A Practical Method For Stabilizing Lithiated Halogenated Aromatic Compounds

Abstract

An exothermic decomposition was observed during a metalation/acylation of 3,4-difluoroanisole (5), resulting in a significant thermal hazard. The lithiated anion 6 was found to decompose exothermically at temperatures above −47 °C showing an adiabatic temperature rise at a peak rate of 120 °C/min. A literature search revealed similar observations for metalation/acylation in analogous aromatic difluoro compounds. This sequence of reactions was evaluated thermochemically. Control experiments at −55 °C over 2 h indicated anion 6 was stable at temperatures below −55 °C under dilute reaction concentrations. This runaway hazard could be addressed using MgCl2 to stabilize the reactive species and thereby decrease its decomposition rate. Thermochemical experiments suggested MgCl2 forms a weak interaction with lithiated species 6, rather than via complete lithium−magnesium exchange. The process was successfully piloted on a multikilo scale by use of MgCl2 as an additive.

Flow Grignard and Lithiation: Screening Tools and Development of Continuous Processes for a Benzyl Alcohol Starting Material

“…3 Due to the high heat of reaction and unstable aryl lithium species, these processes are normally conducted below −50 °C. 4 Such temperatures are achievable in batch at large scale but require specialized equipment that is not common to most pilot plant environments. Additionally, the mixing characteristics in large batch equipment may result in hot spots, byproduct formation, and reduced yield.…”

“…The resulting aryl lithium species can be unstable, especially when benzyne formation or anion migration pathways are possible . Due to the high heat of reaction and unstable aryl lithium species, these processes are normally conducted below −50 °C . Such temperatures are achievable in batch at large scale but require specialized equipment that is not common to most pilot plant environments.…”

Enantioselective Synthesis of a Highly Substituted Tetrahydrofluorene Derivative as a Potent and Selective Estrogen Receptor Beta Agonist

“…After addition of aqueous HCl and filtration, the methanol stream was used directly in the subsequent triazole formation which smoothly occurred upon treatment with NaNO 2 to furnish 43 in 93% yield over two steps. Although lithiation with LDA had worked well previously, obtaining temperatures as low as <−60 °C was inconvenient on large scale, and more importantly safety concerns associated with potential runaway benzyne formation necessitated an alternative. For this purpose, magnesiation with in situ prepared Bu 3 (TMP)­MgLi 2 at −40 °C in THF provided enhanced thermal stability and resolved these concerns, and following trapping with DMF furnished aldehyde 44 in 91 A%.…”

Synthesis of Multideuterated (Hetero)aryl Bromides by Ag(I)-Catalyzed H/D Exchange

“…Despite many efforts on the extension of substrate scope, the reported transition-metal-catalyzed H/D exchange protocols still relied on the use of directing groups containing an N or O atom to assist H/D exchange processes and to control site-selectivity. Direct H/D exchange of aryl bromides is still a great challenge, mainly due to their relatively lower reactivity of C–H bond and fragile nature of C–Br bond . For example, complete debromination was observed in H/D exchange process with Pd/C as catalyst .…”