A B₂(OH)₄-Mediated Synthesis of 2-Substituted Indazolone and Its Application in a DNA-Encoded Library

Abstract

Indazolone cores are among the most common structural components in medicinal chemistry and can be found in many biologically active molecules. In this report, a mild and efficient approach to 2-substituted indazolones via B 2 (OH) 4 -mediated reductive N−N bond formation is developed. This strategy features mild conditions, no request for a metal catalyst, and a wide scope for both aliphatic and aromatic amines. Meanwhile, this method was further successfully applied on DNA to construct indazolone cores for a DNA-encoded library. This will enable the production of a very attractive indazolone-cored library from simple amines and scaffolds, which will provide considerable diversity.

Electrochemical synthesis of N,N′-disubstituted indazolin-3-ones via an intramolecular anodic dehydrogenative N–N coupling reaction

“…Conventionally, indazolin-3-ones can be synthesized by N-C bond formation, starting from hydrazino aryl compounds, [11][12][13][14][15][16][17] via N-N bond formation, starting from o-azidobenzamides, 18 or by oxidative or reductive intramolecular N-N bond formation in o-aminobenzamides [19][20][21][22] or o-nitrobenzamides, [23][24][25] respectively. However, these methods involve harsh reaction conditions, such as high temperatures, strong bases or acids and the use of highly toxic and carcinogenic hydrazine or azide precursors containing leaving groups.…”

“…[11][12][13][14][15][16][17][18] Further, dangerous oxidizing and reducing agents in stoichiometric amounts or transition metal catalysts are necessary. [19][20][21][22][23][24][25][26] This leads to a high amount of reagent waste, a poor atom economy and safety hazards.…”

Development of on-DNA vinyl sulfone synthesis for DNA-encoded chemical libraries

“…DNA conjugate aa7 , previously obtained via our method, underwent the Buchwald–Hartwig amination to afford the C–N bond linkage 27 product with 70% conversion. Besides, we carried out functional group transformation by reducing the nitro group 28 on the DNA conjugate aa6 to the corresponding amine that could be further capped with various carboxylic acids. Similarly, generating a drug-like tetrazole scaffold from the precursor cyano group was validated 29 herein by using DNA conjugate aa12 .…”

Synthesis of a DNA‐Encoded Library of Pyrrolo[2,3‐d]pyrimidines

“…Consequently, DEL enables the synthesis and affinity‐based screening of a vast number of molecules ( e.g ., millions to billions), thereby quickly providing high‐affinity ligands for biological targets 15,17,21 . Due to the simplicity and speed of DEL technology in comparison with traditional high‐throughput screens, a great deal of efforts has been devoted to development of DEL of various molecules, including drug‐like privileged scaffolds 22–25 . In this regards, vast DELs of pyrrolopyrimidine derivatives would serve as an excellent source of biologically active molecules.…”