Phenyl N-Phenylphosphoramidochloridate

[51766-21-3]  · C12H11ClNO2P  · Phenyl N-Phenylphosphoramidochloridate  · (MW 267.66)

(phosphorylating agent in oligonucleotide synthesis via the phosphotriester approach; for the conversion of acids to their symmetrical anhydrides and for the coupling of acids and amines to give amides; two important derivatives are also considered)

Physical Data: mp 132-134 °C.

Solubility: sol org solvents, e.g. acetone, dichloromethane.

Form Supplied in: white solid; widely available commercially.

Analysis of Reagent Purity: FT-IR;22 Rf (pure) = 0.63 (chloroform-acetone (5:1) on silica). Drying: is moisture sensitive; dry in vacuo (<=10-2 mmHg) over P2O5 at rt.

Preparative Methods: obtainable from phenyl phosphorodichloridate (2) and aniline (eq 1).1

Handling, Storage, and Precautions: irritant and moisture sensitive. May be harmful by inhalation (irritating to mucous membranes and upper respiratory tract), ingestion, or skin absorption. Incompatible with strong oxidizing agents and strong bases.

Phosphorylating Agent.

Phenyl N-phenylphosphoramidochloridate (1) reacts readily at 0 °C in dry pyridine with equimolar amounts of a corresponding alcohol or phenol to give the O-alkyl-O-phenyl-N-phenylphosphoramides (eq 2).2

The compound (3) is a useful intermediate for the synthesis of mixed diesters of phosphoric acid (4). There are several methods of cleaving the N-P bond, of which the method of Ikehara is the most convenient.3 Reaction of (3) with a 40 molar excess of 3-methylbutyl nitrite in acetic acid-pyridine (1:1 v/v) is successful in removing the aniline protecting group from the phosphoryl moiety in almost quantitative yields, giving the O-alkyl/aryl-O-phenyl hydrogen phosphate.

Given the good yields and simplicity of the process, this procedure has been used to prepare intermediates for oligonucleotide synthesis, e.g. in the synthesis of 5-O-monomethoxytritylthymidine 3-phenylphosphate (7) (eq 3). Phosphorylation of 5-O-monomethoxytritylthymidine (5) gave the protected nucleoside phosphate (6) in 98% yield which, after removal of the aniline protecting group and workup, gave the pyridinium salt in 85% yield.

This chemistry has additionally been utilized in the preparation of nucleoside phosphorothioates.4 Reaction of (6) with NaH to remove the P-anilido group followed by CS2 gave the corresponding 5-monomethoxytritylthymidine 3-O-phenylphosphorothioate (as a mixture of diastereomers, 8) which was converted to the S-methyl ester (9) (eq 4). Owing to the chiral nature of pentavalent phosphorus, the compound (9) could exist as a mixture of diastereomers; however, the above reaction was the first example of an asymmetric synthesis of a phosphorothioate. There are now more examples of stereospecific synthesis of nucleoside derivatives utilizing this type of chemistry.5

There are numerous reviews on phosphorylation methods in biological molecules, some of which include aryl phosphoramidochloridates.6

Activation of Carboxylic Acids.

Formation of Symmetrical Anhydrides.

Symmetrical carboxylic anhydrides are useful reagents for peptide or amide synthesis.7,8 Unfortunately, most methods require transformation of the acid first into the acid chloride or the use of condensation agents, e.g. 1,3-Dicyclohexylcarbodiimide (DCC), which can lead to separation problems of the product anhydride from the hydrated derivatives of the condensation reagents. The use of Thionyl Chloride/Pyridine to form the acid chloride is often complicated by racemization with amino acid derivatives.

However, carboxylic acids are converted almost quantitatively to their corresponding symmetrical anhydride by treatment with 1 equiv of Triethylamine or 1-Ethylpiperidine and 0.5 equiv of phenyl N-phenylphosphoramidochloridate (or Diphenyl Phosphorochloridate) in acetone or dichloromethane, with the product anhydride (10) being obtained by filtration or from evaporation of the solvent after washing with water.9 The resulting crude products are very nearly pure and the phenyl N-phenylphosphoramidochloridate can be regenerated as the aqueous solutions yield the phosphoramidic acid on acidification, which can be converted to (1) by reaction with Phosphorus(V) Chloride. The proposed pathway for this is through the mixed anhydride (11), which then reacts with a second molecule of acid. The only limitation of this method is the reaction of some of the anhydrides with water, e.g. as observed with trichloroacetic acid.

The Synthesis of Polyanhydrides by Dehydrative Coupling.

The synthesis of polyanhydrides was first reported in 190910 and led on to a series of aliphatic polyanhydrides being prepared in the 1930s, as potential materials for the textile industry. One method for the formation of such polyanhydrides, particularly where sensitive monomers are involved, is to find suitably powerful dehydrating agents that function in mild reaction conditions. Organophosphorus compounds appear to be one such group of compounds. Phenyl N-phenylphosphoramidochloridate was found to be one of the most successful dehydrating agents.11 The proposed mechanism of polyanhydride formation is shown in eq 6.

Formation of Carboxamides.

There are many reagents for the conversion of carboxylic acids to carboxamides.8,12-14 Activating agents such as DCC15 can lead to purification problems, whilst involvement of the acid chloride can lead to racemization; there are also examples using phosphorus containing reagents, e.g. Diethyl Phosphorocyanidate,13,16 but again these reagents only react well in certain systems. Other methods involve long reaction times, high temperatures, or low yields.

However, the use of phenyl N-phenylphosphoramidochloridate as a condensing agent for carboxylic acids and amines yields carboxamides in a one-step method (eq 7).17 The amide (12) is prepared from the carboxylic acid, 2 equiv of triethylamine, 1 equiv of amine, and 1 equiv of reagent (1) and isolated by filtration or evaporation of solvent and washing with water. Once again, a mixed anhydride intermediate (13) is presumed, which results from nucleophilic attack by the carboxylate anion on the phosphorus atom with elimination of a chloride ion; a further nucleophilic attack by the amine on the carbonyl group of (13) and breakdown of the complex yields the amide (12) and phenyl N-phenylphosphoramidate (14) which can be recycled to (1) by reaction with phosphorus pentachloride.

A distinct order of reactivity is observed in these reactions with (1): carboxylate anion &egt; aliphatic amines  >> aromatic amines. This has led to slight variations in the practical procedures for preparing the amides but these are well documented in the literature.17 The first route involves a one-step procedure; the second involves reaction of (1) with the carboxylate anion and subsequent treatment with the amine and is the preferred method for converting alkanamines to the amides since the first one-step method produces large amounts of phenyl phosphorodiamidates as well as the amide, by nucleophilic attack of (1) by the amine. The final method prevents the formation of phenyl phosphorodiamidates as the carboxylic acid first reacts with 0.5 equiv of (1) to form its anhydride, which is then converted to the amide in almost quantitative yield (this is largely utilizing the anhydride-formation chemistry described above) (eq 8).

Generally, phenyl N-phenylphosphoramidochloridate and other very similar related organophosphorus reagents e.g. phosphorus oxychloride, phenyl dichlorophosphate, diphenylchlorophosphate and N,N-bis(2-oxo-3-oxazolinyl)phosphorodiamidic chloride have been utilised in recent years not only to form symmetrical carboxylic acid anhydrides but also in esterification and thiol esterification reactions; although phenyl N-phenylphosphoramidochloridate is not so efficient for the latter two reactions compared to its analogs but is probably the best choice for forming the anhydride.18

Two Important Derivatives of Phenyl N-Phenylphosphoramidochloridate.

Phenyl N-Phenylphosphoramidoazidate.

This compound (15) is a white solid, which is easily prepared from (1) (eq 9).19 It is obtained in excellent yields and is unusual for an organophosphorus compound in that it shows little sensitivity to moisture at room temperature for several months.

It is an excellent reagent for the preparation of N,N-diarylureas. Reaction of a carboxylic acid, primary amine, and (15) in acetonitrile leads to the disubstituted urea (16) (eq 10). There is an additional competing reaction to the formation of the diarylurea: formation of phenyl N-phenylphosphorodiamidates, involving nucleophilic attack of the carboxylate ion and the alkylamine on the phosphorus atom of phenyl N-phenylphosphoramidoazidate. This work has been fully reviewed.20

Phenyl N-Methyl-N-phenylphosphoramidochloridate.

Like (1), phenyl N-methyl-N-phenylphosphoramidochloridate (17) reacts under analogous conditions to give anhydrides and carboxamides (see above). However, phenyl N-methyl-N-phenylphosphoramidochloridate undergoes one additional reaction which is not observed to any significant degree in (1). It is used for the conversion of imines to a-substituted b-lactams (eq 11).21 The reaction is believed not to work for (1) as it requires an excess of triethylamine in the presence of a less nucleophilic imine, which is unfavorable to a mixed anhydride intermediate. The proposed pathway for this reaction is shown in eq 11, and has been performed on a wide variety of imines, proceeding in good yields (44-78%).


1. Cremlyn, R. W. J.; Kishore, D. N. JCS(P1) 1972, 585.
2. Zielinski, W. S.; Lesnikowski, Z. J. S 1976, 185.
3. Ikehara, M.; Uesugi, S.; Fukui, T. CPB 1967, 15, 440.
4. Zielinski, W. S.; Lesnikowski, Z. J.; Stec, W. J. CC 1976, 772.
5. Lesnikowski, Z. J.; Niewiarowski, W.; Zielinski, W. S.; Stec, W. J. T 1984, 40, 15.
6. Slotin, L. A. S 1977, 737 and references therein.
7. Chen, F. M. F.; Koroda, K.; Benoiton, N. L. S 1978, 928.
8. Jones, J. H. In The Peptides Gross, E.; Meienhofer, J., Eds.; Academic: New York, 1979; p 65.
9. Mestres, R.; Palomo, C. S 1981, 219.
10. Bucher, J. E.; Slade, W. C. JACS 1909, 31, 1319.
11. Leong, K. W.; Simonte, V.; Langer, R. Macromolecules 1987, 20, 705.
12. Ogliaruso, M. A.; Wolfe, J. F. In The Chemistry of Acid Derivatives Wiley: New York, 1979; Part 1, p 474.
13. Haslam, E., CI(L) 1979, 610.
14. Haslam, E. T 1980, 36, 2409.
15. Mikolajczyk, M.; Kielbasinski, P. T 1981, 37, 233.
16. Shiori, T.; Yokoyama, Y.; Kasai, Y.; Yamada, S. T 1976, 32, 2213.
17. Mestres, R.; Palomo, C. S 1982, 288.
18. Arrieta, A.; Garcia, T.; Lago, J. M.; Palomo, C. SC 1983, 13, 471.
19. Arrieta, A.; Palomo, C. TL 1981, 22, 1729.
20. Arrieta, A.; Palomo, C. BSF(2) 1982, 7.
21. Shridhar, D. R.; Bhagat, R.; Narayana, V. L.; Awasthi, A. K.; Reddy, G. J. S 1984, 846.
22. Pouchert, C. J. Aldrich Library of FT-IR Spectra; Aldrich: Milwaukee, WI, 1989; Vol. 1, p 556C.

Adrian P. Dobbs

King's College London, UK



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