Synthesis of Tetra-ortho-substituted, Phosphorus-Containing and Carbonyl-Containing Biaryls Utilizing a Diels−Alder Approach

The application of the Diels−Alder approach to biaryls (DAB) is described for the synthesis of
tetra-ortho-substituted biaryl compounds containing orthogonally functionalized substituents. The syntheses
of phosphorus-containing, disubstituted alkynes and carbonyl-containing, disubstituted alkynes were
accomplished in two to three steps from commercially available reagents. Subsequent Diels−Alder
cycloadditions with a range of oxygenated dienes yielded the target biaryls. Further functionalization through
palladium-couplings is demonstrated on the phosphorus-containing biaryls. In addition, selective manipulation
of each of the remaining ortho substituents on the phosphorus-containing biaryls is demonstrated. One of
these phosphorus-containing derivatives is utilized as a highly active catalyst for Suzuki coupling. For the
carbonyl-containing series, a wide range of dienophile substituents were screened including esters, ketones,
and amides. The key Diels−Alder cycloadditions proceeded smoothly with the commercially available
1-methoxy-1,3-cyclohexadiene to yield the resultant tetra-ortho-substituted biaryls with excellent regioselectivity. The scope of the cycloaddition process was also explored on the carbonyl-containing dienophiles
with a series of cyclic dienes. Acyclic dienes were also screened; however, they did not prove effective in
the Diels−Alder process with the carbonyl-containing acetylenes. The ability to isolate enantiomerically
pure biaryl atropisomers using a benzyl oxazolidinone is disclosed. Finally, the subsequent conversion to
an axially chiral anilino alcohol is also reported.