Indole 2,3-quinodimethane

Pyrano[3,4-b]indol-3-ones are the most useful equivalents of the indol-2,3-quinodimethane synthon which are currently available for synthetic application. These compounds can be synthesized readily from indole-3-acetic acids and carboxylic anhydrides[5,6]. On heating with electrophilic alkenes or alkynes, adducts are formed which undergo decarboxylation to 1,2-dihydro-carbazoles or carbazoles, respectively. 

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 aspidospenna[l9 ] and kopsine[20] structures. The fundamental reaction pattern is illustrated in equation 16.7. An indole-2,3-quinodimethane is generated by W-acylation of an Ai-(pent-4-enyl)-imine of a 2-methyl-3-formylindole. Intramolecular 2 -P 4 cydoaddition then occurs. 

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 have also been exploited as the key intermediates in indolo[2,3-a]caibazole synthesis, allowing the preparation of several interesting systems. Thus, when the starting materials 74a-b (obtained from the condensation of protected indole-2-carboxaldehydes with 2-aminostyrene) underwent treatment with methyl chloroformate in hot chlorobenzene, the carbamates 75a-b were obtained, and could subsequently be dehydrogenated into the aromatic compounds 76a-b (Scheme 11). However, all functionalization attempts of the methyl... 

Indole-2,3-quinodimethanes [44] 44 are bicyclic outer-ring dienes that are widely used to prepare a variety of heterocyclic polycyclic compounds. These dienes, generated by extrusion of CO2 from lactones, are then trapped by dienophiles. Some examples of Diels Alder reactions of the dienes 44 are reported in Scheme 2.19. 

In 1984, a facile synthesis of pyrrolo[3,4-/7]indole (5) as a stable indole-2,3-quinodimethane analogue using an intramolecular azide-alkene cycloaddition-cycloreversion strategy was reported (Scheme 9.2) (3). Treatment of bromo compound 3 with NaNs in aqueous tetrahydrofuran (THF) produced the triazoline 4 via an intramolecular 1,3-dipolar cycloaddition of an intermediate azide. Treatment of the triazoline 4 with p-toluenesulfonic acid (p-TSA) effected 1,3-dipolar cycloreversion of 4 to give pyrroloindole 5 in 82% yield along with diethyl diazomalonate. 

Diels-Alder reaction of indole-2,3-quinodimethanes, 164-169 of pyrrole-2,3-quinodimethanes, 85-87 of vinylindoles, 159 -164 of vinylpyrroles, 79, 84-85 N.N-dihexyl 2-phenylindole-3-acetamide, procedure for. 62... 

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

Synthesis of indole alkaloids from indole-2,3-quinodimethanes 84ACR35. Synthesis of indole alkaloids, introduction of ethylidene substituent ... 

DiffCTent methods for the generation of indolo-2,3-quinodimethanes and subsequent cycloaddition have been reported. Indole-2,3-quinodimethane precursors include 3-cyanomethyl-2-vinylindoles <05BMC2263> and furoindolones <05SL994>. 

As part of a project to synthesize stable analogs of the indole-2,3-quinodimethane system, the 2,4-di-hydropyrrolo[3,4]indole (251) has been prepared from formylindole (249). Knoevenagel condensation with ethyl malonate followed by bromination and nucleophilic substitution of the bromide with azide yields (250), which immediately undergoes intramolecular 1,3-dipolar cycloaddition to give the triazoline (252). Treatment of (252) with toluene-p-sulfonic acid affords diethyl diazomalonate and (251 ... 

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. 

---