Optimization of the Ugi reaction using parallel synthesis and automated liquid handling.
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.
Bradley
Jean-Claude
JC
Department of Chemistry, Drexel University.
Mirza
Khalid Baig
KB
Osborne
Tom
T
Wiliams
Antony
A
Owens
Kevin
K
D000962:Antimalarials / Q000138:chemical synthesis; D001547:Benzaldehydes / Q000737:chemistry*; D002219:Carbamates / Q000138:chemical synthesis*; D011232:Chemical Precipitation; D002625:Chemistry, Organic / Q000379:methods*; D005663:Furans / Q000737:chemistry*; D005998:Glycine / Q000031:analogs & derivatives* / Q000737:chemistry; D009570:Nitriles / Q000737:chemistry*
D000962:Antimalarials; D001547:Benzaldehydes; D002219:Carbamates; D005663:Furans; D009570:Nitriles; C029052:BOC-glycine; C439622:furfurylamine; C099535:tert-butyl isocyanide; C032175:benzaldehyde; D005998:Glycine