Reduction, please! The title reaction affords α-hydroxyketones, a common structural motif in biologically active natural products, in good yields and high enantioselectivities at room temperature. The commercially available ansa-titanocene 1 was found to be an efficient catalyst for this process, which presumably proceeds by addition of a ketyl radical to a nitrile.
A catalytic reductive C1-acylation of 3,4-dihydroisoquinolines is presented that gives direct access to 1,1-disubstituted tetrahydroisoquinolines. The reaction is a titanium(III)-catalyzed reductive umpolung process in which nitriles act as effective acylation agents. The method is highly chemo- and regioselective and is demonstrated in 20 examples. It is well-suited for the large-scale synthesis of functionalized tetrahydroisoquinoline products, which is exemplified in the form of a six-step synthesis of (±)-3-demethoxyerythratidinone.
The titanium(III)-catalyzed cross-coupling between ketones and nitriles provides an efficient stereoselective synthesis of α-hydroxyketones. A detailed mechanistic investigation of this reaction is presented, which involves a combination of several methods such as EPR, ESI-MS, X-ray, in situ IR kinetics, and DFT calculations. Our findings reveal that C-C bond formation is turnover-limiting and occurs by a catalyst-controlled radical combination involving two titanium(III) species. The resting state is identified as a cationic titanocene-nitrile complex and the beneficial effect of added Et3N·HCl on yield and enantioselectivity is elucidated: chloride coordination initiates the radical coupling. The results are fundamental for the understanding of titanium(III)-catalysis and of relevance for other metal-catalyzed radical reactions. Our conclusions might apply to a number of reductive coupling reactions for which conventional mechanisms were proposed before.
A titanium(III)-catalysed intermolecular reductive coupling of ketones or imines with nitriles is described, which gives direct access to α-hydroxylated and α-aminated ketones. This coupling reaction is cross-selective and a catalytic version of the classical acyloin condensation. A reaction mechanism that is supported by first DFT calculations is discussed.
A new method for titanium-catalyzed reductive umpolung reactions is reported that overcomes the traditional requirement for a stoichiometric metallic reductant. With N,N'-disilylated tetramethyldihydropyrazine as a potent organic reducing agent, reductive carbonyl-nitrile, enone-acrylonitrile and pinacol coupling reactions can be achieved in good yields and stereoselectivities. [Cp2TiI2] is a superior catalyst to [Cp2TiCl2], which is rationalized by a faster generation of the active catalyst [Cp2TiI]. A mechanism is proposed that is in agreement with the experimental results.
Auf zwei Arten: Eine Titan(III)‐katalysierte reduktive radikalische Cyclisierung von Iminonitrilen wurde entwickelt, die zur direkten Synthese von α‐aminierten Ketonen führt. Je nach Anbindung des Nitrils an den Iminkohlenstoff oder ‐stickstoff werden α‐tetrasubstituierte cyclische Aminoketone oder Pyrrolidin‐3‐one in bis zu quantitativer Ausbeute erhalten. Im letzten Fall entsprechen Iminkondensation und TiIII‐Katalyse einer formalen [4+1]‐Cycloaddition.
Bitte reduzieren! Die Titelreaktion liefert α‐Hydroxyketone, die ein Strukturmerkmal vieler biologisch aktiver Naturstoffe sind, in guten Ausbeuten und hohen Enantioselektivitäten. Das kommerziell erhältliche Ansa‐Titanocen 1 wird als effizienter Katalysator für diesen Prozess eingesetzt, der vermutlich über die Addition eines Ketylradikals an ein Nitril verläuft.
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