Investigation of a Lithium–Halogen Exchange Flow Process for the Preparation of Boronates by Using a Cryo‐Flow Reactor

Abstract

Conducting low-temperature organometallic reactions under continuous flow conditions offers the potential to more accurately control exotherms and thus provide more reproducible and scalable processes. Herein, progress towards this goal with regards to the lithium-halogen exchange/borylation reaction is reported. In addition to improving the scope of substrates available on a research scale, methods to improve reaction profiles and expedite purification of the products are also described. On moving to a continuous system, thermocouple measurements have been used to track exotherms and provide a level of safety for continuous processing of organometallic reagents. The use of an in-line continuous liquid-liquid separation device to circumvent labour intensive downstream off-line processing is also reported.

Chemical reaction engineering, process design and scale-up issues at the frontier of synthesis: Flow chemistry

“…the Li-halogen exchange can be kept under control by the use of microreactors. Continuous monitoring of temperature allowed to exclude runaway [147]. Similar concepts were applied by the same authors to a full platform of organic reactions carried out under cryogenic conditions [148].…”

Hydrolysis of 8-(pinacolboranyl)quinoline: where is the 8-quinolylboronic acid?

“…With respect to the degree of hydration, 8-quinolylboronic acid is an intermediate in the conversion of 2 to 3 since loss of an equivalent of water from 2 or addition of an equivalent of water to 3 should yield the uncoordinated, monomeric 8-quinolylboronic acid. Although several papers report the synthesis and application of 8-quinolylboronic acid, [3][4][5][6][7][24][25][26] its crystal structure has not been determined except its dimer form. In fact, a powder X-ray pattern of a commercially obtained sample of '8-quinolylboronic acid' indicates that the sample is actually 3·H 2 O (CCDC 635581) [15] according to simulation of its powder pattern from the single crystal data (Fig.…”

Technology for Continuous Production of Fine Chemicals

“…However, most flow applications for the synthesis of fine or pharmaceutical chemicals are still confined to lab scale in terms of capacity (Table 2). And there are only a few reports to date regarding prototype/ commercial cryo-reactors (71)(72)(73), (please also see the following section titled as "Scalable Modules for Flow Chemistry") or pilot plants (74,75) for organolithium chemistry in flow microreactors. Clearly, this is an area for industry to exploit to enable large scale preparations of previously unattainable chemistry.…”

“…In general, many common electrophiles may be reacted with organolithio intermediates including: aryl halides (25), heteroaryl halides (26)(27)(28), vinyl halides (29), perfluoroalkyl halides (30,31), phosphinates (32), epoxides (33) and aziridines (34). For example electrophiles such as iodomethane (35), methanol (36), chlorotrimethylsilane (35), chlorotributylstannane (35,36), methyl triflate (36), trimethylsilyl triflate (36), chlorotributylstannane (36), aldehydes (35,36), ketones (25,26,35,36), dimethyl sulfate (DMS) (37), dimethylformamide (DMF, (38), borate (39)(40)(41)(42) and carbon dioxide (43,44) have been utilized in flow chemistry syntheses. In addition, reduction reactions with LiBH 4 , LiAlH 4 or their modified forms may be optimized by using flow chemistry to give better selectivity and/or higher chemical yields (45,46).…”