Synthesis of 2-(1H-indazol-4-yl) Acetic Acid

Our synthesis began from commercially available 3-fluoro-5-methylphenol (20) (). The phenol was alkylated with cesium carbonate and methyl iodide in DMF to give 21. We expected the methoxy and fluorine functions to direct ortho lithiation, which occurred at the desired position and led to formylation with DMF to afford 22 as a single regioisomer. We synthesised the aniline using pyrrolidine under SNAr conditions (DSMO, potassium carbonate, 100 °C) to give 23 in good yield. The cyclization cascade of this compound went smoothly on the gram scale to yield methylated nigeglanine 24. Deprotection of the methoxy group was carried out with Kelly’s reported method, using BBr3 in DCM to give 1.6 grams of the natural product nigeglanine as the HBr salt (1), in 5 steps and ~47 % overall yield. Pentane diffusion into a methanol/chloroform solution of 1 provided single crystals suitable for X-ray diffraction. The pale yellow bars crystallized as a non-merohedral twin and refinement confirmed the structure of 1.

Synthesis of 3-methyl-1-H-indazole (a)

Synthesis of Ethyl 2-(1-(tetrahydro-2H-pyran-2-yl)1H-indazol-4-yl)acetate

Synthesis of 3-methyl-1-carbethoxy ethyl indazole (b)

0.25 ml of 1% acetic acid solution was administered intra peritoneally to produce writhing in mice. The severity of pain response (writhing) was assessed by counting the number of wriths (constriction of abdomen, turning of trunk (twist) and extension of hind limbs) in mice. Number of wriths per animal was counted during a 30 minute session beginning 3 minutes after injection of acetic acid. The protective role of synthesized compounds on acetic acid induced writhing was evaluated.

Synthesis of 3-methyl-1-carbethoxy methyl indazole (c)

In summary we report the serendipitous discovery of a new precursor for the one step preparation of indazoles, and crystal structures of oxime 2 and the corresponding indazole 3 that provide clues to the reaction mechanism. The reaction conditions were generalized to afford several examples of the tricyclic pyridazino[1,2-a]indazolium ring system (9-18), and extended to the gram scale synthesis of nigeglanine hydrobromide 1. We note in passing that many of these indazolium ions are fluorescent with colors of blue (9), blue/green (1), and purple (15). As this method quickly affords indazollium analogs of the natural product, their fluorescence may provide an opportunity for cellular imaging studies in the future.


Indazole synthesis - Organic chemistry

In general indazoles, or heterocycles, are synthesized by N–C bond forming reactions but examples of indazoles formed from creating N–N bonds have also been reported. Electrophilic amination of this type has been exploited previously by Hassner and more recently by Stambuli. In both examples an activating agent — DCC in the former and MsCl in the later — was used to promote attack of the oxime nitrogen to form the N–N bond. In our approach, no such activating agent is required.

Synthesis and biological evaluation of indazole derivatives

Aanandhi M. V, Joseph A. A, ChandraKumar R, Koilraj M, Sujatha R, Shanmugasundaram P. Synthesis and biological activities of a novel series of indazole derivatives. Biosci Biotechnol Res Asia 2008;5(1)

Synthesis of indazole motifs and their medicinal ..

ABSTRACT: The newly synthesized indazole derivatives were evaluated for analgesic, anti-inflammatory and antipyretic activities. The synthesized compounds have been characterized on the basis of IR, NMR, mass and elemental analysis. Compound (b) showed significant analgesic, anti-inflammatory and antipyretic activities at the dose level of 500mg/kg when compared to standard.

Regioselective synthesis of novel substituted indazole …

To highlight our method we set out to synthesize a member of the indazole natural product family— nigeglanine. Isolated from nigella glandulifera, nigeglanine is one member of a small family of four indazole natural products, all of which contain the tricyclic pyridazino[1,2-a]indazolium ring system. Located largely in southwest and western China, the whole herb has been used as a folk remedy for a variety of aliments such as cold, cough, insomnia, and bronchial asthma. Nigeglanine and related nigellicine, have been synthesized previously by Kelly and co-workers. Their synthesis of nigeglanine proceeds by transformation of an isatin to give an advanced indazole intermediate, followed by alkylation of the indazole with 1,4,-dibromobutane, and subsequent decarboxylation and deprotection to give nigeglanine as the HBr salt (1) in 12 steps and 13 % overall yield.