Organocatalysis and Continuous Flow Reactors as Enabling Tools in Organic Synthesis

Antti Kataja

    Research output: ThesisDoctoral ThesisMonograph

    Abstract

    Enabling synthetic technologies are a collection of modern tools created to aid synthetic organic chemists to achieve rapid and efficient synthesis and analysis of complex reaction products in the laboratory environment. These techniques include e.g. microwave reactors, heterogenized catalysts and continuous flow reactor systems. The application of enabling technologies to known methods of organic synthesis such as organocatalysis is paramount for chemists in adapting to a changing world where the ready availability natural resources is by no means a given. The first part of this thesis describes studies towards elucidating the mechanism of cinchona alkaloid derived bifunctional thiourea organocatalysts. The activity of N-trityl substituted thiourea catalyst in the asymmetric Michael addition of Meldrum’s acid and other soft carbon nucleophiles to nitroalkenes was studied. The catalyst was found to be inactive with malonate diester nucleophiles, and subsequent studies revealed that the catalyst is unable to efficiently activate a non-enolic nucleophile, thus arresting the catalytic cycle. The second part of this thesis focuses on the use of asymmetric organocatalytic ketone aldol addition in the total synthesis of marine alkaloid (–)-hennoxazole A. Two routes were investigated for the synthesis of the western pyran fragment. A prolineamide derivative was identified as the optimal catalyst. The addition of acetone to a bisoxazole aldehyde was then optimized in batch conditions and studied further in continuous flow conditions. Conditions for the O-methylation of the aldol addition product were also identified. The final part of this thesis concentrates on the use of continuous flow reactors in industrially important aromatic nitration reactions. The nitration of vanillin was studied as the model reaction. Blockage of flow channels due to product precipitation was identified as a serious problem and the concentration of starting material stock solutions and reaction temperatures had to be adjusted accordingly. Reaction selectivity did not essentially differ from batch conditions in spite of radically different conditions, but product isolation was more difficult. Demethylation of the methoxy substituent of vanillin and subsequent nitration was identified to be the main side reaction, along with a deformylative ipso-nitration. The nitration protocol was studied with other substrates and it was found to function best for relatively electron rich aromatic compounds.
    Translated title of the contributionOrganokatalyysi ja jatkuvatoimiset virtausreaktorit mahdollistavina työkaluina orgaanisessa synteesissä
    Original languageEnglish
    QualificationDoctor's degree
    Awarding Institution
    • Aalto University
    Supervisors/Advisors
    • Koskinen, Ari, Supervising Professor
    Publisher
    Print ISBNs978-952-60-5061-4
    Electronic ISBNs978-952-60-5062-1
    Publication statusPublished - 2013
    MoE publication typeG4 Doctoral dissertation (monograph)

    Keywords

    • organocatalysis
    • continuous flow reactors
    • bifunctional thiourea catalysts
    • hydrogen bonding
    • proline
    • enamine catalysis
    • aldol reaction
    • Michael-addition
    • aromatic nitration

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