Catalytic Aerobic Carbooxygenation for the Construction of Vicinal Tetrasubstituted Centers: Application to the Synthesis of Hexasubstituted γ-Lactones.

Strategic design for the construction of contiguous tetrasubstituted carbons represents a daunting challenge in synthetic organic chemistry. Herein, we report a combined experimental and computational investigation aimed at developing catalytic aerobic carbooxygenation, involving the intramolecular addition of tertiary radicals to geminally di-substituted-alkenes followed by aerobic oxygenation. This reaction provides a straightforward route to various α,α,ß,ß-tetrasubstituted γ-lactones, which can be readily transformed into hexasubstituted γ-lactones through allylation/translactonization. Computational analysis reveals that the key mechanistic foundation for achieving the developed aerobic carbooxygenation involves the design of endothermic (energetically uphill) C-C bond formation followed by exothermic (energetically downhill) oxygenation. Furthermore, we highlight a unique fluorine- induced stereoelectronic effect that stabilizes the endothermic stereo-determining transition state.

Solvent-dependent copper-catalyzed synthesis of pyrazoles under aerobic conditions.

We present a copper-catalyzed oxidative cyclization of ß,γ-unsaturated hydrazones, utilizing molecular oxygen as a stoichiometric oxidant. The methodology provides distinct classes of pyrazoles simply by changing the reaction solvent. Tris-substituted pyrazoles, having a ketone functionality at the C-5 position, were obtained as the major product in ethanol, while di-substituted pyrazoles were predominantly formed in 1,1,1,3,3,3-hexafluoro-2-propanol.

Cobalt-Catalyzed Cross-Benzannulation of Conjugated Enynes and Diynes.

The [4 + 2] cross-benzannulation of conjugated enynes and diynes under cobalt-catalysis led to 1,2,3-trisubstituted benzene derivatives in good yields. The reaction proceeds smoothly in absolute regiospecific control when symmetrical diynes are applied. Moreover, the use of unsymmetrical diynes was investigated, resulting in the formation of the unprecedented regioisomers as major products, which is in contrast to the results obtained in palladium-catalyzed benzannulation reactions. Also, 4-bromophenyl-substituted starting materials could be applied successfully in the cobalt-catalyzed process, which can be problematic in the palladium-catalyzed counterpart.

Zinc-mediated CH-activation of tetrahydrofuran under mild conditions for the regioselective addition to aryl-propiolates.

The CH-activation of THF is realized in a zinc-mediated process using a dibromocyclopropane as a crucial additive. The highly regioselective addition to aryl-substituted propiolates as well as the regio- and stereoselective addition to diynes are described.

Synthesis of fluorenone and anthraquinone derivatives from aryl- and aroyl-substituted propiolates.

Fluorenone derivatives were generated from aryl-substituted propiolates via a cobalt-catalyzed Diels-Alder reaction/DDQ-oxidation and Friedel-Crafts-type cyclization. Several functional groups are tolerated, and good to excellent overall yields (up to 89%) could be achieved. For the synthesis of anthraquinone derivatives, aroyl-substituted propiolates were applied in a zinc iodide catalyzed Diels-Alder reaction with 1,3-dienes. The subsequent DDQ oxidation and Friedel-Crafts-type cyclization led to symmetrical as well as some unsymmetrical anthraquinones in good to excellent yields of up to 87% over the three-step reaction sequence.

Regioselective solvent-dependent benzannulation of conjugated enynes.

The transformation of enynes under cobalt-catalysis leads to symmetrical benzannulation products in dichloromethane. In tetrahydrofuran the cobalt-catalysed reactions afforded the unprecedented unsymmetrical benzannulation products in moderate to good yields and good regioselectivities. In addition, cyclotrimerisation of the alkyne subunit can be realised when electron-deficient enynes are applied in the cobalt-catalysed transformations to generate 1,2,4-trivinylbenzene derivatives using tetrahydrofuran as solvent.