Construction of the Pyrrole Rings

Besides serving as a platform for the construction of the pyrrole ring (see Chapter 3.), the Sonogashira coupling is also effective in functionalising the same system. Trimethylsilylacetylene was used as a surrogate to introduce acetylene groups into the 2 and 5-positions of pyrrole (6.43.), 2,5-diiodo-... 

Reactions in this category correspond to construction of the pyrrole ring from ammonia or a substituted derivative and a preassembled carbon array. These can be subdivided into cyclizative condensations and metal-promoted processes. 

Several structural features of (-)-rhazinilam 3 raise interesting synthetic challenges the axially chiral phenyl-pyrrole A-C biaryl bond, the fused pyrrole-piperidine C-D rings, the stereogenic quaternary carbon (C-20) ortho to the phenyl-pyrrole axis, the nine-membered lactam firing. Three racemic (Smith, Sames, Magnus) and one asymmetric (Sames) total syntheses have been published to date, which all proceed via construction of the pyrrole ring and diastereoselective control of the axial chirality by the central chirality at C-20. 

Total syntheses with construction of the pyrrole ring... 

In the three different approaches envisaged for the total syntheses of rhazinilam, the construction of the pyrrole ring was operated in two different manners a Knorr-type reaction in the Smith synthesis and a 1,5-electrocyclization of an allyl-iminium compound in the Sames and Magnus syntheses. 

In 2001, Magnus and co-workers reported a straightforward synthesis of racemic rhazinilam by initial construction of the pyrrole ring from a piperidone, Fig. (33) [154]. The sequential alkylation of piperidone 155 with iodoethane and allyl bromide furnished piperidone 156, having the requisite C-20 substitution of rhazinilam. After formation of the thiophenyl iminoether 157, A-alkylation with allyl bromide 158 furnished the corresponding iminium intermediate which underwent 1,5-... 

The synthesis of a structurally somewhat more complex indolone tyrosine kinase inhibitor starts with the construction of the pyrrole ring. Reaction of tert-butyl acetoacetate (87) with nitrous acid leads to nitrosa-tion on the activated methylene carbon. This reaction introduces the nitrogen atom that will appear in the target pyrrole. Condensation of 88 with... 

The first total synthesis of ( )-obscurinervidine (50) (309) starts essentially from the benzoxazine 524, which was prepared from pyrogallol. Construction of the pyrrole ring on the IV-amino derivative of 524 gave, after... 

Wardani and Lhomme (93TL6411) used a different pathway for the construction of the pyrrole ring. Base-catalyzed alkylation of N-acetyl-N -tosylproflavine 60 with bromoacetaldehyde diethyl acetal, followed by deprotection of the acetal function with concomitant ring closure and deacylation in acidic media yielded 9-amino-3-tosylpyrrolo[2,3-c]acridine 301. Detosylation was achieved by basic hydrolysis to give 9-aminopyr-rolo[2,3-c]acridine 302 (Scheme 55). 

The 1,3-dipolar cycloaddition of acetylenes and alkenes with oxazolones is widely used for the construction of the pyrrole ring. The presence of a CFs-group in the 1,3-dipolar component opens a pathway to 2-CF3-pyrroles, while the application of trifluoromethylated dipolarophiles provides 3-CF3-pyiroles. For example, the dimethyl pyrroledicarboxylate 120 was synthesized in 78 % yield by the reaction of the CFs-containing oxazolone 118, prepared from proline 117 and trifluoroacetic anhydride (TFAA), with dimethyl acetylene dicarboxylate (DMAD) [53]. 

Indoles have proved a popular target for synthetic methodologies utilizing key palladium- and copper-catalyzed C—N bond formations. A plethora of routes have been developed for construction of the pyrrole ring incorporated in an indole system [11-15]. The main disconnections [D-1 to D-7] which feature a catalysed C—N bond-forming step, are illustrated in Scheme 24.1. 

A possibility of successful application of the Trofimov reaction for the construction of the pyrrole ring bonded to the steroid skeleton has been exemplified by oximes of ketosteroids. 

Apparently, the intermediate carbanion A, in the case of O-vinyl oxime with the pyrrole moiety, is additionally quenched by acidic pyrrole proton, which is absent in di(O-vinyl) dioxime (Scheme 1.95). As a consequence, the formation of next intermediate, divinylhydroxylamine B, and the construction of the pyrrole ring slow down. 

The following questions are important for an understanding of the reaction mechanism and for better preparative use of the reaction Which of the two groups of the ketoxime, the methyl (when R =H) or methylene group, primarily participates in the construction of the pyrrole ring Are there differences in the reactivity of the two a-methylene moieties (R R, R =Alk) related to different alkyl groups with normal structures Do the reaction conditions affect the ratios of the structural isomers The answers to these questions have been found during a study of the interaction between a number of unsymmetrical ketoximes with acetylene in the presence of the KOH/DMSO system under conditions that lead to N-vinylpyrroles [188]. 

The reaction of benzyl methyl ketoxime with excess acetylene (100°C, KOH) furnishes 2-methyl-3-phenyl-N-vinylpyrrole only (Scheme 1.106). The regioselectivity of the reaction is not violated even under harsher conditions (120°C) and when the reaction is carried out in the system LiOH/DMSO (120 C). Under these conditions, 2-methyl-3-phenyl-N-vinylpyrrole and its nonvinylated precursor are formed in approximately equal amounts (Scheme 1.106). Structural isomer, 2-benzylpyrrole, has been isolated only at increased concentrations of the reactants and base at 120 C. Thus, the methyl group also begins to participate in the construction of the pyrrole ring under these conditions (Schane 1.106). 

In the light of the data on the key role of O-vinyl oximes as primary intermediates in the construction of the pyrrole ring, to explain this phenomenon, one should admit a dramatic difference in vinylation rates of ketoxime E- and Z-isomers. 

Particularly, the book deals with regioselectivity of the reaction between asymmetric methyl alkyl ketoximes and acetylenes involving the construction of the pyrrole ring preferably via the methylene group of the alkyl radical. Also, the reasons of the process selectivity violation at the elevated temperature are discussed. It is shown that the latter phenomenon can be used for the preparation of not only 2,3-dialkyl substituted but also 2-alkyl substituted N-vinylpyrroles. 

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