Mechanism of the Ti^III-Catalyzed Acyloin-Type Umpolung: A Catalyst-Controlled Radical Reaction

Abstract

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.

Reactivity Study of Pyridyl‐Substituted 1‐Metalla‐2,5‐diaza‐cyclopenta‐2,4‐dienes of Group 4 Metallocenes

“…An example for the first case is the formation of the diimine complex Cp* 2 Zr[N=C(H,pTo l)] 2 upon addition of H 2 to Cp* 2 Zr(N=C(pTo l)ÀC(pTo l)=N). [3] Other products of reactions of group 4m etallocenes with nitriles are knownt odimerise to dinuclear compounds (Scheme 1, A) [4] or to couple with acetone, anilines, [5] dimethyl acetylenedicarboxylate [6] or further nitriles [7] to heterometallacycles (B, C).…”

“…This was rationalised by DFT calculations and proven by testingt he catalytic activity of Cp* 2 Ti(N = C(R)ÀC(R)=N) (R = Ph, 2-py, 4 -py) in the ring-opening polymerisation of e-caprolactone. [17] Moreover, the tetranuclear [Cp* 2 Ti(N=C(m-C 6 H 3 N)ÀC=N)] 4 ,o btainedi nt he reactiono f Cp* 2 Ti(h 2 -Me 3 SiC 2 SiMe 3 )w ith 2,6-dicyanopyridine, didn ot decompose rapidly under inert conditions. Thesed ifferences might influence the reactivity of the 1-metalla-2,5-diaza-cyclopenta-2,4-dienes significantly.T he highers tabilityo ft he pyridyl-substituted compounds should enable different reactions or ah ighers electivity towards new metallocene complexes.…”

Development of an Efficient Synthesis of rac‐3‐Demethoxyerythratidinone via a Titanium(III) Catalyzed Imine‐Nitrile Coupling

“…As part of our ongoing research program for the development of unconventional C‐C coupling methods, we have developed a series of titanium(III) catalyzed intra‐ and intermolecular reductive umpolung reactions . This included a reductive iminonitrile cyclization giving α‐aminoketones or pyrrolidinones and corresponding intermolecular imine–nitrile couplings providing acyclic α‐aminoketones .…”

Katalytische reduktive Synthese und direkte Derivatisierung ungeschützter Aminoindole, Aminopyrrole und Iminoindoline

“…[8] In Übereinstimmung mit früheren Arbeiten zu Ti III -katalysierten Cyclisierungen an Nitrile [9,10] würde dies einen katalysatorkontrollierten Angriff des Radikals an das Nitril zur Folge haben, [11,12] aus dem je nach Iminvorstufe Aminoindole,A minopyrrole oder Iminoindoline hervorgehen. [8] In Übereinstimmung mit früheren Arbeiten zu Ti III -katalysierten Cyclisierungen an Nitrile [9,10] würde dies einen katalysatorkontrollierten Angriff des Radikals an das Nitril zur Folge haben, [11,12] aus dem je nach Iminvorstufe Aminoindole,A minopyrrole oder Iminoindoline hervorgehen.…”

“…B. Brevianamid Ao der einige Duocarmycine). Die Strategie konnte ebenfalls auf eine Peptidkupplung mit Boc-Ala-OH und T3P angewendet werden (11). [15] Eine Kombination aus rac-(ebthi)TiCl 2 als Katalysator und Mangan als Reduktionsmittel ergab bei 80 8 8Cd ie besten Ergebnisse und verringerte die Bildung nicht identifizierbarer Nebenprodukte.E ntsprechend wurden die Produkte 6a-c in 43-66 %g ebildet.…”