Phenacyl Bromide

[70-11-1]  · C8H7BrO  · Phenacyl Bromide  · (MW 199.05)

(protecting group for acids and phenols;1 removable by zinc reduction)

Alternate Name: 2-bromoacetophenone.

Physical Data: mp 48-51 °C; bp 135°/18 mmHg.

Solubility: insol H2O; sol common organic solvents.

Form Supplied in: white solid; widely available.

Handling, Storage, and Precautions: corrosive lachrymator; use in a fume hood.

Carboxylic Acids.

The phenacyl group was introduced1 as a useful protecting group for carboxylic acids since it is easily attached, stable to a range of conditions, and removable again under conditions which do not affect most other functional groups. The ester is made by SN2 displacement of phenacyl bromide by the salt of the acid, in water or other solvents, rapidly and in good yields.2 It has also been made using crown ethers,3 phase transfer,4,5 KF catalysis,6 and with ion-exchange resins loaded with the carboxylate salt.7 It may be removed again by zinc reduction in glacial or aqueous acetic acid in about an hour at room temperature, affording the acid and acetophenone.1 The Zinc-Acetic Acid reduction has been improved by using chelating agents to sequester the formed zinc salts.8 It has also been expeditiously removed by displacement with thiophenoxide9 and telluride5 ions, which do not affect carbonyls. As a variation, the p-bromophenacyl esters have been used in the same way and have the advantage of higher melting points and of clear AB patterns in the NMR.

Because of its ease of introduction, high yields, and selectivity, the phenacyl protecting group has found extensive use in peptide synthesis10 as it is stable to the hydrogenation conditions used to remove benzyl protecting groups and to the acid conditions removing Boc. In general, the phenacyl esters have not caused racemization during amino acid coupling, except for a report of racemization of proline.11 Phenacyl esters have also been employed to derivatize fatty acid mixtures for chromatographic analysis.12

A special feature of the method lies in the opening of lactones that spontaneously reclose. Since esterification of 4-bromophenacyl bromide occurs via SN2 displacement with the carboxylate anion, from the base-opened lactone, the hydroxy ester can often be isolated, for further reactions on the hydroxyl group. This is illustrated in the conversion of the trans-lactone of santonin to its cis-lactone diastereomer13 in eq 1. Conversion in the reverse direction in this case was not effective, however, since alkali on the cis-lactone only caused elimination.

Phenols.

While much used for acids, the phenacyl group has seen less use for phenol protection.14,15 Commonly made by alkylation of the phenols with K2CO3 in refluxing acetone for 1-2 hours, the phenacyl ethers are as easily removed with zinc.1 As in peptide synthesis the group is valued for its selectivity, being stable to hydrogenation and the acid conditions used to remove MEM ethers.15 Under stronger acid conditions, however, the phenacyl ethers are apt to cyclize to benzofurans, as in eq 2.

Amines.

In a variant on the Gabriel synthesis, phenacylsulfonyl amines were made (from phenacylsulfonyl chloride and primary amines) and could be efficiently monoalkylated on nitrogen, then the phenacylsulfonyl group removed as above with zinc and acid, releasing the secondary amine product with SO2 and acetophenone (eq 3).16 As protecting groups, these were found to be sensitive to alkali (cleavage to benzoic acid), and in the monoalkylation of the nitrogen, the methylene of phenacylsulfonyl was also alkylated.


1. Hendrickson, J. B.; Kendall, C. TL 1970, 343.
2. Haslam, E. T 1980, 36, 2409.
3. Durst, H. D. TL 1974, 2421.
4. Bartsch, R. S.; Phillips, J. B. SC 1986, 16, 1777.
5. Huang, Z. Z.; Huang, X. A.; Xie, L. H. SC 1988, 18, 1167.
6. Clark, C. H.; Miller, J. M. TL 1977, 599.
7. Mahajan, S. D.; Jagdale, M. H.; Mane, R. B.; Salunkha, M. M. IJC(B) 1987, 26, 186. Thorat, M.; Jagdale, M.; Mane, R.; Salunkha, M. OPP 1986, 18, 203.
8. Hagiwara, D.; Neya, M.; Hashimoto, M. TL 1990, 31, 6539.
9. Sheehan, J.; Daves, Jr., G. D. JOC 1964, 29, 2006.
10. Fischer, P. M. TL 1992, 33, 7605. Hashimoto, C.; Muramatsu, I. BCJ 1989, 62, 1900. Aoyagi, H.; Ando, S.; Lee, S.; Izumiya, N. T 1988, 44, 877. Kimura, T.; Morikawa, T. Takai, M.; Sakakibara, S. CC 1982, 340; Biopolymers 1981, 20, 1823. Popova, O. Y.; Yung, R.; Mitin, Y. V. ZOR 1982, 18, 1716; Mitchell, A. R.; Kent, S. B. H.; Engelhard, M.; Merrifield, R. B. JOC 1978, 43, 2845.
11. Kuroda, H.; Kubo, S.; Chino, N.; Kimura, T.; Sakakibara, S. Int. J. Peptide Protein Res. 1992, 40, 114.
12. Korte, K.; Chien, K. R.; Casey, M. L. J. Chromatogr. 1986, 375, 225.
13. Thieme, P. Unpublished results.
14. ApSimon, J. W.; Herman, L. W.; Huber, C. CJC 1985, 63, 2589.
15. Crombie, L.; Jamieson, S. V. JCS(P1) 1982, 1467.
16. Hendrickson, J. B.; Bergeron, R. TL 1970, 345; Hendrickson, J. B.; Bergeron, R.; Sternbach, D. D. T 1975, 31, 2517.

James B. Hendrickson

Brandeis University, Waltham, MA, USA



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