Bromoacetone1

[598-31-2]  · C3H5BrO  · Bromoacetone  · (MW 136.98)

(acetonylation; synthesis of heterocycles)

Alternate Name: 1-bromo-2-propanone.

Physical Data: bp 40-42 °C/13 mmHg;2 63.5-64 °C/50 mmHg;3 37-45 °C/12 mmHg;4 138-140 °C;5 n15D 1.4697.

Solubility: sol most organic solvents; the use of nucleophilic solvents has to be avoided due to the high reactivity of the reagent for nucleophilic substitution.

Preparative Methods: bromoacetone is most conveniently prepared by bromination of Acetone with Bromine in aqueous acetic acid (eq 1)2 or in aqueous medium in the presence of potassium chlorate (eq 2).3 The yields are never excellent but these procedures are recommended due to the ease of operation and the inexpensive starting materials. However, it has been reported that acetone is brominated to give bromoacetone in almost quantitative yields by bromination with (Z)-5-nitro-2-furylvinylpyridinium tribromide5 or 6-chloroperfluorohexanesulfonyl bromide.6

Handling, Storage, and Precautions: strong lachrymator; strong alkylating agent; toxic; strong vesicant; only use in a well-ventilated hood. The stability of bromoacetone is notably dependent upon its purity.3 In the absence of any stabilizer the crude product appears to keep much better than the purified material, but the situation is reversed when a trace of magnesium oxide is present. Complete decomposition occurs after several months on standing at rt in the dark. Pure bromoacetone can be kept over a trace of magnesium oxide as colorless liquid for years. Traces of water (0.01%) seem to stabilize this reagent.3

Introduction.

Like a-halo ketones in general, bromoacetone is an extremely versatile reagent or building block in organic chemistry.1 A major application of bromoacetone is its use as an acetonylation reagent for a whole range of nucleophilic heteroatoms, e.g. oxygen, sulfur, nitrogen, phosphorus, and halides. Nucleophilic additions across the carbonyl group are also observed. In the former application, two major reactions are utilized in ring closure reactions with difunctional and polyfunctional substrates. To a lesser extent, aldol-type reactions of bromoacetone have been reported. Bromoacetone has been isolated from the red alga Asparagopsis taxiformis.7

Acetonylation of Oxygen Nucleophiles.

Reaction of bromoacetone with aqueous sodium hydroxide gives hydroxyacetone.8 In this case the mechanism may occur by direct substitution or via rearrangement of the corresponding hydroxyepoxide. Phenolates easily substitute bromoacetone (eq 3).9 When applied to functionalized phenols, e.g. pyrocatechol,10 5-bromosalicaldehyde (eq 4),11 or 2-acetamidophenol (eq 5),12 benzodioxanes,10 2-acetyl-5-bromobenzofuran,11 or 4-acetyl-3-methyl-4H-1,4-benzoxazine12 are produced, respectively. Also phenolic p-t-butylcalix[4]arenes are tetraacetonylated with bromoacetone.13 Esterification of fatty acid chains by bromoacetone is quantitatively accomplished in the presence of quaternary ammonium salts (eq 6).14

Acetonylation of Sulfur Nucleophiles.

Thiolates react smoothly with bromoacetone to afford a-sulfenylated acetones (eq 7).15,16 However, lower alkyl thiolates give very low yields.17 The substitution product with sodium thiolate undergoes cyclocondensation with ammonia in the presence of an aldehyde or ketone to yield 3-thiazolines.18 Potassum thiocyanate19 and thioacetic acid20 undergo acetonylation by bromoacetone, the latter substitution product undergoing cyclization to 2,4-dimethylthiazole (eq 8).20 This thiazole synthesis can also be accomplished in a one-step process.20

Thioamide-type compounds, e.g. pyrrolidine-2-thiones21 and 2,4-dihydro-5-methyl-4-phenyl-3H-1,2,4-triazole-3-thione,22 react with bromoacetone at sulfur. These acetonylated compounds are useful for desulfurization and further elaboration into (±)- hygrine (eq 9),21 or can be cyclized into 1H-thiazolo[3,2-b]-s-triazolium salts.22 Also thiourea reacts similarly with bromoacetone to give 2-amino-4-methylthiazole directly (eq 10).8,23

Acetonylation of Nitrogen Nucleophiles.

Primary amines are mono- or diacetonylated by bromoacetone (eq 11).24,25 The diacetonylated compounds are useful substrates for the acid-catalyzed ring closure to tetrahydropyridin-3-ones (eq 11).24,25 When mixed at rt for 4 days with excess primary amines, e.g. isopropylamine, bromoacetone is converted to the corresponding a-(N-alkylamino)imine, which undergoes cyclocondensation with ethyl acetoacetate to give pyrroles.26 Secondary amines also give rise to nucleophilic substitution of the halogen in bromoacetone.27-29 Heating of N-methyl formimidate with bromoacetone in toluene/1,2-dimethoxyethane gives access to the corresponding N-methylformamide (eq 12), which is a precursor for 1-(N-methylamino)-2-propanone.30

Imide-type compounds, e.g. thiazolidine-2,4-dione31 and phthalimide,32 are acetonylated by bromoacetone, while tosylamides33 and 2-imidazolinones34 are similarly alkylated at nitrogen. Quaternizations at nitrogen of pyridines (eq 13)35,36 and other aza heterocycles, such as 2,4-dimethylthiazole (eq 14),37 have been performed with bromoacetone. Some of these salts are useful for further cyclization into fused heterocycles, e.g. pyrrolothiazoles.37

Acetonylation of Carbon Nucleophiles.

Active methylene functions of malonates (eq 15),38 dicarboxylic esters (eq 16),39 b-keto esters (eq 17),40 b-diones,41 and b-oxo sulfones (eq 18)42 are alkylated by bromoacetone.

The methylcopper-catalyzed hydroalumination of 2-cyclohexenone with Diisobutylaluminum Hydride generates an aluminum enolate, which is trapped by bromoacetone to afford a-acetonylated cyclohexanone (eq 19).43

Enamines are useful nucleophiles towards bromoacetone, affording 1,4-dicarbonyl compounds (eq 20).4,44,45 A convenient route to methyl ketones from bromoacetone consists of the reaction with boranes, e.g. tri-n-butylborane, in the presence of the potassium salt of 2,6-di-t-butylphenol (eq 21).46

Reactions with Phosphorus Reagents.

The reaction of a-halo ketones and trialkyl phosphites is extremely complex and usually leads to vinyl phosphates and b-ketophosphonates according to Perkov and Arbuzov reaction mechanisms.48 However, the reaction of bromoacetone with trimethyl phosphate in methanol is a suitable entry to dimethyl 1-methylvinyl phosphate (eq 22).48,49 It has been reported that bromoacetone reacts with triethyl phosphite in ether at -70 °C in the presence of hydrogen chloride to give the adduct across the carbonyl group (eq 23).50 Phosphines, e.g. 2-anisyldiphenylphosphine, give nucleophilic substitution, the resulting phosphonium salt being a precursor for phosphorus heterocycles (eq 24).51

Addition Reactions across the Carbonyl Group.

Grignard reagents add to the carbonyl function of bromoacetone at low temperature.52,53 These adducts can be used for further elaboration, such as in the synthesis of homologated tertiary alcohols (eq 25).52 Acetalization of bromoacetone occurs smoothly under the usual conditions.54 The dimethyl acetal of bromoacetone is converted into 3-bromo-2-methoxypropane, a suitable acetonylation reagent (eq 26).54

The oxime of bromoacetone is readily formed upon reaction with Hydroxylamine and is shown to be a suitable building block, after protection of the hydroxy function, for the synthesis of oxazaphospholines and 2-methylazirine (eq 27).55 Bromoacetone condenses with p-Toluenesulfonylhydrazide to give the syn-N-tosylhydrazone exclusively,56 while with Phenylhydrazine it gives rise to the s-anti-(E,E)-1,2-dihydrazone.47

Aldol-Type Reactions.

The condensation of bromoacetone with aldehydes in the presence of Tin(II) Trifluoromethanesulfonate and a tertiary amine affords aldol-type adducts in which the bromo atom is retained in the final product (eq 28) allowing further elaboration, i.e. oxirane formation.57,58

Aldol condensation with removal of the halogen is obtained under reducing conditions with Cerium(III) Chloride and Tin(II) Chloride (eq 29).59

Synthesis of Heterocycles.

The condensation of bromoacetone with various multifunctional reagents leads to a whole range of heterocycles. In many cases the condensation proceeds by consecutive reactions, the order of which is not easily determined. Furans are obtained from bromoacetone by reaction with a-(tri-n-butyltin) ketones (eq 30)59-61 and the sodio salt of Ethyl Acetoacetate (eq 31).62 Furanones are obtained by condensation of bromoacetone with phosphonates under Wittig-Horner conditions,63 while isocoumarins and benzofurans are accessible by reaction of bromoacetone with 3,5-dimethoxybenzoic acid64 or 5-bromosalicaldehyde.11 The reaction of bromoacetone with enamino thioketones leads to thiophenes (eq 32),65 which are also accessible from the same bromo ketone and ketones in the presence of Sodium Sulfide.66 Dithiins result from the cyclocondensation of bromoacetone with 1,2-Ethanedithiol67 and thiazolines are produced from bromoacetone, sodium sulfide, and ammonia.18 Thiazoles are accessible from bromoacetone via Hantzsch condensation with thioureas (eq 33),8,23,68 or by a one-pot synthesis with thioacids in the presence of ammonium acetate and acetic acid.20 Thienoazepines are formed upon condensation of enaminothiones with bromoacetone.69

Imidazoles result from a three-component reaction, consisting of bromoacetone, ammonia, and imidates under pressure (eq 34),70 while functionalized imidazoles are formed upon reaction of bromoacetone with functionalized isothiourea derivatives.71

Pyrroles are accessible from the reaction of bromoacetone with N-vinyliminophosphoranes (eq 35)72 or lithiated aldimines or ketimines.73 In addition, the condensation of acetone dicarboxylic methyl ester with Ethanolamine and bromoacetone gives access to pyrroles.74 Ethoxycarbonylacetamidine can be used as substrate for a pyrrole synthesis as well.84

Bromoacetone is an especially useful building block for the construction of fused heterocycles. Cyclocondensation of heterocycles containing an amidino functionality with an exocyclic amino group, e.g. 3,9-dialkylguanines,76 3-methylguanine (eq 36),77 2-aminothiazole,75 and 2-aminopyridines (eq 37),83 readily condense with bromoacetone to give heterocycles with a fused imidazole ring. Pyrimidines also react with bromoacetone to give ring-fused heterocycles, e.g. 6-azaindolizines,78,79 while 4-aminopyrimidines give rise to imidazo[1,2-c]pyrimidines.80 8-Aminoquinoline cyclocondenses with bromoacetone to produce fused heterocycles, which can be further elaborated to indolizinoquinoxalines.81 Other examples leading to different fused heterocycles have been reported.82,85


1. De Kimpe, N.; Verhé, R. The Chemistry of a-Haloketones, a-Haloaldehydes and a-Haloimines; Wiley: Chichester, 1988.
2. Levene, P. A. OSC 1947, 2, 88.
3. Catch, J. R.; Elliot, D. F.; Hey, D. H.; Jones, E. R. JCS 1948, 272.
4. De Boer, A.; Ellwanger, R. E. JOC 1974, 39, 77.
5. Vegh, D.; Kovac, J.; Dandarova, M.; Bris, V.; Seman, M. CCC 1983, 48, 1891.
6. Huang, W.-Y.; Chen, J.-L.; Hu, L.-Q. BSF 1986, 881.
7. Burreson, B. J.; Moore, R. E.; Roller, P. TL 1975, 473.
8. Crank, G.; Khan, H. R. AJC 1985, 38, 447.
9. Protiva, M.; Valenta, V.; Trcka, V.; Hladovec, J.; Nemec, J. CCC 1977, 42, 3628.
10. Dzvinchuk, I. B.; Kuznetsov, N. V.; Lozinskii, M. O. KGS 1987, 472 (CA 1987, 106, 84 511).
11. Bevinakatti, H. S.; Badiger, V. V. JHC 1982, 19, 69.
12. Chioccara, F.; Novellino, E. JHC 1985, 22, 1021.
13. Fergusson, G.; Kaitner, B.; McKervey, M. A.; Seward, E. M. CC 1987, 584.
14. Nishizawa, M.; Adachi, K.; Hayashi, Y. TL 1983, 24, 4447.
15. Tedjamulia, M. L.; Tominaga, Y.; Castle, R. N.; Lee, M. L. JHC 1983, 20, 1143.
16. Tishchenko, I. G.; Malashko, P. M. Vestn. Belorus. Un-ta, Ser. 2, 1978, 22 (CA 1979, 91, 74 299).
17. Guth, J. J.; Gross, R. L.; Carson, F. W. JOC 1982, 47, 2666.
18. Dubief, R.; Robbe, Y.; Fernandez, J. P.; Subra, G.; Terol, A.; Chapat, J. P.; Sentenac-Roumanou, H.; Fatome, M. Eur. J. Med. Chem. - Chim. Ther. 1986, 21, 461.
19. Ivanova, Z. M.; Kim, T. V.; Boldeskul, I. E.; Gololobov, Y. G. ZOR 1979, 49, 1464 (CA 1979, 91, 157 197).
20. Dubs, P.; Stuessi, R. S 1976, 696.
21. Ghirlando, R.; Howard, A. S.; Katz, R. B.; Michael, J. P. T 1984, 40, 2879.
22. Kovtunenko, V. A.; Bubnovskaya, V. N.; Babichev, F. S. KGS 1975, 138 (CA 1975, 82, 140 028).
23. Dickey, J. B.; Beyers, J. R. OSC 1943, 2, 31.
24. Katvalyan, G. T.; Semenova, N. A.; Mistryukov, E. A. IZV 1976, 129 (CA 1976, 84, 164 577d).
25. Katvalyan, G. T.; Mistryukov, E. A. IZV 1976, 1335 (CA 1976, 85, 123 228t).
26. Valnot, J.-Y. S 1978, 590.
27. Katvalyan, G. T.; Shashkov, A. S.; Mistryakov, E. A. JHC 1985, 22, 53.
28. Suzuki, T.; Takamoto, M.; Okamoto, T.; Takayama, H. CPB 1986, 34, 1888.
29. Takayama, H.; Suzuki, T.; Takamoto, M.; Okamoto, T. H 1978, 9, 1429.
30. Guzman, A.; Muchowski, J. M.; Naal, N. T. JOC 1981, 46, 1224.
31. Shvaika, O. P.; Korotkikh, N. I.; Chervinskii, A. Y.; Artemov, V. N. ZOB 1983, 19, 1728 (CA 1984, 100, 103 228).
32. Parry, D.; Moreau, J.; Bayle, M. Eur. J. Med. Chem. - Chim. Ther. 1975, 10, 147.
33. Bartsch, H.; Haubold, G. M 1981, 112, 1451.
34. Zavyalov, S. I.; Rodionova, N. A.; Skoblik, T. I.; Shcherbak, I. V. IZV 1974, 2778 (CA 1975, 82, 111 998).
35. Bobrovskii, S. I.; Babaev, E. V.; Gromov, S. P.; Paseshnichenko; Bundel, Y. G. KGS 1987, 209 (CA 1988, 108, 5809).
36. Schliemann, W.; Buege, A. Pharmazie 1980, 35, 203.
37. Brindley, J. C.; Gillon, D. G.; Meakins, G. D. JCS(P1) 1986, 1255.
38. Sakai, T.; Katayama, T.; Takeda, A. JOC 1981, 46, 2924.
39. Setsune, J.-i.; Ueda, T.; Shikata, K.; Matsukawa, K.; Iida, T.; Kitao, T. T 1986, 42, 2647.
40. Pattenden, G.; Whybrov, D. JCS(P1) 1981, 1046.
41. Maini, P. N.; Sammes, M. P.; Katritzky, A. R. JCS(P1) 1988, 161.
42. Koutek, B.; Pavlickova, L.; Soucek, M. CCC 1974, 39, 192.
43. Tsuda, T.; Satomi, H.; Hayashi, T.; Saegusa, T. JOC 1987, 52, 439.
44. Baumgarten, H. E.; Creger, P. L.; Villars, C. E. JACS 1958, 80, 6609.
45. Acholonu, K. U.; Wedegaertner, D. K. TL 1974, 3253.
46. Brown, H. C.; Nambu, H.; Rogic, M. M. JACS 1969, 91, 6852.
47. Korotkikh, N. I.; Chervinskii, A. Yu.; Baranov, S. N.; Kapkan, L. M.; Shvaika, O. P. ZOB 1979, 15, 962 (CA 1979, 91, 74 124u).
48. Chopard, P. A.; Clark, V. M.; Hudson, R. F.; Kirby, A. J. T 1965, 21, 1961.
49. Kluger, R.; Chow, J. F.; Croke, J. J. JACS 1984, 106, 4017.
50. Gazizov, T. K.; Sudarev, Y. I.; Pudovik, A. N. ZOB 1976, 46, 2383 (CA 1977, 86, 16 753j).
51. Marszak, M. B.; Simalty, M. T 1979, 35, 775.
52. Normant, J. F.; Mulamba, T.; Scott, F.; Alexakis, A.; Cahiez, G. TL 1978, 3711.
53. Cherkasova, T. I.; Khutoretskii, V. M.; Okhlobystina, L. V. IZV 1983, 1125 (CA 1983, 99, 104 726).
54. Jacobson, R. M.; Raths, R. A.; McDonald, J. H., III. JOC 1977, 42, 2545.
55. Hassner, A.; Alexanian, V. JOC 1979, 44, 3861.
56. Bunnell, C. A.; Fuchs, P. L. JOC 1977, 42, 2614.
57. Mukaiyama, T.; Iwasawa, N.; Stevens, R. W.; Haga, T. T 1984, 40, 1381.
58. Oehler, E.; Kang, H.-S.; Zbiral, E. CB 1988, 121, 299.
59. Kosugi, M.; Takano, I.; Hoshino, I.; Migita, T. CC 1983, 1031.
60. Kosugi, M.; Takano, I.; Hoshino, I.; Migita, T. CC 1983, 989.
61. Vijayaraghavan, S. T.; Balasubramanian, T. R. JOM 1985, 282, 17.
62. Kagan, J.; Mattes, K. C. JOC 1980, 45, 1524.
63. Falsone, G.; Wingen, H. P. AP 1984, 317, 802.
64. Arora, P. K.; Ray, S. JIC 1985, 62, 383.
65. Meslin, J. C.; N'Guessan, Y. T.; Quiniou, H.; Tonnard, F. T 1975, 31, 2679.
66. Cagniant, P.; Kirsch, G. CR(C) 1975, 281, 35.
67. Giusti, G.; Schembri, G. CR(C) 1978, 287, 213.
68. Gillon, D. W.; Forrest, I. J.; Meakins, G. D.; Tirel, M. D.; Wallis, J. D. JCS(P1) 1983, 341.
69. Dannhardt, G.; Grobe, A.; Obergrusberger, R. AP 1987, 320, 582.
70. Wegner, K.; Schunack, W. AP 1974, 307, 972.
71. Yamazaki, C. TL 1978, 1295.
72. Iino, Y.; Kobayashi, T.; Nitta, M. H 1986, 24, 2437.
73. Wittig, G.; Röderer, R.; Fischer, S. TL 1973, 3517.
74. Carpio, H.; Galeazzi, E.; Greenhouse, R.; Guzman, A.; Velarde, E.; Antonio, Y.; Franco, F.; Leon, A.; Perez, V.; Salas, R.; Valdes, D. CJC 1982, 60, 2295.
75. Marchetti, L.; Pentimalli, L.; Lazzeretti, P.; Schenetti, L.; Taddei, F. JCS(P2) 1973, 1926.
76. Itaya, T.; Ogawa, K. T 1982, 38, 1767.
77. Frihart, C. R.; Feinberg, A. M.; Nakanishi, K. JOC 1978, 43, 1644.
78. Buchan, R.; Fraser, M.; Shand, C. JOC 1976, 41, 351.
79. Buchan, R.; Fraser, M.; Shand, C. JOC 1977, 42, 2448.
80. Rogulchenko, G. K.; Mazur, I. A.; Kochergin, P. M. KGS 1975, 93 (CA 1975, 83, 9955).
81. Kanemasa, S.; Kobira, S.; Kajigaeshi, S. H 1980, 14, 1107.
82. Glover, E. E.; Vaughan, K. D. JCS(P1) 1974, 1137.
83. Elliott, A. J.; Guzik, H.; Soler, J. R. JHC 1982, 19, 1437.
84. Toja, E.; Tarzia, G.; Ferrari, P.; Tuan, G. JHC 1986, 23, 1555.
85. Chuiguk, V. A.; Komar, E. L. KGS 1983, 1134 (CA 1983, 99, 212 491).

Norbert De Kimpe

University of Gent, Belgium



Copyright 1995-2000 by John Wiley & Sons, Ltd. All rights reserved.