Method for preparing N-(hetero) aryl compound through heterogeneous catalysis Ullmann type C-N coupling reaction

The Ullmann coupling reaction of nitrogen heterocyclic compounds and aromatic iodides was achieved in an air atmosphere using CuNPs/HKUST-1 catalyst, which solved the problems of low reaction yield and difficult catalyst recovery in the existing technology, and achieved efficient and economical N-arylation synthesis of nitrogen heterocyclic compounds. It is suitable for the synthesis of various nitrogen heterocyclic compounds and aromatic iodides.

CN120647581APending Publication Date: 2025-09-16XINJIANG UNIVERSITY
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Patent Information

Application Number
CN202510669068.7
Authority / Receiving Office
CN · China
Patent Type
Applications(China)
Current Assignee / Owner
Filing Date
2025-05-23
Publication Date
2025-09-16

AI Technical Summary

Technical Problem

Existing N-arylation modification reactions of nitrogen heterocyclic compounds have problems such as low reaction yield, harsh conditions, poor economy and difficult catalyst recovery. In particular, in Ullmann-type N-arylation reactions, the high temperature, high pressure and long reaction time of traditional catalysts limit their large-scale application.

Method used

CuNPs/HKUST-1 was used as a catalyst, potassium hydroxide as a base, and dimethyl sulfoxide as a solvent in an air atmosphere to achieve the Ullmann coupling reaction of nitrogen heterocyclic compounds with aromatic iodides. By optimizing the reaction conditions, including molar ratio, temperature, and time, the reaction efficiency and catalyst recyclability were improved.

Benefits of technology

An efficient and recyclable Ullmann-type CN coupling reaction of nitrogen heterocycles and aromatic iodides was achieved with a yield of up to 99%. The substrate has good universality and is suitable for the synthesis of a variety of nitrogen heterocycles and aromatic iodides, reducing production costs.

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Abstract

The invention discloses a method for preparing an N-(hetero) aryl compound by heterogeneous catalysis Ullmann type C-N coupling reaction, which comprises the following steps: by taking CuNPs / HKUST-1 as a catalyst, catalyzing Ullmann coupling reaction of a nitrogen heterocyclic compound and aryl iodide, adding reactants, namely the nitrogen heterocyclic compound and the (hetero) aryl iodide according to a molar ratio of 1: 1.5, taking CuNPs / HKUST-1 (10mg) as a catalyst, taking potassium hydroxide (1.5 eq. According to the method, different aryl halogenated hydrocarbons can be coupled with nitrogen heterocyclic compounds such as imidazole, indole, pyrrole, pyrazole, indazole, morpholine, piperidine and the like under the optimal conditions that dimethyl sulfoxide (DMSO, 1mL) is used as a solvent and the reaction temperature is 120 DEG C, and the corresponding arylated nitrogen heterocyclic compounds can be synthesized at the highest separation yield of 99%. In addition, the method also has the advantages of good substrate universality, gram-scale synthesis, cyclic utilization of the catalyst and the like.
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Claims

1. A method for preparing N-(hetero)aryl compounds by a heterogeneously catalyzed Ullmann-type CN coupling reaction, characterized in that: A nitrogen heterocycle (1) and a (hetero)aryl iodide (2) are used as substrates, CuNPs / HKUST-1 is used as a catalyst, and a base and solvent are added to heat to synthesize N-(hetero)aryl Ullmann-type coupling products (3 or 4); the reaction process is shown in the following reaction formula; R represents different substituents on the iodobenzene ring, specifically one or more of H, C1-C10 alkyl, C1-C4 alkoxy, trifluoromethoxy, thiomethyl, acetyl, cyano, halogen, nitro and phenyl, wherein the halogen is one or more of fluorine, chlorine, bromine and iodine. Preferably, the C2 and C4 positions are one or more of a C1-C4 alkyl group, a methoxy group, a trifluoromethoxy group, a thiomethyl group, an acetyl group, a cyano group, a halogen group, a nitro group and a phenyl group. R has a disubstituted group at the 3 and 5 positions of iodobenzene, such as one or more of H, 3,5-dimethyl, 3,5-difluoro, 3,5-dibromo and 3,5-ditrifluoromethyl. The (hetero)aryl iodide 2 can also be 2-iodopyridine, 3-iodopyridine or 2-iodonaphthalene compound, and the nitrogen heterocycle (1) is one or more of imidazole, pyrazole, indazole, indole, pyrrole, tetrahydropyrrole, morpholine and piperidine.

2. The method according to claim 1, wherein: The solvent is one or more of dimethyl sulfoxide (DMSO), ethanol (EtOH), methanol (MeOH), glycerol (GI), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), acetonitrile (MeCN), 1,2-chloroethane (DCE), ethyl acetate (EA), water (H2O), toluene and 1,4-dioxane. The amount of the solvent is 1-2 mL of the solvent added to 1 mmol of the nitrogen heterocycle (1), wherein the optimal solvent is DMSO, and the added amount is preferably 1 mL of the solvent added to 1 mmol of the nitrogen heterocycle (1).

3. The method according to claim 1, wherein: The base is one or more of sodium hydroxide (NaOH), lithium hydroxide (LiOH), aluminum hydroxide (Al(OH)3), barium hydroxide (Ba(OH)2), cesium hydroxide hydrate (CsOH·H2O), calcium hydroxide (Ca(OH)2), cesium carbonate (Cs2CO3), potassium phosphate (K3PO4), sodium carbonate (Na2CO3), sodium bicarbonate (NaHCO3), potassium tert-butoxide (t-BuOK), sodium tert-butoxide (t-BuONa), sodium acetate (NaOAc), sodium methoxide (NaOMe), triethylamine (Et3N), 1,8-diazabicycloundec-7-ene (DBU), 4-lutidine (DMAP), and triethylenediamine (DABCO). The amount of the base is 1-2 mmol of the base added to 1 mmol of the nitrogen heterocycle (1), wherein the optimal base is KOH, and the added amount is preferably 1.5 mmol of the base added to 1 mmol of the nitrogen heterocycle (1).

4. The method according to claim 1, wherein: The molar ratio of the nitrogen heterocycle (1) to the (hetero)aryl iodide (2) in the reaction was screened to be 1.5-1:1-1.5, wherein the optimal molar ratio was 1:1.

5.

5. The method according to claim 1, wherein: The reaction is carried out in the presence of the catalyst CuNPs / HKUST-1, and the amount of catalyst added to 1 mmol of the nitrogen heterocycle (1) is 5 mg to 15 mg, with 10 mg being the optimal amount.

6. The method according to claim 1, wherein: The reaction temperature is 80-120°C, with the optimal reaction temperature being 110-120°C.

7. The method according to claim 1, wherein: The reaction time is 3h-7h, and the optimal reaction time is 6-7h.

8. The method according to claim 1, wherein: The catalyst preparation method comprises the following steps: dispersing 1-1.5 mmol of Cu powder in methanol, sequentially adding 2.25-3 mmol of H3BTC and 2.5-3 mmol of 2-MI, stirring the mixture at room temperature for 6-10 hours, allowing it to stand and being filtered or centrifuged, washing it with methanol for 2-5 times, and vacuum drying it at 60-90° C. for 8-16 hours to obtain the material CuNPs / HKUST-1.