Ethyl Nitroacetate

[626-35-7]  · C4H7NO4  · Ethyl Nitroacetate  · (MW 133.12)

(alkylations;3,5,6 Michael additions;4 amidoalkylations;7 Knoevenagel condensations;8-11 palladium-catalyzed allylations;12-14 a-alkoxyallylation;15 generation of alkyl nitronates;16,17 generation of hydroxynitrilium ions for synthesis of (E)-oximes;18 synthesis of 4-hydroxy-2-isoxazolines;19 oxidant for alcohols;20 synthesis of a-amino esters21)

Physical Data: bp 194-195 °C; d 1.203 g cm-3; n20D 1.425.

Solubility: sol ethanol, diethyl ether.

Form Supplied in: colorless liquid; widely available.

Preparative Methods: from Nitromethane by self-condensation to produce methazonic acid, followed by dehydration to nitroacetonitrile, hydrolysis, and esterification.22 Alternatively, it is accessible from Ethyl Acetoacetate by nitration; the resultant ethyl nitroacetoacetate is decomposed with ethanol.23

Purification: fractional vacuum distillation.

Handling, Storage, and Precautions: stable for at least six months if stored in the refrigerator.

C-Alkylation.

Due to its strong acidity (pKa (DMSO) = 9.2),24 ethyl nitroacetate (1) can easily be deprotonated by a number of weak bases or electrochemically at the cathode.1 The anion typically reacts with alkyl halides, enones, acetates, carbonates, amines, and alcohols or it can be condensed with aldehydes, ketones, or imines.2 Thus the sodium salt of ethyl nitroacetate (1) is alkylated with Benzyl Bromide (2) (eq 1).3

In a Michael addition, (1) reacts with 2-acetyl-1,4-dihydroxyanthracene-9,10-dione (3) in the presence of 1,8-Diazabicyclo[5.4.0]undec-7-ene (eq 2).4 Aromatization of the Michael adduct (4) is achieved either by elimination of nitric acid with DBU in an inert atmosphere to form ester (5), or by oxidation of the quinone moiety in an air atmosphere to afford ester (6) (eq 2).

Ethyl nitroacetate can be alkylated by gramine in refluxing toluene in quantitative yield (eq 3).5 Heating of (1) with trityl alcohol (7) and trichloroacetic acid gives ethyl 3,3,3-triphenyl-2-nitropropanoate (8) in 41% yield (eq 4).6

N-(1-Benzotriazol-1-ylalkyl)amides (9) react with (1) under mild conditions to give rise to the a-amidoalkylation products (10) (eq 5).7

Ethyl nitroacetate (1) undergoes Knoevenagel condensations8 with aldehydes, ketones, and imines. Acid-base combinations like Titanium(IV) Chloride/Pyridine9 or Acetic Acid/Piperidine10 are particularly good catalysts for this reaction. Iminophosphate (11) is converted to the Knoevenagel product (12) upon exposure to the sodium salt of ethyl nitroacetate (eq 6).11

Under palladium catalysis, ethyl nitroacetate (1) reacts with allylic carbonates, acetates, and phenoxides to give the allylated compounds.12 Thus C-glycopyranosides (14) are accessible from 2,3-unsaturated glycals (13) (eq 7).13 The key step in the synthesis of the carbocyclic nucleoside carbovir is a Pd0-catalyzed addition of (1) to the carbonate (15) followed by a Krapcho-deethoxycarbonylation (eq 8).14 Both reactions are completely regio- and stereoselective.

Ethyl nitroacetate (1) can be a-alkoxyallylated when treated with acetals (16) of a,b-enals.15 The first step of the reaction is the formation of the Claisen system (17) which, when heated at 200 °C, undergoes the [3,3]-sigmatropic rearrangement, albeit in poor yield (eq 9).

O-Alkylation.

Under Mitsunobu conditions, ethyl nitroacetate (1) reacts with alcohols by way of exclusive O-alkylation to afford alkyl nitronates (18) (eq 10).16 These have been shown to be reactive 1,3-dipoles in cycloadditions with alkenes, alkynes, and hetero dipolarophiles.2 Versatile heterocycles like isoxazolines are accessible by this transformation.17

By the action of a strong acid like Trifluoromethanesulfonic Acid, (1) is converted to the highly electrophilic hydroxynitrilium ion (19).18 Aromatic compounds can easily add to (19) to furnish (E)-oximes (20) stereoselectively (eq 11).

Ethyl nitroacetate (1) condenses with a-bromo aldehydes (21) in the presence of Alumina in a synthesis of 4-hydroxy-2-isoxazolines (22) (eq 12).19 This reaction can be analyzed in terms of a nitroaldol-cyclization sequence. The primarily formed oxides (23) are reduced to the desired isoxazolines (22) with Trimethyl Phosphite (eq 12).

Oxidation.

A combination of Diethyl Azodicarboxylate, Triphenylphosphine, and ethyl nitroacetate (1) is an effective system for the oxidation of primary and secondary alcohols (eq 13).20 Aldehydes and ketones are formed under neutral conditions. An aci-nitro ester (24) is the intermediate of the reduction and decomposes slowly when heated in THF (eq 13).

Ethyl glycinate (25) can be obtained via reduction of ethyl nitroacetate (1) using Ammonium Formate as a catalytic hydrogen transfer agent in a Palladium on Carbon suspension in methanol (eq 14).21

Related Reagents.

Methyl 4-Nitrobutanoate; Methyl 3-Nitropropanoate; Nitromethane; Phenylsulfonylnitromethane.


1. Niyazymbetov, M. E.; Evans, D. H. JOC 1993, 58, 779.
2. Review: Shipchandler, M. T. S 1979, 666.
3. Manthey, M. K.; Pyne, S. G.; Truscott, R. J. W. JOC 1990, 55, 4581.
4. (a) Carr, K.; Greener, N. A.; Mullah, K. B.; Somerville, F. M.; Sutherland, J. K. JCS(P1) 1992, 1975; (b) Carr, K.; Sutherland, J. K. CC 1987, 567.
5. Largman, T. U.S. Patent 3 627 782, 1971.
6. Ryaboi, V. I.; Ginzburg, O. F. ZOR 1967, 2228.
7. Katritzky, A. R.; Pernak, J.; Fan, W. Q.; Saczewski, F. JOC 1991, 56, 4439.
8. Review: Tietze, L. F.; Beifuss, U. COS 1991, 2, 341.
9. (a) Lehnert, W. TL 1970, 4723; (b) Lehnert, W. T 1972, 28, 663; (c) Lehnert, W. T 1973, 29, 635.
10. Popp, F. D.; Catala, A. JOC 1961, 26, 2738.
11. Fryer, R. I.; Kudzma, L. V.; Gu, Z. Q.; Lin, K. Y.; Rafalko, P. W. JOC 1991, 56, 3715.
12. (a) Genet, J. P.; Juge, S.; Besnier, I.; Uziel, J.; Ferroud, D.; Kardos, N.; Achi, S.; Ruiz-Montes, J.; Thorimbert, S. BSF 1990, 781; (b) Genet, J. P.; Blart, E.; Savignac, M. SL 1992, 715.
13. Brakta, M.; Lhoste, P.; Sinou, D. JOC 1989, 54, 1890.
14. Peel, M. R.; Sternbach, D. D.; Johnson, M. R. JOC 1991, 56, 4990.
15. Coates, R. M.; Hobbes, S. J. JOC 1984, 49, 140.
16. Falck, J. R.; Yu, J. TL 1992, 33, 6723.
17. Wade, P. A.; Amin, N. V.; Yen, H. K.; Price, D. T.; Huhn, G. F. JOC 1984, 49, 4595.
18. Coustard, J. M.; Jacquesy, J. C.; Violeau, B. TL 1991, 32, 3075.
19. (a) Rosini, G.; Galarini, R.; Marotta, E.; Righi, P. JOC 1990, 55, 781; (b) Rosini, G.; Marotta, E.; Righi, P.; Seerden, J. P. JOC 1991, 56, 6258; (c) Melot, J. M.; Texier-Boullet, F.; Foucaud, A. S 1988, 558.
20. Mitsunobu, O.; Yoshida, N. TL 1981, 2295.
21. Ram, S.; Ehrenkaufer, R. E. S 1986, 133.
22. Zen, S.; Koyama, M.; Koto, S. OS 1976, 55, 77.
23. Sifniades, S. CA 1974, 80, 14551.
24. Bordwell, F. G. PAC 1977, 49, 963.

Lutz F. Tietze & Christoph Schneider

Georg-August-Universität zu Göttingen, Germany



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