Nitro-Substituted Benzaldehydes in the Generation of Azomethine Ylides and Retro-1,3-Dipolar Cycloadditions

1,3-Dipolar cycloaddition of 2- and 3-nitrobenzaldehydes with 2-aminomethylpyridine and ethyl (2E)-2-cyano-3-(4-nitrophenyl)prop-2-enoate yielded endo-cycloadducts as the sole products under various reaction conditions. Fortuitously, 4-nitrobenzaldehyde behaved differently in three- and four-component cascades to produce a mixture of endo- and exo'-cycloadducts. This reaction is solvent- and temperature-dependent, and consequently, both the endo- and exo'-cycloadducts were synthesized in an excellent regio-, stereo-, and chemoselective fashion. Retro-1,3-dipolar cycloadditions of the endo-cycloadducts were conducted under mild reaction conditions, and the generated syn-dipoles were stereomutated into anti-dipoles which recycloadded with the dipolarophiles to provide the exo'-cycloadducts. Mechanistic studies were carried out to support the proposed mechanisms. Unprecedentedly, particular arylidene scaffolds participated as aldehyde or activated methylene precursors. Density functional theory calculations were performed to shed light on the importance of AcOH in the generation and isomerization of dipoles and to explain the high selectivity and the possibility of retro-cycloaddition.