The syntheses in good yields of a considerable number of moderately to severely sterically-crowded 1,2,5-trisubstituted pyrroles by means of modifications of the Knorr-Paal condensation are described. Notwithstanding reports to the contrary, the classical procedure; succeeded in moderately sterically-crowded cases, e.g., R2 = R5 = Me, R1 = i-Pr, Me2CHMeCH-, Me2N-, Ph2N-, 9-carbazolo, subst. 4-morpholino, 1-piperazino, 1-piperidino, etc. A product-water azeotroping procedure succeeded in more severely sterically-crowded cases e.g., R2 = R5 = Et, R1 = i-Pr; R2 = R5 = Me, R1 = Me3CCH2-, R2 = R5 = i-Pr, R1 = PhCH2-. Highly sterically-crowded pyrroles, e.g., R2 = R5 = Me, R1 = t-Bu, adamantyl, PhCH2CMe2; R2 = R5 = Et, R1 = t-Bu; R1 = R2 = R5 = i-Pr; R2 = R5 = t-Ru, R1 = Me, Et, PhCH2-, were obtained using titanium tetrachloride as a Lewis acid catalyst and as a water scavenger. Infrared spectra of the reacting mixtures provided evidence pertinent to the mechanism of the reaction, which is discussed.
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