TAKE ME TO ONE SIDE
by Paweł Czerwiński,12.11.2017
A few days ago, Frank Glorius and co-workers published impressive results of their research on the hydrogenation of fluoroarenes. The synthesis of monofluorinated substituted cyclohexanes from unfunctionalized precursors (Groves and Lectka) or from carboxylic acids (MacMillan) has been reported previously, but the trans isomers are dominant due to the radical nature of these processes. The cis selectivity could be available by nucleophilic substitution (opening of epoxides, substitution of leaving groups or deoxyfluorination). However, this approach requires diastereoselectively pre-decorated substrates. The formation of all-cis-1,2,3,4,5,6-hexafluorocyclohexane seems to be an intimidating challenge in this field of chemistry. A nucleophilic substitution strategy developed by O’Hagan allows to obtain this compound in 12 steps with overall 0.5% yield.
For this reason, highly cis-selective, scalable, chemoselective, and catalytic hydrogenation of fluorinated arenes enabling access to fluorinated cyclohexanes is incredibly desirable. That is just the method developed by Glorius and co-workers based on hydrogen reduction catalyzed by rhodium complex with (alkyl)(amino)carbene (CAAC), which was used to hydrogenate aromatic compounds for the first time by Zeng. This catalyst allows to attenuate the unwanted products. This is an important consideration since the reaction could proceed to oxidative addition, aromatic substitution, hydrodefluorination, β-fluorine elimination, or hydrogen fluoride elimination products.
It's worth reading! Jump to the article now: Science, 2017, 357, 908-912
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A broad scope of substrates, including heteroarenes and, what is most important, practical applications of the developed methodology (examples of products prepared on a gram scale) makes this work notable. It is interesting to focus in particular on the yield of all-cis fluorinated cyclohexane achieved by Glorius and O’Hagan (34% versus 0.5%, respectively).
Of note is also the presented synthesis of a fluorinated analogue of the popular and commonly utilized NHC ligand, 1,3-dicyclohexyl-imidazol-2-ylidene (ICy). The incorporation of fluorine atoms in this molecule could influence the catalytic activity of NHC-transition metal complexes. The icing on the cake are the also described syntheses of fluorinated analogues of anticancer drug lomustine, mucolytic agent bromhexine or liquid crystal materials.