Wacker indole synthesis

While the Mori-Ban indole synthesis is catalyzed by a Pd(0) species, the Hegedus indole synthesis is catalyzed by a Pd(II) complex. In addition, the Mori-Ban indole synthesis is accomplished via a Pd-catalyzed vinylation (a Heck recation), whereas the Hegedus indole synthesis established the pyrrole ring via a Pd(II)-catalyzed amination (a Wacker-type process). Hegedus conducted the Pd-induced amination of alkenes [430] to an intramolecular version leading to indoles from o-allylanilines and o-vinylanilines [291-293, 295, 250, 251]. Three of the original examples from the work of Hegedus are shown below. 

The solid-phase version of the Madeiung indole synthesis was developed by D.A. Wacker et al. for the preparation of 2,3-disubstituted indoles.The ort/ o-substituted aniline substrate was first attached to the Bal resin using reductive amination. The resin-bound aniline was then acylated and the cyclization was brought about with a variety of bases to afford high yields of the disubstituted indoles. The products were quantitatively removed from the resin with TFAiEtsSiH (95 5). 

The synthesis of a variety of other heterocycles has been achieved using similar methodology [108], For example, benzopyran derivatives are readily prepared from 2-allyl phenols [110] note that the Pd( 0) precatalyst is oxidized to Pd(ll) by air before the reaction commences. Nitrogen heterocycles are also accessible from Wacker-type transformations, as demonstrated by the Hegedus indole synthesis described below in Section 1.10. 

Scheme 5 Wacker Solid-Phase Madelung Indole Synthesis...

One of the first applications of palladium to indole synthesis was due to Hegedus [12-17], who adapted the known Pd-mediated amination of alkenes [18] to the intramoleclar amination of o-vinyl- or o-allylanilines (Scheme 1, equations 1 and 2). This Wacker-like process involves Pd(II) and can be stoichiometric or catalytic. For an excellent review of the Hegedus indole synthesis, see Johnston [19]. Although it is rarely referred to as such, the Hegedus reaction has found several applications and extensions in indole synthesis (equations 3-5) [20, 21, 23]. The preparation of ethyl indole-2-carboxylates (equation 4) [21] has been improved by McNulty and Keskar [22], and Danheiser synthesized 6- -butyl-l,2-dimethyl-4-hydroxyindole via a... 

Combinatorial chemistry has played an increasing role in drug discovery. Wacker et al. extended the Madelung indole process successfully to solid phase library synthesis for the preparation of 2,3-disubstituted indoles. A number of examples follow in the table. 

Oxidative addition consumes one equivalent of expensive Pd(OAc)2 in most cases. However, progress has been made towards the catalytic oxidative addition pathway. Knolker s group described one of the first oxidative cyclizations using catalytic Pd(OAc)2 in the synthesis of indoles [19]. They reoxidized Pd(0) to Pd(II) with cupric acetate similar to the Wacker reaction, making the reaction catalytic with respect to palladium [20]. 

Wacker, D. A., Kasireddy, P. Efficient solid-phase synthesis of 2,3-substituted indoles. Tetrahedron Lett. 2002, 43, 5189-5191. 

Wacker and Kasireddy described a solid-phase synthesis of 2,3-disubstituted indoles (Scheme 5) [37] via the modified Madelung synthesis reported by Reinhoudt [34, 35]. The basic approach is shown in equation 1, and several synthesized indoles are posted. 

Regioselective synthesis of indoles is accomplished by in situ trapping of Wacker aldehydes with (1) (eq 4). o-Vinylacetanilides give indoles directly under similar reaction conditions. Iso-coumarins and 1-isoquinolinones are also prepared by this chemistry. Electron-deficient alkenes give acetals with (1) under Wacker conditions (see PaUadium(H) Chloride-Copper(I) Chloride) ... 

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