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Teo, Yong Chua
This study focused on finding the optimal conditions for the copper-catalysed cross coupling between pyrazole and N,N-dibenzyl-4-iodobenzenesulfonamide in a ligand-free system. This was found to be achieved with copper(I) oxide as catalyst, caesium carbonate as base at an experimental temperature of 130 oC for 24 hours. These experimental conditions were then applied to a series of different nitrogen nucleophile substrates to achieve moderate to good yields. Subsequently, the synthesis of Celecoxib by implementing this experimental protocol was explored.
The transition metal-catalysed formation of carbon and nitrogen bonds has long served as an important and powerful tool in organic syntheses. Since many pharmaceutical agents and drugs are modelled after naturally-occuring biomolecules which contain many of such carbon-nitrogen bonds, it has become imperative to develop robust, novel and environmentally-safe approaches to the synthesis of such bonds. Traditional methods that have been developed, while successful in achieving its desired goal, suffer from various problems; the use of expensive palladium metal catalyst which is air and moisture sensitive; experimental protocols which require strong heating or anhydrous solvents and the need for complicated separation techniques to obtain the final desired products. Recently, more breakthroughs in this arena have been achieved, through the use of complicated ligands in the reaction system. While employing ligands have eradicated the need for harsh and inert reaction conditions, it still begets the problem of complicated separation techniques and eventual ligand removal which is not environmentally-friendly.
This study looks at the success of coupling reactions in a ligand-free system. The optimised conditions for the carbon-nitrogen coupling of various nitrogen heterocycles with N,N-dibenzyl-4-iodobenzenesulfonamide were found to require a catalytic amount of copper (I) oxide, 130 oC and 0.5 mL dimethylformamide (DMF) as solvent. These conditions were capable of enabling the N-arylation between N,N-dibenzyl-4-iodobenzenesulfonamide with heterocycles and sulfonamides with generally substantive yields (upwards of 50% or better). The resultant samples were purified via column chromatography and analysed using 1H NMR. Factors that played chief contributions to the successes (or failures) of these reactions – such as electronic or steric effects – are discussed. The impact of this study plays homage to N,N-dibenzyl-4-(3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide which is a critical intermediate in the synthesis of Celecoxib. Celecoxib is a commercially-available drug commonly used for the treatment of pain, fever and inflammation in various diseases and medical conditions such as acute pain, osteoarthritis, rheumatoid arthritis and primary dysmenorrhea. Therefore, with such benefits, there has been an impetus to develop and design novel Celecoxib derivatives with a greater efficacy and a lower degree of side effects.
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