Indole-2,3-quinodimethanes, cycloaddition reactions

Another strategy for annelation of pyrroles and indoles involves cycloaddition reactions. Because the heteroaromatic rings have substantial aromatic stabilization, the C2—C3 bond is not very reactive toward cycloaddition and there are only a few examples of the heterocycles acting as dienophiles. The carbocyclic ring of indole, like benzene, is unreactive toward cycloaddition. However, vinylpyrroles and indoles are quite reactive and react as electron-rich dienes because of the electron-donating nature of the ring. Other cycloaddition reactions involve the 2,3-dimethylene derivatives of pyrrole and indole, the so-called quinodimethanes, which are very reactive dienes. These intermediates, and more stable synthetic equivalents, are useful in cycloadditions with a variety of dienophiles. 27/-Isoindole, which itself can be thought of as a quinodimethane, is a very reactive diene. 

Aminomethylindoles are particularly important synthetic intermediates. 3-Dimethyl-aminomethylindole (gramine) (153) and especially its quaternary salts readily undergo displacement reactions with nucleophiles (Scheme 60). Indole-2,3-quinodimethanes, generated from 2-methylgramine as shown in Scheme 61, undergo intermolecular cycloaddition reactions with dienophiles to yield carbazole derivatives (82T2745). 

Indole-2,3-quinodimethanes, generated from 2-methylgramine, undergo intermolecular cycloaddition reactions with dienophiles similar to that of (325) (82T2745). 

The pyrrolo[3,4-Z ]indoles offer an alternative approach to access indolo-2,3-quinodimethane analogs and have also been used in Diels-Alder cycloaddition reactions with acetylenes to produce a variety of substituted carbazoles. The most widely used methods developed for the synthesis of pyrrolo[3,4-b]indoles have already been reviewed [126, 127] and thus wiU not be discussed here. 

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. 

As was the case with reactions of vinylindoles, the most elaborate synthetic targets approached by the indole-2,3-quinodimethane route have been alka-loids[18]. The route has been applied to aspidosperma[ 19] and kopsine[20] structures. The fundamental reaction pattern is illustrated in equation 16.7. An indole-2,3-quinodimethane is generated by /V-acylation of an AT-(pent-4-enyl)-imine of a 2-methyl-3-formylindole. Intramolecular 2 + 4 cycloaddition then occurs. 

Heterocyclic o-quinodimethanes are unstable and reactive dienes that must be generated in situ. In solution and in the pre.sence of a dienophile the -quinodimethanes can be intercepted in a Diels-Alder reaction, often in high yield. Most of the dienophiles investigated so far have been electron deficient A-phenylmaleiinide. acrylonitrile, methyl vinyl ketone, acrylate, ftimarate and acetylenedicarboxylic esters are typically used. However, since the objective of most of the work was simply to establish that the o-quinodimethane was being formed, the scope of the reaction has not been adequately explored. The pyridine derived o-quinodimethane 12 has recently been shown to undergo cycloaddition to ethyl vinyl ether (Scheme 2) and to dihydroftiran <96T11889>, and it is thus clear that the scope of the Diels-Alder reaction extends beyond electron deficient alkenes and alkynes. Heterodienophiles (azodicarbonyl compounds and nitrosobenzene) have been added to indole-2,3-quinodimethanes <91T192,S> and this type of hetero Diels-Alder reaction is also potentially of wider application. 

A pyrrolo[3,4-Z>]indole (320), which can be prepared by an intramolecular aza-Wittig reaction and JV -protection, acts as a quinodimethane and undergoes cycloaddition to 3,4-pyridyne to yield a mixture of isomeric adducts (321) and (322) which are precursors of ellipticine and isoellipticine (Scheme 98) <84CC1552, 92T10645>. 

The Chi group further developed a highly enantioselective formal [4 + 2] cycloaddition of a-branched indole 3-carboxaldehydes with trifluoromethyl ketones or isatins to give polyeyelic and spiro lactones, respectively. The reaction is postulated to undergo a catalytic cycle of NHC-eatalyzed aetiva-tion of the C(sp )—H bond of 2-methyl indole 3-carboxaldehydes to produee ort/ o-quinodimethane intermediates. Notably, 2-methyl benzofuran and ben-zothiophene aldehydes are also suitable substrates for this reaction, while 2-methylbenzaldehyde gives the partially oxidized carboxylic acid under these conditions without the observation of the desired lactone product (Scheme 7.115). 

The first example of an indole-2,3-quinodimethane (IQM) undergoing a Diels-Alder cycloaddition to furnish a carbazole was reported by Plieninger and coworkers in 1964 [9], Thus, indole-3-acetic acid was readily converted to pyrano[3,4-fe]indol-3-ones upon treatment with carboxylic acid anhydrides (Scheme 1, equation 1). These stable synthetic equivalents of IQMs undergo Diels-Alder reactions with electron-deficient dienophiles (A-phenytma-leimide,maleicanhydride,dimethylacetylenedicarboxylate) (equation 2). Plieninger s discovery notwithstanding, it was Moody and coworkers who parlayed this chemistry into a powerful carbazole synthesis (equations 3,4) [10-18],... 

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