Mechanistic investigations into the sulfonamide metathesis and copper(I)-catalyzed nitrile oxide-alkyne cyclization reactions, the synthesis of chemogenetic and proteomic tools and ligands for novel imaging agents, and theoretical calculations on carbenes
Rein U. Kirss
Philip M. Warner, Edmund Harrington
Date of Award
Northeastern University, 2009
Master of Science
Department or Academic Unit
College of Arts and Sciences. Department of Chemistry and Chemical Biology.
Chemistry, Pharmaceutical, Chemical biology
The sulfonamide metathesis reaction became of interest to my research group after use of electron-poor benzylic sulfonamides in a palladium-catalyzed coupling with aryl halides. The scope and mechanism of the reaction were of critical interest in developing this coupling reaction into a useful synthetic handle for complex molecule synthesis. The scope of the reaction was explored both for the possible metathesis substrates--it was found that benzylic group next to the sulfur is essential for reasonable reactivity, and the use of heterocyclic sulfonamides rather than those of primary or secondary amines are stable to acids and neutral nucleophiles, but were extremely sensitive to basic conditions. This result scales with the pKa of the nitrogenous leaving group. The mechanism of the reaction was elucidated using chemical kinetics experiments--the possible mechanisms include the nucleophilic displacement of the protonated leaving group or the elimination of the leaving group across the benzylic position to create a sulfene. The rate law for the reaction was found, the reaction is first order in both reactants. A secondary kinetic isotope effect was measured for the reaction of the sulfonamide deuterated at the benzylic position. Chemogenetic and proteomic techniques are of great utility for the greater study of proteins through the small molecules that interact with them, providing valuable insights both into their function in the cell and in the phenotype induced by their potentiation or inhibition. The synthetic efforts performed at Novartis were focused on creating effective affinity probes for identification of the protein target, and in synthesis of chimeric compounds that would probe the SAR between the many different SMIMs. These syntheses were not brought to their logical conclusion due to difficulties inherent within the synthetic route. A SMIM bioconjugate for use in biological assays was also synthesized. It was noted that when performing a [3+2] copper(I)-catalyzed nitrile oxide-alkyne cyclization, upon the incidental addition of palladium, a new intermediate ""ynoxime"" was formed as an initial product, which was shown by NMR to slowly convert to the isoxazole formed under Cu(I) catalysis. This observation reveals a heretofore-unanticipated mechanistic pathway within catalyzed [3+2] isoxazole forming reactions, though its scope is unknown. To date, investigations into this mechanistic pathway fall into three categories: identification and isolation of ynoxime under catalytic conditions, synthesis of ynoxime protected from further cyclization, and synthesis of unprotected ynoxime under non-catalytic conditions. For the first category, various electronically diverse oximoyl chlorides, alkynes, and catalyst and solvent conditions were examined. The generation of ynoxime appears highly dependent on oximoyl chloride electronics, solvent and catalyst. The use of electron-poor oximoyl chlorides appears essential, as does the use protic solvent and both palladium and copper. This would indicate a Sonogashira-like mechanism. Though some possible cases of ynoxime generation were noted for electronically different alkynes by LCMS, these intermediates have been the small parts of a ratio of ynoxime to isoxazole, and have yet to be confirmed by NMR. For the second category, attempts have been made to form an O-benzylated oxime, from which an ynoxime product is possible. This has been attempted from both O-benzyloxime and from the N-benzoxyamide. In the case of the benzyloxime, the formation of the oxime is facile, but chlorination of that oxime is fairly difficult, this difficulty in chlorination is also true for the amide. Mydriad conditions have been attempted with no success, possibly due to difficulties in assaying the formation of the chlorinated products. For the third category, attempts have been made to make the ynone, and hydroxylaminating it. The ynone is easily synthesized from either palladium- or copper-catalyzed addition of the alkyne to the benzoyl chloride. However, further hydroxylamination is extremely difficult--under forcing conditions, the Michael adduct is observed. The use of rhenium in the design of imaging agents is known. Synthetic efforts have been made toward novel ligands for the chelation of rhenium and subsequent tethering to estrogen-type molecules for the specific imaging of breast cancer. The first attempt at creation of a ligand centered around 6-ethynyl-2-pyridinethiosemicarbazide. The alkynyl functionality was to be tethered to an estrogen functionalized by an azide utilizing the copper(I) catalyzed azide-alkyne cyclization, or [3+2] ""click"" reaction. Final product formed in small quantity due to difficulties in optimization of Sonogashira coupling using TMS-acetylene. Because of the difficulty in performing that route, synthetic efforts have recently been redirected to the use of 5-(2,2'-bipyridyl)methyl azide and of 5-ethynyl-2,2'-bipyridine. 5-ethynyl-2,2'-bipyridine is known, but 5-(2,2'-bipyridyl)methyl azide is as-yet unknown. In addition, the tethering of of 5-ethynyl-2,2'-bipyridine to various nitrile oxides through the application of the copper(I) catalyzed nitrile oxide-alkyne cyclization was attempted. In extension of my research on the mechanistic details of the copper(I)-catalyzed [3+2] nitrile oxide-alkyne cyclization studies were planned stoichiometric copper acetylide. In recent years the utility of carbenes as ligands in organometallic compounds of interest in catalysis has been recognized. The nature of the bonding in these ligands is more significantly electron donating than typical two electron donating ligands like phosphines and amines, sigma donors used to induce or enhance catalytic activity. It is known that carbenes are stabilized by pi donation, i.e. F, OH, NRH. Density functional theory analysis performed using the B3LYP hybrid functional and 6-31G* basis set. The calculated energies of the species investigated were compared using the isodesmic reaction of the carbene species and its corresponding saturated species with difluorocarbene and difluoromethane. In recent years the utility of carbenes as ligands in organometallic compounds of interest in catalysis has been recognized. The nature of the bonding in these ligands is more significantly electron donating than typical two electron donating ligands like phosphines and amines, sigma donors used to induce or enhance catalytic activity. It is known that carbenes are stabilized by pi donation, i.e. F, OH, NRH. Density functional theory analysis performed using the B3LYP hybrid functional and 6-31G* basis set. The calculated energies of the species investigated were compared using the isodesmic reaction of the carbene species and its corresponding saturated species with difluorocarbene and difluoromethane.
Gregory F. Morehouse
Morehouse, Gregory F., "Mechanistic investigations into the sulfonamide metathesis and copper(I)-catalyzed nitrile oxide-alkyne cyclization reactions, the synthesis of chemogenetic and proteomic tools and ligands for novel imaging agents, and theoretical calculations on carbenes" (2009). Chemistry Master's Theses. Paper 2. http://hdl.handle.net/2047/d10018839
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