title: Synthesis of unsymmetrical 3,4-diaryl-3-pyrrolin-2-ones utilizing pyrrole Weinreb amides.
abstract: A regiocontrolled synthesis of unsymmetrical 3,4-diaryl-3-pyrrolin-2-ones has been achieved in three steps from 1,2-diaryl-1-nitroethenes with pyrrole-2-carboxamides (pyrrole Weinreb amides) serving as the key linchpin intermediates. Two different methods for the preparation of the requisite nitroalkenes were investigated: (1) modified Henry reaction between arylnitromethanes and arylimines; and (2) Suzuki-Miyaura cross-coupling reaction of 2-aryl-1-bromo-1-nitroethenes with arylboronic acids. Some difficulty was encountered in the preparation of arylnitromethanes, thus leading to the exploration of a cross-coupling strategy that proved more useful. A Barton-Zard pyrrole cyclocondensation reaction between 1,2-diaryl-1-nitroethenes and N-methoxy-N-methyl-2-isocyanoacetamide gave the corresponding pyrrole Weinreb amides, which were then converted into the desired 3-pyrrolin-2-ones in two steps. Overall, this method allowed for the construction of 3,4-diaryl-3-pyrrolin-2-ones with complete regiocontrol of the substituents with respect to the lactam carbonyl. The utility of this synthetic methodology was demonstrated by the preparation of eight unsymmetrical and symmetrical 3,4-diaryl-3-pyrrolin-2-ones including the N-H lactam analogue of the selective COX-II inhibitor, rofecoxib.
authors.affiliation: Department of Chemistry, Hobart College, Geneva, New York 14456, United States.
authors.forename: Jessica G
authors.initials: JG
authors.lastname: Greger
authors.forename: Sarah J P
authors.initials: SJ
authors.lastname: Yoon-Miller
authors.forename: Nathan R
authors.initials: NR
authors.lastname: Bechtold
authors.forename: Scott A
authors.initials: SA
authors.lastname: Flewelling
authors.forename: Jacob P
authors.initials: JP
authors.lastname: MacDonald
authors.forename: Catherine R
authors.initials: CR
authors.lastname: Downey
authors.forename: Eric A
authors.initials: EA
authors.lastname: Cohen
authors.forename: Erin T
authors.initials: ET
authors.lastname: Pelkey
mesh_terms: D000475:Alkenes / Q000737:chemistry; D000577:Amides / Q000737:chemistry; D001897:Boronic Acids / Q000737:chemistry; D002384:Catalysis; D051546:Cyclooxygenase 2 / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007769:Lactams / Q000138:chemical synthesis*; D007783:Lactones / Q000737:chemistry / Q000494:pharmacology; D057054:Molecular Imaging / Q000379:methods*; D015335:Molecular Probes / Q000138:chemical synthesis*; D015394:Molecular Structure; D011758:Pyrroles / Q000138:chemical synthesis*; D013450:Sulfones / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000475:Alkenes; D000577:Amides; D001897:Boronic Acids; D052246:Cyclooxygenase 2 Inhibitors; D007769:Lactams; D007783:Lactones; D015335:Molecular Probes; D011758:Pyrroles; D013450:Sulfones; C116926:rofecoxib; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human