Conjugate addition of 1,3-dicarbonyl compounds to maleimides using bifunctional primary amine‒(thio)phosphoramide organocatalysts

Abstract

Asymmetric Michael additions of 1,3-dicarbonyl compounds to N-substituted maleimides were carried out using primary amine-(thio)phosphoramide bifunctional chiral organocatalysts derived from optically pure C2-symmetric 1,2-diamines. The addition of ethyl 2-fluoroacetoacetate using the 1,2-diphenylethane-1,2-diamine derived thiophosphoramide catalyst afforded various succinimides substituted with fluorine bearing quaternary carbon in high yields, good diastereomeric ratios and excellent enantiomeric excesses. Alicyclic β-ketoesters provided the diastereomerically pure Michael adducts in good yields and high enantioselectivities, whereas 2,4-pentanedione afforded products with slightly lower enantiomeric excesses. The bulkiness of the N-substituent of the maleimide ring influenced mostly the conversions. The thiophosphoramide catalyst was found also efficient in the addition of ethyl 2-fluoroacetoacetate to β-nitrostyrenes. Unprecedentedly, during this work the highly enantioselective addition of 1,3-dicarbonyl compounds to maleimides were catalyzed by a primary amine‒hydrogen-bond donor groups containing bifunctional organocatalyst. These reactions occurred through enamine intermediate, as evidenced by electrospray-ionization mass spectrometry and NMR spectroscopy.