One-step Catalyst-Transfer Macrocyclization: Expanding the Chemical Space of Azaparacyclophanes

In this paper, we report on a one-step catalyst-transfer macrocyclization (CTM) reaction, based on the Pd-catalyzed Buchwald-Hartwig cross-coupling reaction, selectively affording only cyclic structures. This route offers a versatile and efficient approach to synthesize aza[1n]paracyclophanes (APCs) featuring diverse functionalities and lumens. The method operates at mild reaction temperatures (40 °C) and short reaction times (~2 h), delivering excellent isolated yields (>75% macrocycles) and up to 30% of the 6-membered cyclophane, all under non-high-dilution concentrations (35-350 mM). Structural insights into APCs reveal variations in product distribution based on different endocyclic substituents, with steric properties of exocyclic substituents having minimal influence on the macrocyclization. Aryl-type endocyclic substituents predominantly yield 6-membered macrocycles, while polycyclic aromatic units such as fluorene and carbazole favor 4-membered species. Experimental and computational studies support a proposed mechanism of ring-walking catalyst-transfer that promotes the macrocycle formation. It has been found that the macrocyclization is driven by the formation of cyclic conformers during the oligomerization step favoring an intramolecular C–N bond formation that, depending on the cycle size, hinges on either pre-organization effect or kinetic increase of the reductive elimination step or a combination of the two. The CTM process exhibits a "living" behavior, facilitating sequential synthesis of other macrocycles by introducing relevant monomers, thus providing a practical synthetic platform for chemical libraries. Notably, CTM operates both under diluted and concentrated regimes, offering scalability potential, unlike typical macrocyclization reactions usually operating in the 0.1–1 mM range.