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 analog of the selective COX-II inhibitor, rofecoxib.

Synthesis and evaluation of the anti-proliferative activity of diaryl-3-pyrrolin-2-ones and fused analogs

“…Building on our expertise in preparing aryl-substituted 3-pyrrolin-2-ones, [22][23][24][25] we systematically studied the effects of changing the aryl groups around the central 3-pyrrolin-2-one ring on cancer cell viability. In our study (Figure 3), we prepared a small library of analogs that differed in the following ways: (i) analogs with different numbers (and locations) of aryl groups and methoxy substituents around the aryl periphery; (ii) analogs with indole groups located at different positions; and (iii) cyclized analogs (central ring fusion).…”

Enantioselective aza-Henry reaction of t-Boc protected imines and nitroalkanes with bifunctional squaramide organocatalysts

“…The following literature procedure is performed: 57 To a rt stirred solution of β-nitrostyrene 21 (5.0 mmol) in pyridine (6.5 mmol) and cyclohexane (20 mL) was added neat Br 2 (6.0 mmol) dropwise over 5 min. The cloudy yellow reaction was then heated to reflux and stirred for 4-12 h (monitored by TLC).…”

Highly Selective Detection of Nerve‐Agent Simulants with BODIPY Dyes

“…In 2011, Suzuki–Miyaura cross‐coupling between 2‐aryl‐1‐bromo‐1‐nitroethenes and arylboronic acids was used for the preparation of 1,2‐diaryl‐1‐nitroethenes, intermediates in the synthesis of 3,4‐diaryl‐3‐pyrrolin‐2‐ones. The reaction between 1‐bromonitrostyrene ( 54q ) and phenylboronic acid afforded 1‐nitro‐1,2‐diphenylethene ( 79g ), which was efficiently converted into 3,4‐diphenyl‐3‐pyrrolin‐2‐one ( 85 ) in three steps (Scheme ) 62…”