Ether moiety is proposed to weaken the benzylic C-O bond, facilitating oxidative addition. We postulated that a equivalent approach could accelerate cross-coupling reactions with dimethylzinc. A leaving group bearing a pendant FP Inhibitor MedChemExpress ligand could serve two functions (Scheme 1c). Coordination to a zinc reagent could IL-6 Inhibitor list activate the substrate for oxidative addition and facilitate the subsequent transmetallation step. We anticipated that tuning the properties of the X and L groups would supply a synergistic enhancement of reactivity.Final results AND DISCUSSIONIdentification of traceless directing group for Negishi coupling To test our hypothesis we examined a variety of activating groups to market the crosscoupling of benzylic electrophiles with dimethylzinc (Figure 2). As anticipated, simple benzylic ether four was unreactive. Subsequent, we employed a thioether using the thought that formation with the zinc-sulfur bond would deliver a robust thermodynamic driving force forJ Am Chem Soc. Author manuscript; obtainable in PMC 2014 June 19.Wisniewska et al.Pagethe reaction.21 Whilst substrate 5 was much more reactive, elimination to provide styrene 23 was the major pathway. We reasoned that if thioether 5 underwent oxidative addition, sluggish transmetallation could have resulted in -hydride elimination to give alkene 23 because the major product. To promote transmetallation over -hydride elimination, we examined ethers and thioethers bearing a second ligand (Group 2). While acetal six and 2-methoxyethyl ether 8 remained unreactive, hydroxyethyl thioether 7 afforded the preferred cross-coupled solution 22 as the major species, albeit with low enantiospecificity (es).22 To boost the yield and enantiospecificity in the transformation, we increased the cooridinating capability on the 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 item with fantastic es. In contrast, pyridyl thioether 11, afforded lower yields than 7, with considerable erosion of enantiomeric excess. Carboxylic acids 12 and 13 afforded the preferred item in moderate yield, but with significantly less than satisfactory es. We reasoned that as a way to obtain greater reactivity and high es we could invert the carboxylic acid to an isomeric ester. These compounds would be much less most likely to undergo radical racemization, which can be far more probably for thioethers than ethers, enhancing the es. Also, maintaining the thiol functionality would permit for powerful coordination of zinc for the leaving group. Certainly, a series of isomeric ester leaving groups provided the desired product in each synthetically valuable yields and higher es (Group three). Although the ester leaving groups addressed the problem of chirality transfer, their synthesis necessitated employing protecting groups to mask the cost-free thiol, which added a step towards the synthetic sequence (see SI for specifics). Moreover, cost-free thiols usually are not optimal substrates simply because they’re susceptible to oxidative decomposition. We postulated that using 2(methylthio)ester 18 instead would simplify substrate synthesis and avoid oxidative decomposition on the beginning material. This directing group is especially easy given that (methylthio)acetic acid is commercially available and may be quickly appended onto the benzylic alcohol via a DCC coupling.23 Functionalized together with the thioether directing group, (R)-18 cross-coupled to afford (S)-22 in 81 and great es with general inversion of configuratio.
