Sulfur-Rich Heterocycles from 2-Metalated Benzo[b]thiophene and Benzo[b]furan: Synthesis and Structure Tomasz Janosik,†,‡ Birgitta Stensland,§ and Jan Bergman*,†,‡ Unit for Organic Chemistry, CNT, Department of Biosciences at Novum, Karolinska Institute, Novum Research Park, SE-141 57 Huddinge, Sweden, So¨ derto¨ rn University College, SE-141 04 Huddinge, Sweden, and Preformulation and Biopharmaceutics, Solid State Analysis, AstraZeneca PAR & D/SBBG B341:3, SE-151 85 So¨ derta¨ lje, Sweden
represents yet another example of a naturally occurring pentathiepin. A few additional metabolites belonging to this class have been isolated from other Lissoclinum species, as well as from Polycitor and Eudistoma species.9 Numerous reports dealing with preparation of synthetic pentathiepins have appeared,1-3,10 and preparative routes aiming at acyclic pentasulfides have also been explored.10e,11 Despite all previous contributions in this field, many aspects of pentathiepin chemistry still remain to be explored, and there is also a need for developing routes to new pentathiepins in order to provide material for biological studies.
[email protected] Received March 12, 2002
Abstract: The reaction of 2-lithiated benzo[b]thiophene with 8 equiv of elemental sulfur was found to give pentathiepino[6,7-b]benzo[d]thiophene. In contrast, treatment of 2-lithiated benzo[b]furan with sulfur under similar conditions produced the interesting ring system bis(benzo[4,5]furo)[2,3-e:3′,2′-g][1,2,3,4]tetrathiocine. Both of these new cyclic polysulfides were studied by X-ray crystallography. Two polymorphic forms of pentathiepino[6,7-b]benzo[d]thiophene were found, displaying similar conformations but different packing schemes, which was also evident from powder diffraction data.
Previous studies performed in our group on the thionation of isatin with P4S10 in pyridine led to the isolation of pentathiepino[6,7-b]indole (1),1 which was also prepared later using a rational protocol based on the treatment of 2-lithiated indoles with elemental sulfur.2 The pentathiepins constitute a class of compounds that has attracted considerable interest. Thus, e.g., compound 2 has been demonstrated to exhibit a wide range of powerful antifungal activities,3 while the benzo-fused pentathiepin 3 was recently shown to display DNAcleaving properties.4 Considerable effort has also been devoted to developing syntheses5 of the cytotoxic alkaloid varacin (4), isolated from the ascidian Lissoclinum vareau.6 The closely related lissoclinotoxin A7 (5) from Lissoclinum perforatum, the correct structure of which was not elucidated until several years after its isolation,8 †
Karolinska Institute. So¨derto¨rn University College. Solid State Analysis, AstraZeneca PAR & D. (1) Bergman, J.; Sta˚lhandske, C. Tetrahedron Lett. 1994, 35, 52795782. (2) Rewcastle, G. W.; Janosik, T.; Bergman, J. Tetrahedron 2001, 57, 7185-7189. (3) (a) Vladuchick, S. A.; Fukanaga, T.; Simmons, H. E.; Webster O. W. J. Org. Chem. 1980, 45, 5122-5130. (b) Vladuchick, S. A. US Patent 4 094 985, June 13, 1978. (4) Chatterji, T.; Gates, K. S. Bioorg. Med. Chem. Lett. 1998, 8, 535538. (5) (a) Behar, V.; Danishefsky, S. J. J. Am. Chem. Soc. 1993, 115, 7017-7018. (b) Ford, P. W.; Davidson, B. S. J. Org. Chem. 1993, 58, 4522-4523. (c) Toste, F. D.; Still, I. W. J. J. Am. Chem. Soc. 1995, 117, 7261-7262. (d) Ford, P. W.; Narbut, M. R.; Belli, J.; Davidson, B. S. J. Org. Chem. 1994, 59, 5955-5960. (6) Davidson, B. S.; Molinski, T. F.; Barrows, L. R.; Ireland, C. M. J. Am. Chem. Soc. 1991, 113, 4709-4710. (7) Litaudon, M.; Guyot, M. Tetrahedron Lett. 1991, 32, 911-914. (8) Litaudon, M.; Trigalo, F.; Martin, M.-T.; Frappier, F.; Guyot, M. Tetrahedron 1994, 50, 5323-5334. ‡ §
In an extension of our work on pentathiepino[6,7-b]indoles1,2 and other indole-containing cyclic polysulfides or [1,2]dithiins,12 the reaction of 2-lithiated benzo[b]thiophene (6) with elemental sulfur has now been studied, as it was envisaged that a pentathiepin could be formed under appropriate conditions, in similarity with the behavior of 2-lithiated indoles.2 2-Lithiation of benzo[b]thiophene (6), followed by quenching of the anion with 1 equiv of sulfur, has been reported to produce benzo[b]thiophene-2-thiol (7) in a good yield.13 However, reactions of 2-lithiated benzo[b]thiophene with a larger excess of sulfur never have been described. Therefore, we have treated 2-metalated benzo[b]thiophene (6) with 8 equiv of sulfur, which gave the new ring system pentathiepino[6,7-b]benzo[d]thiophene (8) in 28% yield as the only isolable product (Scheme 1). It has previously been recognized that organic polysulfides can adopt many different ring sizes, e.g., fivemembered rings14 or even 10-membered10e,15 or 20membered15 macrocycles incorporating eight consecutive sulfur atoms. Even sulfur itself has been shown to consist of an equilibrium mixture of S6, S7, and S8 on dissolution (9) (a) Searle, P. A.; Molinski, T. F. J. Org. Chem. 1994, 59, 66006605. (b) Makarieva, T. N.; Stonik, V. A.; Dmitrenok, A. S.; Grebnev, B. B.; Isakov, V. V.; Rebachyk, N. M.; Rashkes, Y. W. J. Nat. Prod. 1995, 58, 254-258. (c) Compagnone, R. S.; Faulkner, D. J.; Carte´, B. K.; Chan, G.; Freyer, A.; Hemling, M. E.; Hofmann, G. A.; Mattern, M. R. Tetrahedron 1994, 50, 12785-12792. (10) For selected references, see: (a) Chenard, B. L.; Miller, T. J. J. Org. Chem. 1984, 49, 1221-1224. (b) Chenard, B. L.; Harlow, R. L.; Johnson, A. L.; Vladuchick, S. A. J. Am. Chem. Soc. 1985, 107, 38713879. (c) Sato, R.; Ohyama, T.; Ogawa, S. Heterocycles 1995, 41, 893896. (d) Sato, R.; Ohyama, T.; Kawagoe, T.; Baba, M.; Nakayo, S.; Kimura, T.; Ogawa, S. Heterocycles 2001, 55, 145-154. (e) Steudel, R.; Hassenberg, K.; Mu¨nchow, V.; Schumann, O.; Pickardt, J. Eur. J. Inorg. Chem. 2000, 921-928. (f) Macho, S.; Rees, C. W.; Rodrı´guez, T.; Torroba, T. Chem. Commun. 2001, 403-404. (11) Hou, Y.; Abu-Yousef, I. A.; Harpp, D. N. Tetrahedron Lett. 2000, 41, 7809-7812, and references therein. (12) (a) Janosik, T.; Bergman, J.; Stensland, B.; Sta˚lhandske, C. J. Chem. Soc., Perkin Trans. 1 2002, 330-334. (b) Janosik, T.; Bergman, J.; Romero, I.; Stensland, B.; Sta˚lhandske, C.; Marques, M. M. B.; Santos, M. M. M.; Lobo, A. M.; Prabhakar, S.; Duarte, M. F.; Floreˆncio, M. H. Eur. J. Org. Chem. 2002, 1392-1396. (13) Chapman, N. B.; Hughes, C. G.; Scrowston, R. M. J. Chem. Soc. (C) 1970, 2431-2435. 10.1021/jo0257086 CCC: $22.00 © 2002 American Chemical Society
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Published on Web 07/19/2002
SCHEME 1a
a Reagents and conditions: (i) BuLi, THF, from -78 °C to room temperature; (ii) S8 (8 equiv), from -10 °C to room temperature, 24 h.
SCHEME 2a
a Reagents and conditions: (i) NaH, THF, -10 °C; (ii) S (5 8 equiv), from -10 °C to room temperature; (iii) NaBH4, CH3I, EtOH, rt.
in polar solvents at ambient temperature.16 Therefore, the relatively easy formation of the pentathiepin 8 is not completely understood. We speculate, that the process leading to the formation of the pentathiepin ring involves initial formation of benzo[b]thiophene-2-thiol (7), which then reacts further in its thiolate anion form with the sulfur present in excess, and the growing sulfur chain so obtained finally attacks the neighboring 3-position of the thiophene ring, thus producing the pentathiepin 8. This hypothesis was supported by an experiment, wherein treatment of the readily available benzo[b]thiophene-2thiol13 (7) with NaH in THF, followed by reaction of the resulting anion with sulfur (5 equiv), produced pentathiepino[6,7-b]benzo[d]thiophene (8) in 25% yield (Scheme 2). In our thionation experiments on benzo[b]thiophene, we could not isolate any species possessing larger rings than the pentathiepin 8, although the formation of such products cannot be ruled out, as the slower moving fractions obtained from the chromatography (eluted with hexane) contained nonseparable mixtures of several compounds. In analogy to some previous studies involving pentathiepins,2,10b compound 8 was also treated with NaBH4 in the presence of CH3I to give an excellent yield (95%) of the previously reported 2,3-bis(methylthio)benzo[b]thiophene17 (9) (Scheme 2), a useful precursor for the preparation of tetrathiafulvalene derivatives for application in the synthesis of organic conducting materials.17b,d Now, the attention has been turned toward the reaction of 2-lithiated benzo[b]furan (10) with elemental sulfur under conditions similar to those used for the preparation of 8, as we reasoned that the corresponding pentathiepin can be formed in analogy with the results described above. However, a product assigned the struc(14) For example, see: (a) Bartlett, P. D.; Ghosh, T. J. Org. Chem. 1987, 52, 4937-4943. (b) Ghosh, T.; Bartlett, T. J. Am. Chem. Soc. 1988, 110, 7499-7506. (c) Sato, R. Pure Appl. Chem. 1999, 71, 489494 and references therein. (15) Steudel, R.; Hassenberg, K.; Pickardt, J. Eur. J. Org. Chem. 2001, 2815-2817 and references therein. (16) Tebbe, F. N.; Wasserman, E.; Peet, W. G.; Vatvars, A.; Hayman, A. C. J. Am. Chem. Soc. 1982, 104, 4971-4972. (17) (a) Clark, P. D.; Mesher, S. T. E.; Primak, A. Phosphorus, Sulfur Silicon Relat. Elem. 1996, 114, 99-108. (b) Clark, P. D.; Mesher, S. T. E.; Primak, A.; Yao, H. Phosphorus, Sulfur Silicon Relat. Elem. 1997, 120-121, 413-414. (c) Clark, P. D.; Mesher, S. T. E.; Primak, A.; Yao, H. Catal. Lett. 1997, 48, 79-82. (d) Clark, P. D.; Hinman, A. S.; Mesher, S. T. E. Phosphorus, Sulfur Silicon Relat. Elem. 2000, 164, 153-159.
SCHEME 3a
a Reagents and conditions: (i) BuLi, THF, -78 °C; (ii) S (8 8 equiv), from -78 °C to room temperature, 6.5 h.
ture 11, containing a central eight-membered ring incorporating a chain of four sulfur atoms and a 3,3′bibenzo[b]furan core,18 was instead isolated in 35% yield (Scheme 3). The structure of 11 was supported by both low- and high-resolution mass spectrometry, as a molecular ion at m/z 360 suggested the presence of two benzo[b]furan units and four sulfur atoms, while both the 1H and 13C NMR data displayed only one set of aromatic signals, implying a symmetrical molecule. The tetrasulfide 11 was also the only isolable product (22% yield) when the lithiation of benzo[b]furan (10) was performed using LDA, followed by quenching with sulfur. Although no intermediate species could ever be isolated from the reaction mixture, the formation of the tetrathiocine 11 can be rationalized in terms of the initial formation of the assumed primary product, the pentathiepin 12. Pentathiepin 12 may then undergo a baseinduced cleavage of the seven-membered ring, possibly generating an intermediate 3-thiocarbonyl species, which might then in turn undergo 3,3′-coupling with concomitant extrusion of sulfur, finally leading to 11 after adopting a stable arrangement in form of an eightmembered ring by incorporation of a suitable number of sulfur atoms. A mechanism involving a related 2,2′coupling has previously been proposed in the benzo[b]thiophene series during a synthesis of 13, which was assumed to take place via the nonisolable thione 14.19 Likewise, it has been demonstrated that tetrathiocines can be obtained via a similar dimerization process by thionation of imidazolidine-2-thione-4,5-diones.20 Interestingly, transformation of a pentathiepin into a tetrathiocine induced by triethylamine has been observed previously, as exemplified by the easy formation of 15 from 16.2
Although the difference in reactivity between the Sand O-containing systems cannot be exhaustively explained at present, the relatively high stability of 8 (18) (a) Benincori, T.; Brenna, E.; Sannicolo`, F.; Trimarco, L.; Antognazza, P.; Cesarotti, E.; Demartin, F.; Pilati, T. J. Org. Chem. 1996, 61, 6244-6251. (b) For an excellent review on aromatic biheterocycles, see also: Steel, P. J. Adv. Heterocycl. Chem. 1997, 67, 1-117.
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FIGURE 1. Observed powder diffraction patterns for the two polymorphs of compound 8, forms I and II. Form I (lower graph) crystallizes from hexane in the space group P21/c with four molecules in the unit-cell. Form II (upper graph) crystallizes from a 4:1 mixture of hexane-CH2Cl2 in the space group P21/n with four molecules in the unit-cell.
SCHEME 4a
a Reagents and conditions: (i) NaH, THF, -10 °C; (ii) S , from 8 -10 °C to room temperature, 23 h.
compared to that of the putative structure 12 might be rationalized in terms of the effect exerted by the electronegativity of the oxygen atom in the benzo[b]furan system, which could result in an increase in the electrophilic character of the pentasulfide moiety of 12. In contrast, the considerably less electronegative sulfur atom present in the five-membered ring of 8 can be expected to stabilize the system due to the longer bonds and larger bond angles. The preference for formation of the tetrasulfide 11 rather than the pentathiepin 12 was further demonstrated by an experiment wherein the readily available benzo[b]furan-2-thiol21 (17) was converted into its thiolate anion, which was subsequently treated with sulfur to give 11 in 39% yield (Scheme 4). X-ray diffraction provided the final evidence for the structures 8 and 11. Interestingly, two polymorphs of 8 were observed. Form I crystallized from a 4:1 mixture of hexane-CH2Cl2 in the space group P21/c with the unit-cell parameters a ) 4.467(1), b ) 13.514(1), c ) 18.049(1) Å and β ) 94.59(1)°, V ) 1086.1(3) Å3, whereas form II was obtained from hexane, adopting the space group P21/n with the unit-cell dimensions a ) 8.997(1), b ) 10.115(1), c ) 12.116(1) Å and β ) 93.89(1)°, V ) (19) Hoepping, A.; Mayer, R. Phosphorus, Sulfur Silicon Relat. Elem. 1995, 107, 285-288. (20) (a) Aragoni, M. C.; Arca, M.; Demartin, F.; Devillanova, F. A.; Garau, A.; Isaia, F.; Lejl, F.; Lippolis, V.; Verani, G. J. Am. Chem. Soc. 1999, 121, 7098-7107. (b) Bigoli, F.; Pellinghelli, M. A.; Atzei, D.; Deplano, P.; Trogu, E. F. Phosphorus, Sulfur Relat. Elem. 1988, 37, 189-194. (21) Anisimov, A. V.; Babaitsev, V. S.; Kolosova, T. A.; Viktorova, E. A. Khim. Geterotsikl. Soedin. 1982, 1335-1337.
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FIGURE 2. Compound 8, forms I (above) and II (below). Molecules are viewed perpendicular to the five-membered ring planes to facilitate a conformational comparison.
1100.1(2) Å3. Their powder diffraction patterns are illustrated in Figure 1. The molecular conformations of the two forms of 8 are quite similar, and the largest difference in the torsion angles is less than 5° (Figure 2). In contrast, the packing schemes of the two polymorphs display some major differences (Figure 3). Experimental Section NMR spectra were recorded on at 300 MHz for 1H and 75.4 MHz for 13C. IR spectra were acquired on a FT-IR instrument. Mass spectra were performed by E. Nilsson, University of Lund, Sweden. Elemental analyses were performed by H. Kolbe Mikroanalytisches Laboratorium, Mu¨lheim an der Ruhr, Germany. Melting points were taken on a capillary apparatus and
FIGURE 3. Molecular packing projections of compound 8, forms I (above) and II (below) viewed perpendicular to the acplanes. are uncorrected. Silica gel was used for column chromatography. Solvents were of analytical grade and used as received, except THF, which was distilled from sodium and benzophenone. Pentathiepino[6,7-b]benzo[d]thiophene (8) via Lithiation of Benzo[b]thiophene (6). To a solution of benzo[b]thiophene (6) (1.34 g, 10 mmol) in THF (30 mL) under N2 was added BuLi in hexanes (2.5 M, 4.8 mL, 12 mmol) at -78 °C. The resulting mixture was kept for 30 min at -78 °C, after which the cooling bath was removed. After warming to room temperature, the mixture was kept for an additional 30 min at room temperature and thereafter cooled to -10 °C (ice-salt bath), followed by addition of sulfur (2.56 g, 80 mmol) in one portion. The resulting red mixture was allowed to reach room temperature over ∼2 h and then stirred at room temperature for 24 h. After careful quenching with aqueous HCl (1 M, 50 mL), CHCl3 (50 mL) was added, and the mixture was passed through a plug of Celite, which was washed with CHCl3 (50 mL). The organic layer from the combined filtrate and washing was separated,
washed with water, and dried (Na2SO4). After concentration, the residue was subjected to column chromatography. Elution with hexane gave some residual sulfur, followed by pentathiepino[6,7-b]benzo[d]thiophene (8) (820 mg, 28%) as a yellow crystalline solid: mp (hexane) 126-127 °C; IR (KBr) 1447 (w), 1398 (w), 1242 (w), 1158 (w), 1072 (w), 1003 (w), 940 (w), 785 (w), 754, 725, 712 (w) cm-1; 1H NMR (CDCl3) δ 7.96 (ddd, J ) 7.8, 1.6, 0.8 Hz, 1H), 7.78 (ddd, J ) 7.8, 1.5, 0.8 Hz, 1H), 7.53 (ddd, J ) 7.8, 7.1, 1.5 Hz, 1H), 7.47 (ddd, J ) 7.8, 7.1, 1.6 Hz, 1H); 13C NMR (CDCl ) δ 142.9 (s), 141.2 (s), 139.8 (s), 139.2 (s), 126.8 3 (d), 126.0 (d), 125.0 (d), 122.5 (d); MS (EI) m/z 292 (30, M+), 228 (100, M - S2), 196 (6, M - S3), 164 (4), 152 (28), 120 (33); HRMS (EI) m/z calcd for C8H4S6 291.8637, found 291.8643. Anal. Calcd for C8H4S6: C, 32.85; H, 1.38; S, 65.77. Found: C, 32.72; H, 1.32; S, 65.63. Bis(benzo[4,5]furo)[2,3-e:3′,2′-g][1,2,3,4]tetrathiocine (11). To a solution of benzo[b]furan (10) (2.20 mL, 20 mmol) in THF (30 mL) under N2 at -78 °C was added BuLi in hexanes (2.5 M, 9.5 mL, 24 mmol) over 10 min. The resulting mixture was stirred for 30 min at -78 °C, followed by addition of sulfur (5.12 g, 0.16 mol) at -78 °C. The red mixture was then allowed to reach room temperature over 6.5 h. After careful quenching with aqueous HCl (1 M, 100 mL), the stirring was continued for 5 min. The mixture was filtered through Celite, and the pad was washed with CHCl3 (2 × 50 mL). The organic phase from the combined filtrate and washings was separated, washed with water, and dried (Na2SO4). Evaporation of the solvents gave a yellow residue, which was treated with CH2Cl2 (∼50 mL), and the precipitate consisting of some residual sulfur was removed by filtration. After concentration of the filtrate, the residue was subjected to column chromatography using hexane as an eluent to give some sulfur, followed by compound 11 (1.26 g, 35%) as a pale yellowish crystalline solid: mp (hexane) 204-206 °C; IR (KBr) 1612 (w), 1586 (w), 1511 (w), 1443, 1336, 1227, 1121, 1094, 1006, 925, 821 747 cm-1; 1H NMR (CDCl3) δ 7.64-7.61 (m, 1H), 7.53-7.48 (m, 2H), 7.33-7.28 (m, 1H); 13C NMR (CDCl3) δ 155.3 (s), 145.0 (s), 127.8 (s), 127.8 (d), 124.0 (d), 123.1 (s), 121.4 (d), 112.4 (d); MS (EI) m/z 360 (M+, 15), 296 (M - S2, 100); HRMS (EI) m/z calcd for C16H8O2S4 359.9407, found 359.9411. Anal. Calcd for C16H8O2S4: C, 53.31; H, 2.24; S, 35.58. Found: C, 53.30; H, 2.22; S, 35.52.
Supporting Information Available: Additional experimental details and tables of final coordinates, equivalent isotropic and anisotropic displacement parameters, bond lengths, and bond angles for compounds 8, forms I and II, and 11. This material is available free of charge via the Internet at http://pubs.acs.org. JO0257086
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