Kurzfassung

Abstract:
This study deals with the synthesis of tert-O-alkyl thiohydroxamates and their use as tert-alkoxyl radical precursors. tert-Alkoxyl radicals were applied in mechanistic studies to determine rate constants of (i) p-chlorocumyloxyl radical addition to bicyclo[2.2.1]heptene (k = 1 107 M–1 s–1), (ii) 2-phenylhex-5-en-2-oxyl radical 5-exo-trig-cyclization (kcis = 3 109 s–1, ktrans = 1 109 s–1), and (iii) 2-methyl-5-phenylpent-2-oxyl to 2-hydroxy-2-methyl-5-phenypent-5-yl radical...Abstract:
This study deals with the synthesis of tert-O-alkyl thiohydroxamates and their use as tert-alkoxyl radical precursors. tert-Alkoxyl radicals were applied in mechanistic studies to determine rate constants of (i) p-chlorocumyloxyl radical addition to bicyclo[2.2.1]heptene (k = 1 × 107 M–1 s–1), (ii) 2-phenylhex-5-en-2-oxyl radical 5-exo-trig-cyclization (kcis = 3 × 109 s–1, ktrans = 1 × 109 s–1), and (iii) 2-methyl-5-phenylpent-2-oxyl to 2-hydroxy-2-methyl-5-phenypent-5-yl radical isomerization (1,5-H-atom shift; k = 0.4–1.5108 s–1). The reactions pose key steps in synthesis of 2,2,5-substituted tetrahydrofurans and 2-bromo-3-alkoxybicyclo[2.2.1]heptanes. Stereoselectivity in 5-exo-trig cyclization (2,5-cis) and intramolecular addition (>99:1), originates from torsional strain in transition structures of alkoxyl radical reactions.

Conclusion:
The strong affinity of 3-hydroxy-5-(4-methoxyphenyl)-4-methylthiazole-2(3H)-thione for alkylatation at oxygen, in combination with the driving force of O-alkyl isoureas to transfer tert-alkyl groups to nucleophiles paved the road to synthesis of a new class of tert-alkoxyl radical progenitors. Although the chosen compounds pose a selection from our laboratory, we think that the method offers a general solution for converting trialkyl-substituted alcohols into tert-alkoxyl radical precursors. Synthetic problems arose in esterifications of 2-arylalcohols, due to extensive elimination. Fortunately, an upscaling in such cases was feasible. This approach may also be helpful in other instances instances, to prepare sufficient material for conducting more specialized investigations using the thiohydroxamate method for tert-alkoxyl radical generation.
Using O-alkyl thiohydroxamates, we were for the first time able to prepare 2,2,5-substituted tetrahydrofurans and 2-bromo-3-alkoxynorbornans from an alkoxyl radical pathway, which operates under mild and neutral conditions. The rate constants from the mechanistic part of the study show that tert-alkyl substitution near oxygen does not necessarily reduce alkoxyl radical reactivity, at least in the investigated cases. However, we believe that true value of these data lies in the possibility they offer for more precisely setting up selectivity requirement in the design of new syntheses based on tert-alkoxyl radical chemistry.
Bicyclo[2.2.1]heptene was rewarding alkene to explore intermolecular alkoxyl radical additions. Its strained double bond and comparatively strong C,H-bonds offer favorable characteristics for the addition. Still we conclude from the kinetic data that intermolecular alkoxyl radical additions have the potential to become more and more important, as the knowledge about this reaction increases.
Coming to the final remark, we wish to address the aspect of stereoselectivity in tert-alkoxyl radical additions. It is well understood that stereoselectivity in cyclization is attainable via substrate control. However, it seems worth to emphasize that stereoelectronic effects and geometrical changes within the -bond, as a system approches its transition structure, add another important component to this picture. With the wisdom of hindsight, it could have been anticipated that similar means for stereocontrol in intermolecular additions must exist, because the underlying reaction is the same. As we continue to seek for new stereoselective radical additions, the seemingly insignificant geometrical change in the early phase of the alkoxyl radical addition may be the most valuable hint, where to look

Leading References:
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[3] On the Stereoselectivity of C,O Bond Formations in Esterifications of Cyclic Thiohydroxamic Acids. J. Hartung, I. Kempter, T. Gottwald, R. Kneuer, Tetrahedron:Asymmetry 2009, 20, 2097–2104. DOI: 10.1016/j.tetasy.2009.08.020.
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[7] On the Stereoselectivity of Alkenoxyl Radical 6-exo-trig Cyclizations. N. Schneiders, T. Gottwald, J. Hartung, Eur. J. Org. Chem. 2009, 799–801.
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