Palladium-Catalyzed Synthesis of 2-Aminobenzoxazinones by Aerobic Oxidative Coupling of Anthranilic Acids and Isocyanides

Abstract

Isocyanides have emerged as valuable C1 building blocks in palladium catalysis. Their potential has, however, mainly been exploited for the synthesis of amidines and amidine-containing heterocycles. To illustrate the broader applicability of isocyanides, we have recently developed a novel oxidative coupling of diamines and isocyanides furnishing valuable guanidine-containing heterocycles. We here report the extension of this protocol to the coupling of anthranilic acids and isocyanides leading to medicinally relevant 2-aminobenzoxazinones. This is a particularly challenging substrate class for this reaction due to the possibility of undesired decarboxylative pathways and the susceptibility of the products to nucleophilic attack. Therefore, this work underlines the generality and broad potential of the oxidative coupling of bisnucleophiles and isocyanides, facilitating the further implementation of this chemistry in library design.

One-Pot Palladium-Catalyzed Ligand- and Metal-Oxidant-Free Aerobic Oxidative Isocyanide Insertion Leading to 2-Amino-substituted-4(3H)-quinazolinones

“…So far most of the previous approaches for isocyanide insertion reactions have demonstrated that the scope of reaction with respect to isocyanide is limited to tertbutylisocyanide. [16][17][18][19][20] In contrast, we obtained better results with secondary cyclohexyl isocyanide, whereas tert-butyl isocyanide and others gave very poor or no yields of the desired products (Table 2).…”

“…Moreover, isocyanides also have several advantages over CO, such as ease in handling, being less hazardous, and ability to bring about high diversity and further transformations with the use of functionalized isocyanides. Nowadays, the importance of isocyanide insertion reactions using palladium is realized by the number of reports that are being published for the synthesis of various heterocyclic molecules, including (a) multicomponent synthesis of oxazoline and benzoxazole, [16] (b) synthesis of pyridopyrimidines by isocyanide insertion, [17 ] (c) synthesis of 4-aminophthalazine-1(2H)-ones by isocyanide insertion, [18] (d) synthesis of 2-aminobenzoxazinones by aerobic oxidative coupling, [19] and (e) synthesis of isoquinolin-1 (2H)-ones. [20] In continuation of our work in developing newer and efficient methodologies for the synthesis of novel and bio-potent heterocyclic molecules, [21] herein we desired to synthesize 2-amino-substituted-4(3H)-quinazolinones via isocyanide insertion between less reactive secondary amide and an aromatic amine utilizing palladium as catalyst and molecular oxygen as an oxidant in one-pot fashion.…”

Microwave-assisted palladium-catalysed isonitrile insertion in 2-bromophenylureas for efficient synthesis of 4-substituted imino 4H-benzo[d][1,3]oxazin-2-amines

“…4 They also reported that in the presence of TsOH in methanol/THF as medium, methanolysis of the imidate takes place leading to the isolation of anthranilate in excellent yields. 5 The 2-substituted amino-benzoxazin-4-ones are considered important as they are endowed with diverse pharmacological activities including antiviral, antiobesity, cardiovascular, and anti-inammatory. 5 The 2-substituted amino-benzoxazin-4-ones are considered important as they are endowed with diverse pharmacological activities including antiviral, antiobesity, cardiovascular, and anti-inammatory.…”

Catalytic Isonitrile Insertions and Condensations Initiated by RNC–X Complexation

“…(67)]. [101] Primary, secondary, and tertiary isonitriles participate in the reaction although the yield with butyl isonitrile was distinctly reduced. The condensation tolerates electronically diverse substituents in the anthranilic acid without adversely affecting the reaction efficiency.…”