Rh(III)-Catalyzed [4+3] Annulation: Temperature Dependent Ste-reodivergent Synthesis of Point-Planar Chiral Ferrocene Fused Azepines

Abstract

Planar chiral ferrocenes are extensively investigated structures in asymmetric catalysis, materials science, and medicinal chemistry. Although, the synthetic approaches for six-membered fused planar chiral ferrocenes are well-established, the construction of a seven-membered fused ring via [4+3] annulation has remained unexplored and seems to be challenging. Allenes are valuable synthons and well explored for [4+1] and [4+2] annulation but not yet explored for [4+3] annulation. Herein, an efficient rhodium-catalyzed temperature-dependent stereodivergent [4+3] annulation reaction has been devel-oped for the synthesis of novel seven-membered ferrocenylazepines via C-H activation of substituted ferrocene-p-tosylamides with allenes. At room temperature, Rh-catalyzed [4+3] annulation selectively offered one diastereomer (>20:1 dr), whereas at 60 ºC, another diastereomer was obtained exclusively with >20:1 dr. Further, [4+3] annulation reaction in the presence of a chiral RhCpX catalyst (2.0 mol %) yielded chiral ferrocenyl azepines in 56% yield and up to 90:10 er. Mecha-nistic investigations by control experiments and isotopic labeling study suggested that the reaction proceeds via a formation of a σ-bonded rhodacycle, having low energy due to less steric repulsion between the phenyl ring of allene and Cp*(pentamethyl cyclopentadienyl), which upon reductive elimination offered kinetically controlled diastereomer at room temperature. Under heating (60 ºC) conditions, kinetically controlled diastereomer undergo CH-allylic isomerization to af-ford completely thermodynamically controlled diastereomer, which has also been observed experimentally and computa-tionally for isolated kinetically controlled diastereomer.