Indoles, oxidation/cydization

Sperry, J. and Moody, C.J. (2010) Diazonamide studies. A direct synthesis of the indole bis-oxazole fragment from tri- and tetra-peptides using biomimetic oxidative cydizations. Tetrahedron, 66, 6483-6495. 

The core skeleton of geissoschizine, an important biosynthetic precursor to numerous polycyclic indole scaffolds, was the target of a nickel-catalyzed alkylative coupling strategy. Cyclization precursor 13 was prepared by ozonolysis and double reductive amination of cyclopentene 12 (Scheme 8.13) [35]. Nickeldeprotection/oxidation sequence followed, and chromatography led to complete inversion of the C3 stereocenter. A Fisher indole synthesis followed to afford ( )-deformyl-isogeissoschizine, the core skeleton of geissoschizine. 

One of the most common examples of this approach involves the coupling of aryl or vinyl halides with palladium-catalyzed cydization. This chemistry typically employs palladium(O) catalysts, which are postulated to undergo an initial oxidative addition of aryl or vinyl halides to form a palladium(II) complex to mediate cydization. This is followed by reductive elimination of the heterocyde-aryl or heterocyde-vinyl bond. This approach has been employed to construct a range of polysubstituted indoles. For example, Cacchi has shown that the Pd(PPh3)4 catalyzed coupling of trifluoroace-tanilides with aryl halides or vinyl halides/triflates proceeds to substituted indoles in good yield (Scheme 6.14) [18]. 

As a replacement for alkynylanilines, Yamamoto has reported that indoles can he generated via the Pd(PPh3)4/CuCl-catalyzed coupling of 2-aIkynylaryUsocyanates with allylcarbonates (Scheme 6.18) [26]. In this case, fragmentation of the carbonate anion to an alkoxide upon oxidative addition to palladium allows conversion of the isocyanate into a carbamate for subsequent cydization. A number of substituted alkynes can participate in this reaction, and it can be performed with alcohols instead of allylcarbonates to form 3-unsubstituted indoles. A variant of this reaction involved the use of isocyanides in concert TMS-azide, providing a route to substituted N-cyanoindoles [27]. 

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