Palladium-Catalyzed Heteroannulation Approach to 1,2-Bis(3-indolyl)ethanes

Abstract

Palladium-catalyzed heteroannulation between indole-3-butanal and various o-iodoanilines provides a straightforward synthesis of 1,2-bis(3-indolyl)ethanes, which are useful precursors to valued indolo[2,3a]carbazoles. 1,2-Bis(3-indolyl)ethanes bearing a variety of substituents are available by using this methodology, with one transformed into the natural product 1,2-bis(3-indolyl)ethane-1,2-dione through a novel double Yonemitsu oxidation.

Key words

indole - heteroannulation - indole derivatives - palladium - natural products

• References and Notes

• 1a Gilbert EJ, Van Vranken DL. J. Am. Chem. Soc. 1996; 118: 5500
• 1b Gilbert EJ, Ziller JW, Van Vranken DL. Tetrahedron 1997; 53: 16553

For further applications of this Mannich dimerization, see:
• 1c Gilbert EJ, Chisholm JD, Van Vranken DL. J. Org. Chem. 1999; 64: 5670
• 1d Voldoire A, Moreau P, Sancelme M, Matulova M, Léonce S, Pierré A, Hickman J, Pfeiffer B, Renard P, Dias N, Bailly C, Prudhomme M. Bioorg. Med. Chem. 2004; 12: 1955
• 2 For an early example of an intramolecular acid-promoted indole dimerization, see: Gribble GW, Pelcman B. J. Org. Chem. 1992; 57: 3636

For reviews on the isolation and synthesis of indolocarbazoles, see:
• 3a Janosik T, Wahlström N, Bergman J. Tetrahedron 2008; 64: 9159
• 3b Sánchez C, Mendéz C, Salas JA. Nat. Prod. Rep. 2006; 23: 1007
• 4a Strappaghetti A, Rabere G, Fravolini A, Jacquignon P. Heterocycles 1980; 14: 935
• 4b Royer H, Joseph D, Prim D, Kirsch G. Synth. Commun. 1998; 28: 1239
• 4c Balamurali R, Prasad KJ. R. Farmaco 2001; 56: 229
• 4d Hu Y.-Z, Chen Y.-Q. Synlett 2005; 42
• 4e Curiel D, Cowley A, Beer PD. Chem. Commun. 2005; 236

Using (dimethylamino)acetaldehyde dialkyl acetals, see:
• 5a Chang K.-J, Chae MK, Lee C, Lee J.-Y, Jeong K.-S. Tetrahedron Lett. 2006; 47: 6385
• 5b Kuethe JT, Wong A, Davies IW. Org. Lett. 2003; 5: 3721
• 5c For reductive cyclization of 2,2′-bisindole-3,3′-dicarbaldehydes with SmI₂, see: Banerji A, Bandyopadhyay D, Basak B, Biswas PK, Banerji J, Chatterjee A. Bull. Chem. Soc. Jpn. 2007; 80: 1199
• 5d For ring-closing metathesis, see: Pelly SC, Parkinson CJ, van Otterlo WA. L, de Koning CB. J. Org. Chem. 2005; 70: 10474

Existing methods only allow access to symmetrical products, see:
• 6a Bergman J, Venemalm L. Tetrahedron 1990; 46: 6061
• 6b Aoki K, Peat AJ, Buchwald SL. J. Am. Chem. Soc. 1998; 120: 3068
• 6c Mohanakrishnan AK, Ramesh N, Prakash C. Tetrahedron Lett. 2005; 46: 6983
• 6d Banerjee S, Barnea E, Odom AL. Organometallics 2008; 27: 1005
• 6e Koshima H, Ding K, Matsuura T. J. Chem. Soc., Chem. Commun. 1994; 2053
• 6f Bergman J, Carlsson R. J. Heterocycl. Chem. 1972; 9: 833. For the only example of an unsymmetrical 1,2-bis(3-indolyl)ethane, see ref. 1b
• 7a Iida H, Yuasa Y, Kibayashi C. J. Org. Chem. 1980; 45: 2938
• 7b Chen C.-Y, Lieberman DR, Larsen RD, Verhoeven TR, Reider PJ. J. Org. Chem. 1997; 62: 2676
• 7c Cho CS, Shim HS, Choi H.-J, Kim T.-J, Shim SC. Bull. Kor. Chem. Soc. 2004; 25: 441
• 7d Jia Y, Zhu J. J. Org. Chem. 2006; 71: 7826
• 8 Pedras MS. C, Minic Z, Thongbam PD, Bhaskar V, Montaut S. Phytochemistry 2010; 71: 1952
• 9 Perregaard J, Moltzen EK, Meier E, Sánchez C. J. Med. Chem. 1995; 38: 1998
• 10 Indole-3-butanol (8): To a solution of indole-3-butyric acid (7; 0.50 g, 2.46 mmol) in THF (30 mL) at 0 °C was slowly added LiAlH₄ (0.47 g, 12.31 mmol) and the reaction mixture was allowed to warm to r.t. over 18 h. EtOAc (10 mL) was added slowly followed by H₂O (10 mL) and the mixture was poured onto a solution of Rochelle’s salt (40 mL). The resulting suspension was extracted with EtOAc (3 × 40 mL) and the combined organic extracts were dried (MgSO₄), filtered and concentrated in vacuo. Purification by filtration through a short plug of silica gel (hexanes–EtOAc, 1:3) gave the title compound as a yellow oil (0.45 g, 2.36 mmol, 96%). Spectroscopic data were consistent with literature data.⁹ IR: 3385, 3288, 2927, 1455, 1423, 1340, 1225, 1091, 1062, 1047, 1033, 1007, 984, 932, 911, 749, 739, 687, 667, 615 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.93 (br s, 1 H, NH), 7.61 (d, J = 7.9 Hz, 1 H, ArH), 7.35 (d, J = 8.0 Hz, 1 H, ArH), 7.19 (td, J = 7.6, 1.1 Hz, 1 H, ArH), 7.12 (td, J = 7.6, 1.1 Hz, 1 H, ArH), 6.98 (s, 1 H, ArH), 3.69 (t, J = 6.5 Hz, 2 H, CH ₂OH), 2.81 (t, J = 7.3 Hz, 2 H, CH₂), 1.74 (m, 4 H, 2 × CH₂); OH not observed. ¹³C NMR (100 MHz, CDCl₃): δ = 136.5 (C), 127.7 (C), 122.0 (CH), 121.3 (CH), 119.3 (CH), 119.1 (CH), 116.8 (C), 111.2 (CH), 63.1 (CH₂), 32.8 (CH₂), 26.4 (CH₂), 25.0 (CH₂). ESI-MS: m/z (%) = 212 (100) [M + Na]⁺, 196 (8), 190 (5). ESI-HRMS: m/z [M + Na]⁺ calcd for [C₁₂H₁₅NO + Na]⁺: 212.1046; found: 212.1047.
• 11 Indole-3-butanal (5): A solution of indole-3-butanol (8; 0.10 g, 0.53 mmol) and IBX (0.59 g, 2.11 mmol) in EtOAc (15 mL) was heated to 75 °C for 5 h. The reaction mixture was cooled, filtered through a short plug of Celite, and the cake was washed with EtOAc (10 mL). The filtrate was then concentrated in vacuo to afford aldehyde 5 (ca. 100 mg) as an unstable yellow oil which was used immediately in the subsequent heteroannulation. Note: Using aldehyde 5 that has been stored in a freezer under argon leads to significantly reduced yields in the heteroannulation reaction.
• 12 o-Iodoanilines 6a–i were purchased from commercial sources.
• 13 Synthesis of 1,2-bis(3-indolyl)ethanes 1a–i; Heteroannulation General Procedure: A quantitative yield for the oxidation step (8→5)¹⁶ is presumed and hence the molar amounts of each reagent are based on alcohol 8. A sealed tube charged with DMF (1–2 mL) was degassed with nitrogen for 30 min. Freshly prepared aldehyde 5 (0.15–0.26 mmol) was added, followed by the appropriate o-iodoaniline 6a–i (0.17–0.29 mmol), DABCO (0.45–0.79 mmol) and Pd(OAc)₂ (5 mol%). The tube was then sealed under a blanket of nitrogen and stirred at 85 °C for 18–90 h. The cooled solution was poured onto H₂O (10 mL) and extracted with Et₂O (3 × 10 mL). The combined organic extracts were dried (MgSO₄), filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel (hexanes–EtOAc) gave the desired products 1a–i, the yields of which were calculated over two steps from alcohol 8. Compound 1a: According to the general procedure, a mixture of aldehyde 5, 2-iodoaniline (6a; 60 mg, 0.27 mmol), DABCO (83 mg, 0.74 mmol) and Pd(OAc)₂ (3 mg, 0.012 mmol, 5 mol%) in DMF (2.0 mL) was heated at 85 °C for 60 h. The title compound (12 mg, 0.046 mmol, 19% over two steps) was obtained after flash chromatography (4:1) as a yellow solid; mp 210 –220 °C (dec.) [Lit.^6e 263–265 °C (MeCN)], (Lit.^6f 161–162 °C). IR: 3390, 3049, 2900, 2847, 1618, 1456, 1423, 1355, 1337, 1301, 1267, 1248, 1220, 1090, 1051, 1007, 930, 808, 766, 738 cm^–1. ¹H NMR [400 MHz, (CD₃)₂CO]: δ = 10.74 (br s, 2 H, 2 × NH), 7.56 (d, J = 7.8 Hz, 2 H, 2 × ArH), 7.33 (d, J = 8.1 Hz, 2 H, 2 × ArH), 7.15 (d, J = 2.0 Hz, 2 H, 2 × ArH), 7.06 (td, J = 7.4, 1.0 Hz, 2 H, 2 × ArH), 6.98 (td, J = 7.4, 1.0 Hz, 2 H, 2 × ArH), 3.06 (s, 4 H, 2 × CH₂). ¹³C NMR [100 MHz, (CD₃)₂CO]: δ = 136.3 (2 × C), 127.2 (2 × C), 122.2 (2 × CH), 120.8 (2 × CH), 118.3 (2 × CH), 118.1 (2 × CH), 114.8 (2 × C), 111.3 (2 × CH), 25.9 (2 × CH₂). ESI-MS: m/z (%) = 283 (100) [M + Na]⁺, 156 (80), 144 (13), 130 (80). ESI-HRMS: m/z [M + Na]⁺ calcd for [C₁₈H₁₆N₂ + Na]⁺: 283.1206; found: 283.1197. Compound 1b: According to the general procedure, a mixture of aldehyde 5, 2-iodo-4-methylaniline (6b; 68 mg, 0.29 mmol), DABCO (89 mg, 0.79 mmol) and Pd(OAc)₂ (3 mg, 0.013 mmol, 5 mol%) in DMF (2.0 mL) was heated at 85 °C for 42 h. The title compound (19 mg, 0.069 mmol, 26% over two steps) was obtained after flash chromatography (7:3) as a brown solid; mp 193–196 °C. IR: 3393, 2918, 2848, 1483, 1456, 1423, 1330, 1230, 1250, 1223, 1182, 1090, 1047, 1005, 927, 874, 794, 771, 742, 694 cm^–1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 9.91 (br s, 1 H, NH), 9.77 (br s, 1 H, NH), 7.64 (d, J = 7.8 Hz, 1 H, ArH), 7.39 (m, 2 H, 2 × ArH), 7.26 (d, J = 8.2 Hz, 1 H, ArH), 7.15 (d, J = 2.2 Hz, 1 H, ArH), 7.10 (m, 2 H, 2 × ArH), 7.02 (td, J = 7.4, 1.0 Hz, 1 H, ArH), 6.93 (dd, J = 8.3, 1.0 Hz, 1 H, ArH), 3.14 (m, 4 H, 2 × CH₂), 2.41 (s, 3 H, Me). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 137.8 (C), 136.2 (C), 128.9 (C), 128.7 (C), 128.0 (C), 123.6 (CH), 122.8 (CH), 122.7 (CH), 122.0 (CH), 119.4 (CH), 119.3 (CH), 119.1 (CH), 116.7 (C), 116.2 (C), 112.1 (CH), 111.8 (CH), 27.11 (CH₂), 27.07 (CH₂), 21.7 (Me). ESI-MS: m/z (%) = 297 (100) [M + Na]⁺, 170 (9). ESI-HRMS: m/z [M + Na]⁺ calcd for [C₁₉H₁₈N₂ + Na]⁺: 297.1362; found: 297.1366. Compound 1c: According to the general procedure, a mixture of aldehyde 5, 2-iodo-4-methoxylaniline (6c; 72 mg, 0.29 mmol), DABCO (89 mg, 0.79 mmol) and Pd(OAc)₂ (3 mg, 0.013 mmol, 5 mol%) in DMF (2.0 mL) was heated at 85 °C for 17 h. The title compound (17 mg, 0.059 mmol, 22% over two steps) was obtained after flash chromatography (4:1) as a brown solid; mp 136 –140 °C. IR: 3400, 1484, 1454, 1435, 1335, 1294, 1266, 1207, 1168, 1093, 1052, 1030, 1008, 967, 923, 829, 811, 795, 770, 747 cm^–1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 10.73 (s, 1 H, NH), 10.57 (s, 1 H, NH), 7.57 (d, J = 7.8 Hz, 1 H, ArH), 7.34 (d, J = 8.0 Hz, 1 H, ArH), 7.22 (d, J = 8.7 Hz, 1 H, ArH), 7.13 (m, 2 H, 2 × ArH), 7.07 (td, J = 7.5, 0.9 Hz, 1 H, ArH), 6.97 (m, 2 H, 2 × ArH), 6.70 (dd, J = 8.7, 2.4 Hz, 1 H, ArH), 3.72 (s, 3 H, OMe), 3.05 (m, 4 H, 2 × CH₂). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 152.9 (C), 136.3 (C), 131.4 (C), 127.6 (C), 127.3 (C), 122.9 (CH), 122.3 (CH), 120.8 (CH), 118.3 (CH), 118.1 (CH), 114.8 (C), 114.6 (C), 111.9 (CH), 111.3 (CH), 110.9 (CH), 100.2 (CH), 55.3 (OMe), 25.8 (2 × CH₂). ESI-MS: m/z (%) = 313 (100) [M + Na]⁺, 143 (9). ESI-HRMS: m/z [M + Na]⁺ calcd for [C₁₉H₁₈N₂O + Na]⁺: 313.1311; found: 313.1315. Compound 1d: According to the general procedure, a mixture of aldehyde 5, 4-chloro-2-iodoaniline (6d; 49 mg, 0.193 mmol), DABCO (60 mg, 0.535 mmol) and Pd(OAc)₂ (2 mg, 0.009 mmol, 5 mol%) in DMF (1.3 mL) was heated at 85 °C for 18 h. The title compound (9 mg, 0.031 mmol, 17% over two steps) was obtained after flash chromatography (7:3) as a brown solid; mp 175 –178 °C (Lit.^1b 178–180 °C). IR: 3397, 2907, 1454, 1421, 1394, 1328, 1299, 1283, 1251, 1214, 1091, 1043, 1007, 927, 895, 871, 797, 777, 768, 738 cm^–1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 10.96 (s, 1 H, NH), 10.74 (s, 1 H, NH), 7.55 (m, 2 H, 2 × ArH), 7.34 (m, 2 H, 2 × ArH), 7.24 (d, J = 2.2 Hz, 1 H, ArH), 7.15 (d, J = 2.0 Hz, 1 H, ArH), 7.06 (m, 2 H, 2 × ArH), 6.97 (td, J = 7.3, 0.7 Hz, 1 H, ArH), 3.04 (s, 4 H, 2 × CH₂). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 136.2 (C), 134.6 (C), 128.4 (C), 127.2 (C), 124.2 (CH), 122.8 (C), 122.3 (CH), 120.8 (CH), 120.7 (CH), 118.3 (CH), 118.1 (CH), 117.6 (CH), 114.8 (C), 114.5 (C), 112.8 (CH), 111.3 (CH), 25.8 (CH₂), 25.5 (CH₂). ESI-MS: m/z (%) = 317 (100) [M + Na]⁺, 143 (18). ESI-HRMS: m/z [M + Na]⁺ calcd for [C₁₈H₁₅ ³⁵ClN₂ + Na]⁺: 317.0816; found: 317.0807. Spectroscopic data is consistent with the literature.^1b Compound 1e: According to the general procedure, a mixture of aldehyde 5, 4-fluoro-2-iodoaniline (6e; 46 mg, 0.194 mmol), DABCO (60 mg, 0.535 mmol) and Pd(OAc)₂ (2 mg, 0.009 mmol, 5 mol%) in DMF (1.3 mL) was heated at 85 °C for 60 h. The title compound (10 mg, 0.037 mmol, 21% over two steps) was obtained after flash chromatography (7:3) as a brown solid; mp 200 – 220 °C (dec.). IR: 3401, 1579, 1483, 1453, 1423, 1358, 1332, 1260, 1215, 1167, 1092, 1041, 1008, 938, 866, 797, 769, 739, 695, 610 cm^–1. ¹H NMR [400 MHz, (CD₃)₂CO]: δ = 10.02 (br s, 1 H, NH), 9.92 (br s, 1 H, NH), 7.63 (d, J = 8.0 Hz, 1 H, ArH), 7.37 (m, 2 H, 2 × ArH), 7.29 (dd, J = 10.0, 2.5 Hz, 1 H, ArH), 7.23 (d, J = 2.3 Hz, 1 H, ArH), 7.15 (d, J = 2.3 Hz, 1 H, ArH), 7.09 (td, J = 7.5, 1.2 Hz, 1 H, ArH), 7.02 (td, J = 7.5, 1.0 Hz, 1 H, ArH), 6.88 (td, J = 9.1, 2.5 Hz, 1 H, ArH), 3.13 (m, 4 H, 2 × CH₂). ¹³C NMR [100 MHz, (CD₃)₂CO]: δ = 158.3 (d, J _C–F = 231.4 Hz, C), 137.8 (C), 134.3 (C), 129.0 (d, J _C–F = 9.4 Hz, C), 128.7 (C), 125.0 (CH), 122.8 (CH), 122.0 (CH), 119.4 (CH), 119.3 (CH), 116.9 (d, J _C–F = 4.9 Hz, C), 116.5 (C), 112.9 (d, J _C–F = 9.7 Hz, CH), 112.1 (CH), 109.9 (d, J _C–F = 26.4 Hz, CH), 104.0 (d, J _C–F = 23.2 Hz, CH), 26.9 (2 × CH₂). ESI-MS: m/z (%) = 301 (100) [M + Na]⁺, 242 (4), 210 (3). ESI-HRMS: m/z [M + Na]⁺ calcd for [C₁₈H₁₅FN₂ + Na]⁺: 301.1111; found: 301.1124. Compound 1f: According to the general procedure, a mixture of aldehyde 5, 2-iodo-4-(trifluoromethyl)aniline (6f; 47 mg, 0.165 mmol), DABCO (51 mg, 0.450 mmol) and Pd(OAc)₂ (2 mg, 0.008 mmol, 5 mol%) in DMF (1.1 mL) was heated at 85 °C for 21 h. The title compound (16 mg, 0.049 mmol, 33% over two steps) was obtained after flash chromatography (7:3) as a brown solid; mp 142–145 °C. IR: 3388, 1458, 1328, 1282, 1261, 1215, 1153, 1130, 1096, 1080, 1044, 1026, 1006, 904, 891, 802, 771, 751, 714, 661 cm^–1. ¹H NMR [400 MHz, (CD₃)₂CO]: δ = 10.38 (br s, 1 H, NH), 9.92 (br s, 1 H, NH), 7.93 (s, 1 H, ArH), 7.61 (d, J = 7.9 Hz, 1 H, ArH), 7.56 (d, J = 8.7 Hz, 1 H, ArH), 7.37 (d, J = 8.2 Hz, 2 H, 2 × ArH), 7.33 (s, 1 H, ArH), 7.14 (d, J = 2.1 Hz, 1 H, ArH), 7.08 (td, J = 7.4, 0.8 Hz, 1 H, ArH), 7.00 (t, J = 7.4 Hz, 1 H, ArH), 3.19 (m, 4 H, 2 × CH₂); ¹³C NMR [100 MHz, (CD₃)₂CO]: δ = 139.1 (C), 137.8 (C), 128.6 (C), 128.0 (CF₃), 125.1 (CH), 125.0 (C), 122.9 (CH), 122.0 (CH), 121.3 (C), 119.3 (2 × CH), 118.5 (d, J _C–F = 3.5 Hz, CH), 117.9 (C), 117.1 (q, J _C–F = 4.2 Hz, CH), 116.3 (C), 112.7 (CH), 112.1 (CH), 27.0 (CH₂), 26.6 (CH₂). ESI-MS: m/z (%) = 351 (100) [M + Na]⁺, 250 (7). ESI-HRMS: m/z [M + Na]⁺ calcd for [C₁₉H₁₅F₃N₂ + Na]⁺: 351.1080; found: 351.1076. Compound 1g: According to the general procedure, a mixture of aldehyde 5, 4-amino-3-iodobenzonitrile (6g; 71 mg, 0.29 mmol), DABCO (89 mg, 0.79 mmol) and Pd(OAc)₂ (3 mg, 0.013 mmol, 5 mol%) in DMF (2.0 mL) was heated at 85 °C for 90 h. The title compound (24 mg, 0.085 mmol, 32% over two steps) was obtained after flash chromatography (3:2) as a brown solid; mp 162–165 °C. IR: 3406, 2223, 1614, 1469, 1456, 1422, 1361, 1322, 1221, 1098, 1082, 1066, 1008, 883, 827, 813, 801, 787, 764, 737 cm^–1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 11.36 (s, 1 H, NH), 10.74 (s, 1 H, NH), 8.05 (s, 1 H, ArH), 7.53 (m, 2 H, 2 × ArH), 7.37 (m, 3 H, 3 × ArH), 7.15 (s, 1 H, ArH), 7.06 (t, J = 7.5 Hz, 1 H, ArH), 6.97 (t, J = 7.5 Hz, 1 H, ArH), 3.08 (m, 4 H, 2 × CH₂). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 137.9 (C), 136.2 (C), 127.2 (C), 127.1 (C), 125.0 (CH), 124.3 (CH), 123.5 (CH), 122.4 (CH), 121.0 (C), 120.8 (CH), 118.4 (CH), 118.1 (CH), 116.2 (C), 114.4 (C), 112.5 (CH), 111.3 (CH), 100.2 (C), 25.8 (CH₂), 25.4 (CH₂). ESI-MS: m/z (%) = 308 (100) [M + Na]⁺. ESI-HRMS: m/z [M + Na]⁺ calcd for [C₁₉H₁₅N₃ + Na]⁺: 308.1158; found: 308.1153. Compound 1h: According to the general procedure, a mixture of aldehyde 5, 2-iodo-5-nitroaniline (6h; 77 mg, 0.29 mmol), DABCO (89 mg, 0.79 mmol) and Pd(OAc)₂ (3 mg, 0.013 mmol, 5 mol%) in DMF (2.0 mL) was heated at 85 °C for 20 h. The title compound (40 mg, 0.131 mmol, 50% over two steps) was obtained after flash chromatography (7:3) as an orange solid; mp 170–173 °C. IR: 3416, 3218, 1494, 1458, 1420, 1345, 1310, 1291, 1241, 1216, 1124, 1105, 1095, 1076, 1053, 1010, 865, 815, 782, 738, 724, 665 cm^–1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 11.58 (s, 1 H, NH), 10.75 (s, 1 H, NH), 8.31 (d, J = 1.9 Hz, 1 H, ArH), 7.86 (dd, J = 8.9, 1.9 Hz, 1 H, ArH), 7.70 (d, J = 8.9 Hz, 1 H, ArH), 7.62 (s, 1 H, ArH), 7.56 (d, J = 8.0 Hz, 1 H, ArH), 7.34 (d, J = 8.0 Hz, 1 H, ArH), 7.14 (s, 1 H, ArH), 7.07 (t, J = 7.5 Hz, 1 H, ArH), 6.97 (t, J = 7.5 Hz, 1 H, ArH), 3.10 (m, 4 H, 2 × CH₂). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 141.7 (C), 136.3 (C), 134.5 (C), 131.9 (C), 129.8 (CH), 127.2 (C), 122.3 (CH), 120.8 (CH), 118.6 (CH), 118.3 (CH), 118.1 (CH), 116.3 (C), 114.3 (C), 113.4 (CH), 111.3 (CH), 108.2 (CH), 25.8 (CH₂), 25.4 (CH₂). ESI-MS: m/z (%) = 328 (100) [M + Na]⁺. ESI-HRMS: m/z [M + Na]⁺ calcd for [C₁₈H₁₅N₃O₂ + Na]⁺: 328.1056; found: 328.1063. Compound 1i: According to the general procedure, a mixture of aldehyde 5, 4-chloro-2-fluoro-6-iodoaniline (6i; 79 mg, 0.29 mmol), DABCO (89 mg, 0.79 mmol) and Pd(OAc)₂ (3 mg, 0.013 mmol, 5 mol%) in DMF (2.0 mL) was heated at 85 °C for 19 h. The title compound (42 mg, 0.134 mmol, 51% over two steps) was obtained after flash chromatography (3:1) as a yellow solid; mp 132–135 °C. IR: 3386, 1474, 1457, 1435, 1363, 1297, 1221, 1085, 1071, 1061, 1008, 968, 890, 862, 855, 821, 812, 772, 746, 705 cm^–1. ¹H NMR [400 MHz, (CD₃)₂CO]: δ =10.56 (br s, 1 H, NH), 9.93 (br s, 1 H, NH), 7.61 (d, J = 7.6 Hz, 1 H, ArH), 7.43 (d, J = 2.0 Hz, 1 H, ArH), 7.38 (d, J = 8.3 Hz, 1 H, ArH), 7.30 (d, J = 1.9 Hz, 1 H, ArH), 7.14 (d, J = 2.2 Hz, 1 H, ArH), 7.09 (td, J = 7.6, 1.2, 1 H, ArH), 7.01 (td, J = 7.6, 1.0 Hz, 1 H), 6.93 (dd, J = 10.8, 1.7 Hz, 1 H, ArH), 3.15 (s, 4 H, 2 × CH₂). ¹³C NMR [100 MHz, (CD₃)₂CO]: δ =150.0 (d, J _C–F = 246.3 Hz, C), 137.8 (C), 132.9 (d, J _C–F = 6.5 Hz, C), 128.6 (C), 125.7 (CH), 124.1 (C), 123.9 (d, J _C–F = 8.6 Hz, C), 129.9 (CH), 122.0 (CH), 119.33 (CH), 119.31 (CH), 117.8 (d, J _C–F = 5.9 Hz, C), 116.2 (C), 115.3 (d, J _C–F = 3.2 Hz, CH), 112.2 (CH), 107.7 (d, J _C–F = 20.4 Hz, CH), 26.9 (CH₂), 26.6 (CH₂). ESI-MS: m/z (%) = 335 (100) [M + Na]⁺, 278 (23). ESI-HRMS: m/z [M + Na]⁺ calcd for [C₁₈H₁₄ ³⁵ClFN₂ + Na]⁺: 335.0722; found: 335.0734.
• 14 Oikawa Y, Yoshioka T, Mohri K, Yonemitsu O. Heterocycles 1979; 12: 1457

Isolation:
• 15a McKay MJ, Carroll AR, Quinn RJ, Hooper JN. A. J. Nat. Prod. 2002; 65: 595

For previous syntheses, see:
• 15b Bergman J, Carlsson R, Sjöberg B. J. Heterocycl. Chem. 1977; 14: 1123
• 15c Wang T, Bai Y, Ma L, Yan X.-P. Org. Biomol. Chem. 2008; 6: 1751
• 15d Sessler JL, Cho D.-G, Lynch V. J. Am. Chem. Soc. 2006; 128: 16518
• 15e Krayushkin MM, Yarovenko VN, Sedishev IP, Zavarzin IV, Vorontsova LG, Starikova ZA. Russ. J. Org. Chem. 2005; 41: 875 ; See also ref. 6a

Isolation:
• 16a Kobayashi J, Murayama T, Ishibashi M, Kosuge S, Takamatsu M, Ohizumi Y, Kobayashi H, Ohta T, Nozoe S, Sasaki T. Tetrahedron 1990; 46: 7699
• 16b For a previous synthesis, see: Bergman J, Janosik T, Johnsson A.-L. Synthesis 1999; 4: 580
• 17 Lee H.-S, Moon K.-M, Han Y.-R, Lee KJ, Chung S.-C, Kim T.-I, Lee S.-H, Shin J, Oh K.-B. Bioorg. Med. Chem. Lett. 2009; 19: 1051
• 18 1,2-Bis(3-indol-3-yl)ethane-1,2-dione (10): To a mixture of 1a (30 mg, 0.12 mmol) in THF–H₂O (3 mL, 9:1) at 0 °C was added DDQ (58 mg, 0.25 mmol) and the reaction mixture was stirred at r.t. for 2.5 h. A second portion of DDQ (58 mg, 0.25 mmol) was added and the reaction mixture stirred for a further 2.5 h. The mixture was poured onto a saturated solution of NaHCO₃ (20 mL) and extracted with EtOAc (20 mL). The organic extract was further washed with a saturated solution of NaHCO₃ (5 × 20 mL), dried (MgSO₄), filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel (hexanes–EtOAc, 1:1) gave the title compound (9 mg, 0.031 mmol, 27%) as an orange solid; mp 278–280 °C [Lit.^6a 278–280 °C]. Spectroscopic data is consistent with the literature.^6a IR: 3297, 1595, 1505, 1454, 1430, 1410, 1357, 1336, 1308, 1237, 1115, 1098, 1084, 1009, 874, 775, 757, 745, 732 cm^–1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 12.22 (s, 2 H, 2 × NH), 8.27 (m, 2 H, 2 × ArH), 8.22 (d, J = 2.8 Hz, 2 H, 2 × ArH), 7.54 (m, 2 H, 2 × ArH), 7.29 (m, 4 H, 4 × ArH). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 188.8 (2 × C), 137.3 (2 × CH), 136.7 (2 × C), 125.6 (2 × C), 123.4 (2 × CH), 122.4 (2 × CH), 121.3 (2 × CH), 112.54 (2 × CH), 112.47 (2 × C). ESI-MS: m/z (%) = 311 (100) [M + Na]⁺, 178 (36), 109 (9). ESI-HRMS: m/z [M + Na]⁺ calcd for [C₁₈H₁₂N₂O₂ + Na]⁺: 311.0791; found: 311.0787.

Indole-3-butanals are readily available from the corresponding butanols or butanoic acids, which are themselves easily assembled, see:
• 19a Soubhye J, Prévost M, Van Antwerpen P, Boudjeltia KZ, Rousseau A, Furtmüller PG, Obinger C, Vanhaeverbeek M, Ducobu J, Néve J, Gelbcke M, Dufrasne F. J. Med. Chem. 2010; 53: 8747
• 19b Csende F. Arch. Pharm. Pharm. Med. Chem. 2001; 334: 253