Transition-metal-catalyzed [4+4] cycloaddition leading to cyclooctanoids has centered on dimerization between 1,3-diene-type substrates. Herein, we describe a [4σ+4π-1] and [4σ+4π] cycloaddition strategy to access 7/8-membered fused carbocycles through rhodium-catalyzed coupling between the 4σ-donor (benzocyclobutenones) and pendant diene (4π) motifs. The two pathways can be controlled by adjusting the solvated CO concentration. A broad range (>40 examples) of 5-6-7 and 5-6-8 polyfused carbocycles was obtained in good yields (up to 90 %). DFT calculations, kinetic monitoring and 13C-labeling experiments were carried out, suggesting a plausible mechanism. Notably, one 5-6-7 tricycle was found to be a very rare, potent, and selective ligand for the liver X receptor β (KD=0.64 μM), which is a potential therapeutic target for cholesterol-metabolism-related fatal diseases.

Controlling the chemo- and regioselectivity of transition-metal-catalyzed C-C activation remains a great challenge. The transformations of benzocyclobutenones (BCBs) usually involve the cleavage of C1-C2 bond. In this work, an unprecedented highly selective cleavage of C1-C8 bond with the insertion of alkynes is achieved by using blocking strategy via Ni catalysis, providing an efficient method for synthesis of 1,8-disubstituted naphthalenes. Notably, the blocking group could be readily removed after the transformation.

A Co(0)-catalyzed intramolecular alkyne/benzocyclobutenone coupling through C-C cleavage of benzocyclobutenones is described. Co2(CO)8/P[3, 5-(CF3)2C6H3]3 was discovered to be an effective metal/ligand combination, which exhibits complementary catalytic activity to the previously established rhodium catalyst. In particular, the C8-substituted substrates failed in the Rh system, but succeeded with the Co catalysis. Experimental and computational studies show that the initially formed tetrahedral dicobalt-alkyne complex undergoes C1-C2 activation via oxidative addition with Co(0), followed by migratory insertion and reductive elimination to give the β-naphthol products.

The nickel-catalyzed intermolecular cycloadditions of benzocyclobutenones with 1,3-dienes developed by Martin and co-workers are featured with the exclusive proximal C-C bond cleavage and a high chemoselectivity of the [4+4] over the [4+2] cycloaddition. In this report, the detailed reaction mechanism and the origins of the selectivities were investigated by means of density functional theory calculations. The results show that the reaction is initiated by a C-C oxidative addition of the benzocyclobutenone to form the five-membered nickelacycles. A subsequent exo 1,4-insertion/C-C reductive elimination and an endo 1,4-insertion/C-C reductive elimination lead to the [4+4] and [4+2] cycloaddition products, respectively. The 1,4-insertion of the 1,3-diene into the Ni-C bond was calculated to be the rate- and selectivity-determining step of the reaction. The calculations reproduced quite well the experimentally observed exclusive proximal C-C bond cleavage and the high chemoselectivity of the [4+4] over the [4+2] cycloaddition. In particular, it was found that the steric repulsion between the phosphine ligand and the α-substituent of the benzocyclobutenone has a dramatic impact on the 1,4-insertion, which enables the experimentally observed selectivities.

The first catalytic intermolecular proximal C1-C2 cleavage of benzocyclobutenones (BCB) without prior carbonyl activation or employing noble metals has been developed. This protocol operates at room temperature and is characterized by an exquisite chemo-, regio- and diastereoselectivity profile, constituting a unique platform for preparing an array of elusive carbocyclic skeletons.