Discovery of N–X anomeric amides as electrophilic halogenation reagents

• Published in: Nature chemistry 2024-09, Vol.16 (9), p.1539-1545
• Main Authors: Wang, Yu, Bi, Cheng, Kawamata, Yu, Grant, Lauren N., Samp, Lacey, Richardson, Paul F., Zhang, Shasha, Harper, Kaid C., Palkowitz, Maximilian D., Vasilopoulos, Aristidis, Collins, Michael R., Oderinde, Martins S., Tyrol, Chet C., Chen, Doris, LaChapelle, Erik A., Bailey, Jake B., Qiao, Jennifer X., Baran, Phil S.
• Format: Article
• Language: English
• Subjects: 639/638/309/2144; 639/638/403/933; 639/638/549/933; Amides; Analytical Chemistry; Biochemistry; Chemical bonds; Chemistry; Chemistry and Materials Science; Chemistry/Food Science; Complex compounds; Drug additives; Drug discovery; Functional groups; Halogenation; Hydrogen bonding; Inorganic Chemistry; Nitrogen; Organic Chemistry; Physical Chemistry; Reagents
• ISSN: 1755-4330; 1755-4349; 1755-4349
• DOI: 10.1038/s41557-024-01539-4

Electrophilic halogenation is a widely used tool employed by medicinal chemists to either pre-functionalize molecules for further diversity or incorporate a halogen atom into drugs or drug-like compounds to solve metabolic problems or modulate off-target effects. Current methods to increase the power of halogenation rely on either the invention of new reagents or activating commercially available reagents with various additives such as Lewis or Brønsted acids, Lewis bases and hydrogen-bonding activators. There is a high demand for new reagents that can halogenate otherwise unreactive compounds under mild conditions. Here we report the invention of a class of halogenating reagents based on anomeric amides, taking advantage of the energy stored in the pyramidalized nitrogen of N–X anomeric amides as a driving force. These robust halogenating methods are compatible with a variety of functional groups and heterocycles, as exemplified on over 50 compounds (including 13 gram-scale examples and 1 flow chemistry scale-up). Electrophilic halogenation approaches often suffer from low reactivity and chemoselectivity when it comes to complex compounds. Now a class of halogenating reagents based on anomeric amides that can halogenate complex bioactive molecules with diverse functional groups and heterocycles has been developed. The higher reactivity of these anomeric amide reagents is attributed to the energy stored in the pyramidalized nitrogen.