Green Synthesis of Substituted Anilines and Quinazolines from Isatoic Anhydride-8-amide

Abstract

Synthetic methods used to generate substituted anilines and quinazolines, both privileged pharmacological structures, are cumbersome, hazardous or, in some cases, unavailable. We developed a straightforward method for making isatoic anhydride-8-amide from isatin-7-carboxylic acid as a tool to easily produce a range of quinazoline and substituted aniline derivatives using adaptable pH-sensitive cyclization chemistry. The approaches are inexpensive, simple, fast, efficient at room temperature and scalable, enabling the synthesis of both established and new quinazolines and also highly substituted anilines including cyano derivatives.

Study of Local Reactivity of Isatoic Anhydride Applying Quantum Molecular Similarity

“…On the other hand, the global softness, S, is determined within the approximation of finite differences as: [38] S ¼ 1 ðI À AÞ (6) where I is the first ionization potential and A is the electronic affinity. In this case:…”

“…[2] Thus, some protocols with palladium catalysed process are available for the synthesis of this important intermediary. [3] Recently, ISA has gained importance as synthetic precursor of known pharmacological agents; its reactivity, characterized by decar-bonylative and ring opening reactions, has been successfully applied in the synthesis of quinazolin-4(3H)-ones, [4] quinazoline benzamides, [5] anilines, [6] and quinolones, [7] in a wide collection of new and outstanding synthetic methodologies. Hence the relevance of characterizing the reactivity of ISA, which offers the possibility to contribute to the design of improved and versatile synthetic methodologies and, to the best of our knowledge, it has not been yet described.…”

Acid-Catalyzed Synthesis of Isatoic Anhydride-8-Secondary Amides Enables IASA Transformations for Medicinal Chemistry

“…Here, we describe the flexible chemistry for generation of novel isatoic anhydride-8- sec amides (Scheme ), which can be used to achieve diverse products, such as quinazoline-N3 alkyl-8-acid or amides, 2-substituted quinazoline-8-amides, and 2,4-disubstituted quinazoline-8-amides. This work builds upon our prior studies showing that 8-substituted quinazoline could be synthesized by utilizing isatoic anhydride-8-amide (IASA) . However, this work is different because we present the direct preparation of novel isatoic anhydride-8-secondary amides in the presence of secondary alcohol.…”

Cyclic Anhydrides as Powerful Tools for Bioconjugation and Smart Delivery

“…This last functional group has a limited reactivity, so to broaden the scope of the ligation, other derivatives with a halide, such as N -(3-iodopropyl)­isatoic anhydride (IPIA), have been developed and successfully used for ligation with lysine side chains of BSA with a controlled degree of labeling, and further for binding RNA for selective 2′-hydroxyl acylation analyzed by primer extension. A green synthesis of this type of anhydrides is also available …”