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UBC Theses and Dissertations

Synthesis of 4-alkyl-1, 4-dihydropyridines and related compounds ; Synthesis and thermolysis of β-cyclopropyl-⍺, β-unsaturated ketones and related compounds Lau, Cheuk Kun


This thesis is composed of three separate parts. Part I describes the synthesis of a series of 1-carbomethoxy-4-alkyl(aryl)-1,4-dihydro-pyridines by the reaction of pyridine with lithium phenylthio(alkyl or aryl)cuprate reagents in the presence of methyl chloroformate. In general, the yields of the reactions were reasonably good and the reactions were very regioselective. The efficiency of lithium phenylthio(alkyl or aryl)-cuprate reagents in the preparation of 4-alkyl-1,4-dihydropyridine derivatives was compared with that of lithium dialkyl(aryl)cuprates. It was found that, in most cases, the former reagents offered no advantages over the latter reagents. The use of electrophiles other than methyl chloroformate was also investigated. Acetyl bromide gave reasonable yields of the corresponding 4-alkyl-1,4-dihydropyridine derivatives but when chlorotrimethylsilane and diethylphosphorochloridate were employed, the yields of the corresponding 4-alkyl-1,4-dihydropyridine derivatives were fairly poor. Finally, the 1-carbomethoxy-4-alkyl-1,4-dihydropyridines prepared as outlined above were transformed in good yields into the corresponding 4-alkylpyridines by treatment of the former with methyl-lithium, followed by oxidation of the resulting 1-lithio-1,4-dihydropyridine derivatives with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone. The synthesis of 1-carbomethoxy-4-alkyl(aryl)-1,4-dihydropyridinesand their subsequent conversion into the corresponding 4-alkylpyridines introduces a new and fairly efficient way of synthesizing these compounds. Part II describes the synthesis and thermal rearrangement of a number of β-cyclopropyl-⍺,β-unsaturated ketones and in certain cases, their trimethyl- silyl enol ether derivatives. The β-cyclopropyl-⍺,β-unsaturated ketones were prepared in good yields from the corresponding β-iodo enones by treating the latter with lithium phenylthio(cyclopropyl)-cuprate. The β-iodo enones were obtained in good yields by the reaction of the corresponding β-diketones and a-hydroxymethylenecycloalkanones with triphenylphosphine diiodide. When the cyclic β-cyclopropyl-⍺, β-unsaturated ketones were thermolyzed, they underwent the expected vinylcyclopropane-cyclopentene rearrangement, giving the corresponding annelated cyclopentenes in reasonable yields. In the case of ⍺-cyclo-propylmethylenecycloalkanones, pyrolysis of the corresponding trimethyl-silyl enol ethers gave better yields of the corresponding spiroannelated cyclopentenes than did pyrolysis of the parent enones. This new spiro cyclopentene annelation reaction was applied to the preparation of the spiro ketone 198, a key intermediate for the synthesis of a number of spirovetivane sesquiterpenes. The key steps in the synthesis of the spiro ketone 198 involved the preparation and thermolysis of the trimethylsilyl enol ether 200. Copper catalysed conjugate addition of methyl magnesium iodide to 2-cyclohexen-1-one, followed by trapping of the resulting enolate anion with cyclopropanecarboxaldehyde gave the β-hydroxyketone 203 in ~98% yield. Overall dehydration of 203, via base-promoted elimination of acetic acid from the corresponding acetate 211 gave a 78% yield of a mixture of the g-cyclopropyl enones 155 and 156, in a ratio of 13:1, respectively. Treatment of the latter mixture with lithium diisopropylamide, followed by trapping the resulting enolates with chlorotrimethylsilane gave the enol silyl ethers 200 in ~95% yield. Pyrolysis of 200, followed by hydrolysis of the crude product, gave a 57% yield of a mixture of the spiro enone 212 and 213, in the ratio of 2.5:1, respectively. The desired isomer 212 was isolated from the mixture and was subsequently transformed into the spiro ketone 198 via a straightforward, four-step sequence of reactions. Part III describes the synthesis and thermal rearrangement of the tricyclic enones 39 and related compounds. Reaction of lithium phenylthio(syn-7-norcar-2-enyl)cuprate (38) with 3-iodo-2-cyclohexen-l-one and 3-iodo-2-cyclopenten-1-one gave the tricyclic enones 55 and 56, respectively. It was thus clear that the initially formed enones 39 underwent facile Cope rearrangement to give the tricyclic enones 55 or 56 during work-up and/or purification. Reaction of a 1:1 mixture of syn and anti lithium phenylthio(7-norcar-2-enyl)cuprates with 3-iodo-2-cyclohexen-l-one gave a 1:1 mixture of the tricyclic enones 55 and 57. Similarly, reaction of the same cuprate reagent mixture with 3-iodo-2-cyclopenten-1-one gave a 1:1 mixture of the enones 56 and 58. When o-dichlorobenzene solutions of the enones 57 and 58 were refluxed, these compounds readily rearranged to the tricyclic enones 55 and 56, respectively.

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