Pyrroles, synthesis of N-substituted

Mainly C-substituted pyrroles have been synthesized by application of the Knorr pyrrole synthesis however N-substituted pyrroles can also be prepared, when starting with secondary aminoketones, e.g. bearing an N-methyl or N-phenyl substituent. 

Huisgen and co-workers486,490 have described a useful synthesis of N-substituted pyrroles (41) from mesoionic oxazolones (39) via the intermediates 40, which were not isolated. A variety of acetylenic esters (phenylpropiolic, propiolic, tetrolic, and DMAD) were used. The kinetics of these reactions have been studied.491 The addition of carbon... 

G. Trebicka, A. Chemoselective N-alkylation of 2-hydroxycarbazole as a model for the synthesis of N-substituted pyrrole derivatives containing acidic functions. Tetrahedron 1995, 51, 5681-5688. 

A pyrrole ring is the core structure found in the skeletons of many naturally occurring biomolecules such as globins, porphyrins, vitamins, and so on and constitutes a unit of pharmaceuticals. Most commonly, pyrroles are synthesized by multistep synthetic methods. A one-pot three-component synthesis of 2,3,4,5-tetrasubstituted pyrroles from benzoin, 1,3-dicarbonyls, and ammonium acetate was carried out using SSA under solvent-free conditions (Tamaddon and Farahi, 2012) (Scheme 5.21). Veisi (2010) reported a room temperature synthesis of N-substituted... 

SCHEME 8 Lewis add-catalyzed synthesis of N-substituted pyrroles. 

D. Bandyopadhyay, S. Mukheijee, B.K. Baruk, An expeditious synthesis of N-substituted pyrroles via microwave-induced iodine-catalyzed reaction imder solventless conditions. Molecules 15 (2010) 2520-2525. 

Bandyopadhyay et al. [50] synthesized a series of novel N-substituted pyrrole derivatives. The autiiors sought a simple and solvent-free ultrasound-assisted reaction for tiie synthesis of N-substituted pyrroles (12) by reacting 2,5-dime-thoxytetrahydrofuran (10) with aromatic, aliphatic, polyaromatic, and heteropolyaromatic amines (11) using bismuth nitrate pentahydrate as catalyst (Scheme 4). It should be mentioned that the addition of the bismuth salt, which is environmentally benign and nontoxic, increased tiie reaction yield from 55% to 99% and reduced the reaction time from 5h to 5 min. 5-(lH-Pyrrol-l-yl)-l,10-phenantiiroline and l-(phenanthren-2-yl)-lH-pyrrole have demonstrated cytotoxic specificity against liver cancer cell lines in vitro when compared with normal cultured primary hepatocytes. 

H.M.C. Ferraz, F.L.C. Pereira, F.S. Leite, M.R.S. Nunes, M.E. Payret-Arriia, Synthesis of N-substituted pyrrole and tetrahydroindole derivatives from alkenyl p-dicarbonyl compounds. Tetrahedron 55 (1999) 10915-10924. 

The Clauson-Kaas pyrrole synthesis involving the reaction of primary amines with 2, 5-dialkoxytetrahydrofurans was traditionally carried out in refluxing acetic acid (AcOH). Extension to less activated nitrogen nucleophiles often necessitates the use of acidic promoters. Miles et al. (2009) reported that the synthesis of N-substituted pyrroles can be carried out under microwave conditions (10-30 min) using acetic acid or water without additional catalysts. The reaction is successful for all common nitrogen inputs in the case of acetic acid, where as benzamide and benzylamine are resistant to cyclocondensation under aqueous conditions. 

The 5-dig-mode of cyclization has been applied in the synthesis of N-heterocycles. For example, treatment of the /i-allenyl dithiosemicarbazide 37 with Bu3SnH and AIBN in hot benzene furnishes the substituted 3H-pyrrole 38 in 41% yield and the isomeric heterocycle 39 in 30% yield (Scheme 11.13) [68], Iminyl radical 40 is formed via Bu3Sn addition to the thiocarbonyl group of the radical precursor 37 and fragmentation of the adduct (not shown). Nitrogen-centered radical 40 adds 5-dig-selectively to provide substituted allyl radical 41. The latter intermediate is trapped by Bu3SnH to furnish preferentially product 38 with an endocydic double bond. 

Synthesis of 2-Substituted Pyrroles via a-LiTHiATiON of N-Protected Derivatives... 

Large 1-alkyl substituents increase -substitution in the Vilsmeier formylation of pyrroles. A similar trend occurs in trifluoroacetylation of N-alkyl pyrroles. The trifluoroacetylation, formylation, and bromination of 1-tritylpyrrole occur regioselectively at the 3-position in high yield. The same effect is seen in 1-triisopropylsilylpyrrole and the ease of removal of the fV-silyl substituent makes the use of such substitutions for the synthesis of 3-substituted N-unsubsti-... 

A synthesis of N-benzylthieno[2,3-b]pyrrole (7) demonstrates ready substitution of a pyrrole ring. ... 

From a retrosynfhetic viewpoint, N-aryl-l,2-diimine Ni precatalysts are synthesized by (i) reaction of 1,2 diimines with nickel halides from (ii) 1,2-diimine ligands which in turn are obtained by (iii) condensing 1,2-dicarbonyl substrates with two equivalents of primary aromatic amines, usually under acidic conditions [11]. In analogy, the synthesis of N-hetaryl 1,2 diimine catalysts starts from the corresponding substituted N-heterocyclic primary amines as the amine building blocks. The synthesis of three types of such heterocycles, N-amino-pyrroles, -indoles and -carbazoles, and their corresponding diimine derivatives is presented in the following sections. 

Synthesis of bis(pyrrole) monomers. The condensation of ethyl diacetyl succinate with amines to give dialkyl esters of N substituted pyrroles proceeds in near quantitative yields to the bis(dicarboethoxy dimethyl pyrrole). 

V. Cadiemo, J. Gimeno, N. Nebra, Chem. Eur. J. 2007, 13, 9973-9981. One-pot three-component eatalytie synthesis of fully substituted pyrroles from readily available propaigylic... 

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