HETEROCYCLES

Note | Regular issue | Vol. 78, No. 11, 2009, pp. 2845-2850
Received, 27th July, 2009, Accepted, 3rd September, 2009, Published online, 7th September, 2009.
DOI: 10.3987/COM-09-11802

■ Decarboxylative Bromination of Indole-2,3-dicarboxylic Acids Using Oxone® or CAN in the Presence of Lithium Bromide

Hideaki Umemoto, Misako Umemoto, Chiaki Ohta, Masashi Dohshita, Hiroki Tanaka, Syo Hattori, Hiromi Hamamoto, and Yasuyoshi Miki*

Faculty of Pharmaceutical Sciences, Kinki University, 3-4-1, Kowakae, Higashi-Osaka 577-8502, Japan

Abstract

The treatment of 1-methylindole-2,3-dicarboxylic acid with Oxone® and lithium bromide produced 3,3-dibromo-1-methyloxindole. However, the reaction of 1-benzenesulfonylindole-2,3-dicarboxylic acid with Oxone® and lithium bromide afforded 1-benzenesulfonyl-2,3-dibromoindole. In a similar manner, 2,3,5,6-tetrabromoindole was synthesized from 1-benzenesulfonyl-5,6-dibromoindole-2,3-dicarboxylic acid.

Bromoarenes are an important class of compounds due to their conversion to other functionalities by the Heck-type reaction in the presence of a palladium catalyst, etc. The bromination of activated arenes is usually performed by conventional bromination methods typically using toxic bromine. Commercial available Oxone® (2KHSO5 · KHSO · K2SO4) is an inexpensive, and stable oxidant and in the presence of sodium bromide or potassium bromide, Oxone® can be used as an efficient bromination reagent for activated arenes.1 The decarboxylative bromination of aromatic carboxylic acids using Oxone® and sodium bromide is also a useful method,2 but there is no report about the decarboxylative bromination of indolecarboxylic acids. Bromoindole alkaloids have also been isolated as secondary metabolites of marine organisms, such as sponges, tunicates, etc., and are promising sources of new biologically active molecules.3 2,3,5,6-Tetrabromoindole4,5 having antibacterial and antitumor activities was isolated and synthesized by Castillo.6 3,6-Dibromoindole also was isolated.7 We have shown that the dimethyl indole-2,3-dicarboxylates and indole-2,3-dicarboxylic anhydrides are useful synthons in the synthesis of pratosine,8 hippadine,8 murrayaquinone-A,9 ellipticine,10-12 olivacine,13 caulersin14 and cryptosanguinolentine.15 In this report we describe the synthesis of bromoindoles by the decarboxylative bromination of indole-2,3-dicarboxylic acids using a combination of Oxone® or CAN (ceric ammonium nitrate) 16 and lithium bromide
The reaction of 1-methylindole-2,3-dicarboxylic acid (1a)17 with 0.5 equivalent of Oxone® (2KHSO5 · KHSO · K2SO4) 2 in the presence of 5 equivalents of sodium bromide and 1 equivalent of sodium carbonate in MeOH-H2O (1 : 1) gave 3-bromoindole-2-carboxylic acid (2a)18 in 44% yield, but the treatment of 1a with Oxone® in the presence of lithium bromide and lithium carbonate afforded 2a in 62% yield. (Entries 1, 2) However, when the reaction of 1a with 2 equivalents of Oxone® in the presence of 10 equivalents of lithium bromide and 2 equivalents of lithium carbonate, 3,3-dibromooxindole (3a)19 was obtained in 36% yield instead of 2a, but the 2,3-dibromoindole (4a) was not isolated. (Entry 3) 1a was treated with 1 equivalent or 3 equivalents of CAN in the presence of lithium bromide in acetonitrile to afford a mixture of 2a and 3a in 51-69% and 20-34% yields, respectively. (Entries 4, 5) (Table 1)

The treatment of 1-benzenesulfonylindole-2,3-dicarboxylic acid (1b)20 with 1 equivalent of Oxone® in the presence of lithium bromide and lithium carbonate gave a mixture of 3-bromoindole-2-carboxylic acid (2b) and 2,3-dibromoindole (4b)21 in 26% or 57% yields, respectively, but 1b was reacted with 2 equivalents of Oxone® to provide 4b in 88% instead of the corresponding 3,3-dibromooxindole (Entries 1, 2) However, treatment of 1b with CAN led to a mixture of 2b and 4b in low yields, respectively. (Entries 3, 4) (Table 2)

Next, we evaluated the syntheses of the 2,3-dichloroindoles (5) or 2,3-diiodoindoles (6) by the reaction of 1 with Oxone® in the presence of lithium chloride or lithium iodide. The reaction of 1-methylindole-2,3- dicarboxylic acid (1a) or 1-benzenesulfonylindole-2,3-dicarboxylic acid (1b) with 2 equivalents of Oxone® and lithium chloride or 3 equivalents of CAN and lithium chloride resulted in a complex mixture. When 1a or 1b was treated with Oxone® or CAN in the presence of lithium iodide, the corresponding 2,3-diiodoindoles (6) were also not isolated.

The treatment of dimethyl 1-benzenesulfonyl-5,6-dibromoindole-2,3-dicarboxylate (7)22 with boron tribromide gave the corresponding dicarboxylic acid (8) (92%), which was treated with Oxone® (2 equivalents) in the presence of lithium bromide and lithium carbonate to provide 1-benzenesulfonyl-2,3,5,6-tetrabromoindole (9) in 66% yield. 9 could be converted to 2,3,5,6- tetrabromoindole (10)6 by treatment with tetrabutylammonium fluoride in THF in 92% yield.

ACKNOWLEDGEMENTS
This work was supported by a Grand-in-Aid for Scientific Research (C) and also in part “High-Tech
Research Center Project” for Private Universities and matching fund subsidy from the Ministry of Education, Culture, Sports, Scientific and Technology-Japan (MEXT).

EXPERIMENTAL
Melting points were determined using a Yanagimoto micromelting point apparatus and are uncorrected. The 1H-NMR spectra were determined by a JEOL JNM-GSX 270 spectrometer using tetramethylsilane as the internal standard. The IR spectra were recorded by a JASCO FT/IR-7000 spectrophotometer. The high MS were recorded using a JOEL JMS-HX100 spectrometer. Column chromatography was performed on E. Merck silica gel 60 (70-230 mesh or 230-400 mesh).
General Procedure: Reaction of Indole-2,3-dicarboxylic Acid (1) with Oxone® in the presence of a lithium halide and lithium carbonate
Indole-2,3-dicarboxylic acid (1)(1 mmol) was added to the mixture of Oxone®, lithium halide, and lithium carbonate in MeOH-H2O (1 : 1). The mixture was then stirred at room temperature. A 2 % sodium thiosulfate aqueous solution was added to the reaction mixture and the mixture was extracted with CH2Cl2, washed with water, and dried over Na2SO4. The extracts were concentrated under reduced pressure to afford a residue, which was purified by column chromatography.
General Procedure: Reaction of 1 with CAN in the presence of a lithium halide
CAN was added to the mixture of indole-2,3-dicarboxylic acid (1)(1 mmol) and lithium halide in MeCN. The mixture was then stirred at room temperature. A 2 % sodium thiosulfate aqueous solution was added to the reaction mixture and the aqueous mixture was extracted with CH2Cl2, washed with water, and dried over Na2SO4. The extracts were concentrated under reduced pressure to afford a residue, which was purified by column chromatography.
3-Bromo-1-methylindole-2-carboxylic acid (2a); mp 184-186 °C (lit.,18 mp 180 °C (dec). IR (KBr) ν: 1671 cm-1; 1H-NMR (CDCl3) δ: 3.99 (3H, s, CH3), 7.22 (1H, t, J = 8 Hz, H-5 or H-6), 7.40 (1H, t, J = 8 Hz, H-6 or H-5), 7.54 (1H, d, J = 8 Hz, H-4 or H-7), 7.62 (1H, d, J = 8 Hz, H-7 or H-4).
3,3-Dibromo-1-methyloxindole (3a); mp 202-204 °C (EtOAc) (lit.,19 mp 204-205 °C). IR (CHCl3) ν: 1737 cm-1; 1H-NMR (CDCl3) δ: 3.26 (3H, s, CH3), 6.86 (1H, d, J = 8 Hz, H-4 or H-7), 7.17 (1H, dt, J = 8, 1.5 Hz, H-5 or H-6), 7.34 (1H, dt, J = 8, 1.5 Hz, H-6 or H-5), 7.62 (1H, dd, J = 8, 1.5 Hz, H-7 or H-4). 13C-NMR (DMSO-d6) δ: 169.16, 139.64, 131.87, 130.37, 125.38, 124.05, 110.08, 45.28, 27.03. HRMS (EI) m/z: Calcd for C9H7NOBr2: 302.8895. Found: 302.8883.
1-Benzenesulfonyl-3-bromoindole-2-carboxylic acid (2b); mp 219-222 °C (EtOAc). IR (Nujol) ν: 1697 cm-1; 1H-NMR (CDCl3) δ: 7.24-7.36 (3H, m, aromatic protons), 7.50-7.68 (3H, m, aromatic protons), 7.91 (1H, dd, J = 8, 1.5 Hz, aromatic protons), 8.25-8.32 (2H, m, aromatic protons). HRMS (EI) m/z: Calcd for C15H11NSO4Br2S: 379.9592. Found: 379.9602.
1-Benzenesulfonyl-2,3-dibromoindole (4b); mp 143 °C (lit.,21 mp 141-143 °C). 1H-NMR (CDCl3) δ: 7.22-7.40 (5H, m, aromatic protons), 7.46-7.54 (1H, m, aromatic protons), 7.78-7.84 (2H, m, aromatic protons), 8.19-8.25 (1H, m, aromatic protons).
2,3,5,6-Tetrabromoindole (10)
To a solution of dimethyl 1-benzenesulfonyl-5,6-dibromoindole-2,3-dicarboxylate (7)22 (531 mg, 1 mmol) in toluene (10 mL) was added 1M boron tribromide in a CH2Cl2 solution (3 mL). The mixture was then stirred at room temperature overnight. Water was added to reaction mixture and the precipitate was collected by filtration and washed with water, then with n-hexane. The 1-benzenesulfonyl-5,6-dibromoindole-2,3-dicarboxylic acid (8) (464 mg, 92%) was used without purification.
8; IR (KBr) ν: 1763, 1692 cm-1; 1H-NMR (DMSO-d6) δ: 7.65-7.82 (3H, m, aromatic protons), 8.10-8.15 (2H, m, aromatic protons), 8.27 (1H, s, H-4 or H-7), 8.33 (1H, s, H-7 or H-4).
1-Benzenesulfonyl-5,6-dibromoindole-2,3-dicarboxylic acid (8) (25 mg, 0.05 mmol) was added to the mixture of Oxone® (62 mg, 0.1 mmol), lithium bromide (47 mg, 0.5 mmol), and lithium carbonate (7 mg, 0.1 mmol) in MeOH-H2O (1 : 1)(2 mL), then the mixture was stirred at room temperature overnight. A 2 % sodium thiosulfate aqueous solution was added to the reaction mixture which was then extracted with CHCl3, washed with water, and dried over Na2SO4. The extracts were concentrated under reduced pressure to afford a residue, which was purified by column chromatography (n-hexane : EtOAc = 3 : 1) to give 1-benzenesulfonyl-2,3,5,6-tetrabromoindole (9)(19 mg, 66%).
9; mp 158-161 °C (CHCl3), 1H-NMR (CDCl3) δ: 7.41-7.60 (3H, m, aromatic protons), 7.64 (1H, s, H-4), 7.80-7.86 (2H, m, aromatic protons), 8.56 (1H, s, H-7).
A 1M solution of tetrabutylammonium fluoride in THF (0.04 mL) was added to a mixture of 1-benzenesulfonyl-2,3,5,6-tetrabromoindole (9)(11 mg, 0.02 mmol) in THF (1 mL) at -20 °C under argon and the reaction mixture was stirred for 1 h at the same temperature. Hydrochloric acid (2 %) was added to the mixture and then extracted with CHCl3. The extracts were washed with water, dried over Na2SO4, then concentrated under reduced pressure to afford a residue, which was purified by column chromatography (n-hexane : AcOEt = 3:1) to give the 2,3,5,6-tetrabromoindole (10)4 (8 mg, 92%), mp 153-154 °C (lit.,4 mp 152.5-154 °C, lit.,6 mp 153-154 °C), 1H-NMR (CDCl3) δ: 7.61 (1H, s, H-4 or H-7), 7.76 (1H, s, H-7 or H-4), 8.38 (1H, br s, NH).

References

1. K. J. Lee, H. K. Cho, and C. E. Song, Bull. Korean, Chem. Soc., 2002, 23, 773; B. V. Tamhankar, U. V. Desai, R. B. Mane, P. P. Wadgaonkar, and A. V. Bedekar, Synth. Commun., 2001, 31, 2021; CrossRef N. Narendar, P. Srinivasu, M. R. Prasad, S. J. Kulkarni, and K. V. Raghavan, Synth. Commun., 2002, 32, 2313. CrossRef
2. B.-S. Koo, E.-H. Kim, and K.-J. Lee, Synth. Commun., 2002, 32, 2275. CrossRef
3. Halogenoindoles Reviews, G. R. Gribble, Chem. Soc. Rev., 1999, 28, 335; CrossRef G. W. Gribble, Acc. Chem. Res., 1998, 31, 141; CrossRef G. W. Gribble, J. Nat. Prod., 1992, 55, 1353; CrossRef M. Alvarez and M. Salas, Heterocycles, 1991, 32, 1391. CrossRef
4. G. T. Carter, K. L. Rinehart Jr., L. H. Li, S. L. Kuentzel, and J. L. Connor, Tetrahedron Lett., 1978, 4479. CrossRef
5. C. S. Vairappan, T. Kawamoto, H. Miwa, and M. Suzuki, Planta. Med., 2004, 70, 1087. CrossRef
6. O. R. S. Castillo, L. B. Granados, M. M. Rodríguez, A. Á. Hernández, M. S. M. Ríos, and P. J. Nathan, J. Nat. Prod., 2006, 69, 1596. CrossRef
7. A. Qureshi and D. J. Faulkner, Nat. Prod. Letters, 1999, 13, 59.
8. Y. Miki, H. Shirokoshi, and K. Matsushita, Tetrahedron Lett., 1999, 40, 4347. CrossRef
9. Y. Miki and H. Hachiken, Synlett, 1993, 333. CrossRef
10. Y. Miki, Y. Tada, N. Yanase, H. Hachiken, and K. Matsushita, Tetrahedron Lett., 1996, 37, 7753. CrossRef
11. Y. Miki, Y. Tada, and K. Matsushita, Heterocycles, 1998, 48, 1593. CrossRef
12. Y. Miki, Y. Aoki, Y. Tsuzaki, M. Umemoto, and H. Hibino, Heterocycles, 2005, 65, 2693. CrossRef
13. Y. Miki Y. Tsuzaki, H. Hibino, and Y. Aoki, Synlett, 2004, 2206. CrossRef
14. Y. Miki, Y. Aoki, H. Miyatake, T. Minematsu, and H. Hibino, Tetrahedron Lett., 2006, 47, 5215. CrossRef
15. Y. Miki, M. Kuromatsu, H. Miyatake, and H. Hamamoto, Tetrahedron Lett., 2007, 48, 9093. CrossRef
16. S. C. Roy, C. Guin, K. K. Rana, and G. Maiti, Tetrahedron Lett., 2001, 42, 6941. CrossRef
17. L. Baiocchi and M. Giannangeli, J. Heterocycl. Chem., 1988, 25, 1905. CrossRef
18. Y. Liu and G. W. Gribble, Tetrahedron Lett., 2002, 43, 7135. CrossRef
19. M. Janda, J. Šrogl, and P. Holý, Coll. Czech. Chem. Commun., 1981, 46, 3278.
20. Y. Miki, H. Hachiken, and I. Yoshikawa, Heterocycles, 1997, 45, 1143. CrossRef
21. S. C. Conway and G. W. Gribble, Heterocycles, 1992, 34, 2095. CrossRef
22. Y. Miki, M. Umemoto, M. Nakamura, H. Hibino, N. Ohkita, A. Kato, and Y. Aoki, Heterocycles, 2006, 68, 1893. CrossRef