A facile approach to the synthesis of 5,7-disubstituted indoles via a highly selective lithium-bromine exchange of 5,7-dibromoindoles

Tetrahedron Letters

Volumn 44, Issue 4, 2003, Pages 689-692

  Li, Lianhai ^a   Martins, Andrew ^a  

^a MERCK FROSST CENTRE FOR THERAPEUTIC RESEARCH   (Canada)

Author keywords

[No Author keywords available]

Indexed keywords

5,7 DIBROMOINDOLE; BROMINE; INDOLE DERIVATIVE; LITHIUM; UNCLASSIFIED DRUG;

ARTICLE; CHEMICAL REACTION; ION EXCHANGE; SYNTHESIS;

EID: 0037455028     PISSN: 00404039     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0040-4039(02)02658-8     Document Type: Article

References (35)

1. The indole nucleus is a common substructure of many biologically active compounds. For examples see: Sundberg R.J. Indoles. 1996;Academic Press, London.
2. For reviews, see: (a) Gribble, G. W. J. Chem. Soc., Perkin Trans. 1 2000, 1045-1075; (b) Robinson, B. The Fischer Indole Synthesis; John Wiley and Sons: Chichester, 1982; © Sundberg, R. J. In Comprehensive Heterocyclic Chemistry; Clive, W. B.; Cheeseman, G. W. H., Eds.; Pergamon: Oxford, 1984; Vol. 4, pp. 313-368; (d) Pindur, U.; Adam, R. J. Heterocycl. Chem. 1988, 25, 1-8.
3. For reviews, see: (a) Gribble, G. W. J. Chem. Soc., Perkin Trans. 1 2000, 1045-1075; (b) Robinson, B. The Fischer Indole Synthesis; John Wiley and Sons: Chichester, 1982; © Sundberg, R. J. In Comprehensive Heterocyclic Chemistry; Clive, W. B.; Cheeseman, G. W. H., Eds.; Pergamon: Oxford, 1984; Vol. 4, pp. 313-368; (d) Pindur, U.; Adam, R. J. Heterocycl. Chem. 1988, 25, 1-8.
4. For reviews, see: (a) Gribble, G. W. J. Chem. Soc., Perkin Trans. 1 2000, 1045-1075; (b) Robinson, B. The Fischer Indole Synthesis; John Wiley and Sons: Chichester, 1982; © Sundberg, R. J. In Comprehensive Heterocyclic Chemistry; Clive, W. B.; Cheeseman, G. W. H., Eds.; Pergamon: Oxford, 1984; Vol. 4, pp. 313-368; (d) Pindur, U.; Adam, R. J. Heterocycl. Chem. 1988, 25, 1-8.
5. For reviews, see: (a) Gribble, G. W. J. Chem. Soc., Perkin Trans. 1 2000, 1045-1075; (b) Robinson, B. The Fischer Indole Synthesis; John Wiley and Sons: Chichester, 1982; © Sundberg, R. J. In Comprehensive Heterocyclic Chemistry; Clive, W. B.; Cheeseman, G. W. H., Eds.; Pergamon: Oxford, 1984; Vol. 4, pp. 313-368; (d) Pindur, U.; Adam, R. J. Heterocycl. Chem. 1988, 25, 1-8.
6. For synthesis of indoles with substituent(s) on the benzenoid portion, see: (a) Ezquerra, J.; Pedregal, C.; Lamas, C. J. Org. Chem. 1996, 61, 5804-5812 and references cited therein; (b) Dobbs, A. J. Org. Chem. 2001, 66, 638-641 and references cited therein; © Aoki, K.; Peat, A. J.; Buchwald, S. L. J. Am. Chem. Soc. 1998, 120, 3068-3073.
7. For synthesis of indoles with substituent(s) on the benzenoid portion, see: (a) Ezquerra, J.; Pedregal, C.; Lamas, C. J. Org. Chem. 1996, 61, 5804-5812 and references cited therein; (b) Dobbs, A. J. Org. Chem. 2001, 66, 638-641 and references cited therein; © Aoki, K.; Peat, A. J.; Buchwald, S. L. J. Am. Chem. Soc. 1998, 120, 3068-3073.
8. For synthesis of indoles with substituent(s) on the benzenoid portion, see: (a) Ezquerra, J.; Pedregal, C.; Lamas, C. J. Org. Chem. 1996, 61, 5804-5812 and references cited therein; (b) Dobbs, A. J. Org. Chem. 2001, 66, 638-641 and references cited therein; © Aoki, K.; Peat, A. J.; Buchwald, S. L. J. Am. Chem. Soc. 1998, 120, 3068-3073.
9. For example, Friedel-Crafts acylation of indole without EW group on the pyrrole portion takes place preferentially at the 3-position. See: (a) Ottoni, O.; Neder, A. D. V. F.; Dias, A. K. B.; Cruz, R. P. A.; Aquino, L. B. Org. Lett. 2001, 3, 1005-1007 and references cited therein. For examples of acylation on the benzenoid portion, see: (b) Ref. 1, chapter 14, and references cited therein.
10. For example, Friedel-Crafts acylation of indole without EW group on the pyrrole portion takes place preferentially at the 3-position. See: (a) Ottoni, O.; Neder, A. D. V. F.; Dias, A. K. B.; Cruz, R. P. A.; Aquino, L. B. Org. Lett. 2001, 3, 1005-1007 and references cited therein. For examples of acylation on the benzenoid portion, see: (b) Ref. 1, chapter 14, and references cited therein.
11. Bromination on indole's benzenoid portion, see: (a) Liu, Y.; Gribble, G. W. J. Nat. Prod. 2002, 65, 748-749; (b) Settimo, A. D.; Nannipieri, E. N. J. Org. Chem. 1970, 35, 2546-2550 and references cited therein.
12. Bromination on indole's benzenoid portion, see: (a) Liu, Y.; Gribble, G. W. J. Nat. Prod. 2002, 65, 748-749; (b) Settimo, A. D.; Nannipieri, E. N. J. Org. Chem. 1970, 35, 2546-2550 and references cited therein.
13. Nitration, see: (a) Leclerc, V.; Yous, S.; Delagrange, P.; Boutin, J. A.; Renard, P.; Lesieur, D. J. Med. Chem. 2002, 45, 1853-1859; (b) Noland, W. E.; Rush, K. R. J. Org. Chem. 1966, 31, 70-77 and references cited therein.
14. Nitration, see: (a) Leclerc, V.; Yous, S.; Delagrange, P.; Boutin, J. A.; Renard, P.; Lesieur, D. J. Med. Chem. 2002, 45, 1853-1859; (b) Noland, W. E.; Rush, K. R. J. Org. Chem. 1966, 31, 70-77 and references cited therein.
15. For example, the indole used in this study can be easily prepared by: (a) Fisher indole preparation from 2.4-dibromophenyl hydrazine with corresponding cyclohexanone or cyclopentanone (refluxing for 20 min in AcOH) in 70-80% yield, followed by alkylation; (b) by Swern oxidation of the 5,7-dibromoindoline or 5,7-dibromo-2-methylindoline to afforded indole in more than 90% yield, see: Kiers, D.; Overton, K. J. Chem. Soc., Chem. Commun. 1987, 21, 1660.
16. For example, the indole used in this study can be easily prepared by: (a) Fisher indole preparation from 2.4-dibromophenyl hydrazine with corresponding cyclohexanone or cyclopentanone (refluxing for 20 min in AcOH) in 70-80% yield, followed by alkylation; (b) by Swern oxidation of the 5,7-dibromoindoline or 5,7-dibromo-2-methylindoline to afforded indole in more than 90% yield, see: Kiers, D.; Overton, K. J. Chem. Soc., Chem. Commun. 1987, 21, 1660.
17. Applications to the synthesis of substituted benzenes and naphathalenes, see: (a) Baldwin, J. E.; Jesudason, C. D.; Moloney, M. G.; Morgan, D. R.; Pratt, A. J. Tetrahedron 1991, 47, 5603-5614; (b) Asami, T.; Kim, B.-T.; Yoshida, S. Tetrahedron Lett. 1994, 35, 6117-6118; © Duerr, B. F.; Chung, Y. S.; Czarnik, A. W. J. Org. Chem. 1988, 53, 2120-2122 and references cited therein; (d) Parham, W. E.; Piccirilli, R. M. J. Org. Chem. 1977, 42, 257-260.
18. Applications to the synthesis of substituted benzenes and naphathalenes, see: (a) Baldwin, J. E.; Jesudason, C. D.; Moloney, M. G.; Morgan, D. R.; Pratt, A. J. Tetrahedron 1991, 47, 5603-5614; (b) Asami, T.; Kim, B.-T.; Yoshida, S. Tetrahedron Lett. 1994, 35, 6117-6118; © Duerr, B. F.; Chung, Y. S.; Czarnik, A. W. J. Org. Chem. 1988, 53, 2120-2122 and references cited therein; (d) Parham, W. E.; Piccirilli, R. M. J. Org. Chem. 1977, 42, 257-260.
19. Applications to the synthesis of substituted benzenes and naphathalenes, see: (a) Baldwin, J. E.; Jesudason, C. D.; Moloney, M. G.; Morgan, D. R.; Pratt, A. J. Tetrahedron 1991, 47, 5603-5614; (b) Asami, T.; Kim, B.-T.; Yoshida, S. Tetrahedron Lett. 1994, 35, 6117-6118; © Duerr, B. F.; Chung, Y. S.; Czarnik, A. W. J. Org. Chem. 1988, 53, 2120-2122 and references cited therein; (d) Parham, W. E.; Piccirilli, R. M. J. Org. Chem. 1977, 42, 257-260.
20. Applications to the synthesis of substituted benzenes and naphathalenes, see: (a) Baldwin, J. E.; Jesudason, C. D.; Moloney, M. G.; Morgan, D. R.; Pratt, A. J. Tetrahedron 1991, 47, 5603-5614; (b) Asami, T.; Kim, B.-T.; Yoshida, S. Tetrahedron Lett. 1994, 35, 6117-6118; © Duerr, B. F.; Chung, Y. S.; Czarnik, A. W. J. Org. Chem. 1988, 53, 2120-2122 and references cited therein; (d) Parham, W. E.; Piccirilli, R. M. J. Org. Chem. 1977, 42, 257-260.
21. Applications to the synthesis of substituted pyridines, see: (a) Peterson, M. A.; Mitchell, J. R. J. Org. Chem. 1997, 62, 8237-8239 and references cited therein; (b) Gu, Y. G.; Bayburt, E. K. Tetrahedron Lett. 1996, 37, 2537-2540 and references cited therein.
22. Applications to the synthesis of substituted pyridines, see: (a) Peterson, M. A.; Mitchell, J. R. J. Org. Chem. 1997, 62, 8237-8239 and references cited therein; (b) Gu, Y. G.; Bayburt, E. K. Tetrahedron Lett. 1996, 37, 2537-2540 and references cited therein.
23. Applications to the synthesis of substituted quinolines, see: Mongin F., Fourquez J.-M., Rault S., Levacher V., Godard A., Trecourt F., Queguiner G. Tetrahedron Lett. 36:1995;8415-8418.
24. For previous example to introduce substituents to indole's pyrrole portion by using selective lithium-bromine exchange, see: Liu Y., Gribble G.W. Tetrahedron Lett. 43:2002;7135-7137.
25. In THF, both n-BuLi and t-BuLi afforded 4b and 5b as a mixture of ratio 79:21. In ether, n-BuLi afforded 4b in 50% yield with 50% of 2b intact.
26. Previous example of lithium-bromine exchange performed on 1-potassio indoles, see: (a) Moyer, M. P.; Shiurba, J. F.; Rapoport, H. J. Org. Chem. 1986, 51, 5106-5110; (b) Yang, Y.; Martin, A. R.; Nelson, D. L.; Regan, J. Heterocycles 1976, 34, 1169-1175.
27. Previous example of lithium-bromine exchange performed on 1-potassio indoles, see: (a) Moyer, M. P.; Shiurba, J. F.; Rapoport, H. J. Org. Chem. 1986, 51, 5106-5110; (b) Yang, Y.; Martin, A. R.; Nelson, D. L.; Regan, J. Heterocycles 1976, 34, 1169-1175.
28. Muchowski J.M., Solas D.R. J. Org. Chem. 49:1984;203-205.
29. For example, palladium-catalyzed coupling reaction has been widely used for such purpose. Heck coupling, see: (a) Yokoyama, Y.; Takahashi, M.; Takashima, M.; Kohno, Y.; Kobayashi, H.; Kataoka, K.; Shidori, K.; Murakami, Y. Chem. Pharm. Bull. 1994, 42, 832-838; (b) Yokoyama, Y.; Matsumoto, T.; Murakami, Y. J. Org. Chem. 1995, 60, 1486-1487. Still coupling, see: © Pearce, B. C. Synth. Commun. 1992, 22, 1627-1643. Suzuki coupling, see: (d) Carrera, G. M., Jr.; Sheppard, G. S. Synlett 1994, 93-94. (e) Davidsen, S. K.; Summers, J. B.; Albert, D. H.; Holms, J. H.; Heyman, H. R.; Magoc, T. J.; Conway, R. G.; Rhein, D. A.; Carter, G. W. J. Med. Chem. 1994, 37, 4423-4429.
30. For example, palladium-catalyzed coupling reaction has been widely used for such purpose. Heck coupling, see: (a) Yokoyama, Y.; Takahashi, M.; Takashima, M.; Kohno, Y.; Kobayashi, H.; Kataoka, K.; Shidori, K.; Murakami, Y. Chem. Pharm. Bull. 1994, 42, 832-838; (b) Yokoyama, Y.; Matsumoto, T.; Murakami, Y. J. Org. Chem. 1995, 60, 1486-1487. Still coupling, see: © Pearce, B. C. Synth. Commun. 1992, 22, 1627-1643. Suzuki coupling, see: (d) Carrera, G. M., Jr.; Sheppard, G. S. Synlett 1994, 93-94. (e) Davidsen, S. K.; Summers, J. B.; Albert, D. H.; Holms, J. H.; Heyman, H. R.; Magoc, T. J.; Conway, R. G.; Rhein, D. A.; Carter, G. W. J. Med. Chem. 1994, 37, 4423-4429.
31. For example, palladium-catalyzed coupling reaction has been widely used for such purpose. Heck coupling, see: (a) Yokoyama, Y.; Takahashi, M.; Takashima, M.; Kohno, Y.; Kobayashi, H.; Kataoka, K.; Shidori, K.; Murakami, Y. Chem. Pharm. Bull. 1994, 42, 832-838; (b) Yokoyama, Y.; Matsumoto, T.; Murakami, Y. J. Org. Chem. 1995, 60, 1486-1487. Still coupling, see: © Pearce, B. C. Synth. Commun. 1992, 22, 1627-1643. Suzuki coupling, see: (d) Carrera, G. M., Jr.; Sheppard, G. S. Synlett 1994, 93-94. (e) Davidsen, S. K.; Summers, J. B.; Albert, D. H.; Holms, J. H.; Heyman, H. R.; Magoc, T. J.; Conway, R. G.; Rhein, D. A.; Carter, G. W. J. Med. Chem. 1994, 37, 4423-4429.
32. For example, palladium-catalyzed coupling reaction has been widely used for such purpose. Heck coupling, see: (a) Yokoyama, Y.; Takahashi, M.; Takashima, M.; Kohno, Y.; Kobayashi, H.; Kataoka, K.; Shidori, K.; Murakami, Y. Chem. Pharm. Bull. 1994, 42, 832-838; (b) Yokoyama, Y.; Matsumoto, T.; Murakami, Y. J. Org. Chem. 1995, 60, 1486-1487. Still coupling, see: © Pearce, B. C. Synth. Commun. 1992, 22, 1627-1643. Suzuki coupling, see: (d) Carrera, G. M., Jr.; Sheppard, G. S. Synlett 1994, 93-94. (e) Davidsen, S. K.; Summers, J. B.; Albert, D. H.; Holms, J. H.; Heyman, H. R.; Magoc, T. J.; Conway, R. G.; Rhein, D. A.; Carter, G. W. J. Med. Chem. 1994, 37, 4423-4429.
33. For example, palladium-catalyzed coupling reaction has been widely used for such purpose. Heck coupling, see: (a) Yokoyama, Y.; Takahashi, M.; Takashima, M.; Kohno, Y.; Kobayashi, H.; Kataoka, K.; Shidori, K.; Murakami, Y. Chem. Pharm. Bull. 1994, 42, 832-838; (b) Yokoyama, Y.; Matsumoto, T.; Murakami, Y. J. Org. Chem. 1995, 60, 1486-1487. Still coupling, see: © Pearce, B. C. Synth. Commun. 1992, 22, 1627-1643. Suzuki coupling, see: (d) Carrera, G. M., Jr.; Sheppard, G. S. Synlett 1994, 93-94. (e) Davidsen, S. K.; Summers, J. B.; Albert, D. H.; Holms, J. H.; Heyman, H. R.; Magoc, T. J.; Conway, R. G.; Rhein, D. A.; Carter, G. W. J. Med. Chem. 1994, 37, 4423-4429.
34. Lithium-bromine exchange reaction was well tolerated by substrates bearing electrophilic functionals, see: review: Parham W.E., Bradsher C.K. Acc. Chem. Res. 15:1982;300-305.
35. 3: C, 75.20; H, 6.31; N, 4.18. Found: C, 75.21; H, 6.40; N, 4.17%.