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“Site Selective” Formation of Low-Valent Titanium Reagents: An “Instant” Procedure for the Reductive Coupling of Oxo Amides to Indoles

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http://pubman.mpdl.mpg.de/cone/persons/resource/persons58380

Fürstner,  Alois
Research Department Fürstner, Max-Planck-Institut für Kohlenforschung, Max Planck Society;

http://pubman.mpdl.mpg.de/cone/persons/resource/persons132879

Hupperts,  Achim
Research Department Fürstner, Max-Planck-Institut für Kohlenforschung, Max Planck Society;

http://pubman.mpdl.mpg.de/cone/persons/resource/persons132881

Ptock,  Arne
Research Department Fürstner, Max-Planck-Institut für Kohlenforschung, Max Planck Society;

Janssen,  Edo
Research Department Lehmkuhl, Max-Planck-Institut für Kohlenforschung, Max Planck Society;

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Citation

Fürstner, A., Hupperts, A., Ptock, A., & Janssen, E. (1994). “Site Selective” Formation of Low-Valent Titanium Reagents: An “Instant” Procedure for the Reductive Coupling of Oxo Amides to Indoles. The Journal of Organic Chemistry, 59(18), 5215-5229. doi:10.1021/jo00097a024.


Cite as: http://hdl.handle.net/11858/00-001M-0000-0014-A489-4
Abstract
Aromatic acylamido carbonyl compounds are readily cyclized to indole derivatives upon treatment with low-valent titanium reagents of the formal oxidation states 0, +1, and +2. Other strong reducing agents such as SmIz and low-valent zirconium, niobium, and tungsten complexes are also capable of effecting such intramolecular alkylidenation reactions of amides. From the preparative point of view these heterocycle syntheses are best effected with an active titanium species which is prepared in the presence of the carbonyl compound upon coordination of TiCl, (n = 3,4) to the oxo amide substrate and reduction of this complex with zinc dust (“instant” method). This procedure turned out to be as effective as the titanium graphite-based methodology previously described but is much easier to perform as all hazardous reagents are avoided. “Instant” cyclizations can also be run in nonethereal solvents such as DMF, ethyl acetate, or acetonitrile and turned out to be compatible with many functional groups. The method was used to cyclize oxo amide 16 to (+Iaristoteline, and it applies nicely to the synthesis of strained indole derivatives, the formation of benzo[b]furans, conventional McMuny reactions of aldehydes and ketones, and the dimerization of alkynes. Metals such as zirconium can also be activated in situ by reduction of ZrCl4 in the presence of a carbonyl compound. On the basis of the results obtained with substrates bearing appropriate structural probes a mechanism for such intramolecular keto-amide coupling processes is proposed. Carbonyl dianions, formed upon two-electron reduction of the keto group, are the most likely reactive intermediates. Electrochemical investigations support this mechanistic interpretation.