Indole as dienophiles

Indoles as Dienophiles in Normal Electron Demand Diels-Alder Reactions.335... 

Snyder and Lee [9] were the last to comprehensively review the role of indoles as dienophiles in IDA and related reactions. In this chapter, we will mainly focus on the reports that have appeared in the literature since the above article appeared in press. 

Based on the above reports, hyperbaric conditions and Lewis acid catalysis are both helpful in reducing reaction times for difficult normal electron demand Diels-Alder reactions with indoles as dienophiles. Microwave-assisted Diels-Alder reactions have also been reported, where reaction times have been cut down to less than 1 h [35]. 

The majority of cycloaddition reactions which involve indoles as dienophiles occur using the 2,3-bond in some manner (IDA or normal electron demand Diels-Alder reactions). However, cycloaddition reactions on the benzoid portion of the indole nucleus have also been explored. These reactions, which mainly involve the use of an aryne species as the dienophile component, will be reviewed below. On the other hand, the use of 4,7-indoloquinone species in which the 5,6-bond may act as a dienophile [41-50], or reactions involving other similarly oxidized systems as dienophiles [51, 52], will not be further discussed. 

Chretien A, Chataigner I et al (2003) Complete and remarkable reversal of chemoselectivity in [4 + 2] cycloadditions involving electron-poor indoles as dienophiles. Diels-Alder versus hetero-Diels-Alder processes. J Org Chem 68 7990-8002... 

A large number of pyridazines are synthetically available from [44-2] cycloaddition reactions. In one general method, azo or diazo compounds are used as dienophiles, and a second approach is based on the reaction between 1,2,4,5-tetrazines and various unsaturated compounds. The most useful azo dienophile is a dialkyl azodicarboxylate which reacts with appropriate dienes to give reduced pyridazines and cinnolines (Scheme 89). With highly substituted dienes the normal cycloaddition reaction is prevented, and, if the ethylenic group in styrenes is substituted with aryl groups, indoles are formed preferentially. The cycloadduct with 2,3-pentadienal acetal is a tetrahydropyridazine derivative which has been used for the preparation of 2,5-diamino-2,5-dideoxyribose (80LA1307). 

Lee L., Snyder J. K. Indole As a Dienophile in Inverse Electron Demand Diels-Alder and Related Reactions Adv. Cycloaddit. 1999 6 119-171... 

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... 

Imidates, rearrangement of, 14, 1 Imines, additions of allyl, allenyl, propargyl stannanes, 64, 1 additions of cyanide, 70, 1 as dienophiles, 65, 2 synthesis, 70, 1 Iminium ions, 39, 2 65, 2 Imino Diels-Alder reactions, 65, 2 Indoles, by Nenitzescu reaction, 20, 3 by reaction with TosMIC, 57, 3 Ionic hydrogenation, 71, 1 Isocyanides, in the Passerini reaction, 65, 1... 

The indole a-pyrones 376 (R = Me or Et) acted as dienophiles with diethylacetylenedicarboxylate producing the 1-substituted carbazole-2,3-diesters in good yield by loss of carbon dioxide from the initial adduct. ... 

Indoles, which are especially electron-rich and thus unsuitable for ordinary Diels-Alder reactions, have performed successfully in the cation-radical reaction as dienophiles (Scheme 44)107 and as dienes (Scheme 45)126. Interestingly, the site of annulation (across the C—C or the C—N bond) in vinylindole cation radicals (functioning as dienes for eneamine dienophiles) may be manipulated by varying the substituent on the enamine and thereby altering its push-pull nature (Scheme 45). 

As a result of bond fixation within the indole system, the mesomeric interaction between the 2-vinyl group and the 7r-excessive heteroaromatic system is less than that for the 3-vinylindoles, and in the few reported reactions they have been shown to behave as dienophiles in [4 + 21-cycloaddition reactions (81CC37). 

Here again, the cycloaddition is endo-selective, with only regioisomers 79 being formed, and, when using 2- and/or 3-substituted furans, only the unsubstituted furan double-bond reacts in these inverse electron-demand Diels-Alder processes [134-136]. Indoles, pyrroles, and thiophenes can also be made to react as dienophiles with ortho-quinone monoketals... 

Indoles may as well serve as dienophilic compounds for hetero Diels-Alder reactions with nitrosoalkenes. However, the resulting adducts are not stable and undergo further conversion to oximes which represent useful intermediates for the straightforward synthesis of tryptophane derivatives [376,377]. 

Easily prepared from glycols, enones have been investigated as dienophiles. They react with butadiene under Lewis acid catalysis to form chiral cyclohexenes used in the synthesis of compactin analogs [353]. Levoglucosenone has been used in a Diels-Alder reaction with acetoxy-butadiene to construct a part of the indole alkaloid reserpine [354], and in synthetic studies toward tetrodotoxin [355]. Analogs of the anthracycline rhodomycinone have been similarly prepared [356]. [4 + 2]-Cycloaddition of the same enone with silyloxydiene allowed the creation of the fused ring system present in actinobolin [357]. 

Lee, L., Snyder, J. K. Indole as a dienophile in inverse electron demand Diels-Alder and related reactions. Adv. Cycloadd. 1999, 6,119-171. 

It is well established that 3-alkyl pyridines are selectively reduced at N1-C2, to produce 3-alkyl-l,2-DHPs [58,59,60], 5-Alkyl-l,2-DHPs, which result from hydride addition at C-6, are potentially valuable synthetic intermediates [61]. Substituent effects on the regiochemistry of the reduction of A-carbalkoxypyridinium salts have been studied in detail by Sundberg [62]. These DHPs have served as useful dienes for the synthesis of ISQs. Methyl 2-[l-phenylsulfonyl-lH-indol-2-yl]-2-propenoate (62) served as dienophile in most of these reactions [61,62,63,64,65,66,67,68]. Palladium-catalyzed radical cyclization [63], photocyclization [64] or thermal cyclization [61,65,66,67,68] reactions have all been employed to furnish the Diels-Alder adducts (e.g., 63). 

XIII). A thermal retro-Diels-Alder reaction of 39 liberating cyclopen-tadiene was used to afford a diene oxime ether which cyclized to give a tetracyclic indole as a 3 2 mixture of diastereomers. Three additional steps served to convert this adduct to ( )-lysergic acid (40). Of particular interest here is the fact that simple oximino compounds are not normally reactive dienophiles, and the intramolecularity of the conversion is apparently crucial to the success of this transformation. 

Indole as a dienophile In Inverse electron demand Diels-Alder reaction Snyder [90JOC3257]... 

Some highly substituted carbazoles were obtained by photo-induced Diels-Alder reactions of 2-(l-cyano-vinyl)indoles using stabilized enamines as dienophiles. <94SL141>... 

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. 

There are a few reactions in which pyrroles and indoles act as dienophiles at the 2,3-double bond. These reactions typically occur with strong N-EW substituents which tend to diminish the aromatic character of the heterocycle. An additional EW-substituent activates the 2,3-bond toward addition to conventional dienes. This reaction is accelerated by AICI3 and the regioselectivity is also improved under catalyzed conditions (Equations (133) and (134)) <88JA7188>. 

Examples of indole 2,3-bonds acting as dienophiles have been observed in situations where intramolecular addition is possible (Equations (135) and (136)) <88TL5605>. 

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