· (MW 252.73)
(used in the synthesis of mono- and dibromocyclopropanes,1 allenes2 and cumulenes,3 cyclopentadienes and fulvenes, a- and b-bromo-a,b-unsaturated carbonyl compounds, 1,1,3-tribromides, tribromomethyllithium carbonyl adducts, isocyanides,4 a-hydroxy and a-aminoaryl acetic acids)
Alternate Name: tribromomethane.
Physical Data: mp 8.5 °C; bp 146-150 °C; d 2.827 g cm-3.
Solubility: sol acetone, benzene, chloroform, ethanol, ether, petroleum ether.
Form Supplied in: commercially available with inhibitors present.
Analysis of Reagent Purity: technical (94%) and high purity (99+%).
Preparative Method: by reaction of acetone with sodium hypobromite.
Purification: wash with concentrated sulfuric acid and then water. The liquid is dried over CaCl2 or K2CO3 then fractionally distilled.
Handling, Storage, and Precautions: store in closed containers away from light. Diphenylamine and ethanol are commonly used inhibitors. Do not breathe vapors as addiction may occur. Suspected cancer agent; lachrymator. Use in a fume hood.
Bromoform is a routinely used precursor to dibromocarbene which can be generated by many different methods (eq 1).6 Dibromocarbene adds stereospecifically to alkenes7 and its reactivity towards alkyl substituted alkenes is analogous to that of dichlorocarbene: tetrasubstituted > trisubstituted > unsymmetrical disubstituted > symmetrical disubstituted > monosubstituted alkenes.8 Dibromocarbene has been prepared by treatment of bromoform with Potassium t-Butoxide.9 The yields of dibromocyclopropanes obtained using this method are typically no more than 70% for good cases and are usually lower. For example, reaction of cyclooctene with bromoform and potassium t-butoxide gave a 52-65% yield of
dibromide (eq 2).10 Dibromocarbene has also been generated by adsorbing a mixture of alkene and bromoform on basic Alumina.11 At elevated temperatures, Potassium Carbonate can generate dibromocarbene from bromoform in the presence of 18-Crown-6. Cycloheptatriene at 140 °C with these reagents gave 1-bromobenzocyclobutane in 18-45% yield (eq 3).12
A significant improvement in the rate and yield of halocyclopropanes is realized if phase transfer catalysts13 like triethylbenzylammonium chloride are used.14 Yields for dibromocyclopropanes, however, while generally less than 50%, can be somewhat improved if a considerable excess of bromoform and 24-96 h reaction times are used.15 Addition of a small amount of ethanol to the reaction mixture often results in 10-30% increase in the yield of dibromocyclopropanes. In a typical procedure, 50% aqueous NaOH is added over 10 min to a stirred mixture of bromoform, alkene, triethylbenzylammonium chloride (TEBA) and a small amount of ethanol at 40-45 °C. After 3 h at the same temperature the mixture is diluted with dichloromethane and poured into
water. An extractive work-up and concentration of the organic phases provides the crude product which is typically purified by distillation. For this method a two- to three-fold molar excess of bromoform to alkene or the converse is ordinarily used.16
It has been observed that the nature of the phase transfer catalyst (PTC) can have a profound effect on the yield of product obtained.17 For example, reaction of allylic bromides with bromoform can give either cyclopropanes or substitution products depending on the type of catalyst used (eq 4). When the phase transfer catalyst cetrimide [(C16H33)NMe3Br] is used, the cyclopropane product predominates. The product ratio is reversed when tetraphenylarsonium chloride (Ph4AsCl) is used as the catalyst and the substitution pathway is preferred.18 When a,b-unsaturated carbonyls are used, the choice of phase transfer catalyst also impacts the product distribution obtained between the cyclopropyl product and that of Michael addition.19
For systems where only ring formation is expected, the reaction selectivities between different alkenes are not affected by alteration of the phase transfer catalyst.20 The use of an optically active phase transfer catalyst has led to unprecedented but low levels of asymmetric induction.21
Dibromocarbene is also made via Seyferth's reagent.22 The reagent, Phenyl(tribromomethyl)mercury, is typically prepared from bromoform, a phenylmercury(II) halide, and potassium t-butoxide.23 Another procedure for the synthesis of phenyl(tribromomethyl)mercury24 using a phase transfer catalyst, Potassium Fluoride, and Sodium Hydroxide has also been reported.25 Using these types of methods, the carbene is released with elimination of phenylmercury(II) halide.26 The ring expansion of 1-methylindenes into 3-bromo-1-methylnaphthalenes is accomplished in moderate yields (~55%) by reaction of the dibromocarbene released from this type of mercury reagent (eq 5). The same reaction using bromoform/potassium t-butoxide gave a 2-bromo-1-methylnaphthalene
in only 14% yield.27 An alternative to other straightforward syntheses of monobromocyclopropanes28 from alkenes (eq 6) uses Diethylzinc-Bromoform-Oxygen.29
Once having obtained the dibromocyclopropanes resulting from addition of dibromocarbene to different types of double bonds, chemists have been able to prepare a myriad of different structures (see also Chloroform and Iodoform).
Allenes and Cumulenes.
Allenes have been prepared by reaction of dibromocyclopropanes with Magnesium, but in low yield.30 The use of alkyllithiums leads to improved yields with Methyllithium being the reagent of choice.31 9,9-Dibromobicyclo[6.1.0]nonane is converted to 1,2-cyclononadiene with methyllithium (eq 7)10,32,33 while the lower homolog, 8,8-dibromobicyclo[5.1.0]octane, leads to a complex mixture of products.34 This is due, in large part, to intramolecular carbenoid insertions competing with allene formation. This property has been used to gain entry into the tricyclo[4.1.0.02,7]heptene ring system (eq 8).35
Reaction of dibromocarbene with allenes leads to cumulenes upon treatment of the intermediate dibromocyclopropane with methyllithium.36,37 An example of the utility of this approach is shown in eq 9.38,39
Cyclopentadienes and Fulvenes.
The Skattebøl rearrangement occurs when conjugated dienes are converted into 1,1-dibromo-2-vinylcyclopropanes and then treated with MeLi at -78 °C. The major products are typically cyclopentadienes with small amounts of vinylallenes (eq 10). The ratio of products vary with the substitution on the starting vinylcyclopropane.40 An example of the Skattebøl rearrangement in the synthesis of an optically active cyclopentadiene is shown in eq 11.41,42
Similar treatment of 3,3,3´3´-tetramethyl-2,2,2´,2´-tetrabromobicyclopropyl with methyllithium yields a diallene as the major product (eq 12). When the dimethylbicyclopropyl analog is used, a fulvene is the major product with a diallene being a minor product (eq 13). This change in product distribution is believed to result from the difference in rates of allene formation versus that of rearrangement to a cyclopentylcarbene.40,43
a-Bromo-a,b-Unsaturated Carbonyl Compounds.
Addition of dibromocarbene to a silyl enol ether has been shown to generate a-bromo-a,b-unsaturated carbonyl compounds after thermal or acid-catalyzed rearrangement of the intermediate dibromocyclopropane (eq 14).44,45
Reaction of unsubstituted ketene trialkylsilyl acetals with bromoform and a catalytic amount of Triethylborane affords 3-bromoacrylate (eq 15). The same conditions using a substituted ketene acetal provides a 2-dibromomethyl ester (eq 16).46
Unlike chloroform, which adds under radical conditions across the double bond through the C-H bond,47 bromoform typically reacts through one of the C-Br bonds (eq 17),48 although mixtures of products are often obtained.49
Bromoform is converted in situ into Tribromomethyllithium upon treatment with lithium dicyclohexylamide. The anion reacts with cyclohexanone to afford the corresponding tribromomethyl alcohol (eq 18).50
The use of phase transfer catalysis in the Hofmann isocyanide synthesis51 is reported to result in improved yields.52 Either chloroform or bromoform can be used. Bromoform is often used in the preparation of low-boiling isocyanides since the products can be easily removed from the reaction mixture (eq 19).
a-Hydroxyarylacetic and a-Aminoarylacetic Acids.
A one-pot synthesis of a-hydroxyarylacetic acids from bromoform, an aryl aldehyde, and Potassium Hydroxide occurs with Lithium Chloride as catalyst (eq 20).53 By a similar process, a-aminoarylacetic acids can be made using bromoform, an aryl aldehyde, and Ammonia with potassium hydroxide and Lithium Amide as catalyst. This method reportedly gives higher yields than other single-pot procedures.54
- 1. (a) Chinoporos, E. CRV 1963, 63, 235. (b) Parham, W. E.; Schweizer, E. E. OR 1963, 13, 55.
- 2. The Chemistry of the Allenes; Landor, S. R., Ed.; Academic: New York, 1983.
- 3. Brandsma, L.; Verkruijsse, H. D. Synthesis of Acetylenes, Allenes and Cumulenes; A Laboratory Manual; Studies in Organic Chemistry, Vol. 8; Elsevier: New York, 1981.
- 4. Ugi, I. Isonitrile Chemistry; Academic: New York, 1971.
- 5. For reviews of carbenes in general, see (a) Kirmse, W. E. Carbene Chemistry, 2nd ed.; Academic: New York, 1971. (b) Hine, J. Divalent Carbon; Ronald: New York, 1964.
- 6. Dehmlow, E. V. MOC 1989, E19b, 1608.
- 7. (a) Skell, P. S.; Garner, A. Y. JACS 1956, 78, 3409. (b) Skell, P. S.; Woodworth, R. C. JACS 1956, 78, 4496.
- 8. Doering, W. von E.; Henderson Jr., W. A. JACS 1958, 80, 5274.
- 9. Doering, W. von E.; Hoffman, A. K. JACS 1954, 76, 6162.
- 10. Skattebøl, L.; Solomon, S. OSC 1973, 5, 306.
- 11. Serratosa, F. J. Chem. Educ. 1964, 41, 564.
- 12. DeCamp, M. R.; Viscogliosi, L. A. JOC 1981, 46, 3918.
- 13. For a survey see: Dehmlow, E. V.; Dehmlow, S. S. Phase Transfer Catalysis; VCH: Weinheim, 1993.
- 14. Makosza, M.; Wawrzyniewicz, M. TL 1969, 4659.
- 15. Skattebøl, L.; Abskharoun, G. A.; Greibrokk, T. TL 1973, 1367.
- 16. Makosza, M.; Fedorynski, M. SC 1969, 4659.
- 17. (a) Fedorynski, M. S 1977, 783. (b) Mandel'shtam, T. V.; Kharicheva, E. M.; Labeish, N. N.; Kostikov, R. R. ZOR 1980, 16, 2513 (CA 1981, 94, 120 501b) (c) Baird, M. S.; Baxter, A. G. W.; Devlin, B. R. J.; Searle, R. J. G. CC 1979, 210.
- 18. Dehmlow, E. V.; Wilkenloh, J. LA 1990, 125 (CA 1990, 112, 138 566b).
- 19. Dehmlow, E. V.; Wilkenloh, J. CB 1990, 123, 583 (CA 1990, 112, 157 708r).
- 20. Dehmlow, E. V.; Fastabend, U. CC 1993, 1241.
- 21. Hiyama, T.; Sawada, H.; Tsukanaka, M.; Nozaki, H. TL 1975, 3013.
- 22. (a) Seyferth, D.; Burlitch, J. M.; Minasz, R. J.; Mui, J. Y.-P.; Simmons Jr, H. D.; Treiber; A. J. H.; Dowd, S. R. JACS 1965, 87, 4259. (b) Seyferth, D.; Gordon, M. E.; Mui, J. Y.-P.; Burlitch, J. M. JACS 1967, 89, 959.
- 23. Seyferth, D. Burlitch, J. M. JOM 1965, 4, 127.
- 24. (a) Logan, T. J. OSC 1973, 5, 969. (b) Schweizer, E. E.; O'Neill, G. J. JOC 1963, 28, 851.
- 25. Fedorynski, M.; Makosza, M. JOM 1973, 51, 89.
- 26. (a) Seyferth, D.; Lambert Jr., R. L. JOM 1969, 16, 21. (b) Seyferth, D. ACR 1972, 5, 65.
- 27. Gillespie Jr., J. S.; Acharya, S. P.; Shamblee, D. A. JOC 1975, 40, 1838.
- 28. (a) Closs, G. L.; Coyle, J. J. JACS 1965, 87, 4270. (b) Seyferth, D.; Simmons Jr., H. D.; Singh, G. JOM 1965, 3, 337. (c) Nishimura, J.; Furukawa, J. CC 1971, 1375. (d) Martel, B.; Hiriat, J. M. S 1972, 201.
- 29. Miyano, S.; Matsumoto, Y.; Hashimoto, H. CC 1975, 364.
- 30. (a) Doering, W. von E.; LaFlamme, P. M. T 1958, 2, 75. (b) Gardner, P. D.; Narayana, M. JOC 1961, 26, 3518.
- 31. (a) Moore, W. R.; Ward, H. R. JOC 1962, 27, 4179. (b) Skattebøl, L. TL 1961, 167.
- 32. (a) Skattebøl, L. ACS 1963, 17, 1683. (b) Skattebøl, L. JOC 1964, 29, 2951. (c) Skattebøl, L. JOC 1966, 31, 2789.
- 33. For an example resulting in the synthesis of cyclononadienones, see Perez, G. H.; Weyerstahl, P. S 1985, 174.
- 34. Marquis, E. T.; Gardner, P. D. TL 1966, 2793.
- 35. Paquette, L. A.; Taylor, R. T. JACS 1977, 99, 5708.
- 36. (a) Skattebøl, L. TL 1965, 2175. (b) Ball, W. J.; Landor, S. R.; Punja, N. JCS(C) 1967, 194.
- 37. Dunkelblum, E.; Singer, B. S 1975, 323.
- 38. Bee, L. K.; Beeby, J.; Everett, J. W.; Garratt, P. J. JOC 1975, 40, 2212.
- 39. (a) Garratt, P. J.; Nicolaou, K. C.; Sondheimer, F. CC 1971, 1018. (b) Garratt, P. J.; Nicolaou, K. C.; Sondheimer, F. JOC 1973, 38, 2715.
- 40. Skattebøl, L. T 1967, 23, 1107.
- 41. Paquette, L. A.; McLaughlin, M. L. OS 1990, 68, 220.
- 42. For other examples see (a) Butler, D. N.; Gupta, I. CJC 1978, 56, 80. (b) Charumilind, P.; Paquette, L. A. JACS 1984, 106, 8225. (c) McLaughlin, M. L.; McKinney, J. A.; Paquette, L. A. TL 1986, 27, 5595. (d) Paquette, L. A.; Sivik, M. R. OM 1992, 11, 3503.
- 43. 6-Bromofulvene can be made directly from cyclopentadiene and bromoform: Washburn, W. N.; Zahler, R.; Chen, I. JACS 1978, 100, 5863.
- 44. Amice, P.; Blanco, L.; Conia, J. M. S 1976, 196.
- 45. Hirao, T.; Hayashi, K.; Fujihara, Y.; Ohshiro, Y.; Agawa, T. JOC 1985, 50, 279.
- 46. Sugimoto, J.; Miura, K.; Oshima, K.; Utimoto, K. CL 1991, 1319.
- 47. (a) Kharasch, M. S.; Jensen, E. V.; Urry, W. H. JACS 1946, 68, 154. (b) Kharasch, M. S.; Jensen, E. V.; Urry, W. H. JACS 1947, 69, 1100.
- 48. Meyers, A. I.; Babiak, K. A.; Campbell, A. L.; Comins, D. L.; Fleming, M. P.; Henning, R.; Heuschmann, M.; Hudspeth, J. P.; Kane, J. M.; Reider, P. J.; Roland, D. M.; Shimizu, K.; Tomioka, K.; Walkup, R. D. JACS 1983, 105, 5015.
- 49. Tamura, T.; Kunieda, T.; Takizawa, T. JOC 1974, 39, 38.
- 50. Taguchi, H., Yamamoto, H.; Nozaki, H. JACS 1974, 96, 3010.
- 51. Hofmann, A. W. CB 1870, 3, 761.
- 52. Weber, W. P.; Gokel, G. W.; Ugi, I. K. AG(E) 1972, 11, 530.
- 53. Compere, E. L., Jr. JOC 1968, 33, 2565.
- 54. Compere, E. L., Jr.; Weinstein, D. A. S 1977, 852.
Matthew R. Sivik
The Lubrizol Corporation, Wickliffe, OH, USA
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