N-arylation method taking substituted adipic dihydrazide as ligand in aqueous phase system

A dihydrazide and arylation technology, applied in the field of chemistry, can solve the problems of inability to popularize and use, cost defects, and high ligand dosage, and achieve the effects of wide application range of substrates, improved environmental friendliness, and broad application prospects.

Active Publication Date: 2010-04-07
SHOUGUANG SYNTECH FINE CHEM
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  • Abstract
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Problems solved by technology

However, the above-mentioned reactions can only be carried out for specific compounds, so they cannot be widely used.
While Buchwald et al. reported Pd-catalyzed C-N bond formation in aqueous solution (Huang, X.; Anderson, K.W.; Zim, D.; Jiang, L.; Klapars, A.; Buchwald, S.L.J. Am. Chem. Soc. 2003, 125, 6653) is defective due to the cost of the catalytic system
The applicant once proposed patent applications 200610033067 and 200710026860, which overcome the shortcomings of the previous C-N coupling reaction method to a certain extent, but also have the disadvantage of excessive ligand usage

Method used

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  • N-arylation method taking substituted adipic dihydrazide as ligand in aqueous phase system
  • N-arylation method taking substituted adipic dihydrazide as ligand in aqueous phase system
  • N-arylation method taking substituted adipic dihydrazide as ligand in aqueous phase system

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] Embodiment 1: the synthesis of N-p-methoxyphenylaniline

[0027]

[0028] 2mg (0.025mmol) CuO, 48mg (0.125mmol) ligand, 96mg (0.5mmol) p-methoxybromobenzene, 279mg (2.0mmol) aniline, 0.28mg (0.5mmol) KOH, 32mg (0.1mmol) TBAB, 5.0ml H 2 O was added to a 50ml round bottom flask, and the reaction was stirred at room temperature for 96h. After the reaction stopped, it was extracted with ethyl acetate, washed with water, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure, and the obtained reaction mixture was separated and purified by silica gel column chromatography [eluent: petroleum ether / ethyl acetate (20:1)] to obtain 83 mg of N-p-methoxyphenylaniline, with a yield of 83%.

[0029] N-p-methoxyphenylaniline: 1 H NMR (300MHz, CDCl 3 )δ: 7.26-7.19 (m, 2H), 7.10 (d, J=8.7, 2H), 6.93-6.81 (m, 5H), 5.62 (br s, 1H), 3.81 (s, 3H); MS (ESI , m / z): 200[M+H] +

[0030] Ligand:1 H NMR (30...

Embodiment 2

[0031] Embodiment 2: the synthesis of N-phenylbenzylamine

[0032]

[0033] 1.1mg (0.0125mmol) CuCl, 48mg (0.125mmol) ligand, 96mg (0.5mmol) p-methoxybromobenzene, 214mg (2.0mmol) benzylamine, 0.56mg (1mmol) KOH, 32mg (0.1mmol) TBAB , 2mlH 2 O, 78mg (0.5mmol) of bromobenzene was added to a 50ml round bottom flask, and the reaction was stirred at room temperature for 24h. After the reaction stopped, it was extracted with ethyl acetate, washed with water, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure, and the obtained reaction mixture was separated and purified by silica gel column chromatography [eluent: petroleum ether / ethyl acetate (20:1)] to obtain 46 mg of N-phenylbenzylamine with a yield of 50%.

[0034] N-Phenylbenzylamine: 1 H NMR (300MHz, CDCl 3 )δ: 7.42-7.41 (m, 7H), 6.81-6.68 (m, 3H), 4.38 (s, 2H), 4.07 (br s, 1H). MS (ESI, m / z): 184 [M+H ] +

[0035] Ligand: 1 H NMR (...

Embodiment 3

[0036] Embodiment 3: the synthesis of N-paraacetylphenylbenzylamine

[0037]

[0038] 47.5mg (0.25mmol) CuI, 104mg (0.25mmol) ligand, 0.1mg (0.5mmol) p-acetyl bromide, 214mg (2.0mmol) benzylamine, 212mg (1.0mmol) K 3 PO 4 , 94mg (0.25mmol) tetraphenyl phosphorus chloride, 5.0ml H 2 O was added to a 50ml round bottom flask, and the reaction was stirred at 90°C for 24h. After the reaction stopped, it was extracted with ethyl acetate, washed with water, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure, and the obtained reaction mixture was separated and purified by silica gel column chromatography [eluent: petroleum ether / ethyl acetate (10:1)] to obtain 56 mg of N-p-acetylphenylaniline, with a yield of 50%.

[0039] N-P-Acetaminophen: 1 H NMR (400MHz, CDCl 3 )δ: 7.83 (d, J=8.8, 2H), 7.36-7.30 (m, 5H), 6.61-6.59 (d, J=8.8, 2H), 4.41 (s, 2H), 2.49 (s, 3H). ESI-MS: m / z=226[M+H] +

[004...

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Abstract

The invention provides an N-arylation method in an aqueous phase system, which is simple and convenient and environmentally friendly, and has mild reaction condition and economic process. The method comprises the following steps: taking aryl halide and amine as raw materials, and water as solvent, metallic copper, or oxide of copper, or cuprous salt or cupric salt as catalytic agent, and using adipic dihydrazide compound as a ligand to generate C-N coupling reaction; the reaction steps are as follows: adding catalyst, ligand, aryl halide, amine, alkali, surface active agent and water into a microwave reactor or a reaction vessel; reacting by stirring by adopting the mode of microwave assistant heating, or common heating bath heating or direct room temperature reaction; separating and purifying the reaction mixed liquor after the reaction is completed to obtain the N-arylation product. The method of the invention has the characteristics of simple operation, wide substrate application range, simple products which can be separated easily, high yield, economic process and environmental friendliness and the like, and takes water as solvent, has wide application range of the substrate, and has wide application prospects in preparation aspects of natural products, drugs and pesticides.

Description

technical field [0001] The invention relates to the technical field of chemistry, in particular to an N-arylation method. technical background [0002] Arylamines are an important class of compounds that widely exist in natural and non-natural products with physiological activities. The study of C-N bond formation reactions has been widely valued. [0003] The Ullmann reaction of carbon-nitrogen cross-coupling has a long history since it was first reported in 1903 (Ley, S.V.; Thomas, A.W. Angew. Chem. Int. Ed. 2003, 42, 5400 and related citations). Since this reaction is usually carried out in a polar solvent with a high boiling point, under the condition of high temperature, catalytic amount or equivalent amount of copper powder as a catalyst, the reaction time is long, the follow-up treatment of the reaction is difficult, and the reaction product is complex and difficult. The disadvantages such as low reaction yield. In 1983, Migita et al. first discovered the Pd-catalyz...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07B43/04B01J31/22C07C217/92C07C217/84C07C213/02C07C211/48C07C211/56C07C211/52C07C209/10C07C225/22C07C221/00
Inventor 万一千朱新海孟飞汪晨霞谢建伟宋化灿
Owner SHOUGUANG SYNTECH FINE CHEM
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