Titanocene Catalyzed 4-exo Cyclizations:  Mechanism, Experiment, Catalyst Design

Abstract

A method for the preparation of a variety of cyclobutanes via 4-exo cyclization of radicals is presented. Radical generation is carried out by electron transfer from titanocene(III) chlorides to epoxides. The reaction relies on the acceleration of the cyclization through the use of alpha,beta-unsaturated carbonyl compounds as radical traps and the thermodynamic stabilization of the cyclobutylcarbinyl radicals through conjugation. The mechanism of the transformation was investigated by a combined theoretical and experimental study. The computational results provide the crucial energetic and structural features of pertinent intermediates and transition structures. Moreover, the origins of the diastereoselectivity of the 4-exo cyclization are outlined for the first time. Catalysts for those cases where "Cp2TiCl" did not perform in a satisfactory manner have been devised. Through the introduction of tert-butyl or cyclo-hexyl substituted cyclopentadienyl ligands the longevity of the pivotal beta-titanoxy radicals is increased sufficiently enough to enable the slow but often surprisingly diastereoselective formation of the cyclobutylcarbinyl radical. The resulting transformation constitutes the first general approach to cyclobutanes using radical chemistry.

Metal‐Catalyzed β‐Functionalization of Michael Acceptors through Reductive Radical Addition Reactions

“…[17] Theu se of Kagan'st itanocene complex results in an enantioselective reaction that exhibits ah igher diastereoselectivity than [Cp 2 TiCl].Reagent control is,thus,exerted both at the stage of radical generation (control of regioselectivity of ring opening) and at the stage of the ensuing radical reaction (addition to the Michael acceptor). [18] Ti III -catalyzed regioselective epoxide opening was later successfully applied to radical cyclizations for the synthesis of small rings,namely cyclopropanes and cyclobutanes, [19] as well as trisubstituted cyclopentanols. [18] Ti III -catalyzed regioselective epoxide opening was later successfully applied to radical cyclizations for the synthesis of small rings,namely cyclopropanes and cyclobutanes, [19] as well as trisubstituted cyclopentanols.…”

“…Forthe planning of tandem sequences,itisimportant to note that typical 5-exo cyclizations are faster than the intermolecular Michael additions. [18] Ti III -catalyzed regioselective epoxide opening was later successfully applied to radical cyclizations for the synthesis of small rings,namely cyclopropanes and cyclobutanes, [19] as well as trisubstituted cyclopentanols. [20] Here,r adical reduction is reagent controlled, since the cyclized carbonyl-substituted electrophilic radicals are reduced much faster than the epoxide-derived nucleophilic alkyl-substituted radicals (Scheme 4, bottom).…”

The Nugent Reagent: A Formidable Tool in Contemporary Radical and Organometallic Chemistry

“…Gansäuer et al24 reported a combined computational and experimental study used for the development of the first general titanocene‐catalysed synthesis of substituted cyclobutanes through 4‐ exo cyclisations of unsaturated epoxides (Scheme ).…”

New Advances in Titanium-Mediated Free Radical Reactions

“…The use of Cp 2 TiCl (in stoichiometric or catalytic amounts) allowed to promote the synthesis of natural products by the construction of three- to six- and eight-membered carbocycles in good to excellent yields [ 115 , 116 , 117 , 118 , 119 , 120 ]. Small ring 3- exo and 4- exo cyclizations were achieved by nucleophilic intramolecular radical addition to aldehydes and ketones [ 117 ] and natural products, like (E)- endo -bergamoten-12-oic acids [ 115 ] or carbacephams, are significant examples of synthetic applications ( Scheme 39 ) [ 121 , 122 , 123 , 124 , 125 ].…”