Synthetic Applications of Cyanoacetylated Bisindoles: Synthesis of Novel Cycloheptadiindoles, Indolocarbazoles, and Related Aza Analogues Niklas Wahlstro¨m,† Johnny Sla¨tt,† Birgitta Stensland,‡ Anne Ertan,‡ Jan Bergman,*,† and Tomasz Janosik*,† Unit for Organic Chemistry, Department of Biosciences and Nutrition, Karolinska Institute, NoVum Research Park, SE-141 57 Huddinge, Sweden and Early DeVelopment, AstraZeneca R&D, SE-151 85 So¨derta¨lje, Sweden
[email protected] (J.B.);
[email protected] (T.J.) ReceiVed April 2, 2007
FIGURE 1. Some examples of indolocarbazoles (1-3) and related alkaloids featuring a central seven-membered ring (4 and 5).
Cyclization reactions involving cyanoacetylated bisindoles have been studied, providing access to various novel cyclohepta[2,1-b:3,4-b′]diindole derivatives as well as some related fused pentacyclic systems. Treatment of 3-cyanoacetyl-2,3′diindolylmethane with methanesulfonic acid gave 6-(cyanomethyl)indolo[3,2-b]carbazole in a good yield. Fused or open systems containing two indole units are rather well studied classes of heteroaromatics with diverse and sometimes striking biological effects. The indolocarbazoles1 constitute an important group among these compounds, in particular the indolo[2,3-a]carbazole skeleton, which is present in numerous alkaloids, for example, tjipanazoles B (1, Figure 1) and F1 (2) from the blue-green alga Tolypothrix tjipanasensis.2 The natural products 13 and 24 have also been studied as targets for total synthesis. Likewise, the related family of indolo[3,2-b]carbazoles embodies a number of compounds with potent biological effects, for instance, 6-formylindolo[3,2-b]carbazole (3),5 which is an extremely powerful aromatic hydrocarbon receptor (AhR) ligand.6 On the other hand, the related fused systems featuring a central seven-membered ring are relatively † ‡
Karolinska Institute. AstraZeneca R&D.
(1) For reviews, see: (a) Bergman, J.; Janosik, T.; Wahlstro¨m, N. AdV. Heterocycl. Chem. 2001, 80, 1-71. (b) Kno¨lker, H.-J.; Reddy, K. R. Chem. ReV. 2002, 102, 4303-4427. (c) Prudhomme, M. Curr. Pharm. Des. 1997, 3, 265-290. (d) Sa´nchez, C.; Me´ndez, C.; Salas, J. A. Nat. Prod. Rep. 2006, 23, 1007-1045. (2) Bonjouklian, R.; Smitka, T. A.; Doolin, L. E.; Molloy, R. M.; Debono, M.; Shaffer, S. A.; Moore, R. E.; Stewart, J. B.; Patterson, G. M. L. Tetrahedron 1991, 47, 7739-7750. (3) Kuethe, J. T.; Wong, A.; Davies, I. W. Org. Lett. 2003, 5, 37213723. (4) Gilbert, E. J.; Ziller, J. W.; Van Vranken, D. L. Tetrahedron 1997, 53, 16553-16564.
rare7 but may nevertheless also be encountered in nature as demonstrated by isolation of the natural product caulersin (4),8 the structure of which has also been confirmed by total syntheses,9 or iheyamine A (5), which incorporates an azepine ring between the two indole moieties.10 The ready access of 3-cyanoacetyl-2,2′-biindolyl11 (6) has prompted us to investigate routes to the cyclohepta[2,1-b:3,4b′]diindole skeleton as it was anticipated that the reactivity of the vacant indole 3 position in combination with the synthetic versatility of the cyanoacetyl moiety12 might offer an opportunity for construction of the central seven-membered ring. Indeed, heating of 6 with 4-chlorobenzaldehyde in acetic acid in the presence of sodium acetate gave a good yield of the cycloheptadiindole 7 as a 4:1 mixture of cis and trans isomers (Scheme 1). Repeated recrystallization of this isomeric mixture from acetonitrile allowed enrichment of the cis isomers (JH-5-H-6 ) 3.2 Hz for the cis isomers; JH-5-H-6 ) 5.1 Hz for the trans isomers) to a cis/trans ratio higher than 20:1 as determined by (5) (a) Tholander, J.; Bergman, J. Tetrahedron 1999, 55, 6243-6260. (b) Wahlstro¨m, N.; Romero, I.; Bergman, J. Eur. J. Org. Chem. 2004, 25932602. (6) (a) Rannug, A.; Rannug, U.; Rosenkranz, H. S.; Winqvist, L.; Westerholm, R.; Agurell, E.; Grafstro¨m, A.-K. J. Biol. Chem. 1987, 262, 15422-15427. (b) Rannug, U.; Rannug, A.; Sjo¨berg, U.; Li, H.; Westerholm, R.; Bergman, J. Chem. Biol. 1995, 2, 841-845. (7) (a) Bergman, J.; Norrby, P.-O.; Tilstam, U.; Venemalm, L. Tetrahedron 1989, 45, 5549-5564. (b) Mahboobi, S.; Burgemeister, T.; Dove, S.; Kuhr, S.; Popp, A. J. Org. Chem. 1999, 64, 8130-8137. (c) Bergman, J.; Janosik, T.; Yudina, L.; Desarbre, E.; Lidgren, G.; Venemalm, L. Tetrahedron 2000, 56, 1911-1916. (d) Thummel, R. P.; Hegde, V. J. Org. Chem. 1989, 54, 1720-1725. (e) Kuckla¨nder, U.; To¨berich, H. Chem. Ber. 1981, 114, 2238-2244. (f) Baraznenok, I. L.; Nenajdenko, V. G.; Balenkova, E. S. Chem. Heterocycl. Compd. (Engl. Transl.) 2003, 39, 776779. (g) Kavitha, C.; Prasad, K. J. R. Asian J. Chem. 2004, 16, 40-48. (8) Su, J.-Y.; Zhu, Y.; Zeng, L.-M.; Xu, X.-H. J. Nat. Prod. 1997, 60, 1043-1044. (9) (a) Wahlstro¨m, N.; Stensland, B.; Bergman, J. Tetrahedron 2004, 60, 2147-2153. (b) Fresneda, P. M.; Molina, P.; Saez, M. A. Synlett 1999, 1651-1653. (c) Miki, Y.; Aoki, Y.; Miyatake, H.; Minematsu, T.; Hibino, H. Tetrahedron Lett. 2006, 47, 5215-5218. (10) Sasaki, T.; Ohtani, I. I.; Tanaka, J.; Higa, T. Tetrahedron Lett. 1999, 40, 303-306. (11) Sla¨tt, J.; Romero, I.; Bergman, J. Synthesis 2004, 2760-2765. (12) (a) Sla¨tt, J.; Wahlstro¨m, N.; Janosik, T.; Bergman, J. J. Heterocycl. Chem. 2005, 42, 141-145. (b) Johnson, A.-L.; Sla¨tt, J.; Janosik, T.; Bergman, J. Heterocycles 2006, 68, 2165-2170. (c) Radwan, M. A. A.; El-Sherbiny, M. Bioorg. Med. Chem. 2007, 15, 1206-1211. 10.1021/jo0706729 CCC: $37.00 © 2007 American Chemical Society
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Published on Web 06/22/2007
SCHEME 1 a
a Reagents and conditions: (i) 4-chlorobenzaldehyde, NaOAc, AcOH, reflux, 72%; (ii) DMFDMA, DMF, 60 °C, 91%; (iii) salicylaldehyde, piperidine, EtOH, rt, then aq HCl (2 M), DMF, 140-150 °C, 50%.
1H
NMR. The synthetic versatility of the activated methylene moiety in compound 6 was further demonstrated by heating this substrate with dimethylformamide dimethyl acetal (DMFDMA) in DMF, providing a high-yielding route to the new fused pentacyclic system 8. Reaction of 6 with salicylaldehyde followed by treatment with acid took a somewhat different course as the amide 9 was isolated in moderate yields during the initial experiments provided that crystallization of the crude product mixture from aqueous DMF was performed. On the other hand, attempted purification of the crude product mixture by trituration with warm acetonitrile gave instead the heptacyclic compound 10, implying that formation of the amide 9 took place during crystallization from aqueous DMF. The reaction conditions were therefore modified, allowing direct isolation of 9, which was exclusively obtained as a racemic mixture of the trans isomers. The series of events leading to 9 could involve neighboring group participation of the hydroxyl group, where intramolecular cyclization of the initially formed compound 11 would give the second isolable intermediate 10, eventually rendering the final product after ring opening by water (Scheme 1). An X-ray crystallographic study provided final proof for the structure of the amide 9. Our attention was thereafter turned to studies of the behavior of the isomeric precursor 3-cyanoacetyl-2,3′-biindolyl (12). The required starting material 2,3′-biindolyl (13) was prepared by exposure of indole to anhydrous hydrogen chloride in ether13 followed by treatment with aqueous NaHCO3, providing the intermediate dimer 14 (Scheme 2). This set of operations proved to be more convenient than the classical reaction conditions which involve use of benzene as the solvent and conversion of the resulting hydrochloride to the free base by treatment with aqueous ammonia.14 Subsequent dehydrogenation of 14 employing 10% palladium on carbon in refluxing toluene furnished 2,3′-biindolyl (13) of high purity, thereby also supplanting use of decalin15 as the solvent in this particular application. These practical modifications of this sequence allowed convenient (13) Weinmann, J. M. Ph.D. Thesis, University of Minnesota, Minneapolis, 1964. (14) Schmitz-Dumont, O.; Nicolojannis, B. Chem. Ber. 1930, 63, 323328. (15) Young, T. E. J. Org. Chem. 1962, 27, 507-510.
SCHEME 2 a
a Reagents and conditions: (i) HCl (g), Et O, rt; (ii) aq NaHCO ; (iii) 2 3 Pd/C, PhMe, reflux, (65% overall from indole); (iv) NCCH2CO2H, Ac2O, 90-95 °C, 95%; (v) NaNO2, AcOH, rt, 64%.
access to the biindolyl 13 in 65% overall yield from indole. The key intermediate 3-cyanoacetyl-2,3′-biindolyl (12) could thereafter be prepared in a high yield by heating 13 with cyanoacetic acid in acetic anhydride. Treatment of 12 with NaNO2 in acetic acid gave the novel system 15, where the two indole moieties are fused to an unusual azepine-3-one-1-oxide unit. This transformation probably proceeds via an initial nitrosation on the methylene unit adjacent to the nitrile functionality and subsequent nucleophilic attack of the presumed intermediate oxime nitrogen atom on the 2 position of the neighboring protonated indole. The only previously known example of the central seven-membered heterocyclic ring present in 15 has been encountered in very low yield (2.6%) as a product from the reaction of 2-iodo-2′-nitrobiphenyl with cuprous phenylacetylide in refluxing pyridine.16 (16) Leznoff, C. C.; Hayward, R. J. Can. J. Chem. 1971, 49, 35963601.
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SCHEME 3
a
a Reagents and conditions: (i) NCCH CO H, Ac O, 40-75 °C, 89%; 2 2 2 (ii) MeSO3H, 1,4-dioxane, reflux, 81%; (iii) NaNO2, AcOH, 45 °C, 16%.
In analogy with the approaches outlined above, cyanoacetylation of 2,3′-diindolylmethane17 (16) with cyanoacetic acid in acetic anhydride gave access to the intermediate 17 (Scheme 3). Subsequent cyclization of the latter compound under acidic conditions provided an efficient route to the new 6-(cyanomethyl)indolo[3,2-b]carbazole (18). Moreover, treatment of 17 with NaNO2 in acetic acid produced a low yield of the deep red tropolone 19. In contrast to the cyclization leading to the azepine derivative 15, there was no evidence for incorporation of an additional nitrogen atom into the system as this would have resulted in formation of a central eight-membered ring. In conclusion, the synthetic approaches described in this paper may constitute a useful contribution to the current repertoire of transformations for construction of new indolocarbazoles and related cycloheptadiindoles with potential biological effects. However, additional studies involving other similar acylated bisindole substrates are necessary to probe the scope and limitations of these routes as tools for synthesis of further derivatives. Experimental Section 5-(4-Chlorophenyl)-7-oxo-6,7,12,13-tetrahydro-5H-cyclohepta[2,1-b:3,4-b′]diindole-6-carbonitrile (7). 3-Cyanoacetyl-2,2′-biindolyl (6) (0.60 g, 2.0 mmol), sodium acetate (0.49 g, 6.0 mmol), and 4-chlorobenzaldehyde (0.31 g, 2.2 mmol) were suspended in acetic acid (25 mL). The resulting mixture was heated at reflux for 6 h. After cooling, the precipitate formed was collected by filtration and washed with a small amount of acetic acid followed by excess water to give the product 7 (0.61 g, 72%) as a yellow crystalline solid as a 4:1 mixture of cis and trans isomers. Repeated recrystallizations from acetonitrile increased the isomer ratio to more than 20:1 in favor of the cis isomers as determined by 1H NMR. Data for the major isomers (cis): mp 294-297.5 °C; IR (neat) 3301, 2246, 1589, 1569, 1431, 1335, 738, 726 cm-1; 1H NMR (DMSOd6) δ 12.17 (s, 1H), 11.55 (s, 1H), 8.15 (d, J ) 7.4 Hz, 1H), 7.69 (d, J ) 8.1 Hz, 1H), 7.61-7.55 (m, 2H), 7.33-7.21 (m, 7H), 7.117.06 (m, 1H), 5.51 (d, J ) 3.2 Hz, 1H), 5.25 (d, J ) 3.2 Hz, 1H); 13C NMR (DMSO-d ) δ 183.7 (s), 136.6 (s), 136.4 (s), 136.2 (s), 6 135.8 (s), 132.3 (s), 129.9 (d), 128.5 (d), 127.2 (s), 126.5 (s), 125.8 (s), 124.5 (d), 124.0 (d), 122.9 (d), 121.2 (d), 120.3 (d), 119.3 (d), 118.2 (s), 118.1 (s), 111.9 (d), 111.8 (d), 111.6 (s), 49.6 (d), 39.1 (17) Wahlstro¨m, N.; Stensland, B.; Bergman, J. Synthesis 2004, 11871194.
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(d); MS (ESI-) m/z 420 [M-H]-. Anal. Calcd for C26H16ClN3O: C, 74.02; H, 3.82; N, 9.96. Found: C, 73.93; H, 3.73; N, 10.10. Compound 8. A solution of 3-cyanoacetyl-2,2′-biindolyl (6) (299 mg, 1.0 mmol) and DMFDMA (0.16 mL, 1.2 mmol) in DMF (10 mL) was heated at 60 °C for 30 min and thereafter allowed to cool. The crystals which appeared upon slow evaporation of the mixture were collected and washed with a small amount of acetonitrile followed by a mixture of i-Pr2O/i-PrOH (∼1:1) to give the product 8 (280 mg, 91%) as yellow needles, which contained cocrystallized DMF even after drying in vacuo for prolonged periods of time: mp >400 °C; IR (neat) 3226, 2236, 1625, 1423, 1413, 1406, 1384, 1324, 1313, 745, 733 cm-1; 1H NMR (DMSO-d6) δ 12.71 (br s, 1H), 9.23 (s, 1H), 8.49-8.43 (m, 2H), 7.94-7.88 (m, 2H), 7.597.47 (m, 3H), 7.42-7.37 (m, 1H), 7.32-7.27 (m, 1H); 13C NMR (DMSO-d6) δ 177.1 (s), 138.2 (d), 137.3 (s), 137.0 (s), 133.0 (s), 130.3 (s), 127.6 (s), 126.6 (s), 125.5 (d), 125.4 (d), 125.1 (d), 122.7 (d), 122.6 (d), 121.5 (d), 117.9 (s), 113.7 (s), 112.5 (d), 111.6 (d), 108.7 (d), 99.1 (s); HRMS (FAB+) m/z 310.0979 [M + H]+, C20H11N3O + H requires 310.0980. 5-(2-Hydroxyphenyl)-7-oxo-6,7,12,13-tetrahydro-5H-cyclohepta[2,1-b:3,4-b′]diindole-6-carboxamide (9). Piperidine (110 µL, mmol) was added to a suspension of 3-cyanoacetyl-2,2′-biindolyl (299 mg, 1.0 mmol) containing salicylaldehyde (110 µL, 1.0 mmol) in ethanol (10 mL). The flask was sealed, and the resulting mixture was stirred at room temperature for 20 h, whereupon aqueous HCl (5 M, 25 mL) was added and stirring was continued for 30 min. The resulting precipitate was collected by filtration, washed with water, and dried. (At this point the intermediate 10 could be isolated. However, the isolation procedure described below gave material of higher purity.) The solid was suspended in DMF (10 mL), and aqueous HCl (2 M, 5 mL) was added. The mixture was heated at 150-160 °C for 1 h, whereupon water (10 mL) was added to the hot solution. The material which separated after cooling was collected by filtration, suspended in hot acetonitrile, filtered while hot, and washed with two portions of hot acetonitrile to give 9 (211 mg, 50%) as a yellow crystalline solid: mp 274-277 °C; IR (neat) 3292, 1655, 1588, 1570, 1433, 1337, 739 cm-1; 1H NMR (DMSO-d6) δ 11.88 (s, 1H), 11.33 (s, 1H), 9.85 (s, 1H), 8.16 (d, J ) 7.6 Hz, 1H), 7.55-7.47 (m, 3H), 7.26-6.84 (m, 8H), 6.456.41 (m, 1H), 6.35-6.30 (m, 1H), 5.50 (d, J ) 4.3 Hz, 1H), 4.24 (d, J ) 4.3 Hz, 1H); 13C NMR (DMSO-d6) δ 191.2 (s), 170.5 (s), 154.8 (s), 136.6 (s), 136.4 (s), 135.7 (s), 128.0 (d), 127.9 (s), 127.7 (s), 127.5 (d), 127.3 (s), 125.2 (s), 123.6 (d), 123.3 (d), 122.1 (d), 121.8 (d), 119.7 (d), 119.2 (d), 118.6 (d), 117.5 (s), 115.3 (d), 113.2 (s), 111.6 (d), 111.5 (d), 61.4 (d), 33.2 (d); HRMS (ESI+) m/z 444.1321 [M + Na]+, C26H19N3O3 + Na requires 444.1324. Isolation of Intermediate 10. Piperidine (20 µL, 0.2 mmol) was added to a suspension of 3-cyanoacetyl-2,2′-biindolyl (299 mg, 1.0 mmol) containing salicylaldehyde (110 µL, 1.0 mmol) in ethanol (10 mL). The flask was sealed, and the resulting mixture was stirred at room temperature for 24 h, whereupon aqueous HCl (1 M, 40 mL) was added, and stirring was continued overnight. The resulting precipitate was collected by filtration, washed with water, and dried. This material was triturated with boiling acetonitrile. After cooling, the precipitate was collected, washed with acetonitrile, and dried to give 10 (290 mg, 72%) as a yellow amorphous solid which deteriorated slowly on extended storage at room temperature: IR (neat) 3405, 1628, 1608, 1434, 1420, 1333, 1247, 1211, 1183, 818, 760, 735 cm-1; 1H NMR (DMSO-d6) δ 11.80 (s, 1H), 11.40 (s, 1H), 8.80 (br s, 2H), 8.14 (d, J ) 7.9 Hz, 1H), 7.55-7.40 (m, 3H), 7.34 (d, J ) 7.4 Hz, 1H), 7.26-7.14 (m, 4H), 7.04-7.00 (m, 1H), 6.69-6.64 (m, 1H), 5.72 (d, J ) 8.2 Hz, 1H), 4.92 (s, 1H); 13C NMR (DMSO-d6) δ 185.1 (s), 159.3 (s), 150.0 (s), 137.2 (s), 136.4 (s), 132.0 (s), 130.9 (d), 128.7 (d), 127.7 (s), 126.6 (s), 124.4 (d), 124.3 (s), 122.9 (d), 122.5 (s), 121.9 (d), 121.8 (d), 120.6 (d), 119.1 (s), 119.1 (d), 118.8 (d), 116.9 (s), 115.6 (d), 111.9 (d), 111.4 (d), 88.2 (s), 32.0 (d); MS (ESI+) m/z 404 [M + H]+.
3-Cyanoacetyl-2,3′-biindolyl (12). 2,3′-Biindolyl (13) (2.32 g, 10 mmol) was added to a preheated solution of cyanoacetic acid (0.94 g, 11 mmol) in acetic anhydride (22 mL) at 50 °C. The resulting mixture was heated to 90-95 °C over 10 min and thereafter stirred at this temperature for an additional period of 10 min. After cooling, the solvent was removed in vacuo, and the resulting solid was triturated with i-Pr2O (∼30 mL). The precipitate was collected by filtration and dried to provide 12 (2.84 g, 95%) as a yellow crystalline solid: mp 228-229.5 °C; IR (neat) 3365, 3218, 2259, 1623, 1613, 1423, 751, 714 cm-1; 1H NMR (DMSOd6) δ 12.15 (s, 1H), 11.84 (s, 1H), 8.20-8.17 (m, 1H), 7.94 (d, J ) 2.6 Hz, 1H), 7.58-7.53 (m, 2H), 7.50-7.44 (m, 1H), 7.287.14 (m, 4H), 4.03 (s, 2H); 13C NMR (DMSO-d6) δ 183.4 (s), 141.1 (s), 136.1 (s), 135.8 (s), 128.2 (d), 127.1 (s), 126.1 (s), 122.9 (d), 122.3 (d), 122.0 (d), 121.0 (d), 120.5 (d), 119.0 (d), 116.1 (s), 112.3 (d), 112.0 (s), 111.6 (d), 105.6 (s), 31.0 (t); MS (ESI-) m/z 298 [M-H]-. Anal. Calcd for C19H13N3O: C, 76.24; H, 4.38; N, 14.04. Found: C, 76.24; H, 4.38; N, 14.00. Azepine Derivative 15. Sodium nitrite (180 mg, 2.61 mmol) was added in one portion to a suspension of 3-cyanoacetyl-2,3′biindolyl (12) (598 mg, 2.0 mmol) in acetic acid (20 mL). The flask was sealed, and the reaction mixture was stirred at room temperature for 45 h. The dark precipitate was collected by filtration, washed with acetic acid, and dried. This crude product was suspended in acetone (∼50 mL) with stirring. Compound 15 (419 mg, 64%) of good quality could thereafter be collected by filtration the following day and washed with several portions of acetone. If necessary, further purification could be accomplished by recrystallization from DMA, providing 15 as a dark reddish-brown amorphous solid: IR (neat) 3374, 3295, 2228, 1577, 1486, 1399, 1165, 1143, 737, 714 cm-1; 1H NMR (DMSO-d6) δ 13.42 (s, 1H), 12.16 (s, 1H), 8.77 (d, J ) 8.1 Hz, 1H), 8.59 (d, J ) 7.9 Hz, 1H), 7.79 (d, J ) 8.1 Hz, 1H), 7.72 (d, J ) 8.1 Hz, 1H), 7.66-7.61 (m, 1H), 7.51-7.47 (m, 2H), 7.36-7.31 (m, 1H); 13C NMR (DMSOd6) δ 168.9 (s), 140.3 (s), 138.2 (s), 135.9 (s), 135.7 (s), 128.4 (d), 127.1 (s), 126.6 (d), 125.5 (s), 123.2 (d), 122.8 (d), 122.8 (d), 122.6 (d), 121.6 (s), 118.2 (s), 114.1 (s), 113.4 (d), 112.4 (d), 102.9 (s); HRMS (FAB+) m/z 327.0901 [M + H]+, C19H10N4O2 + H requires 327.0882. 3-Cyanoacetyl-2,3′-diindolylmethane (17). 2,3′-Diindolylmethane (16) (1.00 g, 4.1 mmol) was added to a mixture of cyanoacetic acid (0.47 g, 5.5 mmol) and acetic anhydride (25 mL) at 40 °C. The reaction mixture was heated to 75 °C and then allowed to cool. The precipitate formed was collected by filtration and recrystallized from acetonitrile to give product 17 (1.13 g, 89%) as colorless crystals: mp 126.5-130.5 °C; IR (neat) 3591, 3369, 2945, 2265, 1630, 1457, 1422, 750 cm-1; 1H NMR (DMSO-d6) δ 11.90 (s, 1H), 10.98 (s, 1H), 7.92-7.89 (m, 1H), 7.51 (d, J ) 7.8 Hz, 1H), 7.46-7.41 (m, 1H), 7.38 (dd, J ) 8.1, 0.7 Hz, 1H), 7.22 (d, J ) 2.1 Hz, 1H), 7.20-7.14 (m, 2H), 7.08-7.05 (m, 1H), 6.98-
6.93 (m, 1H), 4.60-4.59 (m, 4H); 13C NMR (DMSO-d6) δ 183.6 (s), 148.9 (s), 136.2 (s), 135.0 (s), 126.9 (s), 126.0 (s), 124.0 (d), 122.2 (d), 121.8 (d), 121.1 (d), 120.4 (d), 118.5 (d), 118.3 (d), 116.3 (s), 112.0 (d), 111.5 (d), 110.7 (s), 109.9 (s), 32.9 (t), 24.1 (t); MS (ESI-) m/z 312 [M-H]-. Anal. Calcd for C20H15N3O: C, 76.66; H, 4.82; N, 13.41. Found: C, 76.61; H, 4.71; N, 13.33. 6-(Cyanomethyl)indolo[3,2-b]carbazole (18). Methanesulfonic acid (1 mL) was added to a suspension of 3-cyanoacetyl-2,3′diindolylmethane (17) (0.60 g, 1.9 mmol) in 1,4-dioxane (50 mL). The resulting mixture was heated at reflux protected by a drying tube for 3.5 h. After cooling, the mixture was concentrated in vacuo together with silica gel (6 g). Column chromatography on silica gel [EtOAc/n-heptane (1:1 to 3:1)] gave 18 (0.46 g, 81%) as a yellow amorphous solid: IR (neat) 3375, 3346, 2249, 1617, 1531, 1459, 1432, 1332, 1324, 1265, 1242, 855, 738 cm-1; 1H NMR (DMSO-d6) δ 11.31 (s, 1H), 11.26 (s, 1H), 8.31 (d, J ) 7.8 Hz, 1H), 8.25 (d, J ) 7.7 Hz, 1H), 8.19 (s, 1H), 7.56-7.52 (m, 2H), 7.48-7.43 (m, 2H), 7.25-7.18 (m, 2H), 4.80 (s, 2H); 13C NMR (DMSO-d6) δ 141.2 (s), 141.1 (s), 135.3 (s), 134.0 (s), 126.0 (d), 125.5 (d), 122.9 (s), 122.6 (s), 122.2 (d), 121.5 (s), 120.5 (d), 120.2 (s), 118.5 (s), 118.2 (d), 118.0 (d), 110.6 (d), 110.6 (d), 104.9 (s), 100.8 (d), 17.0 (t). Anal. Calcd for C20H13N3: C, 81.34; H, 4.44; N, 14.23. Found: C, 81.48; H, 4.56; N, 14.18. 7-Oxo-5,12-dihydro-7H-cyclohepta[1,2-b:4,5-b′]diindole-6carbonitrile (19). NaNO2 (466 mg, 6.8 mmol) was added at room temperature to a suspension of 3-cyanoacetyl-2,3′-diindolylmethane (17) (1.68 g, 5.4 mmol) in acetic acid (150 mL). The reaction was slowly heated to 45 °C over 1 h to give a dark black solution. After an additional period of 3 h the heating was discontinued, and upon cooling to rt, compound 19 (227 mg) was collected by filtration as a dark red solid. An additional crop (33 mg) could be obtained from the mother liquor the following day. The total yield of the bisindolotropolone 19 was 260 mg (16%): mp > 400 °C; IR (neat) 3172, 2210, 1626, 1504, 1455, 1388, 1329, 1226, 1139, 1108, 1020, 742 cm-1; 1H NMR (DMSO-d6) δ 12.81 (s, 1H), 11.76 (s, 1H), 8.91 (d, J ) 8.2 Hz, 1H), 8.80 (s, 1H), 8.16 (d, J ) 7.7 Hz, 1H), 7.73 (d, J ) 8.3 Hz, 1H), 7.60-7.50 (m, 3H), 7.41-7.29 (m, 2H); 13C NMR (DMSO-d ) δ 176.0 (s), 150.4 (s), 142.2 (s), 138.0 (s), 6 136.3 (s), 130.1 (d), 129.5 (s), 127.3 (d), 126.9 (s), 124.2 (d), 124.0 (s), 122.1 (d), 122.1 (d), 121.7 (s), 121.7 (d), 120.6 (d), 118.4 (s), 111.9 (d), 111.8 (d), 96.2 (s); HRMS (FAB+) m/z 310.0981 [M + H]+, C20H11N3O + H requires 310.0980. Supporting Information Available: General experimental procedures, experimental details for the synthesis of biindolyl 13, 1H and 13C NMR spectra for all new compounds, ORTEP diagram of 9, and crystallographic data for 9 in CIF format. This material is available free of charge via the Internet at http://pubs.acs.org. JO0706729
J. Org. Chem, Vol. 72, No. 15, 2007 5889
