HETEROCYCLES

Short Paper | Regular issue | Vol. 91, No. 7, 2015, pp. 1423-1428
Received, 15th April, 2015, Accepted, 20th May, 2015, Published online, 29th May, 2015.
DOI: 10.3987/COM-15-13228

■ Cu-Mediated Oxidative Dimerization of Skatole to Tryptanthrin, an Indolo[2,1-b]quinazolone Alkaloid

Tomoki Itoh, Takumi Abe, Shuhei Nakamura, and Minoru Ishikura*

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

Abstract

A one-pot conversion of skatole to tryptanthrin, an indolo[2,1-b]quinazoline alkaloid, was achieved by Cu-mediated oxidation.

Tryptanthrin (1a) is an indole alkaloid that was first isolated from a culture of the fungus Candida lipolytica.1 This compound contains an intriguing indolo[2,1-b]quinazoline moiety and has potent biological activities,2 including strong inhibition of pathogenic microorganisms, antifungal activity, antiparasitic activity, and antitumor activity. Therefore, several synthetic methods for 1a have been reported,3 typically involving the condensation of isatin with isatoic acid4 and the reaction of anthranilic acid with isatin in the presence of SOCl2.5 However, oxidative dimerization of indole-3-carbaldehyde (2a) provides a straightforward approach to 1a. The one-pot formation of 1a based on the oxone-induced oxidative dimerization of 2a was achieved by Grundt.6 We reported the Dakin oxidation of 2a with urea hydrogen peroxide as an oxidant, where 1a was obtained through the condensation of 2a with isatoic anhydride generated in situ from 2a and further oxidation/cyclization sequences.7 Recently, a facile formation of 1-methyl-3-indolecarbaldehyde by Cu-catalyzed oxidation of 1-methylskatole and 1-methylgramine using CuBr2·SMe2 and DABCO in DMF under O2 (1 atm) was reported.8 Therefore, we were interested in investigating the feasibility of a one-pot conversion of skatole (3a) and gramine (4a) to 1a involving the intermediate formation of aldehyde 2a via the oxidation of 3a and 4a. Herein, we report one-pot access to 1a based on Cu-mediated oxidation of 3a and 4a.
Initially, 3a was subjected to aerobic oxidation with CuBr2·SMe2 (0.2 equiv) and DABCO (1 equiv) in DMF at 100 °C for 24 h (Table 1). This allowed the isolation of 1a in 15% yield accompanied by 2a in 40% yield (Entry 1). However, replacing CuBr2·SMe2 with Cu(OTf)2 produced 2a in 72% yield, and the formation of 1a was not observed (Entry 2). Using CuBr2·SMe2, Cu(OAc)2, and CuBr with PCC as an oxidant did not improve the yield (Entries 3–5). In contrast, using CuI with PCC afforded 1a in 30% yield without the formation of 2a. Increasing the catalyst loading to 0.5 equiv provided 1a in 37% yield (Entries 6 and 7). Moreover, the reaction was accelerated by increasing the amounts of PCC (2 equiv) and CuI (1.1 equiv), which produced 1a in 52% yield (Entry 9). Oxidation of 3a with PCC resulted in the formation of 2a in 20% yield (Entry 10). In addition, treating 5-substituted skatoles 3b, 3c, and 3d under the identified conditions provided 1b, 1c, and 1d in 33%, 30%, and 27% yields, respectively (Entries 11–13). The formation of 1 from 3 is explicable according to the previously proposed reaction path,7 involving intermediate formation of 2 from 3 in the initial step.

Since 1-methyl-3-indolecarbaldehyde was also obtainable through the oxidation of 1-methylgramine,8 we next examined whether gramine (4a) would tolerate the dimerization conditions (Table 2). First, 4a was oxidized with CuI and PCC, although only trace amounts of 1a were obtained, accompanied by the formation of significant amounts of 2a (Entry 1). Trace conversion of 4a to 1a remained unaltered even in additional reactions, in which the formation of 2a also predominated (Entries 2–4). Although 4a did not tolerate the oxidative dimerization, heating 4a with PCC (1.1 equiv) in DMF at 100 °C for 0.5 h afforded 2a in 85% yield without the formation of 1a (Entry 5). These conditions also worked for the oxidation of gramines 4b–4g, producing corresponding aldehydes 2b–2h in high yields (Entries 6–12).
In summary, during the present investigation of the oxidation of skatoles 3 and gramines 4, a difference in the reaction outcome between 3 and 4 was observed. Thus, Cu-mediated oxidative dimerization of skatoles 3 provided indoloquinazolones 1 in a one-pot reaction, which involved intermediate formation of aldehydes 2. However, evaluation of the oxidation of gramines 4 showed that the oxidation of 4 predominantly produced aldehydes 2 instead of dimerization products 1.9

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.
General procedure for the oxidation of 3: After a mixture of CuI (4.4 mmol) and PCC (8 mmol) in DMF (30 mL) was stirred at room temperature for 30 min, 3 (4 mmol) was then added to the mixture and the mixture was stirred at 100 °C for 24 h. After cooling, the resulting mixture was added to 10% aqueous HCl solution, extracted with AcOEt (100 mL), washed with brine, and dried over MgSO4. The solvent was removed, and the residue was purified by silica gel column chromatography with CH2Cl2 to give 1.
Tryptanthrin (1a): Yellow solid. Mp 266-268 °C. IR (CHCl3): 1728, 1694 cm-1. 1H-NMR (CDCl3) δ: 7.42 (t, J = 8.0 Hz, 1H), 7.66 (t, J = 7.5 Hz, 1H), 7.78 (td, J = 1.2, 7.5 Hz, 1H), 7.84 (td, J = 1.2, 8.0 Hz, 1H), 7.90 (d, J = 7.5 Hz, 1H), 8.01 (d, J = 8.0 Hz, 1H), 8.41 (dd, J = 1.2, 8.0 Hz, 1H), 8.60 (d, J = 8.0 Hz, 1H). 13C-NMR (CDCl3) δ: 118.1, 122.0, 123.8, 125.5, 127.3, 127.6, 130.3, 130.8, 135.2, 138.4, 144.4, 146.4, 146.7, 158.2, 182.7. HR-MS (ESI) m/z: Calcd for C15H9N2O2 [(M+H) +]: 249.0664. Found: 249.0669.
2,8-Dimethylindolo[2,1-b]quinazoline-6,12-dione (1b): Yellow solid. Mp 251-253 °C. IR (CHCl3): 1724, 1694 cm-1. 1H-NMR (CDCl3) δ: 2.44 (s, 3H), 2.54 (s, 3H), 7.55 (d, J = 8.6 Hz, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.68 (s, 1H), 7.89 (t, J = 8.1 Hz, 1H), 8.20 (s, 1H), 8.46 (d, J = 8.6 Hz, 1H). 13C-NMR (CDCl3) δ: 21.2, 21.7, 117.8, 122.2, 123.6, 125.5, 127.3, 130.6, 136.3, 137.4, 138.9, 141.2, 144.1, 144.4, 144.7, 158.1, 182.8. HR-MS (ESI) m/z: Calcd for C17H13N2O2 [(M+H)+]: 277.0977. Found: 277.0977.
2,8-Dimethoxyindolo[2,1-b]quinazoline-6,12-dione (1c): Yellow solid. Mp 281-283 °C (EtOH). IR (CHCl3): 1730, 1687 cm-1. 1H-NMR (CDCl3) δ: 3.88 (s, 3H), 3.97 (s, 3H), 7.29 (dd, J = 2.9, 8.6 Hz, 1H), 7.36 (d, J = 3.5 Hz, 1H), 7.38 (dd, J = 2.9, 9.2 Hz, 1H), 7.80 (d, J = 2.9 Hz, 1H), 7.92 (d, J = 8.6 Hz, 1H), 8.49 (d, J = 9.2 Hz, 1H). 13C-NMR (CDCl3) δ: 56.1, 56.2, 108.2, 108.4, 119.2, 123.4, 124.2, 124.9, 125.4, 132.5, 140.3, 140.9, 143.1, 157.6, 158.8, 161.4, 182.6. HR-MS (ESI) m/z: Calcd for C17H12N2NaO4 [(M+Na)+]: 331.0695. Found: 331.0693.
2,8-Dichloroindolo[2,1-b]quinazoline-6,12-dione (1d): Yellow solid. Mp 287-289 °C. IR (CHCl3): 1736, 1689 cm-1. 1H-NMR (CDCl3) δ: 7.75 (dd, J = 2.3, 8.6 Hz, 1H), 7.80 (dd, J = 2.3, 8.6 Hz, 1H), 7.87 (d, J = 2.3 Hz, 1H), 7.96 (d, J = 8.6 Hz, 1H), 8.39 (d, J = 2.5 Hz, 1H), 8.57 (d, J = 8.6 Hz, 1H). 13C-NMR (CDCl3) δ: 119.4, 123.2, 124.9, 125.4, 127.3, 132.3, 133.7, 135.8, 137.1, 137.9, 144.1, 144.3, 145.1, 156.9, 181.2. HR-MS (ESI) m/z: Calcd for C15H7Cl2N2O2 [(M+H)+]: 316.9885, 318.9855. Found: 316.9882, 318.9843.
General procedure for the oxidation of 4: PCC (1.1 mmol) was added to a stirred solution of 4 (1 mmol) in DMF (5 mL) at 100 °C (pre-heated oil bath) and the mixture was stirred at 100 °C for 0.5 h. After cooling, the resulting mixture was added to 10% aqueous HCl solution, extracted with AcOEt (100 mL), washed with brine, and dried over MgSO4. The solvent was removed, and the residue was purified by silica gel column chromatography with CH2Cl2 to give 2.
1-Methylindole-3-carbaldehyde (2b): Colorless solid. Mp 69-70 °C. IR (CHCl3): 1659 cm-1. 1H-NMR (DMSO-d6) δ: 3.85 (s, 3H), 7.23 (t, J = 8.0 Hz, 1H), 7.29 (t, J = 7.5 Hz, 1H), 7.53 (d, J = 8.0 Hz, 1H), 8.07 (d, J = 8.0 Hz, 1H), 8.22 (s, 1H), 9.86 (s, 1H). 13C-NMR (CDCl3) δ: 33.9, 111.5, 117.5, 121.4, 123.0, 124.0, 125.1, 138.2, 142.1, 184.9. HR-MS (ESI) m/z: Calcd for C10H9NNaO [(M+Na)+]: 182.0582. Found: 182.0585.
1-Methoxyindole-3-carbaldehyde (2c): Colorless solid. Mp 50-51 °C. IR (CHCl3): 1658 cm-1. 1H-NMR (CDCl3) δ: 4.19 (s, 3H), 7.33 (t, J = 8.0 Hz, 1H), 7.38 (t, J = 7.5 Hz, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.88 (s, 1H), 8.30 (d, J = 7.4 Hz, 1H), 9.99 (br s, 1H). 13C-NMR (CDCl3) δ: 66.9, 108.8, 114.2, 121.8, 122.2, 123.6, 124.7, 131.8, 132.8, 184.2. HR-MS (ESI) m/z: Calcd for C10H10NO2 [(M+H)+]: 176.0712. Found: 176.0705.
5-Methyl-1H-indole-3-carbaldehyde (2d): Colorless solid. Mp 147-148 °C. IR (CHCl3) δ: 3419, 1647, 1628 cm-1. 1H-NMR (DMSO-d6) δ: 2.36 (s, 3H), 7.04 (dd, J = 1.7, 8.6 Hz, 1H), 7.35 (d, J = 8.5 Hz, 1H), 7.87 (s, 1H), 8.18 (s, 1H), 9.86 (s, 1H), 11.98 (br s, 1H). 13C-NMR (DMSO-d6) δ: 21.7, 112.6, 118.4, 121.1, 124.9, 125.5, 131.6, 135.9, 138.9, 185.4. HR-MS (ESI) m/z: Calcd for C10H10NO [(M+H)+]: 160.0762. Found: 160.0734.
5-Methoxy-1H-indole-3-carbaldehyde (2e): Colorless solid. Mp 182-183 °C. IR (CHCl3): 3462, 1660 cm-1. 1H-NMR (DMSO-d6) δ: 3.75 (s, 3H), 6.85 (dd, J = 2.3, 8.6 Hz, 1H), 7.37 (d, J = 8.6 Hz, 1H), 7.55 (d, J = 2.9 Hz, 1H), 8.17 (s, 1H), 9.86 (s, 1H), 11.99 (br s, 1H). 13C-NMR (DMSO-d6) δ: 55.8, 103.0, 113.7, 113.8, 118.6, 125.4, 132.3, 138.9, 156.2, 185.4. HRMS (ESI): calcd for C10H9NNaO2 [(M+Na)+]: 198.0531. Found 198.0494.
5-Bromo-1H-indole-3-carbaldehyde (2f): Colorless solid. Mp 204-206 °C. IR (CHCl3): 3460, 3446, 1667 cm-1. 1H-NMR (DMSO-d6) δ: 7.35 (d, J = 8.1 Hz, 1H), 7.46 (d, J = 7.5 Hz, 1H), 8.18 (s, 1H), 8.31 (s, 1H), 9.89 (s, 1H), 12.29 (br s, 1H). 13C-NMR (DMSO-d6) δ: 115.1, 115.4, 117.9, 123.5, 126.4, 126.6, 136.3, 139.8, 185.7. HR-MS (ESI) m/z: Calcd for C9H6BrNNaO [(M+Na)+]: 245.9530, 247.9510. Found: 245.9545, 247.9512.
4-Bromo-1H-indole-3-carbaldehyde (2g): Colorless solid. Mp 182-184 °C. IR (CHCl3): 3447, 1657 cm-1. 1H-NMR (DMSO-d6) δ: 7.14 (t, J = 7.7 Hz, 1H), 7.43 (d, J = 7.7 Hz, 1H), 7.53 (d, J = 8.1 Hz, 1H), 8.27 (s, 1H), 10.64 (s, 1H), 12.55 (br s, 1H). 13C-NMR (DMSO-d6) δ: 112.8, 112.9, 118.3, 124.3, 125.2, 126.5, 134.4, 138.8, 185.1. HR-MS (ESI) m/z: Calcd for C9H7BrNO [(M+H)+]: 223.9711, 225.9691. Found: 223.9694, 225.9725.
7-Bromo-1H-indole-3-carbaldehyde (2h): Colorless solid. Mp 169-171 °C. IR (CHCl3): 3447, 1668 cm-1. 1H-NMR (DMSO-d6) δ: 7.14 (d, J = 8.0 Hz, 1H), 7.46 (d, J = 6.9 Hz, 1H), 8.06 (dd, J = 1.2, 8.1 Hz, 1H), 8.34 (s, 1H), 9.93 (s, 1H), 12.36 (br s, 1H). 13C-NMR (DMSO-d6) δ: 105.4, 119.4, 120.8, 124.2, 126.3, 126.7, 136.0, 139.6, 185.9. HR-MS (ESI) m/z: Calcd for C9H7BrNO [(M+H)+]: 223.9711, 225.9691. Found: 223.9719, 225.9721.

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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