A Catalyst‐Free Amination of Functional Organolithium Reagents by Flow Chemistry

Abstract

Reported is the electrophilic amination of functional organolithium intermediates with well-designed aminating reagents under mild reaction conditions using flow microreactors. The aminating reagents were optimized to achieve efficient C-N bond formation without using any catalyst. The electrophilic amination reactions of functionalized aryllithiums were successfully conducted under mild reaction conditions, within 1 minute, by using flow microreactors. The aminating reagent was also prepared by the flow method. Based on stopped-flow NMR analysis, the reaction time for the preparation of the aminating reagent was quickly optimized without the necessity of work-up. Integrated one-flow synthesis consisting of the generation of an aryllithium, the preparation of an aminating reagent, and their combined reaction was successfully achieved to give the desired amine within 5 minutes of total reaction time.

Memory of Chirality in a Flow‐Based System: Enantioselective Synthesis of Quaternary α‐Amino Acids Using Flow Microreactors

“…Highly unstable intermediates can be used for the next reaction before they decompose or isomerize by virtue of extremely short reaction times. It is also really interesting in the field of labile organometallic anion chemistry . This concept of flash chemistry seemed thus to be perfectly adapted to our MOC reactions and it has never been tried before for enantioselective synthesis by MOC.…”

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.…”

Multi‐Step Continuous‐Flow Organic Synthesis: Opportunities and Challenges

“…Yoshida and co-workersstudied the amination of the in situ generated organolithiums for in-flow CÀNb ond formation under mild reactionc onditions withoutr equiring catalysts or additives. [15] As ar esult of the process optimization,t he best aminatingr eagent (prepared in flow) was found to have a2 ,6-dichlorobenzoyl group and gave the desired amine 48 in 81 %y ield. The continuous-flow synthesis was successfully completed within 5min ( Figure 13).…”

“…The direct nucleophilic substitution of organolithium on the nitrogen atom, or the formation of C−N bonds through the electrophilic amination of organolithium, is an exciting method of amination. Yoshida and co‐workers studied the amination of the in situ generated organolithiums for in‐flow C−N bond formation under mild reaction conditions without requiring catalysts or additives [15] . As a result of the process optimization, the best aminating reagent (prepared in flow) was found to have a 2,6‐dichlorobenzoyl group and gave the desired amine 48 in 81 % yield.…”