Abstract
The one-pot synthesis of 3,6-bis(5’-bromo-3’-indolyl)-1,4-dimethylpiperazine-2,5-dione is reported. Sarcosine anhydride is brominated and immediately reacted with 5-bromoindole to produce the product, which is characterized by 1H NMR, MS and microanalysis.
1. Introduction
Isolated from the marine sponge series Dragmacidin, Hexadella, and Spongosorites, unique bis-indolylpiperazine alkaloids have received significant attention in recent years for their antiviral, cytotoxic, and anti-inflammatory properties [1,2,3,4,5,6,7,8,9,10]. The dragmacidin series of alkaloids each contain a central piperazine ring with indole units attached at the 2- and 5- positions. The corresponding author successfully synthesized the first member of the dragmacidin series [11] and recently reported an improved procedure for preparing 1,4-dimethylpiperazine-2,5-dione, an important precursor [12]. We now report the synthesis of 3,6-bis(5’-bromo-3’-indolyl)-1,4-dimethylpiperazine-2,5-dione (3), a novel bis-indolylpiperazinedione utilizing the newly-developed procedure. This product will be utilized in the preparation of novel dragmacidin derivatives.
2. Results and Discussion
The synthesis of 3 is shown in Scheme 1. Bromine is directly added to 1 with heat and the illumination of a sun lamp. After one hour, the solution is cooled to provide the dibrominated product as an unstable precipitate. This precipitate is then reacted with 5-bromoindole in DMF to produce 3. In conclusion, an important precursor to a dragmacidin derivative has been prepared by efficient means.
3. Experimental Section
To a solution of sarcosine anhydride (1) (1.50 g, 10.6 mmol) in o-dichlorobenzene (15 mL), at 150°C, was added dropwise Br2 (2.5 mL, 96.6 mmoL), under illumination of a sun lamp. The solution was heated for 1 h and then cooled to room temperature. The solution was decanted leaving beige crystals (2). To a solution of 5-bromoindole (2.21 g, 11.3 mmol) in DMF (20 mL) was slowly added 2 (1.50 g, 5.0 mmol), while the reaction temperature was maintained at room temperature with a water bath. The reaction mixture was stirred for 18 h, concentrated and diluted with methanol. The resulting solid was filtered to yield the product (3) as a white crystalline solid (1.92 g; 72.5%): mp > 250°C. 1H NMR (d6-DMSO): 2.67 (s, 3H), 5.64 (s, 1H), 7.25 (dd, 1H, J = 1.9, 8.6), 7.39 (d, 1H, J = 8.7), 7.49 (d, 1H, J = 2.5), 7.69 (d, 1H, J = 1.8), 9.67 (bs, 1H); MS: 532 (m+, 17.3), 530 (54.5), 528 (51.3), 335 (100.0), 333 (99.9), 307 (31.9), 305 (30.7), 239 (47.9), 237 (91.8), 235 (68.0), 209 (30.6), 207 (30.9), 197 (30.2), 195 (29.7); Anal. Calcd. For C22H16Br2N4O2: C, 48.84; H, 3.42; N, 10.57. Found: C, 49.80; H, 3.50; N, 10.64. Sarcosine anhydride (99.5%) was obtained from Acros Organics, and 5-bromoindole (99%) was obtained from Sigma-Aldrich, Inc.
Supplementary materials
Supplementary File 1Supplementary File 2Supplementary File 3Acknowledgements
This work was supported by the Allen E. Paulson College of Science and Technology Scholars Program and the Department of Chemistry at Georgia Southern University, and the Cava research group at The University of Alabama.
References and Notes
- Kohmoto, S.; Kashman, Y.; McConnell, O.J.; Rinehart, K.L., Jr.; Wright, A.; Koehn, F. Dragmacidin, a new cytotoxic bis(indole) alkaloid from a deep water marine sponge, Dragmacidon sp. J. Org. Chem. 1988, 53, 3116–3118. [Google Scholar] [CrossRef]
- Wright, A.E.; Pomponi, S.A.; Cross, S.S.; McCarthy, P. A new bis-(indole) alkaloid from a deep-water marine sponge of the genus Spongosorites. J. Org. Chem. 1992, 57, 4772–4775. [Google Scholar] [CrossRef]
- Capon, R.J.; Rooney, F.; Murray, L.M.; Collins, E.; Sim, A.T.R.; Rostas, J.A.P.; Butler, M.S.; Carroll, A.R. Dragmacidins: New protein phosphatase inhibitors from a southern Australian deep-water marine sponge, Spongosorites sp. J. Nat. Prod. 1998, 61, 660–662. [Google Scholar] [CrossRef] [PubMed]
- Capon, R.J.; Rooney, F.; Murray, L.M. 1,9-Dimethylhypoxanthine from a southern Australian marine sponge Spongosorites species. J. Nat. Prod. 2000, 63, 261–262. [Google Scholar] [CrossRef] [PubMed]
- Bao, B.; Sun, Q.; Yao, X.; Hong, J.; Lee, C.O.; Cho, H.Y.; Jung, J.H. Bisindole alkaloids of the topsentin and hamacanthin classes from a marine sponge Spongosorites sp. J. Nat. Prod. 2007, 70, 2–8. [Google Scholar] [CrossRef] [PubMed]
- Morris, S.A.; Andersen, R.J. Brominated bis(indole) alkaloids from the marine sponge hexadella sp. Tetrahedron 1990, 46, 715–720. [Google Scholar] [CrossRef]
- Yang, C.-G.; Huang, H.; Jiang, B. Progress in studies of novel marine bis(indole) alkaloids. Curr. Org. Chem. 2004, 8, 1691–1720. [Google Scholar] [CrossRef]
- Bao, B.; Sun, Q.; Xinsheng, Y.; Hong, J.; Lee, C.-O.; Sim, C.J.; Im, K.S.; Jung, J.H. Cytotoxic bisindole alkaloids from a marine sponge Spongosorites sp. J. Nat. Prod. 2005, 68, 711–715. [Google Scholar] [CrossRef] [PubMed]
- Sakemi, S.; Sun, H.H. Nortopsentins A, B, and C. Cytotoxic and antifungal imidazolediylbis[indoles] from the sponge Spongosorites ruetzleri. J. Org. Chem. 1991, 56, 4304–4307. [Google Scholar] [CrossRef]
- Gunasekera, S.P.; McCarthy, P.J.; Kelly-Borges, M. Hamacanthins A and B, new antifungal bis indole alkaloids from the deep-water marine sponge, Hamacantha sp. J. Nat. Prod. 1994, 57, 1437–1441. [Google Scholar] [CrossRef] [PubMed]
- Whitlock, C.R.; Cava, M.P. A total synthesis of dragmacidin B. Tetrahedron Lett. 1994, 35, 371–374. [Google Scholar] [CrossRef]
- Miles, D.; Whitlock, C. An improved, one-pot synthesis of 3,6-bis(3’-indolyl)-1,4-dimethylpiperazine-2,5-dione. Het. Comm. 2009, 15, 61–62. [Google Scholar]
© 2009 by the authors; licensee Molecular Diversity Preservation International, Basel, Switzerland. This article is an open-access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/3.0/).