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Preparation and Activity of Multidentate beta-Amino Sulfoxide Ligands and Expedited Catalytic Preparation of Bupropion

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Title: Preparation and Activity of Multidentate beta-Amino Sulfoxide Ligands and Expedited Catalytic Preparation of Bupropion
Author: Remigio, Erwin
Department: Department of Chemistry
Program: Chemistry
Advisor: Schwan, Adrian
Abstract: Preparation and activity of multidentate β-amino sulfoxide ligands: Amino sulfoxide (and related derivative) functionalities have seen an increased utility in the field of asymmetric synthesis. Many chiral ligands have incorporated these moieties to successfully catalyze carbon-carbon bond forming reaction. In this work, an N-Boc heteroaryl (2-pyridyl and 8-quinolyl) multidentate amino sulfoxide motif has been constructed through diastereoselective sulfenate anion-based chemistry and traditional sulfide oxidation to access the complementary diastereomer. The 2-pyridyl sulfenate anion provided low diastereoselectivity (d.r. = 1.3:1), while the 8-quinolyl sulfenate anion provided one lone diastereomer. Unfortunately, the diastereopure sulfoxides generated via sulfide oxidation were not accessed due to difficulties in recrystallization. These ligands were further diversified by condensation with an additional heteroaryl aldehyde (2-picolinaldehyde and salicylaldehyde) to form their imine derivatives, which provided an additional coordination site. In total, five ligands were prepared and probed for reactivity in the asymmetric Henry (nitroaldol) reaction. Two ligands were probed as a diastereomeric mixture, while the remaining three were probed as diastereopure ligands. In some cases high yields were obtained (as high as 99%), however as a whole, these ligands failed to impart any meaningful enantioselectivity (as high as ee = 32%). The reactivity of the sulfenate anion was also further investigated. Here, lithiated sulfenate anions were complexed with chiral PyBox ligands in an attempt to generate enantiopure sulfoxides. Unfortunately, the resultant sulfoxides were accessed in low yields with poor accompanying enenatioselectivities (49 – 56%; ee = 0 – 1.4%). Moreover, attempts to generate a [SO]-2 species were unsuccessful and led only to the expected products arising form reaction with the heteroaryl sulfenate anions. Expedited catalytic preparation of Bupropion: α-Amino carbonyl compounds represent a diverse group of synthetically valuable compounds ranging from synthetically valuable compounds, ranging from synthetic building blocks to biologically significant natural products. Moreover, the presence of this motif in pharmaceutical compounds, such as Bupropion, make this a desirable synthetic target. A common pathway to access this family of compounds involve an enol-type nucleophile and an electrophilic nitrogen species (e.g. azodicarboxylates and nitroso compounds). This pathway has been extensively investigated, however it presents an inherent drawback, which requires additional post-functionalization in order to access the desired α-amino target. Recently, the literature has provided examples of direct C(sp3)-N bond forming reaction via catalytic oxidative means. Specifically, the catalytic Cu(II)-mediated and I2 radical oxidative coupling methodologies, reported by MacMillan et al. and Guo et al., respectively, have shown promise towards the facile acquisition of α-amino aryl ketones. Here, these methodologies were probed for their utility towards Bupropion synthesis, via the coupling of tbutyl amine and 3’-chloropropiopheone. The Cu(II)-mediated pathway did not seem to be compatible with primary amines, and was not able to be generate Bupropion. In contrast, the I2-mediated pathway was able to yield the desired target. In this system, NH4I in catalytic amounts and sodium percarbonate in ethyl acetate, led to generation of Bupropion. An extensive optimization led us to conclude that a reloading the reaction system with additional sodium percarbonate and amine led to a complete reaction. This reaction was probed with various iodine and acidic components (e.g. I2¬/AcOH, and I2/Phenol) in place of NH4I to successfully yield Bupropion. As such, an alternative ionic mechanism was proposed in order to account for unfavourable bond dissociation enthalpies required for the originally proposed radical coupling. Unfortunately, isolation of Bupropion via flash-column chromatography proved to be problematic. Therefore efforts were put forth towards reaction optimization to force the complete consumption of the starting ketone substrate, and its direct subsequent isolation as an HCl salt. Acquisition of HCl salt proved to be successful, however it was accompanied by the unavoidable formation of the corresponding tbutyl ammonium salt.
URI: http://hdl.handle.net/10214/10190
Date: 2017-01-06


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