Indoles, synthesis Smith

Smith-modified Madelung Indole synthesis (Smith indoie synthesis) ... 

The Larock indolization was applied to solid-phase indole synthesis (Smith) [32], to phosphine-free (Guo [33], Djakovitch [34]) and salt-free (Djakovitch [34]) conditions, to 2-chloroanilines (Senanayake [35], Ackermann... 

Scheme 2 Smith s Application of the Cassman Indole Synthesis...

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. 

Several other groups have made use of the Smith indole synthesis, and a summary of this work is shown in Table 1. Gribble and cowoikers prepared 2-(2-pyridinyl)indoles en route to syntheses of several zwitterionic indolo[2,3-fl] quinolizine alkaloids (Entry 1) [13], and Husson and Hashimoto synthesized a derivative of the alkaloid goni-omitine via a Smith indole synthesis (Entry 2) [14]. Henegar and Hunt reported a very convenient synthesis of 2-trifluoromethylindole (Entry 3) [15], in which TMEDA was found to be necessary. Two bis-indoles were prepared in low yield (Entry 4), bnt this approach failed for n = 1 [16], The bridged indole shown in Entry 5 was synthesized following acid-catalyzed cyclization of the initially formed indole [17]. 

Many 3-substituted indoles have also been prepared with the use of a-alkyl or a-aryl-p-keto sulfides. Thus indolization of aniline 5 with 3-methylthio-2-butanone 27 furnished indolenine 28, presumably via the same mechanism discussed earlier. The indolenine 28 was relatively unstable and reduced to the indole 29 without purification. Tetrahydrocarbazole 32 was prepared in 58% overall yield. Smith et al. made excellent use of the Gassman process in the total synthesis of (-i-)-paspalicine and (+)-paspalinine. ... 

Allen et al mainly on the evaluation of data reported by previous workers, advanced structure (5) for 2-methylpyrrole dimer. These data were (a) the monobasic nature of the dimer and (b) the conversion by aqueous acid into an indole which they showed by elimination (i.e., by the synthesis of 2,5-, 2,6-, and 2,7-dimethylindoIes) to be 2,4-dimethyIindole (this compound has since been synthesized by Marion and Oldfield ). Structure (5) for the dimer was confirmed by Edwards and Smith by conversion, by way of the methiodide (6), into the pyrrolidinopyrrole (7), the structure of which was proved by synthesis l,5-dimethylpyrrolid-2-one was condensed with 2-methyI-pyrrole by means of POCI3 to give the cation (8), isomeric with the... 

The Ir-catalyzed borylation of the indole nucleus is another important development that promises to find widespread use in complex molecule synthesis. Early reports include the functionalization of C(7) and also of C(2), reported by Malezcka and Smith and by Hartwig, respectively [39, 40]. In a report in 2011, Movassaghi, Miller, and coworkers demonstrated the borylation of tryptamine derivative 61 to afford 62 in 70 % yield [41]. This material was subjected to Suzuki-Miyaura cross coupling with 7-bromoindole (63) to set the stage for studying the oxidative rearrangement of 64, which would eventually provide diketopiperazine indole alkaloids such as asperazine (Scheme 11.11). 

Madindoline A and (-)-madindoline B are potent and selective inhibitors of interleukin 6. The relative and absolute configuration of these natural products was determined by means of their total synthesis by A.B. Smith and S. Omura." The key step was the SAE of the indole double bond, which led to the formation of the hydroxyfuroindole ring of both compounds. 

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