The work presented in this Thesis falls within the context of transition metal-catalyzed isomerization of π-bonds and its application in multi-step “one-pot” processes. Predominantly, we combined the atom-, step- and redox-economical migration of double bonds with in-situ functionalization reactions, thus generating molecular complexity in an efficient and environmentally friendly fashion.
The inherent reactivity of 1,3-dienes is strongly influenced by the nature and position of the substituents on the molecular scaffold as well as the relative stereochemistry of the double bonds. For this reason, the development of efficient and selective methods towards their synthesis receives continuous effort. Aware of the paucity of highly stereoselective methods to access 2,4-disubstituted branched dienes, we developed a new complementary synthetic approach based on the Ru-catalyzed (remote) conjugative isomerization of distal alkenes. Salient features of this mild and operationally simple method were its high chemo- and regioselectivity towards the kinetic products instead of the more stable linear dienes. Moreover, the catalytic system proved highly stereoselective and showed a broad functional group tolerance. Mechanistic investigations supported a metal-hydride mechanism consisting of iterative migratory insertions/β-H eliminations. The potential of the method was further highlighted by performing one-pot [4+2] cycloaddition reactions and sequential catalytic reactions that capitalized on the transiently generated branched diene.
Tackling the scarcity of regio- and stereoselective methods to access trisubstituted enol ethers via Heck cross-coupling, we developed an assisted-tandem Pd-catalyzed isomerization/Heck arylation sequence towards their synthesis. Readily available alkenyl ethers were isomerized to vinyl ethers by means of a [Pd–H] catalyst. Such species was subsequently modified in-situ to trigger the arylation step in a regiodivergent fashion. When a bidentate ligand and an organic base (NCy2Me) were added in solution along with aryl triflates as coupling partners, the α-arylated trisubstituted enol ethers could be isolated in moderate to high yields and excellent regioselectivity. Complementarily, the β arylation pathway was favored by addition of Et3N in large excess and aryl bromides as coupling partner. In this case, the method showed good yields and high regioselectivity only when electron-poor or electron-neutral aryl electrophiles were employed. To gain insight into the strong dependence of the regioselectivity of insertion on the electronics of the aryl bromides, experimental as well computational analysis were performed. As proof of concept, examples of assisted tandem long-range isomerization/β-Heck arylations were reported as well as strategies to improve the E/Z ratio of the products.
Driven by our interest in the isomerization of π-bonds, we developed an unprecedent regiodivergent Pd-catalyzed isomerization of alkynyl alcohols. This operationally simple method required the use of a [Pd–H] precatalyst supported by monodentate phosphines. When the catalytic system operated at 25 °C, the alkyne-to-diene isomerization afforded the dienol products selectively. Alternatively, at 80 °C the π system was completely migrated along the hydrocarbon chain and the corresponding α,β-unsaturated carbonyls were generated in good yields and in a stereoselective fashion.
