Cycloaddition of indoles

In contrast to the failure of Diels-Alder reactions, dipolar cycloadditions of indoles are much more successful, and the Boger group has reported a fascinating [4+2]/l,3-dipolar cycloaddition cascade involving indole as the dipolarophile in their impressive synthesis of vindoline (Scheme 4.8) [26]. After the initial... 

Apreparation of pyrrolo[3,4-3]indoles 495 from pyridazino[4,5- ]indoles 494 using aZn/AcOH reductive ring contraction has been described <1997TL8611>. Since 494 are easily prepared from the inverse electron demand cycloaddition of indoles 492 with tetrazine 493, this represents a simple, two-step sequence to prepare the pyrro-loindoles 495 (Scheme 62). 

TABLE 7. Results of PIET-induced cycloaddition of indole diene 65 with dienophile 66 ... 

TABLE 8. Results of PIET- or electrochemically-induced cycloaddition of indole dienes with dienophilesa... 

The radical cation Diels-Alder reaction has been the subject of many mechanistic and theoretical investigations and has been shown to have much synthetic potential. With regard to heteroaromatics, the reaction has been exploited by Steckhan in the cycloaddition of indoles and 1,3-dienes. This reaction occurs smoothly upon photosensitization by triarylpyrrilium tetrafluoroborates. The reaction is satisfactory rationalized as involving addition of the indole radical cation to electron-rich dienes (Scheme 35), and the regioselectivity is in accord with theoretical predictions [104]. The reaction with exocyclic dienes has been developed for the synthesis of carbazole derivatives such as 52 and 53 [105]. 

Cycloadditions only proceeding after electron transfer activation via the radical cation of one partner are illustrated by the final examples. According to K. Mizono various bis-enolethers tethered by long chains (polyether or alkyl) can be cyclisized to bicyclic cyclobutanes using electron transfer sensitizer like dicyanonaphthalene or dicyano-anthracene. Note that this type of dimerization starting from enol ethers are not possible under triplet sensitization or by direct irradiation. Only the intramolecular cyclization ci the silane-bridged 2>. s-styrene can be carried out under direct photolysis. E. Steckhan made use of this procedure to perform an intermolecular [4+2] cycloaddition of indole to a chiral 1,3-cyclohexadiene. He has used successfully the sensitizer triphenylpyrylium salt in many examples. Here, the reaction follows a general course which has been developed Bauld and which may be called "hole catalyzed Diels-Alder reaction". 

Among the variety of reactions discussed in this section, only the photochemical cycloadditions of indoles have been recently reviewed by Weedon [11]. In the interest of completeness, we will also discuss (albeit briefly) some of the papers already covered by the Weedon review. 

Other reports on the [3+2] cycloadditions of indoles and nitrile oxides focus on intermolecular reactions. For example, Gribble [80] has investigated the reaction of (phenylsulfonyl)-2-(tri-n alkylstannyl)indoles 169 with tetranitromethane to give the novel isoxazolo[5,4-b]indole derivative 173 (Scheme 49). The mechanism cascade is thought to proceed through the degradation of the dinitromethyl anion to a nitrile oxide 171, followed by a 1,3-dipolar cycloaddition to form a nitroindole intermediate 172 and subsequent loss of nitrous acid or SnR3N02. Treatment of the isoxazole 173 with base then leads to the formation of the oxindole tautomer 175 as the major product. 

In this chapter, we have attempted to comprehensively review [4-1-2] cycloadditions of indoles, in which the indole nucleus serves as either the diene or the dienophile compruient. In most cases, the discussion will be limited to the cycloaddition reactirai itself, and the reader is encouraged to consult the cited references for further details regarding the preparation of starting materials, as well as further manipulations of the cycloadducts. Wherever the cycloaddition was highlighted as a key strategic step in a complex natural product synthesis, some discussion on how the cycloadduct was further elaborated has been included. While we have chosen to focus on reports published after 1990, occasimial older precedents may be discussed or cited. In cases of subtopics for which a major review had been... 

Quinones are widely used dienes in IDA reactions. It is therefore no surprise that a few reports have appeared in the literature which use the IDA cycloadditions of indoles with quinones to form novel heterocycles. 

Indole and dihydroindole moieties are prevalent structural features in a variety of biologically interesting and synthetically challenging natural product molecules. A number of approaches to the preparation of indole-containing natural products have relied on the IDA cycloadditions of indoles as a key synthetic step. In particular, the IDA reaction has been especially fruitful in providing access to the key stmctural skeleton of the communesin family, a series of structurally interesting and biologically active Penicillium metabolites. 

Pindur U, Gonzalez E et al (1997) [4+2]Cycloaddition of indole derivatives with bismalei-mides a route to new biscarbazoles. J Chem Soc, Perkin Trans 1 1861-1867... 

A plano-convex lens was used to collimate and focus, an IR mirror was employed to eliminate non-productive IR irradiation and minimize associated heat, and a variety of UV filters could be employed to control wavelength. After evaluation of 728 reactions, they identified five which were further explored. Examples included a wavelength dependent [2-I-2]-cycloaddition of indole 27 to afford a mixture of indole 28 cyclobutane 29 (Scheme 5A). They observed that the photo-Fries rearrangement was predominant at shorter wavelengths while the [2 -I- 2]-cycloaddition was favoured at longer wavelengths. A second reaction they identified was an oxa-di-7i-methane reaction with bicycle 39 to afford the caged cyclopropane 35 in 70% yield after 2 min (Scheme 5B). In the screen they found both direct excitation and triplet sensitization conditions for the reaction. They also identified a 1,3-acyl shift with ketol 32 to afford cyclohutanone 33 in modest yield (Scheme 5C). This platform demonstrated that flow photochemistry can enable automated reaction discovery. 

Magnus published a S37nthetic methodology to selectively protect staurosporinones, just after Winterfeld s report [54]. Intramolecular Diels-Alder cycloaddition of indole-2,3-quinidome-thane 130a was the crucial step in his synthetic strategy (see Scheme 22). Imine 130 was... 

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