Diethyl Phosphorocyanidate1

[2942-58-7]  · C5H10NO3P  · Diethyl Phosphorocyanidate  · (MW 163.11)

(synthesis of amides,3 esters,2 a-aminonitriles,12 aryl thiocyanates,15 and cyanophosphates17)

Alternate Names: diethyl cyanophosphonate; diethylphosphoryl cyanide; diethoxyphosphoryl cyanide; diethyl cyanophosphate; DEPC.

Physical Data: bp 93-96 °C/14 mmHg; fp 80 °C; d 1.075 g cm-3.

Solubility: sol DMF, THF, Et2O, toluene.

Form Supplied in: pale yellow liquid; 93% (technical grade).

Preparative Method: can be readily prepared from Triethyl Phosphite and Cyanogen Bromide.2

Purification: in most cases, commercial samples are used without purification. However, freshly prepared DEPC contains an impurity of diethyl phosporoisocyanidate. Addition of anhydrous Cobalt(II) Chloride to a sample of crude DEPC, followed by dilution with ether forms a green precipitate which is removed by filtration; distillation of the filtrate gives pure DEPC.2

Handling, Storage, and Precautions: is very toxic and corrosive. It must be handled in a fume hood. The reagent is moisture sensitive and should be stored under nitrogen in a refrigerator.

Synthesis of Amides.

DEPC is an efficient and useful reagent for amide formation and is applicable to racemization-free peptide synthesis. Amides of various types can be obtained by the simple mixing of carboxylic acids and amines with DEPC in the presence of Triethylamine (eq 1).3 Both aromatic and aliphatic acids easily react with aromatic and aliphatic amines. The reaction is rapid, clean, and usually free of contamination from side products.

Studies of selected coupling methods for the attachment of amino acid derivatives to cis- and trans-4-aminocyclohexanecarboxylic acid have shown DEPC to be the reagent of choice as coupling agent.4 A study directed towards racemization during peptide coupling of benzyloxycarbonyl-L-phenylalanyl-L-valine with L-proline t-butyl ester revealed that, among different coupling agents, DEPC coupling afforded the least racemization.5

Following their application as effective peptide coupling agents in the solution phase, both DEPC and Diphenyl Phosphorazidate (DPPA)6 have been shown to be useful in solid-phase peptide synthesis.7,8 Using these reagents, synthesis of porcine motilin, comprising 22 amino acids, was successfully achieved.7

Synthesis of Esters and Thioesters.

Reaction of DEPC with carboxylic acids in the presence of triethylamine gives transient acyl cyanides, which in the presence of alcohols2 or thiols9 results in the formation of the corresponding esters or thiolesters (eq 2).

Although esterification yields are not generally satisfactory, the advantage of this method is that the reaction proceeds under mild and almost neutral conditions. The method can be efficiently applied to the synthesis of thiolesters in high yields with little racemization, as demonstrated by the formation of the ethylthiol ester of benzoyl-L-leucine.9


A direct C-acylation of active methylene compounds can be achieved using a carboxylic acid and DEPC in the presence of base under exceptionally mild conditions (eq 3).10,11 The reactions are best carried out in DMF solution, though hexane, toluene, ether, or THF may be used. Triethylamine, 1,8-Diazabicyclo[5.4.0]undec-7-ene, N,N,N,N-Tetramethylethylenediamine, Sodium Hydride, or Potassium Carbonate may be used as a base.

Synthesis of a-Aminonitriles.

a-Aminonitriles can be efficiently prepared from carbonyl compounds with DEPC and amines under mild conditions, in a modified Strecker synthesis.12 Since the nitrile functionality of a-aminonitrile can be easily converted to the acid, this constitutes a convenient method for the preparation of a-amino acids. The superiority of this method over the classical Strecker synthesis of a-aminonitriles was demonstrated by the reaction of 4-cholesten-3-one (1) with DEPC and Pyrrolidine, which afforded the a-aminonitrile (2) in 62% yield (eq 4). The classical Strecker conditions using a mixture of KCN and pyrrolidine hydrochloride in aqueous THF did not yield any a-aminonitriles.

Modified Reissert-Henze Reaction.

The a-cyanation of aromatic amine oxides (Reissert-Henze reaction) is usually carried out using benzoyl chloride and potassium cyanide.13 Alternatively, a-cyano-substituted aromatic nitrogen heterocycles can be prepared by reaction of their corresponding N-oxide with DEPC in the presence of triethylamine (eq 5).14

Synthesis of Aryl Thiocyanates.

Aryl thiocyanates can be prepared in one step from the sodium salt of the arylsulfinic acid by treatment with DEPC in refluxing THF. The thiocyanates are obtained in good yields and even hindered substrates like adamantane give the corresponding thiocyanate in moderate yield (eq 6).15

Epoxidation of Alkenes.

A mixture of DEPC and Hydrogen Peroxide smoothly epoxidizes alkenes at rt in the presence of 2-Hydroxypyridine or 1,2,4-Triazole.16 Methylene chloride is reported to be the solvent of choice. Various alkenes were epoxidized in 60-93% yields. trans-Stilbene and 1-dodecene, which are less susceptible to electrophilic attack by peroxycarboxylic acids, smoothly underwent this DEPC/H2O2 reaction.

Synthesis of Cyanophosphates as Versatile Intermediates.

Reaction of aldehydes or ketones with DEPC in the presence of a catalytic amount of Lithium Diisopropylamide (LDA) in THF gives cyanophosphates in high yield (eq 7).17 Various cyclic and aromatic ketones react with DEPC to give cyanophosphates. Even conjugated or hindered ketones such as a-tetralone or benzophenone, which are known not to give cyanohydrins under the usual reaction conditions, react smoothly with DEPC to give cyanophosphates.

Reductive Cyanation of Ketones and Aldehydes.

Saturated and unsaturated carbonyl compounds react with DEPC and Lithium Cyanide to give intermediate cyanophosphates which can be reduced with Samarium(II) Iodide in the presence of t-butanol to give nitriles (eq 8).18

a,b-Unsaturated Nitriles.

Cyanophosphates prepared by the reaction of aromatic ketones in the presence of lithium cyanide can be readily converted into a,b-unsaturated nitriles by treatment with Boron Trifluoride Etherate at rt (eq 9).19 This reaction was used to convert 4-isobutylacetophenone to a-cyanostyrene, which upon hydrogenation followed by hydrolysis gives ibuprofen in 70% overall yield (eq 10).19a

Deoxygenation of a,b-Unsaturated Ketones.

Cyanophosphates, prepared from a,b-unsaturated ketones or aromatic ketones by treatment with DEPC and lithium cyanide, can be reductively cleaved with Lithium in liquid ammonia to give the corresponding methylene compounds (eq 11).20 In the case of a,b-enones, this procedure is superior to the more commonly employed thioacetal and desulfurization deoxygenation method. This method for a,b-enones is simple and the products are obtained in excellent yields without isomerization or reduction of the double bond.

1. Saunders, B. C.; Stacey, G. T.; Wild, F.; Wilding, I. G. E. JCS 1948, 699.
2. Shioiri, T.; Yokoyama, Y.; Kasai, Y.; Yamada, S. T 1976, 32, 2211.
3. Yamada, S.; Kasai, Y.; Shioiri, T. TL 1973, 1595.
4. Chen, W.-Y.; Olsen, R. K. JOC 1975, 40, 350.
5. Takuma, S.; Hamada, Y.; Shioiri, T. CPB 1982, 30, 3147.
6. Hamada, Y.; Rishi, S.; Shioiri, T.; Yamada, S. CPB 1977, 25, 224.
7. Yamada, S.; Ikota, N.; Shioiri, T.; Tachibana, S. JACS 1975, 97, 7174.
8. (a) Ikota, N.; Shioiri, T.; Yamada, S. CPB 1980, 28, 3064. (b) Ikota, N.; Shioiri, T.; Yamada, S.; Tachibana, S. CPB 1980, 28, 3347.
9. (a) Yamada, S.; Yokoyama, Y.; Shioiri, T. JOC 1974, 39, 3302. (b) Yokoyama, Y.; Shioiri, T.; Yamada, S. CPB 1997, 25, 2423.
10. Shioiri, T.; Hamada, Y. JOC 1978, 43, 3631.
11. (a) Kato, N.; Hamada, Y.; Shioiri, T. CPB 1984, 32, 1679. (b) Kato, N.; Hamada, Y.; Shioiri, T. CPB 1984, 32, 3323.
12. Harusawa, S.; Hamada, Y.; Shioiri, T. TL 1979, 4663.
13. Henze, M. CB 1936, 69, 1566.
14. Harusawa, S.; Hamada, Y.; Shioiri, T. H 1981, 15, 981.
15. Harusawa, S.; Shioiri, T. TL 1982, 23, 447.
16. Mizuno, A.; Hamada, Y.; Shioiri, T. CPB 1981, 29, 1774.
17. Harusawa, S.; Yoneda, R.; Kurihara, T.; Hamada, Y.; Shioiri, T. CPB 1983, 31, 2932.
18. (a) Yoneda, R.; Harusawa, S.; Kurihara, T. TL 1989, 30, 3681. (b) Yoneda, R.; Harusawa, S.; Kurihara, T. JOC 1989, 56, 1827.
19. (a) Harusawa, S.; Yoneda, R.; Kurihara, T.; Hamada, Y.; Shioiri, T. TL 1984, 25, 427. (b) Yoneda, R.; Terada, T.; Harusawa, S.; Kurihara, T. H 1985, 23, 557. (c) Kurihara, T.; Terada, T.; Satoda, S.; Yoneda, R. CPB 1986, 34, 2786.
20. Yoneda, R.; Osaki, H.; Harusawa, S.; Kurihara, T. CPB 1989, 37, 2817.

Hemantkumar H. Patel

Abbott Laboratories, North Chicago, IL, USA

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