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Antitumour Heterocycles. Part 16.1The Synthesis of 7,10-Dimethoxyellipticine and its Py...
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Antitumour Heterocycles. Part 16.1The Synthesis of 7,10-Dimethoxyellipticine and its Pyrrolo[2,3-f]carbazole and Pyrrolo[3,2-f] Analogues
作者:
Pryanthi Dharmasena,
期刊:
Journal of Chemical Research, Synopses
(RSC Available online 1997)
卷期:
Volume 0,
issue 11
页码: 398-399
ISSN:0308-2342
年代: 1997
DOI:10.1039/a704615d
出版商: RSC
数据来源: RSC
摘要:
N N OMe OMe H N N OMe OMe H CO2Et H N N OMe OMe H N OMe OMe H CO2Et H 1a 1 3 4 5 6 7 8 9 10 11 2a 1 3 4 5 9 8 7 6 10 11 2 3a 3 1 4 5 6 7 8 9 10 4 R1 = R2 = H 5 R1 = H; R2 = CHO 7c R1 = CHO; R2 = H 2 R2 R1 OMe OMe Br HN COMe CN CN OMe OMe N COMe CN OMe MeO N H CN MeO MeO N H CN OMe OMe N H O C O Me 11c 12 13c Cu+ 15c 14c KOH–ethanol–H2O Pd(OAc)2 16 + OMe OMe NH Tos Br OMe OMe N Tos OMe OMe NH Me OMe OMe N H Br H OMe OMe N H OMe OMe N H Br H Br + 20 Cu 4 hn 21 8% 10% Pyridinium hydrobromide perbromide in [2H5]pyridine Pyridinium hydrobromide perbromide 27 HBr CD2Cl2, 4 days + NOE 398 J.CHEM. RESEARCH (S), 1997 J. Chem. Research (S), 1997, 398–399 J. Chem. Research (M), 1997, 2501–2532 Antitumour Heterocycles. Part 16.1 The Synthesis of 7,10-Dimethoxyellipticine and its Pyrrolo[2,3-f]carbazole and Pyrrolo[3,2-f] Analogues Pryanthi Dharmasena,a Ana M. F. Oliveira-Campos,b Maria J. R. P. Queiroz,b M. Manuela M. Raposo,b Patrick V. R. Shannon*a and Christine M.Webba aDepartment of Chemistry, University of Wales, Cardiff, P.O. Box 912, Cardiff, UK bDepartment of Chemistry, University of Minho, Campus de Gualtar, 4700 Braga, Portugal The final examples in our ellipticine/pyrrolocarbazole synthesis programme are 7,10-dimethoxyellipticine 1a and the corresponding pyrrolocarbazoles 2a and 3a which have been synthesised from 4,6-dimethoxyindole. This paper describes an efficient synthesis of the novel 7,10-dimethoxyellipticine 1a and of the pyrrolocarbazole analogues 2a and 3a.Earlier work3 had shown that formylation of the carbazole 4 gave, predictably, the aldehyde 5 but experience suggested that its isomer 7c would prove a successful precursor to the new ellipticine 1a. Following the use of a carbazole nitrile in our synthesis of 8,10-dimethoxyellipticine,4 Goldberg6 coupling of the nitrile 12 with the bromide 11c gave the amide 13c (70%) which on alkaline hydrolysis afforded the diphenylamine 14c (71%).Palladium acetate oxidation of the latter, however, gave only a very poor yield of the desired cyanocarbazole 15c, together with a major by-product 16 (ca. 9%) (Scheme 1) and other acetoxylated products. The carbazole 4, prepared either as previously3 or by the route shown in Scheme 2, was brominated with pyridinium hydrobromide perbromide in dichloromethane to give almost exclusively the required 6-bromo derivative 21. In order to investigate the possibility of a rearrangement from an initially formed 3-bromo intermediate 27 (Scheme 4) we first carried out the bromination in [2H5]pyridine with step-wise addition of an excess of brominating agent, and 1H NMR analysis of the reaction mixture.Both the bromides 27 and 21, which were formed simultaneously, were identified from their 1H NMR spectra in the ratio 2:1 as intermediates to the 3,6-dibromide 28 (Scheme 5), these being the only compounds observed. Chromatography afforded pure samples of the carbazoles 21, 27 and 28.When the reaction was repeated in dichloro[2H2]methane (the synthetic intermediate was prepared in dichloromethane), the predominant intermediate to the dibromocarbazole 28 was the bromocarbazole 21 with only a minute trace of the 3-bromocarbazole 27. When a 1:1 mixture of carbazoles 4 and 27 was kept in dichloro[2H2]- methane in the presence of an excess of HBr, no change was evident during the first 5 h. However, on standing for 4 days the 3-bromocarbazole 27 had completely rearranged to the 5-bromo isomer 21.This rearrangement was much too slow to implicate the bromo derivative 27 as a significant intermediate in the rapid bromination of carbazole 4 to 21 in dichloromethane. We conclude that bromination of carbazole 4 to 21 is rapid and direct in dichloromethane in contrast to the reaction in pyridine in which the predominant monobromocarbazole is 27; presumably rearrangement is precluded by the absence of free HBr.Treatment of the bromide 21 with copper(I) cyanide in refluxing dimethylformamide (cf. ref. 7) gave the carbazole nitrile 22 (52%) instead of the 6-cyanocarbazole. This solid (mp 289–291 °C) was clearly in the conformation with the two carbazole systems in orthogonal planes; two OMe singlets, the 4- and 1p-signals, were at abnormally high field and the 8p-methyl singlet, similarly, was at d 1.88. The bromo- *To receive any correspondence. Scheme 1 Scheme 2 and 4OMe OMe N H OMe OMe N H Br OMe OMe N H Br Br OMe OMe N H Br 4 Pyridinium hydrobromide perbromide [2H5]pyridine 27 28 21 + + CN OMe OMe N CN OMe OMe N Br OMe OMe N CHO OMe OMe N OMe OMe N OMe OMe N Y X EtO OEt H OMe OMe N NTos H 23 X–Y = CH N 24 X–Y = CH2 NH 25 X–Y = CH2 NTos OMe OMe N N H H H H H 22 1¢ 2 4 6 8¢ + 21 7c 4 26 1a OMe OMe N H H2C O OAc N H CO2Et OMe OMe N H CO2Et OMe OMe N H CO2Et H N H H H Me N H N H CO2Et H OMe EtO2C O C H H H OMe N H OMe OMe O EtO2C EtO2C O N H N H OMe EtO2C O C H H H OMe N CO2 Et H N N H OMe EtO2C O C H H H OMe C CO2Et H H N O 29 + K10 clay 2a (9%) 14% 4% 2% 14% 4% 10% 3a (14%) + 30 (16%) 10% 0.7% 7% 12.5% 32 (0.5%) + 31 (16%) 7% 1.5% 10% 1.5% 0.7% 7 4 3 10 33 (5%) 12.5% 0.7% 7 H H 2.6% 2.6% + J. CHEM.RESEARCH (S), 1997 399 carbazole 21 was, however, converted directly into the aldehyde 7c (74%) with tert-butyllithium and dimethylformamide (cf. ref. 12). The aldehyde was condensed with aminoacetaldehyde diethyl acetal to the Schiff’s base 23 (97%) which was converted into the amine 24 (94%) and the sulfonamide 25 (37%) before cyclisation in hydrochloric acid–dimethyl sulfoxide to give a mixture of the N-tosyldihydroellipticine 26 (27.6%) and ellipticine 1c (63%) (Scheme 3).Chromatography and crystallisation gave the ellipticine 1c (mp 235–237 °C). Considerable losses of the ellipticine occurred on chromatography. Condensation of 4,7-dimethoxyindole with the pyrrole 29 in the presence of K-10 montmorillonite clay was expected to give a complex range of products. After extensive chromatography and fractional crystallisation, pure samples of the expected pyrrolocarbazoles 3a and 2a were isolated.The structures of these isomers and the by-products 30, 31, 32 and 33 (Scheme 6) followed unambiguously from their spectroscopic properties. Techniques used: 1H-NMR, mass spectrometry References: 13 Schemes: 6 Received, 1st July 1997; Accepted, 12th August 1997 Paper E/7/04615D References cited in this synopsis 1 Part 15, L. Chunchatprasert, W. Cocker and P. V. R. Shannon, J. Chem. Res., 1997, (S) 2; (M) 0101. 3 R. J. Hall, P. Dharmasena, J. Marchant, A. M.-F. Oliveira- Campos, M. J. R. P. Queiroz, M. M. Raposo and P. V. R. Shannon, J. Chem. Soc., Perkin Trans. 1, 1993, 1879. 4 L. Chunchatprasert, P. Dharmasena, A. M. F. Oliveira-Campos, M. J. R. P. Queiroz, M. M. M. Raposo and P. V. R. Shannon, J. Chem. Res., 1996, (S) 84; (M) 630. 6 (a) P. E. Weston and H. Adkins, J. Am. Chem. Soc., 1928, 50, 859. (b) P. M. Dharmasena, A. M. F. Oliveira-Campos, M. M. M. Raposo and P. V. R. Shannon, J. Chem. Res., 1994, (S) 296; (M) 1601. 7 L. Friedman and H. Shechter, J. Org. Chem., 1961, 26, 2522. 12 R. E. Bolton, C. J. Moody, C. W. Rees and G. Tojo, J. Chem. Soc., Perkin Trans. 1, 1987, 931. Scheme 3 Scheme 5 Scheme 6
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