59th Annual Report on Research 2014

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Reports: DNI152782-DNI1: Direct Access of Chemically Differentiated 1,2-Diols from Oxime-Masked Mono-Alcohols

[Scientific Goals]: Our objective during the funding periord is to develop a Pd-catalyzed C¨CH functionalization strategy towards vicinal functionalization of mono-alcohols by using oximes as a removable directing group (Figure 1). [Progress]: During the first year, significant progress has been made towards the above goal. We recently developed a Pd-catalyzed vicinal oxidation of unactivated C¨CH bonds (non-allylic/aromatic) using alcohol-derived oximes as directing groups (DG). As illustrated in Figure 2, the oxime was employed as both a DG and an alcohol surrogate for this transformation. As demonstrated in a range of substrates, the C¨CH bonds ¦Á to the oxime group are selectively oxidized. Besides activation of the methyl groups, methylene groups (CH₂) in cyclic substrates and methine groups (CH) at bridge-head positions can also be functionalized. In addition, an intriguing oxidative skeleton rearrangement was observed using the menthol-derived substrate. The oxime moiety can be easily removed and give back the alcohol. The use of exo-directing groups in C¨CH activation, as illustrated in this work, would potentially open doors for discovery of new transformations and new cleavable DGs. Recently, we also discovered besides OAc group, the OTFA group can also be installed when trifluoroacetyl amide was used as the substrate (equation 1). We recently also focused on a fundamental study of a direct oxidation of an unactivated sp³ C¨CH bond into a sulfonate (such as OTs) group (Fig. 3). This method is significant because the OTs group is well known to be a good leaving group, thus it can serve as a surrogate for many other functional groups, such as amine, sulfide, esters, ethers, through a S_N2 reaction. The success of this transformation would ease introduction of functional groups intro alkanes.  We have carefully optimized the reaction conditions to achieve synthetically useful yields, and then examined the substrate scope (Figure 4). Various alcohol-derived substrates all underwent the transformation.   In addition, we discovered other sulfonic acids can also react and give good yields of corresponding sulfonates (Figure 5). Finally, we demonstrated that this method can serve as a divergent strategy to introduce different functional groups via S_N2 reactions (Figure 6).   [Significance and Impact]: Our progress has made a significant impact: (1) it disclosed a new mode of activity by allowing installation of a good leaving group via activation of aliphatic C¨CH bonds; (2) it established a new strategy for introduction of diverse functional groups, including nitrogen-containing moiety; (3) it would be beneficial for library synthesis because various compounds can come from a single intermediate. Current research progress laid foundation for the future work on developing diverse and general reactions for the ¦Â-alcohol functionalization.