Polyphosphate Ester

[-]  · C8H20O12P4  · Polyphosphate Ester  · (MW 432.14)

(dehydrating agent; used in the Bischler-Napieralski reaction;1 Friedel-Crafts acylation;2 conversion of carboxylic acids to esters,3 thiol esters,4 amides,5,6 and nitriles;6,7 Beckmann rearrangement;7 and heterocycle preparation; an alternative to PPA in dehydration reactions)

Alternate Name: PPE.

Physical Data: d 1.463 g cm-3; n 1.440.8

Solubility: sol CHCl3; reacts vigorously with H2O.

Form Supplied in: not commercially available. May be prepared as described below. It is a colorless to yellowish substance which forms a stiff gel below 0 °C.

Analysis of Reagent Purity: PPE (3% solution in CHCl3) shows a characteristic band in its IR spectrum at 1330 cm-1. This band disappears and a new, broad band appears at 1200-1260 cm-1 when PPE is treated with a trace amount of H2O.5 1H and 31P NMR techniques may be employed to determine composition of the mixture and structural features of each component.9 Elemental analysis is not reliable.9

Preparative Methods: was originally prepared by Langheld,12 and has been referred to as Langheld esters.9,10 The preparation reported by Cava et al.13 is a compilation of three previous procedures.8,14,15 Phosphorus(V) Oxide (150 g) is added to a solution of anhydrous ether (300 mL) and alcohol-free Chloroform (150 mL). The reaction mixture is refluxed under dry nitrogen for 4 d and the resulting clear solution decanted from a small amount of residue. The solution is concentrated to a colorless syrup in a rotary evaporator; residual traces of solvent are removed by heating the syrup for 36 h at 40 °C in vacuo.13 More harsh conditions result in unusable material.11 While this preparation is sufficient for most synthetic applications, Van Wazer et al. reported that PPE prepared from triethyl orthophosphate and phosphorus pentoxide was superior for biochemical studies.9

Handling, Storage, and Precautions: Usually prepared fresh, but may be stored for at least 1 month.4 PPE is unstable above 110-120 °C. A gradual decomposition occurs which becomes vigorous with evolution of gas at 150-160 °C.11 Direct contact with PPE should be avoided. Use in a fume hood.

Reagent Description.

PPE is another of the phosphate-based reagents that are related to Polyphosphoric Acid (PPA) (see also Phosphorus(V) Oxide-Methanesulfonic Acid). It differs from PPA in that it is aprotic and soluble in organic media. It is often compared to the related polyphosphoric acid trimethylsilyl ester (PPSE). In general, the advantages of PPE include its solubility in organic solvents, the mild conditions under which it is used, and its relatively nonhazardous, nonnoxious nature. A disadvantage is its time-consuming preparation.16 The reagent is composed of a mixture of polymeric phosphoric acid esters.8-10 Variations in the reactants and the reaction conditions may result in differences in the reagent's composition.5,9,10 It is presumed to activate carboxylic acids through formation of mixed anhydrides.17

Bischler-Napieralski Reaction.1,18

One of the most cited uses of PPE is as a reagent in the Bischler-Napieralski reaction (eq 1).18a The utility of PPE compares favorably to other reagents, such as Phosphorus Oxychloride, Phosphorus(V) Oxide, and PPA.18a,b,h,i

Friedel-Crafts Acylation.2,19

Intramolecular Friedel-Crafts acylations have been carried out by treatment of aromatic acids with PPE (eq 2).19a Depending on the substrate, PPE may be as effective20 or more effective21 than other reagents.

Carboxylic Acid Derivatives.

Esters,3 lactones,22 thiol esters,4 thiolactones,23 amides,5 and acylureas24 have all been prepared from a PPE-mediated reaction of a carboxylic acid and the appropriate coupling partner. There are many excellent methods for effecting the above transformations;25 PPE is distinguished from these mainly by its low cost. Eq 3 describes the synthesis of phenyl esters,3a which were shown to be stable in PPE. This is in contrast to PPA, which can effect the Fries rearrangement of phenyl esters.3a Aryl and alkyl thiols have been condensed with alkyl, alkenyl, and aryl carboxylic acids,4 and malonic acid.26 Hindered thiol esters can be prepared by this method (eq 4).4 Sensitive substrates such as penicillin G could be reacted at low temperature with the addition of pyridine.4

Conversion of Carboxylic Acids and Amides to Nitriles.

PPE has been used to dehydrate amides to nitriles.27 More recently, a one-pot conversion of carboxylic acids to nitriles has been reported.6 Treatment of an acid with PPE under an atmosphere of ammonia results in the formation of an intermediate amide, which upon further treatment with PPE undergoes dehydration to provide the nitrile (eq 5).6 The amide may be obtained upon quenching the reaction after the initial condensation. Advantages of this method include use of a nonnoxious reagent, and reaction conditions that are relatively mild.5,6,16 In an example of this reaction in a more complex substrate, this methodology has been applied to a synthesis of the canthine alkaloid skeleton.28

Beckmann Rearrangement.

Upon treatment with PPA, ketoximes have undergone the Beckmann rearrangement (eq 6).7 Under more forcing conditions, ketoximes provide amidines (eq 6). Submission of the oxime of benzaldehyde to similar conditions failed to produce benzamide; the only product obtained was benzonitrile. Treatment of benzamide under the same conditions did not lead to the nitrile. This suggests that dehydration of the aldoxime did not proceed through the intermediacy of the amide.7 PPE was found to be equivalent to PPSE in terms of yields obtained in the Beckmann rearrangement of oximes.29

Fischer Indole Synthesis.

PPE has been utilized in the Fischer indole synthesis. Yields obtained ranged from 21 to 86% (eq 7).30 A side product was the C-3 alkylated indole (see the section on ethylation).30

Heterocycle Preparation.

Various heterocycles have been produced through PPE-mediated cyclization reactions. Benzimidazoles (eq 8),14 benzoxazoles,31 and benzothiazoles31 have been prepared through condensation of an ortho-substituted aniline and an acid (eq 8).14

In related work, it was reported that PPE was utilized in the synthesis of benzothiazoles.32 However, in the preparation of benzimidazoles, 6 N HCl was reported to be the preferred reagent; in the preparation of benzoxazoles, PPA was a better reagent.32a Other heterocycles prepared using PPE as a reagent include pyrrolo[2,3-b]pyridines,33 pyrrolo[3,4-b]pyridines,34 pyrrolo[3,2-b]pyridines,35 benzimidazo[1,2-c]indazolo[2,3-a]quinazolines,36 1,3-diazepines,37 1,3-diazocines,37 1,4-dihydro-4-oxoquinolines,38 and 1,3-thiazin-4-ones.39

Miscellaneous Transformations.

5,6-Dihydro-2(1H)-pyridinones have been prepared stereoselectively by condensing 3-alkenamides with aryl aldehydes (eq 9).40 PPA is also effective in this reaction; however, the yields are lower.

A one-carbon homologation of benzyl alcohols to amides or esters is shown in eq 10. Alkyl (and aryl) alcohols and secondary amines react with a cobalt intermediate to provide products with yields ranging from 20-82%.41


During a Fischer indole synthesis, PPE was observed to alkylate indoles.30 Further studies revealed that at 160 °C the ethyl indolenine was obtained in moderate yield. The diethyl and N-ethyl compounds were obtained in minor amounts (eq 11).11

N-Alkylation of various amines has been reported. A tautomeric imidazole was alkylated in 74% yield (eq 12).42 Yields for other methylation (polyphosphate methyl ester) or ethylation (polyphosphate ethyl ester) reactions varied from 44-74%.42

1. For a general discussion of the Bischler-Napieralski reaction, see: (a) Whaley, W. M.; Govindachari, T. R. OR 1951, 6, 74. (b) Fodor, G.; Nagubandi, S. T 1980, 36, 1279. (c) Kametani, T.; Fukumoto, K. In The Chemistry of Heterocyclic Compounds; Grethe, G., Ed.; Wiley: New York, 1981; Vol. 38, Part 1, pp 139-274.
2. For general references, see: March, J. Advanced Organic Chemistry, 3rd ed.; Wiley: New York, 1985; pp 484-487.
3. (a) Kanaoka, Y.; Tanizawa, K.; Sato, E.; Yonemitsu, O.; Ban, Y. CPB 1967, 15, 593. (b) El Seoud, O. A.; Pivetta, F.; El Seoud, M. I.; Farah, J. P. S.; Martins, A. JOC 1979, 44, 4832.
4. Imamoto, T.; Kodera, M.; Yokoyama, M. S 1982, 134.
5. Kanaoka, Y.; Machida, M.; Yonemitsu, O.; Ban, Y. CPB 1965, 13, 1065.
6. Imamoto, T.; Takaoka, T.; Yokoyama, M. S 1983, 142.
7. Kanaoka, Y.; Yonemitsu, O.; Sato, E.; Ban, Y. CPB 1968, 16, 280.
8. Pollmann, W.; Schramm, G. BBA 1964, 80, 1.
9. Van Wazer, J. R.; Norval, S. JACS 1966, 88, 4415.
10. Burkhardt, G.; Klein, M. P.; Calvin, M. JACS 1965, 87, 591.
11. Yonemitsu, O.; Miyashita, K.; Ban, Y.; Kanaoka, Y. T 1969, 25, 95.
12. Langheld, K. CB 1910, 43, 1857.
13. Cava, M. P.; Lakshmikantham, M. V.; Mitchell, M. J. JOC 1969, 34, 2665.
14. Kanaoka, Y.; Yonemitsu, O.; Tanizawa, K.; Ban, Y. CPB 1964, 12, 773.
15. Schramm, G.; Grotsch, H.; Pollmann, W. AG(E) 1962, 1, 1.
16. Yokoyama, M.; Yoshida, S.; Imamoto, T. S 1982, 591.
17. Cheng, K.-F.; Wong, T.-T.; Wong, W.-T.; Lai, T.-F. JCS(P1) 1990, 2487.
18. (a) Kanaoka, Y.; Sato, E.; Ban, Y. CPB 1967, 15, 101. (b) Doskotch, R. W.; Phillipson, J. D.; Ray, A. B.; Beal, J. L. JOC 1971, 36, 2409. (c) Matsuo, K.; Okumura, M.; Tanaka, K. CPB 1982, 30, 4170. (d) Matsuo, K.; Okumura, M.; Tanaka, K. CL 1982, 1339. (e) Pandit, U. K.; Das, B.; Chatterjee, A. T 1987, 43, 4235. (f) Fujii, T.; Yamada, K.; Minami, S.; Yoshifuji, S.; Ohba, M. CPB 1983, 31, 2583. (g) Lenz, G. R.; Woo, C.-M. JHC 1981, 18, 691. (h) Ishida, A.; Nakamura, T.; Irie, K.; Oh-ishi, T. CPB 1985, 33, 3237. (i) Sano, T.; Toda, J.; Maehara, N.; Tsuda, Y. CJC 1987, 65, 94. (j) Kanaoka, Y.; Sato, E.; Yonemitsu, O.; Ban, Y. TL 1964, 2419.
19. (a) Zjawiony, J.; Peterson, J. R. OPP 1991, 23, 163. (b) Girard, Y.; Atkinson, J. G.; Belanger, P. C.; Fuentes, J. J.; Rokach, J.; Rooney, C. S.; Remy, D. C.; Hunt, C. A. JOC 1983, 48, 3220.
20. Feliz, M.; Bosch, J.; Mauleón, D.; Amat, M.; Domingo, A. JOC 1982, 47, 2435.
21. (a) Kelly, T. R.; Chandrakumar, N. S.; Saha, J. K. JOC 1989, 54, 980. (b) Imanishi, T.; Nakai, A.; Yagi, N.; Hanaoka, M. CPB 1981, 29, 901. (c) Begley, W. J.; Grimshaw, J. JCS(P1) 1977, 2324.
22. Lele, S. R.; Hosangadi, B. D. IJC(B) 1979, 18, 533.
23. Vegh, D.; Morel, J.; Decroix, B.; Zalupsky, P. SC 1992, 22, 2057.
24. Heinicke, G.; Hung, T. V.; Prager, R. H.; Ward, A. D. AJC 1984, 37, 831.
25. (a) For other methods of ester and lactone formation, see: March, J. Advanced Organic Chemistry, 3rd ed.; Wiley: New York, 1985; pp 348-351, 353-354. (b) For esterification of carboxylic acids using alkylphosphoric esters (APEs), see: Balasubramaniyan, V.; Bhatia, V. G.; Wagh, S. B. T 1983, 39, 1475. (c) For other methods of thiol ester formation, see Ref. 5 and March, J. Advanced Organic Chemistry, 3rd ed.; Wiley: New York, 1985; pp 362-363. (d) For other methods of amide formation, see March, J. Advanced Organic Chemistry, 3rd ed.; Wiley: New York, 1985; pp 370-377.
26. Imamoto, T.; Kodera, M.; Yokoyama, M. BCJ 1982, 55, 2303.
27. (a) Kanaoka, Y.; Kuga, T.; Tanizawa, K. CPB 1970, 18, 397. (b) For a list of other reagents used in the amide to nitrile conversion, see Ref. 16.
28. Benson, S. C.; Li, J.-H.; Snyder, J. K. JOC 1992, 57, 5285.
29. Imamoto, T.; Yokoyama, H.; Yokoyama, M. TL 1981, 22, 1803.
30. Kanaoka, Y.; Ban, Y.; Miyashita, K.; Irie, K.; Yonemitsu, O. CPB 1966, 14, 934.
31. Kanaoka, Y.; Hamada, T.; Yonemitsu, O. CPB 1970, 18, 587.
32. (a) Yalcin, I.; Oren, I.; Sener, E.; Akin, A.; Ucarturk, N. Eur. J. Med. Chem. 1992, 27, 395. (b) Yoshino, K.; Kohno, T.; Uno, T.; Morita, T.; Tsukamoto, G. JMC 1986, 29, 820.
33. Vishwakarma, L. C.; Sowell, J. W. JHC 1985, 22, 1429.
34. Bayomi, S. M.; Price, K. E.; Sowell, J. W. JHC 1985, 22, 729.
35. Bayomi, S. M.; Price, K. E.; Sowell, J. W. JHC 1985, 22, 83.
36. Reddy, V. R. K.; Reddy, P. S. N.; Ratnam, C. V. SC 1991, 21, 49.
37. Perillo, I.; Fernández, B.; Lamdan, S. JCS(P2) 1977, 2068.
38. Okumura, K.; Adachi, T.; Tomie, M.; Kondo, K.; Inoue, I. JCS(P1) 1972, 173.
39. (a) Yokoyama, M.; Sato, K.; Tateno, H.; Hatanaka, H. JCS(P1) 1987, 623. (b) Yokoyama, M.; Kodera, M.; Imamoto, T. JOC 1984, 49, 74.
40. Marson, C. M.; Grabowska, U.; Walsgrove, T. JOC 1992, 57, 5045.
41. Imamoto, T.; Kusumoto, T.; Yokoyama, M. BCJ 1982, 55, 643.
42. Oklobdzija, M.; Sunjic, V.; Kajfez, F.; Caplar, V.; Kolbah, D. S 1975, 596.

Lisa A. Dixon

The R. W. Johnson Pharmaceutical Research Institute, Raritan, NJ, USA

Copyright 1995-2000 by John Wiley & Sons, Ltd. All rights reserved.