Azomethine ylides, pyrrole synthesis

Type Ilbd pyrrole syntheses fall into three general categories (1) Hinsberg-type (2) azomethine ylide cycloadditions and (3) isocyanide-based cyclocondensations. The Hinsberg pyrrole synthesis, the cyclocondensation between iminodiacetates and oxalates, has been further exploited in the total synthesis of the lamellarins <06T594,06TL3755>. 

Huisgen and coworkers have also described the cycloaddition behavior of the munchnones , unstable mesoionic A2-oxazolium 5-oxides with azomethine ylide character.166 Their reactions closely parallel those of the related sydnones. These mesoionic dipoles are readily prepared by cyclodehydration of N-acyl amino acids (216) with reagents such as acetic anhydride. The reaction of munchnones with alkynic dipolarophiles constitutes a pyrrole synthesis of broad scope.158-160 1,3-Dipolar cycloaddition of alkynes to the A2-oxazolium 5-oxide (217), followed by cycloreversion of carbon dioxide from the initially formed adduct (218), gives pyrrole derivative (219 Scheme 51) in good yield. Cycloaddition studies of munchnones with other dipolarophiles have resulted in practical, unique syntheses of numerous functionalized monocyclic and ring-annulated heterocycles.167-169... 

Supercritical carbon dioxide with a minute co-solvent addition is an effective medium for the 1,3-dipolar cycloaddition of azomethine ylides with DMAD to produce substituted pyrroles.67 The 1,3-dipolar cycloaddition of nitrile ylides [e.g. benzonitrile (4-nitrobenzylide) and 4-nitrobenzonitrile(benzylide)] with acrylamides provided a synthesis of 3,4-dihydro-2//-pyrroles with moderate to good yields.68 The Pt(II)-or Au(III)-catalysed 3 + 2-cycloaddition of the transition metal-containing azomethine ylide (63) with electron-rich alkenes provided a carbene complex (64), which yields tricyclic indoles (65) having a substituent at 3-position (Scheme 17).69 The 1,3-dipolar cycloadditions of azomethine ylides with aryl vinyl sulfones are catalysed by Cu(MeCN)4C104-Taniaphos with nearly complete exo- selectivity and enantioselec-tivities up to 85% ee.10 The 3 + 2-cycloaddition of benzol/>]thiophene 1,1-dioxide... 

Aziridines in the synthesis of azomethine ylides 89AHC(45)231. Aziridines in the synthesis of natural products 86AHC(39)I81. Azirines as intermediates in pyrrole formation 87KGS1299. 3-Amino-2-//-azirines, synthesis and properties 90KGS867. Ethynylaziridines 87MI6. 

During the last decade we have been carrying out a systematic study of the reactions of nitroarenes with N-alkyl azomethine ylides. A fundamentally new approach has been advanced for the synthesis of polycyclic heterosystems bearing important pharmacophoric fragments, such as pyrrolidines, pyrrolines, and pyrroles. 

The azomethine ylide represents one of the most reactive and versatile classes of 1,3-dipoles and is trapped readily by a range of dipolarophiles, forming substituted pyrroles or pyrrolidines (Coldham and Hufton 2005). Synthesis of aziridines by reaction of a fluorocarbene with imines under ultrasonic irradiation was described previously (Konev et al. 2005). This reaction proceeds by the formation of an azomethine ylide (9), which can be trapped with dimethyl maleate (13) to produce pyrrolidines (14) or pyrrole rings (15) in moderate yields (Scheme 8.5). 

Solid-phase synthesis of pyrroles was reported by Mjalli et al. " Pyrroles were prepared via Rink resin-bound mesoionic munchnones (Scheme 11.12). Munchnones behave as azomethine ylides in 1,3-dipolar cycloaddition. Cycloadditions with alkynes give pyrroles after aromatization and spontaneous release of carbon dioxide. A set of compounds was obtained from simple starting materials, aldehyde, amine, carboxylic acid, and isocyanide via the Ugi four-component condensation. Trifluoroacetic acid released highly substituted pyrroles as amides from the Rink resin in high overall yield and purity. A related method via the miinchnone pathway was reported by Strocker et al., and two pyrroles were obtained in 4% and 17% yields. 

Kathiravan and Raghxmathan reported the synthesis of pyrrole-fused polycyclic heterocycles via intramolecular 1,3-dipolar cycloaddition reaction of azomethine ylides derived from pyrrole-2-carbaldehyde 28 and secondary amino acids in IL [BM1M][BF4]. The methodology involved the synthesis of N-alkenyl carboxaldehyde from 28 followed by freafment with sarcosine in [BM1M][BF4] as reaction medium at 85-95 C for about 3h to afford pyrrolo-pyrrolidines 29 in good yield (Scheme 3). The same reaction when carried out in organic solvents such as toluene, methanol, and acetonitrile, the reactions observed were slow, giving product in low yield [80]. 

CuOTf-catalyzed synthesis of polysubstituted pyrroles from a-diazoketones, nitroalkenes, and amines was reported by Lu, Wang, and coworkers. The corresponding polysubstituted pyrroles could be obtained in moderate yields using air as the oxidant. This cascade process of the polysubstituted pyrrole formation involves an NH insertion of carbene, a copper-catalyzed oxidative dehydrogenation of amine, and a [3+2] cycloaddition of azomethine ylide [21] (Scheme 8.9). 

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