Studies Of A Tandem Iminium Cyclization And Smiles Rearrangement In 5-(1H-pyrrol-1-yl) Pyrimidine And Analogous Systems

This dissertation is divided into three chapters. A new methodology involving tandem iminium cyclization and Smiles rearrangement was developed. The studies of this tandem reaction in 5-(1H-pyrrol-1-yl)pyrimidine and analogous systems provided an efficient approach to novel pyrrolo[1,2-f]pteridine and pyrido[2,3-e]pyrrolo[1,2-a]pyrazine derivatives.In Chapter One, the biological activities and synthetic methodologies of the pyrrolo[1,2-f]pteridine and pyrido[2,3-e]pyrrolo[1,2-a]pyrazine were summarized. The design of tandem iminium cyclization and Smiles rearrangement was described. Novel fused heterocyclic systems are often considered important scaffolds in medicinal chemistry. Pyrrole[1,2-a]piperazine, pyrimidine and pyridine compounds, as a structural component of several key bio-molecules, have been widely employed in design of biologically active agents. However, few synthetic methodologies to access pyrrolo[1, 2-f]pteridines and pyrido[2,3-e]pyrrolo[1,2-a] pyrazines are available.Tandem reactions are efficient strategies in organic synthesis, since they enable multiple transformations via a series of cascade reactions. Consequently, they have found wide application in the preparation of complex molecules, several interesting nitrogen-containing natural products have been synthesized using tandem reactions. Iminium cyclization have been widely used for C-C bond formation to build various nitrogen ring systems. Another important reaction often reported in the synthesis of condensed heterocyclic systems is the Smiles rearrangement. Iminium cyclization could be promoted by a acid and Smiles rearrangement could be effected under various conditions (such as in the presence of a protic acid or a base or under thermal conditions). A new synthetic strategies combine iminium cyclization and Smiles rearrangement into a single operation-new tandem reactions under an acidic condition was designed for the synthesis of pyrrolo[1,2-f] pteridines and pyrido[2,3-e]pyrrolo[1,2-a]pyrazines derivatives.In Chapter Two, the scope of tandem iminium cyclization and Smiles rearrangement in pyrimidine systems, including the studies of tandem iminium cyclization and N-N Smiles rearrangement, tandem iminium cyclization and O-N Smiles rearrangement and the diastereoselectivity of tandem iminium cyclization and N-N Smiles rearrangement, was investigatedTandem iminium cyclization and Smiles rearrangement are validated in the synthesis of pyrimidine fused heterocycles under TFA/DCM conditions. The reaction of pyrimidine amino aldehyde with an amine under an acidic condition yielded the iminium cyclization product diazepine which readily undergoes Smiles rearrangement to give a novel pyrrolo[1,2-f]pteridine derivative. Both aromatic and aliphatic amines can be employed for this tandem reaction in 21%-62% yields. To unambiguously identify the progress of this tandem reaction, X-ray structures of both seven-membered ring intermediate and product were obtained. To explore the scope of these types of tandem reactions, tandem iminium cyclization and O-N Smiles rearrangement reaction was investigated. Under the optimized conditions of TiCl₄/CH₃CN, various amines ranging from ammonia to aliphatic and aromatic amines are compatable for the current reactions to produce the expected pyrrolo[1,2-f]pteridines in 12%-73% yields. It is also noted that no intermediate oxazepine was observed, which indicated that O-N Smiles rearrangement was indeed faster than the N-N version as expected. To further expand the scope of the method, the diastereoselective synthesis of pyrrolo[1,2-f]pteridine via tandem iminium cyclization and Smiles rearrangement reaction was investigated under TFA/DCM conditions. Both aliphatic and aromatic amines can be employed for this tandem reaction to produce the expected pyrrolo[1,2-f]pteridines as a single isomer in 31%-59% yields.The application of these tandem reaction provided an efficient strategy to access novel pyrrolo[1,2-f]pteridine derivatives with three diversification points. The chloro atom on the pyrrolo[1,2-f]pteridine is highly reactive towards a nucleophile, such as an amine, alcohol, thiol, which further increases the structural diversity of this novel scaffold. The above results provided an efficient methodology to prepare libraries of novel pyrrolo[1,2-f]pteridine with high structural diversity of pharmaceutically interests.To expand the scope of applications, an efficient strategies to access to structurally diverse libraries of pyrido[2,3-e]pyrrolo[1,2-a]pyrazine via tandem iminium cyclization and O-N Smiles rearrangement reaction in pyridine systems were developed in Chapter Three.The scope of the tandem iminium cyclization and O-N Smiles rearrangement reaction in pyridine systems was investigated. It is noteworthy that iminium cyclization intermediate was isolated. This result is consistent with the proposed cascade reaction of iminium cyclization and Smiles rearrangement. For aromatic amine, the optimized conditions (TFA/CH₃CN) were applied to a number of aromatic amines, the reactions of pyridinyloxyacetaldehyde with aromatic amines gave the expected products pyrido[2,3-e]pyrrolo[1,2-a]pyrazine in 26%-97% yields. For aliphatic amine, it is noteworthy that the iminium cyclization product was initially formed under TiCl₄/DCM conditions, and the desired product pyrido[2,3-e]pyrrolo[1,2-a]pyrazine was obtained only after treatment with saturated aqueous NaHCO₃ solution. This observation is different from the cascade reaction of the pyrimidine system since the TiCl₄ catalyzed reaction of pyrimidines proceeded without the treatment by a base. This result may be attributed to the stronger pyridine-oxygen bond compared to the pyrimidine one which is more favorable towards Smiles rearrangement. Under the conditions of TiCl₄/DCM followed by NaHCO₃ treatment, pyridinyloxyacetaldehyde reacted with several aliphatic amines to yield the desired pyrido[2,3-e]pyrrolo[1,2-a]pyrazines in 31%-66% yields. The above synthetic methodology complements existing pyridine chemistry by allowing access to libraries of pyrido[2,3-e]pyrrolo[1,2-a]pyrazine derivatives.