C. Wang et al, Nat. Chem. 2025, 10.1038/s41557-025-01849-1
https://doi.org/10.1038/s41557-025-01849-1
Amines are one of the most ubiquitous functional groups in bioactive natural products, pharmaceuticals, agrochemicals and catalysts. However, synthesis of medium sized cyclic (8-11) and macrocyclic (>12) amines is difficult and compounded by low availability as off-the-shelf commercial materials.
A recent paper by Wang et al published in Nature Chemistry reports a borane-catalysed method for selective alkyne insertion into C(sp³)–C(sp³) bonds of amines, enabling ring expansion of cyclic amines and chain elongation of acyclic analogues. The method utilizes a catalytic combination of tris(pentafluorophenyl)borane and TMSOTf to generate reactive enamine intermediates from unfunctionalized amines. These intermediates undergo regioselective [2+2] cycloaddition with electrophilic alkynes, followed by strain-driven electrocyclic ring opening to yield expanded-ring or elongated-chain amines.
The transformation is compatible with an array of cyclic and acyclic tertiary amines and alkynes bearing electron-withdrawing groups, including esters, nitriles, and sulfonyl groups. It proceeds without the need for pre-activation or leaving groups and is tolerant of diverse functional groups, enabling late-stage functionalization of complex drug molecules. Mechanistic studies, including isotopic labelling and DFT calculations, suggest that hydrogen transfer and zwitterionic intermediates govern the stereochemical outcomes and thermodynamic product distribution.
The methodology grants access to both medium-sized and macrocyclic amines, directly addressing the synthetic challenges associated with these privileged motifs. The modular approach is amenable to iterative homologation, allowing controlled growth of C–C frameworks. This strategy constitutes a rare example of C–C bond functionalization via catalytic enamine intermediates, expanding the synthetic toolbox for amine diversification and expansion of chemical space.
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