Browsing by Author "Chetty, Lloyd Christopher."

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Computationally aided direct electrophilic trifluoromethylation and trifluoromethylthiolation via sulfonimidamides.
(2020) Chetty, Lloyd Christopher.; Naicker, Tricia.; Kruger, Hendrik Gerhardus.
Fluorination chemistry is of interest due to fluorine being recognized as a crucial element in pharmaceuticals, and agrochemicals, with 30% of new small molecule drugs incorporating fluorine. The trifluoromethylation and trifluoromethylthiolation of the active pharmaceutical ingredients formed the basis for the modern trend of fluorination of pharmaceutical compounds. The incorporation of a trifluoromethyl group (CF3) into an organic molecule has a significant effect on its lipophilicity, permeability, and metabolic stability. Radical mediated trifluoromethylation facilitated by photoredox catalysis offers mild and highly selective reaction conditions. While there are several commercially available trifluoromethylation reagents, some limitations include the use of gaseous, volatile, and expensive reagents. Therefore, the development of cheaper and safer trifluoromethylation reagents is crucial. The utilisation of computational chemistry can facilitate the design of new potential agents. This study focused on the computational design and thereafter, the synthesis of sulfonimidamides as potential radical trifluoromethylation agents via photoredox catalysis. Despite all efforts to synthesise trifluoromethylated sulfonimidamides being unsuccessful, the synthesis and characterisation of precsuors compounds 5a-d were successful and resulted in 6 novel X-ray crystal structures. In addition, a simple yet efficient computational method for calculating redox potentials was developed. The decision was then to synthesise trifluoromethylthiolated sulfonimidamides based on the success of sulfonamides as trifluoromethylthiolating agents. The trifluoromethylthio group (SCF3) has attracted particular interest in medicinal chemistry due to its remarkable lipophilicity. Due to its high lipophilicity and strong electronwithdrawing ability, the SCF3 greatly improves the pharmacokinetic properties of lead compounds. Among the various electrophilic reagents available, N-SCF3 reagents are the most utilised. Previously developed reagents require a strong Brønsted or Lewis acid for activation of the reaction. To address this problem, the second part of this study focused on the computational design and thereafter synthesis of more efficient sulfonimidamide based electrophilic trifluoromethylthiolation agents. Sulfonimidamides 5c, f were successfully trifluoromethylthiolated, resulting in the corresponding N-trifluoromethylthio sulfonimidamides 7c, f. Novel X-ray crystal structures for 5e and 5f are also obtained. The computationally calculated SCF3 electrophilic donation potential of sulfonimidamides 7c, e, f revealed that sulfonimidamide 7c possessed the greatest potential for donation (36.51 Kcal mol-1) and has the potential to be more electrophilic than previously applied delivering agents (ranging from 9.8-59.1 Kcal mol-1). Therefore, sulfonimidamide 7c was chosen as the donating agent for the further electrophilic trifluoromethylthiolation of ethyl cyanoacetate and 2,4-dimethylpyrrole. The results from the trifluoromethylthiolation model reactions indicated that sulfonimidamide 7c is a potentially new SCF3 donating agent, due to the trifluoromethylthio group leaving from sulfonimidamide 7c as confirmed by crude 19F NMR and LC-MS analysis. However, further method optimisation is required and is ongoing to determine the substrate scope and reaction conditions. Various characterisation techniques were used to confirm the chemical synthesis of the compounds which include liquid chromatography-mass spectrometry (LC-MS), nuclear magnetic resonance (NMR), high resolution mass spectrometry (HRMS), X-ray powder diffraction (XRD), and infrared spectrometry (IR). A potential future recommendation for the N-trifluoromethylthiolation of the sp2 type nitrogen’s and N-trifluoromethylation of sulfonimidamides is the use of trifluoromethylthiolated and trifluoromethylated amines for the amination of the sulfonimidoyl chlorides.