A Simple Scale-up Strategy for Organolithium Chemistry in Flow Mode: From Feasibility to Kilogram Quantities

Abstract

A platform for conducting organolithium chemistry in continuous flow mode, covering the scales from medicinal chemistry to later phase process development, is described. The use of this flow setup, which mimics the concept of f lash chemistry on scale, has been demonstrated by the exemplary, large-scale preparation of (4-fluoro-2-(trifluoromethyl)phenyl)boronic acid following a reaction sequence of halogen/lithium exchange, borylation, and semibatch workup. Furthermore, the key factors and corresponding practical assessments required for the streamlined and seamless scale-up from lab environment to higher productivity are highlighted.

Overcoming the Hurdles and Challenges Associated with Developing Continuous Industrial Processes

“…Sedelmeier et al [ 9 ] followed up their preliminary work with a further publication discussing the key factors and corresponding practical assessments undertaken to ensure a streamlined and seamless scale up from lab to higher throughput and productivity (Scheme 2). It is essential that redevelopment upon scale‐up is minimal and in batch processing, differing vessel geometries, the cooling capacity of the reactor, and deviations in holding or dosing times can all change the reaction outcome.…”

Flow Chemistry in Contemporary Chemical Sciences: A Real Variety of Its Applications

“…In numerous cases, a 2-3-step telescoping process is ended in a batch reactor with a quenching step. This mostly concerns the works published in recent years, including, for instance, the preparation of boronic acid 6 [155], the generation of dichloromethyllithium [156], or the running of tube-in-tube reactions with diazo-methane in a batch reactor [157], among many others. As a particular achievement in this area, the development of an automated platform integrating batch and flow reactions should be pointed out [158].…”

Synthesis of Polyfunctional Diorganomagnesium and Diorganozinc Reagents through In Situ Trapping Halogen–Lithium Exchange of Highly Functionalized (Hetero)aryl Halides in Continuous Flow

“…[2,6a] Electron-rich aryl bromides (1e,f)w ere also transmetalated in situ in the presence of MgCl 2 ·LiCl and quenched with acyl chloride 3i or subjected to aN egishi cross-coupling [14] after batch transmetalation with ZnCl 2 using Organsc atalyst PEPPSI-i Pr. [16] To further demonstrate the broad applicability of in situ trapping exchange reactions in flow,w ei nvestigated the compatibility of these exchanges with aryl halides bearing challenging functional groups such as ester, ketone,nitro,and heterocumulene groups,f or example,a na zide or isothiocyanate. While most examples were performed on a0 .5 mmol scale,t hese in situ trapping exchange reactions can be easily scaled up by simply extending the runtime.Thus, benzophenone 4g was prepared on a1 0mmol scale in 76 % yield (entry 6) without further optimization.…”

“…While most examples were performed on a0 .5 mmol scale,t hese in situ trapping exchange reactions can be easily scaled up by simply extending the runtime.Thus, benzophenone 4g was prepared on a1 0mmol scale in 76 % yield (entry 6) without further optimization. [16] To further demonstrate the broad applicability of in situ trapping exchange reactions in flow,w ei nvestigated the compatibility of these exchanges with aryl halides bearing challenging functional groups such as ester, ketone,nitro,and heterocumulene groups,f or example,a na zide or isothiocyanate. [2][3][4][5][6] Notably,only halogen-lithium exchanges of o-nitroarenes [2,6] and an alkenyl iodide containing an aliphatic azide [6] at À100 8 8Cu nder batch conditions are known, as well as several flow methods for ester-, ketone-, and nitrocontaining arenes that involve applying ultrafast micromixing and residence times down to 0.0015 s. [8] Again, we found that in the absence of am etal salt, 4-iodophenyl azide [17] (5a) decomposes completely when performing the reaction in flow.…”