60th Annual Report on Research 2015

N,N-containing five membered ring heterocycles are among the most privileged scaffolds in natural products and synthetic drugs. Among these pyrazolines and imidazolines are of special importance due to their proven pharmacophoric properties. Pyrazolines have displayed antimicrobial, antifungal, antidepressant, anticancer and anti-inflammatory properties. Imidazolines, despite possessing similar pharmacophoric properties, have recently become very important as ligands in homogenous catalysis. Thus, the continued development of novel and more efficient methods for the synthesis of these scaffolds remains an important goal in organic chemistry.

In our laboratory, we have established a strong research platform for the development of synthetic methods to produce N,N-containing heterocycles. We discovered that aldehydes and amines react under mild basic conditions in the presence of HOSA to form diaziridines in high yields and diastereoselectivities. Moreover, we were also interested in establishing whether these diaziridines can be used as chemical synthons for the synthesis of 5-membered ring N,N-containing heterocycles. We hypothesized that the difference in electronic properties of the groups around the nitrogen atoms in the diaziridine substrate would control the chemoselectivity of the cycloaddition. Thus; groups of opposing electronic properties would undergo cycloaddition across the C-N bond; and groups of similar electronic properties would react across the N-N bond. These then were exposed to optimized cycloaddition conditions based on their protecting groups. When the electronic relationship between each group bound to the N atoms was mismatched (Bn/CBz), we were able to synthesize a large variety of pyrazolines (AuPPh₃Cl for dipolar cycloaddition with alkynes) and pyrazolidines (Cu(TFA)₂ for dipolar cycloaddition with alkenes) in very good yields and regioselectivities. Based on our observations, we proposed an azomethine imine dipole intermediate for the formation of the respective pyrazolines and pyrazolidines. Moreover, when the relationship among the protecting groups bound to N was matched (Cyp/Bn), we found complete reversal of the chemoselectivity for the formation of imidazolines (AuPPh₃Cl for dipolar cycloaddition with alkynes) and imidazolidines (TiCl₄ for dipolar cycloaddition with alkenes) in very good yields and regioselectivities. Accordingly, we proposed an isodiazomethine diradical intermediate for the formation of the respective imidazolines and imidazolidines. These results demonstrated that heterocycles like diaziridines undergo cycloaddition reactions with high yields and stereoselectivities. Moreover, we also found that high levels of chemocontrol could be achieved by changing the electronic relationship (match/mismatch) between the groups bound to the N atoms. The success that we had on this project has allowed my laboratory to launch a robust research platform for the synthesis of small and medium size heterocyclic scaffolds. This success has manifested in publications and more importantly on the training of undergraduate students in performing state-of-the-art research in organic chemistry. Four of the students involve in this project would be applying for chemistry PhD programs this fall, and the research experience they have accumulated would be fundamental during their next academic experience.