Saegusa indole synthesis

The Saegusa indole synthesis has been used by several groups as tabulated in Table 1. Indole 34 in Entry 1 arises from a vicarious nucleophilic substitution of hydrogen for chloromethyl phaiyl sulfone on m ta-isocyanonitrobenzene, one of the products of which is isocyanide 33, which cyclizes to indole 34 [7]. The yield shown is that from the 

Indole Ring Synthesis From Natural Products to Drug Discovery, First Edition. Gordon W. Gribble. 2016 John Wiley Sons, Ltd. Published 2016 by John Wiley Sons, Ltd. 

The initially formed A-sodioindole in Entry 3 is arylated by activated fluorobenzenes to give A-aryl-3-(ethoxycar-bonyl)indoles in excellent yield [10]. The synthesis of 2-(methylsulfanyl)indoles in Entry 4 involves initial formation of isothiocyanates from the isocyanide, then sodium hydride-induced cyclization to the disodium 

Mironov and Mokrushin described the extraordinary formation of 35 from the reaction between triethylamine and aryl isocyanides bearing electron-withdrawing groups (Entry 7) [14], An x-ray crystal determination of 35 (R =R =H, R =R =CFj) confirmed the structure of this 2-triethylammonium-3-arylaminoindolate. Even more bizarre is the isolation, and x-ray crystal structure, of N-lithioindole 36 from the reaction of phenyl isocyanide and LiCH(TMS), (Entry 8) [15], 

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

The Saegusa indole synthesis involves the strong-base promoted cyclization of ort/ o-tolylisocyanides to indoles (Scheme 1) [1-5], Thus the Saegusa indolization resembles the Madelung indole synthesis. The reaction proceeds by a 5-endo-dig cyclization of 2 to form indole (equation 1). The isocyanide anion 2 was alkylated and subsequently cyclized to form 3-substituted indoles (equation 2). The quenching of 2 with epoxides yielded tryptophols (equation 3 and 4 and 5). Reaction of the ultimately formed N-lithioindole with electrophiles gave Af-substituted indoles (equation 4). 

R= -Bu) afforded l,3-benzodiazepin-4-one (22). With 15 (R=cyclohexyl), amixture of indole-3-carboxamide (25%) and l,3-benzodiazepin-4-one (58%) was obtained. The latter cyclized product probably arises from a nitrogen-copper species. In a full account of their indole syntheses methodology, Saegusa presented more examples of the chemistfy already given in this chapter, plus a new application was the synthesis of 2,3-disubstituted indoles 24. Thus, as shown in equation 4 (Scheme 3) base-induced alkylation of ortto-(acylmethyl)phenyl isocyamides 10 prior to cyclization led to 2,3-disubstituted indoles 24 [5]. 

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