Ether moiety is proposed to weaken the benzylic C-O bond, facilitating oxidative addition. We postulated that a equivalent technique could accelerate cross-coupling reactions with dimethylzinc. A leaving group bearing a pendant ligand could serve two functions (Scheme 1c). Coordination to a zinc reagent could activate the substrate for oxidative D3 Receptor Agonist Compound addition and facilitate the subsequent transmetallation step. We anticipated that tuning the properties on the X and L groups would give a synergistic enhancement of reactivity.Benefits AND DISCUSSIONIdentification of traceless directing group for Negishi coupling To test our hypothesis we examined a range of activating groups to promote the crosscoupling of benzylic electrophiles with dimethylzinc (Figure two). As anticipated, basic benzylic ether four was unreactive. Next, we employed a thioether together with the believed that formation of the zinc-sulfur bond would provide a robust thermodynamic driving force forJ Am Chem Soc. Author manuscript; obtainable in PMC 2014 June 19.Wisniewska et al.Pagethe reaction.21 Though substrate five was far more reactive, elimination to supply styrene 23 was the important pathway. We reasoned that if thioether five underwent oxidative addition, sluggish transmetallation could have resulted in -hydride elimination to provide alkene 23 as the main solution. To promote transmetallation over -hydride elimination, we examined ethers and thioethers bearing a second ligand (Group two). Whilst acetal six and 2-methoxyethyl ether 8 remained unreactive, hydroxyethyl thioether 7 afforded the preferred cross-coupled solution 22 because the key species, albeit with low enantiospecificity (es).22 To boost the yield and enantiospecificity of your transformation, we enhanced the cooridinating ability of your directing group by switching to a pendant pyridyl ligand. Pyridyl ether 10 was the first of the oxygen series to afford an appreciable yield of desired solution with fantastic es. In contrast, pyridyl thioether 11, afforded lower yields than 7, with significant erosion of enantiomeric excess. Carboxylic acids 12 and 13 afforded the desired solution in moderate yield, but with much less than satisfactory es. We reasoned that in order to attain larger reactivity and high es we could invert the carboxylic acid to an isomeric ester. These compounds could be much less most likely to undergo radical racemization, which can be extra probably for thioethers than ethers, enhancing the es. Also, preserving the thiol functionality would enable for robust coordination of zinc to the leaving group. Certainly, a series of isomeric ester leaving groups supplied the preferred solution in each synthetically valuable yields and high es (Group three). Though the ester leaving groups addressed the issue of chirality transfer, their CB1 Activator supplier synthesis necessitated employing protecting groups to mask the absolutely free thiol, which added a step to the synthetic sequence (see SI for details). On top of that, free thiols aren’t optimal substrates for the reason that they may be susceptible to oxidative decomposition. We postulated that using 2(methylthio)ester 18 alternatively would simplify substrate synthesis and avoid oxidative decomposition on the beginning material. This directing group is especially easy considering that (methylthio)acetic acid is commercially readily available and can be conveniently appended onto the benzylic alcohol by way of a DCC coupling.23 Functionalized together with the thioether directing group, (R)-18 cross-coupled to afford (S)-22 in 81 and superb es with overall inversion of configuratio.
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