A Novel and Efficient Synthesis of 2-Aryl-2H-indazoles via SnCl₂-Mediated Cyclization of 2-Nitrobenzylamines

Abstract

A mild, efficient, and novel synthesis of 2-aryl-2H-indazoles via cyclization of 2-nitrobenzylamines promoted by SnCl₂·2H₂O has been described. This method applies to a wide scope of substrates containing electron-donating and electron-withdrawing substituents.

2-aryl-2H-indazole - 2-nitrobenzylamine - SnCl₂

References and Notes

1a Bistochi GA. De Meo G. Pedini M. Ricci A. Brouilhet H. Bucherie S. Rabaud M. Jacquignon P. Farmaco Ed. Sci.  1981,  36:  315 

1b Picciola G. Ravenna F. Carenimi G. Gentili P. Riva M. Farmaco Ed. Sci.  1981,  36:  1037 

2 Keppler BK. Hartmann M. Met.-Based Drugs  1994,  1:  145 

3a Sun J.-H. Teleha CA. Yan J.-S. Rodgers JD. Nugiel DA. J. Org. Chem.  1997,  62:  5627 

3b Rodgers JD. Johnson BL. Wang H. Greenberg RA. Erickson-Viitanen S. Klabe RM. Cordova BC. Rayner MM. Lam GN. Chang C.-H. Bio. Med. Chem. Lett.  1996,  6:  2919 

4 Ykeda Y. Takano N. Matsushita H. Shiraki Y. Koide T. Nagashima R. Fujimura Y. Shindo M. Suzuki S. Iwasaki T. Arzneim. Forsch.  1979,  29:  511 

5 Corsi G. Palazzo G. Germani C. Barcellona PS. Silvestrini B. J. Med. Chem.  1976,  19:  778 

6 Cerecetto H. Gerpe A. Gonzalez M. Aran VJ. de Ocarizi CO. Mini-Rev. Med. Chem.  2005,  5:  869 

7 Aran VJ. Ochoa C. Boiani L. Buccino P. Cerecetto H. Gerpe A. Gonzalez M. Montero D. Nogal JJ. Gomez-Barrio A. Azqueta A. de Cerain AL. Piro OE. Castellano EE. Bioorg. Med. Chem.  2005,  13:  3197 

8 Stadlbauer W. Science of Synthesis   Vol. 12:  Neier RR. Thieme; Stuttgart: 2002.  p.227 

9a Paal C. Krecke F. Chem. Ber.  1890,  23:  2640 

9b Paal C. Chem. Ber.  1891,  24:  959 

9c Busch V. Hartman P. J. Prakt. Chem.  1895,  2:  404 

9d Campi EM. Habsuda J. Jackson WR. . Cartrin AM. McCubbin QJ. Aust. J. Chem.  1995,  48:  2023 

10a Auwers KV. Schaich W. Chem. Ber.  1921,  54:  1738 

10b Albini A. Bettinetti G. Minoli G. Heterocycles  1988,  27:  1207 

10c Seela F. Bourgeois W. Helv. Chim. Acta.  1991,  74:  315 

11a Cerrada ML. Elguero J. de la Fuente J. Pardo C. Ramos M. Synth. Commun.  1993,  23:  1947 

11b Rosevear J. Wilshire JFK. Aust. J. Chem.  1991,  44:  1097 

12a Cadogan JIG. Cameron-Wood M. Mackie RK. Searle RJG. J. Chem. Soc.  1965,  4831 

12b Armour MA. Cadogan JIG. Grace DSB. J. Chem. Soc., Perkin Trans. 1  1975,  1185 

12c Cadogan JIG. Mackie RK. Org. Synth.  1968,  48:  113 

12d Varughese DJ. Manhas MS. Bose AK. Tetrahedron Lett.  2006,  47:  6795 

13 Frontana-Oribe BA. Moinet C. Tetrahedron  1998,  54:  3197 

14 Akazome M. Kondo T. Watanabe Y. J. Org. Chem.  1994,  59:  3375 

15 Song JJ. Yee NK. Org. Lett.  2000,  2:  519 

16 Mills AD. Nazer MZ. Haddadin MJ. Kurth MJ. J. Org. Chem.  2006,  71:  2687 

17 Kuo CY. Wu MJ. J. Chin. Chem. Soc.  2005,  52:  965 

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General Procedure for the Synthesis of 2-Aryl-2 H -indazoles
A solution of 2-nitrobenzylamine (3 mmol) and SnCl₂·2H₂O (6 mmol) in 95% EtOH (20 mL) was allowed to stir at 40 °C for 2 h. The reaction mixture was quenched with 3% HCl (100 mL), filtrated, the crude product was purified by crystallization from 95% EtOH to give the pure products 2.

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Representative Spectral Data for 2b
¹H NMR (400 MHz, DMSO-d ₆): δ = 9.12 (s, 1 H, H-3), 8.10 (d, 2 H, J = 8.0 Hz, ArH), 7.78 (d, 2 H, J = 8.4 Hz, ArH), 7.72 (d, 2 H, J = 8.4 Hz, ArH), 7.46 (t, 1 H, J = 7.2 Hz, ArH), 7.32 (t, 1 H, J = 8.0 Hz, ArH), 7.11 (t, 1 H, J = 7.6 Hz, ArH) ppm. ¹³C NMR (100 MHz, DMSO-d ₆): δ = 149.12, 140.12, 129.86, 128.02, 126.96, 122.64, 122.28, 121.74, 121.11, 120.42, 117.65 ppm. IR (KBr): ν = 3131, 3066, 1626, 1593, 1518, 1494, 1464, 1407, 1378, 1349, 1314, 1250, 1231, 1201, 1143, 1129, 1073, 1044, 950, 907, 820, 780, 754, 685 cm^-1. MS: m/z (%) = 194 (100) [M⁺]. Anal. Calcd for C₁₃H₁₀N₂: C, 80.39; H, 5.19; N, 14.42. Found: C, 80.55; H, 5.29; N, 14.26.

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Crystallographic data for the structure of 2i has been deposited at the Cambridge Crystallographic Data Centre under the deposit number CCDC-655981. Copies of available material can be obtained free of charge on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax: [phone]; e-mail: [e-mail]]. Crystal data for 2i: C₁₄H₁₀Cl₂N₂; M = 277.14, colorless block crystals, 0.43 × 0.40 × 0.32 mm, monoclinic, space group P2₁/c, a = 14.234(3) Å, b = 14.438(3) Å, c = 6.0511(15) Å, α = 90°, β = 92.338(7)°, γ = 90°, V = 1242.5(5) ų, Z = 4, D _c = 1.481 g cm^-1, F(000) = 568, µ (Mo Kα) = 0.503 mm^-1. Intensity data were collected on a diffractometer with graphite monochromated Mo Kα radiation (λ = 0.71073 Å) using ω scan mode with 1.43° < θ < 25.00°; 2183 unique reflections were measured and 1532 reflections with I > 2σ(I) were used in the refinement. The structures were solved by direct methods and expanded using Fourier techniques. The final cycle of full-matrix least squares technique to R = 0.0460 and wR = 0.1283.