Radical 2-tetrahydropyranyl

The rate-determining step in the formation of the x-lithio ethers is the formation of a carbon radical as a precursor to the anion. The intermediate radical in the tetrahydropyranyl system is expected to be nonplanar, to be capable of rapid equilibration between the quasiequatorial and quasiaxial epimers, and to exist largely or entirely in the axial configuration at — 78 °C. However, treatment of the a-phenylthio ether 4 with LDMAN at higher temperature in the presence of A, A, lV, ./V -tetramethylethylenediamine leads to the more stable equatorial epimer of the lithio ether 5 and, after addition to benzaldehyde, the axial- and equatorial-substituted products were obtained in a ratio of 13 87. 

Dilworth, J.R., Griffiths, D.V., Hughes, J.M., and Morton, S., Synthesis of 2-S-(2-tetrahydropyranyl)thioethylphosphines and 2-mercaptoethylphosphines by free radical addition of phosphines to 2-(vinylthio)tetrahydropyran, Phos-ph Sulf, Silic. Relat. Elem., 71, 249, 1992. 

Unsaturated tetrahydropyran derivatives have received only cursory attention in the literature as heterocyclic monomers. 2,3-Dihydropyran and several of its substituted derivatives apparently undergo cationic polymerization in a manner typical of vinyl ethers (72MI11103), while tetrahydropyranyl esters of methacrylic acid (123) are fairly typical free radically polymerizable monomers (Scheme 35) (74MI11105). The THP group was used in this study as a protecting group for the acid functionality, and it was found that deprotection of polymers (124) could be accomplished under extremely mild conditions. 

Alkyl tetrahydropyranyl ethers (118 R = Et or Bu) behave similarly (68JOC2266). In both cases, the base peak occurs at m/e 85, resulting from loss of an RO radical from [M]t. Pathways which involve ring cleavage of the molecular ion are also operative and appear to be of greater importance.for the ethyl ether (118 R = Et). 

In the study involving a tetrahydropyranyl radical illustrated in Scheme 10.17, Rychnovsky was attempting to establish whether cyclisation was from the radical or the anionic intermediate in the reductive lithiation of nitrile 11 to give 14. The radical intermediate, 12,... 

In order to determine the degree of competition between both processes, the photo -stimulated reaction of the radical probe 3-bromo-2-tetrahydropyranyl allyl ether (83) with Ph2P ions in liquid ammonia was studied. In this reaction both the substitution 84 (20% yield) and the cyclized 85 (69% yield) substitution products were formed (equation 67)54,151. 

The reactions of nucleophiles with oxygen-substituted radical cations seem to be slower than the reactions of closed-shell molecules. In trifluoroethanol-acetonitrile-water mixtures the tetrahydropyranyl 2,3-radical cation " reacts with water at ambient temperature with a rate constant of 1.0 X 10" M This extrapolates to a lifetime in pure water of 18 ns, whereas that of the tetrahydropyranyl cation, " probably similar to that of the... 

Heterocyclic cyclopentyl radicals formed in the solvomercuration/reductivc alkylation reaction of dihydrofuran give products with tram- selectivity in a slightly higher ratio than the corresponding carbocyclic analogs34. This is attributed to anomeric effects, which lead to a more pronounced axial orientation of the /J-alkoxy substituent in the tetrahydropyranyl radical. 

Recently, it has been shown by Rychnovsky that slow conformational interconversion can be an important factor in the reaction of simple 2-tetrahydropyranyl radicals [16]. These non-equilibrium radical reactions provide a strategy for the... 

Stereoelectronic effects dominate in the reactivities of simple 2-tetrahydropyranyl radicals [1]. In these ring systems, anomeric radicals are best characterized as an equilibrating mixture of pseudoaxial and pseudoequatorial radicals, which tend to be slightly pyramidalized because of the presence of the a-oxygen atom. Moreover,... 

In contrast to tetrahydropyranyl and carbohydrate anomeric radicals, the corresponding radical structures in tetrahydrofuranyl and medium-sized rings are not well documented, although in certain instances, they can exhibit stereoselective reactivities (see below). 

In general, free radicals are rapidly equilibrating intermediates, which makes stereoselective radical reactions extremely challenging. In ring systems that have little or no conformational bias, reactive radical intermediates can racemize either by a conformational interconversion (i.e., ring flip) or by a simple radical inversion. For simple 2-tetrahydropyranyl radicals, the barrier to radical inversion has been estimated to be <1 kcal/mol, while the barrier to ring inversion is 10 kcal/mol. Therefore, if conformational interconversion is slow relative to reaction of the radical intermediate, then non-equilibrium radical reactions are possible. Recently it has been shown that reduction of 2-tetrahydropyranyl radicals can be competitive with conformational interconversions, which allows for a new strategy for the control of stereochemistry in radical reactions [28]. 

The inversion of the cyclohexyl radical can occur by a conformational process. This is expected to have a higher barrier than the radical inversion, since it involves bond rotations very similar to the ring inversion in cyclohexane. An of 5.6kcal/mol has been measured for the cyclohexyl radical. " A measurement of the rate of inversion of a tetrahydropyranyl radical k = 5.7 x 10 at 22°C) has been reported. ... 

Beckwith AU, Duggan PJ (1998) The quasi-homo-anomeric interaction in substituted tetrahydropyranyl radicals structure and kinetics of formation. Tetrahedron 54 4623-4632... 

Scheme 11.23 Synthetic outcomes guided by the weakening of bonds adjacent to radical cations (DCE = dichloroethane, THP = tetrahydropyranyl, PhMe = toluene).

---