Synthesis Of Pyrrole And Imidazole Containing Heterocycles

Heterocyclic chemistry is an important part of modern organic chemistry and has been one of the most active fields in organic chemistry. Heterocyclic compounds widely exists in nature. Heterocyclics are numerous, and have yet to a third of the known organic compounds. Nitrogen containing heterocycles have emerged as a class of important heterocyclic compounds, and they are present in broad spectrum of nature. Alkaloids are active ingredients of Chinese herbal medicine, and many of them are nitrogen heterocycles. Nitrogen heterocyclic compounds have close relationship with life science, exhibit a wide range of biological and medicinal activities. Nitrogen heterocyclics are the main body of the pesticide development. In the last decade, about70%of new pesticides are nitrogen heterocyclics. In addition, nitrogen heterocyclics are also an important part of organic materials, play an important role in our daily lives.In the second chapter, we used1-fluoro-2-nitrobenzene and pyrrole-2-carboxamides as the substrate, cesium as the base, acetonitrile as the solvent in one-pot. The expected pyrrolo[1,2-a]quinoxalines were obtained in good yields. Then we studied the reaction of N-(p-tolyl)-1H-pyrrole-2-carboxamide with a variety of1,2-dihalobenzenes or2-halonitroarenes were studied under the same reaction conditions. The reactions worked well afford pyrrolo[1,2-a]quinoxalines in good yields. Indole-2-carboxamides were compatible with this approach, giving indolo[1,2-a]quinoxalines in high yields. This transition metal-free process has potential applications in the synthesis of biologically and medicinally relevant compounds.In the third part, we used2-tetrahydropyranyl-4,5-dichloropyridazin-3-one and pyrrole-2-carboxamides as substrates, synthesized pyrrolopyrazino [2,3-d]pyridazinedione derivatives in one-pot. The reactions provided two regioisomers via two paths:direct cyclization and Smiles rearrangement. Finally, we speculated on the possible mechanism. The configuration of the product via Smiles rearrangement was determined by X-ray crystallographic analysis. Indole-2-carboxamides were also compatible with this method. Further studies on its application in the synthesis of biologically relevant compounds are currently in progress.The ligand-assisted copper-catalyzed Ullmann reactions have made significant progress, These reactions have some advantages, such as low cost of the catalyst, mild reaction conditions. This strategy has been used in the synthesis of nature products and bioactive nitrogen-containing heterocycles. We used copper-mediated C-N bond formation in the assembly of bioactive nitrogen-containing heterocycles. Three series of heterocycles were synthesized.In the fourth chapter, we have developed an efficient synthetic approach for the synthesis of pyrrolobenzoxazepinones via copper/L-proline system catalyzed process. We prepared2-iodophenols and2-chloro-1-(1H-pyrrol-2-yl)ethanone. Nucleophilic substitution of2-iodophenol and2-chloro-1-(1H-pyrrol-2-yl)ethanone provided2-(2-iodophenoxy)-1-(1H-pyrrol-2-yl)ethanones. The Cu-catalyzed intramolecular reaction of the2-(2-iodophenoxy)-1-(1H-pyrrol-2-yl)ethanone was chosen as a model reaction to screen for suitable reaction conditions. Under the optimized conditions, we studied the reactions of2-iodophenol and2-chloro-l-(1H-pyrrol-2-yl)ethanone. Substituted pyrrolobenzoxazepinones were synthesized by intramolecular Cu-catalyzed Ullmann N-arylations.In the fifth chapter,2-iodophenol and2-(chloromethyl)-1H-benzo[d]imidazole were chosen as the model substrates to optimize reaction conditions including catalysts, ligands, bases and solvents. The optimized reaction condition was Cul as the catalyst, L-proline as the ligand, CS2CO3as the base reacted in NMP. A series of6H-benzo[6]benzo[4,5]imidazo[1,2-d][1,4]oxazine derivatives were synthesized from reactions of substituted2-halophenols with2-(chloromethyl)-1H-benzo[d]imidazole under the optimized conditions. Then substituted2-(chloromethyl)-1H-benzo[d] imidazoles were prepared according to literature procedures. Reactions of substituted benzimidazoles with2-iodophenol,4-chloro-2-iodophenol, and2-bromopyridin-3-ol provided the desired products in moderate to good yields. In the sixth chapter, we have developed a convenient and efficient copper-catalyzed domino process for the construction of benzo[4,5]imidazo[1,2-a]quinoxalines under air. Copper-catalyzed Ullmann coupling reactions have made significant progress, and the N-arylation strategy has been extensively explored to construct nitrogen heterocycles. Many pharmaceutical molecules have been synthesized by the use of copper-catalyzed coupling strategy. However, most of these reactions were performed under nitrogen or argon atmosphere, which could prevent oxidation of the catalysts. In particular, the use of inexpensive but less reactive aryl chlorides in copper-catalyzed coupling is still a challenge compared to the commonly used aryl bromides and aryl iodides. N-tosyl-2-iodoaniline and2-(chloromethyl)-1H-benzo[d]imidazole were chosen as the model substrates to optimize reaction conditions. Reactions of various substituted N-tosyl-2-haloanilines or N-tosyl-2-bromoanilines with2-(chloromethyl)-1H-benzo[d]imidazoles were examined. All reactions worked well under the optimized conditions afforded the desired products in excellent yields. In general, no significant difference of reactivity was observed between N-tosyl-2-iodoanilines and N-tosyl-2-bromoanilines. N-tosyl-2-chloroanilines were compatible with this process, giving the corresponding products in good yields. This copper-catalyzed one-pot process has potential applications in the synthesis of biologically and medicinally relevant compounds.