Expedient Synthesis of 6-Acylindolo[1,2-a]quinoxalines

Abstract

A novel route leading to 6-acylindolo[1,2-a]quinoxalines ­involving condensation of N-(2-iodoaryl)-2-nitrosoanilines with β-di­ketones followed by Heck cyclization is described.

Key words

cyclization - condensation - heterocycles - annulation - Heck reaction - indoles

• References and Notes

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• 8 General Procedure for the Synthesis of N-(2-Iodoaryl)-2-nitrosoanilines 1a–i To a cooled solution of KOt-Bu (3,7 g, 30 mmol) in DMF (50 mL) was added dropwise at –60 °C a solution of the appropriate 2-iodoaniline (9.6 mmol) in DMF (3 mL) and the nitroarene (9.6 mmol) in DMF (8 mL). The mixture was stirred at –60 °C for 0.5 h then the temperature was raised slowly to –30 °C, and the reaction was continued for an additional 1 h, poured into sat. NH₄Cl solution (200 mL) and extracted with EtOAc. The extract was washed with H₂O, brine, and dried with Na₂SO₄. After evaporation, the crude product mixture was subjected to column chromatography (SiO₂, hexane–toluene). For analytical data, see the Supporting Information.
• 9 General Procedure for the Preparation of Compounds 4 To a solution of the N-(2-iodoaryl)-2-nitrosobenzamine 1 (2 mmol) and an appropriate 1,3-diketone 2 (2 mmol) in dry MeCN (10 mL) was added t-BuNH₂ (4 mmol). The mixture was stirred at r.t. for 1–4 d (see the Supporting Information). The solvent and other volatile materials were then evaporated in vacuo, and the crude product was used in the next step without purification. The reaction vial containing the crude product was charged with Pd(OAc)₂ (45 mg, 0.2 mmol), n-Bu₄NCl·H₂O (method A; 1050 mg, 3.5 mmol) or n-Bu₄NBr (method B; 1127 mg, 3.5 mmol) and KOAc (1000 mg, 10.2 mmol). The flask was purged with argon, then DMF (10 mL) was added, and argon was continuously bubbled via the reaction mixture for 20 min. The mixture was then heated under a positive argon pressure in an oil bath at 60–65 °C for 24 h. After cooling down some amount of H₂O (ca. 5 mL) was added. In the cases when a solid product precipitated it was filtered off and washed with EtOH, H₂O, and EtOAc repeatedly, to yield the product pure on TLC. Analytical sample was obtained by recrystallization from DMF. In the cases of soluble products (4ec,ha,hb,ia) the mixture was diluted with H₂O and extracted with EtOAc. The extract was thoroughly washed with H₂O, dried (Na₂SO₄), and the solvent was evaporated. The residue was separated by column chromatography (SiO₂, hexane–EtOAc). Analytical sample was recrystallized from hexane–EtOAc.
• 10 Analytical Data for the Selected 6-Acylindolo[1,2-a]quinoxalines 4 Compound 4ba (condensation time 4 d): orange crystals; mp 273–275 °C (DMF). ¹H NMR (500 MHz, CF₃CO₂D): δ = 7.59–7.64 (m, 2 H), 7.72 (d, J = 8.7 Hz, 1 H), 7.78 (s, 1 H), 7.84–7.92 (m, 2 H), 8.00–8.04 (m, 3 H), 8.10 (d, J = 8.7 Hz, 1 H), 8.52 (d, J = 9.4 Hz, 1 H), 8.74 (s, 1 H). ¹³C NMR (125 MHz, CF₃CO₂D): δ = 115.17, 115.51, 116.38, 121.91, 123.23, 123.65, 125.72, 127.67, 129.44, 130.44, 130.62, 131.44, 132.93, 132.97, 134.90, 137.61, 140.74, 147.55, 161.34, 185.62. MS (EI): m/z (%) = 394 (13), 393 (18), 392 (68), 391 (36), 390 (100) [M^+•], 389 (18), 364 (15), 363 (23), 362 (23), 261 (28), 357 (10), 355 (29), 327 (15), 250 (14), 177 (12). HRMS (EI): m/z calcd for C₂₂H₁₂N₂OCl₂: 390.0327; found: 390.0324. Compound 4fa (condensation time 1 d): orange crystals; mp 252–254 °C (DMF). ¹H NMR (500 MHz, CF₃CO₂D): δ = 7.54–7.94 (m, 7 H), 7.96–8.12 (m, 2 H), 8.14–8.26 (m, 1 H), 8.54–8.68 (m, 1 H), 8.77 (s, 1 H). ¹³C NMR (125 MHz, CF₃CO₂D): δ =107.88 (d, J _CF = 24 Hz), 116.21, 121.92, 122.44 (d, J _CF = 28 Hz), 123.81, 125.91, 125.97, 127.56, 129.45, 130.83, 131.56, 131.65, 131.74, 131.78 (d, J _CF = 255 MHz), 133.63, 137.63, 140.71, 147.26, 185.80 (one C invisible). MS (EI): m/z (%) = 376 (37), 374 (100) [M^+•], 373 (31), 348 (10), 347 (19), 346 (31), 345 (38), 234 (12), 105 (43), 77 (41). HRMS (EI): m/z calcd for C₂₂H₁₂N₂OClF: 374.0622; found: 374.0618. Compound 4hb (condensation time 1 d): orange crystals; mp 185–187 °C (hexane–EtOAc). ¹H NMR (400 MHz, CDCl₃): δ = 1.46 (s, 9 H), 2.79 (s, 3 H), 7.33 (dd, J = 8.8, 2.0 Hz, 1 H), 7.65 (dd, J = 9.2, 2.0 Hz, 1 H), 7.86–7.91 (m, 2 H), 7.92 (d, J = 2.0 Hz, 1 H), 8.17 (d, J = 9.2 Hz, 1 H), 8.30 (d, J = 2.0 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 26.3, 31.7, 35.0, 104.4, 113.78, 114.8, 119.0, 123.9, 124.3, 126.0, 130.4, 130.4, 132.0, 132.6, 133.2, 136.6, 146.6, 148.6, 199.4. MS (EI): m/z (%) = 352 (35), 351 (24), 350 (100) [M^+•], 337 (30), 336 (20), 335 (87), 44 (32). HRMS (EI): m/z calcd for C₂₁H₁₉N₂OCl: 350.1186; found: 350.1190.