2,4,4,6-Tetrabromo-2,5-cyclohexadienone1

[20244-61-5]  · C6H2Br4O  · 2,4,4,6-Tetrabromo-2,5-cyclohexadienone  · (MW 409.68)

(selective bromination of polyalkenes;2-4 monobromination of phenols,5,6 unprotected arylamines,7,8 and aza heterocycles;9 oxidation of thiols to disulfides;10 synthesis of a-bromo-a,b-unsaturated ketones;11 electron acceptor in photosensitization reactions;12 cyclization of alkenols3,13)

Alternate Name: TBCHD.

Physical Data: mp 125-130 °C (dec).

Solubility: sol CH2Cl2, Et2O, CHCl3, MeNO2, MeOH.

Form Supplied in: crystalline material; commercially available.

Preparative Methods: bromination of 2,4,6-tribromophenol with Bromine in acetic acid in the presence of sodium acetate (eq 1).6,7,8,14

Analysis of Reagent Purity: 1H NMR.

Handling, Storage, and Precautions: the reagent should be kept in a dark vessel, well-protected from light.

Brominative Cyclization of Polyalkenes.

Electrophilic bromination of 1,5-dienes with 2,4,4,6-tetrabromo-2,5-cyclohexadienone results in the formation of brominated six-membered carbocycles. This brominative cyclization does not always proceed in good yield, but has been used for the biomimetic construction of marine natural products.15 Nerolidol thus reacts with TBCHD to give the monocyclic sesquiterpenes a- and b-snyderol (from the red algae Laurencia species) in low yield (eq 2).2,4 When used as solvent, acetonitrile may participate in the reaction, depending upon the temperature.16 In a similar fashion, brominative cyclization of methyl farnesate has been used in the total synthesis of acoratriene (eq 3)16 and 10-bromo-a-chamigrene.17

In contrast, geranyl acetate,17 carvone,18 and farnesyl cyanide18 undergo selective bromination to the dibromo adducts with TBCHD (e.g. eq 4). Natural products from Desmia hornemanni have been synthesized by bromination of myrcene,19 and the synthesis of isoconcinndiol has been achieved in a fashion similar to that outlined above.20

Monobromination of Phenols, Arylamines, and Aza Heterocycles.

Phenols are selectively monobrominated at the ortho position by TBCHD.5,6 Phenol is brominated in CCl4 to give a 87:13 ratio of o-bromo- and p-bromophenol (95% yield).5 Estradiol is brominated at the 2- and 4-positions.21 Of more potential use is the selective monobromination of anilines at the para position (eq 5);5,7,8,22,28 the following arylamines have been brominated in this fashion: aniline (92%), N-methylaniline (94%), N,N-dimethylaniline (91%), o-toluidine (88%), m-toluidine (90%), 2,3-dimethylaniline (91%), 2-chloroaniline (86%), 3-chloroaniline (86%), 3-bromoaniline (82%), 2-nitroaniline (91%), o-anisidine (85%), 2-aminopyridine (75%), 2-N,N-dimethylaminopyridine (70%), and 3-N,N-dimethylaminopyridine (60%). Monobromination of Imidazole, N-Methylimidazole and indole has also been achieved with TBCHD (eq 6).9

Oxidation of Thiols to Disulfides.

Thiols (as their sodium salts) are oxidized by TBCHD to give disulfides (eq 7).10 The use of benzene as solvent is particularly recommended as all byproducts are then easily removed as insoluble precipitates. The reagent behaves as an oxidizing agent towards sulfides, converting them into sulfoxides.23

Selective a-Bromination of a,b-Unsaturated Ketones.

Monobromination of a,b-unsaturated ketones at the a-position without affecting the double bond was performed with TBCHD (eqs 8 and 9).11,29 The rate of the reaction is very slow, but can be enhanced by the addition of a catalytic amount of gaseous Hydrogen Chloride or Hydrogen Bromide.

Electron Acceptor in Photosensitization Reactions.

TBCHD is an electron acceptor in the photosensitized oxidation of unsaturated substrates, e.g. alkynes,12 stilbene,12 tetraphenylethylene,12 a-methylstyrene,12 dioxenes,24 and 2,3,5,6-tetraphenyl-p-dioxin.24

Cyclization of Alkenols.

Cyclization of alkenols with TBCHD gives brominated tetrahydropyrans accompanied by minor amounts of brominated tetrahydrofurans (eq 10).3,13,25 This reaction has been used for the synthesis of (±)-incensole from (±)-mukulol. In addition, this methodology allows the stereospecific construction of trans-2,5-disubstituted tetrahydrofurans by the cyclization of g,d-unsaturated alcohols to 3-bromotetrahydropyrans followed by silver-induced ring contraction (eq 11).13

Allylic Bromination and Synthesis of Spiroisoxazolines.

Allylic brominations of cephem derivatives have been achieved with the dienone reagent under irradiation (eq 12).26 Spiroisoxazolines are formed by oxidative cyclization of o-hydroxybenzyl oximes. This methodology was used in the synthesis of the sponge metabolite cis,cis-aerothionine (eq 13).27


1. Lemaire, M.; Guy, A.; Hoa, H. A.; Guetté, J.-P. Janssen Chim. Acta 1987, 5, 3.
2. Kato, T.; Ichinose, I.; Kamoshida, A.; Kitahara, Y. CC 1976, 518.
3. Kato, T.; Yen, C. C.; Kobayashi, T.; Kitahara, Y. CL 1976, 1191.
4. Kato, T.; Ishii, K.; Ichinose, I.; Nakai, Y.; Kumagai, T. CC 1980, 1106.
5. (a) Caló, V.; Ciminale, F.; Lopez, L.; Pesce, G.; Todesco, P. E. Chim. Ind. (Milan) 1971, 53, 467. (b) Caló, V.; Lopez, L.; Pesce, G.; Ciminale, F.; Todesco, P. E. JCS(P2) 1974, 1189.
6. Caló, V.; Ciminale, F.; Lopez, L.; Todesco, P. E. JCS(C) 1971, 3652.
7. Fox, G. J.; Hallas, G.; Hepworth, J. D.; Paskins, K. N. OS 1976, 55, 20.
8. Fox, G. J.; Hallas, G.; Hepworth, J. D.; Paskins, K. N. OSC 1988, 6, 181.
9. Caló, V.; Ciminale, F.; Lopez, L.; Naso, F.; Todesco, P. E. JCS(P1) 1972, 2567.
10. Ho, T.-L.; Hall, T. W.; Wong, C. M. S 1974, 872.
11. Caló, V.; Lopez, L.; Pesce, G.; Todesco, P. E. T 1973, 29, 1625.
12. Lopez, L.; Caló, V. CC 1984, 1266.
13. Ting, P. C.; Bartlett, P. A. JACS 1984, 106, 2668.
14. Benedikt, R. LA 1879, 199, 127.
15. Kato, T.; Ichinose, I.; Kumazawa, S.; Kitahara, Y. Bioorg. Chem. 1975, 4, 188.
16. Kato, T.; Mochizuki, M.; Hirano, T.; Fujiwara, S.; Uyehara, T. CC 1984, 1077.
17. Kuraray Co. Ltd. Jpn. Patent 80 157 519, 1980 (CA 1981, 95, 7509).
18. Kitahara, Y.; Kato, T.; Ichinose, I. CL 1976, 283.
19. Yoshihara, K.; Hirose, Y. BCJ 1978, 51, 653.
20. Fujiwara, S.; Takeda, K.; Uyehara, T.; Kato, T. CL 1986, 1763.
21. Zontova, V. N.; Rzheznikov, V. M.; Pivnitskii, K. K. Steroids 1975, 25, 827.
22. Markgraf, J. H.; Marshall, G. T.; Greeley, M. A. CI(L) 1987, 298.
23. Caló, V.; Ciminale, F.; Lopez, G.; Todesco, P. E. IJS 1971, 1, 130.
24. Lopez, L.; Caló, V.; Aurora, R. J. Photochem. 1986, 32, 95.
25. Kato, T.; Ichinose, I.; Hosogai, T.; Kitahara, Y. CL 1976, 1187.
26. Meji Seika Kaisha Ltd. Jpn. Patent 59 88 489, 1984 (CA 1984, 101, 170 973).
27. Forrester, A. R.; Thomson, R. H.; Woo, S.-O. LA 1978, 66.
28. Fox, G. J.; Hepworth, J. D.; Hallas, G. JCS(P1) 1973, 68.
29. Mehta, G.; Krishnamurthy, N. CC 1986, 1319.

Norbert De Kimpe

University of Gent, Belgium



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