Pd-catalyzed, oxidant-promoted, chelation-assisted, regioselective direct ortho-nitration of 1-aryl-1H-indazoles via C–H bond activation: direct access to novel indazole-based antiproliferative agents
- 1Laboratory of Bioactive Heterocycles and Catalysis (BHC lab), Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research-Raebareli (Transit Campus) Bijnor-Sisendi Road, Near CRPF Base Camp, Sarojini Nagar Lucknow-226002 India [email protected] [email protected].
- 2Laboratory of Molecular Neurotherapeutics, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research-Raebareli (Transit Campus) Bijnor-Sisendi Road, Near CRPF Base Camp, Sarojini Nagar Lucknow-226002 India.
Abstract
Herein, we developed a highly efficient palladium-catalyzed, oxidant-promoted, chelation-assisted, regioselective strategy to introduce the nitro group directly at the ortho-position of the pendant aryl ring of the 1-aryl-1H-indazoles. The newly developed methodology is bench-stable and exclusively furnishes the C2' (ortho)-substituted 1-(2-nitroaryl)-1H-indazoles 2a-z/2aa-ad in up to 87% yield. The nitrated product serves as a versatile precursor and is reduced to a key amine functionality, which paves the path for several transformed pharmacologically and medicinally relevant derivatives, such as sulfonamide, N-benzylated compound, amide, thiourea, etc. To shed light on the underlying mechanistic pathway, several control experiments were conducted. The free-radical scavengers (TEMPO and BHT) successfully trapped the in situ formed free radical in the reaction mixture, and the TEMPO-nitro adduct was detected by HRMS analysis, thereby confirming the involvement of the free-radical pathway in our developed protocol. The key features of this methodology involve an operationally simple regioselective protocol, a wide substrate scope, excellent functional group tolerance, high yields, scalable gram-scale synthesis, and direct access to N-containing congeners via post-functional modifications. Furthermore, the antiproliferative activity of selected derivatives has been evaluated against the human glioblastoma U-87 MG cancer cell line. Among the tested derivatives, compound 2k exhibited the most potent antiproliferative activity against the cancer cells, with an IC₅₀ value of 51.99 ± 14.96 µM compared to the standard drug dihydroartemisinin (DHA) 80.44 ± 7.5 µM.
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BibTeX
@article{sen2026pdcatalyzed,
title = {{Pd-catalyzed, oxidant-promoted, chelation-assisted, regioselective direct ortho-nitration of 1-aryl-1H-indazoles via C–H bond activation: direct access to novel indazole-based antiproliferative agents}},
author = {Janmejaya Sen and Shivani and Pushpendra Kumar and Ashok Kumar Datusalia and Sandeep Chaudhary},
journal = {RSC advances},
year = {2026},
month = nov,
doi = {10.1039/d6ra08657h},
url = {https://europepmc.org/article/PMC/PMC13726133},
note = {CC BY-NC},
}
RIS
TY - JOUR
TI - Pd-catalyzed, oxidant-promoted, chelation-assisted, regioselective direct ortho-nitration of 1-aryl-1H-indazoles via C–H bond activation: direct access to novel indazole-based antiproliferative agents
AU - Janmejaya Sen
AU - Shivani
AU - Pushpendra Kumar
AU - Ashok Kumar Datusalia
AU - Sandeep Chaudhary
PY - 2026
DA - 2026/11/02
JO - RSC advances
DO - 10.1039/d6ra08657h
UR - https://europepmc.org/article/PMC/PMC13726133
AB - Herein, we developed a highly efficient palladium-catalyzed, oxidant-promoted, chelation-assisted, regioselective strategy to introduce the nitro group directly at the ortho-position of the pendant aryl ring of the 1-aryl-1H-indazoles. The newly developed methodology is bench-stable and exclusively furnishes the C2' (ortho)-substituted 1-(2-nitroaryl)-1H-indazoles 2a-z/2aa-ad in up to 87% yield. The nitrated product serves as a versatile precursor and is reduced to a key amine functionality, which paves the path for several transformed pharmacologically and medicinally relevant derivatives, such as sulfonamide, N-benzylated compound, amide, thiourea, etc. To shed light on the underlying mechanistic pathway, several control experiments were conducted. The free-radical scavengers (TEMPO and BHT) successfully trapped the in situ formed free radical in the reaction mixture, and the TEMPO-nitro adduct was detected by HRMS analysis, thereby confirming the involvement of the free-radical pathway in our developed protocol. The key features of this methodology involve an operationally simple regioselective protocol, a wide substrate scope, excellent functional group tolerance, high yields, scalable gram-scale synthesis, and direct access to N-containing congeners via post-functional modifications. Furthermore, the antiproliferative activity of selected derivatives has been evaluated against the human glioblastoma U-87 MG cancer cell line. Among the tested derivatives, compound 2k exhibited the most potent antiproliferative activity against the cancer cells, with an IC₅₀ value of 51.99 ± 14.96 µM compared to the standard drug dihydroartemisinin (DHA) 80.44 ± 7.5 µM.
SN - 2046-2069
ER -