Browsing by Author "Behnke, Nicole Erin"

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    Copper-Catalyzed Synthesis of Hindered Ethers from α-Bromo Carbonyl Compounds
    (American Chemical Society, 2018) Zhou, Zhe; Behnke, Nicole Erin; Kürti, László
    A catalytic method for the synthesis of sterically hindered ethers and thioethers from α-bromo carbonyl compounds and the corresponding nucleophiles using an inexpensive Cu(I) catalytic system is reported. This facile transformation takes place at ambient temperature and does not require the exclusion of air or moisture; thus, it is well-suited for the functionalization and derivatization of complex organic molecules.
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    New Strategies for the Synthesis of Amines, Ethers and Small Strained Rings
    (2021-08-12) Behnke, Nicole Erin; Kurti, Laszlo
    Amines, ethers and small strained rings are ubiquitous structural motifs in biologically active compounds and consumer products. The motivation for this work was to develop operationally simple and efficient strategies for the formation C–N, C–O, and C–C bonds in structurally diverse molecules. Chapter 1 describes the development of two novel methods for the synthesis of primary aromatic and aliphatic amines via the electrophilic amination of the corresponding organometallic reagents. The key advance in these transformations is the application of sterically hindered NH-oxaziridines as chemoselective aminating reagents. The first method involves the transmetalation of aryl Grignard, organolithium, or organozinc reagents to the corresponding organocopper species and subsequent reaction with a di-tert-butyl NH-oxaziridine. The use of less basic organocopper reagents expands the substrate scope to incorporate electron-deficient and heterocyclic aryl rings as well as sensitive electrophilic functional groups in the desired primary amine products. The second method is an extension of the oxaziridine N-transfer chemistry that includes aliphatic organometallic reagents. The developed route is applied to sterically and electronically diverse primary, secondary, and tertiary alkyl Grignard and organozinc reagents to form the corresponding primary amines in good yields. Chapter 2 outlines the work conducted for the copper-catalyzed synthesis of sterically hindered ethers from -bromo carbonyl compounds. Coupling of an -bromocarboxamide or an -bromocarboxylic acid is successful with a wide variety of phenols in addition to primary, secondary, or tertiary alcohols under mild conditions. To showcase potential applications of the ether-forming method in medicinal chemistry, a mild route that improves upon literature precedent is designed and applied to the synthesis of a novel PAR-1 antagonist analogue. Chapter 3 describes advances made in the synthesis of spirocyclic NH-azetidine rings through a Ti(IV)-mediated Kulinkovich-type coupling of oxime ethers with primary alkyl Grignard reagents or terminal olefins. A significant development in this project is related to the purification and handling of the sensitive and basic NH-azetidine compounds. Oxime ether coupling with structurally and electronically diverse primary Grignard reagents evaluates the scope of NH-azetidine products while coupling with terminal olefins validates the proposed Kulinkovich-type reaction mechanism. Finally, Chapter 4 outlines another project dedicated to the synthesis of small, strained rings. A combination of three synthetic steps is used for the formation of highly substituted cyclopropane rings. First, the formation of alpha,alpha-dichlorocyclobutanone rings proceeds via a [2+2] Staudinger ketene cycloaddition from cis- or terminal olefins. Next, a complete optimization study for the generation of alpha,alpha-dichlorocyclobutanols via 1,2-addition of organocerium reagents is described. Last, a base-mediated quasi-Favorskii reaction induces a ring-contraction of the alpha,alpha-dichlorocyclobutanol ring under mild reaction conditions to the corresponding highly substituted cyclopropane product. Overall, these five methods significantly contribute to advancements in the synthesis of compounds containing amine, ether or strained ring functional groups. In addition to studying innovative reactivity patterns, a wide variety of novel compounds with structurally and electronically diverse properties are characterized.
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    Non-Deprotonative Primary and Secondary Amination of (Hetero)Arylmetals
    (American Chemical Society, 2017) Zhou, Zhe; Ma, Zhiwei; Behnke, Nicole Erin; Gao, Hongyin; Kürti, László; BioScience Research Collaborative
    Herein we disclose a novel method for the facile transfer of primary (−NH2) and secondary amino groups (−NHR) to heteroaryl- as well as arylcuprates at low temperature without the need for precious metal catalysts, ligands, excess reagents, protecting and/or directing groups. This one-pot transformation allows unprecedented functional group tolerance and it is well-suited for the amination of electron-rich, electron-deficient as well as structurally complex (hetero)arylmetals. In some of the cases, only catalytic amounts of a copper(I) salt is required.
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    Rapid heteroatom transfer to arylmetals utilizing multifunctional reagent scaffolds
    (Springer Nature, 2016) Gao, Hongyin; Zhou, Zhe; Kwon, Doo-Hyun; Coombs, James; Jones, Steven; Behnke, Nicole Erin; Ess, Daniel H.; Kürti, László; BioScience Research Collaborative
    Arylmetals are highly valuable carbon nucleophiles that are readily and inexpensively prepared from aryl halides or arenes and widely used on both laboratory and industrial scales to react directly with a wide range of electrophiles. Although C−C bond formation has been a staple of organic synthesis, the direct transfer of primary amino (−NH2) and hydroxyl (−OH) groups to arylmetals in a scalable and environmentally friendly fashion remains a formidable synthetic challenge because of the absence of suitable heteroatom-transfer reagents. Here, we demonstrate the use of bench-stable N−H and N−alkyl oxaziridines derived from readily available terpenoid scaffolds as efficient multifunctional reagents for the direct primary amination and hydroxylation of structurally diverse aryl- and heteroarylmetals. This practical and scalable method provides one-step synthetic access to primary anilines and phenols at low temperature and avoids the use of transition-metal catalysts, ligands and additives, nitrogen-protecting groups, excess reagents and harsh workup conditions.