Diels-Alder reaction pyrrole

Yeo WC, Vittal JJ, Koh LL, Tan GK, Leung PH (2(X)4) Chiral metal template promoted asymmetric pyrrole Diels-Alder reaction between N-(diphenylphosphino)pyrrole and diphenylvinylphosphine. Organometallics 23 3474—3482... 

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. 

In keeping with its aromatic character, pyrrole is relatively difficult to hydrogenate, it does not ordinarily serve as a diene for Diels-Alder reactions, and does not undergo typical olefin reactions. Klectrophilic substitutions are the most characteristic reactions, and pyrrole has often been compared to phenol or... 

Benzo[Z)]furans and indoles do not take part in Diels-Alder reactions but 2-vinyl-benzo[Z)]furan and 2- and 3-vinylindoles give adducts involving the exocyclic double bond. In contrast, the benzo[c]-fused heterocycles function as highly reactive dienes in [4 + 2] cycloaddition reactions. Thus benzo[c]furan, isoindole (benzo[c]pyrrole) and benzo[c]thiophene all yield Diels-Alder adducts (137) with maleic anhydride. Adducts of this type are used to characterize these unstable molecules and in a similar way benzo[c]selenophene, which polymerizes on attempted isolation, was characterized by formation of an adduct with tetracyanoethylene (76JA867). 

Alkynes substituted with one or two trifluoromethyl groups are also highly reactive dienophiles [9] Indeed, hexafluoro-2-butyne is used increasingly as a definitive acetylenic dienophile in "difficult Diels-Alder reactions. It was used, for example, to prepare novel inside-outside bicycloalkanes via its reaction with cir,trnns -l,3-undecadiene [74] (equation 67) and to do a tandem Diels-Alder reaction with a l,l-bis(pyrrole)methane [75] (equation 68) Indeed, its reactions with pyrrole derivatives and furan have been used in the syntheses of 3,4-bis(tri-fluoromethyl)pyrrole [76, 77] (equation 69) and ],4-bis(trifluoromethyl)benzene-2,3-oxide [78] (equation 70), respectively. 

A small number of pyrroles undergo addition of acetylenedi-carboxylic acid across the 2,5-positions yielding adducts similar to those obtained from cyclopentadiene. In the case of 1-benzylpyrrole and the acid, some (13) is formed, probably through the intermediary of a species such as (8) a strong case has been made for the supposition that the Diels-Alder reaction occurs in two distinct stages,... 

The combination of the Diels-Alder reaction of fi-sulfonylnitroethylene and the Barton-Zard reaction provides a new synthesis of pyrroles fused with polycyclic skeletons fEq 10 31 Pyrroles fused with bicycle [3 3 3 Qctodiene are important precursors for synthesis of isoindoles via the retro Diels-Alder reaction fEq 10 33 ... 

Pyrano-[4,2-b]-pyrrol-5-ones (40) and pyrano-[4,3-b]-pyrrol-6-ones (41) (Figure 2.4) are stable cyclic analogs of pyrrole 2,3-quinodimethane and undergo Diels Alder reaction [40, 41] with various dienophiles to afford indole derivatives after loss of carbon dioxide. 

It has been known that aromatic heterocycles such as furan, thiophene, and pyrrole undergo Diels-Alder reactions despite their aromaticity and hence expected inertness. Furans have been especially used efficiently as dienes due to their electron-rich properties. Thiophenes and pyrroles are less reactive as dienes than furans. But pyrroles with A-elecIron-withdrawing substituents are efficient dienes. There exists a limited number of examples of five-membered, aromatic heterocycles acting as dienophiles in Diels-Alder reactions. Some nitro heteroaromatics serve as dienophiles in the Diels-Alder reactions. Heating a mixture of l-(phenylsulfonyl)-3-nitropyrrole and isoprene at 175 °C followed by oxidation results in the formation of indoles (see Eq. 8.22).35a A-Tosyl-3-nitroindole undergoes high-yielding Diels-Alder reactions with... 

Yu and co-workers also used CAN to catalyze an aza-Diels-Alder reaction <06TL3545>. Aryl imines were reacted with /V-vinyl pyrrol idin-2-one or IV-methyl-lV-vinyl-acetamide in the presence of 10 mol% CAN resulting in the desired 2,4-cw-tetrahydroquinolines in good yields. 

The Boger pyrrole synthesis based on a heterocyclic azadiene Diels-Alder strategy (1,2,4,5-tetrazine to 2,2-diazine to pyrrole) was employed by the author for the total synthesis of ningalin B . Thus a Diels-Alder reaction of the electron-rich acetylene 52 with the electron deficient 1,2,4,5-tetrazine 53 proceeded to give the desired diazine 54 which underwent subsequent ring contraction to afford the core pyrrole structure 55. 

Alder/retrograde Diels-Alder reaction sequence of a diaryl alkyne with a 3,6-dicarbomethoxy tetrazine. The resulting diazine (14) is then reduced, cleaved and cyclized with Zn/acetic acid to the 2,3,4,5-tetrasubstituted pyrrole (15), which is then N-alkylated with a-bromo-4-methoxyacetophenone to give a pentasubstituted pyrrole (16). The synthesis of lukianol A is completed by ester hydrolysis, decarboxylation, ring closure and deprotection. 

Arai and coworkers197 reported the utilization of a chiral pyrrole sulfoxide as a chiral auxiliary in the asymmetric Diels-Alder reactions of its /V-cinnamoyl and /V-crotonyl derivatives 313 with cyclopentadiene which gave 314-317 (equation 87). The results have been summarized in Table 18. The yield as well as the endo/exo selectivity and the de proved to depend on the type and amount of Lewis acid used. 

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]. 

Although pyrroles do not generally participate in Diels-Alder reactions with olefinic dienophiles, the very reactive hexafluoro-Dewar benzene with pyrrole gives the 1 1 and 1 2 adducts, 27 and 28, both of which probably have all-ea o stereochemistry. Some other 7-azabicyclo-heptene derivatives have been obtained via cycloaddition reactions of 7-azaquadricyclanes (see Section II, F). 

At higher temperatures retro-Diels-Alder reaction may also occur in the opposite sense to addition, as in the reaction of methyl pyrrole-1-carhoxylate with dimethyl acetylenedicarboxylate at 200°, which affords acetylene and the pyrrole triester (56). The decomposition of the suspected intermediate Diels-Alder adduct (11) at 170° has been separately established. Compounds 19 and 20 are intermediates in similar addition-elimination reactions leading to pyrrole-l,3,4-triesters, in which removal of acetylene from the system makes the reaction sequence effectively irreversible. 

Flouk has also considered the alkylation reactions of pyrroles and indoles using the same class of catalyst. The report addresses the fact that while catalyst 12 provides high ees in the alkylation of pyrroles (Scheme 15), the same is not true of indoles and catalyst 21 is required instead (Scheme 16). A thorough examination of the accessible transition states for the reaction of iminium ion 184 with pyrrole and with indole led to the conclusion that the two reactions occur through different transition states. Pyrrole adopts a closed transition state reminiscent of that of the Diels-Alder reaction whereas indole adopts an open transition state (Fig. 19) [233]. 

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... 

For the first time, application of sequential Diels-Alder reactions to an in situ-generated 2,3-dimethylenepyrrole was shown with various dienophiles 548 to afford 2,3,6,7-tetrasubstituted carbazoles (549). This novel tandem Diels-Alder reaction leads to carbazole derivatives in two steps, starting from pyrrole 547 and 2 equivalents of a dienophile, and is followed by 2,3-dichloro-5,6-dicyano-l,4-benzoquinone (DDQ) oxidation of the intermediate octahydrocarbazole. Mechanistically, the formation of the intermediate octahydrocarbazole appears to involve two sequential [4+2] cycloadditions between the exocyclic diene generated by the thermal elimination of acetic acid and a dienophile (529) (Scheme 5.17). 

Boger et al. reported the first total synthesis of ningaline D (282) starting from the diphenylacetylene 1092 and dimethyl l,2,3,4-tetrazine-3,6-dicarboxylate (1093) (687). In this synthesis, the key step is the formation of the fully substituted pyrrole core using an inverse electron demand heterocyclic azadiene Diels-Alder reaction followed by a reductive ring contraction of the resultant 1,2-diazine. 

The idea of employing the reaction of a nitroarene or nitroheterocycle with a mtinchnone to synthesize a fused pyrrole ring system has been developed by two groups. Nesi et al. (109) found that mtinchnone 38 reacts with 3-methyl-4-nitroisoxazole (196) and 4-nitro-3-phenylisoxazole (197) to give the corresponding 5//-pyrrolo[3,4-tf]isoxazoles 198 and 199, respectively, in good yield. Presumably loss of carbon dioxide in a retro-Diels-Alder reaction follows loss of nitrous acid. 

An unprecedented nitrogen elimination reaction of 4-amino-7-benzylpyrrolo [23- f][133]triazine-5-caibonitrile (72) to give the pyrrole derivative 74 has been described. The following mechanism, presumably via a a retro Diels-Alder reaction of the imino tautomer 73, has been proposed <990L537>. 

The furo[3,4- ]pyrroles 132, 133 <2002TL6983>, thieno[2,3-f]furan 134, <1996JOC6166>, and furo[2,3-f]pyrrole 135 <1995T193>, which are mostly less stable than the benzo-fused analogues, were trapped by Diels-Alder reactions with dienophiles followed by elimination of water to give the corresponding indoles 136-139, 140, 141, and benzothiephenes 142, 143, and 144 with good to excellent yields (Scheme 13). 

The Diels-Alder reaction of furo[2,3-f]pyrrole 135 with either 1 or 2 equiv of DM AD in benzene gave a stable 1 2 cycloadduct 145 in 88% yield <1995T193>. 

Pyrrole-fused 3-sulfolenes 221 undergo thermal extrusion of sulfur dioxide to produce highly reactive o-quinodi-methanes which can be trapped in Diels-Alder reactions (Scheme 23) <1997H(46)199, 1997TL3639>. The resulting cycloadducts 222-227 are important starting compounds in porphyrin synthesis. 

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