Ethyl Metaphosphate1

[4697-37-4]  · C2H5O3P  · Ethyl Metaphosphate  · (MW 108.04)

(reagent used for phosphorylation of nucleophiles when generated in situ and used as a monomer1)

Monomeric Metaphosphates.

The chemistry of metaphosphates has been reviewed.1 Monomeric metaphosphates are highly reactive species and are typically prepared in situ via various fragmentation processes and then trapped with appropriate nucleophiles. For example, ethyl metaphosphate has been generated by photolytic2 and thermal3 fragmentation of ethyloxaphosphabicyclo[2.2.2]octene. The resulting reactive ethyl metaphosphate monomer can then be trapped with various alcohols to afford phosphate derivatives (eq 1). Another preparation involves the fragmentation of alkyl a-(oximino)benzylphosphonates using anhydrous HCl in the presence of various hydroxylic trapping agents.4 An application for this methodology was demonstrated with the modification of silica gel for potential development of new phosphorylated chromatographic materials (eq 2).5

Metaphosphates are highly electrophilic species and also react with various activated aromatic compounds to afford products of electrophilic aromatic substitution,3 as well as with epoxides to afford dioxaphospholanes.6 Due to the highly reactive nature of monomeric metaphosphates, however, the use of these reagents for organic synthesis remains limited in scope.

Cyclic Tetramer of Ethyl Metaphosphate.

While the monomeric form of ethyl metaphosphate has only limited synthetic utility, the polymeric form commonly known as Polyphosphate Ester (PPE) has been used for a number of valuable synthetic transformations including dehydrations,7 Beckmann rearrangements,8 Fischer indole synthesis,9 and N-alkylation.10 A convenient large scale preparation of PPE has been described by Cava and co-workers.11 Thus, to a mixture of 300 mL of anhydrous diethyl ether in 150 mL of chloroform is added 150 g of phosphorus pentoxide. The mixture is warmed under reflux for 4 days. The resulting solution is filtered and the filtrate concentrated in vacuo at 40 °C to afford PPE as a clear colorless oil. Polyphosphate ester, sometimes referred to as ethyl polyphosphate or polyphosphoric ester, exists as a complex mixture of polymeric cyclic and acyclic esters. (1) shows the structure of the cyclic tetramer [801-24-1] (MW 432.14). Some applications of PPE in organic synthesis are described below.

Dehydration Reactions.

PPE is commonly used to promote cyclodehydration reactions, such as the Bischler-Napieralski reaction. Thus, a key step in the synthesis of (±)-hernandine involves the cyclization of a secondary amide using PPE to afford the requisite dihydroisoquinoline (eq 3).12 Another example of this reaction is the preparation of 5H-2-benzazepine analogs.13 Polyphosphate ester is reported to be the reagent of choice for conversion of phenylpropylamines to the corresponding benzazepines (eq 4).

PPE has also been used for the preparation of 2-substituted benzimidazoles,14 benzoxazoles, and benzothiazoles.15 For example, condensation of o-aminophenol with acetic acid in the presence of PPE at 100 °C affords 2-methylbenzoxazole in 75% yield (eq 5).15 Likewise, condensation of o-aminothiophenol with furan-2-carboxylic acid in the presence of PPE under refluxing chloroform gives 2-(2-furyl)benzothiazole in 64% yield (eq 6).15 The preparation of the aforementioned benzazoles using PPE is reported to be superior to that using Polyphosphoric Acid (PPA). A general synthesis of 2,3-dihydro-4H-1,3-benzoxazin-4-ones based on the same protocol has also been reported. Thus condensation of a salicylamide with aldehydes or ketones using PPE affords good yields of the corresponding benzoxazinone (eq 7).16

Cyclization via Friedel-Crafts acylation using PPE has also been reported. For example, the ring closure of substituted 2-(2-methoxycarbonylphenylamino)benzoic acids affords the corresponding 9-oxoacridan-4-carboxylic acids in excellent yield (eq 8).17 Other examples involving the PPE activation or dehydration of carboxylic acid moieties include the conversion of carboxylic acids to nitriles18,19 and the preparation of thioesters from acids.20

Beckmann Rearrangement and Fischer Indole Synthesis.

The use of PPE to effect certain rearrangements has also been reported. For example, the oxime derived from adamantanone readily undergoes the Beckmann rearrangement to afford the corresponding lactam in 65% yield (eq 9).8 The procedure is reported to be superior to standard procedures which give primarily second-order Beckmann fragmentation products. The preparation of indoles via Fischer indole synthesis using PPE has also been described. For example, cyclohexanone phenylhydrazone undergoes rearrangement to the indole under mild conditions (eq 10).9

N-Alkylation.

PPE is also an effective alkylating agent for primary and secondary amines as well as for certain nitrogen containing heterocycles. The reaction usually occurs at temperatures higher than those typically used for the previously described transformations. Thus 2-aminobenzophenone N-(2-hydroxyalkyl)imines are conveniently N-alkylated and cyclocondensed at 160 °C to afford good yields of the corresponding benzodiazepine derivatives (eq 11).10


1. Westheimer, F. H. CRV 1981, 81, 313.
2. Quin, L. D.; Pete, B.; Szewczyk, J.; Hughes, A. N. TL 1988, 29, 2627.
3. Quin, L. D.; Marsi, B. G. JACS 1985, 107, 3389.
4. Breuer, E.; Karaman, R.; Leader, H.; Goldblum, A. CC 1987, 671.
5. Quin, L. D.; Wu, X.-P. TL 1990, 31, 6281.
6. Quin, L. D.; Bodalski, R. JOC 1991, 56, 2666.
7. (a) For an overview of applications of this reagent see also: Fieser, L.; Fieser, M. FF 1967, 1, 892 and further references cited therein. (b) Kanaoka, Y. Kagaku 1969, 24, 234.
8. Narayanan, V. L.; Setescak, L. JHC 1969, 6, 445.
9. Yonemitsu, O.; Miyashita, K.; Ban, Y.; Kanaoka, Y. T 1969, 25, 95.
10. Oklobdzija, M.; Sunjic, V.; Kajfez, F.; Caplar, V.; Kolbah, D. S 1975, 596.
11. Cava, M. P.; Lakshmikantham, M. V.; Mitchell, M. J. JOC 1969, 34, 2665.
12. Soh, K. S.; Lahey, F. N. TL 1968, 19.
13. Kanaoka, Y.; Sato, E.; Yonemitsu, O.; Ban, Y. TL 1964, 2419.
14. Kanaoka, Y.; Tanizawa, K.; Yonemitsu, O. CPB 1969, 17, 2381.
15. Kanaoka, Y.; Hamada, T.; Yonemitsu, O. CPB 1970, 18, 587.
16. Irvine, J. L.; Piantadosi, C. S 1972, 568.
17. Rewcastle, G. W.; Denny, W. A. S 1985, 220.
18. Imamoto, T.; Takaoka, T.; Yokoyama, M. S 1983, 142.
19. Kanaoka, Y.; Kuga, T.; Tanizawa, K. CPB 1970, 18, 397.
20. Imamoto, T.; Kodera, M.; Yokoyama, M. S 1982, 134.

Gregory Merriman

Hoechst-Roussel Pharmaceuticals, Somerville, NJ, USA



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