Nitrogen‐substituted alkynes such as ynamines and ynamides are competent partners in [4+2] cycloaddition reactions. This microreview aims to discuss in a historical context the main achievements in the work on this class of reactions that leads to valuable nitrogen‐containing heterocycles in a single‐step fashion. In the last section, our own work in the field of inverse‐electron‐demand Diels–Alder reactions between ynamides and pyrimidines is discussed.
Pyrimidines are almost unreactive partners in Diels-Alder cycloadditions with alkenes and alkynes, and only reactions under drastic conditions have previously been reported. We describe how 2-hydrazonylpyrimidines, easily obtained in two steps from commercially available 2-halopyrimidines can be exceptionally activated by trifluoroacetylation. This allows a Diels-Alder cycloaddition under very mild reaction conditions, leading to a large diversity of aza-indazoles, a ubiquitous scaffold in medicinal chemistry. This reaction is general, scalable and has an excellent functional group tolerance. A straightforward synthesis of a key intermediate of Bayer's Vericiguat illustrates the potential of this cycloaddition strategy. Quantum mechanical calculations show how the simple N-trifluoromethylation of 2-hydrazonylpyrimidines distorts the substrate into a transition state-like geometry that readily undergoes the intramolecular Diels-Alder cycloaddition.
Although pyrimidines are not among the most reactive partners in intramolecular inverse-electron demand [4ps+2ps] reactions with alkynes, they could be activated under mild and practical conditions, leading to fused nitrogen-containing heterocycles. We report an optimized synthesis of a 5-iodo-7-aza-indazole by a one-pot Diels-Alder cascade that starts from a pyrimidine substituted in the 2-position by an (alkynyl)hydrazone. The safety of the process and the environmental impact were thoroughly evaluated. Eventually, a selection of crosscoupling reactions of 17 was studied and allowed the introduction of carbon-and nitrogen-based nucleophiles at the C5-position in good to excellent yields.
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