Exploring the conformational bias of amides to unlock reactivity Mehul H. Jesani and Jonathan Clayden University of Bristol, UK The Clayden group has shown the conformational restriction imposed by urea, carbamate and thiocarbamate tethers can pre-organise substrates for intramolecular S N Ar reactions. 1 We are now investigating amide linkages as the conformational controller: benzanilides 1 can undergo a Truce–Smiles rearrangement to triarylmethanes (TRAMs) 2 , a privileged class of molecules, with the motif featuring broadly across chemistry, including in pharmaceutical agents, dyes, building blocks in materials chemistry, and red light-absorbing photoredox catalysts. 2 The transformation succeeds even without electronic activation of the migrating arene, being instead accelerated by the conformation preference of the substrate. A ring-expanding variant of the reaction provided access to novel medium ring scaffolds, whose balance of rigidity and flexibility offers promise within drug design. 3 Surprisingly, under the reaction conditions, CF 3 -substituted benzanilide 1a produced CF 2 H-bearing isoindolinone 3a , which was proposed to form by aryl migration, 1,6-elimination to intermediate 4a − , and trapping by the pendant amidate nucleophile. 4 Currently, work is under way to generalise this approach to access arenes functionalised with a CF 2 H group, which can serve as a lipophilic hydrogen bond donor and a bioisostere of hydroxyl and thiol functional groups. 5
References 1. S. M. Wales, R. K. Saunthwal, J. Clayden, Acc. Chem. Res. 2022 , 55 , 1731–1747 2. R. Abrams, M. H. Jesani, A. Browning, J. Clayden, Angew. Chem Int. Ed. 2021 , 60 , 11272–11277 3. A. K. Clarke, W. P. Unsworth, Chem. Sci. 2020 , 11 , 2876–2881 4. A. Browning, MSci Thesis, University of Bristol, 2019 5. Y. Zafrani, D. Yeffet, G. Sod-Moriah, A. Berliner, D. Amir, D. Marciano, E. Gershonov, S. Saphier, J. Med. Chem. 2017 , 60 , 797–804
P22
© The Author(s), 2022
Made with FlippingBook Learn more on our blog