Oxidation of Cycloalkan[b]indoles with Iodine Pentoxide (1205)

Transcription

1 4700 Vol. 35 (1987) Chem. Pharm. Bull. 35(12) (1987) Oxidation of Cycloalkan[b]indoles with Iodine Pentoxide (1205) KIYOSHI YOSHIDA,*, a JIRO GOTO,a and YOSHIO BAN*, b Faculty of Pharmaceutical Sciences, Hokkaido University,a Sapporo 060, Japan and School of Pharmaceutical Science, Toho University,b Miyama, 2-2-1, Funabashi, Chiba 274, Japan (Received April 25, 1987) Oxidation of cycloalkan[b]indoles (3) with iodine pentoxide (1205) in 80% aqueous tetrahydrofuran (THF) at room temperature regioselectively afforded 6-oxocycloalkan[b]indoles (4) in various yields. The yield of this oxidation depends on the size of the ring fused with the indole nucleus. The essential reaction species is I2O5, not HIO3, which might be generated by hydrolysis of 1205 in the aqueous reaction medium. Oxidation of 1-hydroxytetrahydrocarbazole (5) under the above conditions afforded spiro oxindoles 6 and 7 in 36 and 39% yields, respectively, accompanied with only a trace of 1-oxotetrahydrocarbazole (4a). Keywords \indole oxidation; iodine pentoxide; cycloalkan[b]indole; 6-oxocycloalkan[b]- indole; 2-acylindole; 1-hydroxytetrahydrocarbazole; spiro oxindole It has been shown' that 2,3-disubstituted indole derivatives react easily with various oxidants. Most oxidizing agents act as electrophiles and initially attack the C-3 position of the indole ring, leading to the formation of 2-acyl-2-6) or 3-acylindoles,7,8) and to the oxidative cleavage of the C-2, C-3 double bond.9,10) We discovered that iodine pentoxide (I2O5), which had not been utilized in organic syntheses, oxidized the nine-membered amide (la) to provide 2-acylindole (2a) in good yield. This reaction was successfully applied to the total synthesis of "strychnos" type indole alkaloids.11) In the present paper, we wish to describe an application of the I2O5 oxidation to cycloalkan[b]indoles (3) for a convenient and regioselective oxidation of the C-2 side chain of indoles. 2 a b Chart 1 Cycloalkan[b]indoles (3a \d) were treated with 1.2 eq of I2O5 in 80% (v/v) aqueous tetrahydrofuran (THF) at room temperature to provide 6-oxocycloalkan[b]indoles (4a \d). The structures of the products were established by comparison of melting points and spectral data with the reported values.2'12' 13) In particular, the ultraviolet (UV) spectra') showed characteristic absorptions at about 240 and 310 nm due to Ĕ Ĕ* and Ĕ Ĕ*, transitions respectively. It is interesting that the oxidation yield is strongly dependent on the size of the ring fused with the indole nucleus.14) In the cases of 3b15) and 3d, the reactions quite smoothly

2 No TABLE I. Oxidation of Cycloalkan[b]indoles (3) with 1205 afforded products (4b and 4d)3) in 99 and 84% yields, respectively. In the oxidation of tetrahydrocarbazole (3a),16) however, the starting material disappeared within 0.5 h and the product (4a)12 obtained in 53% yield, while several unstable by-products were detected by thin-layer chromatography (TLC). Oxidation of 3c2) afforded the desired product (4c)2) in 14% yield, accompanied with 6-(3-indolyl)hexanal as an unstable oil in 6.6% isolated yield. The latter was characterized on the basis of the spectral data. The reason why the oxidation yields of 3 vary widely may be differences in the ring strain of the intermediates (Chart 3). For comparative studies of this reagent with other known oxidants, lc was treated with 1205 (1.2 eq) in 80% THF for 2 h to afford 2c in 48% yield. This result might be compared with the previous report of the oxidation of lc with Se026) to give the same product in 26% yield. Oxidation of lb under the same conditions also proceeded smoothly to give 2b in 87% yield. Other oxidants, for example, H51065) and Mn02,4) which oxidize cycloalkan[b]- indoles to 6-oxocycloalkan[b]indoles were not effective for lb and lc, and the starting materials were recovered. To clarify the oxidation mechanism, the following experiments were carried out. Oxidation of 3b with 0.5 eq of 1205 for 3 h gave (4b) in 83% yield, whereas with less than 0.5 eq of the reagent, several spots were monitored on TLC together with those of 3b and 4b. On the other hand, compound 3b when treated with 1.0 eq of iodic acid (HIO3) provided 4b in 81% yield as a single product. However, it took 4 h to complete the reaction. Reaction of compounds 3a and 3c with 1.2 eq of H103 provided none of the desired products, but the starting materials were recovered. From these experiments, it is clear that 1205 is the essential reaction species, and not HIO3 which might be generated in the aqueous reaction medium. Exceptionally, the most oxidizable substrate (3b) reacted with HI03 slowly to give 4b. In order to determine whether 6-hydroxycycloalkan[b]indoles are intermediates of this reaction or not, 1-hydroxytetrahydrocarbazole (5)17) was treated with 1.2 eq of 1205 under the standard conditions. To our surprise, spiro oxindoles (6 and 7) were obtained in 36% and 39% yields, respectively,18) accompanied with only a trace amount of 1-oxotetrahydrocarbazole (4a). The structures of the spiro oxindoles (6 and 7) were determined by the following chemical conversions. Compound 6, which crystallized as a single isomer, though its stereochemistry was unknown, was oxidized with pyridinium chlorochromate (PCC) to give 8 in 80% yield. The infrared (IR) spectrum of 8 showed an absorption at 1755 cm 1, which indicates the presence of a five-membered ketone. The unstable hemiacetal (7) of a mixture of the stereoisomers was oxidized with PCC to provide the lactone (9) in 67% yield. From these experiments, 6-hydroxycycloalkan[b]indoles should not be intermediates. Although the mechanism of the 1205 oxidation reaction has not yet been established, a possible mechanism is shown in Chart 3. Further mechanistic studies of the oxidation of

3 4702 Vol. 35 (1987) Chart 2 Chart 3 1-hydroxytetrahydrocarbazole (5) to the Spiro oxindoles (6 and 7) are in progress. It may be concluded that 1205 effectively oxidizes the C-2 side chain of indoles under aqueous conditions at room temperature to provide 2-acylindoles regioselectively. It is advantageous that the reagent is a stable crystalline compound, commercially available, and inexpensive. Experimental Melting points were determined on a Yamato M-P melting point apparatus and are uncorrected. IR spectra were recorded on a JASCO A-302 spectrometer and UV spectra were measured on a Hitachi ESP-3T spectrophotometer. Mass spectra (MS) were taken on a JEOL D-300 spectrometer. Proton nuclear magnetic resonance ('H-NMR) spectra were determined on a JEOL FX-100 spectrometer, and chemical shifts (6) are given in parts per million (ppm) downfield from tetramethylsilane as an internal standard. Coupling constants, J, are given in hertz (Hz);s, d, t, m, and br indicate singlet, doublet, triplet, multiplet, and broad, respectively. 6,7,8,9,10,11,12,13,14,15-Decahydro-5H-cyclododec[b]indole (3d) \Freshly distilled phenylhydrazine (2.59 g, 24.0 mmol) was added to a solution of cyclododecanone (3.64 g, 20.0 mmol) in 20 ml of ethanol and the mixture was allowed to stand at room temperature for 0.5 h. After evaporation of the solvent, the crude phenylhydrazone was heated at reflux temperature in 100 ml of 10% H2SO4 for 1.5 h. The separated oil was extracted with CH2C12, then the extract was dried and concentrated to give a brown solid, which was recrystallized from hexane to afford colorless crystals (3.85 g, 75.5%); mp C. IR (Nujol): 3280 cm -1. Anal. Calcd for C18H25N: C, 84.65; H, 9.87; N, Found: C, 84.61; H, 9.93; N, General Procedure for the Iodine Pentoxide ('205) Oxidation of Cycloalkan[b]indoles (3) Iodine pentoxide (400 mg, 1.20 mmol) was added to a solution of a cycloalkan[b]indole 3 (1.00 mmol) in 25 ml of 80% (v/v) aqueous THF. The mixture was stirred at room temperature, the solvent was evaporated off at room temperature and the residue was extracted with ethyl acetate. The extract was successively washed with water, 5%-Na2S2O3, saturated NaHCO3 and brine, and dried over Na2SO4. After evaporation of the solvent, the crude residue was purified by silica gel column chromatography to obtain the corresponding 6-oxocycloalkan[b]indole (4). 1-Oxo-1,2,3,4-tetrahydrocarbazole (4a) \mp Ž (from ethanol) [lit.12b) Ž]. IR (Nujol): 3340, l635 cm-1.

4 No Oxo-6,7,8,9,10-pentahydrocyclohept[b]indole (4b) mp C (from ethyl acetate-hexane) [lit.13) 148 Ž]. IR (Nujol): 3300, 1640 cm-1. 6-Oxo-6,7,8,9,10,11-hexahydro-5H-cycloct[b]indole (4c) mp C (from methanol) [lit.2) 185 Ž]. IR (Nujol): 3300, 1630 cm-1. 6-(3-Indolyl)hexanal \IR (CHCl3): 3380, 2729, 1719 cm-1. NMR (CCl4).ƒÂ: (6H, m), 2.28 (2H, t, J= 7.0 Hz), 2.64 (2H, t, J=7.0 Hz), (5H, m), 8.63 (1H, br), 9.77 (1H, t, J=2 Hz). 6-Oxo-6,7,8,9,10,11,12,13,14,15-decahydro-5H-cyclododec[b]indole (4d) mp C (from ethanol). IR (Nujol): 3310, 1640cm-1. Anal. Calcd for C18H23NO: C, 80.25; H, 8.61; N, Found: C, 80.36; H, 8.67; N, Acety1-7-oxo-1,2,3,4,5,6,7,8-octahydroazonino[5,4-b]indole (2c) Yield 48%; mp C [lit.6) Ž]. IR (Nujol): 3250, 1625, 1575, 1530 cm-1. UV ƒéetohmaxnm: 314, Anm: 269. Anal. Calcd for C16H18N202: C, 71.09; H, 6.71; N, Found: C, 70.91; H, 6.64; N, (2-Bromobutyry1)-7-oxo-1,2,3,4,5,6,7,8-octahydroazonino[5,4-Mindole (2b) \Yield 87%; mp C (from ether-hexane). IR (Nujol): 3320, 1630, 1610 cm-1. UV ƒéetohmaxnm: 238, 314. Anal. Calcd for C18H21BrN2O2: C, 57.30; H, 5.61; N, Found: C, 57.46; H, 5.71; N, O5 Oxidation of 1-Hydroxy-1,2,3,4,-tetrahydrocarbazole (5) \Iodine pentoxide (800 mg, 2.40 mmol) was added to a solution of 5 (374 mg, 2.00 mmol) in 50 ml of 80% aqueous THF and the mixture was stirred at room temperature for 50 min. After general work up described above, the crude residue was purified by flash chromatography (ethyl acetate : benzene= 1: 1) to obtain 7 (171 mg, 39%) as an unstable solid and 6 (145 mg, 36%); mp Ž (from ethyl acetate). IR (CHCl3): 3340, 1710, 1620cm-1. MS m/z: 203 (M+), 175, 146, 128. UV 253, 282; H n m : 228. NMR (CDCl3)ƒÂ (5: (6H, m), 4.4 (1H, m), (4H, m), 8.24 (1H, br). Anal. Calcd for C12H13NO2: C, 70.91; H, 6.45; N, Found: C, 70.61; H, 6.44; N, The Spiroketone (8) \A solution of 6 (35 mg, mmol) in 1 ml of CH2C12 was added dropwise to a suspension of PCC (185 mg, 0.86 mmol) and Celite (1.0 g) in 4 ml of dry CH2Cl2 and the reaction mixture was stirred for 4 h. The mixture was diluted with 5 ml of ether and filtered through a short column packed with silica gel. After concentration of the filtrate, the residue was purified by silica gel column chromatography (ethyl acetate : hexane = 2 : 3) to give 8 (28 mg, 80%) as colorless crystals; mp C (from ethyl acetate). IR (CHCl3): 3450, 1775, 1710, 1620 cm-1. MS m/z: 201 (M t), 146. NMR (CDCl3) (5: (m, 6H), (m, 4H), 7.80 (br, 1H). Anal. Calcd for C12H11NO2: C, 71.62; H, 5.51; N, Found: C, 71.71; H, 5.49; N, The Spirolactone (9) \The hemiacetal 7 (18 mg, mmol) was treated with PCC (106 mg, 0.49 mmol) and Celite (1.2 g) in 4 ml of dry CH2C12 for 7 h. After work-up as described above, the crude residue was purified by silica gel preparative TLC (ethyl acetate : hexane =1 : 1) to give the lactone 9 (12 mg, 67%); mp C(from ethyl acetate-hexane). IR (CHC13): 3440, 1740, 1625 cm-1. MS m/z: 217 (M +), 189, 161, 146, 133. Anal. Calcd for Cl2H11NO3: C, 66.35; H, 5.10; N, Found: C, 66.19; H, 5.11; N, Acknowledgment We gratefully acknowledge financial support for this work by a Grant-in-Aid for Special Project Research (No , to Professor Michio Kobayashi) from the Ministry of Education, Science and Culture, Japan. We also thank Professors Osamu Yonemitsu and Masakatsu Shibasaki, and Dr. Takeshi Wakamatsu (Hokkaido University), for their encouragement and helpful suggestions. References and Notes 1) R. J. Sundberg, "The Chemistry of Indoles," Academic Press, New York, 1979, pp ) B. Witkop, J. B. Patrick, and M. Rosenblum, J. Am. Chem. Soc., 73, 2641 (1951). 3) F. Y. Chen and E. Leete, Tetrahedron Lett., 1963, ) B. Hughes and H. Suschitzky, J. Chem. Soc., 1965, ) L. J. Dolby and D. L. Booth, J. Am. Chem. Soc., 88, 1049 (1966). 6) S. Sakai, A. Kubo, K. Katsuura, K. Mochinaga, and M. Ezaki, Chem. Pharm. Bull., 20, 76 (1972). 7) M. F. Bartlett, D. F. Dickel, and W. I. Taylor, J. Am. Chem. Soc., 80, 126 (1958). 8) Y. Oikawa and 0. Yonemitsu, J. Org. Chem., 42, 1213 (1977). 9) B. Witkop and S. Goodwin, J. Am. Chem. Soc., 75, 3371 (1953) and references cited therein. 10) a) M. Nakagawa, S. Kato, S. Kataoka, and T. Hino, J. Am. Chem. Soc., 101, 3136 (1979); b) M. Nakagawa, S. Kato, S. Kataoka, S. Kadota, H. Watanabe, H. Okajima, T. Hino, and B. Witkop, Chem. Pharm. Bull., 29, 1013 (1981). 11) a) Y. Ban, K. Yoshida, J. Goto, and T. Oishi, J. Am. Chem. Soc., 103, 6990 (1981); b) Y. Ban, K. Yoshida, J. Goto, T. Oishi, and E. Ishigamori, Tetrahedron, 39, 3657 (1983). 12) a) T. Shioiri, K. Ishizumi, and S. Yamada, Chem. Pharm. Bull., 15, 1010 (1967); b) K. Ishizumi, T. Shioiri, and S. Yamada, ibid., 15, 863 (1967). 13) M. Muhlstadt and W. Treibs, Ann., 608, 38 (1957). 14) Oxidation of cyclopent[b]indole immediately afforded a dark tar. 15) W. H. Perkin and S. G. P. Plant, J. Chem. Soc., 1928, 2583.

5 4704 Vol. 35 (1987) 16) C. U. Rogers and B. B. Corson, "Organic Syntheses," Coll. Vol. IV, ed. by N. Rabjohn, John Wiley and Sons, Inc., New York, 1963, p ) J. S. Beer, L. McGrath, and A. Robertson, J. Chem. Soc., 1950, ) Dolby and Booth reported') that the oxidation of 3a with H5106 afforded no 1-oxotetrahydrocarbazole (4a) although at that time they were not able to characterize the products. In our experiments, unstable products 6 and 7 were separated on TLC only when benzene-ethyl acetate was used as a developing solvent.