Abstract
The combination of palladium catalysis and thermal cycloaddition is shown to transform tricyclic aziridines into complex, stereodefined tetracyclic products in a single step. This highly unusual cascade process involves a diverted Tsuji–Trost sequence leading to a surprisingly facile intramolecular Diels–Alder reaction. The starting materials are accessible on multigram scales from the photochemical rearrangement of simple pyrroles. The tetracyclic amine products can be further elaborated through routine transformations, highlighting their potential as scaffolds for medicinal chemistry.
Highlights
The combination of palladium catalysis and thermal cycloaddition is shown to transform tricyclic aziridines into complex, stereodefined tetracyclic products in a single step
Nitrogen-containing heterocycles are among the most prominent structural motifs within bioactive molecules, showing a wide range of activity, including anticancer, antibacterial, and antiviral activity, and some acting on the central nervous system (CNS)
We have previously shown tricyclic aziridines 2, formed directly from pyrroles 1,8 are versatile intermediates in this respect (Scheme 1a)
Summary
CO2tBu CO2tBu none none aReaction performed at 70 °C. bPerformed in the presence of 1.3 equiv of K2CO3. cReaction performed at 30 °C. dYield determined by 1H NMR using 1,3,5-trimethoxybenzene as the internal standard. Reaction in the absence of an allylating reagent proved to be successful, forming secondary amino-dienes 13a−c in good yield (entries 5−7, respectively). This was found to proceed most efficiently in the absence of K2CO3, and again nitrile 2d proved to be unreactive. Assisted, Pd-catalyzed C−N cleavage of 2 leads to the formation of a π-allyl Pd intermediate 7 This species undergoes direct β-hydride elimination, even in the absence of additional base, to form intermediate diene 20. The mechanism of diene formation likely involves rate-limiting acid-assisted C−N cleavage, followed by direct β-hydride elimination These results underline the power of photochemical/catalytic sequences in preparing complex ring systems. Experimental procedures, spectral and analytical data, copies of 1H and 13C NMR spectra for new compounds, and crystallographic data of 6cd (PDF)
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