Reactions of Indole-2,3-quinodimethanes

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... 

The prominence of the Diels-Alder reaction of quino-2,3-dimethanes (also known as ortfto-quinodimelhanes and < rt/j( -xylylenes) has been established for nearly six decades since the seminal work by Cava [1,2], Several excellent reviews are available [3-7]. The logical extension of this chemistry to the synthesis and Diels-Alder reactions of indole-2,3-quinodimethanes (2,3-dimethylene-2,3-dihy-dro-l/7-indoles) has been recognized as an efficient route to indoles, carbazoles, and related fused indoles [8],... 

Incorporation of the new catalysis concept and N-heterocyclic carbene catalysis into multicatalytic systems emerged as a new direction to build up a complex scaffold such as those often found in natural products. Liu et al. developed an enantioselective Diels-Alder reaction via trienamine catalysis of indole-2,3-quinodimethane and activated alkenes. More recently, they combined this Diels-Alder process with N-heterocyclic carbene catalysis for the rapid generation of chiral cyclopentanone-fused tetrahydrocarbazoles with diverse substitution [30]. Mechanistically, with the... 

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. 

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. 

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. 

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

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. 

Indole-2,3-quinodimethanes stabilized by 1-EW groups can be generated by treatment of the corresponding 2,3-bis-(bromomethyl)indoles with sodium iodide. This reaction proceeds by halide exchange and reductive elimination of iodine. Methyl acrylate can trap the intermediate <84TL5429, 89TL7289>. There is a slight preference for the 2-substituted tetrahydrocarbazole (Equation (148)). 

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],... 

The intramolecular Diels-Alder reaction has featured in a number of elegant syntheses of natural products in the past decade, and this trend shows little sign of diminishing. A particularly pleasing illustration of this approach to synthesis is provided by the synthesis of ( )-aspidospermidine (79) by Magnus et al. whereby the key intermediate (80) was produced by way of intramolecular Diels-Alder reaction of the indole 2,3-quinodimethane (78), generated from treatment of the imine (76) with the mixed anhydride (77) in chlorobenzene at 140 °C. 

Indole-2,3-quinodimethane methodology has been utilized in the synthesis of the above groups of carbazoles 108). The N-sulphophenyl indole-2,3-quinodimethane anologue (136) undergoes the Diels-Alder reaction with benzyne generated from (137). In three steps (138-138B) it furnishes the simple benzo-b-carbazole (139). 

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. 

Miki and Hachiken reported a total synthesis of murrayaquinone A (107) using 4-benzyl-l-ferf-butyldimethylsiloxy-4fT-furo[3,4-f>]indole (854) as an indolo-2,3-quinodimethane equivalent for the Diels-Alder reaction with methyl acrylate (624). 4-Benzyl-3,4-dihydro-lfT-furo[3,4-f>]indol-l-one (853), the precursor for the 4H-furo[3,4-f>]indole (854), was prepared in five steps and 30% overall yield starting from dimethyl indole-2,3-dicarboxylate (851). Alkaline hydrolysis of 851 followed by N-benzylation of the dicarboxylic acid with benzyl bromide and sodium hydride in DMF, and treatment of the corresponding l-benzylindole-2,3-dicarboxylic acid with trifluoroacetic anhydride (TFAA) gave the anhydride 852. Reduction of 852 with sodium borohydride, followed by lactonization of the intermediate 2-hydroxy-methylindole-3-carboxylic acid with l-methyl-2-chloropyridinium iodide, led to the lactone 853. The lactone 853 was transformed to 4-benzyl-l-ferf-butyldimethylsiloxy-4H-furo[3,4- 7]indole 854 by a base-induced silylation. Without isolation, the... 

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. 

Pindur and coworkers have reported the in situ generation and subsequent Diels-Alder reactions of A-substituted 2,3-quinodimethanes with a variety of maleimides [95]. Thus, treatment of bis(bromomethyl)indoles 323a-c with maleimides 324a-c in a 2 1 molar ratio, in the presence of sodium iodide (DME or DMF, 65°C, 1 h), produced the corresponding double Diels-Alder adducts 325 in 60-79% yield (Scheme 69). In all cases, the products formed were the meso isomers, as would be expected from the preference for the endo approach, as well as cis-selectivity (with respect to the dienophiles). 

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. 

Terzidis M, Tsoleridis CA et al (2005) Chromone-3-carboxaldehydes in Diels-Alder reactions with indole-ortho-quinodimethane. Synthesis of tetrahydrochromeno[2, 3-b]carba-zoles. Tetrahedron Lett 46 7239-7242... 

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