Versatility of Weinreb amides in the Knorr pyrrole synthesis

Design, Synthesis, and Biological Evaluation of Classical and Nonclassical 2-Amino-4-oxo-5-substituted-6-methylpyrrolo[3,2-d]pyrimidines as Dual Thymidylate Synthase and Dihydrofolate Reductase Inhibitors

“…A further search of the literature afforded a method that allowed a conjugate addition-elimination of 16 (Scheme 1) with a variety of nucleophiles. 42 Initial attempts to react 16 with diethyl aminomalonate free base with variation of time (up to 8 h) and temperature (at reflux) were unsuccessful. However, the crucial intermediate 20 (E/Z-mixture) was readily obtained from 16 (E/Z-mixture) and diethyl aminomalonate hydrochloride, 17 (rather than the free base), in methanol at room temperature for 5 h. A possible explanation is that the imine is a stronger base than the amine.…”

Crystal structure of methyl-2-methyl-4-(2-oxo-2-phenylethyl)-5-phenyl-1H-pyrrole-3-carboxylate, C21H19NO3

“…Generally, pyrroles possess a broad spectrum of biological activities such as antimicrobial [11], telomerase inhibitory [12], antifungal [13], cardiotonic [14], pheromonal [15], and phytotoxic e ects [16]. The classical approaches for synthesizing pyrroles are Knorr [17,18], Hantzsch [19][20][21], and Paal-Knorr …”

Five‐Membered Heterocycles: Pyrrole and Related Systems

“…Reaction of similar Weinreb amides lacking the Boc group with enamines gives N-methoxy-N-methyla-enaminocarboxamides, which take part in related conversions into a-enaminoketones, and ensuing annulations to pyrroles [118]. In a related approach involving an initial CÀN bond formation between two C 2 -fragments, addition of the a-aminoketones 67 to dimethyl acetylenedicarboxylate (DMAD) yields the intermediates 68, which finally undergo cyclization to give pyrroles 69 (Scheme 4.22) [119].…”