Continuous Flow-Processing of Organometallic Reagents Using an Advanced Peristaltic Pumping System and the Telescoped Flow Synthesis of (E/Z)-Tamoxifen

Abstract

A new enabling technology for the pumping of organometallic reagents such as n-butyllithium, Grignard reagents, and DIBAL-H is reported, which utilises a newly developed, chemically resistant, peristaltic pumping system. Several representative examples of its use in common transformations using these reagents, including metal–halogen exchange, addition, addition–elimination, conjugate addition, and partial reduction, are reported along with examples of telescoping of the anionic reaction products. This platform allows for truly continuous pumping of these highly reactive substances (and examples are demonstrated over periods of several hours) to generate multigram quantities of products. This work culminates in an approach to the telescoped synthesis of (E/Z)-tamoxifen using continuous-flow organometallic reagent-mediated transformations.

Exploiting the C-H bond in metal catalyzed C-C bond forming reactions

“…We also investigated systems in which C(sp 3 )-H and C(sp 2 )-H bonds can be exchanged. Interestingly, in all these examples we found the highest deuterium content in the aliphatic positions (35,(38)(39)(40). Additionally, indole derivatives can be deuterated under microwave irradiation as well, which shortens the reaction time from 3 hours to 15 minutes.…”

“…Additionally, complete reaction sequences towards complex molecules have been carried out under flow conditions. [39][40][41] However, direct arylations have not been included in this reaction portfolio so far. Hence we set out to develop such a protocol.…”

Flow Technology for Organometallic-Mediated Synthesis

“…In another recent work, Ley reported an efficient and telescoped continuous-flow synthesis of (E/Z)-tamoxifen by using a peristaltic pumping system [46].…”

Flow chemistry vs. flow analysis

“…Therefore, similarly to flow analytical systems, the peristaltic pumps find increasing applications also in systems for continuous flow synthesis, e.g. with the fluoropolymer peristaltic tubes or nonliner rotor systems eliminating flow pulsations [80]. The latter should potentially find also applications in analytical flow injection systems.…”