Engler indole synthesis

While the Engler indole synthesis has not been pursued by others, Kita and coworkers developed a related intramolecular amine cyclization onto benzoquinones leading to 5-oxygenated indoles (Scheme 4) [7]. The yields are excellent, and several examples are shown (yields are overall from the starting quinones or quinone acetal). 

Scheme 3 Proposed Mechanism of the Engler Indole Synthesis...

An interesting variant of the Nenitzescu indole synthesis, involving the Lewis acid-directed coupling of enol ethers with benzoquinone mono- and b/s-imides, was developed by T.A. Engler et al. for the synthesis of substituted - and -tetrahydrocarbolines. ... 

Engler has noticed an interesting dichotomy in his indole synthesis involving benzoquinone monoimides <97TL6135>. For instance, while reaction of the quinone monoimide 96 with N-phenylsulfonyl enol ethers in the presence of Ti(IV) Lewis acid catalysts affords the expected tetrahydrocarbolines 97, reactions promoted by BF3 produce substituted benzofurans. 

The mechanistic rationale for the dramatic Lewis acid effect on the course of the Engler indole/benzofuran synthesis involving styrenes is illustrated in Scheme 3. Whereas titanium forms a bidentate complex 11 with the C-1 carbonyl and C-alkoxy oxygens, which leads to the dihydroindole (equation 1), boron trifluoride engages in monodentate complexation 12 with the sulfonyl nitrogen, leading to dihydrobenzofuran formation (equation 2) [3, 4]. Likewise, the reaction between 11 and an enol ether derived from 4-piperidone is depicted in equation 3 [5]. 

The Engler-Kita indole synthesis, combined with the Nenitzescu indohzation, represent powerful and versatile syntheses of 5-hydroxyindoles. 

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