Indole synthesis Hegedus

The Hegedus indole synthesis involves one of the earlier (formal) examples of olefin hydroamination. An ortho-vinyl or ortho-nllyl aniline derivative 1 is treated with palladium(II) to deliver an intermediate resulting from alkene aminopalladation. Subsequent reduction and/or isomerization steps then provide the indoline or indole unit 2, respectively. 

In 1974, Hegedus and coworkers reported the pa]ladium(II)-promoted addition of secondary amines to a-olefins by analogy to the Wacker oxidation of terminal olefins and the platinum(II) promoted variant described earlier. This transformation provided an early example of (formally) alkene hydroamination and a remarkably direct route to tertiary amines without the usual problems associated with the use of alkyl halide electrophiles. 

The intramolecular variant, reported by Hegedus in 1976, expanded the scope to weakly nucleophilic amines. ort/io-Allylaniline 1 delivered 2-methyl indole in 84% yield using a stoichiometric amount of (CH3CN)2PdCl2 and triethylamine in THF via the intermediacy of 5. 

10 mol % (CH3CN)2PdCl2 too mol% benzoquinone LiCI (10 equiv) THF, reflux (86%) 

4-Bromo-A -tosylindole (8) has been converted to arcyriacyanin A (9) by Steglich. Similarly, Rapapport used 3,4-dibromoindole (10) to construct the ergot alkaloid tricyclic core (11), and Murakami reported a relatively short route to costaclavine. Similar uses in other natural product syntheses continue to appear in the literature.  

Stoichiometric Pd(II)-mediated oxidative cyclization of alkenyl anilines to indoles. Cf. Wacker oxidation. 

Johnston, J. N. Hegedus Indole Synthesis In Name Reactions in Heterocyclic Chemistry, Li, J. J. Corey, E. J., Eds. Wiley Sons Hoboken, NJ, 2005, 135—139. (Review). 

Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8 122, Springer-Verlag Berlin Heidelberg 2009 

Name Reactions A Collection of Detailed Mechanisms and Synthetic Applications, DOI 10.1007/978-3-319-03979-4 130, Springer International Publishing Switzerland 2014 

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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 Hegedus indole synthesis can be stoichiometric or catalytic and a range of indoles 340-342 was synthesized from the respective o-allylanilines in modest to very good yields (31-89%) [292],... 

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. 

The Hegedus indole synthesis, also known as the Hegedus reaction, Hegedus-Mori-... 

The Hegedus indole synthesis is not only compatible with a wide range of functional groups on the aromatic ring but is also tolerable for the alkyl groups at the 2 or 3 position of the allyl side chain." Other features of this reaction include (a) general accessibility for the intramolecular amination of mono-olefin from primary amines and weakly basic... 

Other references related to the Hegedus indole synthesis are cited in the literature. ... 

This reaction is related to the Hegedus Indole Synthesis, Castro Indole Synthesis, and Mori-Ban 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... 

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