Pyrrole Knorr reaction

The major development in the Knorr pyrrole synthesis has been access to the amine component. For example, use of preformed diethyl aminomalonate with 1,3-diketones affords much higher yields of pyrroles 14. Reaction of 6-dicarbonyl compounds with hydroxylamine 0-sulfonic acid gives pyrroles 15 in one step. Weinreb a-aminoamides have found use in the Knorr pyrrole synthesis of a wide variety of pyrroles 16. °... 

Another important route to pyrroles is offered by the Paal-Knorr reaction, where the pyrrole system is formed by condensation of a 1,4-diketone 9... 

The use of microwaves for the preparation of aromatic five-membered heterocycles has been intensely investigated with excellent results in terms of yields and purities of the products prepared. The Paal-Knorr reaction, namely the cyclocondensation of a 1,4-dicarbonyl compound to give furans, pyrroles and thiophenes has been successfully carried out with the aid of microwaves. 

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-... 

Scheme 3 Synthesis of 1,4-disubstituted pyrroles via Paal-Knorr reaction...

A two-step procedure was required for the preparation of a diverse set of pyrrole-3-carboxylic acid derivatives. The diketone 15 was prepared using a functional homologation of a 6-ketoester 14 with different aldehydes followed by oxidation with PCC. The Paal-Knorr reaction was carried out in AcOH in a sealed tube under microwave irradiation (180 °C, 5-10 min) to give differently substituted pyrroles with a COOMe group in position 3 (Scheme 5). This group was further transformed to expand the diversity of the products prepared with this method [32]. 

The retro-Paal-Knorr ring opening reaction leading to 1,4-dicarbonyl compounds was accomplished by heating iV-substituted pyrroles in a citrate buffer <06SL1428>. The sequence was coupled with a forward Paal-Knorr reaction enabling the exchange of the N-substituent on pyrroles. 

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. 

Alternatively, Ballini devised a new strategy to synthesize tri-alkylated pyrroles from 2,5-dialkylfurans and nitroalkanes <00SL391>. This method involves initial oxidation of 2,5-dimethylfuran with magnesium monoperoxyphthalate to cA-3-hexen-2,5-dione (6). Conjugate addition of the nitronate anion derived from the nitro compound 7 to 6 followed by chemoselective hydrogenation of the C-C double bond of the resulting enones 8 (obtained by elimination of nitrous acid from the Michael adduct) completes the conversion to the alkylated y-diketones 9. Final cyclization to pyrroles 10 featured improved Paal-Knorr reaction conditions involving reaction of the diketones with primary amines in a bed of basic alumina in the absence of solvent. 

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

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. 

Minetto, G., Raveglia, L. F., Taddei, M. Microwave-assisted Paal-Knorr reaction. A rapid approach to substituted pyrroles and furans. Org. Lett. 2004, 6, 389-392. 

Yu, S.-X., Le Quesne, P. W. Quararibea metabolites. 3. Total synthesis of ( )-funebral, a rotationally restricted pyrrole alkaloid, using a novel Paal-Knorr reaction. Tetrahedron Lett. 1995, 36, 6205-6208. 

Oxime 5 was synthesized by treatment of t-butyl acetoacetate with sodium nitrite in acetic acid. Reaction of 5 wim p-ketoamide 6 in me presence of zinc and acetic acid according to the classic Knorr pyrrole formation conditions led to pyrrole 12. Aimough mis reaction worked fairly well (60 to 70% yield), workup and product isolation proved problematic as the reaction scale was increased (>10 g). Typically, the products of Knorr reactions (when p-ketoesters are used instead of p-ketoamides) are isolated by a water knock-out at me end of me reaction. However, in the case of 12, me presence of me pendant amine functionality rendered precipitation of the product from an acidic reaction mixture impossible. Precipitation of me product required basic conditions unfortunately, at pH 9, gelatinous zinc salts crashed out of solution, making an extraction or isolation... 

Pyrrole is one of the most prominent heterocycles in several natural products and synthetic pharmaceuticals. The most common approach to pyrroles is the Paal-Knorr reaction. Taddei and coworkers have investigated a rapid and versatile synthesis of tetrasubstituted pyrroles in few highly efficient steps ... 

The compounds core comprises a pentasubstituted pyrrole, which results from a convergent synthesis with a Paal-Knorr reaction as its crucial step. This succeeds only under specially designed conditions the reaction faced initially a seemingly insurmountable obstacle, and therefore a range of linear syntheses had been developed as weU. Although they are scientifically very interesting, they will not be discussed here in any greater detail. [395,396]... 

Also known as Knorr reaction. Reaction of hydrazine or substituted hydrazine with 1,3-dicarbonyl compounds to provide the pyrazole or pyrazolone ring system. Cf. Paal-Knorr pyrrole synthesis. 

Approaches to the synthesis and medicinal importance of pyrroles have been reviewed. The synthesis of pyrroles using multicomponent reactions was reviewed and advances in this area from mid-2009 to the end of 2013 are covered (14CSR4633). Another review covered the synthesis of pyrroles using the Paal-Knorr reaction (14AHC95).The synthetic approaches and biosynthetic hypotheses of pyrrole—imidazole alkaloids were discussed in another report (14CC8628). Synthesis of pyrrole-based heterocyclic molecules through metal triflate-catalyzed addition reactions of pyrrole to C—C and C-N bonds was reviewed (14PAC925). 

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