· 4-Bromobenzyl Chloroformate
· (MW 249.49)
(N-protecting agent for a-amino acids)
Alternate Name: p-bromobenzyloxycarbonyl chloride.
Physical Data: mp 12 °C; d (20 °C) 1.5588 g cm-3; n20D 1.6004.
Preparative Methods: not commercially available. It may be prepared1 by the addition of a solution of 4-bromobenzyl alcohol in dioxane to a solution of excess Phosgene in toluene followed by stirring at rt for 24 h. Removal of the solvent by distillation in vacuo at 60 °C leaves a straw-colored oil. Three recrystallizations from hexane at -50 °C gives pure 4-bromobenzyl chloroformate in 78% yield as colorless needles. In a closely related alternate preparative procedure,2 the crude oily product, obtained in 98% yield, was used in a preparative reaction without further purification.
Handling, Storage, and Precautions: although no details are available, the high toxicity and suspected carcinogenic properties of the closely related Benzyl Chloroformate suggest that 4-bromobenzyl chloroformate should be handled with caution.
N-Protection of a-Amino Acids.
Treatment of an a-amino acid1 or an oligopeptide3 with a dioxane solution of 4-bromobenzyl chloroformate and aq NaHCO3 affords the N-(4-bromobenzyl) carbamate derivative in moderate to good yield (eq 1). Use of aq NaOH as the base gives similar results.4 The resulting N-(4-bromobenzyloxycarbonyl)-a-amino acids have higher melting points than the corresponding N-benzyloxycarbonyl-a-amino acids1,5 (see Benzyl Chloroformate). Their highly crystalline nature allows for facile repeated recrystallization,1,5 which makes them well-suited for use in the quantitation of a-amino acid racemization. The 4-bromobenzyl carbamate moiety is stable to the basic conditions (aq NaOH, ethanol) used to hydrolyze a methyl ester,4 but is still readily cleaved by
Protection of Carboxylic Acids.
Given the utility of benzyl chloroformate for the protection of carboxylic acids as their benzyl esters it is likely that the preparation of 4-bromobenzyl esters using 4-bromobenzyl chloroformate would be possible, although such chemistry has not yet been reported. Such a protection method would be useful, since it has been demonstrated that 4-bromobenzyl esters are 5-7 times more stable than the corresponding benzyl esters to acidic hydrolysis. For example, they are stable to 50% CF3COOH used to cleave N-Boc-protected a-amino acids; they are cleaved quantitatively by exposure to HF (0 °C, 10 min).6
- 1. Waterfield, W. R. JCS 1963, 2731.
- 2. Ovchinnikova, Y. I.; Fomin, V. A.; D'yachkov, A. I.; Etlis, V. S. JGU 1981, 51, 2031.
- 3. Lucente, G.; Romeo, A.; Cerrini, S.; Fedeli, W.; Mazza, F. JCS(P1) 1980, 809.
- 4. Cleij, M. C.; Drenth, W.; Nolte, R. J. M. JOC 1991, 56, 3883.
- 5. Channing, D. M.; Turner, P. B.; Young, G. T. Nature 1951, 167, 487.
- 6. Yamashiro, D. JOC 1977, 42, 523.
Kent State University, OH, USA
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