Solvent-free highly regioselective Michael addition of phenytoin to α,β-unsaturated esters in the presence of TBAB under ultrasound irradiation

Abstract

The highly regioselective C-N bond formation between phenytoin and acrylic/fumaric esters was accomplished. Solvent-free media Michael addition of phenytoin to acrylic esters led to the selective synthesis of N3-substituted phenytoins (as mono-Michael adducts) in the presence of tetrabutylammonium bromide (TBAB) and potassium carbonate under ultrasonic irradiation conditions at room temperature. These reactions produced N1,N3-disubstituted phenytoins (as bis-Michael adducts) at 70 ºC. Surprisingly, the addition of phenytoin to fumaric esters, instead of acrylic esters, selectively provided only N3-substituted phenytoins at both room temperature and 70 ºC under the same conditions.

Mechanochemical Preparation of 3,5-Disubstituted Hydantoins from Dipeptides and Unsymmetrical Ureas of Amino Acid Derivatives

“…The reaction of amino acid derivatives with isocyanates led to the formation of such hydantoins, after cyclization of the corresponding ureido derivatives in strong acidic conditions ,,, (Figure a). N -alkylation with halogeno acetates and their derivatives, ,,, and Michael addition reactions, allowed the introduction of the carboxyalkyl group at the N -3 position of hydantoins, with a particular interest in phenytoin derivatives ,− ,, (Figure b). Miscellaneous procedures reported the reaction between acetylenic diesters and isocyanides, or phosphates, in the presence of an hydantoin molecule (Figure b).…”

Recent Advances in the Synthesis of Hydantoins: The State of the Art of a Valuable Scaffold

“…128−131 Besides, 3-substituted phenytoin derivatives were also obtained by nucleophilic addition on formaldehyde 132 and by a solvent-free procedure relying on the aza-Michael addition of phenytoin on α,β-unsaturated esters under ultrasonication. 133 In the latter case the presence of the ionic salt tetrabutylammonium bromide (TBAB) had an effect on the efficiency of the reaction as it acted as a solvent for both organic compounds and inorganic base.…”