Microwave-assisted pyrrole synthesis

Two other examples of microwave-assisted Paal-Knorr reactions were reported in 2004, describing the synthesis of a larger set of pyrroles with different substituents around the ring. The methods differ mainly in the syntheses employed to produce the 1,4 dicarbonyl compounds required for the cyclization. A variation of the Stetter reaction between an acyl silane and dif-... 

One of the most common approaches to pyrrole synthesis is the Paal-Knorr reaction, in which 1,4-dicarbonyl compounds are converted to pyrroles by acid-mediated dehydrative cyclization in the presence of a primary amine. The group of Taddei has reported a microwave-assisted variation of the Paal-Knorr procedure, whereby a small array of tetrasubstituted pyrroles was obtained (Scheme 6.181) [342], The pyrroles were effectively synthesized by heating a solution of the appropriate 1,4-dicarbonyl compound in the presence of 5 equivalents of the primary amine in acetic acid at 180 °C for 3 min. The same result was obtained by heating an identical mixture under open-vessel microwave conditions (reflux) for 5 min. Interestingly, the authors were unable to achieve meaningful product yields when attempting to carry out the same transformation by oil-bath heating. 

Furo[3,4-c]pyrrolediones are important intermediates in the synthesis of diketo-pyrrolopyrrole (DPP) pigments. Smith and coworkers have described the preparation of several different 3,6-diaryl-substituted furo[3,4-c]pyrrole-l,4-diones by microwave-assisted cyclization of readily available 4-aroyl-4,5-dihydro-5-oxo-2-arylpyrrole-3-carboxylates (Scheme 6.192) [353]. While conventional heating in Dowtherm A at 230-240 °C for 64 h provided only moderate product yields, microwave irradiation of the neat starting material at 250 °C for 10 min provided significantly increased yields. 

Danks reported a microwave-assisted variant of the classical Paal-Knoor pyrrole synthesis (Scheme 3.3)5. This solvent-free method provided a considerable rate advantage (reactions complete within 2 min compared to over 12 h in conventional thermal heating) over classical procedures and even non-nucleophilic amines were condensed smoothly in the absence of Lewis acid promoters. Purification consisted of a simple silica gel filtration. The use of an early-dedicated laboratory instrument in this work is also noteworthy however, information of how the reaction temperature was controlled is not provided. 

Danks, T.N., Microwave-assisted synthesis of pyrroles, Tetrahedron Lett., 1999, 40, 3957-3960. 

Similar reaction conditions as those by Bose were used for a range of other applications, for example, the synthesis of heterocycles. A combination of a microwave-assisted Paal-Knorr reaction15 with a transfer hydrogenation takes place in the preparation of 2,5-di- and 1,2,5-trisubstituted pyrroles from -l,4-diaryl-2-butene-l,4-diones in a one-pot operation. Hydrogenation was achieved with ammonium formates and 10% Pd/C as catalyst in PEG-200. Yields of up to 92% were obtained within 0.5-2 min (Scheme 4.2)16. 

The famous Ugi reaction, the one-pot condensation of a carboxylic acid, an amine, an aldehyde or ketone and an isocyanide to yield an a-acylaminoamide, have recently been used as an efficient method for the synthesis of diverse libraries of small organic molecules such as benzodiazepines, pyrroles, lactams and diketopiperazines2. Even though some solution-phase Ugi reactions proceed rapidly, such reactions on solid phase have been found to take between one and several days. In 1999, Hoel and Nielsen17 performed the first microwave assisted, solid phase Ugi four-component condensation (see Scheme 5.5). 

Ranu, B.C., Hajra, A. and Jana U., Microwave-assisted synthesis of substituted pyrroles by a three-component coupling of a, 3-unsaturated carbonyl compounds, amines and nitroalkanes on the surface of silica gel, Synlett, 2000, 1, 75-76. 

Another example of reaction-rate enhancement was reported for the microwave-assisted Paal-Knorr synthesis of a series of tetrasubstituted pyrroles [18]. Following the standard procedure, 1,4-dicarbonyl compounds were converted to pyrrole rings via acid-mediated dehydrative cyclization in presence of primary amines. The main limitation of the standard protocol is the harsh reaction conditions (reflux in acetic acid for extended times). The use of microwaves slashes the reaction times to few minutes, giving good isolated yields of the desired products (Scheme 15.5). 

Scheme 15.5 Synthesis of tetrasubstituted pyrroles by microwave-assisted Paal-Knorr reaction.

This section covers cyclizations to the pyrrole nucleus catalyzed by other metals (Ti, Mn, Ru, Pd, Pt, Zn, In). Dembinski and co-workers used zinc(II) chloride as ligand-free catalyst for the microwave-assisted cyclization of homopropargyl azides 26 to afford substituted pyrroles 27 (Scheme 8) [62]. A similar methodology for the synthesis of 2,4,5-trisubstituted pyrroles was described by Driver et al. employing substituted 1-azidobuta-l,3-dienes in a cyclization reaction using catalytic amounts of zinc(ll) iodide [63]. A three-component zinc-catalyzed one-pot cyclization of aromatic and aliphatic propargylic acetates, silyl enol ethers, and primary amines to substituted pyrroles has been described by Zhan et al. The reaction sequence includes propargylation of the silyl enol ether, amination, 5-exo-(7ig-cyclization, and isomerization [64]. Hiroya and co-workers have shown... 

Pyrrole Chemical synthesis, microwave-assisted synthesis, reactions and applications 13COC2279. 

R. Pereira, M. L. G. Ferreira, Org. Prep. Proced. Int. 2001, 33, 411-454. Recent advances in the synthesis of pyrroles, (b) M. Abid, S. M. Landge, B. Torok, Org. Prep. Proced. Int. 2006, 38, 495-500. An efficient and rapid synthesis of A-snbstitnted pyrroles by microwave assisted solid acid catalysis. 

Pospisil J, Potacek M (2004) Microwave-assisted solvent-free synthesis of hexahydrochromeno[4,3-b] pyrroles. Eur J Org Chem 4 710-716... 

The efficient solvent-free microwave-assisted procedure for C-alkyl pyrroles synthesis using silica gel-supported reagent has been reported. Thus, a general procedure for the Michael addition of pyrroles with electron-deficient olefin has been developed. In the case of the moderately bulky electron-deficient olefins, a catalytic amount of BiCls has to be employed to promote the reaction. The experimental results indicated that BiCla exhibited a high catalytic activity and did not induce polymerization and polyalkylation under microwave (Equation 5) [26a]. 

The condensation of co-propargylic benzaldehydes with methyl sarcosi-nate or ethyl N-benzylglycinate followed by in sitn oxidation was also more efficient under microwave-assisted conditions for the synthesis of benzopyranopyrroles 80 [94]. Oxidation of the hexahydrochromeno[4,3-b]pyrrole cycloadducts could be facilitated by the addition of sulfur and further irradiation for 10 min at 130 °C in a one-pot process to give pyrroles 80 in 70-90% yield (Scheme 35). Although there was little difference between reactions carried out under microwave irradiation and those using classical conductive heating methodology, in terms of product yield, the microwave-assisted reactions had considerably shorter reaction times. Furthermore, a more convenient one-pot procedure, in which a mixture of the aldehyde, a-amino ester, sulfur and a minimal amount of xylene was irradiated for 15 min at 130 °C, provided the pyrrole product without any reduction in yield (90%) in a one-pot MCR. 

Minetto et al. (2004) carried out synthesis of tetrasubstituted pyrroles (and trisub-stituted furans) in a three-step reaction of P-ketoester with an aldehyde followed by oxidation to give number of substituted 1,4-dicarbonyl compounds, which is further cyclized by microwave-assisted with the Paal-Knorr reaction. 

The Paal-Knorr synthesis of furans as well as thiophenes and pyrroles has been carried out on solid support and a library of heterocyclic compounds has been prepared <2003SL711>. It has been shown that the acid-catalyzed synthesis of 2,3>4-substituted furans from 1,4-diketones can be assisted by microwave irradiation <20040L389>. 

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