Pyrrole carboxylates, aryl-substituted

The Paal-Knorr cyclization was employed to produce highly aryl-substituted pyrrole carboxylates as useful medicinal chemistry leads. Therefore, l,4-diketone-2,3-diester was assembled from an Sn2 displacement of ethyl 2-bromoacetoacetate with the anion of the ketoester. Condensation with an aniline then provided a library of fully substituted pyrroles. 

Lautens and Hulcoop developed a Pd-catalyzed annula-tion of 3-aryl substituted pyrroles to yield indoles, following retro-Diels-Alder loss of cyclopentadiene (Scheme 2, equations 1 and 2) [4]. Miura, Satoh, and coworkers found that indoles were formed from Af-methylpyrrole-2 carboxylic acid and alkynes as catalyzed by palladium (equation 3) [5, 6]. The indoles themselves undergo this oxidative coupling with alkynes to form octa-substituted carbazoles, e.g.4[6]. 

In 1999, Mederski s group [93] at Merck preclinic2il pharmaceutical research published an account on the application of this method for the synthesis of Af-aryl-substituted pyrrole- and indole-2-carboxylic esters. These intermediates were important for the synthesis of factor Xa antagonists. 

Recently, the synthesis of 5-aryl-2-oxopyrrole derivative 210 as synthon for the highly substituted pyrrole 211 as starting compound for fused heterocycle 212 was published [56], Diethyl 6-bcnzyl-5-phenyl-6//-thieno[2,3-/ ]pyrrolc-2,4-dicarboxylatc 212 was prepared from ethyl l-benzyl-5-chloro-4-formyl-2-phcnyl-l //-pyrrolc-3-carboxylate 211 and ethyl 2-sulfanylacetate in refluxing ethanol (Scheme 41). 

In terms of A -substitution, Hartwig reported improved conditions for the Pd(0) catalyzed N-arylation of indoles and pyrrole <99JOC5575>. It was found that when commercially available P(<-Bu)3 was employed as ligand and cesium carbonate as base, the reaction between indoles 95 and unhindered aryl bromides 96 or chlorides occurred under milder conditions than the Pd(OAc)2/DPPF system previously reported yielding the A/-arylated products 97. Alternatively, it has been found that pyrrole- and indole-2-carboxylic acid esters can be selectively 7V-arylated with phenylboronic acids in the presence of cupric acetate and either tiiethylamine or pyridine <99T12757>. 

The reaction of aryl isothiocyanates with pyrrole77 has been applied to the heterocyclic isothiocyanate ethyl 3-isothiocyanatopyridine-2-carboxylate and yields ethyl 3- [(pyrrol-2-yl)-thioearbonyl]amino pyridine-2-carboxylate (9), which can be used for cyclization reactions with hydrazine or methylamine to give the corresponding 3-substituted 2-(pyrroI-2-yl)-pyrido[3,2-[Pg.166]

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