Site-selective nucleophilic substitution reactions of pentafluoropyridine with hydroxybenzaldehydes: synthesis of triarylmethanes comprising perfluoropyridine moieties

First, the nucleophilic substitution reactions of pentafluoropyridine (PFP) with hydroxybenzaldehydes were evaluated. It was demonstrated that parameters such as reaction conditions, molar ratio of reactants and nucleophilicity of the derived potassium formylphenolates have decisive roles in determining the selectivity of reactions. The nucleophilic attack of hydroxybenzaldehydes under mildly basic conditions took place solely at the C-4 position of PFP and the corresponding 4-((perfluoropyridin-yl)oxy)benzaldehydes 3a-c were obtained in nearly quantitative yields. However, 3-hydroxybenzaldehyde was found to be an effective nucleophile for the selective replacement of fluorine atoms at C-2 and/or C-6 positions of PFP under harsh conditions. While the controlled site-selective reactions of PFP with two-fold amounts of 3-hydroxy-benzaldhyde under reflux conditions afforded 3,3'-((3,5,6-trifluoropyridine-2,4-diyl)bis(oxy))dibenzaldehyde 4a in excellent yield, their reaction in a 1:3 molar ratio led to producing 3,3',3''-((3,5-difluoropyridine-2,4,6-triyl)tris(oxy))tribenzaldehyde 4b in moderate yield. 3,3'-((3,5-Difluoro-4-(4-formylphenoxy)pyridine-2,6-diyl)bis(oxy))dibenzaldehyde, as a mixed-analogue of 4b, was also prepared employing a two-step strategy. Finally, a novel class of mono-, bis-, and tris(triarylmethane) analogues containing perfluoropyridine subunits 9-10 were synthesized via the SiO2-H2SO4 catalysed Friedel-Crafts alkylation reaction of various arenes and heteroarenes with the derived (oxy)benzaldehydes, yet the selective synthesis of unsymmetrical TRAMs 11a and b applying this procedure was unsuccessful.

Automated summary

The nucleophilic substitution reactions of pentafluoropyridine with hydroxybenzaldehydes were examined, and the selectivity of reactions was found to be influenced by reaction conditions, reactant ratio, and nucleophilicity of the derived potassium formylphenolates. Under mild basic conditions, the nucleophilic attack occurred exclusively at the C-4 position of pentafluoropyridine, resulting in the formation of 4-((perfluoropyridin-yl)oxy)benzaldehydes in high yields. However, under harsh conditions, 3-hydroxybenzaldehyde acted as an effective nucleophile for replacing fluorine atoms at C-2 and/or C-6 positions of pentafluoropyridine. The controlled reactions of pentafluoropyridine with different amounts of 3-hydroxybenzaldehyde led to the synthesis of unsymmetrical products with varying yields.