Synlett 2005(20): 3171-3172  
DOI: 10.1055/s-2005-921920
SPOTLIGHT
© Georg Thieme Verlag Stuttgart · New York

Diethyl Chlorophosphate

Viviana Beatriz Dorn*
Instituto de Investigaciones en Química Orgánica (INIQO), ­Departamento de Química, Universidad Nacional del Sur, Av. Alem 1253, 8000 Bahía Blanca, Argentina
e-Mail: vdorn@uns.edu.ar;

Further Information

Publication History

Publication Date:
28 November 2005 (online)

Biographical Sketches

Viviana B. Dorn was born in La Pampa (Argentina) in 1977. In 1996 she began her undergraduate course of Chemistry at the Universidad Nacional del Sur (Bahía Blanca). In 2001 she received her Diploma. She is currently working towards her Doctorate as a fellow of the CONICET in the group of Professor A. B. Chopa at the Instituto de Investigaciones en Química Orgánica, within a project on the Synthesis of Vinylstannanes from Carbonyl Compounds via SRN1 reactions.

Introduction

Diethyl chlorophosphate [ClP(O)(OEt)2, DECP] is widely used in the synthesis of vinyl phosphates, which can be prepared regio- and stereoselectively by phosphorylation of enolate anions generated from the corresponding ketones under kinetically or thermodynamically controlled conditions. [1] Other important application, include the use of DECP for the phosphorylation of amide enolates to give α-phosphonoamides. [2]

Vinyl phosphates can also be synthesized by the Perkow reaction with trialkyl phosphites, but unlike the above-mentioned method, starting carbonyl compounds must be α-halo ketones, which are not commercially available and, in some cases very difficult to be synthesized. Moreover, the nature of the halogen atom and the reaction temperature have a crucial effect on the final products, i.e. both formation of vinyl phosphate and vinyl phosphonate can take place at the same time. [1c] [3]

Phenols are converted to the corresponding aryl phosphate in high yields by reaction of the phenoxide anion with DECP. [4] This method is more successful in most ­cases than generating diethyl chlorophosphite in situ. [5] In this sense, the selective phosphorylation of hydroxy­phenols has recently been performed using DECP. [6]

On the other hand, the scope of phosphorylation in bio­organic chemistry includes amine precursors in the synthesis of phosphotriesters employing DECP. This synthetic strategy would make available some interesting unnatural phosphates derived from naturally occurring amino sugars, alkaloids and amino acids. [7] This reagent can also be used as a coupling agent in the synthesis of ­oligonucleoside phosphorodithionates [8] and in the synthesis of diethylphosphoric anhydride employed in the N-protection of amino acids. [9]

For the above exposed reasons, DECP has received added interest as phosphorylating reagent, in organic and bio­organic chemistry such as: synthesis of structurally specific olefins, [1a] [b] [10] synthesis of acetylenes, [11] synthesis of phosphonates [12] and bisphosphonates, [13] selective synthesis of thiol esters, [14] cross-coupling reactions in the presence of various heteroatoms, [15] [1d] industrial scale synthesis of vinyl halides, [16] displacement of phosphate as leaving group [17] by an anion (e.g. organotin [18] or tellurolate [19] ­anions) or by alkyl cuprates. [20]

DECP is commercially available. It can also be prepared by reaction of diethyl phosphite with chlorine until the ­liquid assumed a yellow coloration. Excess of gas is ­removed by bubbling dry air through the liquid under ­reduced pressured. The crude oil is vacuum-distilled. Yield 80-90%, bp 92 °C/17 mm Hg. [21]

Caution! DECP is highly toxic by skin contact. It decomposes if exposed to moisture, and thermal decomposition may produce toxic fumes of phosphorus oxides and ­phosphines.

Abstract

(A) A series of enol phosphates were synthesized starting from 2-substituted acetophenones. The ability of these compounds to undergo cross-coupling reactions in the presence of various hetero­atoms, makes the enol phosphate an attractive functional group for the construction of various substituted heterocyclic systems via ring-closing methathesis. [15c]

(B) A new practical synthetic method for the preparation of vinyl halides from acyclic and cyclic ketones and imides via the corresponding phosphate intermediates is proven. This process is satisfactory in an industrial scale production since the work-up procedure is easy to operate. Moreover, this method is applied to the industrial production of SUN N4057, a pharmaceutical candidate for the treatment of cerebral infarction. [16]

(C) A total synthesis of the silphinene IV, a natural product, has been accomplished in 12 steps. Since attempts to trap the ketone as its silyl enol ether in the cleavage reaction were unsuccessful, a study of the enolate formation of I was undertaken in hopes of ­selectively forming enol phosphate II as the direct precursor to ­silphinene. Termodynamic enolization of I and quenching with DECP rendered enolphosphate II as major product. Reduction of this mixture, gave a mixture of silphinene IV and isosilphinene V. An efficient and regioselective formation of enol phosphate II, served to prepare the ()-silphinene IV with high selectivity. [10b]

(D) Monophosphorylated hydroxyphenols, which can be used as flame retardants in polycondensation reactions due to their free ­hydroxy group, were synthesized. The phosphorylation of hydroquinone I by DECP gave predominantly the monophosphate II. [6b]

(E) DECP is used in the oligonucleotides synthesis via N-un­protected methods. The basis of this method is the activation of an hydroxyl group as an alkoxide which undergoes the O-selective ­reaction with DECP to give the nucleoside phosphate in almost quantitative yields. [22]

    References

  • 1a Ireland RE. Pfister G. Tetrahedron Lett.  1969,  2145 
  • 1b Welch SC. Walters ME. J. Org. Chem.  1978,  43:  2715 
  • 1c Borowitz IJ. Firstenberg S. Casper EWR. Crouch RK. J. Org. Chem.  1971,  36:  3282 
  • 1d Hayashi T. Fujiwa T. Okamoto Y. Katsuro Y. Kumada M. Synthesis  1981,  1001 
  • 2 Sudau A. Münch W. Bats J.-W. Nubbemeyer U. Eur. J. Org. Chem.  2002,  19:  3315 
  • 3 Lichtenthaler FW. Chem. Rev.  1961,  61:  607 
  • 4a Goldkamp AH. Hoehn WM. Mikulec RA. Nutting EF. Cook DL. J. Med. Chem.  1965,  8:  409 
  • 4b Rossi RA. Bunnett JF. J. Org. Chem.  1973,  38:  2314 
  • 4c Welch SC. Walters ME. J. Org. Chem.  1978,  43:  4797 
  • 4d Jiang Y.-Y. Li Q. Lu W. Cai J.-C. Tetrahedron Lett.  2003,  44:  2073 
  • 5 Kenner GW. Williams NR. J. Chem. Soc.  1955,  522 
  • 6a Marosi Gy. Toldy A. Parlagh Gy. Nagy Z. Ludányi K. Anna P. Keglevich Gy. Heteroat. Chem.  2002,  13:  126 
  • 6b Toldy A. Anna P. Marosi Gy. Keglevich Gy. Almeras X. Le Bras M. Polym. Degrad. Stab.  2003,  82:  317 
  • 7 Nikolaides N. Ganem B. Tetrahedron Lett.  1990,  31:  1113 
  • 8 Kamaike K. Hirose K. Kayama Y. Kawashima E. Tetrahedron Lett.  2004,  45:  5803 
  • 9 Tarbell DS. Insalaco MA. Proc. Natl. Acad. Sci. U.S.A.  1967,  57:  233 
  • 10a Heathcock CH. Davidsen SK. Mills S. Sanner MA. J. Am. Chem. Soc.  1986,  108:  5650 
  • 10b Crimmins MT. Mascarella SW. J. Am. Chem. Soc.  1986,  108:  3435 
  • 11a Lythgoe B. Waterhouse I. J. Chem. Soc., Perkin Trans. 1  1979,  2429 
  • 11b Barlett PA. Green FR. Rose EH.
    J. Am. Chem. Soc.  1978,  100:  4852 
  • 11c Temmen O. Zoller T. Uguen D. Tetrahedron Lett.  2002,  43:  3181 
  • 12 Iorga B. Savignac P. J. Organomet. Chem.  2001,  624:  203 
  • 13 Steinmeyer A. Schwarz K. Haberey M. Langer G. Wiesinger H. Steroids  2001,  66:  257 
  • 14 Masamune S. Kamata S. Diakur J. Sugihara Y. Bates GS. Can. J. Chem.  1975,  53:  3693 
  • 15a Karlström ASE. Itami K. Bäckvale JE. J. Org. Chem.  1999,  64:  1745 
  • 15b Wu J. Yang Z. J. Org. Chem.  2001,  66:  7875 
  • 15c Whitehead A. Moore JD. Hanson PR. Tetrahedron Lett.  2003,  44:  4275 
  • 16 Kamei K. Maeda N. Tatsuoka T. Tetrahedron Lett.  2005,  46:  229 
  • 17a Bowman WR. Chem. Soc. Rev.  1988,  17:  283 
  • 17b Norris RK. In Comprehensive Organic Synthesis   Vol. 4:  Trost BM. Fleming I. Pergamon; New York: 1991.  p.451 
  • 17c Rossi RA. Pierini AB. Santiago AN. Org. React.  1999,  54:  1 
  • 18 Chopa AB. Dorn VB. Badajoz MA. Lockhart MT. J. Org. Chem.  2004,  69:  3801 
  • 19a Moraes DN. Barrientos-Astigarraga RE. Castelani P. Comasseto JV. Tetrahedron  2000,  56:  3327 
  • 19b Barrientos-Astigarraga RE. Castelani P. Sumida C. Zukerman-Schpector J. Comasseto JV. Tetrahedron  2002,  58:  1051 
  • 20 Moorhoff CM. Schneider DF. Tetrahedron  1998,  54:  3279 
  • 21a Mc Combie H. Saunders BC. Stacey GJ. J. Chem. Soc.  1945,  380 
  • 21b Steinberg GM. J. Org. Chem.  1950,  15:  637 
  • 22 Hayakawa Y. Kawai R. Kataoka M. Eur. J. Pharm. Sci.  2001,  13:  5 

    References

  • 1a Ireland RE. Pfister G. Tetrahedron Lett.  1969,  2145 
  • 1b Welch SC. Walters ME. J. Org. Chem.  1978,  43:  2715 
  • 1c Borowitz IJ. Firstenberg S. Casper EWR. Crouch RK. J. Org. Chem.  1971,  36:  3282 
  • 1d Hayashi T. Fujiwa T. Okamoto Y. Katsuro Y. Kumada M. Synthesis  1981,  1001 
  • 2 Sudau A. Münch W. Bats J.-W. Nubbemeyer U. Eur. J. Org. Chem.  2002,  19:  3315 
  • 3 Lichtenthaler FW. Chem. Rev.  1961,  61:  607 
  • 4a Goldkamp AH. Hoehn WM. Mikulec RA. Nutting EF. Cook DL. J. Med. Chem.  1965,  8:  409 
  • 4b Rossi RA. Bunnett JF. J. Org. Chem.  1973,  38:  2314 
  • 4c Welch SC. Walters ME. J. Org. Chem.  1978,  43:  4797 
  • 4d Jiang Y.-Y. Li Q. Lu W. Cai J.-C. Tetrahedron Lett.  2003,  44:  2073 
  • 5 Kenner GW. Williams NR. J. Chem. Soc.  1955,  522 
  • 6a Marosi Gy. Toldy A. Parlagh Gy. Nagy Z. Ludányi K. Anna P. Keglevich Gy. Heteroat. Chem.  2002,  13:  126 
  • 6b Toldy A. Anna P. Marosi Gy. Keglevich Gy. Almeras X. Le Bras M. Polym. Degrad. Stab.  2003,  82:  317 
  • 7 Nikolaides N. Ganem B. Tetrahedron Lett.  1990,  31:  1113 
  • 8 Kamaike K. Hirose K. Kayama Y. Kawashima E. Tetrahedron Lett.  2004,  45:  5803 
  • 9 Tarbell DS. Insalaco MA. Proc. Natl. Acad. Sci. U.S.A.  1967,  57:  233 
  • 10a Heathcock CH. Davidsen SK. Mills S. Sanner MA. J. Am. Chem. Soc.  1986,  108:  5650 
  • 10b Crimmins MT. Mascarella SW. J. Am. Chem. Soc.  1986,  108:  3435 
  • 11a Lythgoe B. Waterhouse I. J. Chem. Soc., Perkin Trans. 1  1979,  2429 
  • 11b Barlett PA. Green FR. Rose EH.
    J. Am. Chem. Soc.  1978,  100:  4852 
  • 11c Temmen O. Zoller T. Uguen D. Tetrahedron Lett.  2002,  43:  3181 
  • 12 Iorga B. Savignac P. J. Organomet. Chem.  2001,  624:  203 
  • 13 Steinmeyer A. Schwarz K. Haberey M. Langer G. Wiesinger H. Steroids  2001,  66:  257 
  • 14 Masamune S. Kamata S. Diakur J. Sugihara Y. Bates GS. Can. J. Chem.  1975,  53:  3693 
  • 15a Karlström ASE. Itami K. Bäckvale JE. J. Org. Chem.  1999,  64:  1745 
  • 15b Wu J. Yang Z. J. Org. Chem.  2001,  66:  7875 
  • 15c Whitehead A. Moore JD. Hanson PR. Tetrahedron Lett.  2003,  44:  4275 
  • 16 Kamei K. Maeda N. Tatsuoka T. Tetrahedron Lett.  2005,  46:  229 
  • 17a Bowman WR. Chem. Soc. Rev.  1988,  17:  283 
  • 17b Norris RK. In Comprehensive Organic Synthesis   Vol. 4:  Trost BM. Fleming I. Pergamon; New York: 1991.  p.451 
  • 17c Rossi RA. Pierini AB. Santiago AN. Org. React.  1999,  54:  1 
  • 18 Chopa AB. Dorn VB. Badajoz MA. Lockhart MT. J. Org. Chem.  2004,  69:  3801 
  • 19a Moraes DN. Barrientos-Astigarraga RE. Castelani P. Comasseto JV. Tetrahedron  2000,  56:  3327 
  • 19b Barrientos-Astigarraga RE. Castelani P. Sumida C. Zukerman-Schpector J. Comasseto JV. Tetrahedron  2002,  58:  1051 
  • 20 Moorhoff CM. Schneider DF. Tetrahedron  1998,  54:  3279 
  • 21a Mc Combie H. Saunders BC. Stacey GJ. J. Chem. Soc.  1945,  380 
  • 21b Steinberg GM. J. Org. Chem.  1950,  15:  637 
  • 22 Hayakawa Y. Kawai R. Kataoka M. Eur. J. Pharm. Sci.  2001,  13:  5