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Synlett 2007(8): 1203-1206  
DOI: 10.1055/s-2007-977416
LETTER
© Georg Thieme Verlag Stuttgart · New York

Efficient Synthesis of 7-Substituted or 3,7-Disubstituted 1H-Indazoles

Betty Cottyna, Dominique Vichard*a, François Terriera, Pierre Niocheb, C. S. Ramanc
a Institut Lavoisier de Versailles, CNRS UMR 8180, Université de Versailles, 45, Avenue des Etats-Unis, 78035 Versailles Cedex, France
b Université René Descartes, 12, rue de l’Ecole de Médecine, 75270 Paris Cedex 06, France
c Department of Biochemistry & Molecular Biology, University of Texas, Medical School, 6431 Fannin Houston, TX 77030, USA
Fax: +33(1)39254452; e-Mail: vichard@chimie.uvsq.fr;
Further Information

Publication History

Received 10 January 2007
Publication Date:
03 April 2007 (online)

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Abstract

This work reports on the synthesis of the novel indazole scaffolds 7-OTf-1H-indazole (trifluoromethanesulfonic acid 1H-­indazol-7-yl ester), 7-iodo-1H-indazole and 3-bromo-7-iodo-1H-indazole. These new compounds are potent building blocks in ­divergent syntheses of indazoles via palladium cross-coupling ­reactions.

Key words

7-nitro-1H-indazole - indazole - cross-coupling - heterocycles - dihalogenated hetarenes

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9

For 3: mp 94 °C. MS (CI-CH4): m/z = 267 [M + H+]. HRMS: m/z [M + NH4 +] calcd for C8H5N2F3O3S: 326.0422; found: 326.0424. 1H NMR (200 MHz, acetone-d 6): δ = 8.27 (s, 1 H), 7.93 (2 × d, J = 9.2 Hz, 2 H), 7.50 (s, 1 H), 7.27 (t, J = 9.2 Hz, 1 H). 19F NMR (188 MHz, acetone-d 6): δ = -68.92 (s). 13C NMR (75 MHz, acetone-d 6): δ = 128.4, 122.9, 122.5, 121.8, 119.4, 119.0, 115.8, 116.5.

14

To a solution of 2-methyl-6-nitroaniline (5.00 g, 32.9 mmol) in glacial AcOH (235 mL) was added all at once a solution of sodium nitrite (2.27 g, 32.9 mmol) in H2O (5.5 mL). During this addition the temperature was not allowed to rise above 25 °C. After the nitrite solution had been added, stirring was maintained for 20 min. Any yellow precipitate formed during this time was filtered and discarded. Then, the solution was evaporated in vacuo. Cold H2O was added to the residue and the contents of the flask were washed into a beaker where they were stirred. The product was filtered, rinsed with cold H2O and dried to afford 7-nitro-1H-indazole (5.29 g, 98% yield); mp 180 °C.

21

For 10: mp 160.7 °C. MS (EI): m/z = 143 [M+]. HRMS: m/z [M + H]+ calcd for C8H6N3: 144.0562; found: 144.0565. 1H NMR (200 MHz, acetone-d 6): δ = 13.14 (br s, 1 H), 8.28 (s, 1 H), 8.18, 7.87 (2 × d, J = 13.3 Hz, 2 H), 7.32 (t, J = 13.3 Hz, 1 H). 13C NMR (75 MHz, acetone-d 6): δ = 136.2, 132.8, 135.5, 127.5, 125.2, 121.5, 116.9, 94.9.

23

For 12: mp 77.5 °C. MS (EI): m/z =142 [M+·]. HRMS (TOF-MS, ES+): m/z [M + H+] calcd for C9H7N2: 143.0609; found: 143.0620. 1H NMR (200 MHz, CDCl3): δ = 10.70 (br s, 1 H), 8.15 (s, 1 H), 7.78, 7.56 (2 × d, J = 8.1 Hz, 2 H), 7.15 (t, J = 8.1 Hz, 1 H), 3.46 (s, 1 H). 13C NMR (75 MHz, CDCl3): δ = 134.0, 130.8, 122.8, 122.2, 122.1, 121.1, 104.5, 82.5, 79.2. For 5: mp 160.9 °C. MS (EI): m/z = 323 [M+·], 243 [M+· - Br·]+, 116 [M+· - Br· - I·]+. Anal. Calcd for C7H4N2IBr: C, 26.01; H, 1.24; N, 8.67. Found: C, 26.23; H, 1.28; N, 8.61. 1H NMR (200 MHz, CDCl3): δ = 10.10 (br s, 1 H), 7.81, 7.63 (2 × d, J = 8.0 Hz, 2 H), 7.03 (t, J = 8.0 Hz, 1 H). 13C NMR (75 MHz, CDCl3): δ = 143.1, 136.67, 131.12, 124.26, 123.46, 120.43, 112.20.