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

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• 作者：Lekha Gupta ; Alexander C. Hoepker ; Yun Ma ; Mihai S. Viciu ; Marc F. Faggin ; David B. Collum
• 刊名：The Journal of Organic Chemistry
• 出版年：2013
• 出版时间：May 3, 2013
• 年：2013
• 卷：78
• 期：9
• 页码：4214-4230
• 全文大小：735K
• 年卷期：v.78,no.9(May 3, 2013)
• ISSN：1520-6904

文摘

Lithium diisopropylamide (LDA)-mediated ortholithiations of 2-fluoropyridine and 2,6-difluoropyridine in tetrahydrofuran at 鈭?8 掳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鈥揂rLi mixed tetramers. A hypersensitivity of the ortholithiation rates to traces of LiCl derives from LiCl-catalyzed LDA dimer鈥搈onomer exchange and a subsequent monomer-based ortholithiation. Fleeting 2:2 LDA鈥揕iCl 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 鈭?8 掳C.