Engler synthesis

SCHEME 8.10 Engler s synthesis of taxodione 1 via Diels-Alder cycloaddition. 

This picture changed completely as, in February 1908, F. Haber approached the B. A. S. F. with the proposition to obtain their financial assistance for an intensified continuation of his research on the catalytic synthesis of ammonia, following a suggestion of professor K. Engler of Karlsruhe, a member of B. A. S. F. s advisory board. The catalytic synthesis of ammonia had been investigated previously, but without having met with any practical success. 

Engler and Patel published the first synthesis of TSF in 1974 [63]. 1,3-Diselenole-2-selenone was obtained from sodium acetylide, selenium, and... 

Vedejs E, Engler DA, Telschow JE (1978) Transition-Metal Peroxide Reactions. Synthesis of a-Hydroxycarbonyl Compounds from Enolates. J Org Chem 43 188... 

Engler reported [2 + 2] cycloaddition of 1,4-benzoquinones with styrenes using TAD-DOL-Ti complex. The [2 + 2] cycloaddition products can, upon warming the reaction mixture, be transformed to the formal [2 + 5] cycloaddition products, dihydrobenzofur-ans, although with reduced %ee. The dihydrobenzofurans thus obtained are useful intermediates in the synthesis of biologically interesting natural products (Sch. 59) [141]. 

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. 

All this reasoning appeared very plausible until, in 1900, Walden recorded a grave objection. Following up an old observation of Biot (1835) he found that natural petroleums possess a very obvious rotatory power, while the products of synthesis are inactive. The hypothesis of Engler thus appeared fallacious. It, at least, had need of revision, and that is what Neuberg did some years later. Neuberg had the idea that perhaps the rotatory power of natural petroleums was due to the presence, in the fatty materials from whence they are derived, of optically active fatty acids, such as isovaleric acid and isocaproic add. 

This reaction was first reported by Engler and Riehm in 1885. It is a synthesis of 2,4-dimethylquinoline from the thermal condensation of aniline hydrochloride and acetone or mesityl oxide along with the evolution of water and methane, and is known as the Riehm quinoline synthesis. This reaction can occur under the conditions with or without any condensation reagents and may evolve other hydrocarbons as well. ... 

Figure 7 Synthesis of PPLG-fif-PEO. Reproduced from Engler, A. C. Lee, H. L. Hammond, P. T. Angew. Chem. Int Ed. 2009, 48, 9334. ...

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]. 

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...

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