Expedient Synthesis of 1-Hydroxy-4- and 1-Hydroxy-6-nitroindoles

Abstract

Reaction of α-chloroalkyl ketones with 1,3-dinitrobenzenes provides 2,4-dinitrobenzyl ketones which when reduced with tin(II) chloride form 6-nitro derivatives of 1-hydroxyindoles. An alternative approach is the condensation of 2,4- and 2,6-dinitrotoluenes with diethyl oxalate or ethyl trifluoroacetate provides dinitrobenzyl ketones which leads after reduction with tin(II) chloride to nitro derivatives of 1-hydroxyindol-2-carboxylates or 1-hydroxy-2-(trifluoromethyl)indoles, respectively.

Key words

indoles - acylation - reduction - nucleophilic aromatic substitution - tin - ketones

• References and Notes

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For reviews on N-hydroxyindoles, see:
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For reviews, see:
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• 13 General Procedure for the Synthesis of Dinitrobenzyl Ketones 4a–f To a stirred solution of 1,3-dinitrobenzene (10 mmol) and α-chloromethyl ketone (2, 10 mmol) in DMF (25 mL) cooled to –20 °C was added DBU (5.32 g, 5.2 mL, 35 mmol). The stirring was continued for 40 min allowing the reaction mixture to reach r.t. Then the reaction mixture was stirred for additional 20 min and poured into diluted HCl (100 mL). The precipitate was filtered, diluted with EtOAc (50 mL), washed with brine, and dried with Na₂SO₄. After evaporation of the solvent the residue was chromatographed on silica gel with EtOAc–hexane (2:1). The following compounds were obtained. 1-(2,4-Dinitrophenyl)-propan-2-one (3a) Pale yellow crystals, mp 65–67 °C (lit. ¹² 66–67 °C). 1-(2,4-Dinitrophenyl)-3,3-dimethylbutan-2-one (3b) Orange crystals, mp 60–62 °C. ¹H NMR (500 MHz, CDCl₃): δ = 1.20 (s, 9 H), 4.24 (s, 2 H), 7.47 (d, J = 8.3 Hz, 1 H), 8.40 (dd, J = 8.3, 2.3 Hz, 1 H), 8.94 (d, J = 2.3 Hz, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 26.59, 42.70, 44.45, 120.54, 127.09, 128.86, 134.69, 137.92, 147.14, 149.25, 209.54. ESI-MS: m/z = 555 [2M + Na⁺], 289 [M + Na⁺]. ESI-HRMS: m/z calcd for C₁₂H₁₄N₂O₅Na: 289.0795; found: 289.0786. 1-(2,4-Dinitrophenyl)-2-phenylethanone (3c) Pale yellow crystals, mp 133–135 °C (lit.¹² 136–137 °C). ¹H NMR (500 MHz, CDCl₃): δ = 4.87 (s, 2 H), 7.51–7.55 (m, 2 H), 7.59 (d, J = 8.5 Hz, 1 H), 7.63–7.68 (m, 2 H), 8.01–8.04 (m, 2 H), 8.46 (dd, J = 8.5, 2.2 Hz, 1 H), 8.98 (d, J = 2.2 Hz, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 44.14, 120.68, 127.32, 128.27, 128.92, 134.01, 134.93, 135.87, 137.56, 147.37, 149.23, 193.86. ESI-MS: m/z = 309 [M + Na⁺]. ESI-HRMS: m/z calcd for C₁₄H₁₀N₂O₅Na: 309.0482; found: 309.0497. 1-(4-Chlorophenyl)-2-(2,4-dinitrophenyl)-ethanone (3d) Yellow crystals, mp 145–147 °C. ¹H NMR (500 MHz, CDCl₃): δ = 4.83 (s, 2 H), 7.50–7.53 (m, 2 H), 7.59 (d, J = 8.4 Hz, 1 H), 7.95–7.99 (m, 2 H), 8.47 (dd, J = 8.4, 2.4 Hz, 1 H), 9.00 (d, J = 2.4 Hz, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 44.09, 120.75, 127.42, 129.28, 129.66, 134.18, 134.94, 137.17, 140.60, 147.47, 149.09, 192.75. ESI-HRMS: m/z calcd for C₁₄H₉N₂O₅ClNa: 343.0092; found: 343.0106. 1-(2,4-Dinitrophenyl)-2-(4-methoxyphenyl)ethanone (3e) Yellow crystals, mp 102–103 °C (lit.^10b 102–105 °C). ¹H NMR (500 MHz, CDCl₃): δ = 3.90 (s, 3 H), 4.82 (s, 2 H), 6.97–7.01 (m, 2 H), 7.58 (d, J = 8.4 Hz, 1 H), 7.98–8.02 (m, 2 H), 8.43 (dd, J = 8.4, 2.3 Hz, 1 H), 8.97 (d, J = 2.3 Hz, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 43.70, 55.58, 114.06, 120.57, 127.19, 128.86, 130.62, 134.88, 137.86, 147.25, 149.30, 164.19, 192.21. MS (EI, 70 eV): m/z (%) = 316 (2) [M⁺], 152 (1), 135 (100), 107 (4), 92 (7), 77 (10). ESI-HRMS: m/z calcd for C₁₅H₁₂N₂O₆Na: 339.0588; found: 339.0590
• 14 1-Hydroxy-nitroindoles from Dinitrobenzyl Ketones – General Procedure To dinitrobenzyl ketone (2 mmol) dissolved in EtOAc (10 mL) and EtOH (1 mL) SnCl₂ (1.44 g, 7.6 mmol) was added in one portion. The reaction mixture was stirred overnight at r.t. The reaction mixture was then evaporated, and the residue was subjected to column chromatography on silica gel. The product was eluted with EtOAc–hexane (4:1). The following compounds were obtained. 1-Hydroxy-2-methyl-6-nitroindole (4a) Orange crystals, mp 153–155 °C. ¹H NMR [500 MHz, (CD₃)₂CO]: δ = 2.51 (d, J = 1.0 Hz, 3 H), 6.32 (q, J = 1.0 Hz, 1 H), 7.58 (d, J = 8.8 Hz, 1 H), 7.89 (dd, J = 8.8, 2.2 Hz‚ 1 H), 8.28 (d, J = 2.2 Hz, 1 H), 10.49 (br s, 1 H). ¹³C NMR [125 MHz, (CD₃)₂CO]: δ = 11.34, 97.21, 105.24, 115.22, 120.36, 129.22, 133.19, 142.35, 142.98. IR (KBr): ν = 3261, 1609, 1583, 1505, 1458, 1392, 1365, 1326, 1276, 1220, 1134, 865, 762 cm^–1. MS (EI, 70 eV): m/z (%) = 192 (100) [M⁺], 191 (10), 176 (22), 162 (7), 146 (32), 145 (15)130 (12), 129 (23), 128 (16), 117 (23), 103 (16), 102 (17). HRMS (EI): m/z calcd for C₉H₈N₂O₃: 192.0535; found: 192.0541. 2-tert-Butyl-1-hydroxy-6-nitroindole (4b) Orange crystals, mp 147–149 °C. ¹H NMR [500 MHz, (CD₃)₂CO]: δ = 1.51 (s, 9 H), 6.32 (d, J = 0.9 Hz, 1 H), 7.61 (dd, J = 8.6, 0.6 Hz, 1 H), 7.89 (dd, J = 8.7, 2.1 Hz, 1 H), 8.26 (br d, J = 2.2 Hz, 1 H), 10.64 (br s, 1 H). ¹³C NMR [125 MHz, (CD₃)₂CO]: δ = 29.23, 33.33, 95.00, 96.62, 105.29, 115.19, 120.78, 128.44, 134.52, 143.20, 153.52. MS (EI, 70 eV): m/z (%) = 234 (71) [M⁺], 219 (100), 203 (12), 202 (13), 201 (17), 173 (13), 172 (12), 156 (13), 155 (15). HRMS (EI): m/z calcd for C₁₂H₁₄N₂O₃: 234.1004, found: 234.0997. 1-Hydroxy-2-phenyl-6-nitroindole (4c) Red-orange crystals, mp 158–160 °C. ¹H NMR [500 MHz, (CD₃)₂CO]: δ = 6.84 (s, 1 H), 7.45–7.50 (m, 1 H), 7.51–7.56 (m, 2 H), 7.74 (d, J = 8.7 Hz, 1 H), 7.95–7.99 (m, 3 H), 8.41 (d, J = 2.1 Hz, 1 H), 10.72 (br s, 1 H). ¹³C NMR [125 MHz, (CD₃)₂CO]: δ = 97.52, 105.31, 115.06, 120.57, 128.11, 128.36, 128.72, 128.94, 129.94, 134.13, 143.03, 143.08. IR (KBr): ν = 3247, 1607, 1501, 1478, 1467, 1316, 1273, 1081, 818, 763 cm^–1. MS (EI, 70 eV): m/z (%) = 254 (100) [M⁺], 238 (25), 225 (11), 224 (10), 208 (24), 207 (17), 191 (23), 190 (38), 180 (17), 179 (50), 165 10), 164 (10), 163 (11), 152 (10). HRMS (EI): m/z calcd for C₁₄H₁₀N₂O₃: 254.0691; found: 254.0695. 2-(4-Chlorophenyl)-1-hydroxy-6-nitroindole (4d) Orange crystals, mp 201–203 °C. ¹H NMR [500 MHz, (CD₃)₂CO]: δ = 6.86 (d, J = 1.0 Hz, 1 H), 7.54–7.58 (m, 2 H), 7.73 (d, J = 8.7 Hz, 1 H), 7.96 (dd, J = 8.7, 2.1 Hz, 1 H), 7.97–8.00 (m, 2 H), 8.38 (br d, 2.1 Hz, 1 H), 10.81 (br s, 1 H). ¹³C NMR [125 MHz, (CD₃)₂CO]: δ = 98.70, 106.24, 116.01, 121.61, 128.81, 129.58, 129.73, 130.72, 135.06, 135.26, 142.48, 144.09. IR (KBr): ν = 3278, 1608, 1536, 1506, 1479, 1336, 1286, 1279, 1084, 813, 773, 761, 726 cm^–1. MS (EI, 70 eV): m/z (%) = 280 (57) [M⁺], 270 (100), 258 (20), 242 (35), 213 (36), 206 (15), 191 (45), 190 (60), 178 (22). HRMS (EI): m/z calcd for C₁₄H₉ ³⁵ClN₂O₃: 288.0302; found: 288.0299. 1-Hydroxy-2-(4-methoxyphenyl)-6-nitroindole (4e) Red-orange crystals, mp 183–185 °C. ¹H NMR [500 MHz, (CD₃)₂CO]: δ = 3.88 (s, 3 H), 6.74 (d, J = 1.0 Hz, 1 H), 7.07–7.11 (m, 2 H), 7.69 (d, J = 8.7 Hz, 1 H), 7.90–7.94 (m, 2 H), 7.96 (dd, J = 8.5, 2.0 Hz, 1 H), 8.37 (br d, J = 2.0 Hz, 1H), 10.70 (s, 1 H). ¹³C NMR [125 MHz, (CD₃)₂CO]: δ = 54.84, 96.44, 105.10, 114.17, 115.04, 120.11, 122.26, 128.31, 129.76, 133.95, 142.62, 143.20, 150.50. MS (EI, 70 eV): m/z (%) = 284 (15) [M⁺], 268 (100), 254 (14), 238 (29), 223 (13), 222 (44), 209 (13), 208 (9), 207 (20), 206 (10), 191 (9), 190 (7). HRMS (EI): m/z calcd for C₁₅H₁₂N₂O₄: 284.0797; found: 284.0805. Ethyl 1-Hydroxy-6-nitroindole-2-carboxylate (4f) Yellow crystals, mp 160–161 °C. ¹H NMR [500 MHz, (CD₃)₂CO]: δ = 1.40 (t, J = 7.0 Hz, 3 H), 4.41 (q, J = 7.0 Hz, 2 H), 7.22 (br s, 1 H), 7.90 (d, J = 8.8 Hz, 1 H), 7.98 (dd, J = 8.8, 1.9 Hz, 1 H), 8.43 (br s, 1 H), 10.92 (br s, 1 H). ¹³C NMR [125 MHz, (CD₃)₂CO]: δ = 13.61, 61.04, 105.08, 106.29, 115.24, 123.20, 125.60, 131.12, 134.52, 145.45, 159.29. IR (KBr): ν = 3077, 1687, 1620, 1589, 1525, 1505, 1466, 1407, 1337, 1286, 1258, 1218, 1055, 1010, 826, 752, 726 cm^–1. MS (EI, 70 eV): m/z (%) = 250 (33) [M⁺], 234 (8), 222 (6), 205 (14), 204 (100), 188 (10), 158 (9). HRMS (EI): m/z calcd for C₁₁H₁₀N₂O₅: 250.0590; found: 250.0596. 1-Hydroxy-6-nitro-2-(trifluoromethyl)indole (4g) Yellow crystals, mp 113–115 °C. ¹H NMR [500 MHz, (CD₃)₂CO]: δ = 7.12 (dq, J = 1.2, 1.0 Hz, 1 H), 7.95 (d, J = 8.8 Hz, 1 H), 8.04 (dd, J = 8.8, 2.1 Hz, 1 H), 8.45 (br d, J = 2.1 Hz, 1 H), 11.39 (s, 1 H). ¹³C NMR [125 MHz, (CD₃)₂CO]: δ = 101.16 (q, J = 3.4 Hz), 106.79, 116.41, 120.96 (q, J = 268.4 Hz), 124.10, 126.48, 130.06 (q, J = 38.9 Hz), 134.87, 146.78. ¹⁹F NMR [470 MHz, (CD₃)₂CO]: δ = –61.83 (d, J = 1.2 Hz). IR (KBr): ν = 3245, 1559, 1511, 1338, 1290, 1244, 1173, 1148, 1132, 1040, 827, 729 cm^–1. MS (EI, 70 eV): m/z (%) = 246 (100) [M⁺], 245 (23), 230 (60), 227 (13), 226 (41), 200 (32), 199 (12), 184 (42), 183 (35), 164 (12), 163 (17), 157 (10), 152 (20), 144 (15). HRMS (EI): m/z calcd for C₉H₅F₃N₂O₃: 246.0252; found: 246.0246. Ethyl 1-Hydroxy-4-nitroindole-2-carboxylate (4h) Yellow crystals, mp 108–110 °C. ¹H NMR [500 MHz, (CD₃)₂CO]: δ = 1.41 (t, J = 7.4 Hz, 3 H), 4.43 (q, J = 7.4 Hz, 2 H), 7.58 (dd, J = 8.2, 7.8 Hz, 1 H), 8.03 (br d, J = 8.2 Hz, 1 H), 8.19 (br d, J = 7.8 Hz, 1 H), 10.89 (br s, 1 H). ¹³C NMR [125 MHz, (CD₃)₂CO]: δ = 13.62, 61.07, 103.83, 114.73, 117.11, 118.71, 124.14, 129.35, 137.49, 141.04, 159.40. IR (KBr): ν = 3259, 1706, 1529, 1334, 1289, 1245, 1147, 1025, 751, 733 cm^–1. MS (EI, 70 eV): m/z (%) = 250 (26) [M⁺], 234 (24), 205 (14), 204 (100), 188 (26), 158 (10), 142 (11), 114 (27), 102 (14). HRMS (EI): m/z calcd for C₁₁H₁₀N₂O₅: 250.0590; found: 250.0587. 1-Hydroxy-4-nitro-2-(trifluoromethyl)indole (4i) Yellow crystals, mp 159–161 °C. ¹H NMR [500 MHz, (CD₃)₂CO]: δ = 7.46 (br s, 1 H), 7.63 (dd, J = 8.0, 8.0 Hz, 1 H), 8.07 (br d, J = 8.0 Hz, 1 H), 8.23 (br d, J = 8.0 Hz, 1 H), 11.37 (br s, 1 H). ¹³C NMR [125 MHz, (CD₃)₂CO]): δ = 99.09 (q, J = 4.0 Hz), 114.70, 116.95, 118.80, 120.21 (q, J = 268.0 Hz), 124.31, 127.70 (q, J = 38.4 Hz), 136.97, 141.12. ¹⁹F NMR [470 MHz, (CD₃)₂SO]: δ = –61.22 s). IR (KBr): ν = 3216, 1556, 1513, 1331, 1289, 1234, 1145, 799, 737 cm^–1. MS (EI, 70 eV): m/z (%) = 246 (100) [M⁺], 245 (31), 230 (63)227 (17), 226 (43), 200 (40), 199 (30), 184 (51), 183 (11), 172 (13), 164 (15), 163 (23), 152 (22), 144 (18), 133 (12), 130 (14), 114 (22), 102 (44). HRMS (EI): m/z calcd for C₉H₅F₃N₂O₃: 246.0252; found: 246.0256
• 15 Noland WE, Baude FJ. Org. Synth. 1963; 43: 40 ; Org. Synth., Coll. Vol. V 1975, 567
• 16a Bouchon A, Diedrichs N, Hermann A, Lustig K, Meier H, Pernerstorfer J, Reissmüller E, Muneto M, Fujishima H, Tajimi M, Yamamoto N. US 7683076, 2010
• 16b Uchida H, Ogawa S, Makabe M, Maeda Y. EP 2128157, 2009
• 17 Reaction of Dinitrotoluenes with Diethyl Oxalate – Synthesis of Ethyl 3-(2,4-Dinitrophenyl)-2-hydroxyacrylate (3f′) – Typical Procedure 2,4-Dinitrotoluene (5, 6.1 g, 33.5 mmol) in DMF (25 mL) was added dropwise to a cooled solution (–22 °C) of diethyl oxalate (23.7 g, 162 mmol) and DBU (12.2 g, 88 mmol) in DMF (100 mL). The reaction mixture was kept at –15 °C for 3 d and then poured into H₂O (150 mL) and acidified with diluted HCl. The product was extracted with EtOAc (3 × 100 mL), washed with H₂O, and dried with Na₂SO₄. After evaporation of the solvent the product was purified chromatographically on silica gel with hexane–EtOAc (4:1, to remove remaining diethyl oxalate – then 2:1); yield 7.25 g (78%); orange solid, mp 78–83 °C. ¹H NMR (500 MHz, CDCl₃): δ = 1.43 (t, J = 7.1 Hz, 3 H), 4.44 (q, J = 7.1 Hz, 2 H), 6.96 (s, 1 H), 7.13 (d, J = 1.3 Hz, 1 H), 8.42 (dd, J = 8.8, 2.3 Hz, 1 H), 8.52 (d, J = 8.8 Hz, 1 H), 9.02 (d, J = 2.3, 1 H). ¹³C NMR (125 MHz, (CDCl₃): δ = 14.09, 63.85, 101.10, 120.09, 126.63, 132.68, 134.56, 144.18, 145.84, 147.95, 164.87. IR (KBr): ν = 3410, 3090, 1712, 1660, 1651, 1600, 1592, 1535, 1413, 1351, 1331, 1261, 1012, 864, 836, 773 cm^–1. ESI-HRMS: m/z calcd for C₁₁H₁₀N₂O₇Na: 305.0380; found: 305.0387. Compound 3h was obtained analogously from 2,6-dinitrotoluene. Ethyl 2,6-Dinitrophenyl-glyoxalate (3h) Yellow semi-solid; yield 85%. ¹H NMR (500 MHz, CDCl₃): δ = 1.42 (t, J = 7.1 Hz, 3 H), 4.41 (q, J = 7.1 Hz, 2 H), 4.72 (s, 2 H), 7.71 (t, J = 8.2 Hz, 1 H), 8.25 (d, J = 8.2 Hz, 2 H).). ¹³C NMR (125 MHz, (CDCl₃): δ = 13.95, 38.97, 63.25, 124.14, 129.10, 129.41, 150.96, 159.60, 187.10
• 18 For a review on (trifluoromethyl)indoles, see: Muzalevskiy VM, Shastin AV, Balenkova ES, Haufe G, Nenajdenko VG. Synthesis 2009; 3905
• 19 Reaction of 2,4-Dinitrotoluene with Ethyl Trifluoroacetate – Synthesis of 1,1,1-Trifluoro-3-(2,4-dinitrophenyl)propan-2-one (3g) – Typical Procedure 2,4-Dinitrotoluene (5, 1.20 g, 6.6 mmol) in DMF (5 mL) was added dropwise to a cooled solution (–22 °C) of ethyl trifluoroacetate (6.55 g, 46 mmol) and DBU (2.54 g, 16.7 mmol) in DMF (15 mL). The reaction mixture was kept at –15 °C for 3 h and then poured into H₂O (100 mL) and acidified with diluted HCl. The product was extracted with EtOAc (3 × 20 mL), washed with H₂O, and dried with Na₂SO₄. After evaporation of the solvent the product was purified chromatographically on silica gel with hexane–EtOAc (2:1); yield 1.74 g (95%); yellow oil. ¹H NMR (600 MHz, CDCl₃): δ = 4.58 (s, 3 H), 7.61 (d, J = 8.2 Hz, 1 H), 8.53 (dd, J = 8.2, 2.3 Hz, 1 H), 9.07 (d, J = 2.3 Hz, 1 H); for hydrate 3g′: δ = 3.59 (s, 2 H), 7.80 (d, J = 8.6 Hz, 1 H), 8.44 (dd, J = 8.6, 2.4 Hz, 1 H), 8.77 (d, J = 2.4 Hz, 1 H). ¹⁹F NMR (470 MHz, CDCl₃): δ (hydrate 3g′) = –78.50, –86.30. ESI-HRMS: m/z calcd for C₉H₄N₂O₅F₃: 277.0067; found: 277.0064. 1,1,1-Trifluoro-3-(2,6-dinitrophenyl)propan-2-one (3i) and its hydrate 3i′ were obtained analogously from 2,6-dinitrotoluene and ethyl trifluoroacetate. 1,1,1-Trifluoro-3-(2,6-dinitrophenyl)propan-2-one (3i) and Hydrate 3i′ Yellow oil. For 3i: ¹H NMR (500 MHz, CDCl₃): δ = 4.61 (s, 2 H), 7.78 (t, J = 8.3 Hz, 1 H), 8.33 (d, J = 8.3 Hz, 2 H). ¹³C NMR (125 MHz, CDCl₃): δ = 36.90, 115.42 (q, J = 292.5 Hz), 122.00, 129.51, 130.12, 150.84, 185.24 (q, J = 37.2 Hz). ¹⁹F NMR (470 MHz, CDCl₃): δ = –78.27. MS (FD): m/z = 278 [M⁺]
• 20a Yamada K, Kawasaki T, Fujita T, Somei M. Heterocycles 2001; 55: 1151
• 20b Somei M, Tsuchiya M. Chem. Pharm. Bull. 1981; 29: 3145
• 21 Korda A, Wróbel Z. Synlett 2003; 1465
• 22 GC analysis of the reaction mixture revealed the presence of a peak that matched the peak of phenylglyoxal standard
• 23 Dehydroxylation of 1-Hydroxyindoles – General Procedure To a solution of 1-hydroxynitroindole (1 mmol) and α-bromoacetophenone (1 mmol) in MeOH (5 mL) Et₃N (0.23 g, 2.3 mmol) was added in one portion at r.t. The reaction mixture was stirred for 3 h (TLC control). Then the reaction mixture was evaporated under vacuum, and the residue was chromatographed on silica gel with EtOAc–hexane (2:1). The following compounds were obtained. 2-Methyl-6-nitroindole (8a) Yellow crystals, mp 116–118 °C (lit. ²⁴ 118–119 °C). ¹H NMR (500 MHz, CDCl₃): δ = 2.52 (s, 3 H), 6.34 (s, 1 H), 7.51 (d, J = 8.6 Hz, 1 H), 7.98 (dd, J = 8.6, 1.8 Hz, 1 H) 8.26 (d, J = 1.8 Hz, 1 H), 8.45 (br s, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 13.99, 101.77, 107.22, 115.47, 119.13, 134.31, 134.45, 142.14, 142.22. MS (EI, 70 eV): m/z (%) = 176 (100) [M⁺], 146 (35), 130 (58), 118 (13), 103 (44). HRMS (EI): m/z calcd for C₉H₈N₂O₂: 176.0586; found: 176.0589. 2-tert-Butyl-6-nitroindole (8b) Yellow crystals; mp 125–127 °C. ¹H NMR [500 MHz, (CD₃)₂SO]: δ = 1.39 (s, 9 H), 6.40 (dd, J = 2.0, 0.8 Hz, 1 H), 7.59 (d, J = 8.7 Hz, 1 H), 7.87 (dd, J = 8.7, 2.0 Hz, 1 H), 8.23 (br d, J = 2.0 Hz, 1 H), 11.71 (s, 1 H). ¹³C NMR [125 MHz, (CD₃)₂SO]: δ = 29.67, 32.16, 97.47, 107.24, 114.13, 119.29, 133.20, 134.53, 141.03, 156.61. MS (EI, 70 eV): m/z (%) = 218 (48) [M⁺], 203 (100), 173 94), 158 (12), 157 (47), 142 (5), 130 (5), 129 (4), 128 (5). HRMS (EI): m/z calcd for C₁₂H₁₄N₂O₂: 218.1055; found: 218.1059. 6-Nitro-2-phenylindole (8c) Orange crystals, mp 213–215 °C (lit. ²⁴ 214–216 °C). ¹H NMR [500 MHz, (CD₃)₂SO]: δ = 7.42–7.47 (m, 1 H), 7.52–7.57 (m, 2 H), 7.72 (d, J = 8.7 Hz, 1 H), 7.92 (dd, J = 8.7, 2.2 Hz, 1 H), 7.93–7.97 (m, 2 H), 8.31 (d, J = 2.2 Hz, 1 H), 12.34 (s, 1 H). ¹³C NMR [125 MHz, (CD₃)₂SO]: δ = 99.82, 107.76, 114.78, 120.09, 125.74, 128.92, 129.14, 130.82, 133.67, 135.44, 141.88, 144.15. MS (EI, 70 eV): m/z (%) = 238 (100) [M⁺], 208 (29), 192 (36), 191 (27), 190 (14), 165 (22). HRMS (EI): m/z calcd for C₁₄H₁₀N₂O₂: 238.0742; found: 238.0743. 2-(4-Chlorophenyl)-6-nitroindole (8d) Orange crystals, mp >280 °C (lit.²⁵ 260–261 °C). ¹H NMR [500 MHz, (CD₃)₂SO]: δ = 7.15 (br s, 1 H), 7.57–7.61 (m, 2 H), 7.71 (d, J = 8.9 Hz, 1 H), 7.89 (dd, J = 8.9, 2.0 Hz, 1 H), 7.92–7.96 (m, 2 H), 8.27 (d, J = 2.0 Hz, 1 H). ¹³C NMR [125 MHz, (CD₃)₂SO]: δ = 100.35, 107.82, 114.85, 120.29, 127.41, 129.18, 129.73, 133.43, 133.54, 135.52, 142.10, 142.82. MS (EI, 70 eV): m/z (%) = 274 (33) [M⁺ + 2], 272 (100) [M⁺], 244 (9), 242 (29), 228 (11), 226 (32), 214 (7), 199 (7), 191 (39), 190 (31), 164 (8), 163 (10). HRMS (EI): m/z calcd for C₁₄H₉ ³⁵ClN₂O₂: 272.0353; found: 272.0350. 2-(4-Methoxyphenyl)-6-nitroindole (8e) Yellow crystals, mp 235–237 °C (lit. ²⁶ 233–234 °C). ¹H NMR [500 MHz, (CD₃)₂SO]: δ = 3.83 (s, 3 H), 7.00 (s, 1 H), 7.07–7.11 (m, 2 H), 7.65 (d, J = 8.7 Hz, 1 H), 7.85–7.89 (m, 2 H), 7.89 (dd, J = 8.7, 2.1 Hz, 1 H), 8.25 (d, J = 2.1 Hz, 1 H), 12.21 (s, 1 H). ¹³C NMR [125 MHz, (CD₃)₂SO]: δ = 55.30, 98.64, 107.49, 114.60, 114.82, 119.55, 123.35, 127.26, 134.02, 135.28, 141.42, 144.47, 159.93. MS (EI, 70 eV): m/z (%) = 268 (100) [M⁺], 253 (6), 252 (5), 238 (20), 222 (35), 207 (19), 191 (9), 179 (6), 178 (11), 152 (8). HRMS (EI): m/z calcd for C₁₅H₁₂N₂O₃: 268.0848; found: 268.0841. Ethyl 6-Nitroindole-2-carboxylate (8f) Orange crystals, mp 193–195 °C (lit.²⁷ 195–197 °C). ¹H NMR [500 MHz, (CD₃)₂CO]: δ = 1.39 (t, J = 7.0 Hz, 3 H), 4.42 (q, J = 7.0 Hz, 2 H), 7.32 (s, 1 H), 7.90 (d, J = 8.8 Hz, 1 H), 7.99 (dd, J = 8.8, 2.2 Hz, 1 H), 8.48 (br s, 1 H), 11.58 (br s, 1 H). ¹³C NMR [125 MHz, (CD₃)₂CO]: δ = 13.66, 61.09, 107.65, 109.06, 114.99, 122.79, 131.76, 133.11, 135.71, 145.20, 160.55. MS (EI, 70 eV): m/z (%) = 234 (95) [M⁺], 206 (5), 189 (22), 188 (100), 143 (11), 142 (32), 130 (13). HRMS (EI): m/z calcd for C₁₁H₁₀N₂O₄: 234.0641; found: 234.0645. 6-Nitro-2-(trifluoromethyl)indole (8g) Yellow crystals, mp 143–145 °C. ¹H NMR [500 MHz, (CD₃)₂CO]: δ = 7.22 (dq, J = 1.0, 0.9 Hz, 1 H), 7.94 (d, J = 8.7 Hz, 1 H), 8.05 (dd, J = 8.7, 2.1 Hz, 1 H), 8.47 (ddd, J = 2.1, 0.8, 0.8 Hz, 1 H), 12.06 (br s, 1 H).¹⁹ F NMR (470 MHz, [CD₃)₂CO]: δ = –61.80 (d, J = 2.4 Hz). MS (EI, 70 eV): m/z (%) = 230 (100) [M⁺], 214 (7), 211 (11), 200 (27), 184 (71), 172 (13), 164 (913), 157 (17), 152 (13), 137 (12). HRMS (EI): m/z calcd for C₉H₅N₂O₂F₃: 230.0303; found: 230.0300. Ethyl 4-Nitroindole-2-carboxylate (8h) Yellow solid, mp 224–226 °C (lit.²⁸ 227–229 °C). ¹H NMR [500 MHz, (CD₃)₂SO]: δ = 1.39 (t, J = 7.1 Hz, 3 H), 4.41 (q, J = 7.1 Hz, 2 H), 7.50 (dd, J = 8.0, 8.0 Hz, 1 H), 7.95 (br d, J = 8.0 Hz, 1 H), 8.15 (br d, J = 8.0 Hz, 1 H), 12.77 (br s, 1 H). ¹³C NMR [(125 MHz, (CD₃)₂SO]: δ = 14.15, 61.13, 106.31, 118.36, 119.87, 120.59, 123.77, 131.23, 138.88, 141.42, 160.59. MS (EI, 70 eV): m/z (%) = 234 (85) [M⁺], 206 (5), 189 (24), 188 (100), 158 (14), 143 (13), 142 (36), 130 (12), 115 (14), 114 (47). HRMS (EI): m/z calcd for C₁₁H₁₀N₂O₄: 234.0641; found: 234.0643. 4-Nitro-2-(trifluoromethyl)indole (8i) Yellow crystals, mp 219–221 °C. ¹H NMR [500 MHz, (CD₃)₂SO]: δ = 7.50 (dq, J = 0.9, 0.8 Hz, 1 H), 7.55 (dd, J = 8.2, 7.9 Hz, 1 H), 8.01 (ddd, J = 8.2, 0.8, 0.8 Hz, 1 H), 8.20 (dd, J = 7.9, 0.8 Hz, 1 H), 13.25 (s, 1 H). ¹³C NMR [125 MHz, (CD₃)₂SO]: δ = 102.39 (q, J = 3.4 Hz), 118.48, 119.20, 120.49, 120.81 (q, J = 268.5 Hz), 123.81, 128.82 (q, J = 38.6 Hz), 138.41, 140.41. ¹⁹F NMR (470 MHz, CDCl₃): δ = –54.86 (d, J = 1.1 Hz). MS (EI, 70 eV): m/z (%) = 230 (100) [M⁺], 211 (11), 200 (21), 184 (71), 172 (19), 164 (11), 157 (15), 152 (15), 144 (17), 137 (11). HRMS (EI): m/z calcd for C₉H₅F₃N₂O₂: 230.0303; found: 230.0297
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