Advancement in Organic Synthesis Through High Throughput Experimentation

Abstract

and cyanoarenes has also been optimized using an HTE approach. [63] Other Photochemical TransformationsNon-activated alkyl bromides were coupled with Michael acceptors in a photoredox Giese-type reaction. [64] Reaction optimization was performed by studying the effect of photocatalyst, solvent, base, and varying amounts of radical initiator (Me 3 Si) 3 SiH on product and by-product profile. Another study of conjugate addition using photocatalytic methodology was shown for the synthesis of unnatural β-alkyl α-amino acid derivatives via decarboxylative photocatalysis. [65] Photocatalysis was performed with oxime and cyanopyridine precursors (Scheme 4g) to form primary amine products. [66] Four different solvents (acetone, DCE, ACN, DMSO), nine different photocatalysts, and two reductants were used to evaluate 45 unique reactions. DMSO with diisopropylamine and Ir[dF(Me) ppy] 2 dtbbpyPF 6 gave the highest yield by UPLC, although many Scheme 4. Photocatalytic transformations in HTE.

Continuous Flow Synthesis of A2E Guided by Design of Experiments and High-Throughput Studies

“…We then used a Biomek i7 liquid handling robot to transfer the reagents in proportions required for the DoE into the respective wells of glass vial lined 96 well plates and sealed (Figure S1B). − The plates were then transferred to heating blocks set to 25, 37, and 100 °C and heated for 48 h (Figure S1C). After cooling to room temperature, the solutions were transferred from the three 96-well source plates to one 384-well daughter plate (Figure S1D,E) and stored at −80 °C until analysis.…”

“…The Biomek i7 was then used to pin the solutions from the 384-well plate to a DESI-MS plate for MS analysis of all the reactions (Figure S1F,G). − Each reaction was performed in four replicates.…”

“…HTE allows for the grouping of common operations so that a series of experiments can be rapidly performed in parallel at microscale. This approach also allows for the automation of procedures, such as liquid handling and data analysis, so that hundreds of experiments can be executed simultaneously and analyzed using quantitative techniques such LC–MS or semi-quantitatively by DESI-MS. − HTE also allows for facile and automated replication of experiments, making it the ideal pairing with the DoE approach, because the labor burden for implementing replicates does not increase considerably when the experiments are executed in a microscale format. , …”

A General, Multimetallic Cross-Ullmann Biheteroaryl Synthesis from Heteroaryl Halides and Heteroaryl Triflates

“…Modern medicinal chemistry often utilizes HTE to facilitate the synthesis of collections of molecules for biological testing . Generally, μmol scale strikes the right balance between material cost and providing enough material for isolation and characterization (although the actual testing often needs only nanomoles of material). Here, the solid reagent coated glass ChemBeads in combination with our multivariable catalytic system can quickly access arrays of biheteroaryls (Figure E) and efficiently improve the yields of target molecules via fast reoptimizations with a “Toolbox Plate” (Figure F–H).…”

“…Finally, the syntheses of products B3 , C6 , and H2 under these reoptimized conditions were conducted on a 0.5 mmol scale with 14% ( B3 ), 29% ( C6 ), and 44% ( H2 ) isolated yields, respectively. While further optimization could be conducted, these yields would be sufficient for testing and can be obtained quickly with minimal material (2–4 mg of substrate per reaction).…”