High-Yielding Process for the Synthesis of Hydroxychloroquine under Concentrated Conditions: Nucleophilic Amination of Chloropyridines Promoted by Dimethyl Sulfoxide or Catalyzed by 3,5-Bis(trifluoromethyl)phenol

Having aimed at developing alternative pathways for the synthesis of the antimalarial drug hydroxychloroquine, our efforts led to the development of two complementary methods for nucleophilic aromatic substitution (SNAr) reaction of chloropyridines with amines, i.e. aniline, piperidine, cyclohexylamine, and propargylamine. One of which is deemed to be DMSO-promoted through solvent effect, whereas the other method employs 3,5-bis(trifluoromethyl)phenol as the catalyst. In the former case, the quantity of DMSO used was found to be crucial for attaining high yields. A 1.00 equiv amount of DMSO was determined to be the optimum for achieving the highest yield. In the latter case, however, a catalytic amount of 3,5-bis(trifluoromethyl)phenol (50–40 mol %) was found to be effective on SNAr with a high level of activity, thereby delivering the corresponding aminopyridines in yields up to 98%. Experimental results and X-ray crystallography suggest that an addition–elimination mechanism takes place for the latter.