In Situ Quench Reactions of Enantioenriched Secondary Alkyllithium Reagents in Batch and Continuous Flow Using an I/Li‐Exchange

Abstract

We report a practical in situ quench (ISQ) procedure involving the generation of chiral secondary alkyllithiums from secondary alkyl iodides (including functionalized iodides bearing an ester or a nitrile) in the presence of various electrophiles such as aldehydes, ketones, Weinreb amides, isocyanates, sulfides, or boronates. This ISQ‐reaction allowed the preparation of a broad range of optically enriched ketones, alcohols, amides, sulfides and boronic acid esters in typically 90–98 % ee. Remarkably, these reactions were performed at −78 °C or −40 °C in batch. A continuous flow set‐up permitted reaction temperatures between −20 °C and 0 °C and allowed a scale‐up up to a 40‐fold without further optimization.

Calculation-assisted regioselective functionalization of the imidazo[1,2-a]pyrazine scaffold via zinc and magnesium organometallic intermediates

“…In addition, based on previously described nucleophilic addition reactions to pyrazolo[1,5- a ]pyrimidine ( 1 , Scheme 1) 4 c we have examined the addition of Grignard reagents triggered by a coordination at the most basic nitrogen N1 (see 24 ). Thus, we have treated 6-chloroimidazo[1,2- a ]pyrazine ( 6 ) with various organomagnesium halides complexed with lithium chloride of type 23 28 (Scheme 8). Indeed, the reaction of 6 with 4-methoxyphenylmagnesium bromide·lithium chloride ( 23a ) 28 a gave an intermediate magnesium species 25 which after water quenching provided dihydroimidazo[1,2- a ]pyrazine 26a in 63% yield.…”

Trendbericht Organische Chemie 2024

“…Mit einem Mikroflow-Reaktor lässt sich der Prozess auf die 40-fache Menge hochskalieren und bei -20 °C durchführen. 51) Nagaki erzeugte durch Flowsynthese aus Diiodmethan das hochreaktive Lithiumcarbenoid (10) und setzte dieses mit Elektrophilen um. 52) Dass Flowsynthese in mehrstufigen Synthesen nützlich ist, zeigen die effizienten Synthesen von Dithiothreitol (DTT), 53) des HIV-Integrase-Inhibitors Dolutegravir (11) 54) und des CB2-Agonisten RG7774 (12).…”

Recent Advances in Halogen–Metal Exchange Reactions

“…The chiral secondary alkyllithiums were generated in the presence of various electrophiles such as aldehydes, ketones, Weinreb amides, isocyanates, sulfides, or boronates, which allowed the preparation of a broad range of optically enriched products (3a−3e) in typically 90−98% ee (Scheme 2, bottom). 33 The functionalized iodides bearing an ester or a nitrile can be tolerated in this ISQ reaction. Remarkably, these reactions were performed at −78 or −40 °C in batch.…”

“…Very recently, we reported a practical in situ quench (ISQ) procedure by adding t BuLi to premixed secondary alkyl iodides and electrophiles. The chiral secondary alkyllithiums were generated in the presence of various electrophiles such as aldehydes, ketones, Weinreb amides, isocyanates, sulfides, or boronates, which allowed the preparation of a broad range of optically enriched products ( 3a – 3e ) in typically 90–98% ee (Scheme , bottom) . The functionalized iodides bearing an ester or a nitrile can be tolerated in this ISQ reaction.…”