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

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

References and Notes

• 1a For reviews, see: Elguero J. Pyrazoles and their Benzo Derivatives, In Comprehensive Heterocyclic Chemistry   Vol. 5:  Katritzky AR. Rees CW. Pergamon Press; Oxford: 1984.  p.167-303  
• 1b Behr LC. Fusco R. Jacobe CH. In Pyrazoles, Pyrazolines, Pyrazolidines, Indazoles and Condensed Rings   Wiley RH. Wiley Int.; New York: 1969. 
• 1c Minkin VI. Glukhovtsev MN. Simkin BY. Aromaticity and Antiaromaticity, Electronic and Structural Aspects   Wiley; New York: 1994. 
• As recent examples, see:
• 2a Hartinger CG. Zorbas-Seifired S. Jakupec MA. Kynast B. Zorbas H. Keppler BK. J. Inorg. Biochem.  2006,  100:  891 
• 2b Carella A. Vives G. Cox T. Jaud J. Rapenne G. Launay J. Eur. J. Inorg. Chem.  2006,  980 
• As examples, see:
• 3a Tanitame A. Oyamada Y. Ofuji K. Kyoya Y. Suzuki K. Ito H. Kawasaki M. Nagai K. Wachi M. Yamagishi JI. Bioorg. Med. Chem.  2004,  14:  2857 
• 3b Iwakubo M. Takami A. Okada Y. Kawata T. Tagami Y. Ohashi H. Sato M. Sugiyama T. Fukushima K. Iijima H. Bioorg. Med. Chem.  2007, in press
• 3c De Angelis M. Stossi F. Carlson KA. Katzenellenbogen BS. Katzenellenbogen JA. J. Med. Chem.  2005,  48:  1132 
• 4 Lukin K. Hsu MC. Fernando D. Leanna MR. J. Org. Chem.  2006,  71:  8166 
• 5a Collot V. Bovy RB. Rault S. Tetrahedron Lett.  2001,  41:  9053 
• 5b Collot V. Dallemagne P. Bovy RB. Rault S. Tetrahedron  1999,  55:  6917 
• 6a El Kazzouli S. Bouissane L. Khouili M. Guillaumet G. Tetrahedron Lett.  2005,  46:  6163 
• 6b Bouissane L. El Kazzouli S. Léger JM. Jarry C. Rakib EM. Khouili M. Guillaumet G. Tetrahedron  2005,  61:  8218 
• 6c Bouissane L. El Kazzouli S. Léonce S. Pfeiffer B. Rakib EM. Khouili M. Guillaumet G. Bioorg. Med. Chem.  2006,  14:  1078 
• 7 Raman CS. Li H. Martasek P. Southan G. Masters BS. Poulos TL. Biochemistry  2001,  40:  13448 
• 8 Schumann P. Collot V. Hommet Y. Gsell W. Dauphin F. Sopkova J. MacKenzie ET. Duval D. Boulouard M. Rault S. Bioorg. Med. Chem. Lett.  2001,  11:  1153 
• 10 Ritter K. Synthesis  1993,  735 
• 11a Comins DL. Dehghani A. Tetrahedron Lett.  1992,  33:  6299 
• 11b Comins DL. Dehghani A. Foti CJ. Joseph SP. Org. Synth.  1998,  Coll. Vol. IX:  165 
• 12a Porter HD. Peterson WD. Org. Synth.  1955,  Coll. Vol. III:  660 
• 12b Doyle MP. Bryker WJ. J. Org. Chem.  1979,  44:  1572 
• 12c Boulton BE. Coller BAW. Aust. J. Chem.  1974,  27:  2343 
• 12d Suzuki N. Kaneko Y. Nomoto T. Isawa Y. Chem. Commun.  1984,  1523 
• 12e Doyle MP. Siegfried B. Elliot RC. Dellaria JF. J. Org. Chem.  1977,  42:  2431 
• 13 For 4: mp 114.2 °C. MS (EI): m/z = 117 [M - I]⁺·, 127 [I⁺·], 244 [M⁺·]. Anal. Calcd for C₇H₅N₂I: C, 34.43; H, 2.05; N, 11.47. Found: C, 34.46; H, 1.93; N, 11.38. ¹H NMR (200 MHz, CDCl₃): δ = 8.25 (s, 1 H), 7.77, 7.73 (2 × dd, ³ J = 7.5 Hz, ⁴ J = 0.9 Hz, 2 H), 7.55 (br s, 1 H), 6.97 (dd, J = 7.5, 7.5 Hz, 1 H). ¹³C NMR (75 MHz, CDCl₃): δ = 142.4, 136.3, 135.6, 123.2, 122.7, 121.0, 115.7
• 15 Noelting E. Ber. Dtsch. Chem. Ges.  1904,  37:  2584 
• 16 Tsuji J. In Palladium Reagents and Catalysts, New Perspectives for the 21^st Century   Wiley RH. Wiley Int.; New York: 2004. 
• 17a Anderson BA. Bell EC. Ginah FO. Harn NK. Pagh LM. Wepsiec JP. J. Org. Chem.  1998,  63:  8224 
• 17b Sundermeier M. Zapf A. Mutyala S. Baumann W. Sans J. Weiss S. Beller M. Chem. Eur. J.  2003,  9:  1828 
• 17c Ma D. Tian H. J. Chem. Soc., Perkin Trans. 1  1997,  3493 
• 18 Kumar K. Zapf A. Michalik D. Tillac A. Heinrich T. Böttcher H. Arlt M. Beller M. Org. Lett.  2004,  6:  7 
• 19a Gilchrist TL. Heterocycl. Chem.  1997,  315 
• 19b Elguero J. Fruchier A. Jacquier R. Bull. Soc. Chim. Fr.  1966,  9:  3401 
• 19c Elguero J. Fruchier A. Jacquier R. Bull. Soc. Chim. Fr.  1966,  2075 
• 20a Kubota H. Rice KC. Tetrahedron Lett.  1998,  39:  2907 
• 20b Frantz DE. Weaver DG. Carey JP. Kress MH. Dolling UH. Org. Lett.  2002,  4:  4717 
• 20c Jin F. Confalone PN. Tetrahedron Lett.  2000,  41:  3271 
• 22 Lazaro R. Bouchet P. Elguero J. ACH Models Chem.  1999,  136:  497 
• For examples, see:
• 24a Chapman GM. Stanforth SP. Tarbit B. Watson MD. J. Chem. Soc., Perkin Trans. 1  2002,  581 
• 24b Tao W. Nesbitt S. Heck RF. J. Org. Chem.  1990,  55:  63 

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.