Diels-Alder reaction indoles intramolecular cycloaddition

The inverse electron demand Diels-Alder reaction of 3-substituted indoles with 1,2,4-triazines and 1,2,4,5-tetrazines proceeds in excellent yields both inter- and intramolecularly. The cycloaddition of tryptophan 124 with a tethered 1,2,4-triazine produced a diastereomerically pure cycloadduct 125 <96TL5061>. 

When propargylamine 183 was subjected to a homologative allenylation (Crabbe reaction) at 100 °C, the resulting allene underwent a spontaneous Diels-Alder reaction to give the adduct 184. This intramolecular cycloaddition-oxidation sequence provided a simple route to indole alkaloids such as hippadine and ds-trikentrin B [148]. 

Generally, cycloadditions represent powerful reactions for construction of heterocycles. Tandem intramolecular Diels-Alder/retro-Diels-Alder reaction sequences were applied in the syntheses of many A,B-diheteropentalenes <1996GHEC-II(7)1>. Gribble and co-workers <1998SL1061> reported new syntheses of pyrrolo[3,4-, ]indoles 426, benzo[4,5]furo[2,3-f]pyrroles 429, and benzo[4,5]thieno[2,3-4pyrroles 430 using the 1,3-dipolar cycloaddition... 

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". 

This biogenetic proposal has spurred interest in the synthesis of structures such as (70). An especially efficient example of the use of intramolecular Diels-Alder reactions to synthesize aspidosperma alkaloids has been developed by Kuehne and co-workers <8373715, 85JOC924, 85JOC4790, 87JOC347). The azepino[4,S-6]indole structure (72) is condensed with a d-haloaldehyde generating (74), which undergoes fragmentation to (75) which contains the secodine synthon. With the secodine type structure only cycloaddition path b is available and aspidosperma structures are formed (76) (Scheme 148). 

Diels-Alder reactions using 2-vinylindoles as the diene were used as the key step in syntheses of olivacine derivatives (155), ellipticine derivatives (157), and ( )-3-epi-dasycarpidone (162) [65] (Scheme 39). In the synthesis of ( )-3-epi-dasycarpidone, the appropriate 2-vinylindole 159 was prepared via a one-pot procedure, and then subjected to deprotection of the aUyl carbamate, and subsequent enamine formation, followed by an intramolecular Diels-Alder reaction to produce 161, thereby producing the indole alkaloid framework in three steps from a rather simple starting material, 158. The attempted cycloaddition reaction... 

Nitrogen-containing heterocycles are also available via intramolecular hetero Diels-Alder reactions. Williams employed an aza diene to prepare a complex polycyclic synthetic intermediate in his synthesis of versicolamide B. Boger reported a tandem intramolecular hetero Diels-Alder/l,3-dipolar cycloaddition sequence for the synthesis of vindorosine. Cycloaddition precursor 137 undergoes an inverse electron demand Diels-Alder reaction to yield 138. This compound decomposes via a retro dipolar cycloaddition to generate nitrogen gas and a 1,3-dipole that completes the cascade by reacting with the indole alkene to afford 139. Seven more steps enable the completion of vindorosine. ... 

Very recently, Padwa reported a total synthesis of strychnine based on an intramolecular Diels-Alder reaction/rearrangement cascade, which was previously developed in his group to assemble the tetracyclic core ring system of indole alkaloids (Scheme 16) (174-178). Intramolecular cycloaddition reactions often benefit from higher reactivity and greater control of stereoselectivity relative to their intermolecular counterparts. Unlike Bodwell s lEDDA reaction (Scheme 13), the reaction of an electron-rich furan moiety with an N-acyl indole moiety required only a single tether. His synthesis also involved... 

In addition to the above intermolecular reactions, the intramolecular Diels-Alder cycloadditions of furo[3,4-b]indoles have also been reported. Herndon and coworkers [131] used the coupling reaction of the Af-benzylindolynal derivative 396 with Fischer carbenes 397a-b to obtain the carbazoles 398a-b, presumably via the... 

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