Synthesis and process optimization of symmetric and unsymmetric barbiturates C5-coupled with 2,1-benzisoxazoles

• Published in: Molecular diversity Vol. 24; no. 1; pp. 155 - 166
• Main Authors: Serrano, João L., Soeiro, Pedro F., Reis, Melani A., Boto, Renato E. F., Silvestre, Samuel, Almeida, Paulo
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.02.2020; Springer Nature B.V
• Subjects: Additives; Biochemistry; Biomedical and Life Sciences; Drugs; Life Sciences; Optimization; Organic Chemistry; Original Article; Pharmacy; Polymer Sciences; Urea; 2,1-Benzisoxazoles; Anthranils; Process optimization; Barbituric acid derivatives; Nitroaromatic reduction
• ISSN: 1381-1991; 1573-501X
• DOI: 10.1007/s11030-019-09937-4

Benzisoxazoles represent an important pharmacophore in medicinal chemistry. Recently, an unexpected formation of symmetric 3-substituted 2,1-benzisoxazoles through reduction of 5-(2-nitrobenzylidene)barbiturates has been described. This reductive intramolecular heterocyclization probably involves a nitroso intermediary. To improve the previous reaction conditions, the nature of the reducing agent and additives, reaction time and solvents were evaluated. By applying the optimized conditions, several symmetric and unsymmetric barbiturates C5-coupled with 2,1-benzisoxazoles were prepared with an yield of 52–87%. From this set, seven compounds were novel and the unsymmetric nature of the (thio)barbituric acid moiety was explored. For that, the total synthesis, starting from the respective urea or thiourea, was successfully performed, and 11 thiobarbiturates, benzylidene barbiturate and thiobarbiturate precursors are described. Graphical abstract