Bromoacetyl Chloride

[22118-09-8]  · C2H2BrClO  · Bromoacetyl Chloride  · (MW 157.39)

(bifunctional building block;1-8 ketene precursor;9-12 bromoacetylating agent13,14)

Physical Data: bp 127-128 °C; d 1.908 g cm-3.

Form Supplied in: colorless liquid, 98% pure or in lower grades [contaminated with BrCH2C(O)Br and ClCH2C(O)Cl]; widely available.

Handling, Storage, and Precautions: readily hydrolyzed with formation of HCl; corrosive; lachrymator. This reagent should only be handled in a fume hood.

Bifunctional Building Block.

Bromoacetyl chloride has been used extensively as a bifunctional two-carbon building block.1 -8 Since both C-1 and C-2 are electrophilic, it can be used to link two nucleophilic units. Examples of intermolecular couplings1 -4 include sequences to prepare a-amino ketones,1 a-heterosubstituted amides,2 a-heterosubstituted esters (eq 1),3 and Wittig-type reagents (eq 2).4 Where both nucleophilic functionalities are on the same molecule, cyclic compounds result. Such intramolecular couplings5-8 have been employed in syntheses of heterocycles such as morpholin-3-ones (eq 3),5 aza-b-lactams,6 and benzodiazepines.7

Ketene Precursor.

Treatment of bromoacetyl chloride with Et3N in the presence of a suitable trapping agent (e.g. an imine) gives products derived from the expected intermediate ketene.9 -11 Such cycloaddition reactions with imines produce b-lactams (eq 4);9 other heterocyclic compounds have also been prepared by this method.11 Ketene itself may be prepared and distilled in solution by reaction of BrCH2C(O)Cl with pentacarbonylmanganate anion.12

Bromoacetylating Agent.

Bromoacetyl chloride has been used as a reagent for the introduction of bromoacetyl groups.13,14 There is some interest in preparing compounds bearing a bromoacetyl group (typically bromoacetamides) as possible pharmacological agents.13 These compounds would be expected to be alkylating agents which could be anti-cancer drugs (by alkylation of DNA) or enzyme inhibitors (by alkylation of HO- or HS-containing residues in the active site.) The bromoacetyl group has also been used as a hydroxy-protecting group in carbohydrates.14

1. (a) Tashiro, M.; Watanabe, T.; Tsuge, A.; Sawada, T.; Mataka, S. JOC 1989, 54, 2632. (b) Amemiya, Y.; Terada, A.; Wachi, K.; Miyazawa, H.; Hatakeyama, N.; Matsuda, K.; Oshima, T. JMC 1989, 32, 1265. (c) Babad, E.; Carruthers, N. I.; Jaret, R. S.; Steinman, M. S 1988, 966.
2. (a) Gallagher, T.; Magnus, P.; Huffman, J. C. JACS 1983, 105, 4750. (b) Krowicki, K.; Lown, J. W. JOC 1987, 52, 3493. (c) Slater, R. A.; Howson, W.; Swayne, G. T. G.; Taylor, E. M.; Reavill, D. R. JMC 1988, 31, 345.
3. (a) Willson, T.; Kocienski, P.; Faller, A.; Campbell, S. CC 1987, 106. (b) Deprez, P.; Royer, J.; Husson, H.-P. TA 1991, 2, 1189. (c) White, J. D.; Vedananda, T. R.; Kang, M.; Choudhry, S. C. JACS 1986, 108, 8105.
4. (a) Koch, S. S. C.; Chamberlin, A. R. JOC 1993, 58, 2725. (b) Ogawa, T.; Fang, C.-L.; Suemune, H.; Sakai, K. CC 1991, 1438. (c) Farrington, G. K.; Kumar, A.; Wedler, F. C. JMC 1985, 28, 1668.
5. (a) Perrone, R.; Berardi, F.; Leopoldo, M.; Tortorella, V.; Lograno, M. D.; Daniele, E.; Govoni, S. JMC 1992, 35, 3045. (b) Bettoni, G.; Cellucci, C.; Ferorelli, S.; Perrone, R.; Tortorella, V. T 1986, 42, 2117.
6. Greenhill, J. V.; Taylor, E. C. H 1991, 32, 2417.
7. Sugasawa, T.; Adachi, M.; Toyoda, T.; Sasakura, K. JHC 1979, 16, 445.
8. Misztal, S.; Bielecka, Z.; Mokrosz, J. L. JCS(P1) 1991, 1871.
9. (a) Alcaide, B.; Martin-Cantalejo, Y.; Pérez-Castells, J.; Rodríguez-López, J.; Sierra, M. A.; Monge, A.; Pérez-Garcia, V. JOC 1992, 57, 5921. (b) Hakimelahi, G. H. HCA 1984, 67, 902. (c) Casadei, M. A.; Moracci, F. M.; Inesi, A. JCS(P2) 1986, 419.
10. For a review of this approach to b-lactams, see: Ghosez, L.; Marchand-Brynaert, J. COS 1991, 5, 90.
11. Hertzog, D. L.; Nadler, W. R.; Zhang, Z. J.; Padwa, A. TL 1992, 33, 5877.
12. (a) Masters, A. P.; Sorensen, T. S.; Ziegler, T. JOC 1986, 51, 3558. (b) Masters, A. P.; Sorensen, T. S. TL 1989, 30, 5869.
13. (a) Auvin, S.; Cochet, O.; Kucharczyk, N.; Le Goffic, F.; Badet, B. Bioorg. Chem. 1991, 19, 143. (b) Lee, M.; Rhodes, A. L.; Wyatt, M. D.; D'Incalci, M.; Forrow, S.; Hartley, J. A. JMC 1993, 36, 863. (c) Lemus, R. H.; Skibo, E. B. JOC 1992, 57, 5649.
14. Kovac, P.; Glaudemans, C. P. J. CR 1985, 140, 313.

J. Michael Chong

University of Waterloo, Ontario, Canada

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