Azidotris(dimethylamino)phosphonium Hexafluorophosphate

[50281-51-1]  · C6H18F6N6P2  · Azidotris(dimethylamino)phosphonium Hexafluorophosphate  · (MW 350.19)

(coupling reagent for amides and peptide synthesis via an acyl azide;1 in the absence of a nucleophile undergoes a Curtius rearrangement to give the corresponding isocyanate;1,2 by irradiation gives the iminophosphonium salt;3,4 diazo transfer reagent5)

Physical Data: mp >250 °C; IR, v(N3) 2176 cm-1.

Solubility: sol acetone, acetonitrile, DMF.

Form Supplied in: crystalline colorless solid; not available from commercial sources.

Preparative Methods: Bromine (1 equiv) is added dropwise to Hexamethylphosphorous Triamide (1 equiv) in dry diethyl ether. After the addition is complete, Potassium Hexafluorophosphate (1 equiv), dissolved in H2O is added, and the solid formed is filtered and washed with H2O. After drying under vacuum, the solid is dissolved in acetone and Sodium Azide (1.5 equiv) is added. The mixture is stirred overnight at 25 °C, then the sodium bromide formed and the excess of sodium azide is filtered off and the solvent is removed under vacuum.

Purification: by crystallization in a mixture of acetone and diethyl ether.

Handling, Storage, and Precautions: is very stable, not hygroscopic, and can be stored indefinitely under vacuum. The related bromine derivative is an exceptionally safe azide, that does not detonate by shock, friction, rapid heating, or even flame.5 When used in combination with carboxylic acids, the potential carcinogenic Hexamethylphosphoric Triamide is a side-product and the reagent must be handled with caution.6

Coupling Reagent.

Azidotris(dimethylamino)phosphonium hexafluorophosphate has been used as a condensing reagent for the preparation of peptides.1 Reaction of a-amino protected amino acids or dipeptides with equimolar amounts of a-carboxyl protected amino acids or dipeptides and Triethylamine (2 equiv) in DMF proceed cleanly overnight at -10 to 0 °C, giving the corresponding peptides in good yields (81-97%) (eq 1). Neither acylation of the hydroxy group of serine nor dehydration of the side chain of asparagine is reported during the coupling.1

Racemization from azidotris(dimethylamino)phosphonium hexafluorophosphate-mediated couplings is analyzed by different methods. While no racemization is detected by the Anderson7 and Weinstein8 methods, the Young9 method gave some degree (3%) of racemization.

Although azidotris(dimethylamino)phosphonium hexafluorophosphate has not been used in solid-phase peptide synthesis,10 other commercial phosphonium salt derivatives such as Benzotriazol-1-yloxytris(dimethylamino)phosphonium Hexafluorophosphate (BOP),11 benzotriazol-1-yloxytris(pyrrolidino)phosphonium hexafluorophosphate (PyBOP),12 or bromotris(pyrrolidino)phosphonium hexafluorophosphate (PyBroP)13 are commonly used in that strategy.

Isocyanate Formation.

The coupling reaction described above occurs via an acyl azide intermediate, which at 50 °C suffers a Curtius rearrangement to give an isocyanate (eq 2),1 which can further react with amines to give the corresponding ureas.

Iminophosphonium Salt Formation.

Irradiation of azidotris(dimethylamino)phosphonium hexafluorophosphate in acetonitrile at 254 nm using a Rayonnet photochemical reactor for 15 h at 25 °C gives the iminophosphonium salt with release of nitrogen (eq 3). This is the first example reported of a Curtius-type rearrangement involving a charged atom.3,4

Diazo Transfer Reagent.

The related compound azidotris(diethylamino)phosphonium bromide has been used for the preparation of diazo products.5 Active methylene compounds react with azidotris(diethylamino)phosphonium bromide in dry diethyl ether in the presence of only catalytic amounts of base, such as Potassium t-Butoxide or other alkoxide, yielding the corresponding diazo products in good yields (70-78%) (eq 4).

1. Castro, B.; Dormoy J. R. BSF(2) 1973, 12, 3359.
2. Masson, M. A.; Dormoy J. R. J. Labelled Compd. Radiopharm. 1979, 16, 785.
3. Majoral, J. P.; Bertrand, G.; Baceiredo, A.; Mulliez, M.; Schmutzler, R. PS 1983, 18, 221.
4. Mulliez, M.; Majoral, J. P.; Bertrand, G. JCS(C) 1984, 284.
5. McGuiness, M.; Shechter, H. TL 1990, 31, 4987.
6. Zapp, J. A., Jr. Science 1975, 190, 422.
7. (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.
8. Weinstein, B.; Pritchard, A. E. JCS(C) 1972, 1015.
9. Williams, M. W.; Young, G. T. JCS(C) 1963, 881.
10. Fields, G. B.; Tian, Z.; Barany, G. In Synthetic Peptides: A User's Guide; Grant, G. A., Ed.; Freeman: New York, 1992; p 77.
11. Castro, B.; Dormoy J. R.; Evin, G. TL 1975, 1219.
12. Coste, J.; Le-Nguyen, D.; Castro, B. TL 1990, 31, 205.
13. Frérot, E.; Coste, J.; Pantaloni, A.; Dufour, M. N.; Jouin, P. T 1991, 47, 259.

Fernando Albericio & Steven A. Kates

Millipore Corporation, Bedford, MA, USA

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