Computationally aided direct electrophilic trifluoromethylation and trifluoromethylthiolation via sulfonimidamides.
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Date
2020
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Abstract
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.
Description
Masters Degree. University of KwaZulu-Natal, Durban.
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2020