucoblastine is a kind of two indoles type alkaloids, its suppresses the polymerization of tubulin and formation of spindle microtubule, and makes it have significant antitumour activity.In addition, in the flavor molecule in some plant pigmentss and plant, also all comprise the structure that indole ring derives.
As everyone knows, common structural unit in many natural products, is also often the dominance structure (privileged structures) in medicine, indoles no exception [(a) Welsch, M.E.; Snyder, S.A.; Stockwell, B.R.; Curr.Opin.Chem.Biol.2010,14,347. (b) Kochanowska-Karamyan, A.J.; Hamann, M.T.Chem.Rev.2010,110,4489].The ergotocine (ergometrine) obtaining from natural product sphacelic acid derivatize is a kind of Obstetric and Gynecologic Department medication, for prevention and treatment uterine hemorrhage in postpartum.5-hydroxytryptamine receptor is relevant to various diseases, and some are exactly the antagonist of serotonin containing the medicine of indole structure.For example, Ondansetron is a kind of 5-HT
3antagonist, is used for the treatment of nausea and vomiting; A derivative Methysergide of sphacelic acid is a kind of 5-HT
2Aantagonist, for prevention and treatment migraine.The novel 5-HT researching and developing in the last few years
2Athe large class of in antagonist is also with indoles, especially 2-(hetero) aryl indole, the molecule that designs and screen as dominance structure [(a) Smith, A.L.; Stevenson, G.I.; Lewis, S.; Et al.Bioorg.Med.Chem.Lett.2000,10,2693. (b) Rowley, M.; Hallett, D.J.; Goodacre, S.; Et al.J.Med.Chem.2001,44,1603.].Indoles small molecules is also widely used as tubulin stopper, and these molecules often have good antitumour activity, can serve as basis (Patil, the S.A. of development of new cancer therapy drug; Patil, R.; Miller, D.D.Future Med.Chem.2012,4,2085.).In addition, nearest work shows that 3-replacement-2-phenylindone is a kind of dominance structure [(a) Gloriam, the D.E. of GPRC6A antagonist; Pedersen, D.S.;
h.; Et al.Chem.Biol.2011,18,1489. (b) Johansson, H.;
t.B.; Pedersen, D.S.et al.RSC Adv.2013,3,945.].
Due to the outstanding physiologically active of indole derivatives and and using value in medical chemistry, develop convenient and green indoles synthetic method is target [(a) Humphrey, the G.R. that people pursue always; Kuethe, J.T.Chem.Rev.2006,106,2875. (b) Cacchi, S.; Fabrizi, G.Chem.Rev.2011,111, PR215. (c) Vicente, R.Org.Biomol.Chem.2011,9,6469.].As far back as 1883, E.Fischer just developed the method for resetting Cyclization indoles by phenylhydrazone, i.e. synthetic (Li, J.-J. of famous Fischer indoles; Corey, E.J.Name Reactions in Heterocyclic Chemistry; John Wiley & Sons.Inc.:Hoboken, NJ, 2005.).But this cyclization process often need to could realize under strong acid and high temperature, and this has also limited the substrate adaptability of the method.Recent two decades comes, and by the alkynes cyclisation of metal catalytic, is widely used in indoles synthetic (Kr ü ger, K.; Tillack, A.; Beller, M.Adv.Synth.Catal.2008,350,2153.).Wherein the most representative is that Larock indoles is synthetic, and it carrys out synthesis of indole by the adjacent Iodoaniline of palladium catalysis or the alkynes cyclisation of o-bromoaniline.But this method need to be used bifunctional molecule, substrate adaptability is still limited by very large.And by fracture carbon-halogen bond (C – X), realize cyclisation and make the Atom economy of reaction very low, also easily produce the waste material of contaminate environment.Obviously, by the hydrocarbon key that ruptures (C – H), realizing indoles synthetic is a kind of more direct and green synthetic method.But the relative C – of C – H key X wants inertia a lot, often need orientating group to carry out positioning metal it is activated, the arrangement of orientating group has just become a very important problem with removing like this.In several work of recent years development, orientating group all needs to settle in advance, and after becoming indole ring, carries out extra step and remove orientating group [(a) Stuart, D.R.; Alsabeh, P.; Fagnou, K.; Et al.J.Am.Chem.Soc., 2010,132,18326. (b) Chen, J.; Pang, Q.; Sun, Y.; Li, X.J.Org.Chem.2011,76,3523. (c) Ackermann, L.; Lygin, A.V.Org.Lett.2012,14,764.].The job development that Huang etc. are nearest a kind of orientating group removing carry out synthesis of indole, but reaction needed is added the neutralized verdigris of equivalent as additional oxidizer, and orientating group still needs to settle in advance (Wang, C.M.; Sun, H.; Huang, Y.; Et al.Angew.Chem.Int.Ed.2013,52,5795.).Therefore, the more efficient and green indoles synthetic method of design and development still has very large challenge.
Summary of the invention
The object of this invention is to provide a kind of method of being prepared polysubstituted indoles by aryl hydrazines and alkynes.
Shown in preparation formula I provided by the invention, the method for compound, comprises the steps:
Alkynes shown in aryl hydrazines hydrochloride shown in formula II, formula III, catalyzer, alkali and additive are carried out to the alkynes cyclization based on carbon-hydrogen bond activation in solvent, react the complete compound shown in described formula I that obtains;
In described formula I and formula II, R
1all be selected from least one in H, electron-donating group and electron-withdrawing group; R
1the position of substitution be that ortho position, a position or contraposition all can;
Described electron-donating group is methyl, methoxyl group or dimethylin;
Described electron-withdrawing group is fluorine, chlorine, bromine or trifluoromethoxy;
In described formula I and formula III, R
2and R
3identical or different, any one in the alkyl that be all selected from hydrogen, phenyl, contains substituent aryl and C1-C6;
Described containing in substituent aryl, substituting group is selected from least one in methyl, methoxyl group, dimethylin, fluorine, chlorine, bromine and trifluoromethoxy; Described aryl is specially phenyl;
The alkyl of described C1-C6 is methyl, ethyl, propyl group, normal-butyl, the tertiary butyl or n-hexyl.
Work as R
3during for large steric hindrance alkyl (as the tertiary butyl), R
2can be H, now formula III be Terminal Acetylenes hydrocarbon.
Described catalyzer is trivalent rhodium catalyst, is specially [Cp*RhCl
2]
2or [Cp* (CH
3cN)
3rh] (SbF
6)
2,
Described [Cp*RhCl
2]
2or [Cp* (CH
3cN)
3rh] (SbF
6)
2in, Cp* is pentamethyl-cyclopentadienide anion;
The mole dosage that feeds intake of described catalyzer is 1～5% of aryl hydrazines hydrochloride shown in described formula II, preferably 2～3%, be specially 2.5%.
Described alkali is Potassium ethanoate, sodium-acetate, cesium acetate, Lithium Acetate or trimethylacetic acid caesium;
The mole dosage that feeds intake of described alkali is 0.8～1.5 times of aryl hydrazines hydrochloride shown in described formula II, preferably 1.0～1.2 times, is specially 1.1 times, 1.2 times or 1.1-1.2 times.
Described additive is aldehydes or ketones, and its effect is to be aryl hydrazone making the aryl hydrazines converted in-situ shown in formula II, further to react;
Described aldehyde is isobutyric aldehyde, butyraldehyde-n, hexahydrobenzaldehyde, cyclopentyl formaldehyde, 2 methyl butyraldehyde, 2-ethyl butyraldehyde or phenyl aldehyde;
Described ketone is acetone, cyclopentanone or pimelinketone;
The mole dosage that feeds intake of described additive is 1.0～5.0 times of aryl hydrazines hydrochloride shown in described formula II, preferably 1.5～3.0 times, is specially 2.0 times.
The mole dosage that feeds intake of acetylene hydrocarbon compound shown in described formula III is 1.0～2.0 times of aryl hydrazines hydrochloride shown in described formula II, preferably 1.1～1.5 times, specifically can be 1.1,1.2,1.4,2,1.1-2,1.1-1.4,1.2-2 or 1.4-2 doubly.
Concrete, for solid-state alkynes, the mole dosage that feeds intake of acetylene hydrocarbon compound shown in formula III is 1.2 times of aryl hydrazines hydrochloride shown in described formula II;
For liquid alkynes, the mole dosage that feeds intake of acetylene hydrocarbon compound shown in formula III specifically can be 1.4 times of aryl hydrazines hydrochloride shown in described formula II;
For liquid alkynes, the mole dosage that feeds intake of acetylene hydrocarbon compound shown in formula III specifically can be 1.2 times of aryl hydrazines hydrochloride shown in described formula II;
For terminal alkyne, the mole dosage that feeds intake of acetylene hydrocarbon compound shown in formula III specifically can be 2.0 times of aryl hydrazines hydrochloride shown in described formula II;
Described solvent is selected from least one in methyl alcohol, acetone, water, tetrahydrofuran (THF), DMF, methylene dichloride, ethanol and trifluoroethanol.
In described cyclization step, temperature is 60～100 ℃, preferably 80 ℃; Time is 8～24 hours, preferably 12,16,18,12～18,12-16 or 16-18 hour.This reaction times is different and change depending on reactant shown in cotype II not, and whether reaction is complete by thin-layer chromatography or GC-MS monitoring.
Described cyclization carries out in inert atmosphere;
Described inert atmosphere is nitrogen or argon gas atmosphere.
After completion of the reaction, reaction system is carried out separating-purifying according to conventional silica gel column chromatography mode, preferred mode is: use 100～200 object silica gel and sherwood oil dress post, use dry method upper prop, cross post (volume fraction of acetone is generally 0.5～10%) take sherwood oil-acetone mixed solvent as eluent.
The method of synthetic polysubstituted indoles provided by the invention, has following characteristics:
(1) convenient.The raw material that use is easy to get carries out one pot reaction, and orientating group generates at reaction situ, without being preset on substrate.After cyclization, orientating group automatic trip removes, and the NH indoles obtaining conveniently carries out further derivatize and obtains the indoles that N-replaces.
(2) pervasive.Reaction all has good compatibility to multiple substituting group, to being with multiple substituent aryl hydrazines to be also suitable for.Especially, reacting right title alkynes and some Terminal Acetylenes is also suitable for.In addition, this reaction can be amplified to a gram level (seeing embodiment 21) easily.
(3) green.Reaction, without additional oxidizer, can complete cyclization process by the fracture of N – N key in orientating group.Reaction is without strong acid and strong base, and Atom economy is also higher.
(4) economy.Reaction raw materials simple and easy to get, also very cheap and easy to get of alkali, additive and the solvent using, although the catalyzer using is not cheap, required add-on is little.
Accompanying drawing explanation
Fig. 1 is the hydrogen nuclear magnetic resonance spectrogram of embodiment 1 gained target product.
Fig. 2 is the carbon-13 nmr spectra figure of embodiment 1 gained target product.
Fig. 3 is the hydrogen nuclear magnetic resonance spectrogram of embodiment 11 gained target products.
Fig. 4 is the carbon-13 nmr spectra figure of embodiment 11 gained target products.
Fig. 5 is the hydrogen nuclear magnetic resonance spectrogram of embodiment 19 gained target products.
Fig. 6 is the carbon-13 nmr spectra figure of embodiment 19 gained target products.
Embodiment
Below in conjunction with specific embodiment, the present invention is further elaborated, but the present invention is not limited to following examples.Described method is ordinary method if no special instructions.Described starting material all can obtain from open commercial sources if no special instructions.After embodiment, has comparative example, the impact in order to the each key element in the general implementing method of explanation change on implementation result.
Take successively the hydrazinobenzene hydrochloride salt (R of 72.3mg ownership formula II
1for H) (0.5mmol), the dibenzenyl (R of 106.9mg ownership formula III
2and R
3be phenyl) (0.6mmol), 7.7mg catalyzer [Cp*RhCl
2]
2(2.5mol%) and 54.0mg alkali Potassium ethanoate (0.55mmol) in containing in the 25mL tube sealing of magnetic stirring, vacuumize-inflated with nitrogen circulation three times.Under nitrogen protection, add 72.1mg additive isobutyric aldehyde (1.0mmol) and 2.5mL solvent methanol.By tube sealing sealing, put into the oil bath of 80 ℃ and stir the alkynes cyclization that carries out based on carbon-hydrogen bond activation 12 hours.After reaction finishes, carry out post separation, obtain white solid 111.4mg, target product 2, the isolated yield of 3-diphenyl indole is 83%.
Fig. 1 and Fig. 2 are respectively proton nmr spectra and the carbon spectrum that this embodiment prepares products obtained therefrom, and this compound structure is correct as seen from the figure.
Embodiment 2
Take successively 79.3mg ownership formula II to hydrazinobenzoic acid hydrochloride (R
1for methyl) (0.5mmol), the dibenzenyl (R of 106.9mg ownership formula III
2and R
3be phenyl) (0.6mmol), 7.7mg[Cp*RhCl
2]
2(2.5mol%) and 54.0mg Potassium ethanoate (0.55mmol) in containing in the 25mL tube sealing of magnetic stirring, vacuumize-inflated with nitrogen circulation three times.Under nitrogen protection, add 72.1mg isobutyric aldehyde (1.0mmol) and 2.5mL methyl alcohol.By tube sealing sealing, put into the oil bath of 80 ℃ and stir 12 hours.After reaction finishes, carry out post separation, obtain white solid 129.4mg, target product 5-methyl-2, the isolated yield of 3-diphenyl indole is 91%.
Embodiment 3
Take successively 79.3mg ownership formula II between hydrazinobenzoic acid hydrochloride (R
1for methyl) (0.5mmol), the dibenzenyl (R of 106.9mg ownership formula III
2and R
3be phenyl) (0.6mmol), 7.7mg[Cp*RhCl
2]
2(2.5mol%) and 54.0mg Potassium ethanoate (0.55mmol) in containing in the 25mL tube sealing of magnetic stirring, vacuumize-inflated with nitrogen circulation three times.Under nitrogen protection, add 72.1mg isobutyric aldehyde (1.0mmol) and 2.5mL methyl alcohol.By tube sealing sealing, put into the oil bath of 80 ℃ and stir 12 hours.After reaction finishes, carry out post separation, obtain white solid 111.6mg, target product 6-methyl-2, the isolated yield of 3-diphenyl indole is 79%.
Embodiment 4
Take successively the o-methyl-benzene hydrazonium salt hydrochlorate (R of 79.3mg ownership formula II
1for methyl) (0.5mmol), the dibenzenyl (R of 106.9mg ownership formula III
2and R
3be phenyl) (0.6mmol), 7.7mg[Cp*RhCl
2]
2(2.5mol%) and 54.0mg Potassium ethanoate (0.55mmol) in containing in the 25mL tube sealing of magnetic stirring, vacuumize-inflated with nitrogen circulation three times.Under nitrogen protection, add 72.1mg isobutyric aldehyde (1.0mmol) and 2.5mL methyl alcohol.By tube sealing sealing, put into the oil bath of 80 ℃ and stir 12 hours.After reaction finishes, carry out post separation, obtain white solid 127.5mg, target product 7-methyl-2, the isolated yield of 3-diphenyl indole is 90%.
Take successively 87.3mg ownership formula II to methoxyphenyl hydrazine hydrochloride (R
1for methoxyl group) (0.5mmol), the dibenzenyl (R of 106.9mg ownership formula III
2and R
3be phenyl) (0.6mmol), 7.7mg[Cp*RhCl
2]
2(2.5mol%) and 54.0mg Potassium ethanoate (0.55mmol) in containing in the 25mL tube sealing of magnetic stirring, vacuumize-inflated with nitrogen circulation three times.Under nitrogen protection, add 72.1mg isobutyric aldehyde (1.0mmol) and 2.5mL methyl alcohol.By tube sealing sealing, put into the oil bath of 80 ℃ and stir 12 hours.After reaction finishes, carry out post separation, obtain white solid 137.5mg, target product 2, the isolated yield of 3-phenylbenzene-5-methoxy-Indole is 92%.
Embodiment 6
Take successively 81.3mg ownership formula II to fluorophenyl hydrazine hydrochloride (R
1for fluorine) (0.5mmol), the dibenzenyl (R of 106.9mg ownership formula III
2and R
3be phenyl) (0.6mmol), 7.7mg[Cp*RhCl
2]
2(2.5mol%) and 54.0mg Potassium ethanoate (0.55mmol) in containing in the 25mL tube sealing of magnetic stirring, vacuumize-inflated with nitrogen circulation three times.Under nitrogen protection, add 72.1mg isobutyric aldehyde (1.0mmol) and 2.5mL methyl alcohol.By tube sealing sealing, put into the oil bath of 80 ℃ and stir 16 hours.After reaction finishes, carry out post separation, obtain white solid 107.3mg, target product 2, the isolated yield of 3-phenylbenzene-5-fluoro indole is 75%.
Embodiment 7
Take successively the p-hydrochloride (R of 89.5mg ownership formula II
1for chlorine) (0.5mmol), the dibenzenyl (R of 106.9mg ownership formula III
2and R
3be phenyl) (0.6mmol), 7.7mg[Cp*RhCl
2]
2(2.5mol%) and 54.0mg Potassium ethanoate (0.55mmol) in containing in the 25mL tube sealing of magnetic stirring, vacuumize-inflated with nitrogen circulation three times.Under nitrogen protection, add 72.1mg isobutyric aldehyde (1.0mmol) and 2.5mL methyl alcohol.By tube sealing sealing, put into the oil bath of 80 ℃ and stir 16 hours.After reaction finishes, carry out post separation, obtain white solid 87.0mg, target product 2, the isolated yield of 3-phenylbenzene-5-chloro-indole is 57%.
Take successively the para-bromophenyl-hydrazine hydrochloride (R of 111.8mg ownership formula II
1for bromine) (0.5mmol), the dibenzenyl (R of 106.9mg ownership formula III
2and R
3be phenyl) (0.6mmol), 7.7mg[Cp*RhCl
2]
2(2.5mol%) and 54.0mg Potassium ethanoate (0.55mmol) in containing in the 25mL tube sealing of magnetic stirring, vacuumize-inflated with nitrogen circulation three times.Under nitrogen protection, add 72.1mg isobutyric aldehyde (1.0mmol) and 2.5mL methyl alcohol.By tube sealing sealing, put into the oil bath of 80 ℃ and stir 16 hours.After reaction finishes, carry out post separation, obtain white solid 118.0mg, target product 2, the isolated yield of 3-phenylbenzene-5-bromo indole is 68%.
Embodiment 9
Take successively 2-methyl-5-fluorophenyl hydrazine hydrochloride (R of 88.3mg ownership formula II
1for methyl and fluorine) (0.5mmol), the dibenzenyl (R of 106.9mg ownership formula III
2and R
3be phenyl) (0.6mmol), 7.7mg[Cp*RhCl
2]
2(2.5mol%) and 54.0mg Potassium ethanoate (0.55mmol) in containing in the 25mL tube sealing of magnetic stirring, vacuumize-inflated with nitrogen circulation three times.Under nitrogen protection, add 72.1mg isobutyric aldehyde (1.0mmol) and 2.5mL methyl alcohol.By tube sealing sealing, put into the oil bath of 80 ℃ and stir 16 hours.After reaction finishes, carry out post separation, obtain white solid 137.3mg, target product 7-methyl-2, the isolated yield of 3-phenylbenzene-4-fluoro indole is 91%.
Embodiment 10
Take successively 2-methyl-4-chlorophenyl hydrazine hydrochloride (R of 96.5mg ownership formula II
1for methyl and chlorine) (0.5mmol), the dibenzenyl (R of 106.9mg ownership formula III
2and R
3be phenyl) (0.6mmol), 7.7mg[Cp*RhCl
2]
2(2.5mol%) and 54.0mg Potassium ethanoate (0.55mmol) in containing in the 25mL tube sealing of magnetic stirring, vacuumize-inflated with nitrogen circulation three times.Under nitrogen protection, add 72.1mg isobutyric aldehyde (1.0mmol) and 2.5mL methyl alcohol.By tube sealing sealing, put into the oil bath of 80 ℃ and stir 16 hours.After reaction finishes, carry out post separation, obtain white solid 114.8mg, target product 7-methyl-2, the isolated yield of 3-phenylbenzene-5-chloro-indole is 72%.
Embodiment 11
Take successively 4-methyl-3-chlorophenyl hydrazine hydrochloride (R of 96.5mg ownership formula II
1for methyl and chlorine) (0.5mmol), the dibenzenyl (R of 106.9mg ownership formula III
2and R
3be phenyl) (0.6mmol), 7.7mg[Cp*RhCl
2]
2(2.5mol%) and 54.0mg Potassium ethanoate (0.55mmol) in containing in the 25mL tube sealing of magnetic stirring, vacuumize-inflated with nitrogen circulation three times.Under nitrogen protection, add 72.1mg isobutyric aldehyde (1.0mmol) and 2.5mL methyl alcohol.By tube sealing sealing, put into the oil bath of 80 ℃ and stir 16 hours.After reaction finishes, carry out post separation, obtain white solid 97.0mg, target product 5-methyl-2, the isolated yield of 3-phenylbenzene-6-chloro-indole is 61%.
Fig. 3 and Fig. 4 are respectively proton nmr spectra and the carbon spectrum that this embodiment prepares products obtained therefrom, and this compound structure is correct as seen from the figure.
Embodiment 12
Take successively the hydrazinobenzene hydrochloride salt (R of 72.3mg ownership formula II
1for H) (0.5mmol), 123.8mg bis-(p-methylphenyl) acetylene (0.6mmol), 7.7mg[Cp*RhCl
2]
2(2.5mol%) and 54.0mg Potassium ethanoate (0.55mmol) in containing in the 25mL tube sealing of magnetic stirring, vacuumize-inflated with nitrogen circulation three times.Under nitrogen protection, add 72.1mg isobutyric aldehyde (1.0mmol) and 2.5mL methyl alcohol.By tube sealing sealing, put into the oil bath of 80 ℃ and stir 12 hours.After reaction finishes, carry out post separation, obtain white solid 126.1mg, target product 2, the isolated yield of 3-bis-(p-methylphenyl) indoles is 85%.
Take successively the hydrazinobenzene hydrochloride salt (R of 72.3mg ownership formula II
1for H) (0.5mmol), 143.0mg bis-(p-methoxyphenyl) acetylene (0.6mmol), 7.7mg[Cp*RhCl
2]
2(2.5mol%) and 54.0mg Potassium ethanoate (0.55mmol) in containing in the 25mL tube sealing of magnetic stirring, vacuumize-inflated with nitrogen circulation three times.Under nitrogen protection, add 72.1mg isobutyric aldehyde (1.0mmol) and 2.5mL methyl alcohol.By tube sealing sealing, put into the oil bath of 80 ℃ and stir 12 hours.After reaction finishes, carry out post separation, obtain white solid 126.1mg, target product 2, the isolated yield of 3-bis-(p-methoxyphenyl) indoles is 90%.
Take successively the hydrazinobenzene hydrochloride salt (R of 72.3mg ownership formula II
1for H) (0.5mmol), 128.5mg bis-(to fluorophenyl) acetylene (0.6mmol), 7.7mg[Cp*RhCl
2]
2(2.5mol%) and 54.0mg Potassium ethanoate (0.55mmol) in containing in the 25mL tube sealing of magnetic stirring, vacuumize-inflated with nitrogen circulation three times.Under nitrogen protection, add 72.1mg isobutyric aldehyde (1.0mmol) and 2.5mL methyl alcohol.By tube sealing sealing, put into the oil bath of 80 ℃ and stir 12 hours.After reaction finishes, carry out post separation, obtain white solid 111.0mg, target product 2, the isolated yield of 3-bis-(to fluorophenyl) indoles is 73%.
Take successively the hydrazinobenzene hydrochloride salt (R of 72.3mg ownership formula II
1for H) (0.5mmol), 201.6mg bis-(to bromophenyl) acetylene (0.6mmol), 7.7mg[Cp*RhCl
2]
2(2.5mol%) and 54.0mg Potassium ethanoate (0.55mmol) in containing in the 25mL tube sealing of magnetic stirring, vacuumize-inflated with nitrogen circulation three times.Under nitrogen protection, add 72.1mg isobutyric aldehyde (1.0mmol) and 2.5mL methyl alcohol.By tube sealing sealing, put into the oil bath of 80 ℃ and stir 12 hours.After reaction finishes, carry out post separation, obtain white solid 137.5mg, target product 2, the isolated yield of 3-bis-(to bromophenyl) indoles is 64%.
Take successively the hydrazinobenzene hydrochloride salt (R of 72.3mg ownership formula II
1for H) (0.5mmol), 7.7mg[Cp*RhCl
2]
2(2.5mol%) and 54.0mg Potassium ethanoate (0.55mmol) in containing in the 25mL tube sealing of magnetic stirring, vacuumize-inflated with nitrogen circulation three times.Under nitrogen protection, add 81.3mg3-phenyl-2-propine (0.7mmol), 72.1mg isobutyric aldehyde (1.0mmol) and 2.5mL methyl alcohol.By tube sealing sealing, put into the oil bath of 80 ℃ and stir 16 hours.After reaction finishes, carry out post separation, obtain white solid 60.9mg, the isolated yield of target product 3-methyl-2-phenylindone is 59%.
Take successively 79.3mg ownership formula II to hydrazinobenzoic acid hydrochloride (R
1for methyl) (0.5mmol), 7.7mg[Cp*RhCl
2]
2(2.5mol%) and 54.0mg Potassium ethanoate (0.55mmol) in containing in the 25mL tube sealing of magnetic stirring, vacuumize-inflated with nitrogen circulation three times.Under nitrogen protection, add 81.3mg3-phenyl-2-propine (0.7mmol), 72.1mg isobutyric aldehyde (1.0mmol) and 2.5mL methyl alcohol.By tube sealing sealing, put into the oil bath of 80 ℃ and stir 16 hours.After reaction finishes, carry out post separation, obtain white solid 89.3mg, target product 3, the isolated yield of 5-dimethyl-2-phenylindone is 81%.
Take successively the hydrazinobenzene hydrochloride salt (R of 72.3mg ownership formula II
1for H) (0.5mmol), 7.7mg[Cp*RhCl
2]
2(2.5mol%) and 54.0mg Potassium ethanoate (0.55mmol) in containing in the 25mL tube sealing of magnetic stirring, vacuumize-inflated with nitrogen circulation three times.Under nitrogen protection, add 67.3mg4,4-dimethyl-valerylene (0.7mmol), 72.1mg isobutyric aldehyde (1.0mmol) and 2.5mL methyl alcohol.By tube sealing sealing, put into the oil bath of 80 ℃ and stir 16 hours.After reaction finishes, carry out post separation, obtain white solid 65.2mg, the isolated yield of target product 3-methyl-2-tertiary butyl indoles is 70%.
Take successively the hydrazinobenzene hydrochloride salt (R of 72.3mg ownership formula II
1for H) (0.5mmol), 7.7mg[Cp*RhCl
2]
2(2.5mol%) and 54.0mg Potassium ethanoate (0.55mmol) in containing in the 25mL tube sealing of magnetic stirring, vacuumize-inflated with nitrogen circulation three times.Under nitrogen protection, add 92.5mg4-phenyl-1-hydroxyl-3-butine (0.7mmol), 72.1mg isobutyric aldehyde (1.0mmol) and 2.5mL methyl alcohol.By tube sealing sealing, put into the oil bath of 80 ℃ and stir 16 hours.After reaction finishes, carry out post separation, obtain white solid 85.6mg, the isolated yield of target product 2-(2-phenylindone-3-yl) ethanol is 72%.
Fig. 5 and Fig. 6 are respectively proton nmr spectra and the carbon spectrum that this embodiment prepares products obtained therefrom, and this compound structure is correct as seen from the figure.
Take successively 79.3mg ownership formula II to hydrazinobenzoic acid hydrochloride (R
1for methyl) (0.5mmol), 7.7mg[Cp*RhCl
2]
2(2.5mol%) and 54.0mg Potassium ethanoate (0.55mmol) in containing in the 25mL tube sealing of magnetic stirring, vacuumize-inflated with nitrogen circulation three times.Under nitrogen protection, add 82.1mg3,3-dimethyl-ethyl acetylene (1.0mmol), 72.1mg isobutyric aldehyde (1.0mmol) and 2.5mL methyl alcohol.By tube sealing sealing, put into the oil bath of 80 ℃ and stir 12 hours.After reaction finishes, carry out post separation, obtain white solid 70.0mg, the isolated yield of target product 2-tertiary butyl indoles is 75%.
Embodiment 21(gram order reaction)
Take successively the hydrazinobenzene hydrochloride salt (R of 0.723g ownership formula II
1for H) (5mmol), the dibenzenyl (R of 1.069g ownership formula III
2and R
3be phenyl) (6mmol), 46.2mg[Cp*RhCl
2]
2(1.5mol%) and 0.540g Potassium ethanoate (5.5mmol) in containing in the 100mL tube sealing of magnetic stirring, vacuumize-inflated with nitrogen circulation three times.Under nitrogen protection, add 0.721g isobutyric aldehyde (10mmol) and 25mL methyl alcohol.By tube sealing sealing, put into the oil bath of 80 ℃ and stir 18 hours.After reaction finishes, carry out post separation, obtain white solid 1.035g, target product 2, the isolated yield of 3-diphenyl indole is 77%.
Take successively the hydrazinobenzene hydrochloride salt (R of 28.9mg ownership formula II
1for H) (0.2mmol), the dibenzenyl (R of 42.8mg ownership formula III
2and R
3be phenyl) (0.24mmol), 3.1mg[Cp*RhCl
2]
2(2.5mol%) and 21.6mg Potassium ethanoate (0.22mmol) in containing in the 25mL tube sealing of magnetic stirring, vacuumize-inflated with nitrogen circulation three times.Under nitrogen protection, add 44.9mg hexahydrobenzaldehyde (0.4mmol) and 1mL methyl alcohol.By tube sealing sealing, put into the oil bath of 80 ℃ and stir 12 hours.Reaction finishes laggard row gas-chromatography (GC) analysis, target product 2, and the GC productive rate of 3-diphenyl indole is 82%.Illustrate and as additive, also can reach good effect with hexahydrobenzaldehyde.
Take successively the hydrazinobenzene hydrochloride salt (R of 28.9mg ownership formula II
1for H) (0.2mmol), the dibenzenyl (R of 42.8mg ownership formula III
2and R
3be phenyl) (0.24mmol), 3.1mg[Cp*RhCl
2]
2(2.5mol%) and 21.6mg Potassium ethanoate (0.22mmol) in containing in the 25mL tube sealing of magnetic stirring, vacuumize-inflated with nitrogen circulation three times.Under nitrogen protection, add 42.4mg phenyl aldehyde (0.4mmol) and 1mL methyl alcohol.By tube sealing sealing, put into the oil bath of 80 ℃ and stir 12 hours.Reaction finishes laggard row gas-chromatography (GC) analysis, target product 2, and the GC productive rate of 3-diphenyl indole is 82%.Illustrate and as additive, also can reach good effect with phenyl aldehyde.
Take successively the hydrazinobenzene hydrochloride salt (R of 28.9mg ownership formula II
1for H) (0.2mmol), the dibenzenyl (R of 42.8mg ownership formula III
2and R
3be phenyl) (0.24mmol), 3.1mg[Cp*RhCl
2]
2(2.5mol%) and 18.0mg sodium-acetate (0.4mmol) in containing in the 25mL tube sealing of magnetic stirring, vacuumize-inflated with nitrogen circulation three times.Under nitrogen protection, add 28.8mg isobutyric aldehyde (0.4mmol) and 1mL methyl alcohol.By tube sealing sealing, put into the oil bath of 80 ℃ and stir 12 hours.Reaction finishes laggard row gas-chromatography (GC) analysis, target product 2, and the GC productive rate of 3-diphenyl indole is 84%.Illustrate with sodium-acetate suitable as effect and the Potassium ethanoate of alkali.
Take successively the hydrazinobenzene hydrochloride salt (R of 28.9mg ownership formula II
1for H) (0.2mmol), the dibenzenyl (R of 42.8mg ownership formula III
2and R
3be phenyl) (0.24mmol), 3.1mg[Cp*RhCl
2]
2(2.5mol%) and 39.3mg Potassium ethanoate (0.4mmol) in containing in the 25mL tube sealing of magnetic stirring, vacuumize-inflated with nitrogen circulation three times.Under nitrogen protection, add 28.8mg isobutyric aldehyde (0.4mmol) and 1mL methyl alcohol.By tube sealing sealing, put into the oil bath of 80 ℃ and stir 18 hours.Reaction finishes laggard row gas-chromatography (GC) analysis, target product 2, and the GC productive rate of 3-diphenyl indole is 73%.Illustrate when the base excess adding is more and can affect reaction efficiency.
Embodiment 26
Take successively the hydrazinobenzene hydrochloride salt (R of 28.9mg ownership formula II
1for H) (0.2mmol), the dibenzenyl (R of 42.8mg ownership formula III
2and R
3be phenyl) (0.24mmol), 3.1mg[Cp*RhCl
2]
2(2.5mol%) and 21.6mg Potassium ethanoate (0.22mmol) in containing in the 25mL tube sealing of magnetic stirring, vacuumize-inflated with nitrogen circulation three times.Under nitrogen protection, add 28.8mg isobutyric aldehyde (0.4mmol) and 1mL ethanol.By tube sealing sealing, put into the oil bath of 80 ℃ and stir 12 hours.Reaction finishes laggard row gas-chromatography (GC) analysis, target product 2, and the GC productive rate of 3-diphenyl indole is 70%.Illustrate also can make to react as solvent with ethanol to occur, but productive rate reduces.
Comparative example 1
Take successively 28.9mg hydrazinobenzene hydrochloride salt (0.2mmol), 42.8mg tolane (0.24mmol) and 21.6mg Potassium ethanoate (0.22mmol) in containing the 25mL tube sealing of magnetic stirring, vacuumize-inflated with nitrogen circulation three times.Under nitrogen protection, add 28.8mg isobutyric aldehyde (0.4mmol) and 1mL methyl alcohol.By tube sealing sealing, put into the oil bath of 80 ℃ and stir 12 hours.Reaction finishes to detect with GC-MS afterwards, and phenylhydrazine is all converted into corresponding phenylhydrazone, but does not generate with the product of alkynes cyclisation.Illustrate that cyclization can not occur under the condition that does not add catalyzer.
Comparative example 2
Take successively 28.9mg hydrazinobenzene hydrochloride salt (0.2mmol), 42.8mg tolane (0.24mmol), 3.1mg[Cp*RhCl
2]
2(2.5mol%) and 21.6mg Potassium ethanoate (0.22mmol) in containing in the 25mL tube sealing of magnetic stirring, vacuumize-inflated with nitrogen circulation three times.Under nitrogen protection, add 58.1mg acetone (1.0mmol) and 1mL methyl alcohol.By tube sealing sealing, put into the oil bath of 80 ℃ and stir 12 hours.Reaction finishes laggard promoting the circulation of qi analysis of hplc, target product 2, and the GC productive rate of 3-diphenyl indole is 32%.Illustrate also can make to react as additive with acetone to occur, but poor effect.
Comparative example 3
Take successively 28.9mg hydrazinobenzene hydrochloride salt (0.2mmol), 42.8mg tolane (0.24mmol), 3.1mg[Cp*RhCl
2]
2(2.5mol%) in containing the 25mL tube sealing of magnetic stirring, vacuumize-inflated with nitrogen circulation three times.Under nitrogen protection, add 28.8mg isobutyric aldehyde (1.0mmol) and 1mL methyl alcohol.By tube sealing sealing, put into the oil bath of 80 ℃ and stir 12 hours.Reaction finishes rear with GC-MS detection, does not have product to generate.Illustrate with reacting and can not occur under the condition that does not add alkali.
Claims (9)
1. a method for compound shown in preparation formula I, comprises the steps:
Alkynes shown in aryl hydrazines hydrochloride shown in formula II, formula III, catalyzer, alkali and additive are carried out to the alkynes cyclization based on carbon-hydrogen bond activation in solvent, react the complete compound shown in described formula I that obtains;
2. method according to claim 1, is characterized in that: in described formula I and formula II, and R
1all be selected from least one in H, electron-donating group and electron-withdrawing group; R
1the position of substitution be that ortho position, a position or contraposition all can;
Described electron-donating group is methyl, methoxyl group or dimethylin;
Described electron-withdrawing group is fluorine, chlorine, bromine or trifluoromethoxy;
In described formula I and formula III, R
2and R
3identical or different, any one in the alkyl that be all selected from hydrogen, phenyl, contains substituent aryl and C1-C6;
Described containing in substituent aryl, substituting group is selected from least one in methyl, methoxyl group, dimethylin, fluorine, chlorine, bromine and trifluoromethoxy; Described aryl is specially phenyl;
The alkyl of described C1-C6 is methyl, ethyl, propyl group, normal-butyl, the tertiary butyl or n-hexyl.
3. method according to claim 1 and 2, is characterized in that: described catalyzer is trivalent rhodium catalyst, is specially [Cp*RhCl
2]
2or [Cp* (CH
3cN)
3rh] (SbF
6)
2,
Described [Cp*RhCl
2]
2or [Cp* (CH
3cN)
3rh] (SbF
6)
2in, Cp* is pentamethyl-cyclopentadienide anion;
The mole dosage that feeds intake of described catalyzer is 1～5% of aryl hydrazines hydrochloride shown in described formula II, preferably 2～3%, be specially 2.5%.
4. according to the arbitrary described method of claim 1～3, it is characterized in that: described alkali is Potassium ethanoate, sodium-acetate, cesium acetate, Lithium Acetate or trimethylacetic acid caesium;
The mole dosage that feeds intake of described alkali is 0.8～1.5 times of aryl hydrazines hydrochloride shown in described formula II, preferably 1.0～1.2 times, is specially 1.1 times.
5. according to the method described in claim 1～4, it is characterized in that: described additive is aldehydes or ketones;
Described aldehyde is isobutyric aldehyde, butyraldehyde-n, hexahydrobenzaldehyde, cyclopentyl formaldehyde, 2 methyl butyraldehyde, 2-ethyl butyraldehyde or phenyl aldehyde;
Described ketone is acetone, cyclopentanone or pimelinketone;
The mole dosage that feeds intake of described additive is 1.0～5.0 times of aryl hydrazines hydrochloride shown in described formula II, preferably 1.5～3.0 times, is specially 2.0 times.
6. according to the arbitrary described method of claim 1～5, it is characterized in that: the mole dosage that feeds intake of acetylene hydrocarbon compound shown in described formula III is 1.0～2.0 times of aryl hydrazines hydrochloride shown in described formula II, preferably 1.1～1.5 times.
7. according to the arbitrary described method of claim 1～6, it is characterized in that: described solvent is selected from least one in methyl alcohol, acetone, water, tetrahydrofuran (THF), DMF, methylene dichloride, ethanol and trifluoroethanol.
8. according to the method described in claim 1～7, it is characterized in that: in described cyclization step, temperature is 60～100 ℃, preferably 80 ℃; Time is 8～24 hours, preferably 12～16 hours.
9. according to the arbitrary described method of claim 1-8, it is characterized in that: described cyclization carries out in inert atmosphere;
Described inert atmosphere is nitrogen or argon gas atmosphere.
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| WO2008125207A1 (en) * | 2007-04-13 | 2008-10-23 | Sanofi-Aventis | A transition metal catalyzed synthesis of n-aminoindoles |
| CN102731450A (en) * | 2012-07-04 | 2012-10-17 | 中山大学 | Preparation method of benzofuran or indole |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2008125207A1 (en) * | 2007-04-13 | 2008-10-23 | Sanofi-Aventis | A transition metal catalyzed synthesis of n-aminoindoles |
| CN102731450A (en) * | 2012-07-04 | 2012-10-17 | 中山大学 | Preparation method of benzofuran or indole |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105985279A (en) * | 2015-02-04 | 2016-10-05 | 中国科学院大连化学物理研究所 | Method for preparing indole derivative by reaction between nitrone derivative and symmetric alkyne |
| CN105985279B (en) * | 2015-02-04 | 2018-05-18 | 中国科学院大连化学物理研究所 | A kind of method that nitrone analog derivative prepares indole derivatives with symmetrical alkynes reaction |
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