Substituting methoxy groups

Angew.Chem.Int.Ed.http://dx.doi.org/10.1002/anie.201402922(2014)

Methoxy substituents on aromatic molecules are powerful directing groups, widely used in electrophilic aromatic substitution reactions and directed ortho-metallation reactions. And although their stability is useful for allowing them to survive harsh reaction conditions, it follows that removing them after they have served their purpose is challenging. Recent research on the use of nickel catalysts for methoxy removal has shown their utility in these reactions but there is still much room for improvement. Getting sp³-hybridized carbon groups to replace methoxy is surprisingly difficult and currently limited to methyl groups. Similarly, introducing functional groups that are genuinely flexible with respect to further derivatization is also a challenge.

Magnus Rueping and co-workers from RWTH Aachen University encountered these issues during the course of a natural product synthesis but have now shown that methoxy groups can be easily replaced with functionalized aliphatic nucleophiles. Nickel catalysis was an obvious place to start, given the recent successes achieved in that area for the cleavage and replacement of methoxy groups. In particular, the team examined the effects of nickel catalysis with bifunctional sp³-hybridized carbon nucleophiles. Grignard reagents performed poorly, but a silyl-group-bearing organolithium compound (LiCH₂SiMe₃) was a good nucleophile and, after optimization, yields of 99% were achieved with a nickel cyclooctadiene catalyst. The reaction was rapid even at room temperature with 1 mol% of catalyst. The scope for the aromatic coupling partner was broad with a number of functional groups (such as alcohols and amines) tolerated, and reactions could be scaled up without drops in yield.

The products — containing both silicon groups and benzylic hydrogen atoms — were particularly amenable to further functionalization. Silyl groups are well known for increasing the acidity of neighbouring C–H bonds; perhaps the best known use of this effect is in the Peterson olefination, which Rueping and co-workers were able to use to achieve alkene formation. In addition, fluoride-mediated reactions allowed the generation of nucleophilic CH₂ and hence substitution of the trimethylsilyl group. Also, oxidation of the benzylic hydrogens gave acyl silanes, themselves useful building blocks. As such, the role of methoxy groups as precursors seems to have been greatly increased.