Optimization of the Ugi Reaction Using Parallel Synthesis and Automated Liquid Handling

Abstract

The optimization of a Ugi reaction involving the mixing of furfurylamine, benzaldehyde, boc-glycine and t-butylisocyanide is described. Triplicate runs of 48 parallel experiments are reported, varying concentration, solvent and the excess of some of the reagents. The isolation of the product was achieved by a simple filtration and wash procedure. The highest yield obtained was 66% from 0.4 M methanol with 1.2 eq. of imine. This is significantly above the 49% yield obtained from the initial reaction under equimolar concentration at 0.4 M in methanol. Methanol solutions with reagent concentrations of 0.4M or 0.2M gave superior yields while all solvent systems at 0.07M performed poorly. At 0.2M, methanol and ethanol/methanol (60/40) mixtures were statistically equally good while THF/methanol (60/40) was poor and acetonitrile/methanol (60/40) was intermediate. Good reproducibility of the precipitate yields was obtained in these replicate experiments, allowing for subtle interaction effects to be positively identified.

Nanomolar Synthesis in Droplet Microarrays with UV‐Triggered On‐Chip Cell Screening

“…By collecting the solution of five spots after cleavage, each with the same target compound, it was possible to have enough sample volume for LC‐MS analysis of 13 exemplary reactions ( Table 2 , products 24 – 36 ), which showed purities between 21% and 91%. These values are in the expectable range of Ugi reactions without fine tuning of the reaction conditions for every single combination of starting materials …”

Development and Application of Synthetic Affinity Ligands for the Purification of Ferritin-Based Influenza Antigens

“…In previous reports, the Ugi one-pot mixture of furfurylamine, benzalde-hyde, boc-glycine, and tert-butyl isocyanide resulted in an isolated yield of 66%. 17 Moreover, Torroba and workers used cyclohexyl isocyanide in an Ugi reaction to achieve yields >80%. 18 To synthesize ligand Boc-SJ047, the tert-butyl isocyanide was substituted with cyclohexyl isocyanide, in an attempt to increase hydrophobicity for ferritin target region binding.…”

“…Ligands Boc-SJ047 and Boc-SJ055 were synthesized in isolated yields ≥70%. In previous reports, the Ugi one-pot mixture of furfurylamine, benzaldehyde, boc-glycine, and tert -butyl isocyanide resulted in an isolated yield of 66% . Moreover, Torroba and workers used cyclohexyl isocyanide in an Ugi reaction to achieve yields >80% .…”

Beautifying Data in the Real World

“…As part of a wider program of drug discovery research (Bradley 2007) led by Professor Jean-Claude Bradley, we wished to predict the solubility of a wide range of chemicals in nonaqueous solvents such as ethanol, methanol, etc. Of greatest interest was the solubility of aldehydes, carboxylic acids, isonitriles, and primary amines-components required for the Ugi reaction that the Bradley group use to synthesize potential antimalarial targets (Bradley et al 2008). The solubility of a specific compound is the quantity of that compound that can be dissolved in a specific solvent.…”