163064-67-3

Relevant academic research and scientific papers

Carbonyl coupling reactions catalytic in titanium and the use of commercial titanium powder for organic synthesis

The high thermodynamic stability of titanium oxides formed as the inorganic byproducts in McMurry-type reactions has so far prevented the development of a catalytic procedure for such reductive carbonyl coupling processes. Similarly, a tightly bound oxide layer passivates the surface of commercial titanium, which is unreactive toward organic substrates under conventional conditions. This paper outlines a way to overcome both of these problems. Thus, oxoamides 1a-h can be reductively cyclized to indoles 2a-h using only catalytic amounts of low-valent titanium if the reaction is carried out in the presence of a chlorosilane. Specifically, the method is based upon the in situ generation of an activated titanium species from TiCl3 and Zn in the presence of the substrate, followed by regeneration of titanium chloride from the titanium oxides formed via ligand exchange with the admixed chlorosilane. Its proper choice is crucial for obtaining both good turnover numbers and clean conversions. Depending on the product structure, (TMS)Cl, ClMe2SiCH2CH2SiMe2Cl (5), or ClMe2Si(CH2)3CN (6) was found to be best suited. Similarly, chlorosilanes also effect the activation of commercial titanium powder which may then be used as a performant off-the-shelf reagent for various types of carbonyl and acetal coupling reactions, for the deoxygenation of epoxides and for the reductive cyclization of oxoamides or oxoesters to indoles, benzofurans, and 2-quinolones. Under these conditions retinal can be reductively dimerized to β-carotene in good yield. Moreover, the titanium/ chlorosilane reagent combination exhibits a strong template effect, allowing macrocyclization reactions without recourse to high dilution. Up to 36-membered rings have been closed in that way. 29Si NMR studies provide some insight into the elementary steps responsible for the degradation of the surface oxide layer on titanium by the chlorosilane. The effect of Lewis acid additives on the course of the coupling processes is discussed.

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

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 SmI2 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 TiCln (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 nonetheral 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 15 to (+)-aristoteline, and it applies nicely to the synthesis of strained indole derivatives, the formation of benzofurans, conventional McMurry 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.