pubs.acs.org/joc
Palladium-Catalyzed Regioselective Oxidative Coupling of Indoles and One-Pot Synthesis of Acetoxylated Biindolyls Zunjun Liang, Jinlong Zhao, and Yuhong Zhang* Department of Chemistry, Zhejiang University, Hangzhou 310027, P. R. China
[email protected] Received October 21, 2009
Mild conditions have been developed to achieve Pd-catalyzed homocoupling of indoles with excellent regioselectivity in the presence of Cu(OAc)2 3 H2O in DMSO at room temperature in high efficiency. This method provides a simple route to 2,30 -biindolyls from the electron-rich to moderately electronpoor indoles. The reaction tolerates the bromide substituent on indoles. In addition, a one-pot approach to C3-position acetoxylated biindolyls is realized via palladium catalysis by the use of AgOAc under oxygen atmosphere as oxidants.
Introduction Biindolyls are useful structural units that are frequently found in pharmaceuticals and functional materials.1 Both chemical and enzymatic synthetic methods have been reported for the construction of biindolyls,2 and the acidic dimerization of indoles followed by dehydrogenation is the
most traditional method for the preparation of biindolyls.3 For instance, exposing the indole to anhydrous hydrogen chloride and subsequent dehydrogenation using 10 mol % Pd/C results in 2,30 -biindolyls in 65% overall yield.4 It has been reported that 0.5 equiv of thallium(III) trifluoroacetate and 10 equiv of BF3 3 Et2O can transform indoles into biindolyls.5 On the other hand, the methods based on the transition-metal-catalyzed coupling of aryl halides with arylmetals have emerged as versatile tools for the synthesis of biaryls over the past decades,6 and biindolyls have been
(1) (a) Gribble, G. W.; Berthel, S. J. Studies in Natural Products Chemistry; Attaur-Rahman, Ed.; Elsevier: New York, 1993; Vol. 12, pp 365-409. (b) Omura, S.; Sasaki, Y.; Iwai, Y.; Takeshita, H. J. Antibiot. 1995, 48, 535–548. (c) Pindur, U.; Kim, Y. S.; Mehrabani, F. Curr. Med. Chem. 1999, 6, 29–69. (d) Bergman, J.; Janosik, T.; Wahlstr€ om, N. Adv. Heterocycl. Chem. 2001, 80, 1–71. (e) d'Ischia, M.; Napolitano, A.; Pezzella, A.; Meredith, P.; Sarna, T. Angew. Chem., Int. Ed. 2009, 48, 2–10. (f) Ito, S. Pigment Cell Res. 2003, 16, 230–236. (g) Bergman, J.; Janosik, T.; Wahlstr€ om, N. Adv. Heterocycl. Chem. 2001, 80, 1–71. (2) (a) Pezzella, A.; Panzella, L.; Natangelo, A.; Arzillo, M.; Napolitano, A.; d’Ischia, M. J. Org. Chem. 2007, 72, 9225–9230. (b) Panzella, L.; Pezzella, A.; Napolitano, A.; d’Ischia, M. Org. Lett. 2007, 9, 1411–1414. (c) Pezzella, A.; Vogna, D.; Prota, G. Tetrahedron: Asymmetry 2003, 14, 1133–1140. (d) d’Ischia, M.; Napolitano, A.; Pezzella, A.; Land, E. J.; Ramsden, C. A.; Riley, P. A. Adv. Heterocycl. Chem. 2005, 89, 1–63. (e) Kuethe, J. T.; Wong, A.; Davies, I. W. Org. Lett. 2003, 5, 3721–3723. (f) Reference 1e. (3) (a) Gribble, G. W.; Pelcman, B. J. Org. Chem. 1992, 57, 3636–3642. (b) Gilbert, E. J.; Van, Vranken, D. L. J. Am. Chem. Soc. 1996, 118, 5500– 5501. (c) Wada, Y.; Nagasaki, H.; Tokuda, M.; Orito, K. J. Org. Chem. 2007, 72, 2008–2014. (d) Yepuri, N. R.; Haritakul, R.; Keller, P. A.; Skelton, B. W.; White, A. H. Tetrahedron Lett. 2009, 50, 2501–2504. (e) Reference 2d.
(4) Wahlstr€ om, N.; Sl€ att, J.; Stensland, B.; Ertan, A.; Bergman, J.; Janosik, T. J. Org. Chem. 2007, 72, 5886–5889. (5) Keller, P. A.; Yepuri, N. R.; Kelso, M. J.; Mariani, M.; Brian, W.; Skelton, B. W.; White, A. H. Tetrahedron 2008, 64, 7787–7795. (6) (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457–2483. (b) Suzuki, A. In Metal-Catalyzed Cross-Coupling Reactions; Diederich, F., Stang, P. J., Eds.; Wiley-VCH: Weinheim, Germany, 1998; Chapter 2, pp 49-97. (c) Liu, L.; Zhang, Y.; Wang, Y. J. Org. Chem. 2005, 70, 6122–6125. (d) Wang, L.; Zhang, Y.; Liu, L.; Wang, Y. J. Org. Chem. 2006, 71, 1284–1287. (e) Stille, J. K. Angew. Chem., Int. Ed. 1986, 75, 508–524. (f) Mitchell, T. N. In Metal-Catalyzed Cross-Coupling Reactions; Diederich, F., Stang, P. J., Eds.; Wiley-VCH: Weinheim, 1998; pp 167-202. (g) Negishi, E. I. In MetalCatalyzed Cross-Coupling Reactions; Diederich, F., Stang, P. J., Eds.;WileyVCH, Weinheim, 1998; Chapter1, pp 1-48. (h) Huang, J.; Nolan, S. P. J. Am. Chem. Soc. 1999, 121, 9889–9890. (i) Frid, M.; Perez, D.; Peat, A. J.; Buchwald, S. L. J. Am. Chem. Soc. 1999, 121, 9469–9470.
170
Published on Web 12/03/2009
J. Org. Chem. 2010, 75, 170–177
DOI: 10.1021/jo902265s r 2009 American Chemical Society
JOC Article
Liang et al.
constructed facilely by Stille reaction and Suzuki reaction.7 Recently, an efficient strategy by the palladiun-catalyzed annulation of o-ethynylanilines with iodoindoles was reported for the synthesis of biindolyls.8 However, these methods require the prefunctionalization of indoles to their halide or metallic derivatives. From both scientific and environmental points of view, the development of methodology for direct activation of C-H bonds is of great significance, and metal-catalyzed C-H bond functionalization has attracted much attention currently.9 For example, palladium-catalyzed C-H activation has been successfully applied in the homocoupling of thiophenes to approach the bithiophene units in the presence of silver salt,10 and biindolizines have been prepared by combination of palladium catalyst and copper reagent via C-H bond cleavage.11 As part of our ongoing investigations on selective and controllable C-H bond functionalization,12 we studied the palladium-catalyzed oxidative coupling of indoles. Herein, we report a mild and selective method for dimerization of indoles by palladium catalysis to give 2,30 -biindolyls in high yields at room temperature. Moreover, a one-pot procedure for C3-position acetoxylated biindolyls is established by using AgOAc as oxidant at 60 °C for 12 h. Results and Discussion On the outset of our study, we examined the homocoupling of N-methylindole in the presence of palladium catalysts. It was found that the dimerization reaction occurred by use of 5 mol % Pd(OAc)2 catalyst to give the 2,30 -dimer of N-methylindole 1,10 -dimethyl-1H,10 H-2,30 -biindole in 40% yield in the presence of 1.5 equiv of Cu(OAc)2 3 H2O in DMSO at 90 °C for 8 h (Table 1, entry 1). The derivatives (7) Merlic, C. A.; You, Y.; Mclnnes, D. M.; Zechman, A. L.; Miller, M. M.; Deng, Q. Tetrahedron 2001, 57, 5199–5212. (8) (a) Capelli, L.; Manini, P.; Pezzella, A.; Napolitano, A.; d’Ischia, M. J. Org. Chem. 2009, 74, 7191–7194. (b) Abbiati, G.; Arcadi, A.; Beccalli, E.; Bianchi, G.; Marinellib, F.; Rossi, E. Tetrahedron 2006, 62, 3033–3039. (9) (a) Stuart, D. R.; Fagnou, K. Science 2007, 316, 1172–1175. (b) Labinger, J. A.; Bercaw, J. E. Nature 2002, 417, 507–514. (c) Lersch, M. Tilset, M. Chem. Rev. 2005, 105, 2471–2526. (d) Lewis, J. C.; Bergman, R. G.; Ellman, J. A. Acc. Chem. Res. 2008, 41, 1013–1025. (e) Kakiuchi, F.; Murai, S. Acc. Chem. Res. 2002, 35, 826–834. (f) Alberico, D.; Scott, M. E.; Lautens, M. Chem. Rev. 2007, 107, 174–238. (g) Do, H.-Q.; Daugulis, O. J. Am. Chem. Soc. 2007, 129, 12404–12405. (h) Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc. 2007, 129, 11904–11905. (i) Seregin, I. V.; Ryabova, V.; Gevorgyan, V. J. Am. Chem. Soc. 2007, 129, 7742–7743. (j) Shi, B.-F.; Maugel, N.; Zhang, Y.-H.; Yu, J.-Q. Angew. Chem., Int. Ed. 2008, 47, 4882–4886. (k) Zhao, L.; Li, C.-J. Angew. Chem., Int. Ed. 2008, 47, 7075–7078. (l) Nakao, Y.; Kanyiva, K. S.; Hiyama, T. J. Am. Chem. Soc. 2008, 130, 2448–2449. (m) Campeau, L. C.; Parisien, M.; Leblanc, M.; Fagnou, K. J. Am. Chem. Soc. 2004, 126, 9186–9187. (n) Roy, A. H.; Lenges, C. P.; Brookhart, M. J. Am. Chem. Soc. 2007, 129, 2082–2093. (o) Ruan, J.; Saidi, O.; Iggo, J. A.; Xiao, J. J. Am. Chem. Soc. 2008, 130, 10510–10511. (p) Li, B.-J.; Tian, S.-L.; Fang, Z.; Shi, Z.-J. Angew. Chem., Int. Ed. 2008, 47, 1115–1118. (q) Lu, J.; Tan, X.; Chen, C. J. Am. Chem. Soc. 2007, 129, 7768–7769. (r) Brasche, G.; Garca-Fortanet, J.; Buchwald, S. L. Org. Lett. 2008, 10, 2207–2210. (s) Chan, J.; Baucom, K. D.; Murry, J. A. J. Am. Chem. Soc. 2007, 129, 14106–14107. (t) Sezen, B.; Sames, D. J. Am. Chem. Soc. 2003, 125, 10580–10585. (u) Li, L.; Jones, W. D. J. Am. Chem. Soc. 2007, 129, 10707–10713. (v) Ackermann, L.; Nov ak, P.; Vicente, R.; Hofmann, N. Angew. Chem., Int. Ed. 2009, 48, 6045–6048. (w) Xia, J.-B.; You, S.-L. Organometallics 2007, 26, 4869–4871. (10) (a) Masui, K.; Ikegami, H.; Mori, A. J. Am. Chem. Soc. 2003, 126, 5074–5075. (b) Takahashi, M.; Masui, K.; Sekiguchi, H.; Kobayashi, N.; Mori, A.; Funahashi, M.; Tamaoki, N. J. Am. Chem. Soc. 2006, 128, 10930– 10933. (11) Xia, J. B.; Wang, X. Q.; You, S. L. J. Org. Chem. 2009, 74, 456–458. (12) (a) Cheng, K.; Zhang, Y.; Zhao, J.; Xie, C. Synlett 2008, 1325–1330. (b) Cheng, K.; Yao, B.; Zhao, J.; Zhang, Y. Org. Lett. 2008, 22, 5309–5312. (c) Zhao, J.; Zhang, Y.; Cheng., K. J. Org. Chem. 2008, 73, 7428–7431. (d) Cheng, K.; Huang, L.; Zhang, Y. Org. Lett. 2009, 11, 2908–2911. (e) Huang, L.; Zhang, X.; Zhang, Y. Org. Lett. 2009, 11, 3730–3733.
TABLE 1.
Effects of Metals and Oxidants on the Dimarizationa
entry
catalyst
oxidative
temp (°C)
yield (%)b
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
Pd(OAc)2 PdCl2 Pd(CH3CN)2Cl2 Pd(PPh3)4 Pd(dba)2 Pd(TFA)2 Pd(TFA)2 Pd(TFA)2 Pd(TFA)2
Cu(OAc)2 3 H2O Cu(OAc)2 3 H2O Cu(OAc)2 3 H2O Cu(OAc)2 3 H2O Cu(OAc)2 3 H2O Cu(OAc)2 3 H2O Cu(OAc)2 3 H2O Cu(OAc)2 3 H2O Cu(OAc)2 Cu(OAc)2 3 H2O
90 90 90 90 90 90 60 rt rt rt rt rt rt rt rt rt rt rt
40 69 75 75 78 80 86 91 92 nr trace trace 36 trace trace trace trace 15 c
Pd(TFA)2 Pd(TFA)2 Pd(TFA)2 Pd(TFA)2 Pd(TFA)2 Pd(TFA)2 Pd(TFA)2 Pd(TFA)2
CuO AgOAc Ag2O Ag2CO3 K2S2O8 O2 Cu(OAc)2 3 H2O
a Reaction condition: N-methyl indole (1 mmol), oxidant (1.5 mmol), catalyst (0.05 mmol), DMSO (6 mL), 8 h, N2. bIsolated yields based on N-methyl indole. TFA = trifluoroacetate, rt = room temperature, nr = no reaction. c1,4-Dioxane as the solvent instead of DMSO.
of 2,20 - and 3,30 -biindolyls were not observed under the reaction conditions, showing excellent regioselectivity. A higher efficiency was observed by the use of other palladium catalysts such as PdCl2, Pd(CH3CN)2Cl2, Pd(PPh3)4, and Pd(dba)2 (Table 1, entries 2-5), and the best result was obtained with Pd(TFA)2 to give 80% yield (Table 1, entry 6). To our delight, when we performed the reaction at 60 °C, the yield of the product was increased under these reaction conditions (Table 1, entry 7). The reaction was further improved to afford 91% yield at room temperature (Table 1, entry 8). The reaction in the absence of palladium catalysts or copper reagents resulted in no homocoupling (Table 1, entries 10-11). Although Cu(OAc)2 showed slightly higher efficiency than Cu(OAc)2 3 H2O (Table 1, entry 9), Cu(OAc)2 3 H2O was used as oxidant in the subsequent experiments because of its low cost and ease of handling. Silver(I) reagents such as AgOAc, Ag2CO3, and Ag2O were found to be ineffective (Table 1, entries 13-15), and only trace amounts of the product were observed when K2S2O8, CuO, or O2 were used as oxidants (Table 1, entries 12, 16, 17). The reaction in other solvents tested, including 1,4-dioxane, DMF, THF, acetone, and toluene, was sluggish (Table 1, entry 18). The scope of the reaction was examined and Pd(TFA)2/ Cu(OAc)2 3 H2O is an efficient and selective catalytic system for the dimerization of various indoles as summarized in Table 2. The indoles containing electron-donating substitutes such as methyl and methoxy reacted smoothly to give 2,30 -dimers of indoles in high yields (Table 2, entries 3-6 and 13, 14). 4-Methyl-N-methylindole and 4-methyl-N-benzylindole gave relatively lower yield, possibly due to the steric hindrance (Table 2, entries 2 and 12). However, the reaction of 6-methoxy-N-methylindoles and 6-methoxy-N-benzylindole showed similar tendency of reactivity as in the direct arylation of indoles12c and displayed moderate reactivity (Table 2, entries 7 and 15). The presence of bromine in J. Org. Chem. Vol. 75, No. 1, 2010
171
JOC Article TABLE 2.
Oxidative Homocoupling of Various Substituted Indolesa
a Reaction conditions: indole derivatives (1 mmol), Pd(TFA)2 (0.05 mmol), Cu(OAc)2 3 H2O (1.5 mmol), DMSO (6 mL), room temperature, 8 h, N2. bIsolated yields based on indole. c60 °C, 12 h. dPd(TFA)2 (0.05 mmol), AgOAc (1.5 mmol), 90 °C, 12 h.
172
J. Org. Chem. Vol. 75, No. 1, 2010
Liang et al.
indoles did not alter the reaction pathway, and moderate yields were obtained for these moderately electronpoor indoles (Table 2, entries 8 and 16). In the case of strongly electron-poor indoles, the reactivity in the homocoupling reaction dropped markedly (Table 2, entries 9 and 17), albeit the reaction temperature was enhanced and the reaction time was prolonged. A possible reason is that the presence of an electron-withdrawing group might render the indoles highly electron-deficient and retard the electrophilic palladation. Similarly, N-acetyl indole was incompatible with the reaction, and no desired dimerization compound was isolated (Table 2, entry 10). N-Benzyl and N-phenyl indole tolerated the reaction conditions well and generated the homocoupling products in good yields (Table 2, entries 11 and 18). Encouraged by the successful homocoupling of indoles, the homocoupling reaction of thiazoles, which are important π-stacking five-membered rings,13 was next examined. Unfortunately, thiazoles failed to homocouple under the above optimal reaction conditions. To our delight, the homocoupling products of thiazoles were isolated when AgOAc was used as oxidant at 90 °C for 12 h (Table 2, entries 19 and 20). During the screening of reaction conditions for this homocoupling reaction, we isolated a small amount of C3-position acetoxylated biindolyls. Since substituted 3-oxyindoles are common scaffolds in medicinal chemistry14 and their synthesis through direct catalytic methods is very limited,15 we investigated the reaction conditions for selective formation of acetoxylated biindolyl products as shown in Table 3. It was found that oxygen played the key role for the acetoxylation. For example, only a trace of acetoxylated product was detected using the Pd(OAc)2/Cu(OAc)2 3 H2O catalytic system when the reaction was performed under nitrogen, but the yield of acetoxylated product increased to 38% under oxygen (Table 3, entries 1-2). Similar results were obtained by using the Pd(TFA)2/Cu(OAc)2 3 H2O system (Table 3, entries 3 and 4). In addition, the reaction efficiency was decreased when the reaction was performed at lower temperature (Table 3, entry, 5). The replacement of Cu(OAc)2 3 H2O with AgOAc markedly improved the selective acetoxylation (Table 3, entries 6-12), and the best conditions for the formation of acetoxylation product was indole derivatives (1 mmol), Pd(TFA)2 (0.05 mmol), and AgOAc (2 mmol) in DMSO (6.0 mL) at 60 °C for 12 h under oxygen atmosphere (Table 3, entry 13). PhI(OAc)2 was ineffective under the reaction conditions (Table 3, entry 14). (13) (a) Gonz alez Ronda, L.; Martin, D. C. Macromolecules 1997, 30, 1524–1526. (b) Yamamoto, T.; Komarudin, D.; Arai, M.; Lee, B. L.; Suganuma, H.; Asakawa, N.; Inoue, Y.; Kubota, K.; Sasaki, S.; Fukuda, T.; Matsuda, H. J. Am. Chem. Soc. 1998, 120, 2047–2058. (c) Chang, Y. T.; Hsu, S. L.; Chen, G. Y.; Su, M. H.; Singh, T. A.; Diau, E. W. G.; Wei, K. H. Adv. Funct. Mater. 2008, 18, 1–10. (d) Li, K.-C.; Huang, J.-H.; Hsu, Y.-C.; Huang, P.-O.; Chu, C.-W.; Lin, J.-T.; Ho, K.-C.; Wei, K.-H.; Lin, H.-C. Macromolecules 2009, 42, 3681–3693. (14) (a) Campbell, J. A.; Bordunov, V.; Broka, C. A.; Browner, M. F.; Kress, J. M.; Mirzadegan, T.; Ramesha, C.; Sanpablo, B. F.; Stabler, R.; Takahara, P.; Villasenor, A.; Walker, K. A. M.; Wang, J.-H.; Welch, M.; Weller, P. Bioorg. Med. Chem. Lett. 2004, 14, 4741–4745. (b) Bruncko, M.; Song, X.; Ding, H.; Tao, Z.; Kunzer, A. R. WO 130970 A1, 2008; Chem. Abstr. 2008, 149, 493528. (c) MCP-1 antagonists: Kettle, J. G.; Faull, A. W. U.S. Patent 6,833,3872004; Chem. Abstr. 2000, 133, 150463. (d) Dropinski, J. F.; Akiyama, T.; Einstein, M.; Habulihaz, B.; Doebber, T.; Berger, J. P.; Meinke, P. T.; Shi, G. Q. Bioorg. Med. Chem. Lett. 2005, 15, 5035–5038. (15) (a) Sukari, M. A.; Vernon, J. M. J. Chem. Soc., Perkin Trans. 1 1983, 2219–2223. (b) Mutule, I.; Suna, E.; Olofsson, K.; Pelcman, B. J. Org. Chem. 2009, 74, 7195–7198.
JOC Article
Liang et al. TABLE 3.
Optimization of Acetoxylated Biindolylsa
entry
catalyst
oxidant
temp (°C)
atmosphere
yield (%) of 3a
yield (%) of 2a
1 2 3 4 5 6 7 8 9 10 11 12 13 14
Pd(OAc)2 Pd(OAc)2 Pd(TFA)2 Pd(TFA)2 Pd(TFA)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(TFA)2 Pd(TFA)2 Pd(TFA)2 Pd(TFA)2 Pd(TFA)2 Pd(TFA)2
Cu(OAc)2 3 H2O Cu(OAc)2 3 H2O Cu(OAc)2 3 H2O Cu(OAc)2 3 H2O Cu(OAc)2 3 H2O AgOAc AgOAc AgOAc AgOAc AgOAc AgOAc AgOAc AgOAc PhI(OAc)2
90 90 90 90 40 90 90 rt 90 rt 90 40 60 60
N2 O2 N2 O2 O2 N2 O2 O2 N2 N2 O2 O2 O2 O2
trace 38 trace 40 trace 44 51 38 41 41 41 55 80 trace
40 30 80 trace 81 25
