Practical and Regioselective Synthesis of C‑4-Alkylated Pyridines

• Published in: Journal of the American Chemical Society Vol. 143; no. 31; pp. 11927 - 11933
• Main Authors: Choi, Jin, Laudadio, Gabriele, Godineau, Edouard, Baran, Phil S
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 11.08.2021
• Subjects: Alkylation; Carboxylic Acids - chemistry; Molecular Structure; Pyridines - chemical synthesis; Pyridines - chemistry; Stereoisomerism
• ISSN: 0002-7863; 1520-5126; 1520-5126
• DOI: 10.1021/jacs.1c05278

The direct position-selective C-4 alkylation of pyridines has been a long-standing challenge in heterocyclic chemistry, particularly from pyridine itself. Historically this has been addressed using prefunctionalized materials to avoid overalkylation and mixtures of regioisomers. This study reports the invention of a simple maleate-derived blocking group for pyridines that enables exquisite control for Minisci-type decarboxylative alkylation at C-4 that allows for inexpensive access to these valuable building blocks. The method is employed on a variety of different pyridines and carboxylic acid alkyl donors, is operationally simple and scalable, and is applied to access known structures in a rapid and inexpensive fashion. Finally, this work points to an interesting strategic departure for the use of Minisci chemistry at the earliest possible stage (native pyridine) rather than current dogma that almost exclusively employs Minisci chemistry as a late-stage functionalization technique.