Experimental and theoretical studies of selective thiol-ene and thiol-yne click reactions involving N-substituted maleimides.
A combination of experimental and computational methods has been used to understand the reactivity and selectivity of orthogonal thiol-ene and thiol-yne ″click″ reactions involving N-allyl maleimide (1) and N-propargyl maleimide (2). Representative thiols methyl-3-mercaptopropionate and β-mercaptoethanol are shown to add exclusively and quantitatively to the electron poor maleimide alkene of 1 and 2 under base (Et3N) initiated thiol-Michael conditions. Subsequent radical-mediated thiol-ene or thiol-yne reactions can be carried out to further functionalize the remaining allyl or propargyl moieties in near quantitative yields (>95%). Selectivity, however, can only be achieved when base-initiated thiol-Michael reactions are carried out first, as radical-mediated reactions between equimolar amounts of thiol and N-substituted maleimides give complex mixtures of products. CBS-QB3 calculations have been used to investigate the energetics and kinetics of reactions between a representative thiol (methyl mercaptan) with N-allyl and N-propargyl maleimide under both base-initiated and radical-mediated conditions. Calculations help elucidate the factors that underlie the selective base-initiated and nonselective radical-mediated thiol-ene/yne reactions. The results provide additional insights into how to design selective radical-mediated thiol-ene/yne reactions.
Department of Chemistry, Wesleyan University, Middletown, Connecticut 06459, USA.
Robert M
RM
Stolz
Brian H
BH
Northrop
D057930:Click Chemistry; D008301:Maleimides / Q000737:chemistry*; D015394:Molecular Structure; D011789:Quantum Theory; D013438:Sulfhydryl Compounds / Q000138:chemical synthesis* / Q000737:chemistry*
D008301:Maleimides; D013438:Sulfhydryl Compounds; C043592:maleimide