Tricyclic pyrroles

Nitrobenzofurazan 240 and 4-chloro-7-nitrobenzofurazan 232 also condense with isocyanoacetates in the presence of the non-nucleophilic base l,8-diazabicyclo[5.4.0]undec-7-ene (DBU) to give tricyclic pyrrole derivatives 241 in excellent yields (Scheme 60) <2005T11615>. 

Acetylation of the amide (128) produced a fused tricyclic pyrrole in 17% yield (Scheme 39).64 A munchnone intermediate was postulated and could be trapped via intermolecular cycloaddition with diethyl acetylenedicarboxylate. Presumably the direct cyclization product lost carbon dioxide, a known reaction of munchnone cycloadducts.65 An homologous munchnone with an o-(propenyl)phenyl group, rather than o-(butenyl)phenyl group, failed to cyclize, although it could again be trapped with diethyl acetylenedicarboxylate. 

Cyclization of the nitrile ylide generated from amide (150a) via an imidoyl chloride led to an 18% yield of a fused tricyclic pyrrole (Scheme 46).77 Similarly, the nitrile ylide derived from (150b) cyclized in 6% yield. 

Tricyclic pyrrole derivative 2.43 is a drug currently under development for the treatment of schizophrenia. It is prepared by a Knorr pyrrole synthesis. What are the structures of the two starting materials required, and that of the intermediate enamine ... 

The reaction of 2//-heptafluorobut-2-ane with l,8-diazabicyclo[5.4.0]-undecan-7-ene 78 (reagent ratio 1 4) leads to tricyclic pyrrole—1,9-diaza-bicyclo[5.4.0]undecano-[a,Z -2]-difluoromethyl-3-trifluoromethylpyrrole 79 (96JFC(79)121). 

The oxidative dearomatization of para-substituted o-alkynylanilines 290 using (diacetoxyiodo)benzene affords 2-alkynyl cyclohexadienimines 291, which can act as active substrates for reaction with electron-rich styrenes 292 in the presence of metal salts the Bi(OTf)3-catalyzed reactions give 3,4-dihydro-cyclopenta[c,rf indoles 293 and the AgOTf-catalyzed reactions provide tricyclic pyrrole derivatives 294... 

An interesting family of polycyclic pyrroles was described in 2005 using again the synthetic sequence of a Stetter reaction for the preparation of the starting 1,4 diketones followed by a microwave-assisted Paal-Knorr condensation [35]. For example, cyclopentenone 23 (obtained in a Pauson-Khand cyclization) reacted under Stetter reaction conditions to give the amino ketone 25 (Schemes). The microwave-assisted Paal-Knorr cyclization of 25 with different amines gave a small collection of tricyclic pyrrole 2-carbox-amides. 

Several other photochemical trifluoromethylations by CF3I were reported. The regioisomeric substitution products 61 and 62 were formed [32] from the tricyclic pyrrole 60, whereas regioselective a-trifluoromethylation was observed for pyrroles 63 and 65 to give 2-CF3-pyrroles 64 [4] and 66 [8] in moderate and good yields. 

Scheme 12.19 Au-catalyzed synthesis of bicyclic and tricyclic pyrroles.

The utility of the platinum-catalyzed enyne cycloisomerization for the formal synthesis of Rosephilin, which is a member of prodiginine family of alkaloids, was reported by Trost and Doherty (Scheme 7.44) [94]. The critical step in the synthesis was the conversion of enyne 221 to bicyclic diene 222 by platinum-catalyzed enyne cycloisomerization. While palladium catalysis was found to be ineffective, the desired cyclopentene 222 was obtained when 221 was treated with the platinum-based catalytic system developed by Murai. Diene 222 was converted to tricyclic pyrrole intermediate 223 in an 11-step sequence. Since 223 had been converted to roseophilin 224, the entire procedure represented a formal synthesis of the alkaloid. 

Both (17) (74TL2841) and (18) (76JA4325) undergo cycloadditions at the double bond without disruption of the thiirane ring (80JOC2962, 80JA6633). This type of reaction has been used to convert (17) to the Dewar pyrrole (20) via the tricyclic thiirane (19) (77JA7350). 

An efficient synthesis of rigid tricyclic (5 5 5) nitrogen heterocycles 64 has been achieved via sequential and tandem Ugi/intramolecular Diels-Alder (IMDA) cycloaddition of pyrrole derivatives <2004JOC1207> and the trienes 477 were prepared by the acylaton of amines 475 with the anhydride 476. The amines 475 were in turn prepared starting from pyrrole-2-carbaldehyde. The triene 477 on heating in toluene at 80 °C for 15 h underwent the IMDA to afford the tricyclic compound 64 as a single diastereomer in quantitative yield. The sterically bulky N-substitutent on the triene 477 promoted cycloaddition under milder condition at 65 °C in toluene to provide the tricyclic compound 64 in quantitative yield (Scheme 108). 

The bis[l,2]dithiolo[5,4- ][5, 4 -< ][l,4]thiazine ring systems of Rees and co-workers easily extrude sulfur from the thiazine ring and undergo contraction to the fused pyrrole derivatives <1997CC879>. These tricycles generally have a nonplanar, scorpion-like solid-state structure <1998JOC2189> however, the dicarbonyl product of... 

Boiadjiev and Lightner synthesized fluorescent tricyclic-bridged pyrrinones such as 31 by base-catalyzed condensation-cyclization of pyrrolin-2-one 112 with pyrrole aldehyde 113 (Equation 24) <2005M553, 2005JOC689>. 

Diaz-Ortiz and co-workers carried out microwave cycloadditions to synthesize pyrazolo[3,4-A]pyridines, including tricyclic derivative 149 obtained from pyrrole 147 using A-methylmaleimide 148 as the dienophile (Equation 34)... 

In an approach toward the synthesis of tetraponerine, Gevorgyan and co-workers explored the double pyrrolization of pyrimidine derivatives 276 via a copper-catalyzed cyclization to give tricycles 277 (Equation 76) <2002OL4697, 2004JOC5638>. 

Formation of this ring system was also reported in the reaction of a,/3-unsaturated ketones with substituted pyrrol-5-ones, giving the tricyclic products in 41—46% yield <2004PS(179)61>. 4-Thienyl and 4-furyl derivatives of a dihydropyrano[2,3- 5,6-c]dipyrazole were also obtained via the heterocycle-substituted acrylonitrile in 77% and 74% yield, respectively <2005RJ0742>. 

An alternative strategy for the synthesis of these tricyclic compounds involves the reaction of the azidoalkenyl-functionalized furo[3,2-A]pyrrole 30, which reacts with triphenylphosphine to give the corresponding iminophos-phoranes 31 these upon reaction with aryl isocyanates give the pyrrolo[2, 3 4,5]furo[3,2-r-]pyridines 32, via the corresponding carbodiimides which are not isolated < 1994H(37) 1695, 1992M807> (Scheme 9). 

This class of tricyclic compound is dominated by the 377-pyrrolizines (systematically named 3//-pyrrolo[l,2- ]-pyrroles) and related systems, which are fused to another six-membered heterocyclic ring (Figure 1). 

Reactions with dialdehydes allow the introduction of two additional rings in one step. Thus, condensation of 1 -(2-aminoethyl)pyrrole with glutaraldehyde and benzotriazole gives tricyclic intermediate 627 in which the benzotriazolyl moiety can be readily substituted with nucleophiles to give products 628 (Scheme 97) <2002JOC8220>. Condensation of ethyl ester of L-tryptophan with 2,5-dimethoxytetrahydrofuran and benzotriazole in acetic acid gives tetracyclic intermediate 629 which upon treatment with nucleophiles (silyl derivatives) is converted to products 630 <1999T3489>. 

Reaction of iV-[(benzotriazol-l-yl)methyl]amide 707 with PCI5 gives chloroimine 708, which upon treatment with Bu OK is converted to nitrile ylide 709. Benzyl esters of ot,(3-unsaturated acids used as dipolarophiles trap species 709 to generate pyrroles 712 (Scheme 110) <2002JHC759>. When no trapping agent is added, the N-2 atom of benzotriazole act as a nucleophile, and tricyclic system 711 is formed <2001TL9109>. Addition of benzyl bromide... 

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>. 

Grigg has utilized the Heck reaction in several ways, from the simple cyclization of N-(2-iodobenzoyl)pyrrole (139) to afford tricyclic lactam (140) [100] to the complex cascade... 

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. 

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... 

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