Enamines and Enol-ethers: Enabling Dienophiles for Sydnone Cycloadditions

Several new pyrazole syntheses, based on the cycloaddition reactions of sydnones and functionalised alkenes, are reported. The methods take advantage of a cycloaddition-retrocycloaddition-elimination concept to achieve an in situ oxidation level adjustment which leads to the selective formation of pyrazole products. Under thermal promotion, the reactions of sydnones and a range of enol-ethers was found to deliver the corresponding 1,4-disubstituted pyrazoles in good yield and with high levels of regiocontrol. When cyclic enol ethers are employed in these reactions in the absence of any additives, acetal containing pyrazoles are isolated. However, the addition of stoichiometric potassium carbonate leads to the corresponding alcohol containing products. Further investigations found the scope of this process to be limited with respect to both substrates; N-arylsydnones bearing different functional groups are reactive but N-alkylsydnones and C4-substituted sydnones do not form the desired pyrazoles. Additionally, examination of a number of other dipolarophile substrates was met with limited success. Following these investigations, a visible light promoted photocatalytic cycloaddition procedure was developed. The synergistic combination of organocatalysis and visible light photocatalysis was found to promote a reaction between enamines and N-arylsydnones at ambient temperature under irradiation with blue light. This reaction leads to the exclusive formation of 1,4-disubstituted pyrazoles in high yield across a range of structurally varied enamines and N-arylsydnones. However, scope investigations uncovered a number of limitations including the non-reactivity of N-alkyl and C4-substituted sydnones. A series of mechanistic investigations (Stern-Volmer luminescence quenching, radical traps/clocks, cyclic voltammetry and isotopic labelling) indicate that this novel reactivity is driven by a triplet energy transfer from the photocatalyst to the sydnone substrate, leading to an excited state sydnone intermediate which reacts further to form the observed products.