Diethyl Phosphorobromidate1

[51761-27-4]  · C4H10BrO3P  · Diethyl Phosphorobromidate  · (MW 217.00)

(b-lactam formation; peptide synthesis; formation of trifluoroacetyl bromide)

Alternate Names: diethoxyphosphorus oxybromide; diethyl bromophosphate.1

Physical Data: bp 75 °C/1.5 mmHg, bp 58-59 °C/0.25 mmHg.

Solubility: sol CH2Cl2, Et2O, toluene.

Preparative Methods: prepared in good yield from the reaction between N-Bromosuccinimide and diethyl hydrogen phosphite,1 or from the bromination of Triethyl Phosphite with Bromine at -30 °C to -25 °C.2 It can also be prepared in almost quantitative yield by reacting diethyl hydrogen phosphite with Chlorotrimethylsilane followed by bromine at -78 °C.3

Purification: distilled under reduced pressure.1

Handling, Storage, and Precautions: highly toxic, corrosive, and a lachrymator. It should be used in a fume hood. It is highly moisture sensitive and undergoes thermal decomposition. It generates toxic byproducts when decomposition occurs. Should be stored under nitrogen in a cool dry place.

Formation of b-Lactams from b-Amino Acids.

Diethyl phosphorobromidate is a very effective condensing reagent for the formation of b-lactams from b-amino acids.4 This methodology works well for N-substituted b-amino acids, which cyclize to the corresponding b-lactams in moderate to high yield (eq 1). In the case of N-unsubstituted b-amino acids, the b-lactam formation does not give good results. This methodology allows the products to be easily isolated by simple aqueous work-up.

Peptide Formation.

A number of organophosphorus compounds, such as Diphenyl Phosphorazidate and Diethyl Phosphorocyanidate, have been used for peptide synthesis. The expense and rather limited availability of these reagents prevents their general laboratory use. Diethyl phosphorobromidate has been shown to be a useful and inexpensive reagent for the synthesis of amides and, in particular, racemization-free peptide synthesis.2 It forms reactive diethylphosphoric-carboxylic mixed anhydride intermediates with carboxylic acids (eq 2). These reactive intermediates are susceptible to nucleophilic attack at the carbonyl carbon. Diethyl phosphorobromidate is particularly effective for coupling sterically hindered a,a-disubstituted amino acids, while most of the usual coupling methods are of limited value for incorporating these amino acids into peptides.

Trifluoroacetyl Bromide.3

Diethyl phosphorobromidate reacts with Trifluoroacetic Anhydride at ambient temperature in the presence of catalytic amounts of N-Methylimidazole to yield quantitative amounts of trifluoroacetyl bromide and diethylphosphoric-trifluoroacetyl mixed anhydride (eq 3). These can be readily separated.3

1. Goldwhite, H.; Saunders, B. C. JCS 1955, 3564
2. Gorecka, A.; Leplawy, M.; Zabrock, J.; Zwierzak, A. S 1978, 6, 474
3. Helinski, J.; Skrzypczynski, Z.; Wasiak, J.; Michalski, J. PS 1990, 54, 226
4. Chung, B. Y.; Paik, K. C.; Nah, C. S. Bull. Korean Chem. Soc. 1991, 12, 589

Yi-Yin Ku

Abbott Laboratories, North Chicago, IL, USA

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