Diastereoselective Synthesis of Densely Functionalized 1-Pyrrolines

Significance

1-Pyrroline derivatives are found in several bioactive natural products and serve as valuable intermediates to access pharmaceutically relevant substituted pyrrolidines. Several strategies have been developed for the synthesis of 1-pyrrolines, typically involving radical-based cyclization or [3 + 2] cycloaddition, though these can present limitations in terms of the substitution patterns that can be obtained within the products. The current report describes an alternative approach in which the 1-pyrroline nucleus is accessed through an Alder–ene reaction of ynimines generated in situ, with the overall process being viewed as a [4 + 1] heteroannulation reaction in which the terminal alkyne (used to generate the ynimine) serves as a one-carbon donor.

Comment

Model studies on the reaction between 1 and 2 highlighted that the desired 1-pyrroline formed in excellent yields in the presence of a catalytic amount of a copper source in conjunction with a quinoline-based ligand. Subsequent studies suggested that the Cu salt is only required to promote the initial aza-Sonogashira coupling with the Alder–ene reaction then proceeding under base-mediated thermal conditions. A broad scope was demonstrated for both components, and mechanistic studies indicated that the reaction proceeds through a concerted intramolecular Alder–ene process in which the allylic hydrogen of the alkene substituent trans to the oxime ester main chain is selectively transferred to the β-carbon of the nitrogen-substituted alkyne. Further work highlighted the synthetic utility of the 1-pyrrolines, while treatment with acid enabled formation of 2H-pyrroles through a regioselective Wagner–Meerwein rearrangement.

Publication History

Article published online:
20 December 2024

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