Pyrrole Construction

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. 

These two methods are closely related but differ in the point of initial attachment of the substituent from which the carbocyclic indole ring is constructed. One strategy for building up 2-substituted pyrroles capable of... 

This category corresponds to the construction of the carbocyclic ring by 2 + 4 cycloaddition with pyrrole-2,3-quinodimethane intermediates. Such reactions can be particularly useful in the synthesis of 5,6-disubstituted indoles. Although there are a few cases where a pyrrolequinodimethane intermediate is generated, the most useful procedures involve more stable surrogates. Both 1,5-di-hydropyrano[3,4-b]pyrrol-5(lf/)-ones[l] and l,6-dihyropyrano[4,3-b]pyrrol-6-(in)-ones[2] can serve as pyrrole-2,3-quinodimethane equivalents. The adducts undergo elimination of CO2. 

Besides being useful precursors to pyrroles pyridine-2-ones -4-ones, -4-thiones. and -4-imines 4-alkylidene-dihydropyridines thiophenes 1,2,4-triazoles thiapyrane-2-thiones, isoquinoline-3-ones isoben-zothiophenes and 4-mercaptoimidazolium hydroxide inner salts, mesoionic thiazoles are potentially useful in the construction of molecules with herbicidic (39). central nerve stimulating, and antiinflammatory properties (40,41). Application in dye synthesis has likewise been reported (42). 

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). 

Paal and Knorr independently discovered the straightforward reaction of primary amines (or ammonia) with 1,4-diketones to give pyrroles following loss of water7 Like the Knorr pyrrole synthesis, the PK method is a powerful and widely used method of constructing pyrroles (vide infra). 

The major application of the Knorr pyrrole synthesis is in the construction of porphyrins, and many examples exist,particularly from the work of Lash, who also demonstrated the formation of novel pyrroles, such as Cyanopyrroles are available... 

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

In recent years further concepts have been developed for the construction of polymer-based diodes, requiring either two conjugated polymers (PA and poly(A-methyl-pyrrole) 2 > or poly(A-methylpyrrole in a p-type silicon wafer solid-state field-effect transistor By modifying the transistor switching, these electronic devices can also be employed as pH-sensitive chemical sensors or as hydrogen or oxygen sensors 221) in aqueous solutions. Recently a PPy alcohol sensor has also been reported 222). 

Langer and coworkers constructed diverse O- and N-heterocydic scaffolds, such as y-alkylidene-a-hydroxybutenolides and pyrrolo[3,2-b]pyrrol-2,5-diones, exploiting the well-established cyclization strategy of bisnucleophiles with oxalic acid derivatives [163], while Stockman s research group reported in this context on a novel oxime formation/Michael addition providing the structural core of the alkaloid perhydrohistrionicotoxin [164]. 

The intramolecular version of the PKR has attracted much more synthetic interest, leading to valuable bicyclic systems and being more general and viable [97]. Particularly, 1,6-enynes have been extensively used for the construction of the bicyclo[3.3.0]octane [105], cyclopenta[c]furan [106], or cyclopenta[c]pyrrole [107] skeletons in a single step. 

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. 

As will be discussed later, the novel pentacyclic antitumor alkaloid roseophilin continues to attract much synthetic effort and several approaches relied on the venerable Paal-Knorr condensation for construction of the pyrrole moiety. For instance, Trost utilized this reaction upon diketone 1 to afford the tricyclic core 2 of roseophilin in a strategy featuring an enyne metathesis as a key step <00JA3801>, while another formal synthesis of this alkaloid utilized a radical macrocyclization to produce the ketopyrrole core <00JCS(P1)3389>. 

In Scheme 5 under the lukianol section, the Bullington synthesis [17] of 2,3,4-trisubstituted pyrroles was presented. Bullington has used this strategy to prepare ningalin B and the resulting steps in this route are presented in Scheme 17. This route also constitutes a very efficient method for the construction of the ningalin A and B scaffold. 

Pyrrole itself is an obvious precursor of pyrrolidine by catalytic hydrogenation. One example of construction of an ant pyrrolidine analog from a pyrrole has been published (Scheme 24) (169). 

The Sonogashira reaction frequently serves as a platform for the construction of indoles, and we will explore this application in Chapter 3, but it also is a valuable method for the preparation of alkynyl pyrroles. 

An intramolecular heteroaryl Heck was the pivotal step in the synthesis of 5-butyl-1-methyl-l//-imidazo[4,5-c]quinolin-4(5//)-one (63), a potent antiasthmatic agent [46], The optimum yield was obtained under Jeffery s ligand-free conditions, echoing Ohta s observation for the intermolecular version. Once again, the Caryi—Caryi bond was constructed at the C(5) position of the imidazole ring. Another intramolecular heteroaryl Heck cyclization of pyrrole and imidazole derivatives was also reported to assemble annulated isoindoles [47]. 

Several approaches have been undertaken to construct redox active polymermodified electrodes containing such rhodium complexes as mediators. Beley [70] and Cosnier [71] used the electropolymerization of pyrrole-linked rhodium complexes for their fixation at the electrode surface. An effective system for the formation of 1,4-NADH from NAD+ applied a poly-Rh(terpy-py)2 + (terpy = terpyridine py = pyrrole) modified reticulated vitreous carbon electrode [70]. In the presence of liver alcohol dehydrogenase as production enzyme, cyclohexanone was transformed to cyclohexanol with a turnover number of 113 in 31 h. However, the current efficiency was rather small. The films which are obtained by electropolymerization of the pyrrole-linked rhodium complexes do not swell. Therefore, the reaction between the substrate, for example NAD+, and the reduced redox catalyst mostly takes place at the film/solution interface. To obtain a water-swellable film, which allows the easy penetration of the substrate into the film and thus renders the reaction layer larger, we used a different approach. Water-soluble copolymers of substituted vinylbipyridine rhodium complexes with N-vinylpyrrolidone, like 11 and 12, were synthesized chemically and then fixed to the surface of a graphite electrode by /-irradiation. The polymer films obtained swell very well in aqueous... 

Tropone (255) cycloadds to allene 71c to construct a 5,7-fused ring system, probably via a concerted mechanism [109]. The reaction of 71c with azaheptafulvenes 256 took place much more readily at room temperature to produce the relatively unstable adducts 257, which isomerized gradually to the stable pyrroles. 

Scheme 2.70 Rapid construction of tetra-substituted pyrrole scaffolds using supported reagent methodology.

Cycloisomerization represents another approach for the construction of cyclic compounds from acyclic substrates, with iridium complexes functioning as efficient catalysts. The reaction of enynes has been widely studied for example, Chatani et al. reported the transformation of 1,6-enynes into 1-vinylcyclopentenes using [lrCl(CO)3]n (Scheme 11.26) [39]. In contrast, when 1,6-enynes were submitted in the presence of [lrCl(cod)]2 and AcOH, cyclopentanes with two exo-olefin moieties were obtained (Scheme 11.27) [39]. Interestingly, however, when the Ir-DPPF complex was used, the geometry of olefinic moiety in the product was opposite (Scheme 11.28) [17]. The Ir-catalyzed cycloisomerization was efficiently utilized in a tandem reaction along with a Cu(l)-catalyzed three-component coupling, Diels-Alder reaction, and dehydrogenation for the synthesis of polycyclic pyrroles [40]. 

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