Lithium Diisopropylamide-Mediated Ortholithiation of 2‑Fluoropyridines: Rates, Mechanisms, and the Role of Autocatalysis

• Published in: Journal of organic chemistry Vol. 78; no. 9; pp. 4214 - 4230
• Main Authors: Gupta, Lekha, Hoepker, Alexander C, Ma, Yun, Viciu, Mihai S, Faggin, Marc F, Collum, David B
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 03-05-2013
• Subjects: Catalysis; Kinetics; Lithium - chemistry; Lithium Chloride - chemistry; Magnetic Resonance Spectroscopy; Molecular Structure; Organometallic Compounds - chemistry; Propylamines - chemistry; Pyridines - chemistry
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo302408r

Lithium diisopropylamide (LDA)-mediated ortholithiations of 2-fluoropyridine and 2,6-difluoropyridine in tetrahydrofuran at −78 °C were studied using a combination of IR and NMR spectroscopic and computational methods. Rate studies show that a substrate-assisted deaggregation of LDA dimer occurs parallel to an unprecedented tetramer-based pathway. Standard and competitive isotope effects confirm post-rate-limiting proton transfer. Autocatalysis stems from ArLi-catalyzed deaggregation of LDA proceeding via 2:2 LDA–ArLi mixed tetramers. A hypersensitivity of the ortholithiation rates to traces of LiCl derives from LiCl-catalyzed LDA dimer–monomer exchange and a subsequent monomer-based ortholithiation. Fleeting 2:2 LDA–LiCl mixed tetramers are suggested to be key intermediates. The mechanisms of both the uncatalyzed and catalyzed deaggregations are discussed. A general mechanistic paradigm is delineated to explain a number of seemingly disparate LDA-mediated reactions, all of which occur in tetrahydrofuran at −78 °C.