Twofold Radical-Based Synthesis of N,C‑Difunctionalized Bicyclo[1.1.1]pentanes

• Published in: Journal of the American Chemical Society Vol. 143; no. 26; pp. 9729 - 9736
• Main Authors: Pickford, Helena D, Nugent, Jeremy, Owen, Benjamin, Mousseau, James. J, Smith, Russell C, Anderson, Edward A
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 07.07.2021; Amer Chemical Soc
• Subjects: Chemistry; Chemistry, Multidisciplinary; Physical Sciences; Science & Technology; ATOM-TRANSFER; POTENT; DERIVATIVES; ALKYL-HALIDES
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/jacs.1c04180

Bicyclo­[1.1.1]­pentylamines (BCPAs) are of growing importance to the pharmaceutical industry as sp3-rich bioisosteres of anilines and N-tert-butyl groups. Here we report a facile synthesis of 1,3-disubstituted BCPAs using a twofold radical functionalization strategy. Sulfonamidyl radicals, generated through fragmentation of α-iodoaziridines, undergo initial addition to [1.1.1]­propellane to afford iodo-BCPAs; the newly formed C–I bond in these products is then functionalized via a silyl-mediated Giese reaction. This chemistry also translates smoothly to 1,3-disubstituted iodo-BCPs. A wide variety of radical acceptors and iodo-BCPAs are accommodated, providing straightforward access to an array of valuable aniline-like isosteres.