A platform for automated nanomole-scale reaction screening and micromole-scale synthesis in flow

Abstract

The scarcity of complex intermediates in pharmaceutical research motivates the pursuit of reaction optimization protocols on submilligram scales. We report here the development of an automated flow-based synthesis platform, designed from commercially available components, that integrates both rapid nanomole-scale reaction screening and micromole-scale synthesis into a single modular unit. This system was validated by exploring a diverse range of reaction variables in a Suzuki-Miyaura coupling on nanomole scale at elevated temperatures, generating liquid chromatography-mass spectrometry data points for 5760 reactions at a rate of >1500 reactions per 24 hours. Through multiple injections of the same segment, the system directly produced micromole quantities of desired material. The optimal conditions were also replicated in traditional flow and batch mode at 50- to 200-milligram scale to provide good to excellent yields.

High Throughput Experimentation and Continuous Flow Validation of Suzuki–Miyaura Cross‐Coupling Reactions

“…Comparison of the anisole family of precursors (2-5)r evealed thatt he meta-positioned methoxy group (4,F igure 3C)p rovided more desired product than ortho (5,F igure 3D)o rpara (2&3,F igure 3A&B) due to the reduced electron donating contribution from the meta placement of this substituent. [13] Haloanilines (6)(7)(8)(9)(10)(11)w ere also transformed into the corresponding biphenyl products,y ieldingm oderatep eak intensities for the cross-coupled products ( Figure 4A-G). As seen in the anisole family of compounds, the meta product, 17 (1 + 8, Figure 4C), produced ah igher peak intensity than para, 16 (1 + 6/7,F igure 3A&B), for the primary amine substrates.…”

“…After HTE, a quick validation of these hotspots is used to build confidence in the reaction hits identified by the HTE process. Microfluidic reaction evaluation of the HTE hits are an essential step for validating organic transformations under continuous flow conditions. This has been shown to be especially true for catalytic reactions that can be achieved under faster and greener conditions .…”

“…and Santanilla et al. have reported high throughput S‐M cross‐coupling reactions in both flow and batch mode with demonstration of the ability to screen reactions quickly on the nanomole‐scale under different conditions. These efforts encouraged us to explore the S‐M cross‐coupling reactions in the synthesis of precursor compounds of importance in biological, pharmaceutical, and materials applications.…”

“…The S-M reactionw as chosen because carbon-carbon bond formation via palladium-catalyzed S-M cross-couplingi s an important reaction for small molecule synthesis [9] that has been widely used. [10] Recently Perera et al and Santanilla et al have reported [3b,6] high throughput S-M cross-couplingr eactions in both flow andb atch mode with demonstrationo ft he ability to screen reactions quickly on the nanomole-scale under different conditions. These efforts encouraged us to explore the S-M cross-coupling reactions in the synthesis of precursorc ompounds of importance in biological, pharmaceutical, and materialsa pplications.…”

Hochdurchsatzstrategien zur Entdeckung und Optimierung katalytischer Reaktionen

“…[38] [40] Glorius und Mitarbeiter erkannten die Gelegenheit, diese Vorgehensweise bei der Entdeckung photokatalytischer Tr ansformationen zu nutzen. [38] [40] Glorius und Mitarbeiter erkannten die Gelegenheit, diese Vorgehensweise bei der Entdeckung photokatalytischer Tr ansformationen zu nutzen.…”