Synthesis of Unsymmetrical 3,4-Diaryl-3-pyrrolin-2-ones Utilizing Pyrrole Weinreb Amides

• Published in: Journal of organic chemistry Vol. 76; no. 20; pp. 8203 - 8214
• Main Authors: Greger, Jessica G, Yoon-Miller, Sarah J. P, Bechtold, Nathan R, Flewelling, Scott A, MacDonald, Jacob P, Downey, Catherine R, Cohen, Eric A, Pelkey, Erin T
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 21.10.2011; Amer Chemical Soc
• Subjects: Alkenes - chemistry; Amides - chemistry; Boronic Acids - chemistry; Catalysis; Chemistry; Chemistry, Organic; Cyclooxygenase 2 - metabolism; Cyclooxygenase 2 Inhibitors - chemistry; Cyclooxygenase 2 Inhibitors - pharmacology; Exact sciences and technology; Heterocyclic compounds; Heterocyclic compounds with only one n hetero atom and condensed derivatives; Humans; Lactams - chemical synthesis; Lactones - chemistry; Lactones - pharmacology; Molecular Imaging - methods; Molecular Probes - chemical synthesis; Molecular Structure; Organic chemistry; Physical Sciences; Preparations and properties; Pyrroles - chemical synthesis; Science & Technology; Sulfones - chemistry; Sulfones - pharmacology; PROTEIN-KINASE-C; BETA-NITROSTYRENES; COA REDUCTASE INHIBITORS; NITRO-COMPOUNDS; BIOLOGICAL EVALUATION; ALPHA-NITROSTILBENES; HYDROGEN-PEROXIDE; TRANSITION-STATE; ALKYL-HALIDES; NINGALIN-B; Nitro compound; Condensation reaction; Rofecoxib; Regioselectivity; Nitrogen heterocycle; Lactam; Asymmetric molecule; Organic bromine compounds; Cyclooxygenase 2 inhibitor; Selectivity; Ketone; Aldol condensation; Pyrrole derivatives; Cyclization; Suzuki-Miyaura cross-coupling; Cross reaction; Carboxamide; Boron Organic compounds; Bromine Organic compounds; Aromatic compound; Chemical synthesis; Boronic acids; Henry reaction
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo2013516

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.