Theses and Dissertations at Montana State University (MSU)
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Item The expansion and optimization of ZN(II)-mediated intramolecular metalloamination and subsequent CU(I)-catalyzed functionalization for the construction of pyrrolidines and piperidines(Montana State University - Bozeman, College of Letters & Science, 2023) Frabitore, Christian Ames; Chairperson, Graduate Committee: Thomas S. Livinghouse; This is a manuscript style paper that includes co-authored chapters.Nitrogen-containing heterocycles (azacycles) are ubiquitous in pharmaceutical agents. Their ability to moderate and modulate the activity of drugs in the body make them especially powerful, and thus sought after, synthetic targets. While the synthesis of many popular azacycles has been greatly improved in recent years, the production of pyrrolidines and piperidines has not received as much attention despite their standing as the 1st and 5th most common azacycles in FDA-approved drugs. The intramolecular Zn(II)-mediated metalloamination/cyclization of N,Ndimethylhydrazinoalkenes provides structurally diverse pyrrolidines and piperidines with the added advantage of a subsequent functionalization step, efficiently building molecular complexity in one reaction sequence. Herein, this method is optimized and improved by the addition of a new hydrazone reduction method, the inclusion of 1-bromoalkynes in the functionalization step, and multiple key discoveries in the reagents used to effect these transformations. Furthermore, preliminary results adding N,N-dimethylhydrazinoallenes as substrates for this powerful method are presented.Item Diethyl zinc mediated intramolecular metalloamination of N,N-dimethylhydrazines: expanding a novel approach to functionalized pyrrolidines and piperidines. Utilizing synthesis as a tool for medicinal chemistry, environmental remediation, and nonlinear optical chromophore construction(Montana State University - Bozeman, College of Letters & Science, 2017) Mickelsen, Ky James; Chairperson, Graduate Committee: Thomas S. Livinghouse; Dissertation contains an article of which Ky James Mickelsen is not the main author.; Sean Zabawa and Tom Livinghouse were co-authors of the article, 'Diethylzinc mediated metalloamination-alkylation of N,N-dimethylhydrazinoalkenes. Catalysis of carbon-zinc alkylation using simple copper(I) salts' in the journal 'Synlett' which is contained within this thesis.When attempting to develop a novel material for increased second-order nonlinear activity, a strategy was devised to rationally design an architecture that would allow for optimized acentric supramolecular organization. By coupling a liquid crystal tolane to a well-understood NLO chromophore via strategic synthesis, a set of novel chromophores was created. The ferroelectric liquid crystal-like molecules intrinsically favor unidirectional chromophore order while simultaneously containing a high beta chromophore along the polar axis. This system has shown potential for high terminal stability as well as increased nonlinear optical susceptibilities. Carbon tetrachloride poses a large threat to the environment and is the focus of ongoing remediation efforts. It is a well-known carcinogenic pollutant that has contaminated groundwater beneath former grain storage and industrial sites, such as the Department of Energy's Hanford site. Remediation through the use of a small molecule, PDTC, when complexed with copper has been shown to lead to complete dechlorination, resulting in conversion to non-toxic end-products (mostly CO 2) and complete removal of the problematic carbon-chlorine bonds. Synthetic chemistry was employed to develop a modified procedure for large-scale production of PDTC that eliminates harmful byproducts and excess toxic reagents used. Additionally, structural derivatives for increased water solubility have been envisaged from citrazinic acid, which could allow for aqueous destruction of carbon tetrachloride. In medicinal and pharmaceutical chemistry, routes to nitrogenous heterocycles are of great importance due to their prevalence in bioactive molecules. Diethylzinc mediated metalloamination/cyclization of unsaturated N,N-dimethylhydrazines with subsequent electrophilic functionalization could prove to be a powerful tool for constructing pyrrolidines and piperidines. This method was extended to the use of 1,2-disubstituted alkenes as N-Zn migratory insertion acceptors, including various vinylcyclopropyl hydrazines. The potential behind the irreversible cyclopropane scission and development of a new alkene make this class of substrates extremely desirable. The metalloamination-alkylation of N,N-dimethylhydrazinoalkenes was shown to be effectively catalyzed by CuBr x SMe 2, CuCN and CuI. This novel method obviates the prior methodology involving use of stoichiometric CuCN(LiCl) 2 as a promoter for the electrophilic functionalization.Item Electronic structure determination of model complexes of [Mo-3Fe-4S] clusters and method development of in situ reductive amination using amine-boranes(Montana State University - Bozeman, College of Letters & Science, 2014) Towey, Bradley David; Chairperson, Graduate Committee: Thomas S. LivinghouseIn nature, bacteria are able to convert inert nitrogen gas to ammonia using the iron molybdenum-cofactor of the nitrogenase enzyme. Even though the crystal structure and the magnetic coupling of the iron molybdenum-cofactor cluster have been elucidated, the bonding site(s) and the mechanism of the reduction are not understood. The reactivity towards nitrogenase substrates of the iron molybdenum-cofactor from synthetic [Mo-3Fe-4S] biomimetic models has previously been examined, but these models are limited to reducing N,N single and double bonds, protons, acetylene, and acetonitrile. The reactivity of these clusters is dictated by their electronic structure, which is tuned by the chelating ligands. To study the ligand donations, a simpler cluster with a homoleptic ligand environment, the MoFe 3S 4(S 2CNEt 2) 5 complex, was synthesized and analyzed with S K-edge X-ray absorption spectroscopy. The S K-edge is convoluted due to the different sulfur environments and only plausible assignments could be inferred based on Slater's rules for effective oxidation states. Iron sulfide bonds have been characterized using S K-edge X-ray absorption spectroscopy, however, little is known regarding molybdenum sulfide bonding. The tetrahedral MoS 4 2- compound was utilized to understand the Mo-S bonding with X-ray absorption spectroscopy in conjunction with computational methods. The terminal sulfides of MoS 4 2- donate approximately five electrons to the formally +6 charge on the Mo center. Since the charge delocalization of transition metal dithiocarbamate complexes have not been studied extensively, the experimental electronic structure of Zn(II), Cu(II), Fe(II), Fe(III), and Mo(IV) dithiocarbamate complexes were examined. The dithiocarbamate ligands exhibit classical bonding in which the ionic character increases with increasing positive charge on the metal. Piecing these models together, the MoFe 3S 4(S 2CNET 2) 5 cluster contains a covalent [Mo-3Fe-4S] core with ionic dithiocarbamate ligands surrounding and stabilizing the cluster. The last part of this thesis is the development of a new method for reductive amination of dimethylhydrazones to dimethylhydrazines using amine-boranes. Conventionally, the C=N bond is reduced with toxic or less selective reducing agents. A potent, and easy to handle tert-butylamine borane was used and prepared in situ towards the synthesis of dimethylhydrazines containing different functionalities in high yields.Item Synthesis of nitrogenous heterocycles via group 3 metal-catalyzed hydroamination and zinc (II) mediated metalloamination(Montana State University - Bozeman, College of Letters & Science, 2015) Smith, Adrian Robert; Chairperson, Graduate Committee: Thomas S. LivinghousePyrrolidines and piperidines respresent a motif found in a wide array of bioactive compounds. Hydroamination, or the insertion of a carbon-nitrogen bond into a site of unsaturation, represents an atom economical method for accessing substituted pyrrolidines and piperidines. Synthesis of nitrogenous heterocycles through group 3 metal hydroamination and zinc(II) metalloamination has been achieved. The hydroamination of aminoalkenes has been thoroughly screened and has shown good tolerance for ethereal solvents, and solvent choice can result in improved rate and diastereoselectivity. The hydroamination of secondary amines with electron rich heteroatoms has also been realized utilizing a new group 3 metal trisamide developed in these labs. Additionally, zinc(II) metalloamination has been performed on N,N-dimethylhydrazinoalkenes and successfully resulted in the synchronous formation of a nitrogen-carbon bond to form a ring as well as carbon-zinc bond formation at the adjacent carbon. This carbon-zinc bond has been intercepted by different carbon electrophiles to synchronously form a nitrogen-carbon bond and carbon-carbon bond in situ. Ligand studies for these transformations suggest 1,1,1-trifluoroacetylenamines as well as acetoacetamides are promising motifs for future ligand scaffolds due to their ease of synthesis, low cost, and good reactivity with a range of N,N-dimethylhydrazinoalkene substrates.Item Diethyl zinc mediated metalloamination : development and its application to the synthesis of functionalized pyrrolidines and piperidines(Montana State University - Bozeman, College of Letters & Science, 2015) Sunsdahl, Bryce Gregory; Chairperson, Graduate Committee: Thomas S. LivinghouseThe ability to synthesize nitrogen heterocycles of industrial and academic significance remains a central goal of organic synthesis. Substantial effort has been made to develop new methodologies that allow the construction of these targets in an atom economical and efficient manner. Herein, we describe the development of a metalloamination transformation mediated by diethyl zinc. The resulting organozinc intermediates undergo facile electrophilic addition, resulting in a one-pot reaction sequence to access functionalized pyrrolidines and piperidines. Optimization of the reaction conditions for the initial metalloamination/cyclization, as well as the addition of electrophiles was examined. The scope of the metalloamination, including functional group tolerance was evaluated by synthesizing a number of mono- and disubstituted hydrazinoalkenes. This new methodology provides the synthetic community with a variety of new tools for accessing academic and industrial molecules of interest.Item Part 1: study toward the total synthesis of acutumine ; : Part 2: asymmetric intramolecular hydroamination catalyzed by group 3 metal complexes(Montana State University - Bozeman, College of Letters & Science, 2014) Huynh, Khoi Quang; Chairperson, Graduate Committee: Thomas S. Livinghouse; Tao Jiang and Tom Livinghouse were co-authors of the article, 'Substrate structural effect in Y(III)-catalyzed hydroamination/cyclization of 1,2-disubstituted and 1,1,2-trisubstituted aminoalkenes terminated by 2-(2-heteroarenyl) groups' in the journal 'Synlett' which is contained within this thesis.; Tom Livinghouse and Helena Lovick were co-authors of the article, 'N,N'-dibenzosuberyl-1,1'binaphthyl-2,2'-diamine. A highly effective supporting ligand for the enantio-selective cyclization of aminoalkenes catalyzed by chelating diamide complexes of La(III) and Y(III)' in the journal 'Synlett' which is contained within this thesis.Acutumine 1 is a tetracylic alkaloid isolated from Menispermum daurcum, which exhibits selective T-Cell cytotoxicity. It is potentially useful for specific therapy T-Cell related Leukemia and lymphoma. Acutumine is a highly functionalized tetracyclic natural product, containing a [4.3.3]-propellane core and a 5,5-spirocycle. The synthesis of the 5,5-spirocycle is prepared via enantioselective Pd II/IV catalyzed chloro-induced semi pinacol rearrangment. However, studies showed Pd catalyst functioned as Lewis acid to oxidant, PhI(OAc) 2 rather than forming a Pi-complex with the substrate as proposed. Fortunately, the preparation of the spirocycle can be accomplished from an asymmetric Pd II /Brønsted acid cocatalyzed semi pinacol rearrangement via direct allylic C-H activation. [4.3.3] propellane core was concisely synthesized in eight step sequences featuring a phosphoric Brønsted acid catalyzed aldol condensation and radical N-cyclization as the key transformations. Hydroamination, the addition of an amine N-H bond across an unsaturated carbon-carbon linkage, allows a highly atom economical access to industrial and pharmaceutical important alkaloids. The hydroamination of alkene by early transition metal has seen significant process. Herein, we reported the substrate structural effect in Yttrium(III)-catalyzed intramolecular hydroaminations. Aminoalkenes possessing a terminal 2- (5-trimethylsilyl)thienyl group exhibited substantially enhanced reactivity. Cyclization efficiency for a representative aminoalkene possessing a Z-configured 2-(phenyl)ethenyl group is considerably higher than that observed for the corresponding E-isomer. Enantioselective hydroamination/cyclization of representative aminoalkenes catalyzed by chelating diamide complexes of La(III) and Y(III) are described. The La(III) complex derived from the sterically demanding (R)-N,N'-dibenzosuberyl-1,1'-binaphthyl-2,2'-diamine proligand provides enantioselectivities that are in many cases significantly higher than those obtained with the corresponding Y(III) analog.