Convenient Novel Method to Access N-Benzylated Isatoic Anhydride: Reaction Behavior of Isatoic Anhydride with 4-Chlorobenzyl Chloride in the Presence of Bases

Abstract

Sodium hydride, potassium carbonate, and other bases are commonly used for N-alkylation of heterocyclic compounds. This report reveals the problems associated with N-benzylation of isatoic anhydride and identifies the plausible byproduct structures formed during the reaction. Subsequently, a novel breakthrough methodology has been developed using diisopropylamine and tetra butyl ammonium bromide. It gives excellent yields >88% in a short reaction time (2 h) at 30 °C with no byproducts, saving on processes as the pure product is directly obtained.

Utilization of Aryl(TMP)iodonium Salts for Copper-Catalyzed N-Arylation of Isatoic Anhydrides: An Avenue to Fenamic Acid Derivatives and N,N′-Diarylindazol-3-ones

“…Because of the acidic N–H group on isatoic anhydride, both alkylation and arylation of the N–H group are quite possible. The alkylation of isatoic anhydrides has been well explored and easily accessible under basic conditions, although the anhydride group is prone to decarboxylation in many circumstances. Contrary to this, the arylation of isatoic anhydrides is relatively less explored; only a few reports are found for the N -arylation of the isatoic anhydrides, and the limitations, especially on the arylation scope, are noticed in those studies.…”

Sequential analysis for identification of byproduct from N-benzylation reaction: wound healing and anti-inflammatory potential of the byproduct 4-chlorobenzyl 2-((4-chlorobenzyl)amino)benzoate

“…The ring of isatoic anhydride is opened in the presence of a strong base (sodium hydride) under high-temperature conditions. The desired compound was found at only 48% at 30 °C, 13 hence, we investigated the structure of the byproduct to minimize the problem of N -benzylation in the isatoic anhydride reaction.…”

N-Carboxyanhydrides directly from amino acids and carbon dioxide and their tandem reactions to therapeutic alkaloids

“…15–18 For example, about 30–40% of six-membered ring NCA isatoic anhydrides made globally are used for the production of pharmaceuticals and chemical intermediates. 19…”

“…[15][16][17][18] For example, about 30-40% of sixmembered ring NCA isatoic anhydrides made globally are used for the production of pharmaceuticals and chemical intermediates. 19 Although several methods have been reported for the preparation of NCAs from amino acids, they suffer from high toxicity or reactive side products that are difficult to remove (Scheme 1B). NCAs are most commonly synthesized using the Fuchs-Farthing reaction between amino acids and the extremely poisonous gas phosgene, or the treatment of N-alkyloxycarbonylamino acids with coupling reagents.…”