Abstract
Contrary to the general belief that Pd‐catalyzed cross‐coupling at sites of severe steric hindrance are disfavored, we herein show that the oxidative addition to C−Br ortho to an adamantyl group is as favored as the corresponding adamantyl‐free system due to attractive dispersion forces. This enabled the development of a fully selective arylation and alkylation of C−Br ortho to an adamantyl group, even if challenged with competing non‐hindered C−OTf or C−Cl sites. The method makes use of an air‐stable PdI dimer and enables straightforward access to diversely substituted therapeutically important adamantylarenes in 5–30 min.
Highlights
Owing to its exceptional liphophilicity and stability-enhancing properties, the adamantyl group has found widespread applications in materials science,[1] medicinal chemistry, and drug development.[2]
While methods for the introduction of the 1adamantyl group to an arene have significantly advanced in recent years, due to successes in devising radicalbased or organometallic methods,[4c,e–h,5] these approaches predominantly deliver the adamantly group in the meta or para position relative to an alternative substituent in the arene, but not in the ortho position
In the context of Pd0/PdII catalysis, the relative reactivity of aryl triflates and bromides is frequently referred to as roughly the same,[24] and selectivity has historically been a result of a subtle interplay of reaction conditions, catalyst, coupling partner, and the steric and electronic effects imposed by the substrate.[9a,10e,f,24,25] By contrast, we recently established a substrate-independent and a priori predictable Csp2À Csp2 and Csp2ÀCsp3 functionalization exclusively at CÀBr in competition with the CÀOTf and CÀCl sites.[9b,26] Key to this exquisite selectivity was the employment of an air- and moisture stable PdI dimer that facilitated the couplings within 5 min at room temperature.[27]
Summary
Owing to its exceptional liphophilicity and stability-enhancing properties, the adamantyl group has found widespread applications in materials science,[1] medicinal chemistry, and drug development.[2]. The key requirements for success of this strategy are 1) that selective CÀBr versus CÀOTf functionalization can be realized and 2) that coupling ortho to the large adamantyl group is possible.
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