InChI = 1S/C2H3N/c1-2-3/h1H3
InChIKey = WEVYAHXRMPXWCK-UHFFFAOYSA-N
(solvent for inorganic and organometallic reagents; undergoes addition reactions to nitrile group; anion is nucleophilic reagent; Ritter reaction reagent; oxidizing agent in combination with H2O2)
Alternate Name: methyl cyanide; ethanenitrile; cyanomethane.
Physical Data: mp −45 °C; bp 81.6 °C; d 0.787 g cm−3 (20 °C).
Solubility: miscible with water and most organic solvents (but not petroleum); forms constant boiling mixture containing 16% water, bp 76 °C.
Form Supplied in: colorless liquid; widely available.
Drying: fractional distillation from CaH2 or P2O5.
Analysis of Reagent Purity: GLC; HPLC grade (99.9+% purity) commercially available.
Handling, Storage, and Precautions: flammable volatile liquid; keep dry; toxic vapor; mild lachrymator; possible skin irritant; evolves toxic fumes if heated to decomposition; incompatible with fuming HNO3, N2O4/In, 2-cyano-2-propylnitrate, ClF/F2, Cl3HSi/diphenyl sulfoxide, metal perchlorates, HClO4, fuming H2SO4, heat/conc. H2SO4, and N-fluoro compounds.2
[2524-64-3] · C12H10ClO3P · Diphenyl Phosphorochloridate · (MW 268.64)
(phosphorylation;1 synthesis of -substituted -lactams;14 synthesis of anhydrides, esters, and thioesters;18 conversion of aldoximes to nitriles;22 preparation and reaction of enol phosphates25,26,29)
Alternate Names: diphenyl chlorophosphate; diphenylphosphoryl chloride.
Physical Data: bp 314-316 °C/272 mmHg; d 1.296 g cm-3; fp >110 °C.
Solubility: sol dichloromethane, THF.
Form Supplied in: viscous colorless liquid; commercially available.
Preparative Methods: by heating a mixture of 1.1 equiv phosphoryl chloride and 2 equiv of phenol to 180 °C, and distilling the product.1 Prepared in situ by the reaction of diphenyl hydrogen phosphonate and carbon tetrachloride.
Purification: vacuum distillation.
Handling, Storage, and Precautions: moisture sensitive; handle and store under nitrogen. Store in a cool place. Harmful liquid and fumes; inhalation may be fatal. Use in a fume hood. Extremely corrosive; causes burns. Incompatible with strong bases and oxidizing agents. Combustion or decomposition products include carbon monoxide, hydrogen chloride gas, phosphorus oxides, and/or phosphine.
As first demonstrated by Brigl and Müller1 in the synthesis of glucose and fructose phosphates, diphenyl phosphorochloridate is an excellent reagent for the synthesis of monoalkyl phosphates. The reagent has been used to block the amino group in amino sugar and nucleoside synthesis,2 and in the synthesis of glycosyl phosphates,3 key intermediates in the synthesis of nucleotide sugars. The reagent has been used in peptide synthesis,4 one-pot syntheses of sulfinates, sulfinamides, and thiosulfinates,5 and as an intermediate in the synthesis of Diphenyl Phosphorazidate6,7 and diphenyl phosphoroisothiocyanatidate.8 The reagent has been utilized in the study of the -(phosphonooxy)alkyl radical rearrangements,9 involving the 1,2-migration of phosphate esters.
Azidoacetyl Chloride, a valuable reagent for -lactam synthesis10-12 by Sheehan's method,13 tends to decompose explosively unless rigorous precautions are observed. The application of phosphorylating reagents provides a safe and viable alternative to this reaction. The reaction of a Schiff base and carboxylic acid in the presence of diphenyl phosphorochloridate and Triethylamine (eq 1) results in substituted -lactams in 50-70% yield.14
Synthesis of Anhydrides, Esters, and Thioesters.
Phosphorus reagents such as diphenyl phosphorazidate15 and diphenyl phosphorochloridate16 have been used for carboxy group activation through the respective mixed phosphoric acid anhydrides. These have been found suitable for the one-pot preparation of carboxylic acid anhydrides, esters, and thioesters.17 The hydroxy acid (eq 2) does not undergo lactonization under conventional conditions. Activation with diphenyl phosphorochloridate, however, and treatment with 4-Dimethylaminopyridine, results in cyclization to the lactone and a dimer in 32% yield and 25% yield, respectively.18 The diol is generated in quantitative yield with Trifluoroacetic Acid in aqueous acetonitrile.
Reaction with Amide Enolates.
The synthesis of 3-amino-2H-azirines is generally accomplished by the reaction of -chloro enamines with sodium azide.19 The less stable 2-monosubstituted 3-amino-2H-azirines require a modified synthesis and difficult experimental conditions.20 A new and simpler route to these compounds involves the reaction of diphenyl phosphorochloridate with amide enolates,21 followed by reaction with Sodium Azide to give moderate yields of 2-monosubstituted 3-amino-2H-azirines (eq 3).
These 2-substituted aminoazirines react with carboxylic and thiocarboxylic acids to form the respective amides and thioamides (eq 4).
Conversion of Aldoximes to Nitriles.
The reaction of aldoximes with dialkyl hydrogen phosphonates (R = Ph, Me, n-Bu), carbon tetrachloride, and triethylamine at ambient temperatures results in the formation of nitriles in high yields.22 Diphenyl hydrogen phosphonate gives the best yields (85-95%). The reaction proceeds via the in situ generation of diphenyl phosphorochloridate (eq 5),23 followed by the esterification of the aldoxime, and subsequent Beckmann fragmentation (eq 6).
Synthesis and Reactions of Enol (Vinyl) Phosphates.
A general method for the preparation of enol phosphates involves the reaction of lithium enolates with dialkyl phosphorochloridates.24 Enol phosphates have been prepared by a novel cycloaddition reaction. Reaction of the enolate of methyl vinyl ketone with diphenyl phosphorochloridate yields the phosphate diene, which then undergoes [4 + 2] cycloaddition (eq 7) to form the Diels-Alder adduct in 90% yield.25 With relatively poor dienophiles like cyclohexenone, Lewis acid catalysts such as Aluminum Chloride may be required.
Enol phosphates are versatile intermediates which undergo many synthetically useful transformations. The coupling of enol phosphates with lithium dialkylcuprates provides alkyl-substituted alkenes in good yields (eq 8).26
The Pd0-catalyzed cross coupling of organometallics and organic halides has generally been limited to aryl and alkenyl halides.27,28 Thus the palladium-catalyzed cross coupling of vinyl phosphates and organoaluminum compounds, reported by Oshima and co-workers,29 provides an effective tool for the transformation of enolizable ketones into alkyl-, alkenyl-, and alkynyl-substituted alkenes (eq 9).
- 1. Brigl, P.; Müller, H. CB1939, 72, 2121.
- 2. Wolform, M. L.; Conigliaro, P. J.; Soltes, E. J. JOC1967, 32, 653.
- 3. Subramaniam, S.; Neira, S. CR1992, 223, 169.
- 4. Cosmatos, A.; Photaki, I.; Zervas, L. B1961, 94, 2644.
- 5. Noguchi, Y.; Isoda, M.; Kuroki, K.; Furukawa, M. CPB1982, 30, 1646.
- 6. Shioiri, T.; Ninomiya, K.; Yamada, S. JACS1972, 94, 6203.
- 7. Shioiri, T.; Yamada, S. CPB1974, 22, 849.
- 8. Kenner, G. W.; Khorana, H. G.; Stedman, R. J. JCS1953, 673.
- 9. Crich, D.; Yao, Q. JACS1993, 115, 1165.
- 10. (a) Bose, A. K.; Anjaneyulu, B. CI(L)1966, 903. (b) Bose, A. K.; Anjaneyulu, B.; Bhattacharya, S. K.; Manhas, M. S. T1967, 23, 4769.
- 11. Bose, A. K.; Spiegelman, G.; Manhas, M. S. JACS1968, 90, 4506.
- 12. Ratcliffe, R. W.; Christensen, B. G. TL1973, 4649.
- 13. Sheehan, J. C.; Ryan, J. J. JACS1951, 73, 1204, 4367.
- 14. Manhas, M. S.; Lal, B.; Amin, S. G.; Bose, A. K. SC1976, 6, 435.
- 15. Yamada, S.; Yokoyama, Y.; Shioiri, T. JOC1974, 39, 3302.
- 16. (a) Masamune, S.; Kamata, S.; Kakur, J.; Sugihara, Y.; Bates, G. S. CJC1975, 53, 3693. (b) Liu, H. J.; Chan, W. H.; Lee, S. P. TL1978, 4461.
- 17. Arrieta, A.; García, T.; Lago, J. M.; Palomo, C. SC1983, 13, 471.
- 18. Kaiho, T.; Masamune, S.; Toyoda, T. JOC1982, 47, 1612.
- 19. Rens, M.; Ghosez, L. TL1970, 3765.
- 20. Henriet, M.; Houtekie, M.; Techy, B.; Touillaux, R.; Ghosez, L. TL1980, 21, 223.
- 21. Villalgordo, J. M.; Heimgartner, H. HCA1992, 75, 1866.
- 22. Foley, P. J., Jr. JOC1969, 34, 2805.
- 23. Steinberg, G. M. JOC1950, 15, 637.
- 24. Ireland, R. E.; Pfister, G. TL1969, 2145.
- 25. Calogeropoulou, T.; Wiemer, D. F. JOC1988, 53, 2295.
- 26. Blaszczak, L.; Winkler, J.; O'Kuhn, S. TL1976, 4405.
- 27. Murahashi, S.; Yamamura, M.; Yanagisawa, K.; Mita, N.; Kondo, K. JOC1979, 44, 2408.
- 28. Dang, H. P.; Linstrumelle, G. TL1978, 191.
- 29. Takai, K.; Oshima, K.; Nozaki, H. TL1980, 21, 2531.
Albert V. Thomas
Abbott Laboratories, North Chicago, IL, USA