Ethyl Cyanoacetate

(R = Et)

[105-56-6]  · C5H7NO2  · Ethyl Cyanoacetate  · (MW 113.13) (R = Me)

[105-34-0]  · C4H5NO2  · Methyl Cyanoacetate  · (MW 99.10) (R = t-Bu)

[1116-98-9]  · C7H11NO2  · t-Butyl Cyanoacetate  · (MW 141.19)

(reagent with a doubly activated methylene group for free radical cyclizations, for preparing heterocycles, for nucleophilic substitution reactions, for preparing a-alkylidene derivatives, and for carbocyclic ring formation)

Physical Data: R = Me, bp 204-207 °C; d 1.123 g cm-3; R = Et, bp 208-210 °C; d 1.063 g cm-3; R = t-Bu, bp 90 °C/10 mmHg.

Solubility: sol EtOH, ether.

Form Supplied in: liquid; widely available.

Preparative Method: ethyl and methyl cyanoacetate are conveniently prepared from cyanoacetic acid and the corresponding Triethyloxonium Tetrafluoroborate and trimethyloxonium fluoroborate.1 t-Butyl cyanoacetate is prepared from cyanoacetyl chloride and t-butyl alcohol.2

Analysis of Reagent Purity: gas chromatography.

Handling, Storage, and Precautions: ethyl cyanoacetate is a lachrymator irritant. Methyl cyanoacetate is described as an irritant. Keep containers well closed. Inhalation should be avoided. Hydrogen cyanide or other low molecular weight cyano compounds may be liberated in event of overheating. Handle in a fume hood.

Condensation Reactions With Carbonyl Groups.

Ethyl cyanoacetate undergoes the Knoevenagel condensation3 (or the Knoevenagel-Doebner modification) with aldehydes and ketones in the presence of b-alanine,4 glycine,5 ammonium acetate,6,7 Piperidine,8 piperidine acetate,8 bismuth trichloride,9 Dihydridotetrakis(triphenylphosphine)ruthenium(II),10 or weak bases.11 The ammonium acetate-catalyzed reaction of acetophenone and ethyl cyanoacetate affords ethyl (1-phenylethylidene)cyanoacetate (eq 1).7 Condensation of ethyl cyanoacetate with propanal followed by reduction with hydrogen and palladium yielded ethyl butylcyanoacetate.8 Ethyl cyanoacetate and other active hydrogen compounds can also be alkylated by alcohols in modest yields using the combination of Diethyl Azodicarboxylate and Triphenylphosphine.12

Reactions with a,b-Unsaturated Carbonyl Compounds.

Activated nitriles such as ethyl cyanoacetate react with a,b-unsaturated carbonyl compounds in the presence of dihydridotetrakis(triphenylphosphine)ruthenium to afford Michael adducts which can undergo an aldol cyclization stereoselectively to afford cyclohexanes (eq 2).10 Ethyl cyanoacetate reacts with p-benzoquinone to afford diethyl a,a-dicyano-2,5-dihydroxy-p-benzenediacetate which is hydrolyzed to 2,5-dihydroxy-p-benzenediacetic acid (eq 3).13 Methacrylamides react with ethyl cyanoacetate in the presence of Cesium Fluoride-tetramethoxysilane to form dihydropyridinones (eq 4).14

Synthesis of Cyclopropanes and Cyclopentanes.

1-Cyanocyclopropanecarboxylic acid (eq 5)15 or 1-cyanocyclopentane-1-carboxylate16 can be prepared by cyclocondensation (double alkylation) of ethyl cyanoacetate and 1,2-Dibromoethane or 1,4-Dibromobutane under phase transfer conditions. Ethyl cyanoacetate reacts (2 equiv) with alkenes (1 equiv) in the presence of Copper(II) Chloride and Copper(II) Acetate in DMF to afford endo- and exo-cyclopropane derivatives (yields based on the alkene) (eq 6).17 Cyclopropanes were obtained under similar conditions from 1-decene and styrene. Use of dimethyl malonate in place of ethyl cyanoacetate gave lower yields of cyclopropanes.

Alkylation Reactions.

Ethyl cyanoacetate undergoes nucleophilic aromatic substitution with hexafluorobenzene in DMF/Potassium Carbonate to yield ethyl cyano(pentafluorophenyl)acetate which is converted to (pentafluorophenyl)acetonitrile.18 Ethyl cyanoacetate reacts with o,a-dichlorotoluene to afford ethyl 2-(o-chlorobenzyl)cyanoacetic acid which is an intermediate in the synthesis of 1-cyanobenzocyclobutene (bicyclo[4.2.0]octa-1,3,5-triene-7-carbonitrile).19 The nucleophilic substitution reaction of ethyl and t-butyl cyanoacetate with 3-bromochromone (eq 7) or 6-bromofurochromone affords the respective 3-substituted derivative,20 presumably by an addition-elimination mechanism.

Radical Cyclizations.

Ethyl cyanoacetate reacts with the tosylate of (E)-4-hexen-1-ol to afford ethyl (E)-2-cyano-6-octenoate which yields 1-cyano-2-methylcyclohexanecarboxylate on treatment with Dibenzoyl Peroxide (eq 8).21 Similarly, oxidative free radical cyclization of ethyl (4E,8-nonadien-1-yl)cyanoacetate in the presence of the co-oxidants MnIII and CuII acetate afforded ethyl 1-cyano-2-[1-(1,4-pentadienyl)]cyclopentanecarboxylate (35%).22 In the absence of CuII acetate or with benzoyl peroxide alone in cyclohexane, a mixture of the stereoisomers of methylhydrindane is formed (eq 9). The Mitsunobo reactions of 1,n-diols with ethyl cyanoacetate in the presence of triphenylphosphine and diethyl azodicarboxylate afford 1-cyano-1-cycloalkanecarboxylates (eq 10).23

Synthesis of Heterocycles.

Reaction of 2-arylazirines and Hexacarbonylmolybdenum with ethyl cyanoacetate furnishes the trans disubstituted succinimides (eq 11).24 Ethyl cyanoacetate condenses with butanone in the presence of ammonium acetate and ammonia to yield a,a-dicyano-b-ethyl-b-methylglutarimide (70%), which can be converted to b-ethyl-b-methylglutaric acid.25 Ethyl cyanoacetate reacts with aromatic and heterocyclic hydrazines to form 1-aryl-3-amino-5-pyrazolones (eq 12).26

Ethyl cyanoacetate condenses with urea to form 2,6-dihydroxy-5-aminouracil (eq 13), which is the first step in a synthesis of 5,6-diaminouracil hydrochloride.27 Similarly, thiourea and ethyl ethoxymethylenecyanoacetate afford 2-mercapto-4-amino-5-ethoxycarbonylpyrimidine and 2-mercapto-4-hydroxy-5-cyanopyrimidine.28 Guanidine condenses with ethyl cyanoacetate to produce 2,4-diamino-6-hydroxypyrimidine.29

Other Applications.

Novel carbon-carbon bond formation of nonactivated alkenes with ethyl cyanoacetate has been developed by anodic oxidation using MnII and CuII diacetates to give selectively either ethyl cyanoalkanecarboxylates or cyanoalkenecarboxylates (eq 14).30,31 Preparation of cyanomethyl ketone derivatives of N-acetylphenylalanine and N-acetylleucylphenylalanine is accomplished by condensation of the corresponding activated carboxylic acids and the carbanion of t-butyl cyanoacetate.32 Malononitrile, benzoylacetonitrile, and nitroacetonitrile are also reactive. Reaction of ethyl cyanoacetate and butanone in the presence of Potassium Cyanide and Acetic Acid, followed by acidic hydrolysis and heat, affords a-ethyl-a-methylsuccinic acid.33

Related Reagents.

Acetonitrile; Cyanoacetic Acid; 3-Ethoxyacrylonitrile; Ethyl Ethoxymethylenecyanoacetate; Lithioacetonitrile; Malononitrile.

1. Raber, D. J.; Gariano, Jr., P.; Brod, A. O.; Gariano, A. L.; Guida, W. C. OSC 1988, 6, 576.
2. Ireland, R. E.; Chaykovsky, M. OSC 1973, 5, 171.
3. For a review, see: Tietze, L. F.; Beifuss, U. COS 1991, 2, 341.
4. (a) Prout, F. S.; Hartman, R. J.; Huang, E. P.-Y.; Korpics, C. J.; Tichelaar, G. R. OSC 1963, 4, 93. (b) Egawa, Y.; Suzuki, M.; Okuda, T. CPB 1963, 11, 589.
5. Bastus, J. B. TL 1963, 955.
6. Cope, A. C.; Hancock, E. M. OSC 1955, 3, 399.
7. McElvain, S. M.; Clemens, D. H. OSC 1963, 4, 463.
8. Alexander, E. R.; Cope, A. C. OSC 1955, 3, 385.
9. Prajapati, D.; Sandhu, J. S. CL 1992, 1945.
10. Naota, T.; Taki, H.; Mizuno, M.; Murahashi, S.-I. JACS 1989, 111, 5954.
11. Jones, C. OR 1967, 15, 204.
12. Wada, M.; Mitsunobu, O. TL 1972, 1279.
13. Wood, J. H.; Cox, L. OSC 1955, 3, 286.
14. Chuit, C.; Corriu, R. J. P.; Perz, R.; Reye, C. T 1986, 42, 2293.
15. Singh, R. K.; Danishefsky, S. JOC 1975, 40, 2969.
16. Lin, Q.; Liu, Z. Huaxue Shiji 1992, 14, 310 (CA 1993, 118, 101 540).
17. Barreau, M.; Bost, M.; Julia, M.; Lallemand, J.-Y. TL 1975, 3465.
18. Filler, R.; Woods, S. M. OSC 1988, 6, 873.
19. Skorcz, J. A.; Kaminski, F. E. OSC 1973, 5, 263.
20. Gammill, R. B.; Nash, S. A.; Bell, L. T.; Watt, W. TL 1992, 33, 997.
21. Julia, M.; Maumy, M. OSC 1988, 6, 586.
22. Snider, B. B.; Armanetti, L.; Baggio, R. TL 1993, 34, 1701.
23. Kurihara, T.; Nakajima, Y.; Mitsunobu, O. TL 1976, 2455.
24. Alper, H.; Mahatantila, C. P.; Einstein, F. W. B.; Willis, A. C. JACS 1984, 106, 2708.
25. Farmer, H. H.; Rabjohn, N. OSC 1963, 4, 441.
26. Porter, H. D.; Weissberger, A. OSC 1955, 3, 708.
27. Sherman, W. R.; Taylor, Jr., E. C. OSC 1963, 4, 247.
28. Ulbricht, T. L. V.; Okuda, T.; Price, C. C. OSC 1963, 4, 566.
29. VanAllan, J. A. OSC 1963, 4, 245.
30. Shundo, R.; Nishiguchi, I.; Matsubara, Y.; Hirashima, T. CL 1990, 2285.
31. Shundo, R.; Nishiguchi, I.; Matsubara, Y.; Hirashima, T. T 1991, 47, 831.
32. Brillon, D.; Sauve, G. JOC 1992, 57, 1838.
33. Prout, F. S.; Aguilar, V. N.; Girard, F. H.; Lee, D. D.; Shoffner, J. P. OSC 1973, 5, 572.

Fillmore Freeman

University of California, Irvine, CA, USA

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