Facile Synthesis of 1,2,3,4-Tetrasubstituted Pyrroles from Baylis-Hillman Adducts

Suitably fUnctionalized pyrroles are the basic skeleton of many biologically important substances and numerous synthetic methods of pyrroles have been investigated extensively.1,2However, the synthesis of pyrrole derivatives from Baylis-Hillman adducts was not developed much.2Recently, we reported the synthesis of 2,3,4-trisubstituted pyrroles starting from the rearranged aza-Baylis-Hillman adducts (Scheme 1).3Meantime we presumed that we could synthesize 1,2,3,4tetrasubstituted pyrrole derivatives by using the synthetic approach in Scheme 2. As shown in Scheme 2, we imagined that the reaction of Baylis-Hillman acetate 1, as the representative example, and secondary amine derivatives 2a-d could give the corresponding Sn2' product 3a-d, which could be cyclized to 4a-d under basic conditions.The following acid-catalyzed dehydration and concomitant double bond isomerization of 4a-d would provide desired pyrroles 5a-d.Among the examined conditions the use of K2CO3 in CH3CN gave the best results for the preparation of 4a-d.As expected we could not observe the formation of 3 (except for 3c, entry 3 in Table 1),4 instead we obtained 4a-d directly in 50-74% yields as inseparable syn/anti mixtures in a one-pot reaction.Based on the 1H NMR spectra of 4a-d the ratio of syn/anti was 4:1 to 2:1 (footnotes b-d in Table 1), however,