1-Benzotriazolyl Diethyl Phosphate

[96338-11-3]  · C10H14N3O4P  · 1-Benzotriazolyl Diethyl Phosphate  · (MW 271.21)

(coupling reagent for amides and peptide synthesis1,2)

Alternate Name: BDP.

Solubility: sol MeCN, DMF, EtOAc, CH2Cl2, THF.

Form Supplied in: oil; not available from commercial sources.

Preparative Method: by reaction of diethyl chlorophosphate (1 equiv) and 1-hydroxybenzotriazole (1 equiv) in the presence of triethylamine (1 equiv) in dry THF at 0 °C for 30 min, with 90-95% yields.

Purification: by filtration through a short column of silica gel or cellulose.

Handling, Storage, and Precautions: the oil can be stored in a desiccator with drierite at 4 °C for several weeks without decomposition. Distillation in vacuo leads to decomposition.

1-Benzotriazolyl diethyl phosphate (BDP) has been used as a condensing reagent for the preparation of amides. Typically, equimolar amounts of carboxylic acids, amines, and 1-benzotriazolyl diethyl phosphate, in the presence of triethylamine (2.1 equiv) in a broad range of solvents (the relative coupling efficiency is DMF > MeCN = THF > CH2Cl2) react rapidly and cleanly with coupling times in the range of 10-60 min at 25 °C, yielding the corresponding amides in > 90% yields (eq 1).

1-Benzotriazolyl diethyl phosphate is also suitable for hindered carboxylic acids and amines, as well as poorly nucleophilic amines. Thus N-cyclohexylbenzamide is obtained from benzoic acid and cyclohexylamine with the addition of 1-benzotriazolyl diethyl phosphate, whereas the use of 1,3-Dicyclohexylcarbodiimide did not yield any trace of the target product. Benzoic acid is readily converted to the corresponding amides by the reaction with 1-benzotriazolyl diethyl phosphate and benzylamine or aniline. Similarly, reaction of acetic acid with sterically hindered t-butylamine yielded the corresponding acetamide. Finally, crotonic acid is cleanly converted to the corresponding amides without 1,4-addition side-products.

Additionally, 1-benzotriazolyl diethyl phosphate has been used for the preparation, in solution, of dipeptides and tripeptides. The reaction is carried out as described above with N-protected amino acids or dipeptides, and amino acid ester hydrochlorides, in DMF for 4 h, at 25 °C, with a yield superior to 75%. Racemization from 1-benzotriazolyl diethyl phosphate mediated couplings is checked by different methods. Young3 and Anderson4 tests gave low degree (<4%) of racemization when DMF is used as a solvent. Other solvents such as THF, EtOAc, and CH2Cl2 gave more racemization. Furthermore, the Shiori5 test gave a higher degree of racemization even in DMF (18%). A related analog, 1-benzotriazolyl diphenyl phosphate, led to 39% of racemization, indicating that the degree of racemization is also dependent on the nature of organophosphate.

1-Benzotriazolyl diethyl phosphate has not been used in solid-phase peptide synthesis,6 although other commercial triazole derivatives such as Benzotriazol-1-yloxytris(dimethylamino)phosphonium Hexafluorophosphate (BOP)7 or O-Benzotriazol-1-yl-N,N,N,N-tetramethyluronium Hexafluorophosphate (HBTU)8 are commonly used in that strategy.

1. Kim, S.; Chang, H.; Ko, Y. K. TL 1985, 26, 1341.
2. Kim, S.; Chang, H.; Ko, Y. K. Bull. Korean Chem. Soc. 1987, 8, 471.
3. Williams, M. W.; Young, G. T. JCS(C) 1963, 881.
4. (a) Anderson, G. W.; Young, R. W. JACS 1952, 74, 5307. (b) Anderson, G. W.; Zimmermann, J. E.; Callanan, F. M. JACS 1967, 89, 5012.
5. Takuma, S.; Hamada, Y.; Shiori, T. CPB 1982, 30, 3147.
6. Fields, G. B.; Tian, Z.; Barany, G. In Synthetic Peptides: A User's Guide; Grant, G. A., Ed.; Freeman: New York, 1992; pp 77-183.
7. Castro, B.; Dormoy, J. R.; Evin, G. TL 1975, 1219.
8. (a) Dourtoglou, V.; Ziegler, J. C.; Gross, B. TL 1978, 1269. (b) Knorr, R.; Trzeciak, A.; Bannwarth, W.; Gillessen, D. TL 1989, 30, 1927.

Fernando Albericio & Steven A. Kates

Millipore Corporation, Bedford, MA, USA

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