TY - JOUR

T1 - Hydroperoxide-Induced Nitrile Migration in Azolo[1,5-a]pyrimidine-6-carbonitriles: An Original Approach toward Functionalized Azolopyrimidines

AU - Aminov, Semen V.

AU - Fedotov, Victor V.

AU - Moseev, Timofey D.

AU - Varaksin, Mikhail V.

AU - Novikov, Alexander S.

AU - Slepukhin, Pavel A.

AU - Ulomsky, Eugeny N.

AU - Rusinov, Vladimir L.

PY - 2025/9/19

Y1 - 2025/9/19

N2 - Azolo[1,5-a]pyrimidines (APs) are widely recognized as challenging scaffolds for diverse applications in both medicinal chemistry and materials science. Owing to their high potential, active research is focused on developing new derivatives through the derivatization and functionalization of their molecular structure. Herein, we report an unusual transformation in the AP series initiated by a hydroperoxide anion. The transformation proceeds via a nucleophilic attack by the hydroperoxide anion followed by the elimination of a cyanide anion, which subsequently reattacks the heterocyclic system, resulting in the formation of 7-(4-(dimethylamino)phenyl)-6-hydroxy-[1,2,4]azolo[1,5-a]pyrimidine-5-carbonitriles as unexpected nucleophilic transformation products in yields of 55–72%. Mechanistic studies employing computational, chemical, and optical methods allow the most probable pathway for the reaction process to be identified. Furthermore, the new series of prepared APs in this way demonstrates the opportunity for postsynthetic transformations, including alkylation, acylation, Mitsunobu reaction, Ritter reaction, hydrolysis, and salt formation.

AB - Azolo[1,5-a]pyrimidines (APs) are widely recognized as challenging scaffolds for diverse applications in both medicinal chemistry and materials science. Owing to their high potential, active research is focused on developing new derivatives through the derivatization and functionalization of their molecular structure. Herein, we report an unusual transformation in the AP series initiated by a hydroperoxide anion. The transformation proceeds via a nucleophilic attack by the hydroperoxide anion followed by the elimination of a cyanide anion, which subsequently reattacks the heterocyclic system, resulting in the formation of 7-(4-(dimethylamino)phenyl)-6-hydroxy-[1,2,4]azolo[1,5-a]pyrimidine-5-carbonitriles as unexpected nucleophilic transformation products in yields of 55–72%. Mechanistic studies employing computational, chemical, and optical methods allow the most probable pathway for the reaction process to be identified. Furthermore, the new series of prepared APs in this way demonstrates the opportunity for postsynthetic transformations, including alkylation, acylation, Mitsunobu reaction, Ritter reaction, hydrolysis, and salt formation.

UR - https://www.mendeley.com/catalogue/f20c9162-39d5-3eb7-87fa-889221dbd46a/

U2 - 10.1021/acs.joc.5c00896

DO - 10.1021/acs.joc.5c00896

M3 - Article

VL - 90

SP - 12888

EP - 12903

JO - Journal of Organic Chemistry

JF - Journal of Organic Chemistry

SN - 0022-3263

IS - 37

ER -