Pyrrole ring construction

FIGURE 3.29 Rhodium(II)-catalyzed cyclization in pyrrole ring construction. 

Alkali metal hydroxides differ not only in reactivity but also in selectivity of action. For example, LiOH selectively catalyzes the reaction of the pyrrole ring construction from alkyl aryl ketoximes [160,163-165], while it is almost inactive at the stage of vinylation of the pyrrole formed. At the same time, LiOH is ineffective for cycloaliphatic ketoximes at both stages [159] the pyrrole ring formation is accelerated in this case by rubidium and tetrabutylammonium hydroxides [159,161]. 

The reaction smoothly proceeds also at 100°C in the presence of 30% (from ketoxime weight) KOH in DMSO in autoclave under initial acetylene pressure of 8-16 atm. The maximum pressure reached at the reaction temperature is 20-25 atm. Then, intensive consumption of acetylene begins, and pressure quickly decreases. As it was already noted, initially, N-unsubstituted pyrroles are formed, which further are vinylated in the presence of acetylene excess. If it is necessary to obtain the corresponding NH-pyrrole, the synthesis is carried out with calculated amount of acetylene or with its lack. LiOH appears to be a selective catalyst of the pyrrole ring construction, the application of which does not require strict dosing of acetylene. 

However, as emphasized in the monograph [2], it is the synthesis of simple pyrroles, especially alkyl-substituted ones, that still presents a real challenge to chemists. For instance, from 39 reactions of the pyrrole ring construction, reported in the book [1], only few have real synthetic value. The majority of these reactions are multistage and laborious, the starting materials being hardly accessible. 

Indoles are usually constructed from aromatic nitrogen compounds by formation of the pyrrole ring as has been the case for all of the synthetic methods discussed in the preceding chapters. Recently, methods for construction of the carbocyclic ring from pyrrole derivatives have received more attention. Scheme 8.1 illustrates some of the potential disconnections. In paths a and b, the syntheses involve construction of a mono-substituted pyrrole with a substituent at C2 or C3 which is capable of cyclization, usually by electrophilic substitution. Paths c and d involve Diels-Alder reactions of 2- or 3-vinyl-pyrroles. While such reactions lead to tetrahydro or dihydroindoles (the latter from acetylenic dienophiles) the adducts can be readily aromatized. Path e represents a category Iley cyclization based on 2 -I- 4 cycloadditions of pyrrole-2,3-quinodimcthane intermediates. 

Remarkably few examples of this type of ring construction are available. The cobalt carbonyl hydride catalyzed hydroformylation of A/,A/ -diallylcarbamates has provided 3-pyrrolidinones (Scheme 61a) (81JOC4433). The pyrrole synthesis shown in Scheme 61b depends on Michael addition of ethyl a-lithioisocyanoacetate to ethyl a-isocyanocrotonate (77LA1174). 

The pyrrole ring in numerous natural products has been constructed using a PK synthesis. Examples include lamellarin L, funebrine, magnolamide, and... 

In addition to cydocondensation reactions of the Paal-Knorr type, cycloaddition processes play a prominent role in the construction of pyrrole rings. Thus, 1,3-dipo-lar cycloadditions of azomethine ylides with alkene dipolarophiles are very important in the preparation of pyrroles. The group of de la Hoz has studied the micro-wave-induced thermal isomerization of imines, derived from a-aminoesters, to azomethine ylides (Scheme 6.185) [346]. In the presence of equimolar amounts of /i-nitrostyrenes, three isomeric pyrrolidines (nitroproline esters) were obtained under solvent-free conditions in 81-86% yield within 10-15 min at 110-120 °C through a [3+2] cycloaddition process. Interestingly, using classical heating in an oil bath (toluene reflux, 24 h), only two of the three isomers were observed. 

Two major types of transformations are usually used for the synthesis of benzazepines with the fused pyrrole and indole rings. Construction of the... 

The pyrrole ring can also be constructed starting from an 7V-vinyl-2-halobenzoic amide. The /V-(2-iodobcnzoyl)-1,4-dihydropyndine derivative shown in 3.19. underwent palladium catalysed ring closure to give a condensed isoindolone derivative. The use of formic acid as co-solvent led to the reduction of the intermediate palladium complex formed in the insertion step, instead of / -hydride elimination. The transfer of the stereochemical information from the starting material to the product was poor.25... 

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-... 

CONSTRUCTION OF PYRROLE RINGS BY PROCESSES INVOLVING FORMATION OF TWO BONDS... 

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. 

The C-2 and C-3 hydroxy derivatives of pyrrole are special in the sense that the tautomeric equilibria favor the pyrrolinone structures (see Section 3.04.6.2). Furthermore, the general synthetic methods are not usually applicable so that we will call attention in this section not only to the methods of directly introducing these substituents, which are rare, but also to those ring construction processes which specifically give the pyrrolinones and indolinones. The indole derivatives have widely used trivial names, oxindole (5) for indolin-2-one and indoxyl (6) for indolin-3-one, Carbocyclic hydroxy substituents in indole and carbazole, on the other hand, for the most part act as normal aromatic phenolic groups. These compounds are usually prepared by application of the standard ring syntheses. 

In terms of synthetic strategy, approaches to porphyrins from open-chain tetrapyrroles are the only truly general routes. The principle is to construct, in a stepwise manner, an open-chain tetrapyrrole bearing a pre-determined arrangement of peripheral substituents. Cyclization to produce a porphyrin, or an immediate precursor, under mild conditions which do not cause redistribution of the pyrrole rings, should be accomplished after full characterization of the open-chain intermediate. 

Unlike methyl alkyl ketoximes from which the pyrrole ring is preferentially constructed from the alkyl methylene group (78KGS54), oxime 52 utilizes only the methyl group for this. In one case only (80ZOR410), the H-NMR spectrum of the reaction products indicated signals tentatively assigned to the second expected isomer, 3-ethoxy-2-methyl-l-vinylpyrrole. 

An example of the Knorr pyrrole synthesis is provided by the formation of 3,5-diethoxycarbonyl-2,4-dimethylpyrrole (55). Overall ring construction in this case may be related to (46) above. A retrosynthetic analysis involving disconnection of the N—C2 bond, appropriate prototropic shifts, and finally a retro-aldol reaction to effect disconnection of the C3—C4 bond, reveals ethyl acetoacetate and ethyl a-aminoacetoacetate (ethyl 2-amino-3-oxo-butanoate) (56) as reagents. An FGI transform on this latter compound generates the corresponding nitroso (oximino) compound which may also be derived from ethyl acetoacetate. 

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... 

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