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.

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

References and Notes

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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.

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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

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.

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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.

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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.

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