Flow Microreactor Technology for Taming Highly Reactive Chloroiodomethyllithium Carbenoid: Direct and Chemoselective Synthesis of α-Chloroaldehydes

Abstract

A straightforward flow synthesis of α-chloro aldehydes has been developed. The strategy involves, for the first time, the thermal unstable chloroiodomethyllithium carbenoid and carbonyl compounds. A batch versus flow comparative study showcases the superb capability of flow technology in prolonging the lifetime of the lithiated carbenoid, even at −20 °C. Remarkably, the high chemoselectivity realized in flow allowed for preparing polyfunctionalized α-chloro aldehydes not easily accessible with traditional batch procedures.

Solvation Effects on the Structure and Stability of Alkali Metal Carbenoids

“…In the case of lithium and magnesium carbenoids decomposition reactions via metal salt elimination often occur at low temperatures, thus impeding a controlled handling and isolation so that many transformations are still performed with in situ prepared reagents. Despite the synthetic advances [9] and progresses in the stabilization [10] and handling [11] of carbenoids made in past years, only little information has been accrued on the impact of the structures on the reactivity. While the solid-state structures of several s-block metal carbenoids have been elucidated by single-crystal X-ray diffraction analysis (XRD), [12] their solution chemistry is almost unexplored.…”

Lösungsmitteleinflüsse auf die Struktur und Stabilität von Alkalimetallcarbenoiden

“…Im Falle der Lithium-und Magnesiumcarbenoide finden Zersetzungsreaktionen durch Metallsalzeliminierungen häufig bei niedrigen Temperaturen statt, was eine kontrollierte Handhabung und Isolierung erschwert, sodass viele Transformationen immer noch mit in situ hergestellten Reagenzien durchgeführt werden. Trotz der synthetischen Vorteile und Fortschritte [9] der letzten Jahre in der Stabilisierung [10] und Handhabung [11] von Carbenoiden gibt es nur wenige Informationen über den Einfluss der Strukturen auf die Reaktivität. Während zahlreiche Molekülstrukturen von s-Block-Metallcarbenoiden im Festkçrper mittels Einkristallrçntgenstrukturanalyse (XRD) aufgeklärt werden konnten, [12] ist die Strukturchemie in Lçsung nahezu unerforscht.…”

Consecutive and Selective Double Methylene Insertion of Lithium Carbenoids to Isothiocyanates: A Direct Assembly of Four‐Membered Sulfur‐Containing Cycles

“…Crucial for the successful reaction design was ensuring that the homologation sequence could reach completion within the short lifetime of the carbenoid used. [16] To this end, we conceived to generate a first homologation reactive intermediate susceptible of rapid second CH 2 -insertion, furnishing the targeted four-membered cycle. [17] Ideally, an electrophilic platform fulfilling this criterion could be represented by an isothiocyanate (V): in fact, the formation of a nucleophilic thioamidate anion (VI)-after the first homologative event-would induce a fast cyclization to a highly reactive thiiranimine (VII), [18] which would then undergo the second homologation.…”