Periodic Reporting for period 1 - CATSO (New Catalytic Reactions using Sulfur Dioxide)
Okres sprawozdawczy: 2020-02-24 do 2022-02-23
Sulfur (IV & VI) functional groups containing molecules were neglected in medicinal chemistry and agrochemical industries until the last two decades. These molecules gained interest largely in developing inhibitors, anti-viral, anti-bacterial, anti-fungal, anti-inflammatory, anti-cancer, and anti-tumour compounds. There are more than 150 drugs available in the market approved by FDA. The fast growth of these molecules in the drug industry is because of their bioisosteric properties with carboxylic acids and amide compounds with better nucleophilicity, solubility, and stability. For example, amide bioisosteres sulfonamide containing compounds have better stability in the gut. Acyl sulfonamides are using as the bioisosteres of carboxylic acids with better permeability. The synthesis of these molecules is achieved starting from the thiols and sulphides. However, these methods involve a lengthy process and more number of steps to synthesize the desired sulfur pharmacophores. To address these problems, pioneers in the synthetic chemistry have been developing sulfur reagents and reactions. In the Willis group, DABSO regent was prepared from the sulfur dioxide and DABCO, used in the palladium and copper catalysis reactions for the synthesis of sulfonamide and sulfone synthesis. Sharpless SuFEx chemistry and Shi DAST-type reagents which are using sulfur, fluorine exchange chemistry to synthesize the sulfur (VI) compounds. Hydroxylamine-derived reagent as dual oxidant and amino group donor was used for the direct synthesis of primary sulfinamides from the corresponding thiols. Other than these methods, many other methodologies have been developed by Bull, Maruoka, and Zhang groups for the synthesis of the sulfur functional groups. However, the importance of these compounds in the drug industry makes them attractive towards the discovery of new reagents and novel methodologies. In 2017, we rediscovered the importance of the sulfinylamine reagents in our group, synthesized them in very stable forms TrNSO, t-OctNSO, t-BuONSO, and BiPhONSO (known sulfinyl amine reagents are moisture sensitive). By using these compounds, we have synthesized sulfones, sulphonamides, and sulfinimidmides. Most of these sulfinylamine reactions and sulfur dioxide capture reactions with DABSO were employed aliphatic Grignard reagents to attach the first carbon atom to the sulfur group. However, these reactions have very limited scope for the aliphatic groups due to the uncommon availability of the aliphatic Grignard reagents. To overcome the problem of introducing the aliphatic functional groups, in the proposal, we come up with an idea of using the photoredox catalysed decarboxylative generation of alkyl radicals to synthesise the sulfur (IV, VI) compounds. The planned route enables a convenient way to modify the carboxylic compounds to the corresponding bioisosteric sulfur compounds and test them in biological studies. However, the main challenge in the reaction could be finding the compatible photocatalyst under the reactions. We also want to expand the method to check the reactivity of the other sulfinylamine reagents in obtaining the sulfur compounds.
We started our investigation by employing the commercially available amino acid N-Boc-DL-proline with DABSO reagent, olefin acceptor ethyl crotonate, and base cesium carbonate in the presence of (Ir[dF(CF3)ppy]2(dtbpy))PF6 photocatalyst and 455nm blue LED light in dimethylformamide solvent. Unfortunately, the reaction didn’t produce the desired sulfur dioxide captured product, but the protodecarboxylation product N-Boc-pyrrolidine. It could be due to the formed sulfinate anion can be oxidised by the iridium catalyst in a reductive quenching fashion to give the sulfinate radical. The sulfinate radical will undergo desulfonylation followed by protonation to give the N-Boc-pyrrolidine. We expected that using a better olefin acceptor which can react with the sulfinate radical could avoid the formation of the unwanted side products, tried them under the reaction conditions. Unfortunately, both activated and inactivated olefins were failed to give the desired sulfone product. Then we turned out to optimize the photocatalysts acridinium salt and 4CzIPN, which were again unsuccessful under the reaction conditions. After the continuous failure of capturing the sulfur dioxide, we shifted our focus to the sulfinylamine reagents to make the sulfinamide derivatives. Hydrocinnamaldehyde was taken as a model substrate for the reaction with the N-tritylsulfinylamine reagent. All the above photochemical oxidant catalysts were failed to give the sulfinamide product. The reason could be the same as previously mentioned oxidizable sulfinamides products under the given reaction conditions. Davidson group observed that acridine compounds could be used as photosensitizers for the decarboxylation of the carboxylic acids to generate the alkyl radicals. The proton-coupled decarboxylation in the carboxylic acid-acridine complex allows the decarboxylation process. So, we wanted to use acridine (used by Larionov and co-workers for the decarboxylation) catalysts in our system to avoid the decomposition of the formed products. We performed the reaction with the hydrocinnamic acid and N-tritylsulfinylamine in the presence of acridine photocatalyst in DCM solvent and purple LED. To our delight, we got the desired sulfinylamide product in good yield. We optimized the solvents, different acridine catalysts and reaction concentrations to get excellent yields with hydrocinnamic acid. After optimizing the reaction conditions, we explored substrate scope including the 1˚, 2 ˚, and 3 ˚ carboxylic acids, various functional groups containing carboxylic acids olefin, alkyne, ester, ketone, alcohol, amine and different heterocyclic compounds including pyridine, furan, indole. The reaction worked poor to excellent yields with substrates above mentioned. We also methodology applied to modify the biologically active molecules chenodeoxycholic acid, mycophenolic acid and glutamic acid. After completing the sulfinamide scope, we did the primary sulfonamide synthesis by using t-BuONSO instead of the TrNSO. Usually, primary sulfonamides are challenging to prepare by using known synthetic methods. The sulfonamide formation can be done in two steps. The first step is sulfinamide formation from the acid,t-BuONSO and photocatalyst, and the second step is base treatment on the crude product of the first step. We also used the reaction with t-BuONSO to the synthesis of the sulfonimidamides by treating the first step reaction mixture with an amine under microwave conditions.
The methodology developed involves the synthesis of the sulfinamide from readily available carboxylic acids and sulfinylamines, in presence of acridine catalyst and purple light. It is a potential reaction procedure for the modification of the carbolic acids into the corresponding sulfur (IV and VI) derivatives. This method offers a very quick and efficient process to convert carboxylic acid to the sulfur functional group. The reaction procedure can be easily adopted by a chemist with minimum laboratory facilities. Hopefully, the current method will provide a platform for the modification of the drug molecules and relative changes in their biological properties.
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