Substitution 2- substituted pyrrole synthesis

Scheme 15.100 1,2,5-Substituted pyrrole synthesis through the tandem...

Scheme 15.101 A/.protected 2,5-substituted pyrrole synthesis via a one-pot nitro-Mannich reaction followed by hydroamination.

Further examples in the weU-estabHshed use of isoxazolones as precursors for substituted pyrrole synthesis include pyrolysis of the esters 45 to give the pyrroles 46 (Scheme 9 2001ARK(vii)88). 

The synthesis will therefore normally produce a 2,4-substituted pyrrole, with in addition an ester group or an acyl group at the 3-position, if a keto ster or a diketone respectively has been employed, and an ester group or an alkyl (aryl) group at the 5-position, according to the nature of the amino-ketone. 

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. 

Some advances have been made in the Paal-Knorr synthesis of pyrroles by the condensation of primary amines with 1,4-dicarbonyl species. For instance, a new synthetic route to monosubstituted succinaldehydes allows for the facile preparation of 3-substituted pyrroles <96TL4099>. Additionally, a general method for the synthesis of 1-aminopyiroles has been devised by the condensation of commercially available 2,2,2-trichloroethyl- or 2-(tri-methylsilyl)ethylhydrazine with 1,4-dicarbonyl compounds <96JOCl 180>. A related route to such compounds involves the reaction of a-halohydrazones with p-dicarbonyl compounds <96H(43)1447>. Finally, hexamethyldisilazane (HMDS) can be utilized as the amine component in the Paal-Knorr synthesis in the presence of alumina, and this modification has been employed in the synthesis of tm azaprostacyclin analog <96S1336>. 

By adhering to these conditions, Kaupp and coworkers performed a remarkable one-pot synthesis of highly substituted pyrroles [21]. When primary or secondary enamine esters 10-58 were ground with trans- 1,2-dibenzoylethene 10-59 in a ball-mill, the pyrroles 10-60 were obtained in quantitative yield (Scheme 10.15). In contrast, when in solution the yields were much lower and the reaction also required higher reaction temperatures. 

Another pyrrole synthesis based on intramolecular substitution of the nitro group by amino function is presented in Eq. 10.7, in which the Michael addition of enamines to nitroalkenes is used.9... 

Barton-Zard pyrrole synthesis is also applied to synthesis of pyrroles with a variety of substituents. Pyrroles substituted with long alkyl substituents at the 3 and 4 positions,30 pyrroles with P-CF3 (Eq. 10.26),31 3,4-diarypyrroles (Eq. 10.27),32 and pyrrole-2-phophonates (Eq. 10.28)33 are prepared in a similar manner based on isonitrile cyclization. 

Studies by Almerico and co-workers into the synthesis of annelated l,2,3-triazolo[l,5- ]pyrimidines have led to an efficient method for the formation of the five- and six-membered rings onto a substituted pyrrole in good yield <2002T9723>. The reaction proceeds initially via a 1,3-dipolar cycloaddition between the azide group of 300 and the... 

A mixture of metals was utilized to promote a type Ilae synthesis of penta-substituted pyrroles <06OL2151>. Treatment of enyne 37 with a Ag(I) catalyst followed by BnNH2 and a Au(I) catalyst gave pyrrole 38 via a Claisen-type rearrangement and cyclocondensation. 

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... 

Dieter developed a flexible two step synthesis of substituted pyrroles involving initial Beak deprotonation of /ert-butoxycarbonyl (Boc) amines 36 followed by addition of CuX-2LiCl (X = -Cl, -CN) to afford a-aminoalkylcuprates. Such cuprates undergo conjugate addition reactions to a,(3-alkynyl ketones affording a,(3-enones 37, which upon treatment with PhOH/TMSCl undergo carbamate deprotection and intramolecular cyclization to afford the pyrroles 38 . 

Trofimov has extended his previously reported heterocyclization of ketoximes 39 with acetylene to propyne or its isomer allene in superbase systems (MOR/DMSO M = K, Cs, R = H, t-Bu) to afford a facile synthesis of substituted pyrroles 40 and 41 . Due to a fast propyne to allene protropic isomerization under the reaction conditions, the product is the same regardless of which species is employed. 

An early example of this strategy is the palladium black catalyzed conversion of (Z)-2-buten-l,4-diol with primary amines (cyclohexyl amine, 2-aminoethanol, -hexyl amine, aniline) at 120 °C to give A-substituted pyrroles in 46-93% yield [119]. Trost extended this animation to the synthesis of a series of AT-benzyl amines 169 from the readily available a-acetoxy-a-vinylketones 168 [120]. This methodology allowed for the facile preparation of pyrrolo-fused steroids. 

M. Calderelli, J. Habermann, S. V. Ley, Clean Five-Step Synthesis of an Array of 1,2,3,4-Tetra-substituted Pyrroles using Polymer-Supported Reagents , J. Chem. Soc, Perkin Trans. 11999,107-110. 

The reaction of 5(4H)-oxazolones (32) and miinchnones with triphenylvinylphos-phonium bromide (33) provides a mild synthesis of substituted pyrroles (34) (Scheme 11). The cycloaddition-elimination reactions of 5-imino-l,2,4-thiadiazolidin-3-ones with enamines and ester enolates produce 2-iminothiazolidines. " Chiral isomtinchnone dipoles show jr-facial diastereoselectivity with IV-phenyl- or A -methyl-maleimide in refluxing benzene. ... 

Reaction of hydrazine or substituted hydrazine with 1,3-dicarbonyl compounds to provide the pyrazole or pyrazolone ring system. Cf. Paal-Knorr pyrrole synthesis (page 333). 

Metten B, Kostermans M, Van Baelen G, Smet M, Dehaen W (2006) Synthesis of 5-aryl-2-oxopyrrole derivatives as synthons for highly substituted pyrroles. Tetrahedron 62 6018-6028... 

Regioselective synthesis of 2-substituted pyrroles using oximinocyanoacetate esters or related compounds in a Knorr-type reductive condensation with diketones was described . Thus, oximinocyanoacetates 63 reacted with pentane-2,4-diones 64 in hot... 

Boger et al. reported the first total synthesis of ningaline D (282) starting from the diphenylacetylene 1092 and dimethyl l,2,3,4-tetrazine-3,6-dicarboxylate (1093) (687). In this synthesis, the key step is the formation of the fully substituted pyrrole core using an inverse electron demand heterocyclic azadiene Diels-Alder reaction followed by a reductive ring contraction of the resultant 1,2-diazine. 

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

The chelation between a Boc group and Mg(II) is often used to control the stereochemistry in aldol reactions. For instance, Donohoe and House have reported the diasteroselec-tive reductive aldol reactions of Boc-protected electron-deficient pyrroles. The key step of the synthesis is the preparation of an exocyclic magnesium enolate of Boc-protected 2-substituted pyrroles. ... 

Hantszch synthesis A reaction of an a-haloketone with a (3-ketoester and NH3 or a primary amine yields substituted pyrrole. 

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