Catalyst-Controlled Annulations of Strained Cyclic Allenes with π-Allylpalladium Complexes.

Strained cyclic allenes are a class of in situ-generated fleeting intermediates that, despite being discovered more than 50 years ago, has received significantly less attention from the synthetic community compared to related strained intermediates. Examples of trapping strained cyclic allenes that involve transition metal catalysis are especially rare. We report the first annulations of highly reactive cyclic allenes with in situ-generated π-allylpalladium species. By varying the ligand employed, either of two isomeric polycyclic scaffolds can be obtained with high selectivity. The products are heterocyclic and sp3-rich and bear two or three new stereocenters. This study should encourage the further development of fragment couplings that rely on transition metal catalysis and strained cyclic allenes for the rapid assembly of complex scaffolds.

Strain-promoted reactions of 1,2,3-cyclohexatriene and its derivatives.

Since 18251, compounds with the molecular formula C6H6-most notably benzene-have been the subject of rigorous scientific investigation2-7. Of these compounds, 1,2,3-cyclohexatriene has been largely overlooked. This strained isomer is substantially (approximately 100 kcal mol-1) higher in energy compared with benzene and, similar to its relatives benzyne and 1,2-cyclohexadiene, should undergo strain-promoted reactions. However, few experimental studies of 1,2,3-cyclohexatriene are known8-12. Here we demonstrate that 1,2,3-cyclohexatriene and its derivatives participate in a host of reaction modes, including diverse cycloadditions, nucleophilic additions and σ-bond insertions. Experimental and computational studies of an unsymmetrical derivative of 1,2,3-cyclohexatriene demonstrate the potential for highly selective reactions of strained trienes despite their high reactivity and short lifetimes. Finally, the integration of 1,2,3-cyclohexatrienes into multistep syntheses demonstrates their use in rapidly assembling topologically and stereochemically complex molecules. Collectively, these efforts should enable further investigation of the strained C6H6 isomer 1,2,3-cyclohexatriene and its derivatives, as well as their application in the synthesis of important compounds.

Palladium-Catalyzed Annulations of Strained Cyclic Allenes.

We report Pd-catalyzed annulations of in situ generated strained cyclic allenes. This methodology employs aryl halides and cyclic allene precursors as the reaction partners in order to generate fused heterocyclic products. The annulation proceeds via the formation of two new bonds and an sp3 center. Moreover, both diastereo- and enantioselective variants of this methodology are validated, with the latter ultimately enabling the rapid enantioselective synthesis of a complex hexacyclic product. Studies leveraging transition metal catalysis to intercept cyclic allenes represent a departure from the more common, historical modes of cyclic allene trapping that rely on nucleophiles or cycloaddition partners. As such, this study is expected to fuel the development of reactions that strategically merge transition metal catalysis and transient strained intermediate chemistry for the synthesis of complex scaffolds.