A Study On N,O-Bidentate Ligands-Promoted Copper-catalyzed C-N Coupling Reactions

The transition metal-catalyzed C-N coupling reaction is one of the important means for the synthesis of nitrogen-containing organic compounds.It has a wide range of applications in the synthesis of drugs,natural products,and functional materials.Copper as a reaction catalyst has the advantages of low price,low toxicity and green environmental protection.Adding appropriate ligands to the reaction can promote the reaction and increase the efficiency of the reaction.Therefore,synthetic chemists have been developing new green,efficient catalytic systems to achieve C-N coupling reactions.In this paper,we mainly studied the novel N,O-bidentate ligands to promote the copper-catalyzed C-N coupling reaction.This paper mainly includes three parts:Part 1 IntroductionIn this chapter,the recent advances in transition metal-catalyzed Ullmann and Chan-Lam coupling reactions were reviewed.Part 2 CuI/N,O-ligand catalyzed Ullmann reaction of azoles,amines with aromatic halides1.Using imidazole?1a?and iodobenzene?2a?as model substrates,the effects of different ligands on model reactions were investigated.The results showed that N,O-bidentate ligand?L⁶?is the best choice for ligands.Subsequently,we used L⁶ and CuI as a combination catalyst to examine the influence of the amount of catalyst,copper salt,base,solvent,and temperature on the reaction.The optimal reaction conditions were established:CuI?8 mol%?,L⁶?16 mol%?,K₂CO₃?2 equiv?,1a/2a=2:1,DMF?1 mL?,130?,48h.2.The scope of the reaction was further explored.The substrates well participated in the reaction and the corresponding coupling products were obtained in higher yields,which indicate that the reaction has good functional group tolerance.In the reaction of azoles?1?with iodobenzene?2a?,the electron-donor group attached to the benzimidazole is more favorable to the reaction and the yield is up to 93%.Benzotriazole?4a?reacted with iodobenzene?2a?to produce the coupled product?5aa?in 96%yield.In the reaction of amine?6?with iodobenzene?2a?,the aniline containing an electron-withdrawing group is more reactive and the reactivity of the aniline containing an electron-donating group decreased.The reaction of aliphatic amines with iodobenzene also performed well.Part 3 Chan-Lam reactions of amines,azoles with arylboronic acids catalyzed by N,O-coordinated copper complexes1.Using aniline?1a?and phenylboronic acid?2a?as model substrates,the effects of N,O-coordinated copper complex?I-IV?on the reaction activity were investigated.The results show that IV is the best catalyst.Then,the effects of different bases,solvents and temperatures on the reaction were examined.The optimal reaction conditions were obtained:IV?5 mol%?,K₂CO₃?2 equiv?,1a/2a=1:2,CH₃OH?1 mL?,25?,12h.Subsequently,the reaction substrate was extended.The phenylboronic acids with an electron-donating group?such as 4-CH₃,4-t-Bu,2-CH₃,4-OCH₃,4-OCH₂Ph?has good reactivity,providing the products in 80%-86%yields.The phenylboronic acid with an electron-withdrawing group?such as 4-F,3-Cl,3-NO₂?is less reactive.The reactions of 1-naphthylboronic acid?2j?and phenylboronic acid pinacolester?2k?with aniline?1a?also performed well.The anilines with electron-withdrawing groups gave the corresponding coupling product in good yield.But the aniline with electron-donating groups is less reactive.Secondary amines such as N-methylaniline?1i?,morphine?1k?,and piperazine?1m?can also smoothly react with phenylboronic acid.2.Using benzimidazole?4a?and phenylboronic acid?2a?as reaction substrates,the effects of N,O-coordinated copper complexes?I-IV?on the activity of the reaction were investigated.The results showed that the high yield was obtained using IV as catalysts without K₂CO₃.Then the influence of the amount of catalyst,solvent and temperature on the reaction activity was explored to determine the optimal conditions:IV?8 mol%?,4a/2a=1:3,CH₃OH?1 mL?,25?,22h.Next,the reaction of phenylboronic acid with benzimidazole containing different substituents was investigated.Benzoic acids bearing electron-donating groups or electron-withdrawing groups have high reactivity with a yield of 87%-98%.The reactions of 1-naphthylboronic acid?2g?,2-thienylboronic acid?2k?,phenylboronic acid pinacolester?2l?with benzimidazole could take place and the coupling product was obtained in high yield.Finally,the reaction of azole derivatives with phenylboronic acid was studied.When the electron donating group is attached to the imidazole and benzimidazole rings,the coupling reaction proceeded well and the yield could reach over 93%.The electron-withdrawing groups reduced the reactivity of the substrate,but the reaction could still proceed smoothly.In addition,the reactions of 1,2,4-triazole?1h?and benzotriazole?1i?with phenylboronic acid also gave very high yields.