Pyrroles intramolecular approaches

As with the corresponding section on pyrroles, indole syntheses have been categorized utilizing a systematic approach. Intramolecular approaches (type I) and intermolecular approaches (type II) are classified by the number and location of the new bonds that describe the indole forming step (2 examples shown below). In addition, the synthesis of azaindoles,... 

Intramolecular nucleophilic additions by nitrogen functional groups onto pendant alkynes and allenes represent an important class of type la approaches to functionalized pyrroles. A platinum-catalyzed (PtCl4) cyclization of homopropargyl azides provided an entry to 2,5-disubstituted pyrroles and 4,5,6,7-tetrahydroindoles (fused pyrroles) <06OL5349>. 

An interesting approach to the pyrrolizidine skeleton was devised wherein pyrrole-2-carboxaldehyde (70) underwent A-allylation under basic conditions and subsequent olefmation with ethyl p-tolylsulfinylmethanephosphonate to produce the pyrrolyl alkene 71 <00TL1983>. Intramolecular Heck reaction of the iodo species then produced the 1 -p-tolylsulfinyl-1,3-diene 72. 

Similar to the Pd-catalyzed pyrrole and thiophene annulations, an intramolecular Heck reaction of substrate 91 resulted in benzofuran 92 [80], Such an approach has become a popular means of synthesizing fused furans. Muratake et al. exploited the intramolecular Heck cyclization to establish the tricyclic core structure en route to the synthesis of a furan analog of duocarmycin SA, a potent cytotoxic antibiotic [81]. Under Jeffery s phase-transfer catalysis conditions, substrate 93 was converted to tricyclic derivatives 94 and 95 as an inseparable mixture (ca. 4 1) of two double bond isomers. 

In another approach, 2-(alkylamino)alcohol is employed as starting material for aziridine syntheses with the aid of dihalogenophosphoranes (70BCJ1185). Intramolecular transformation of 3-azidopropyloxirane 73 results in a simultaneous formation of a condensed aziridino[l,2-a]pyrrol-idine system (Scheme 39). The azide group is first transformed into imino-phosphorane 74, the nucleophilic N atom cleaves the oxirane to form betaine 75 [as in the Mitsunobu reaction (81S1)], and the phosphorus is shifted from N to O and then eliminated as phosphane oxide under simultaneous cyclization to bicyclic 76 (89JA7500). 

Stang etal. (94JA93) have developed another alkynyliodonium salt mediated approach for the synthesis of y-lactams including bicyclic systems containing the pyrrole moiety. This method is based on the formation of 2-cyclopentenones 114 via intramolecular 1,5-carbon-hydrogen insertion reactions of [/3-(p-toluenesulfonyl)alkylidene]carbenes 113 derived from Michael addition of sodium p-toluenesulfinate to /3-ketoethynyl(phenyl) iodonium triflates 112 (Scheme 32). Replacing 112 by j8-amidoethynyl (phenyl)iodonium triflates 115-119 provides various y-lactams as outlined in Eqs. (26)-(30). 

Paulvannan K (2004) An atom-economical approach to conformationally constrained tricyclic nitrogen heterocycles via sequential and tandem Ugi/intramolecular Diels-Alder reaction of pyrrole. J Org Chem 69 1207-1214... 

The synthetic chemistry for these targets has been most extensively developed for benzopyrrolo[l,2]diazepines. It includes annulation of the pyrrole ring to a pre-formed benzodiazepine core, intramolecular cyclizations of non-cyclic precursors and 6 + 1 and 4 + 3 dicomponent cyclizations. Similar approaches have been reported for a few systems with other fusion modes, and they are surveyed at the end of each section. 

Paulvannan has reported an efficient approach to rigid tricyclic nitrogen heterocycles via sequential and tandem Ugi-4CR/intramolecular Diels-Alder cydoaddi-tion of pyrrole derivatives. The Ugi-4CR was used to prepare trienes 187 from maleic and benzylmaleamic acids, which on heating at 60-120 °C for 12 h yielded... 

Another advantage of this approach is that we can now use electrophilic substitution on the pyrrole to add the rest of the molecule. So the secondary benzylic alcohol 106 might well cyclise to 105 with Lewis acid catalysis as the cation will be reasonably stable and the reaction is intramolecular. But the Friedel-Crafts alkylation to give 107 will not succeed as the cation would be primary. 

Pyrrole syntheses have been organized systematically into intramolecular and intermolecular approaches as well as by the location of the new bonds that describe the pyrrole ring forming step (two examples are illustrated below). Multi-component reactions appear at the end of the section on intermolecular approaches. The final section includes pyrrole syntheses that arise from transformations of other heterocycles. 

A similar approach was described by Kim et al. <01MI1403> to build the Furstner synthon from the vinylogous amide 9, previously described, and the commercially available dimethyl aminomalonate hydrochloride as building block for pyrrole systems. The cyclocondensation reaction between the vinylogous amide 9 and dimethyl aminomalonate hydrochloride was performed in acetic acid at room temperature to yield the presumed Intermediate 12 via an acid-catalyzed nucleophilic substitution reaction. The mixture was then diluted with additional acetic acid and heated under reflux to facilitate the intramolecular ring closure and the loss of the methoxycarbonyl moiety to produce the desired pyrrole. Formation of lamellarin O dimethyl ether was achieved as in the Furstner approach <95JOC6637>. 

An intramolecular cyclization approach has also been used for the synthesis of the fused pyrroles 67, which were obtained by treatment of the Weinreb amides 68 with r-BuLi. The requisite precursors 68 were prepared by A-benzylation of the pyrrole 69 with the benzyl bromides 70 <03OLl 115>. 

The second type of intramolecular Heck reactions involves conversion of an aryl halide into a furan. Similar to the Pd-catalyzed pyrrole and thiophene annulations, an intramolecular Heck reaction of substrate 161 furnishes benzofuran 162 [140], Such an approach has become a popular means of synthesizing fused furans. 

Two short syntheses of racemic ipalbidine ( )-(842) are shown in Scheme 109. The synthesis by Jefford et al. commenced with conjugate addition between pyrrole and Ae atropate ester 849 followed by homologation of the acid 850 with diazomethane and rhodium-induced intramolecular carbene cyclization of the resulting diazoketone 851 (574). The bicyclic product 852 was converted into ( )-842 in a further four steps. The approach taken by Danishefsky and Vogel centered on acid-catalyzed cyclocondensation between the silyl ketene acetal 853 and A -pyrroline (854) to give indolizidinone 855 (575). Reduction of the lactam and cleavage of the aryl ether completed the synthesis of ( )-842. 

Trauner applied a C-H bond activation approach to the synthesis of rhazinilam [81]. The synthetic power of direct C-H arylation on nucleophilic heteroarenes was demonstrated through formation of the strained 9-membered ring using intramolecular coupling to an unactivated pyrrole (Scheme 57). 

More recent approaches include a rhodium(II)-catalyzed intramolecular insertion reaction to form the hve-membered heterocycle. Reformatsky-imine addition of 4-bromo-4,4-difluoroacetoacetate with aldimines gave b-amino-y.y-difluoroacetoa-cetates 67 that were readily converted to the key diazo intermediates 68 through the action of tosyl azide and molecular sieve. Rhodium(II)-catalyzed intramolecular insertion followed by aromatization through loss of HF gave the functionalized pyrroles 69 (Fig. 3.29). 

The pivotal step associated with our approach to compounds 31-34 was an organocatalysed, enantioselective and intramolecular Michael addition reaction of the nucleophilic C-2 carbon of a pyrrole to an iV-tethered a,p-unsaturated aldehyde residue and thereby estabhshing the required CD-ring system. Full details of the reaction sequence are shown in Scheme 4 and this involves initial reaction of the potassium salt, 35, of pyrrole with butyrolactone (36) to give, after acidic workup, compound 37 (60-90%). Conversion of this last species into the corresponding Weinreb amide 38 (87%) followed by its reaction with ethylmagnesium bromide then afforded the ethyl ketone 39 (95%) that was subjected to standard Homer-Wadsworth-Emmons (HWE) conditions and thereby generating the... 

---