Aza-Diels–Alder Reactions of Furans

Diels–Alder (DA) reactions featuring furan as diene have often been plagued with a variety of challenges due to the ease of reversibility.^[1] Factors that contribute to this trend stem from a large HOMO–LUMO gap between furan and the dienophile as well as the greater ring-strain of the newly furnished oxa-norbornene cycloadduct in contrast to cyclopentadiene, its carbo-congener. To address these shortcomings, highly activated furans and/or dienophiles have been developed to achieve the desired cycloaddition. With respect to aza-DA reactions of furan and acyclic aza-dienophiles, this area remains largely underdeveloped. Complications arising from the sensitivity of the newly furnished hemiaminal functionality of these direct cycloadducts often result in undesired C–N or C–O bond cleavage products. As a result, only a select few examples have successfully achieved the desired reactivity, albeit requiring harsh conditions and/or long reaction times to do so.^[2] 

To further advance this area, our group has successfully employed the use of N-aryl ketenimines as highly reactive aza-dienophiles in conjunction with 2,5-bis(tert-butyldimethylsilyloxy)furans to furnish oxygenated pyridones in moderate to excellent yields, displaying excellent regioselectivity, chemoselectivity, and periselectivity.^[3] Benchmarking the reactivity of ketenimines and various imines as aza-dienophiles suggests that ketenimines are far more reactive aza-dienophiles and react under significantly milder conditions in contrast to the imines screened. The newly furnished cycloadducts themselves also contain a new oxa-diene, resulting from hybrid recursive/diene-transmissive DA reactivity, allowing for the formation of pyran-fused pyidones via a one-pot aza/oxa-DA sequence. 

Further application of activated furans in DA settings include the use of 2-(tert-butyldimethylsilyloxy)furans and strained, cyclic dienophiles to furnish cycloadducts containing fused ring systems capable of forming medium-sized rings in the presence of TBSOTf as Lewis acid, resulting in formal [4+3] and [4+4] cycloaddition products. This strategy serves as a compliment to the well-known Büchner ring-expansion, and is currently compatible with azirines, cyclopropenes, and cyclobutenes as dienophile. Future directions involve the extension of this reactivity to azetine dienophiles to access formal aza-[4+4] cycloadducts.

References

[1]   C. J. DeAngelis, C. G. Newton, Organic & Biomolecular Chemistry 2025.

[2]   a) D. vor der Brück, R. Bühler, H. Plieninger, Tetrahedron 1972, 28, 791–795; b) A. A. Krolevets, A. V. Adamov, A. G. Popov, I. V. Martynov, Bulletin of the Academy of Sciences of the USSR Division of Chemical Science 1988, 37, 1737–1737; c) V. A. Al'bekov, A. F. Benda, A. F. Gontar, G. A. Sokol'skii, I. L. Knunyants, Bulletin of the Academy of Sciences of the USSR Division of Chemical Science 1988, 37, 777–780.

[3]   C. J. DeAngelis, G. Goyal, M. J. Liss, J. E. Budwitz, M. S. Herlihy, A. V. Conner, S. E. Wheeler, P. Ma, M. Li, K. N. Houk, C. G. Newton, Journal of the American Chemical Society 2025, 147, 6087–6094.