Madelung synthesis of indoles

The Madelung synthesis of indoles (79 — 80) from A-acyl-o-toluidines originally necessitated heating with sodamide at 250°C however, the stronger bases n-butyllithium or LDA cause reaction at 20°C <81JOC4511 >. Milder conditions can also be employed if the methyl group is activated as in (81 — 82) (68JA7008). 

Treatment of an imidate which is placed ortho to a reactive methylene group with sodium hydroxide-DMSO results in the formation of a new pyrrole ring. Good to xcelient yields of 4-nitroindoles are obtained when 3-nitro-2-methyl-anilines (or acetanilides) are treated with diethyl oxalate in the presence of a strong base (cf. Madelung synthesis of indoles, p. 68). 

The title compound, mapindolol 198, a potent /7-adrenoceptor blocking (antihypertensive) agent, has been synthesized200 by the Madelungs method of indole synthesis using [l-14C]acetyl chloride as starting material (equation 80). 

Somewhat related to the Madelung and Wender indole syntheses is the method developed by Smith and Visnick, which features the dilithio species from ortho-sXkyl-N-in-methylsilyl anilines reacting with carboxylic acid esters to give 2-substitnted and 2,3-disubstituted indoles [1, 2], The value of this indole synthesis is seen by its numerous applications by Smith and coworkers in the synthesis of indole alkaloids [3-12], The basic reaction and some examples are shown in Scheme 1. The requisite silylated anilines were prepared by lithiation (n-bntyllithinm, -78 °C) of the aniline followed by quenching with trimethylsilyl chloride. For the synthesis of 2,3-disubstituted indoles an inverse quench is preferred (equation 3). To lithiate ort/to-ethyl-A -methylsilyl aniline, n-butyllithium-tetramethylethylene-diamine (TMEDA) was required. Indole 1 is an intermediate in the synthesis of (H-)-cinchonamine. 

Retrosynthetic path b in Scheme 3.1 corresponds to reversal of the electrophilic and nucleophilic components with respect to the Madelung synthesis and identifies o-acyl-iV-alkylanilines as potential indole precursors. The known examples require an aryl or EW group on the iV-alkyl substituent and these substituents are presumably required to facilitate deprotonation in the condensation. The preparation of these starting materials usually involves iV-alkyla-tion of an o-acylaniline. Table 3.3 gives some examples of this synthesis. 

The Madelung indole synthesis has been employed in the preparation of some complex indole systems. Uhle et al. reported the conversion of N-formyl-5,6,7,8-tetrahydronaphthylamine 28 into 1,3,4,5-tetrahydrobenz[c,ti]indole 29 with t-BuOK in 11% yield in regard to synthesis of ergot alkaloids. ... 

Processes include the Fischer indole synthesis from arylhydrazones and related sigmatropic syntheses, reductive evclizations of nitni compounds, the Madelung synthesis from anilides and related base-cululyxed condensations. and transition-metal catalyzed cyclizations,... 

Madelung synthesis. Formation of indole derivatives by intramolecular cyclization of an N-(2-alkylphenyl)alkanamide by a strong base at high temperature. 

Two of these reactions are, in the most general terms, examples of intramolecular aldol condensations. Path A, which includes the Madelung method and its variants, uses o-substituted anilides as starting materials. Path B reverses the electrophilic and nucleophilic components for C2—C3 bond formation. Among the classic indole syntheses corresponding to the first pattern is the Madelung synthesis, exemplified by the preparation of 2-methylindole from iV-acetyl-o-toluidine (Equation (16)) <550SC597>. 

An efficient synthesis of iV-ethyl-l-hydroxy-7-methoxymitosane (115) was reported by Verboom and co-workers [39, 40]. This synthesis was based on a variation of the Madelung reaction in which the cyclization to an indole was facilated by an electron-withdrawing cyano group on the benzylic carbon (Scheme 15). The starting material, 2-amino-5-methoxy-4-methylbenzonitrile (110), was treated with 4-chlorobutyryl chloride to give amide 111, which was... 

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. 

A collection of Madelung indole syntheses using electron-withdrawing activation of the benzylic methylene group and other variations is summarized in Table 2 [38 3]. That extreme mildness is possible is shown by the cyclization in Entry 1, and Entry 4 features the synthesis of a new class of in vivo agonists. 

Kraus and his group extended their Wittig-Madelung indole synthesis to other activated benzylic systems as shown in Scheme 6 (equations 1-3) [17]. These include phenylsulfonyl, thiomethyl, and cyano, and this team applied this chemistry to a synthesis of the alkaloid isocryp-tolepine. As we saw twice in the previous chapter, the cycli-zation of phosphonium salt 15 affords quinolone 16, which was used to synthesize both neocryptolepine (17) and isocryptolepine (18). 

Like the venerable Fischer, Madelung, and Nenitzescu indole syntheses, the Bischler indolization has stood the test of time and continnes to find utihty in indole synthesis. This method, which is also known as the Bischler-Mohlau indole synthesis, was discovered by both of these German chemists within the span of a decade [1 ]. Other early pioneers... 

Related to the principle of the Madelung synthesis is the indole formation starting from (o-tolyl)isocyanide (71). The isocyanide 71 can be metalated with Li-dialkylamides at the 0-CH3 group, and the resulting Li compound 72 may either undergo cyclization to indole (via N-lithioindole 74) or - after alkylation to 73 and renewed benzylic metalation and cyclization - produce 3-substituted indoles 75 [164] ... 

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