CN114478351B - Method for synthesizing alpha-alkyl substituted indole-3-formaldehyde compound - Google Patents
Method for synthesizing alpha-alkyl substituted indole-3-formaldehyde compound Download PDFInfo
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- 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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- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
- B01J31/0277—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides comprising ionic liquids, as components in catalyst systems or catalysts per se, the ionic liquid compounds being used in the molten state at the respective reaction temperature
- B01J31/0278—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides comprising ionic liquids, as components in catalyst systems or catalysts per se, the ionic liquid compounds being used in the molten state at the respective reaction temperature containing nitrogen as cationic centre
- B01J31/0281—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides comprising ionic liquids, as components in catalyst systems or catalysts per se, the ionic liquid compounds being used in the molten state at the respective reaction temperature containing nitrogen as cationic centre the nitrogen being a ring member
Abstract
The invention discloses a novel method for synthesizing alpha-alkyl substituted indole-3-formaldehyde compounds, which is characterized in that in the presence of magnesium scraps, an iron (III) complex containing 1, 3-bis (2, 4, 6-trimethylphenyl) imidazole cations is used as a catalyst, and alpha-alkyl substituted indole-3-formaldehyde compounds are synthesized through the hydro-heteroaryl reaction of aryl ethylene and indole-3-formaldehyde imine. Compared with the prior art, the method avoids the use of sensitive and flammable Grignard reagent and TMEDA additive, so the method has higher safety and atom economy, and simultaneously has higher applicability of the substrate, which is the first hydrogen heteroaryl reaction realized by the iron catalyst under the action of magnesium scraps.
Description
Technical Field
The invention belongs to the technical field of organic synthesis and preparation, and particularly relates to a novel method for synthesizing an alpha-alkyl substituted indole-3-formaldehyde compound.
Background
The alpha-alkyl substituted indole-3-formaldehyde is an important structural fragment, widely exists in natural products, medicines and bioactive molecules, and has important synthetic value. Over the past decade, transition metal catalyzed hydroheteroarylation of aryl ethylene with indoles has evolved into a new method for synthesizing alpha-alkyl substituted indoles due to its 100% atomic economy. However, there are only two reports of the literature concerning iron-based catalysts. In 2015, the Yoshikai group was prepared with ferric acetylacetonate (Fe (acca) in the presence of the sensitive and flammable Grignard reagent cyclohexylmagnesium chloride (CyMgCl) and an excess of the additive N, N, N ', N' -tetramethyl ethylenediamine (TMEDA) 3 ) And the imidazole salt SIXyl ∙ HCl (SIXyl is 1, 3-di (2, 6-dimethylphenyl) imidazoline cation) is used as a catalytic system, so that the hydrogen heteroaryl reaction of aryl ethylene and indole-3-formaldehyde imine is realized. In 2017, the Ackermann group was developed as Fe (acca) in the presence of a sensitive flammable grignard reagent CyMgCl and an excess of additive TMEDA 3 And chiral imidazole salt is used as a catalytic system to realize the enantioselective hydrogen heteroaryl reaction of aryl ethylene and indole-3-formaldehyde imine. It can be seen that the presently reported iron-based catalyst-catalyzed hydroheteroarylation of aryl ethylene with indoles requires the use of a sensitive flammable grignard reagent and an excess of TMEDA to allow the reaction to proceed, which both limits the functional group tolerance (e.g., intolerance to trifluoromethyl styrene, trimethylsilyl styrene, p-morpholinyl styrene, 2-vinylpyridine, and 2-vinylbenzofuran) and reduces the atomic economy of the reaction. Therefore, there is a need to develop new preparation methods to improve the synthesisThe safety and industrial applicability of the alpha-alkyl substituted indole-3-formaldehyde compound are realized.
Disclosure of Invention
The invention aims to provide a novel method for synthesizing alpha-alkyl substituted indole-3-formaldehyde compounds, which takes iron (III) complex containing 1, 3-di (2, 4, 6-trimethylphenyl) imidazole cations as a catalyst in the presence of magnesium scraps, and synthesizes the alpha-alkyl substituted indole-3-formaldehyde compounds through the hydro-heteroaryl reaction of aryl ethylene and indole-3-formaldehyde imine.
The invention adopts the following technical scheme:
the method for synthesizing the alpha-alkyl substituted indole-3-formaldehyde compound comprises the following steps of reacting in an inert gas atmosphere with a catalyst, magnesium, indole-3-formaldehyde imine, aryl ethylene and a solvent, and then acidizing to obtain the alpha-alkyl substituted indole-3-formaldehyde compound; specifically, the reaction is acidified by dilute hydrochloric acid, then extracted by ethyl acetate, and separated and purified by column chromatography to obtain the alpha-alkyl substituted indole-3-formaldehyde compound, which can be quantitatively analyzed. The catalyst is an iron (III) complex containing 1, 3-bis (2, 4, 6-trimethylphenyl) imidazole cations.
Use of an iron (III) complex containing 1, 3-bis (2, 4, 6-trimethylphenyl) imidazole cations in the synthesis of alpha-alkyl-substituted indole-3-carbaldehydes.
In the present invention, the iron (III) complex containing 1, 3-bis (2, 4, 6-trimethylphenyl) imidazole cation is [ HIMes ]][FeBr 4 ]The chemical structural formula is as follows:
in the present invention, the indole-3-carbaldehyde imine is represented by the following chemical structural formula:
R 1 is one of hydrogen, methyl, methoxy and fluorine; r is R 2 Is methyl or benzyl.
In the present invention, the arylethylene is represented by the following chemical structural formula:
ar is aryl, substituted aryl or heterocyclic aryl; preferably, the aryl ethylene comprises styrene, o-methoxystyrene, m-methoxystyrene, p-methylstyrene, p-trifluoromethylstyrene, p-trimethylsilylstyrene, p-diphenylamino styrene, p-morpholino styrene, 2-vinylnaphthalene, 2-vinylpyridine or 2-vinylbenzofuran.
In the invention, the alpha-alkyl substituted indole-3-formaldehyde compound is expressed by the following chemical structural formula:
wherein the substituent is derived from indole-3-carbaldehyde imine and aryl ethylene.
In the technical scheme, the reaction temperature is 25-80 ℃ and the reaction time is 16-48 hours.
In the above technical scheme, the inert gas is argon or nitrogen; the solvent is tetrahydrofuran, 2-methyltetrahydrofuran, and the like.
In the technical scheme, the mol ratio of the catalyst to the magnesium to the indole-3-formaldehyde imine to the aryl ethylene is 0.03-0.08:0.8-1:1:1.2-1.6. In the preferred technical scheme, the dosage of the aryl ethylene is 1.5 times of that of the indole compound, the dosage of the magnesium is 1 time of that of the indole compound, and the dosage of the catalyst is 5% of that of the indole compound in terms of mass; the temperature of the reaction was 40℃and the time of the reaction was 24 hours.
The reaction process for preparing the alpha-alkyl substituted indole-3-formaldehyde compound can be expressed as follows:
due to the application of the technical scheme, the invention has the following advantages:
1. in the presence of magnesium scraps, the invention takes the iron (III) complex containing 1, 3-bis (2, 4, 6-trimethylphenyl) imidazole cations as a catalyst, realizes the hydrogen heteroaryl reaction of aryl ethylene and indole-3-formaldehyde imine, and provides a novel method for synthesizing alpha-alkyl substituted indole-3-formaldehyde compounds.
2. The preparation method disclosed by the invention is mild in condition, does not need to use sensitive and flammable Grignard reagent and excessive additives, has good substrate applicability, and is suitable for the aryl ethylene containing electron-donating substituents and the aryl ethylene and heterocyclic olefin containing electron-withdrawing substituents.
Detailed Description
The raw materials of the invention are commercial products, the specific operation method and the testing method are conventional methods in the field, and the yield is separation yield (except the table).
The invention is further described below with reference to examples:
embodiment one: containing 1, 3-bis (2, 4, 6-trimethylphenyl) imidazole cation (formula [ HIMes ]][FeBr 4 ]），（[HIMes]Iron (III) complexes of 1, 3-bis (2, 4, 6-trimethylphenyl) imidazole cation).
1, 3-bis (2, 4, 6-trimethylphenyl) imidazole bromide (0.38 g, 1.0 mmol) was added to a solution of ferric bromide (0.27 g, 0.9 mmol) in tetrahydrofuran, 60 oC The reaction is carried out for 24 hours under the condition of vacuum pumping, solvent removal, hexane washing, pumping, extraction with tetrahydrofuran, centrifugal clear liquid transfer, hexane recrystallization is added into the clear liquid, and reddish brown solid powder is separated out at room temperature, and the yield is 85 percent. The chemical structural formula is as follows:
elemental analysis of the product was performed and the results are shown below:
elemental analysis
Since the iron complex is paramagnetic, it is not characterized by nuclear magnetism.
Complexes [ HIMes ]][FeBr 4 ]In the form of ion pairs, wherein the anions [ FeBr ] 4 ] - Characterization by raman spectroscopy found at 204 cm -1 There are characteristic peaks, which are in agreement with literature reports (Melissa, s.s.; eric, r.s.; eric, v.p.; freeman, r.g., Inorg. Chem., 2001, 40, 2298). Cationic part of the Complex [ HIMes] + Characterization by mass spectrometry revealed a molecular ion peak at 305.2011, which was theoretically 305.2012, found to be consistent with theory. The obtained compound was confirmed to be the target compound.
Example two [ HIMes][FeBr 4 ]As a catalyst, catalyzing the hydro-heteroarylation reaction of N-benzyl indole-3-formaldehyde imine and styrene
Under the protection of argon, a reaction flask was sequentially charged with catalyst (16.9 mg, 0.025 mmol, 5 mol%), magnesium turnings (12.0 mg, 0.5 mmol), N-benzylindole-3-carbaldehyde imine (169.6 mg, 0.5 mmol), styrene (86. Mu.l, 0.75 mmol), tetrahydrofuran (1.5 ml) as a solvent, and the mixture was stirred under a vacuum o The reaction is carried out for 24 hours under the condition of C, water quenching reaction is carried out, dilute hydrochloric acid (2 mol/L, 1.5 ml) is added for acidification, the reaction product is extracted by ethyl acetate, and the reaction product is separated and purified by column chromatography (the mixed solvent of ethyl acetate and petroleum ether with the volume ratio of 1:5 is taken as developing agent), so that the yield is 93 percent.
The product was dissolved in CDCl 3 Middle (about 0.4. 0.4 mL), tube sealingCharacterization was determined on a Unity Inova-400 NMR instrument at room temperature: 1 H NMR (400 MHz, CDCl 3 ) δ 10.23 (s, 1H), 8.42 (d, J = 7.6 Hz, 1H), 7.31 – 7.21 (m, 10H), 7.14 (d, J = 8.1 Hz, 1H), 6.95 – 6.86 (m, 2H), 5.22 (s, 2H), 5.05 (q, J = 7.3, 6.8 Hz, 1H), 1.74 (d, J = 7.3 Hz, 3H)。
the styrene andNthe reaction of benzylindole-3-carbaldehyde imine was varied in one factor and the results were as follows.
a Reaction conditions:Nbenzylindole-3-carbaldehyde imine (0.5 mmol), styrene (0.75 mmol), iron catalyst (5 mol%), additives (0.5 mmol), tetrahydrofuran (1.5 mL), 24 h, yield of product determined by gas phase with n-dodecane as internal standard. b The yield was isolated.
[HItBu][FeBr 4 ]The chemical structural formula is as follows:
example three [ HIMes][FeBr 4 ]As a catalyst, catalyzing the hydro-heteroaryl reaction of N-benzyl indole-3-formaldehyde imine and o-methoxy styrene
Under the protection of argon, a reaction flask was sequentially charged with a catalyst (16.9 mg, 0.025 mmol, 5 mol%), magnesium turnings (12.0 mg, 0.5 mmol), N-benzylindole-3-carbaldehyde imine (169.6 mg, 0.5 mmol), o-methoxystyrene (100. Mu.l, 0.75 mmol), tetrahydrofuran (1.5 ml) as a solvent, and the mixture was stirred at 25 o The mixture was reacted at C for 48 hours, quenched with water, acidified with dilute hydrochloric acid (2 mol/L, 1.5 ml) and the reaction product was acidified with ethyl acetateExtraction and purification by column chromatography (using a mixed solvent of ethyl acetate and petroleum ether with the volume ratio of 1:5 as developing agent) are carried out, and the yield is 96%.
The product was dissolved in CDCl 3 (about 0.4. 0.4 mL), tube sealed, characterization measured on a Unity Inova-400 NMR instrument at room temperature: 1 H NMR (400 MHz, CDCl 3 ) δ 10.21 (s, 1H), 8.44 (d, J = 7.7 Hz, 1H), 7.42 (d, J = 7.5 Hz, 1H), 7.28 (d, J = 3.7 Hz, 2H), 7.24 (d, J = 4.6 Hz, 3H), 7.02 – 6.97 (m, 3H), 6.76 (d, J = 8.2 Hz, 1H), 5.48 (s, 2H), 4.93 (q, J = 7.4 Hz, 1H), 3.61 (s, 3H), 1.66 (d, J = 7.4 Hz, 3H)。
example four [ HIMes][FeBr 4 ]As a catalyst, catalyzing the hydro-heteroaryl reaction of N-benzyl indole-3-formaldehyde imine and m-methoxy styrene
Under the protection of argon, a reaction flask was sequentially charged with a catalyst (16.9 mg, 0.025 mmol, 5 mol%), magnesium turnings (12.0 mg, 0.5 mmol), N-benzylindole-3-carbaldehyde imine (169.6 mg, 0.5 mmol), m-methoxystyrene (100. Mu.l, 0.75 mmol), tetrahydrofuran (1.5 ml) as a solvent, and the mixture was stirred at 25 o The reaction is carried out for 48 hours under the condition of C, water quenching reaction is carried out, diluted hydrochloric acid (2 mol/L, 1.5 ml) is added for acidification, the reaction product is extracted by ethyl acetate, and the reaction product is separated and purified by column chromatography (the mixed solvent of ethyl acetate and petroleum ether with the volume ratio of 1:5 is taken as developing agent), so that the yield is 92 percent.
The product was dissolved in CDCl 3 (about 0.4. 0.4 mL), tube sealed, characterization measured on a Unity Inova-400 NMR instrument at room temperature: 1 H NMR (400 MHz, CDCl 3 ) δ 10.23 (s, 1H), 8.42 (d, J = 7.8 Hz, 1H), 7.31 (t, J = 7.8 Hz, 1H), 7.26 – 7.13 (m, 6H), 6.93 – 6.89 (m, 2H), 6.80 (d, J = 7.8 Hz, 1H), 6.77 – 6.72 (m, 2H), 5.24 (s, 2H), 5.02 (q, J = 7.4 Hz, 1H), 3.72 (s, 3H), 1.73 (d, J = 7.4 Hz, 3H)。
example five [ HIMes][FeBr 4 ]As a catalyst, catalyzing the hydro-heteroaryl reaction of N-benzyl indole-3-formaldehyde imine and p-methoxy styrene
Under the protection of argon, adding the catalyst into the reaction bottle in sequenceAgent (16.9 mg, 0.025 mmol, 5 mol%), magnesium turnings (12.0 mg, 0.5 mmol), N-benzylindole-3-carbaldehyde imine (169.6 mg, 0.5 mmol), p-methoxystyrene (104. Mu.l, 0.75 mmol), tetrahydrofuran (1.5 ml) as solvent, at 40 o The reaction is carried out for 24 hours under the condition of C, water quenching reaction is carried out, diluted hydrochloric acid (2 mol/L, 1.5 ml) is added for acidification, the reaction product is extracted by ethyl acetate, and the reaction product is separated and purified by column chromatography (the mixed solvent of ethyl acetate and petroleum ether with the volume ratio of 1:5 is taken as developing agent), so that the yield is 92 percent.
The product was dissolved in CDCl 3 (about 0.4. 0.4 mL), tube sealed, characterization measured on a Unity Inova-400 NMR instrument at room temperature: 1 H NMR (400 MHz, CDCl 3 ) δ 10.23 (s, 1H), 8.44 (d, J = 7.8 Hz, 1H), 7.31 (t, J = 7.5 Hz, 1H), 7.27 – 7.25 (m, 3H), 7.24 – 7.21 (m, 1H), 7.14 (dd, J = 12.3, 8.3 Hz, 3H), 6.94 – 6.90 (m, 2H), 6.81 (d, J = 8.8 Hz, 2H), 5.24 (s, 2H), 5.00 (q, J = 7.4 Hz, 1H), 3.77 (s, 3H), 1.72 (d, J = 7.4 Hz, 3H)。
EXAMPLE six HIMes][FeBr 4 ]As a catalyst, catalyzing the hydro-heteroaryl reaction of N-benzyl indole-3-formaldehyde imine and p-methyl styrene
Under the protection of argon, a reaction flask was sequentially charged with catalyst (16.9 mg, 0.025 mmol, 5 mol%), magnesium turnings (12.0 mg, 0.5 mmol), N-benzylindole-3-carbaldehyde imine (169.6 mg, 0.5 mmol), p-methylstyrene (99. Mu.l, 0.75 mmol), tetrahydrofuran (1.5 ml) as a solvent, and the mixture was stirred under a vacuum o The reaction is carried out for 16 hours under the condition of C, water quenching reaction is carried out, diluted hydrochloric acid (2 mol/L, 1.5 ml) is added for acidification, the reaction product is extracted by ethyl acetate, and the reaction product is separated and purified by column chromatography (the mixed solvent of ethyl acetate and petroleum ether with the volume ratio of 1:5 is taken as developing agent), so that the yield is 95 percent.
The product was dissolved in CDCl 3 (about 0.4. 0.4 mL), tube sealed, characterization measured on a Unity Inova-400 NMR instrument at room temperature: 1 H NMR (400 MHz, CDCl 3 ) δ 10.26 (s, 1H), 8.52 – 8.46 (m, 1H), 7.33 (t, J = 7.5 Hz, 1H), 7.27 (dt, J = 5.6, 2.6 Hz, 3H), 7.23 (d, J = 8.3 Hz, 1H), 7.17 (d, J = 8.2 Hz, 1H), 7.12 (s, 4H), 6.97 – 6.92 (m, 2H), 5.26 (s, 2H), 5.03 (q, J = 7.4 Hz, 1H), 2.33 (s, 3H), 1.75 (d, J = 7.4 Hz, 3H)。
example seven HIMes][FeBr 4 ]As a catalyst, catalyzing the hydrogen heteroaryl reaction of N-benzyl indole-3-formaldehyde imine and p-trifluoromethyl styrene
Under the protection of argon, a reaction flask was sequentially charged with catalyst (16.9 mg, 0.025 mmol, 5 mol%), magnesium turnings (12.0 mg, 0.5 mmol), N-benzylindole-3-carbaldehyde imine (169.6 mg, 0.5 mmol), p-trifluoromethylstyrene (111. Mu.l, 0.75 mmol), tetrahydrofuran (1.5 ml) as a solvent, and the mixture was stirred under vacuum with water to give a mixture of o The reaction is carried out for 24 hours under the condition of C, water quenching reaction is carried out, diluted hydrochloric acid (2 mol/L, 1.5 ml) is added for acidification, the reaction product is extracted by ethyl acetate, and the reaction product is separated and purified by column chromatography (the mixed solvent of ethyl acetate and petroleum ether with the volume ratio of 1:5 is taken as developing agent), and the yield is 68 percent.
The product was dissolved in CDCl 3 (about 0.4. 0.4 mL), tube sealed, characterization measured on a Unity Inova-400 NMR instrument at room temperature: 1 H NMR (400 MHz, CDCl 3 ) δ 10.23 (s, 1H), 8.41 (d, J = 7.8 Hz, 1H), 7.50 (d, J = 8.2 Hz, 2H), 7.32 (t, J = 8.5 Hz, 3H), 7.27 – 7.23 (m, 4H), 7.20 (d, J = 8.2 Hz, 1H), 6.89 – 6.84 (m, 2H), 5.24 (s, 2H), 5.13 (d, J = 7.4 Hz, 1H), 1.79 (d, J = 7.3 Hz, 3H).
EXAMPLE eight HIMes][FeBr 4 ]As a catalyst, catalyzing the hydrogen heteroaryl reaction of N-benzyl indole-3-formaldehyde imine and p-trimethylsilyl styrene
Under the protection of argon, a reaction flask was sequentially charged with a catalyst (16.9 mg, 0.025 mmol, 5 mol%), magnesium turnings (12.0 mg, 0.5 mmol), N-benzylindole-3-carbaldehyde imine (169.6 mg, 0.5 mmol), trimethylsilylstyrene (154. Mu.l, 0.75 mmol), tetrahydrofuran (1.5 ml) as a solvent, and the mixture was stirred under a vacuum o The mixture was reacted at C for 24 hours, quenched with water, acidified with dilute hydrochloric acid (2 mol/L, 1.5 ml), and the reaction product was extracted with ethyl acetateThe product was purified by column chromatography (using a mixed solvent of ethyl acetate/petroleum ether in a volume ratio of 1:5 as a developing solvent) in 92% yield.
The product was dissolved in CDCl 3 (about 0.4. 0.4 mL), tube sealed, characterization measured on a Unity Inova-400 NMR instrument at room temperature: 1 H NMR (400 MHz, CDCl 3 ) δ 10.26 (s, 1H), 8.47 (d, J = 7.9 Hz, 1H), 7.45 (d, J = 7.7 Hz, 2H), 7.34 (t, J = 7.5 Hz, 1H), 7.27 – 7.22 (m, 6H), 7.18 (d, J = 8.1 Hz, 1H), 6.95 – 6.91 (m, 2H), 5.29 (s, 2H), 5.05 (q, J = 7.4 Hz, 1H), 1.78 (d, J = 7.4 Hz, 3H), 0.28 (s, 9H)。
EXAMPLE nine HIMes][FeBr 4 ]As a catalyst, catalyzing the hydrogen heteroaryl reaction of N-benzyl indole-3-formaldehyde imine and p-diphenyl aminostyrene
Under the protection of argon, a reaction flask was sequentially charged with a catalyst (16.9 mg, 0.025 mmol, 5 mol%), magnesium turnings (12.0 mg, 0.5 mmol), N-benzylindole-3-carbaldehyde imine (169.6 mg, 0.5 mmol), p-benzidine (271.0 mg, 0.75 mmol), tetrahydrofuran (1.5 ml) as a solvent, and the mixture was stirred under a vacuum atmosphere to give a mixture of o The reaction is carried out for 24 hours under the condition of C, water quenching reaction is carried out, diluted hydrochloric acid (2 mol/L, 1.5 ml) is added for acidification, the reaction product is extracted by ethyl acetate, and the reaction product is separated and purified by column chromatography (the mixed solvent of ethyl acetate and petroleum ether with the volume ratio of 1:5 is taken as developing agent), so that the yield is 93 percent.
The product was dissolved in CDCl 3 (about 0.4. 0.4 mL), tube sealed, characterization measured on a Unity Inova-400 NMR instrument at room temperature: 1 H NMR (400 MHz, CDCl 3 ) δ 10.46 (s, 1H), 8.63 (d, J = 7.8 Hz, 1H), 7.48 (d, J = 7.7 Hz, 1H), 7.44 (dt, J = 5.9, 3.2 Hz, 4H), 7.39 (d, J = 7.3 Hz, 3H), 7.32 – 7.26 (m, 3H), 7.23 – 7.14 (m, 9H), 7.12 – 7.09 (m, 2H), 5.57 – 5.45 (m, 2H), 5.19 (q, J = 7.3 Hz, 1H), 1.93 (d, J = 7.3 Hz, 3H)。
example ten HIMes][FeBr 4 ]As a catalyst, catalyzing the hydrogen heteroaryl reaction of N-benzyl indole-3-formaldehyde imine and para-morpholinyl styrene
Under the protection of argon, under the reactionThe flask was charged with catalyst (16.9 mg, 0.025 mmol, 5 mol%), magnesium turnings (12.0 mg, 0.5 mmol), N-benzylindole-3-carbaldehyde imine (169.6 mg, 0.5 mmol), p-morpholinylstyrene (142.0 mg, 0.75 mmol), tetrahydrofuran (1.5 ml) as solvent in sequence at 40 o The reaction is carried out for 24 hours under the condition of C, water quenching reaction is carried out, diluted hydrochloric acid (2 mol/L, 1.5 ml) is added for acidification, the reaction product is extracted by ethyl acetate, and the reaction product is separated and purified by column chromatography (the mixed solvent of ethyl acetate and petroleum ether with the volume ratio of 1:5 is taken as developing agent), so that the yield is 92 percent.
The product was dissolved in CDCl 3 (about 0.4. 0.4 mL), tube sealed, characterization measured on a Unity Inova-400 NMR instrument at room temperature: 1 H NMR (400 MHz, CDCl 3 ) δ 10.24 (s, 1H), 8.45 (d, J = 7.8 Hz, 1H), 7.34 – 7.25 (m, 4H), 7.22 (d, J = 7.2 Hz, 1H), 7.13 (dd, J = 15.1, 8.4 Hz, 3H), 6.92 (d, J = 5.0 Hz, 2H), 6.82 (d, J = 8.4 Hz, 2H), 5.25 (s, 2H), 4.98 (q, J = 7.3 Hz, 1H), 3.86 (s, 4H), 3.12 (s, 4H), 1.72 (d, J = 7.3 Hz, 3H).
example eleven [ HIMes][FeBr 4 ]As a catalyst, catalyzing the hydro-heteroarylation reaction of N-benzyl indole-3-formaldehyde imine and 2-vinyl naphthalene
Under the protection of argon, a reaction flask was sequentially charged with a catalyst (16.9 mg, 0.025 mmol, 5 mol%), magnesium turnings (12.0 mg, 0.5 mmol), N-benzylindole-3-carbaldehyde imine (169.6 mg, 0.5 mmol), 2-vinylnaphthalene (154 mg, 0.75 mmol), tetrahydrofuran (1.5 ml) as a solvent, and the mixture was stirred under a vacuum o The reaction is carried out for 24 hours under the condition of C, water quenching reaction is carried out, diluted hydrochloric acid (2 mol/L, 1.5 ml) is added for acidification, the reaction product is extracted by ethyl acetate, and the reaction product is separated and purified by column chromatography (the mixed solvent of ethyl acetate and petroleum ether with the volume ratio of 1:5 is taken as developing agent), so that the yield is 88 percent.
The product was dissolved in CDCl 3 (about 0.4. 0.4 mL), tube sealed, characterization measured on a Unity Inova-400 NMR instrument at room temperature: 1 H NMR (400 MHz, CDCl 3 ) δ 10.30 (s, 1H), 8.47 (d, J = 7.9 Hz, 1H), 7.90 – 7.72 (m, 5H), 7.50 (dd, J = 6.7, 3.1 Hz, 2H), 7.36 (s, 1H), 7.28 – 7.23 (m, 4H), 7.19 (s, 1H), 6.92 (d, J = 7.8 Hz, 2H), 5.26 (d, J = 7.9 Hz, 3H), 1.89 (s, 3H)。
example twelve [ HIMes][FeBr 4 ]As a catalyst for catalyzing the hydro-heteroarylation reaction of N-benzylindole-3-carbaldehyde imine and 2-vinylpyridine
Under the protection of argon, a reaction flask was sequentially charged with a catalyst (16.9 mg, 0.025 mmol, 5 mol%), magnesium turnings (12.0 mg, 0.5 mmol), N-benzylindole-3-carbaldehyde imine (169.6 mg, 0.5 mmol), 2-vinylpyridine (81. Mu.l, 0.75 mmol), tetrahydrofuran (1.5 ml) as a solvent, and the mixture was stirred in a solvent atmosphere of 50 o The reaction is carried out for 24 hours under the condition of C, water quenching reaction is carried out, diluted hydrochloric acid (2 mol/L, 1.5 ml) is added for acidification, the reaction product is extracted by ethyl acetate, and the reaction product is separated and purified by column chromatography (the mixed solvent of ethyl acetate and petroleum ether with the volume ratio of 1:5 is taken as developing agent), so that the yield is 72 percent.
The product was dissolved in CDCl 3 (about 0.4. 0.4 mL), tube sealed, characterization measured on a Unity Inova-400 NMR instrument at room temperature: 1 H NMR (400 MHz, CDCl 3 ) δ 10.24 (s, 1H), 8.45 (d, J = 7.9 Hz, 1H), 7.33 – 7.26 (m, 3H), 7.25 – 7.19 (m, 6H), 7.14 (d, J = 8.2 Hz, 1H), 6.91 (dd, J = 6.9, 2.4 Hz, 2H), 5.23 (s, 2H), 5.05 (q, J = 7.4 Hz, 1H), 1.75 (d, J = 7.4 Hz, 3H)。
example thirteen [ HIMes ]][FeBr 4 ]As a catalyst for catalyzing the hydro-heteroarylation of N-benzylindole-3-carbaldehyde imine and 2-vinylbenzofuran
Under the protection of argon, a reaction flask was sequentially charged with a catalyst (33.8 mg, 0.05 mmol, 10 mol%), magnesium turnings (12.0 mg, 0.5 mmol), N-benzylindole-3-carbaldehyde-imine (169.6 mg, 0.5 mmol), 2-vinylbenzofuran (102. Mu.l, 0.75 mmol), tetrahydrofuran (1.5 ml) as a solvent, and the mixture was stirred in a flask under a vacuum atmosphere of 50 o Reacting at C for 48 hours, quenching with water, adding dilute hydrochloric acid (2 mol/L, 1.5 ml) for acidification, extracting the reaction product with ethyl acetate, separating and purifying by column chromatography (the volume ratio of ethyl acetate to petroleum ether is 1:5 as developing agent), the yield was 54%.
The product was dissolved in CDCl 3 (about 0.4. 0.4 mL), tube sealed, characterization measured on a Unity Inova-400 NMR instrument at room temperature: 1 H NMR (400 MHz, CDCl 3 δ 10.31 (s, 1H), 8.41 (d, J = 7.8 Hz, 1H), 7.48 (d, J = 6.7 Hz, 1H), 7.31 (dt, J = 13.3, 6.4 Hz, 3H), 7.24 – 7.18 (m, 6H), 6.96 (d, J = 6.3 Hz, 2H), 6.57 (s, 1H), 5.44 (s, 2H), 5.13 (q, J = 7.1 Hz, 1H)。
example fourteen [ HIMes][FeBr 4 ]As a catalyst for catalyzing the hydro-heteroarylation reaction of N-methylindole-3-formaldehyde imine and styrene
Under the protection of argon, a reaction flask was sequentially charged with catalyst (16.9 mg, 0.025 mmol, 5 mol%), magnesium turnings (12.0 mg, 0.5 mmol), N-methylindole-3-carboxaldehyde imine (132.2 mg, 0.5 mmol), styrene (86. Mu.l, 0.75 mmol), tetrahydrofuran (1.5 ml) as a solvent, and the mixture was stirred under a vacuum o The reaction is carried out for 24 hours under the condition of C, water quenching reaction is carried out, diluted hydrochloric acid (2 mol/L, 1.5 ml) is added for acidification, the reaction product is extracted by ethyl acetate, and the reaction product is separated and purified by column chromatography (the mixed solvent of ethyl acetate and petroleum ether with the volume ratio of 1:5 is taken as developing agent), so that the yield is 90 percent.
The product was dissolved in CDCl 3 (about 0.4. 0.4 mL), tube sealed, characterization measured on a Unity Inova-400 NMR instrument at room temperature: 1 H NMR (400 MHz, CDCl 3 ) δ 10.26 (s, 1H), 8.42 – 8.37 (m, 1H), 7.34 – 7.23 (m, 8H), 5.20 (q, J = 7.4 Hz, 1H), 3.44 (s, 3H), 1.87 (d, J = 7.4 Hz, 3H)。
EXAMPLE fifteen HIMes][FeBr 4 ]As a catalyst, catalyzing the hydrogen heteroaryl reaction of N-benzyl-5-methoxyindole-3-formaldehyde imine and styrene
Under the protection of argon, a reaction flask was sequentially charged with catalyst (16.9 mg, 0.025 mmol, 5 mol%), magnesium turnings (12.0 mg, 0.5 mmol), N-methyl-5-methoxyindole-3-carbaldehyde imine (185.1 mg, 0.5 mmol), styrene (86. Mu.l, 0.75 mmol), tetrahydrofuran (1.5 ml) as a solvent, and the mixture was stirred at 40 o The reaction is carried out for 24 hours under the condition of C, water quenching reaction is carried out, diluted hydrochloric acid (2 mol/L, 1.5 ml) is added for acidification, the reaction product is extracted by ethyl acetate, and the reaction product is separated and purified by column chromatography (the mixed solvent of ethyl acetate and petroleum ether with the volume ratio of 1:5 is taken as developing agent), so that the yield is 91 percent.
The product was dissolved in CDCl 3 (about 0.4. 0.4 mL), tube sealed, characterization measured on a Unity Inova-400 NMR instrument at room temperature: 1 H NMR (400 MHz, CDCl 3 ) δ 10.18 (s, 1H), 7.97 (d, J = 2.5 Hz, 1H), 7.31 – 7.26 (m, 5H), 7.22 (d, J = 7.6 Hz, 3H), 7.04 (d, J = 8.9 Hz, 1H), 6.94 – 6.90 (m, 2H), 6.86 (dd, J = 8.9, 2.6 Hz, 1H), 5.21 (s, 2H), 4.98 (q, J = 7.4 Hz, 1H), 3.91 (s, 3H), 1.75 (d, J = 7.4 Hz, 3H)。
example sixteen [ HIMes][FeBr 4 ]As a catalyst for catalyzing the hydro-heteroarylation reaction of N-benzyl-5-fluoro-indole-3-carbaldehyde imine and styrene
Under the protection of argon, a reaction flask was sequentially charged with catalyst (16.9 mg, 0.025 mmol, 5 mol%), magnesium turnings (12.0 mg, 0.5 mmol), N-methyl-5-fluoro-indole-3-carbaldehyde imine (179.1 mg, 0.5 mmol), styrene (86. Mu.l, 0.75 mmol), tetrahydrofuran (1.5 ml) as a solvent, and the mixture was stirred at 40 o The reaction is carried out for 24 hours under the condition of C, water quenching reaction is carried out, diluted hydrochloric acid (2 mol/L, 1.5 ml) is added for acidification, the reaction product is extracted by ethyl acetate, and the reaction product is separated and purified by column chromatography (the mixed solvent of ethyl acetate and petroleum ether with the volume ratio of 1:5 is taken as developing agent), so that the yield is 87%.
The product was dissolved in CDCl 3 (about 0.4. 0.4 mL), tube sealed, characterization measured on a Unity Inova-400 NMR instrument at room temperature: 1 H NMR (400 MHz, CDCl 3 ) δ 10.17 (s, 1H), 8.10 (dd, J = 9.4, 2.6 Hz, 1H), 7.28 (d, J = 7.5 Hz, 5H), 7.25 – 7.19 (m, 3H), 7.07 – 7.03 (m, 1H), 6.95 (td, J = 9.0, 2.6 Hz, 1H), 6.91 – 6.87 (m, 2H), 5.21 (d, J = 1.3 Hz, 2H), 5.00 (q, J = 7.4 Hz, 1H), 1.75 (d, J = 7.4 Hz, 3H)。
example seventeen [ HIMes][FeBr 4 ]As a catalyst, N-benzyl-6-chloro-indole is catalyzedHydrogen heteroarylation of 3-formylimine with styrene
Under the protection of argon, a reaction flask was sequentially charged with catalyst (16.9 mg, 0.025 mmol, 5 mol%), magnesium turnings (12.0 mg, 0.5 mmol), N-methyl-6-chloro-indole-3-carbaldehyde imine (187.1 mg, 0.5 mmol), styrene (86. Mu.l, 0.75 mmol), tetrahydrofuran (1.5 ml) as a solvent, and the mixture was stirred at a temperature of 50 o The reaction is carried out for 24 hours under the condition of C, water quenching reaction is carried out, diluted hydrochloric acid (2 mol/L, 1.5 ml) is added for acidification, the reaction product is extracted by ethyl acetate, and the reaction product is separated and purified by column chromatography (the mixed solvent of ethyl acetate and petroleum ether with the volume ratio of 1:5 is taken as developing agent), so that the yield is 80 percent.
The product was dissolved in CDCl 3 (about 0.4. 0.4 mL), tube sealed, characterization measured on a Unity Inova-400 NMR instrument at room temperature: 1 H NMR (400 MHz, CDCl 3 ) δ 10.18 (s, 1H), 8.34 (d, J = 8.4 Hz, 1H), 7.31 – 7.27 (m, 5H), 7.21 (dd, J = 16.9, 7.5 Hz, 4H), 7.14 (d, J = 1.7 Hz, 1H), 6.89 (dd, J = 7.2, 2.4 Hz, 2H), 5.20 – 5.17 (m, 2H), 4.98 (q, J = 7.4 Hz, 1H), 1.74 (d, J = 7.4 Hz, 3H)。
example eighteen [ HIMes][FeBr 4 ]As a catalyst for catalyzing the hydro-heteroarylation reaction of N-benzyl-7-methylindole-3-formaldehyde imine and styrene
Under the protection of argon, a reaction flask was sequentially charged with catalyst (16.9 mg, 0.025 mmol, 5 mol%), magnesium turnings (12.0 mg, 0.5 mmol), N-benzyl-7-methylindole-3-carboxaldehyde imine (177.1 mg, 0.5 mmol), styrene (86. Mu.l, 0.75 mmol), tetrahydrofuran (1.5 ml) as a solvent, and the mixture was stirred at 80 o The reaction is carried out for 16 hours under the condition of C, water quenching reaction is carried out, diluted hydrochloric acid (2 mol/L, 1.5 ml) is added for acidification, the reaction product is extracted by ethyl acetate, and the reaction product is separated and purified by column chromatography (the mixed solvent of ethyl acetate and petroleum ether with the volume ratio of 1:5 is taken as developing agent), so that the yield is 86 percent.
The product was dissolved in CDCl 3 (about 0.4. 0.4 mL), tube sealed, characterization measured on a Unity Inova-400 NMR instrument at room temperature: 1 H NMR (400 MHz, CDCl 3 ) δ 10.21 (s, 1H), 8.36 (d, J = 7.9 Hz, 1H), 7.31 – 7.26 (m, 5H), 7.20 (t, J = 7.6 Hz, 4H), 6.98 (d, J = 7.2 Hz, 1H), 6.85 (d, J = 6.1 Hz, 2H), 5.48 (d, J = 5.7 Hz, 2H), 4 .97 (q, J = 7.4 Hz, 1H), 2.44 (s, 3H), 1.69 (d, J = 7.3 Hz, 3H)。
the prior art has limited the functional group tolerance and potential application value of the iron-based catalyst-catalyzed hydroheteroarylation of aryl ethylene and indole-3-carbaldehyde imine, which requires the use of a sensitive and flammable grignard reagent and an excess of TMEDA. Therefore, in the presence of magnesium scraps, the method takes the iron (III) complex as a catalyst, and constructs the alpha-alkyl substituted indole-3-formaldehyde compound through the hydrogen heteroaryl reaction of aryl ethylene and indole-3-formaldehyde imine under mild conditions, so that the method has obvious innovation, safety and better potential application value.
Claims (3)
1. The method for synthesizing the alpha-alkyl substituted indole-3-formaldehyde compound is characterized by comprising the following steps of mixing a catalyst, magnesium, indole-3-formaldehyde imine, aryl ethylene and a solvent in an inert gas atmosphere, reacting, and acidifying by hydrochloric acid to obtain the alpha-alkyl substituted indole-3-formaldehyde compound; the catalyst is [ HIMes ]][FeBr 4 ]，[HIMes]Is a 1, 3-bis (2, 4, 6-trimethylphenyl) imidazole cation; the indole-3-carbaldehyde imine is represented by the following chemical structural formula:
R 1 is one of hydrogen, methyl, methoxy and fluorine; r is R 2 Methyl or benzyl;
the aryl ethylene is represented by the following chemical structural formula:
the aryl ethylene is styrene, o-methoxy styrene, m-methoxy styrene, p-methyl styrene, p-trifluoromethyl styrene, p-trimethylsilyl styrene, p-diphenylamino styrene, p-morpholino styrene, 2-vinyl naphthalene, 2-vinyl pyridine or 2-vinyl benzofuran;
the alpha-alkyl substituted indole-3-carbaldehyde compound is expressed by the following chemical structural formula:
wherein the substituent is derived from indole-3-carbaldehyde imine and aryl ethylene.
2. The method for synthesizing an alpha-alkyl substituted indole-3-carbaldehyde compound as claimed in claim 1, wherein the reaction temperature is 25-80 ℃ and the reaction time is 16-48 hours.
3. The method for synthesizing alpha-alkyl substituted indole-3-carbaldehyde compounds as claimed in claim 1, characterized in that the molar ratio of catalyst, magnesium, indole-3-carbaldehyde imine and aryl ethylene is 0.03-0.08:0.8-1:1:1.2-1.6.
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