Functionalization of sulfur-nitrogen compounds and the synthesis of an allicin analogue

  • Funktionalisierung von Schwefel-Stickstoff Verbindungen und die Synthese eines Allicin Analogons

Krauskopf, Felix Dieter Philipp; Bolm, Carsten (Thesis advisor); Albrecht, Markus (Thesis advisor)

Aachen : RWTH Aachen University (2021)
Dissertation / PhD Thesis

Dissertation, RWTH Aachen University, 2021


The scope of this thesis includes four projects aimed at the synthesis and functionalization of aza-sulfur moieties: the synthesis of N-1,2,4-oxadiazolyl and N-1,2,4-triazolyl sulfoximines, the synthesis and reactivity investigation of N-(N'-hydroxy)imine sulfoximines, a mechanochemical Biginelli reaction of terminal sulfonimidamides to yield 2,3-dihydro-1,2,6-thiadiazine 1-oxides, and the imination of diallyl disulfide to produce a sulfilimine in analogy to the natural product allicin.In the first project, a (3+2) dipolar cycloaddition approach was utilized to synthesize five-membered heterocycles using N-cyano sulfoximines as a dipolarophilic building block. Iminoyl and hydrazonoyl chlorides were employed as 1,3-dipole precursors. For the synthesis of N-1,2,4-oxadiazolyl sulfoximines, iminoyl chlorides were employed under refluxing conditions in apolar solvents. The release of the nitrile oxide was found to be ideal without the addition of base. Various Lewis acids were tested as catalysts, but no beneficial effect could be observed. N-1,2,4-Triazolyl sulfoximines were synthesized using nitrile imines, which were generated under reflux with the addition of NaHCO3 as a mild base and Yb(OTf)3 as a Lewis acid catalyst. Subsequently, N-(N'-hydroxy)imine sulfoximines were synthesized in a nucleophilic addition of NH-sulfoximines to in situ generated nitrile oxides. The obtained products were then investigated for their ability to form complexes to transition metals, in an effort to mimic the binding behavior of hydroxamic acids and oximes. However, no metal complexes could be obtained. Further investigations focused on exploiting the N–O bond as a radical precursor to generate iminoyl radicals from substituted N-(N'-hydroxy)imine sulfoximines. While intramolecular cyclizations to yield heterocyclic sulfoximines were possible, intermolecular radical additions were observed in traces, but could not be confirmed. It is likely that under the metal catalyzed conditions used, fragmentation and decomposition of the generated species was proceeding to quickly to make a productive reaction pathway possible. Aside from a hydrolysis side product, only a 1,3,5-triazine was consistently observable. No other reaction products could be isolated or identified. Finally, a Chan-Lam coupling of these compounds was attempted with the aim of producing nitrones. A reaction product was obtained for trans-vinyl phenyl, phenyl, and naphthyl boronic acid. The reaction was optimized, and the products analyzed by 2D-NMR spectroscopy. Based on the interpretation of 1H-15N HMBC spectra, the reaction product is likely not the originally desired nitrone, but instead an O-substituted oxime.A mechanochemical approach to the Biginelli reaction employing sulfonimidamides was pursued using automated ball mills. The substrate scope was broad, though the reaction conditions had to be adapted slightly for aliphatic aldehydes. One compound was subsequently functionalized using standard reaction conditions, highlighting the versatility of the 1,2,6-thiadiazine 1-oxide core. Crucially, the reaction did not proceed in solution under typical Biginelli reaction conditions, highlighting the importance of a mechanochemical approach. In addition, the compounds exhibited epimerization at the benzylic position in CDCl3. Follow-up investigations indicated that a model compound is stable under various mechanochemical conditions and in other solvents in acidic and basic conditions. The reason for the unique reactivity observed for CDCl3 could not be ascertained.During the course of a cooperation project with the group of ALAN SLUSARENKO (RWTH Aachen University) a sulfilimine analogue of allicin was synthesized by imination of diallyl disulfide with cyanamide. The obtained sulfilimine was tested and shown to have a similar biological activity profile to allicin, while being more resistant to thermal decomposition in aqueous solution. Diallyl disulfide remained the only disulfide amenable to imination. Other nitrene based, halogen mediated, or electrophilic iminations were ineffective and did not produce the desired product.