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

Abstract

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.

Figure 1.

SC-XRD molecular structure determination (50% ellipsoids) of the η²-phenyl methyl sulfone complex (2a; full report in SI of reference 29).

Figure 2.

SC-XRD molecular structure determination (50% ellipsoids; mirror image) of the sulfonamide-substituted η²-diene complex 14.

Figure 3.

SC-XRD molecular structure determinations (50% ellipsoids) of the η²-diene complexes (40; mirror image and 41).

Figure 4.

SC-XRD molecular structure determination (50% ellipsoids) of the disubstituted η²-cyclohexene complex (43).

Scheme 1.

Reactivity pattern of a dihapto-coordinated trifluorotoluene complex.

Scheme 2.

Proposed syntheses of functionalized cyclohexenes from sulfones (R = Me, Ph) or sulfonamides (R = NC₄H₈).

Scheme 3.

Preparation of dihapto-coordinated phenyl sulfone complexes of {WTp(NO)(PMe₃)} and the C-H insertion of methyl sulfones (insert).

Scheme 4.

Protonation of dihapto-coordinated phenyl sulfone ligands followed by nucleophilic addition to generate sulfonylated diene complexes (racemic mixtures).

Scheme 5.

(top) kinetic and thermodynamic protonation of η²-(1-sulfonyl-1,3-diene) complexes (10, 11, 13), and conformational change (“allyl shift”), of the resulting η²-allyl complex. (bottom) Conversion of sulfonyldiene complexes to sulfonyl-substituted cyclohexene complexes (29–32) via allyl intermediates (e.g., 28; all compounds are racemic mixtures).

Scheme 6.

Second protonation/nucleophilic addition of cyanide to the arene ring (racemic mixture).

Scheme 7.

Double nucleophilic additions to η²-1-sulfonyl-1,3-diene complexes (racemic mixture).

Scheme 8.

Sulfone substitution reactions (LA = Lewis acid).

Scheme 9.

Formation of disubstituted η²-diene complexes from sulfonylated cyclohexene or sulfonylated cyclohexadiene complexes (racemic mixtures).

Scheme 10.

Addition of the third nucleophile either via replacement of the sulfone or from addition to the η²-diene (racemic mixtures).