Microwave Paal- Knorr synthesis

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). 

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>. 

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. 

A different approach toward highly substituted pyrroles involving a one-pot sila-Stetter/Paal-Knorr strategy was realized by Bharadwaj and Scheidt (Scheme 6.182) [343]. In this multicomponent synthesis, catalyzed by a thiazolium salt, an acyl anion conjugate addition reaction of an acylsilane (sila-Stetter) was coupled in situ with the conventional Paal-Knorr approach. Employing microwave conditions at 160 °C for 15 min, the acylsilane was combined with the cx/l-unsaturated ketone in... 

The Paal Knorr reaction provides an efficient synthesis of l,3,7-triaryl-6-phenyl-2-thioxo-l,2,3,7-tetrahydropyr-rolo[2,3- pyrimidin-4-one derivatives from 2-thiobarbituric acids under microwave conditions <2006JHC1231>. 

The microwave-mediated condensation of hydroxylamine with enaminoketones to generate isoxazoles has been mentioned earlier (refer to Scheme 3.12)17. In a procedure analogous to the Paal-Knorr thiophene synthesis, 2-aminoacyl carbonyl compounds... 

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. 

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

Butene-l,4-diones and 2-butyne-l,4-diones were converted into 2,5-diaryl- and 2,3,5-triarylfurans in high yields in the presence of HCOOH and a catalytic anaount of Pd on carbon under microwave-irradiation conditions <03JOC5392>. This procedure provides a new approach to the starting material used in the Paal-Knorr furan synthesis, as unsaturated diones are reduced to saturated diones in situ by formic acid and palladium. The solid-phase synthesis of 2,3,5-trisubstituted furans from 1,4-diketones was also reported <03SL711>. 

Polshettiwar V, Varma RS (2010) Nano-organocatalyst magnetically retrievable ferrite-anchored glutathione for microwave-assisted Paal-Knorr reaction, aza-Michael addition, and pyrazole synthesis. Tetrahedron 66 1091-1097... 

Catalytic multicomponent synthesis of highly substituted pyrroles has been described. A one-pot reaction uses DBU with the commercially available thiazolium salt 513 to produce the necessary nucleophilic zwitterionic catalyst in situ, which promotes a conjugate addition of acylsilanes (sila-Stetter) and unsaturated ketones to generate 1,4-dicarbonyl compounds in situ. Subsequent addition of various amines promotes a Paal-Knorr reaction, affording the desired polysubstituted pyrrole compounds in a one-pot process in moderate to high yields (Scheme 129) <2004OL2465>. Microwave heating dramatically reduced the reaction time (from 16 h to 30 min), but offered no improvement in yields. 

A microwave-assisted synthesis of polysubstituted furans via the Paal-Knorr reaction was reported. Thus, furans were easily obtained in good yields by heating diketones under microwave irradiation in acid solution <05EJOC5277>. 

SCHEME 34 Ferrite-anchored glutathione-catalyzed Paal-Knorr method for the synthesis of pyrazoles. MW, microwave. 

The ferrite-anchored glutathione-catalyzed Paal-Knorr method, described earlier for the synthesis of pyrroles, [40] has also been used for the synthesis of pyrazoles 105 by taking various hydrazines and hydrazides 104 and the 3-keto esters/1,3-diketones 103 as substrates (Scheme 34). All these reactions proceeded well in aqueous medium and got completed in 20 min under microwave irradiation. 

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. 

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