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

Abstract

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.

Formaldehyde‐Extruding Homolytic Aromatic Substitution via C→O Transposition: Selective ‘Traceless‐Linker’ access to Congested Biaryl Bonds

“…Some sterically hindered biphenyls remain nonetheless difficult to access via any/all of these routes, and (differentially) tetra‐ ortho ‐substituted biaryls are known to be often challenging targets . Discovery of reliable and high‐yielding reactions for their synthesis is considered a valuable goal …”

An Extremely Simple Dibenzopentalene Synthesis from 2‐Bromo‐1‐ethynylbenzenes Using Nickel(0) Complexes: Construction of Its Derivatives with Various Functionalities

“…Trimethylsilylacetylene was purchased from Shin-Etsu Chemical Co., Ltd. Compounds 9 [15] and 16, [16] 3-bromo-4-iodotoluene, [17] 4-bromo-5-iodo-1,2-dimethoxybenzene, [18] and methyl 3-bromo-4-iodobenzoate [19] were prepared according to previously reported procedures.…”

ortho,ortho′‐Substituted KITPHOS Monophosphines: Highly Efficient Ligands for Palladium‐Catalyzed CC and CN Bond Formation

“…[23] Biarylmonophosphines 1-4 are typically prepared in a highly modular straightforward one-pot protocol involving addition of an aryl-Grignard to an in situ generated benzyne followed by trapping of the resulting biaryl-metal intermediate with an appropriate chlorophosphine. [24] However, more recently, the biaryl architecture of electron-rich monophosphines has also been constructed using cycloaddition methodology, including Diels-Alder cycloaddition-elimination between 1-alkynylphosphine oxides and various 1,3-dienes [25] and rhodium-catalyzed [2 + 2 + 2] cycloaddition of tethered diynes with 1-alkynylphosphine sulfides and oxides. [26] We have recently applied this approach to the Diels-Alder cycloaddition between 1-alkynylphosphine oxides and anthracene to develop an architecturally distinct family of electron-rich biaryl-like monophosphines, KITPHOS (11-dicyclohexylphosphino-12-phenyl-9,10-ethenoanthracenes) ( Figure 2).…”