Synthesis of Phenylboronic Acids in Continuous Flow by Means of a Multijet Oscillating Disc Reactor System Operating at Cryogenic Temperatures

Abstract

A multijet oscillating disk (MJOD) millireactor system suitable for operating at cryogenic temperatures has been developed, assembled, and investigated. This new reactor system (cryoMJOD) was realized with the purpose to prepare various phenylboronic acids in a continuous two (three)-step telescoped synthetic process at temperatures in the interval −50 to −75 °C. In this process, n-butyllithium was reacted with a phenylbromide to provide the corresponding phenyllithium derivative, whereupon a borate was added under the formation of target product phenylboronic acid in good selectivity and medium-togood yield (50−75%). These results were competitive with results previously revealed in the literature. The residence times of the telescoped two-step process were considerably shorter compared to those of batch mode operations for the identical syntheses. The flow process was optimized by means of statistical experimental design and multivariate regression, upon which the process was utilized for the production of a series of phenylboronic acid derivatives, all in medium-to-good yield. One of the substrates, 4-methoxyphenylboronic acid, was submitted for throughput improvements, resulting in a process with capability to produce the product phenylboronic acid in a quantity of 2.0 kg × day −1 .

Synthesis of Organometallic Compounds in Flow

“…Other examples of synthesis of boronic acids or boronic esters were reported by Ley and coworkers; in these cases the reactions were conducted at low temperature (−60 °C) using a Cryo‐Flow reactor able to handle cryogenic conditions. Multijet Oscillating Disc (MJOD) reactors can also be used for the synthesis of phenylboronic acids …”

“…Multijet Oscillating Disc (MJOD) reactors can also be used for the synthesis of phenylboronic acids. [33] The Miyaura borylation is an important reaction for the preparation of pharmaceutical intermediates. Usutani and Sedelmeier reported a flow process for the [34] Trifluoroborates are very often a stable alternative to boronic acids in Suzuki-Miyaura reactions.…”

Concepts and Optimization Strategies of Experimental Design in Continuous-Flow Processing

“…The same year, statistical experimental design was exploited for the synthesis of a small library of phenylboronic acids using a multijet oscillating disc (MJOD) millireactor system [27]. The MJOD reactor is a valuable technology for heterogeneous reactions and flow processes that require cryogenic temperatures.…”

Maschinengestützte organische Synthese

“…Auch das in Abschnitt 6 detaillierter beschriebene Multijet‐Oscillating‐Disc‐Mikroreaktorsystem (MJOD) wurde unter kryogenen Bedingungen eingesetzt. Ein Forscherteam stellte bei Temperaturen zwischen −50 °C und −75 °C in einer Durchfluss‐Synthese Phenylboronsäuren her; als Kühlmittel wurde Ethanol verwendet, das durch Wärmetauscher und durch einen Reaktormantel gepumpt wurde 42. Dieses System veranschaulicht, wie mithilfe mehrerer unterschiedlicher maschinengestützter Vorgehensweisen, von der Handhabung von Schlämmen bis hin zur Verarbeitung bei kryogenen Temperaturen, Transformationen möglich werden, die zuvor fehlschlugen.…”