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.
Highlights
Synthetic methods used to generate substituted anilines and quinazolines, both privileged pharmacological structures, are cumbersome, hazardous or, in some cases, unavailable
Broadly applicable, environmentally conscious method to prepare quinazoline and anilines analogues via isatoic anhydride-8-amide (IAA) after observing that IAA can be prepared directly using the Schmidt reaction from 2,3-dioxoindoline-7-carboxylic acid 1a, known as isatin-7-carboxylic acid, which can be obtained from anthranilic acid[13]
We found that IAA is an important intermediate for synthesizing a number of substituted anilines and quinazolines (Fig. 1b)
Summary
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 produce a range of quinazoline and substituted aniline derivatives using adaptable pH-sensitive cyclization chemistry. The 1,3-diazanaphthalene, or quinazoline, structural motif is a privileged pharmacological scaffold[1] found in a wide range of bioactive compounds designed for treating health conditions including cancer, inflammation, hypertension, obesity, and infection[2,3,4,5,6]. Current synthetic methods involve using costly or hazardous reagents under harsh conditions to functionalize quinazolines and substituted anilines at late stages in synthetic schemes, and require labor-intensive purification of chemical intermediates[10,11]. Options for functionalizing these structures are limited and challenging[12]
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