UC San Diego

The work contained within this thesis represents contributions to our understanding of ruthenium-mediated cycloaromatization reactions of trienes and novel cycloaromatization reactions of nitrogen-containing enediynes. Previous work done in the O’Connor lab demonstrated room temperature cyclizations of enediynes and dienynes via proposed hexahapto metal coordination. Preliminary calculations suggest that η6-metal complexation to the π system lowers the activation energy for cyclization. The mechanistic hypothesis for this transformation involves η6-metal complexation to the triene system, followed by a 6π electrocyclization.

The first η6-acyclic conjugated triene ruthenium complex was successfully synthesized by the reaction of [CpRu(NCMe)3]PF6 with an (E,E) diphenyl-substituted 1,2-divinylcyclopentene derivative. The presence of phenyl substituents is thought to inhibit the metal-mediated disrotatory ring closure of the triene due to steric congestion. This complex was further characterized by exploring electronic effects of para-substituted phenyl substituents on the overall geometry. More specifically, electronic effects were examined by hexahapto metal complexation to 1,2-bis((E)-4-(trifluoromethyl)styryl)cyclopentene and 1,2-bis((E)-4-methoxystyryl)cyclopentene. The more electron-deficient η6-triene ruthenium complex adopted an s-cis/s-cis conformation, as determined by X-ray crystallographic analysis. The more electron-rich η6-triene ruthenium complex adopted both s-cis/s-cis and s-cis/s-trans conformations in a 3:1 ratio. Additional analysis of this ratio by cold-probe variable temperature 1H NMR spectroscopy confirms that the two isomers exists in equilibrium at room temperature. The relative stabilities of these diastereomeric complexes were examined by a time course migration study where the migration of ruthenium from (η5-cyclopentadienyl)(η6-1,2-bis((E)-4-(trifluoromethyl)styryl)cyclopentene) ruthenium(II) hexafluorophosphate to 2-bis((E)-4-methoxystyryl)cyclopentene was monitored by 1H NMR spectroscopy. Based on the final ratio of isomers, it was estimated that the more electron-rich ruthenium complex is > -4.0 kcal/mol more stable than the electron-deficient η6-triene ruthenium complex.

Finally, a recently discovered thermal cyclization of enediynes was extended to include pyridine-based enediynes. Thermolysis of 2-(1-pentynyl)-3-(1-propynyl)pyridine in CDX3 (X = Br, I) and 1,4-cyclohexadiene led to the regioselective formation of 5-halo-6-methyl-7-propylquinoline derivatives. Halogen connectivity was established via HMBC and NOE NMR spectroscopic analysis. The cyclization is proposed to involve a key diene intermediate, (E)-3-(1-halo-1-propenyl)-2-(1-pentynyl)pyridine, which may form by one or both of the following mechanisms. The first mechanism involves addition of HX to the alkyne (X = Br, I). The hydrogen halide is proposed to form in situ from the reaction of 1,4-cyclohexadiene with CDX3 (X = Br, I) to form HX, CDHX2, and benzene. In the second mechanism, the diene intermediate is proposed to form through free radical addition of a hydrogen atom from the cyclohexadienyl radical to an alkyne to give a dienyne radical, followed by abstraction of a halogen atom from CDX3 to produce the halo-dienyne intermediate. This key dienyne intermediate is then proposed to undergo a Hopf-type cyclization to yield the halogenated aromatic product.