High-Throughput Screening of Reductive Amination Reactions Using Desorption Electrospray Ionization Mass Spectrometry

Abstract

This study describes the latest generation of a high-throughput screening system that is capable of screening thousands of organic reactions in a single day. This system combines a liquid handling robot with desorption electrospray ionization (DESI) mass spectrometry (MS) for a rapid reaction mixture preparation, accelerated synthesis, and automated MS analysis. A total of 3840 unique reductive amination reactions were screened to demonstrate the throughputs that are capable with the system. Products, byproducts, and intermediates were all monitored in full-scan mass spectra, generating a complete view of the reaction progress. Tandem mass spectrometry experiments were conducted to verify the identity of the products formed. The amine and electrophile reactivity trends represented in the data match what is expected from theory, indicating that the system accurately models the reaction performance. The DESI results correlated well with those generated using more traditional mass spectrometry techniques like liquid chromatography–mass spectrometry, validating the data generated by the system.

Advancement in Organic Synthesis Through High Throughput Experimentation

“…Reactions performed in droplets on the nanomole scale with rapid analysis has been shown, with throughputs of 6144 reactions being analyzed in < 3 h. [49] The power of this method was demonstrated in HTE studies of N-alkylation [50] and reductive amination reactions. [51] Another example of rapid analysis is acoustic droplet ejection (ADE) technology [52] in a miniaturized manner for synthesis of drug-like moieties using a tandem Fischer indole and Ugi multicomponent reaction (Scheme 3f). Analysis was performed by SFC-MS and TLC-UV-MS. Acoustic droplet ejection-open port interface-mass spectrometry (ADE-OPI-MS) has been used for rapid analysis to enhance drug discovery efforts.…”

Glass surface as strong base, ‘green’ heterogeneous catalyst and degradation reagent

“…First, we used the high-throughput system which is capable of screening thousands of reaction conditions per day [16][17][18] to test how various base-catalyzed chemical reactions, including elimination, solvolysis, imine formation, Katritzky reaction and Knoevenagel condensation, are affected by addition of glass microspheres. Methanol was added to containers containing glass microspheres (diameter: 32.5 µm, 0.02 equivalents) and then reactant solutions in methanol were added in stoichiometric amounts to reach a final concentration of 1 mM.…”

“…In this study we use a desorption electrospray ionization mass spectrometry (DESI-MS) 14,15 based high-throughput system 16 with hardware and software features that enable reproducible quantitative data to be generated from minimal amounts (50 nL) of sample solution. The integrated automatic platform allows both synthetic reactions 17 and enzymatic reactions 18 to be studied at a throughput of 1 s per sample. Therefore, we performed a single-day high-throughput experiment using the HTE DESI-MS system to screen a large set of glass-catalyzed reactions.…”

Automated High-Throughput System Combining Small-Scale Synthesis with Bioassays and Reaction Screening

“…are rapidly screened to locate optimal conditions. 6,7 The successful hits from reaction screening can then be used in bioactivity screening and further investigation. 8–13…”

“…The reactions include N-alkylation, 70 N -acylation, 71 Sonogashira coupling, 12 nitrosation, 9 Suzuki cross-coupling, 63,72 aromatic nucleophilic substitution (S N Ar), 7 aldol reaction, 73 and reductive amination. 6 Capabilities have also been demonstrated for studies of enzymatic systems, such as acetylcholinesterase, which include the determination of Michaelis–Menten kinetic parameters, as well as the screening and characterization of both inhibitors and reactivators. 62 Currently the fully automated high-throughput DESI-MS system allows the screening of about 6000 samples/h, with sample analysis rates greater than 1 Hz.…”