Radical 4‐exoCyclizations via Template Catalysis

Abstract

The mechanism of catalytic 4-exo cyclizations without gem-dialkyl substitution was investigated by a comparison of cyclic voltammetry, EPR, and computational studies with previously published synthetic results. The most active catalyst is a super-unsaturated 13-electron titanocene(III) complex that is formed by supramolecular activation through hydrogen bonding. The template catalyst binds radicals via a two-point binding that is mandatory for the success of the 4-exo cyclization. The computational investigations revealed that formation of the observed trans-cyclobutane product is not possible from the most stable substrate radical. Instead, the most stable product is formed with the lowest energy of activation from a disfavored substrate in a Curtin-Hammett related scenario.

Computational study of the rate constants and free energies of intramolecular radical addition to substituted anilines

“…Such reactions and other even slower cyclizations are well documented in titanocene mediated and catalyzed radical processes [61–69]. Therefore, the relatively high computational rate constant for the addition of 1 readily explains the excellent synthetic results with epoxides derived from aryl substituted anilines in the radical arylation of epoxides.…”

Amide‐Substituted Titanocenes in Hydrogen‐Atom Transfer Catalysis

“…[9] Then eutral Zn-1a displays the desired coordination of the pendant amide and could serve as aH AT reagent or catalyst. [9] Then eutral Zn-1a displays the desired coordination of the pendant amide and could serve as aH AT reagent or catalyst.…”

Triazol-substituted titanocenes by strain-driven 1,3-dipolar cycloadditions

“…The acid chloride group is more electrophilic than the [TiCl 2 ] fragment and therefore many titanocenes containing ligands with pending amide, ester, and ketone groups can be prepared with classical organic acylation reactions (Friedel–Crafts reaction, esterification, amide synthesis, Scheme 1). Some of these complexes have been used as organometallic gelators [19–20], as a novel class of cytostatic compounds [26], and catalysts for unusual radical cyclizations [27–31]. The ketone and amide substituted catalysts are cationic due to the intramolecular coordination of the carbonyl group [30–31].…”

“…Some of these complexes have been used as organometallic gelators [19–20], as a novel class of cytostatic compounds [26], and catalysts for unusual radical cyclizations [27–31]. The ketone and amide substituted catalysts are cationic due to the intramolecular coordination of the carbonyl group [30–31]. This feature is essential for the cytostatic and catalytic activity.…”

“…This feature is essential for the cytostatic and catalytic activity. Moreover, in the amide complexes hydrogen bonding of the N–H bond to chloride or [ZnCl 4 ] 2− is a crucial structural feature [31]. The gelation ability of the neutral ester-substituted titanocenes critically depends on the steric demand of the substituents on the cyclopentadienyl ligands.…”