HETEROCYCLES

Short Paper | Special issue | Vol. 90, No. 1, 2015, pp. 673-680
Received, 14th May, 2014, Accepted, 29th May, 2014, Published online, 9th June, 2014.
DOI: 10.3987/COM-14-S(K)28

■ Pd-Catalyzed Intramolecular Oxidative Coupling Reaction of 1,1’-Carbonyldiindoles

Takumi Abe and Minoru Ishikura*

Faculty of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Ishikari-Tobetsu, Hokkaido 061-0293, Japan

Abstract

The palladium-catalyzed intramolecular oxidative coupling reaction of 1,1’-carbonyldiindoles was achieved by using Pd(OAc)2 and Cu(OAc)2, producing 1,1’-carbonyl-2,2’-biindolyls, which were then converted to tjipanazoles D and I.

The indolo[2,3-b]carbazole alkaloids, which contain a 2,2’-biindolyl system as the central moiety, include several natural products, such as staurosporin (1), arcyriaflavin C (2) and tjipanazoles D (3) and I (4). Their structural diversity and wide range of biological activities, including antimicrobial, hypotensive, cytotoxic, and antitumor activities, have made this class of compounds attractive synthetic targets.1

One direct approach to the indolo[2,3-b]carbazole system depends on the construction of a 2,2’-biindolyl system followed by [4 + 2] cycloaddition.2 Recently, the metal-assisted oxidative coupling reaction of aryl compounds has been reported as a straightforward method for producing various biaryls,3 and the oxidative coupling reaction of indole derivatives has been developed for the construction of 2,2’-biindolyls,4 most of which have been the intermolecular reactions.5 However, catalytic intramolecular reactions have presented a synthetic challenge. The syntheses of arcyriaflavins6 and staurosporine aglycone7 were achieved through the Pd-mediated intramolecular oxidative cyclization of 3,3’-bisindolylmaleimides to indolocarbazoles, although PdCl2 (5 equiv) and Pd(OAc)2 (1 equiv) were necessary to complete the coupling reaction. Intramolecular oxidative coupling of 1,1’-carbonyldiindole 5a was carried out using Pd(OAc)2 (1 equiv) to give 6a in 10-84% yields,8 whereas all attempts to make the cyclization reaction catalytic cycle failed. Unsymmetrical 1,1’-carbonyldiindoles can be readily obtained from two different indoles and 1,1’-carbonylimidazole, and are key intermediates for further transformation to unsymmetrical 2,2’-biindolyls. Therefore, in this study, we have re-investigated the catalytic intramolecular cyclization reaction of 5.

Initially, we carried out the reaction of 5a in the presence of Pd(OAc)2 (1 equiv) in AcOH at 100 °C according to the literature8 (Table 1). This provided 6a in 50% yield, and the yield was not improved even when 2 equiv of Pd(OAc)2 was used (entries 1 and 2). Although reducing the amount of Pd(OAc)2 to 10 mol% resulted in only 10% yield of 6a along with substantial amounts of 5a, the addition of Cu(OAc)2 (2 equiv) as an oxidant increased the yield to 38% (entry 5). Replacing Pd(OAc)2 with Pd(OTFA)2 and polymer-bound Pd(OAc)2 had no beneficial effect (entries 6 and 7). However, increasing the catalyst loading to 30 mol% provided 6a in 75% yield (entry 9). The reaction at 180 °C for 3 h generated 6a in 70% yield (entry 10). The reactions of 5b and 5c at 100 °C for 24 h afforded 6b and 6c in 70% and 68% yields, respectively (entries 11-14). Surprisingly, as compared with the reaction of 5a (entry 5), a pronounced acceleration was observed in the reaction of 1,1’-carbonyl-3,3’-dichlorodiindole 5d9 for catalyst loading of 10 mol% as well as 30 mol%, and 6d was obtained in 67% and 70% yields, respectively (entries 15 and 16).
After conditions for the catalytic cyclization reaction of 5 were identified, the 2,2’-biindolyls 6 were used to construct indolocarbazoles 3, 4 and 8. Hydrolysis of 6 was accomplished by heating with KOH in dioxane/tert-BuOH at 120 °C for 0.5 h to give 7. Then, 7a was treated with an excess of aminoacetal in AcOH at 100 °C to afford 8 in 62% yield.10b Compound 8 was also derived from 7d in 60% yield in a similar manner. Tjipanazoles D (3)10 and I (4)10 were likewise obtained from 7b and 7c in 60% and 61% yields, respectively.

In summary, we have shown that the catalytic intramolecular cyclization of 5 was performed with catalytic amounts of Pd(OAc)2 and Cu(OAc)2 (2 equiv) to produce 6, which was followed by conversion to indolocarbazole 8, and tjipanazoles D (3) and I (4).

EXPERIMENTAL
Melting points were recorded with a Yamato MP21 and are uncorrected. High-resolution MS spectra were recorded with a JEOL JMS-T100LP mass spectrometer. IR spectra were measured with a Shimadzu IRAffinity-1 spectrometer. The NMR experiments were performed with a JEOL JNM-ECA500 (500 MHz) spectrometer, and chemical shifts are expressed in ppm (δ) with TMS as an internal reference.
Diindoles 5a, 5b, 5c were prepared from indole, 5-chloroindole and 1,1’-carbonylimidazole.8
Di-1H-indol-1-ylmethanone (5a): Colorless solid. Mp 84-85 °C. IR (CHCl3): 1761, 1713 cm-1. 1H-NMR (CDCl3) δ: 6.74 (d, 2H, J = 4.0 Hz), 7.35 (t, 2H, J = 7.5 Hz), 7.40 (t, 2H, J = 8.0 Hz), 7.46 (d, 2H, J = 3.5 Hz), 7.68 (d, 2H, J = 8.0 Hz), 8.03 (d, 2H, J = 8.6 Hz). 13C-NMR (CDCl3) δ: 108.9, 115.1, 121.5, 123.8, 124.9, 126.9, 130.5, 136.3, 148.8. HR-MS (ESI) m/z: Calcd for C17H12N2NaO [(M+Na)+]: 283.0847. Found: 283.0850.
Bis(5-chloro-1H-indol-1-yl)methanone (5b): Colorless solid. Mp 174-178 °C. IR (CHCl3): 1717 cm-1. 1H-NMR (CDCl3) δ: 6.68 (d, 2H, J = 3.4 Hz), 7.33 (dd, 2H, J = 1.7, 8.6 Hz), 7.45 (d, 2H, J = 4.3 Hz), 7.61 (d, 2H, J = 2.3 Hz), 7.89 (d, 2H, J = 9.2 Hz). 13C-NMR (CDCl3) δ: 108.5, 116.0, 121.1, 125.3, 127.9, 129.6, 131.6, 134.6, 148.2. HR-MS (ESI) m/z: Calcd for C17H10Cl2N2NaO [(M+Na)+]: 351.0068. Found: 351.0060.
(5-Chloro-1H-indol-1-yl)(1H-indol-1-yl)methanone (5c): Pale yellow solid. Mp 170-172 °C. IR (CHCl3): 1713 cm-1. 1H-NMR (CDCl3) δ: 6.66, 6.68 (2 d, 1H, J = 3.4, Hz), 6.72, 6.73 (2 d, 1H, J = 4.0, 5.7 Hz), 7.29-7.39 (m, 3H), 7.43, 7.48 (2 d, 1H, J = 3.4 Hz), 7.45 (d, 1H, J = 3.4 Hz), 7.62 (d, 1H, J = 1.7 Hz), 7.65 (d, 1H, J = 7.5 Hz), 7.89, 7.91 (2 d, 1H, J = 4.0 Hz), 7.97 (t, 1H, J = 8.0 Hz). 13C-NMR (CDCl3) δ: 108.2, 108.5, 108.9, 109.2, 114.9, 116.0, 120.9, 121.1, 121.4, 121.5, 123.7, 123.9, 124.9, 125.0, 125.1, 125.3, 126.6, 126.9, 127.9, 128.1, 129.4, 129.6, 130.4, 131.6, 134.5, 134.6, 136.1, 136.2, 148.2, 148.5, 148.8. HR-MS (ESI) m/z: Calcd for C17H11ClN2NaO [(M+Na)+]: 317.0458. Found: 317.0460.
Bis(3-chloro-1H-indol-1-yl)methanone (5d): Phenyliodine diacetate (12.88 g, 40 mmol) was added to a solution of 5a (5.2 g, 20 mmol) in CH2Cl2 (250 mL) at -78 °C under an argon atmosphere. After stirring for 10 min, TMSCl (12.7 mL, 0.1 mol) was slowly added to the mixture at -78 °C. After stirring at -78 °C for 1 h, the mixture was gradually warmed to room temperature and additionally stirred for 16 h. The organic layer was washed with saturated NaHCO3 aq. solution and brine, and dried over MgSO4. The solvent was removed, and the residue was separated by silica gel column chromatography with hexane/AcOEt (10:1) to give 5d (5.0 g, 76%) as a pale yellow solid. Mp 145-146 °C. IR (CHCl3): 1717 cm-1. 1H-NMR (CDCl3) δ: 7.39-7.45 (m, 4H), 7.46 (s, 2H), 7.68 (d, 2H, J = 7.5 Hz), 7.95 (d, 2H, J = 8.1 Hz). 13C-NMR (CDCl3) δ: 114.4, 115.1, 119.2, 122.6, 124.5, 126.3, 128.1, 135.3, 147.2. HR-MS (ESI) m/z: Calcd for C17H10Cl2N2NaO [(M+Na)+]: 351.0068. Found: 351.0080.
General procedure for the cyclization of 5: Palladium complex (see Table 1 for catalyst structures and amounts) and Cu(OAc)2 (2 mmol) were added to a solution of 5 (1 mmol) in AcOH (10 mL) at room temperature, and the mixture was heated at 100 °C. After 24 h, the mixture was gradually cooled to room temperature and filtered through Celite. The filtrate was diluted with AcOEt, washed with saturated NaHCO3 aq. solution and brine, and dried over MgSO4. The solvent was removed, and the residue was separated by silica gel column chromatography with hexane/AcOEt (10:1) to give 6.
Imidazo[1,5-a:3,4-a']diindol-6-one (6a): Pale yellowish-green solid. Mp 270-272 °C. IR (CHCl3): 1766 cm-1. 1H-NMR (CDCl3) δ: 6.65 (s, 2H), 7.20 (td, 2H, J = 1.2, 7.4 Hz), 7.32 (td, 2H, J = 1.1, 7.5 Hz), 7.52 (d, 2H, J = 8.0 Hz), 7.87 (d, 2H, J = 8.6 Hz). 13C-NMR (CDCl3) δ: 102.4, 112.6, 122.4, 123.8, 125.9, 130.3, 133.1, 133.9, 144.3. HR-MS (ESI) m/z: Calcd for C17H11N2O [(M+H)+]: 259.0871. Found: 259.0876.
2,10-Dichloroimidazo[1,5-a:3,4-a']diindol-6-one (6b): Colorless solid. Mp 255-258 °C (decomp.). IR (CHCl3): 1763, 1717 cm-1. 1H-NMR (CDCl3) δ: 6.63 (s, 2H), 7.30 (dd, 2H, J = 2.3, 8.6 Hz), 7.51 (d, 2H, J = 2.3 Hz), 7.77 (d, 2H, J = 8.6 Hz). 13C-NMR (CDCl3) δ: 102.4, 113.5, 122.2, 126.4, 129.6, 131.1, 131.4, 134.9, 143.7. HR-MS (ESI) m/z: Calcd for C17H8Cl2N2NaO [(M+Na)+]: 348.9911. Found: 348.9960.
2-Chloroimidazo[1,5-a:3,4-a']diindol-6-one (6c): Colorless solid. Mp 242-245 °C (decomp.). IR (CHCl3): 1763, 1717 cm-1. 1H-NMR (CDCl3) δ: 6.60, 6.63 (2 s, 1H), 6.66, 6.69 (2 s, 1H), 7.22 (m, 1H), 7.29 (m, 1H), 7.34 (m, 1H), 7.50, 7.51 (2 d, 1H, J = 1.8 Hz), 7.53, 7.54 (2 d, 1H, J = 3.5 Hz), 7.78, 7.79 (2 d, 1H, J = 4.6 Hz), 7.87 (t, 1H, J = 6.9 Hz). 13C-NMR (CDCl3) δ: 101.5, 102.3, 102.4, 103.3, 112.5, 112.6, 113.3, 113.4, 122.0, 122.3, 122.5, 122.6, 123.8, 124.0, 125.9, 126.0, 126.2, 126.3, 128.9, 129.4, 129.6, 129.8, 130.3, 131.0, 131.2, 131.3, 131.5, 133.0, 133.1, 133.7, 133.8, 134.9, 135.0, 143.6, 143.9, 144.3. HR-MS (ESI) m/z: Calcd for C17H9ClN2NaO [(M+Na)+] 315.0301. Found: 315.0305.
12,13-Dichloroimidazo[1,5-a:3,4-a']diindol-6-one (6d): Pale yellowish-green solid. Mp 210-212 °C. IR (CHCl3): 1763, 1732 cm-1. 1H-NMR (CDCl3) δ: 7.30 (t, 2H, J = 7.5 Hz), 7.40 (t, 2H, J = 8.0 Hz), 7.57 (d, 2H, J = 8.0 Hz), 7.85 (d, 2H, J = 8.1 Hz). 13C-NMR (CDCl3) δ: 108.1, 112.8, 120.1, 124.4, 124.7, 127.3, 131.6, 132.2, 142.8. HR-MS (ESI) m/z: Calcd for C17H8Cl2N2NaO [(M+Na)+]: 348.9911. Found: 348.9928.
General procedure for the conversion of 6 to 7: KOH (168 mg, 3 mmol) and 18-crown-6-ether (793 mg, 3 mmol) were added to a solution of 6 (1 mmol) in 1,4-dioxane (10 mL) and tert-BuOH (1 mL) at room temperature, and the mixture was heated at 120 °C. After 30 min, the mixture was gradually cooled to room temperature. The mixture was diluted with AcOEt (100 mL), washed with H2O and brine, and dried over MgSO4. The solvent was removed, and the residue was separated by silica gel column chromatography with hexane/AcOEt (5:1) to give 7.
1H,1'H-2,2'-Biindole (7a): Colorless solid. Mp 195-197 °C. IR (CHCl3): 3466 cm-1. 1H-NMR (acetone-d6) δ: 6.91 (d, 2H, J = 1.2 Hz), 7.00 (t, 2H, J = 7.5 Hz), 7.09 (td, 2H, J = 1.2, 8.1 Hz), 7.38 (d, 2H, J = 8.1 Hz), 7.53 (d, 2H, J = 8.1 Hz), 10.72 (br s, 2H). 13C-NMR (acetone-d6) δ: 98.7, 111.0, 119.7, 120.2, 122.0, 129.1, 131.5, 137.4. HR-MS (ESI) m/z: Calcd for C16H12N2Na [(M+Na)+]: 255.0898. Found: 255.0900.
5,5'-Dichloro-1H,1'H-2,2'-biindole (7b): Colorless solid. Mp 294-297 °C (decomp.). IR (CHCl3): 3442 cm-1. 1H-NMR (acetone-d6) δ: 6.93 (d, 2H, J = 2.3 Hz), 7.10 (dd, 2H, J = 2.3, 8.6 Hz), 7.40 (d, 2H, J = 8.6 Hz), 7.56 (d, 2H, J = 1.7 Hz), 10.99 (br s, 2H). 13C-NMR (acetone-d6) δ: 98.9, 112.5, 119.5, 122.3, 125.0, 130.2, 132.6, 135.9. HR-MS (ESI) m/z: Calcd for C16H10Cl2N2Na [(M+Na)+]: 323.0119. Found: 323.0131.
5-Chloro-1H,1'H-2,2'-biindole (7c): Colorless solid. Mp 265-267 °C (decomp.). IR (CHCl3): 3450 cm-1. 1H-NMR (acetone-d6) δ: 6.89-6.94 (m, 2H), 6.98-7.02 (m, 1H), 7.06-7.12 (m, 2H), 7.37-7.41 (m, 2H), 7.52-7.56 (m, 2H), 10.90 (br s, 1H), 10.97 (br s, 1H). 13C-NMR (acetone-d6) δ : 98.8, 99.3, 111.1, 112.3, 119.5, 119.8, 120.4, 121.9, 122.2, 125.0, 129.0, 130.2, 130.3, 133.3, 135.9, 137.5. HR-MS (ESI) m/z: Calcd for C16H11ClN2Na [(M+Na)+]: 289.0508. Found: 289.0511.
3,3'-Dichloro-1H,1'H-2,2'-biindole (7d): Colorless solid. Mp 180-183 °C (decomp.). IR (CHCl3): 3455 cm-1. 1H-NMR (CDCl3) δ: 7.24 (t, 2H, J = 8.1 Hz), 7.31 (td, 2H, J = 1.2, 6.6 Hz), 7.44 (d, 2H, J = 8.0 Hz), 7.65 (d, 2H, J = 8.0 Hz), 9.42 (br s, 2H). 13C-NMR (CDCl3) δ: 103.2, 111.5, 118.1, 121.2, 123.8, 124.4, 125.8, 134.7. HR-MS (ESI) m/z: Calcd for C16H10Cl2N2Na [(M+Na)+] 323.0119. Found: 323.0128.
General procedure for the reaction of 7 with dimethylaminoacetaldehyde diethyl acetal: Dimethylaminoacetaldehyde diethyl acetal (5 mmol) was added to a solution of 7 (0.5 mmol) in AcOH (5 mL) at room temperature, and the mixture was heated at 100 °C. After 1 h, the mixture was gradually cooled to room temperature. The mixture was diluted with AcOEt (100 mL), washed with saturated NaHCO3 solution and brine, and dried over MgSO4. The solvent was removed, and the residue was separated by silica gel column chromatography with hexane/AcOEt (5:1) to give 3, 4 and 8.
11,12-Dihydroindolo[2,3-a]carbazole (8): Colorless solid. Mp 353-355 °C (decomp.). IR (CHCl3): 3390 cm-1. 1H-NMR (acetone-d6) δ: 7.20 (t, 2H, J = 6.9 Hz), 7.35 (t, 2H, J = 7.5 Hz), 7.58 (d, 2H, J = 8.1 Hz), 7.93 (s, 2H), 8.14 (d, 2H, J = 7.5 Hz), 10.40 (br s, 2H). 13C-NMR (acetone-d6) δ: 111.3, 111.8, 119.2, 119.7, 121.1, 124.5, 124.7, 126.0, 139.6. HR-MS (ESI) m/z: Calcd for C18H12N2 (M+): 256.1001. Found: 256.1002.
Tjipanazole D (3): Colorless solid. Mp 300-304 °C (decomp.). IR (CHCl3): 3405 cm-1. 1H-NMR (acetone-d6) δ: 7.35 (dd, 2H, J = 1.7, 8.6 Hz), 7.60 (d, 2H, J = 8.6 Hz), 7.99 (s, 2H), 8.18 (d, 2H, J = 2.3 Hz), 10.64 (br s, 2H). 13C-NMR (acetone-d6) δ: 112.5, 112.8, 119.4, 120.7, 124.4, 124.8, 125.6, 126.7, 138.0. HR-MS (ESI) m/z: Calcd for C18H10Cl2N2Na [(M+Na)+]: 347.0119. Found: 347.0088.
Tjipanazole I (4): Colorless solid. Mp 315-318 °C (decomp.). IR (CHCl3): 3400 cm-1. 1H-NMR (acetone-d6) δ: 7.21 (t, 1H, J = 7.5 Hz), 7.33 (dd, 1H, J = 1.7, 8.6 Hz), 7.37 (ddd, 1H, J = 1.2, 6.9, 8.0 Hz), 7.59 (d, 2H, J = 8.6 Hz), 7.95 (s, 2H), 8.14 (d, 1H, J = 8.1 Hz), 8.16 (d, 1H, J = 2.3 Hz), 10.47 (br s, 1H), 10.56 (br s, 1H). 13C-NMR (acetone-d6) δ: 111.4, 111.9, 112.3, 112.6, 119.3, 119.4, 119.9, 120.2, 121.6, 124.2, 124.3, 124.5, 124.9, 125.8, 126.8, 137.9, 139.6 HR-MS (ESI) m/z: Calcd for C18H11ClN2 (M+): 290.0611. Found: 290.0624.

ACKNOWLEDGEMENTS
This work was supported in part by the Ministry of Education, Culture, Sports, Sciences, and Technology of Japan through a Grant-in Aid for Scientific Research (No. 26460012).

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