Scalable Continuous Synthesis of Organozinc Reagents and Their Immediate Subsequent Coupling Reactions

Abstract

The continuous synthesis of organozinc reagents and their immediately following subsequent also continuous consumption in catalyzed and noncatalyzed coupling reactions were investigated. In the first step, a bed of Zn turnings at variable liquid throughputs and concentrations of organic halide solutions was used, and the formed Zn organometallics were analyzed for quality control. They were then directly pumped into a second step, namely, Reformatsky, Saytzeff, and Negishi coupling reactions. In the organozinc halides' formation, a novel process window was employed by using a large molar excess of Zn turnings and investigating mechanical as well as chemical Zn activation. Subsequent couplings of the freshly prepared Zn organometallics were done using examples of a Reformatsky, Saytzeff, and Negishi coupling reaction. For the Zn organometallics' formation, a laboratoryscale reactor setup previously built for Grignard reagent formation was evaluated including a Zn replenishing unit; the same reactor was also used in the metal-catalyzed subsequent step (Negishi coupling). The main objective of this work was to establish the scalable continuous formation of Zn organometallic reagents enabling fast and safe process optimization, analyze the reagents for their purity, and then immediately consume them in various follow-up steps, always only leaving a very small amount of reactive and sensitive organometallic reagent in the setup. It was found that full conversion of the employed halides could be achieved within a single passage through the reactor with organozinc yields of 82−92%, as well as being able to successfully perform subsequent nonand metal-catalyzed coupling steps with yields of up to 92%. A pilot-scale setup allowing a liquid throughput of up to 3−5 L/h has also been built and is ready to be tested with the synthesis as established here.

Synthesis of α‐ and β‐Carbolines by a Metalation/Negishi Cross‐Coupling/SNAr Reaction Sequence

“…Thus, a representative set of carbolines (α‐carbolines 4 a , 4 c , and 4 e and β‐carboline 4 v ) was prepared in similar yields compared to the ones obtained under batch conditions (Table 4). Here, the clear advantage of the continuous flow procedure is the potential to be reproducibly scaled up [22] …”

“…Here, the clear advantage of the continuous flow procedure is the potential to be reproducibly scaled up. [22] In summary, we have developed a highly efficient route towards the synthesis of α-and β-carbolines. Fluoropyridines were subjected to a directed ortholithiation followed by zincation and Negishi crosscoupling with 2-haloanilines to afford 2-aminobiaryls.…”

Impact of residence time distributions in reacting magnesium packed beds on Grignard reagent formation – pump-induced flow behaviour in non-reacting magnesium beds (part 1)

“…The investigated reactor is a laboratory-scaled tubular reactor designed by Fraunhofer IMM and manufactured by 3D laser melting for the formation of organomagnesium halide reagents. 43,44 Fig. 1 shows the reactor in more detail.…”

Impact of residence time distributions in reacting magnesium packed-beds on Grignard reagent formation – Pump-induced flow behaviour in non-reacting magnesium beds (part 1)

“…The investigated reactor is a laboratory-scaled tubular reactor designed by Fraunhofer IMM and manufactured by 3D laser melting for the formation of organomagnesium halide reagents. 36,37 Figure 1 displays the reactor in more detail. It consists of a reactor cartridge and a replenishment unit that can be attached to the main reactor body for replenishing metal turnings during organometallic halide reagent synthesis.…”