Phenyl Sulfones: A Route to a Diverse Family of Trisubstituted Cyclohexenes from Three Independent Nucleophilic Additions

A novel
process is described for the synthesis of di- and trisubstituted
cyclohexenes from an arene. These compounds are prepared from three
independent nucleophilic addition reactions to a phenyl sulfone (PhSO2R; R = Me, Ph, and NC4H8) dihapto-coordinated
to the tungsten complex {WTp­(NO)­(PMe3)}­(Tp = trispyrazolylborate).
Such a coordination renders the dearomatized aryl ring susceptible
to protonation at a carbon ortho to the sulfone group. The resulting
arenium species readily reacts with the first nucleophile to form
a dihapto-coordinated sulfonylated diene complex. This complex can
again be protonated, and the subsequent nucleophilic addition forms
a trisubstituted cyclohexene species bearing a sulfonyl group at an
allylic position. Loss of the sulfinate anion forms a π-allyl
species, to which a third nucleophile can be added. The trisubstituted
cyclohexene can then be oxidatively decomplexed, either before or
after substitution of the sulfonyl group. Nucleophiles employed include
masked enolates, cyanide, amines, amides, and hydride, with all three
additions occurring to the same face of the ring, anti to the metal.
Of the 12 novel functionalized cyclohexenes prepared as examples of
this methodology, nine compounds meet five independent criteria for
evaluating drug likeliness. Structural assignments are supported with
nine crystal structures, density functional theory studies, and full
2D NMR analysis.