Sodium Diisopropylamide in Tetrahydrofuran: Selectivities, Rates, and Mechanisms of Arene Metalations

Abstract

Sodium diisopropylamide (NaDA)-mediated metalations of arenes in tetrahydrofuran (THF)/hexane or THF/Me2NEt solutions are described. A survey of >40 benzenoid- and pyridine-based arenes with a range of substituents demonstrates the efficacy and regioselectivity of metalation. Metalations of activated disubstituted arenes and selected monosubstituted arenes are rapid at −78 °C. Rate studies of 1,3-dimethoxybenzene and related methoxylated arenes show exclusively monomer-based orthometalations with two or three coordinated THF ligands. Rate studies of the isotopic exchange of benzene and monosubstituted arenes with weakly activating groups reveal analogous di- and trisolvated monomer-based metalations. Cooperative inductive, mesomeric, steric, and chelate effects are discussed.

Case for Lithium Tetramethylpiperidide-Mediated Ortholithiations: Reactivity and Mechanisms

“…By contrast, metalation rates for LiTMP and NaDA tend to be comparable. 26 The regioselectivities of LiTMP are distinct from those of either LDA or NaDA. The hindered TMP fragment has two effects: (1) LiTMP metalates less acidic but sterically more accessible sites, 4 such as the 4 position of 2 to give 2-Li; and…”

“…Thermochemically recalcitrant metalations such as arene 3 metalate incompletely at equilibrium using excess LDA or NaDA, whereas metalations by excess LiTMP are generally quantitative. 25,26 However, stoichiometric LiTMP also affords an incomplete metalation of 3 at equilibrium, putting the relative thermochemical boost by LiTMP in the vicinity of 1 order of magnitude (a single pK A unit), consistent with the results of Fraser and co-workers. 7 Comparing and contrasting the metalation rates shows that reactions with LiTMP are 5−500 times faster than those with LDA under comparable conditions for the few substrates slow enough to be monitored.…”

“…26 Similar decomposition is obtained with NaDA. 26 By contrast, the LiTMP-mediated ortholithiation of 8 affords 10, as shown by deuterium quenching, along with limited (15%) decomposition.…”

Flow Technology for the Genesis and Use of (Highly) Reactive Organometallic Reagents

“…Nevertheless, new methods for sodiation of organic molecules have been recently introduced. Collum reported a comprehensive study on the reactivity and stability of the base sodium diisopropylamide (NaDA) . Takai developed a straightforward strategy for accessing organosodium compounds from aryl chlorides and easy‐to‐handle sodium dispersion .…”

“…Collum reported ac omprehensive study on the reactivity and stability of the base sodium diisopropylamide (NaDA). [56] Takai developed astraightforwardstrategy for accessing organosodium compounds from aryl chlorides and easy-to-handle sodium dispersion. [57] It is worth pointingo ut two interesting aspects of the under exploited organosodium chemistry:1 )the better chemoselectivity (as in the case of the use of NaDA) and 2) the fact that sodium is somewhat cheaper and more abundant with respect to lithium or other metals.…”