A copper-catalyzed c-n coupling method using n,n-disubstituted hydrazides as ligands

A two-substitution, copper-catalyzed technology, applied in the chemical field, can solve the problems of narrow substrate application range and high reaction temperature, and achieve the effects of wide application range, simple operation and high chemoselectivity

Active Publication Date: 2019-03-22
SUN YAT SEN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In addition, for the Ullmann C-N coupling reaction catalyzed by copper, it is still disadvantageous in terms of energy saving due to the need for heating in industrial production (Brahmachari, G., Room Temperature Organic Synthesis. Elsevier Inc. 2015.), and it is still faced with big challenge
[0005] In recent years, we have developed various N-arylation methods in aqueous systems (ZL 201010102104.5, ZL200910040649.5), but there are still some defects, such as high reaction temperature, narrow substrate scope, etc.

Method used

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  • A copper-catalyzed c-n coupling method using n,n-disubstituted hydrazides as ligands
  • A copper-catalyzed c-n coupling method using n,n-disubstituted hydrazides as ligands
  • A copper-catalyzed c-n coupling method using n,n-disubstituted hydrazides as ligands

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

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

[0027]

[0028] With 234mg (1mmol) 4-iodoanisole, 93mg (1mmol) aniline, 25mg (0.1mmol) CuSO 4 ·5H 2 O, 14 mg (0.1 mmol) Ligand L1, 138 mg (1 mmol) K 2 CO 3 , 2mL EtOH, added to a 10mL reaction tube, sealed, and reacted at 20°C for 48h. After the reaction stopped, add water, extract with ethyl acetate, wash with water, wash with saturated brine, dry over anhydrous sodium sulfate, filter, distill the filtrate under reduced pressure, and separate and purify by silica gel column chromatography to obtain N-p-methoxyphenyl Aniline 181 mg, yield 91%.

[0029] MS (ESI + ): m / z: 200 ([M+H] + ); 1 H NMR (400MHz, CDCl 3 )δ7.27-7.23(m,2H,ArH),7.15-7.07(m,2H,ArH),6.97-6.95(m,2H,ArH),6.89(d,J=8.7Hz,3H,ArH), 3.83(s,3H,OCH 3 ).

[0030] Ligand: MS (ESI + ): m / z: 300 ([M+Na] + );1H NMR(400MHz,DMSO)δ11.63(s,1H,NH),10.76(s,1H,NH),7.31-7.28(m,4H,ArH),7.16-7.14(m,4H,ArH) , 7.00-6.98 (m, 4H, ArH), 6.16 (br, 1H, ArH).

Embodiment 2

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

[0032]

[0033] With 156mg (1mmol) bromobenzene, 139mg (1.3mmol) benzylamine, 9.5mg (0.05mmol) Cu1, 10.8mg (0.05mmol) ligand L2, 276mg (2mmol) K 2 CO 3 , 2mL of diethylene glycol (DEG), was added into a 10mL reaction tube, sealed, and reacted at 25°C for 72h. After the reaction stopped, add water, extract with ethyl acetate, wash with water, wash with saturated brine, dry over anhydrous sodium sulfate, filter, distill the filtrate under reduced pressure, and separate and purify by silica gel column chromatography to obtain 156 mg of N-phenylbenzylamine. Yield 85%.

[0034] MS (ESI + ): m / z: 184 ([M+H] + ); 1 H NMR (400MHz, CDCl 3 )δ7.45–7.35(m,5H,ArH),7.26(t,J=7.5Hz,2H,ArH),6.81(t,J=7.1Hz,1H,ArH),6.72(d,J=7.8Hz ,2H,ArH),4.40(s,2H,NCH2).

[0035] Ligand: MS (ESI + ): m / z: 238 ([M+Na] + ); 1 H NMR (400MHz, DMSO) δ11.57(s, 1H, NH), 10.18(s, 1H, NH), 7.20(t, J=7.7Hz, 2H, ArH), 6.94-6.92(m, 2H, ArH ),6.80–6.73(m...

Embodiment 3

[0039] Example 3: 2-methoxy-N-phenylaniline

[0040]

[0041] 186mg (1mmol) 2-bromoanisole, 186mg (2mmol) aniline, 9.05mg (0.05mmol) Cu (OAc) 2 , 36.1 mg (0.1 mmol) ligand L3, 489 mg (1.5 mmol) Cs 2 CO 3 , 2mL MeOH, added to a 10mL reaction tube, sealed, and reacted at 60°C for 3h. After the reaction stopped, add water, extract with ethyl acetate, wash with water, wash with saturated brine, dry over anhydrous sodium sulfate, filter, distill the filtrate under reduced pressure, and separate and purify by silica gel column chromatography to obtain 2-methoxy-N- 175mg of phenylaniline, yield 88%. MS (ESI + ): m / z: 200 ([M+H] + ); 1 H NMR (400MHz, CDCl 3 )δ7.37–7.28(m,3H,ArH),7.21(d,J=8.1Hz,2H,ArH),7.01–6.92(m,4H,ArH),3.93(s,3H).

[0042] Ligand: MS (ESI + ): m / z: 362 ([M+H] + ); 1 H NMR (400MHz,DMSO)δ11.40(s,1H,NH),10.45(s,1H,NH),7.30–7.28(m,2H,ArH),7.11–7.03(m,6H,ArH),6.90 -6.86(m,2H,ArH),6.08(d,J=2.1Hz,1H,ArH),3.45-3.40(m,2H,CH),1.03(d,12H,CH 3 );

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Abstract

The invention discloses a copper-catalyzed C-N coupling method adopting N,N-disubstituted hydrazide as a ligand. The method comprises the steps of adopting aromatic halide and an amine compound as raw materials, adopting an alcohol compound as a solvent, adopting copper or a copper compound as a catalyst, adopting the N,N-disubstituted hydrazide with a structural formula as shown in a formula I or a formula II as the ligand, and under the existence of alkali, carrying out C-N coupling reaction at the temperature of 10 to 130 DEG C so as to generate an N-aryl compound. The copper-catalyzed C-N coupling method provided by the invention is mild in reaction conditions, high in chemoselectivity, wide in substrate application range, and simple to operate; a product is simple, easy to separate, green and environment-friendly; and the product yield is higher. According to the figure, R1 and R2 are selected from methyl, phenyl, 4-methoxyphenyl, 4-nitrobenzophenone, 2-methylphenyl, 2-isopropyl phenyl; R3 is hydrogen or methoxyl.

Description

Technical field: [0001] The invention relates to the technical field of chemistry, in particular to a copper-catalyzed C-N coupling method using N,N-disubstituted hydrazide as a ligand. Background technique: [0002] Amine compounds widely exist in natural and non-natural products, drugs, pesticides and materials with physiological activities. Therefore, the formation of C–N bonds has been widely valued by organic synthetic chemists. (Magano, J.; Dunetz, J.R., Chemical reviews 2011, 111, 2177-250.). [0003] Compared with other noble metals, copper-catalyzed reactions of aryl halides and amines have attracted more and more attention because copper is cheap and easy to obtain, and the ligands used are relatively stable and low-toxic. However, the early Ullmann reaction has harsh reaction conditions (such as: high temperature, strong base, stoichiometric copper or copper salt and long reaction time) and moderate reaction yield, which limits its large-scale application. (Jia...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C213/02C07C217/92C07C217/84C07C215/16C07C215/82C07C209/10C07C211/48C07C211/56C07C211/54C07C211/52C07C211/47C07C221/00C07C225/22C07D295/096C07D317/66C07D213/74C07D333/36C07B37/04B01J31/22
CPCB01J31/1815B01J31/183B01J2231/4283B01J2531/0213B01J2531/0241B01J2531/16C07B37/04C07C209/10C07C213/02C07C221/00C07D213/74C07D295/096C07D317/66C07D333/36C07C217/92C07C217/84C07C215/16C07C215/82C07C211/48C07C211/56C07C211/54C07C211/52C07C211/47C07C225/22
Inventor 万一千丁小妹黄漫娜朱新海易洲
Owner SUN YAT SEN UNIV
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