Flow Chemistry on Multigram Scale: Continuous Synthesis of Boronic Acids within 1 s

Abstract

The benefits and limitations of a simple continuous flow setup for handling and performing of organolithium chemistry on the multigram scale is described. The developed metalation platform embodies a valuable complement to existing methodologies, as it combines the benefits of Flash Chemistry (chemical synthesis on a time scale of <1 s) with remarkable throughput (g/min) while mitigating the risk of blockages.

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

“…Chem. Eur.J.2020, 26,[19][20][21][22][23][24][25][26][27][28][29][30][31][32] www.chemeurj.org Concept stable hetero-substituted organolithiums generated in flow by deprotonation has been reported by Barker andc o-workers. [23] Ad ifferent approach, for the introduction of ad ihalomethylenic unit, was recently reported by Knochel, who developed a continuousf low tactic for homologation of esters using di-chloroacetic acid 13.T he reported strategy, was an unprecedented mild and scalable Claisen reactiont hat used an unstable chloroacetated ianion tamed using flow technology (Scheme 6).…”

“…Chem. Eur.J.2020, 26,[19][20][21][22][23][24][25][26][27][28][29][30][31][32] www.chemeurj.org tion of an aldol reactioni nvolving an ester lithium enolate and an aldehydee nding up with adduct 29 (Scheme 14). [41] To comply with recommendations by pharmaceutical regulatory authorities, the process was designedt aking advantages from processa nalytical technology( PAT) that allow for an accurate processd evelopment.…”

“…Furthermore, Sedelmeier reported the generation and use of (dichloromethyl)lithium in continuous flow,b yd eprotonation of dichloromethane 10 (Scheme5). [20] This dihalolithium carbenoid was generated at À30 8C, and used within 0.5 sp roviding the useful synthons 11 and 12,f urther employedi no ther transformations under batch conditions. It is worth notingt hat the generation and use of the lithiated reagents requires À78 8Ci nb atch conditions.…”

“…Negishi and decarboxylative Negishic ross-coupling of flow-prepared organozinc reagents.Chem. Eur.J.2020,26,[19][20][21][22][23][24][25][26][27][28][29][30][31][32] www.chemeurj.org2020 Wiley-VCH Verlag GmbH &Co. KGaA, Weinheim 29…”

Overcoming the Hurdles and Challenges Associated with Developing Continuous Industrial Processes

“…Boronic acids are synthetically useful as a precursor for Suzuki cross‐coupling reactions. [ 5 ] The work of Sedelmeier et al [ 6 ] reports the benefits and critically the limitations of a simple flow set‐up (Scheme 1) for the handling of organolithium chemistry for multi‐gram delivery. The very short residence times (<1 s) and highly efficient mixing at non‐cryogenic reaction temperatures are indicative of Flash Chemistry.…”