A Radical Tandem Reaction with Homolytic Cleavage of a TiO Bond

Abstract

Dedicated to Professor Manfred T. Reetz on the occasion of his 60th birthdayOver the last years radicals have been used increasingly in multistep syntheses due to the mild reaction conditions, high functional group tolerance, and broad accessibility of interesting structures, often obtained in sequential transformations.[1] In this context we wish to report our first results on a novel radical tandem reaction [1b] featuring an unprecedented formal homolytic substitution reaction at a Ti-O bond for the formation of tetrahydrofurans. The planned sequence is shown in Scheme 1. The initial step is based on the titanocene-mediated opening of 1 described by Nugent and RajanBabu, [2] which we have developed into a catalytic reaction, [3] to give the radicals cis-and trans-2. The second and conceptually novel step of our tandem reaction constitutes the attack of the tertiary radical 2 on the Ti-O bond. Mechanistically, this can be viewed as a homolytic substitution of the [Cp 2 TiCl] radical.[4] Our work therefore introduces metal-oxygen bonds as a very useful class of radical traps. As a consequence of this homolytic substitution the redox catalyst [Cp 2 TiCl] is regenerated. To the best of our knowledge, this concept of a catalytic redox isomerization is unknown in the literature. Because the second cyclization is counterintuitive, a supposedly strong Ti-O bond is cleaved and a C-O bond formed, we analyzed the transformation of model system 4 by density functional theory (DFT) calculations as shown in Scheme 2.[5] As expected [1c, 6] both the ring opening of 4 (À8.3 kcal mol À1 ) and the 5-exo cyclization of 5 (À12.2 kcalmol À1 for trans-6; À10.6 kcal mol À1 for cis-6) are exothermic. Despite this thermodynamic preference for trans-6 the formation of cis-6 should be kinetically favored according to the Beckwith-Houk rules [6] and our own calculations on related systems. A detailed analysis of the transition-state structures of titanocene-mediated cyclizations will be published in due course.The key steps of our tandem reaction, formation of cis-7 and trans-7 complexed to [Cp 2 TiCl], were also found to be exothermic by À12.2 and À4.6 kcal mol À1 . Thus, breaking of the TiÀO bond is predicted to be possible! The low energy of formation of trans-7 compared to that of cis-7 can be attributed to the strain in the resulting trans-fused bicyclo[3.3.0] system. The product complexes [7·TiCp 2 Cl] shown in Scheme 2 are slightly more stable (À31.1 and À25.1 kcalmol À1 ) than the separated molecules. Since entropy effects favor the dissociation of the product complex, DG will most likely be negative and the catalyst will be regenerated as desired for efficient catalysis.The relative energies of the transition-state structure, 6, and 7 were also confirmed by MP2 calculations. The transition-state structure for the formation of [cis-7·Cp 2 TiCl] is shown in Figure 1. This final ring closure has a low barrier (+ 11.4 kcal mol À1 ) and should therefore be viable even at low temperatures. The transition state exhibits similar TiÀO...

Radicals in organic synthesis. Part 1

“…The substitution of the titanocene moiety regenerates the active titanocene(III) species; formally the process is a catalytic redox isomerisation. 85 Significantly, the optimum yields are only obtained when the reaction is performed with catalytic titanocene(III) (Cp 2 TiCl 2 /Mn/Coll$HCl), the use of stoichiometric quantities resulting in a decrease in yield, due to reductive trapping of the intermediate radical.…”

A Radical Roundabout for an Unprecedented Tandem Reaction Including a Homolytic Substitution with a Titanium‐Oxygen Bond

“…[35Ϫ37] In this publication we report a methodology that utilizes catalytic ring-closing reactions of radicals containing titanocene alkoxides to yield tetrahydrofurans, as shown in Figure 1. [38] The presence of highly substituted tetrahydrofurans in many natural products should result in a broad synthetic interest in our novel method. The resulting transformation is complementary to the electron-transfer-induced ring opening of tetrahydrofurans by Lewis acid catalysis with Figure 1.…”

Intramolecular Homolytic Substitutions in Synthesis

“…were able to further develop this methodology to tandem radical chemistry that included a step in which the radical underwent homolytic substitution at oxygen, as depicted in Scheme 27. 57,58 In this example, half an equivalent of 2,4,6-trimethylpyridine hydrochloride is required to liberate Cp 2 TiCl 2 which is then reduced by manganese dust (0.2 equiv) to give the reactive species, Cp 2 TiCl. Ultimately, the tetrahydrofuran (67) was isolated in 67% yield as a single diastereomer through a process presumably involving reductive epoxide ring opening (mediated by the titanocene(III) complex), 5-exo cyclization and homolytic substitution at oxygen.…”