Wender indole synthesis

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. 

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Wender and White published a very simple indole ring synthesis that involves the generation of a bis-lithio anion 1 and its reaction with an a-halo carbonyl compound 2, followed by acid- or base-catalyzed dehydration [1,2], The overall transformation is shown in Scheme 1, along with three examples. This chemistry illustrates yet another indole ring synthesis that uses a-halo carbonyl compounds [3]. We will encounter these compounds again with the venerable Bischler indole synthesis in Chapter 23. A summary of several Wender indole ring syntheses is tabulated in Table 1 [1, 2, 4-7], Entry 5 features a directed lithiation method to the bis-lithio nucleophile [5], a modification also described by Wender and White [2], Sainsbury and... 

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. 

Wender and Aube have independently described the use of the Bischler-Napieralski reaction in the synthesis of Yohimban alkaloids. Aube s approach involved the cyclization of indole 50 followed by reduction of the resulting dihydroisoquinoline... 

There are numerous other syntheses of indoles, and a modern example is the Wender synthesis. Here a 2-bromo-iV-(trifluoroacetyl)aniline in THF is deprotonated by butyllithium and then, in the same pot, reacted with fert-butyllithium to effect halogen-metal exchange to give the dilithiated derivative. To this intermediate is added an a-bromo ketone. A carbon-carbon bond is established first between the reactants, and then cyclization occurs to form a hydroxyindoline. Finally, dehydration generates the indole (Scheme 7.16). 

Gschwend reported the ortho lithiadon of aniline pivalamides and subsequent addition to nitriles and carbonyls in 1979. A few years later, Wender used a similar aryllithium (H), obtained by metal-halogen exchange, in a new synthesis of indoles (Scheme 7). An analogous metalation occurs when A -phenylimidazol-2-ones are treated with LDA in THF at -78... 

The adaptation of the Graebe-UUmann carbazole synthesis to indoles was apparently first described by Schmid s group [27, 28], but Wender and Cooper parlayed the... 

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