Ethyl Diazoacetate1

[623-73-4]  · C4H6N2O2  · Ethyl Diazoacetate  · (MW 114.10)

(for synthesis of cyclopropane- and cyclopropenecarboxylic acid derivatives,1-3 b-keto esters,4 and 2-substituted 2-diazoacetic esters,5,6 for homologation of ketones7-9)

Alternate Name: EDA.

Physical Data: mp -22 °C; bp 42 °C/5 mmHg 73 °C/80 mmHg, 141 °C/720 mmHg; d17.64 1.0852, d244 1.083 g cm-3; n17.6D 1.4588, n25D 1.4616; volatile with steam, ether and benzene vapors.

Solubility: sol alcohol, acetone, benzene, ether, ligroin; slightly sol water.

Form Supplied in: yellow oil; commercially available from many suppliers; typical impurities include ethyl chloroacetate and solvents (CH2Cl2, ether).

Preparative Method: by the reaction of Sodium Nitrite with glycine ethyl ester hydrochloride.5,6

Handling, Storage, and Precautions: explodes when heated, or on contact with concentrated H2SO4 or HCl; decomposes under irradiation. The reagent has to be stored in a dark cold place. It is toxic and reactions involving the formation or reaction of this substance should be performed in well-ventilated fume hood and behind a safety shield. The chemist should wear a suitable face shield.

Cyclopropanation of Unsaturated Compounds.

The most useful method of preparation of many cyclopropanecarboxylic acids is catalytic decomposition of ethyl diazoacetate in the presence of alkenes (eq 1).1-3,10-12

Addition of the transient ethoxycarbonyl carbenoid formed under catalytic decomposition of diazoacetate is cis stereospecific (eq 2).1,13 The less sterically hindered cyclopropanecarboxylate usually predominates (eq 3).1-3,11

Decomposition of EDA with heterogeneous copper catalysts requires relatively high temperatures and gives moderate yields of cyclopropanecarboxylates.1,2,14 Utilization of homogeneous catalysts such as Copper(I) Acetylacetonate increases the yields of cyclopropanes (eq 4). Rhodium(II) carboxylates (e.g. Dirhodium(II) Tetraacetate) have been found to be even more effective, allowing the reaction to be carried out at room temperature or at even lower temperatures, with low concentrations of catalyst (0.5 mol %).3,11 RhII complexes with chiral ligands have been used in stereocontrolled synthesis of chrysantemic and related acids.2,15

A wide variety of unsaturated compounds react with EDA in the presence of catalysts to give cyclopropanecarboxylates, for example polynuclear aromatic or heteroaromatic compounds,1,2 enol ethers,12 and ketene dialkyl acetals.16 Catalytic cyclopropanation with EDA has also been used in the synthesis of bicyclobutanes,1 triangulanes,17 and other polycylic systems.10,12

Cyclopropene-3-carboxylate esters usually are prepared by rhodium-catalyzed decomposition of EDA and its analogs in the presence of alkynes. Target compounds can be obtained in a high yield even at room temperature from both terminal and disubstituted alkynes (eq 5).1,18

Copper catalysis requires a temperature of 90-140 °C and gives satisfactory yields of cyclopropene esters only in the case of disubstituted alkynes.18 When double and triple bonds are both present in the same molecule, reaction takes place at both of them, a preference being shown for addition to the double bond.1,6,19 Decomposition of EDA with chiral rhodium(II) compounds allows one to achieve high enantioselectivity in cyclopropene synthesis.20

Homologation of Ketones.

EDA is the most useful diazoalkane for homologation of cyclic and acyclic ketones without the formation of epoxides as byproducts. This reaction is catalyzed by Boron Trifluoride Etherate,7-9 Tin(IV) Chloride,21 or Triethyloxonium Tetrafluoroborate.2 The homologation is not regiospecific and usually gives a mixture of isomeric 2-keto esters, but insertion occurs preferentially at the less substituted side of the carbonyl group (eq 6).8

A procedure for regiospecific homologation of ketones was developed by using a-halo-substituted ketones. Treatment of the halo ketone with EDA is followed by removal of the halogen using Zinc followed by decarboxylation of the resulting b-keto ester (eq 7).7,22

a-Diketones can be converted to b-diketones by reaction with EDA in the presence of Zinc Chloride followed by hydrolysis (eq 8).23

Synthesis of 2-Substituted Acetic Esters.

EDA reacts with trialkylboranes,24 dialkylchloroboranes,25 or alkyl(aryl)dichloroboranes26 with loss of nitrogen to give, after hydrolysis, the homologated ethyl ester in a moderate to high yield. b,g-Unsaturated carboxylic esters have been obtained using this procedure (eq 9).25

Homologated ethyl esters have also been prepared by insertion of ethoxycarbonylcarbene generated by catalytic decomposition of EDA in C-H,12,27 C-O and C-S,6 or Si-H bonds.28 Ethyl 2-alkoxyacetates have been obtained in good yield by RhII-catalyzed decomposition of EDA in the presence of various alcohols.29

Ethyl Lithiodiazoacetate.

This reagent, which is stable only below -50 °C, can be prepared by treating EDA with n-Butyllithium in THF at -115 to -78 °C.5 Reaction of Ethyl Diazolithioacetate with alkyl-, acyl-, and trialkylsilyl halides results in the formation of 2-substituted ethyl diazoesters (eq 10).5,6,30

This reagent also reacts with carbonyl compounds, forming 2-diazo-3-hydroxy esters (eq 11).5,6

Transmetalation of ethyl lithiodiazoacetate gives access to silver, mercury, and tin derivatives of EDA.5,6


Thermal or photochemical decomposition of EDA in benzene and its derivatives leads to the formation of cycloheptatriene esters in moderate yields.1,2 Dirhodium(II) Tetrakis(trifluoroacetate) has been recently reported to be a very effective catalyst for this reaction and increased the yields of cycloheptatrienes (eq 12).31

b-Keto Esters from Aldehydes.

In addition to methods of b-keto ester synthesis described above, these compounds can be prepared by the addition of EDA to aldehydes in the presence of Tin(II) Chloride (eq 13).4

Ylide Rearrangements.

Catalytic decomposition of EDA in the presence of sulfides, tertiary amines, or iodides leads to formation of intermediate ylides which undergo Stevens rearrangement (eq 14).2,3,6 Ylides bearing an allylic double bond give the products of a [2,3]-sigmatropic rearrangement (eq 15).3,32

Dirhodium(II) Tetraacetate has been shown to be the most useful catalyst for this transformation.3

1. Dave, V.; Warnhoff, E. V. OR 1970, 18, 218.
2. Wulfman, D. S.; Linstrumelle, G.; Cooper, C. F. In The Chemistry of Diazonium and Diazo Groups; Patai, S., Ed.; Wiley: New York, 1978; Part 2, p 823.
3. Doyle, M. P. ACR 1986, 19, 348.
4. Holmquist, C. R.; Roskamp, E. J. JOC 1989, 54, 3258.
5. Regitz, M.; Maas, G. Diazo Compounds; Academic: New York, 1986.
6. Regitz, M.; Korobizina, I. K.; Rodina, L. L. In Methodicum Chimicum; Korte, F., Ed.; Thieme: Stuttgart, 1975; Vol. 6, p 205.
7. Fieser, M. FF 1986, 12, 223.
8. Liu, H. J.; Majumdar, S. P. SC 1975, 5, 125.
9. Krow, G. R. T 1987, 43, 3.
10. Mandel'shtam, T. V. RCR 1989, 58, 1250.
11. Doyle, M. P.; van Leusen, D.; Tamblyn, W. H. S 1981, 787.
12. Kulinkovich, O. G. RCR 1989, 58, 1233.
13. D'yakonov, I. A.; Komendantov, M. I.; Korichev, G. L. JGU 1962, 32, 917.
14. Doyle, M. P. In Catalysis of Organic Reactions; Augustine, R. L., Ed.; Dekker: New York, 1985; Chapter 4.
15. (a) Aratani, R.; Yoneyoshi, Y.; Nagase, T. T 1982, 38, 685. (b) Laidler, D. A.; Milner, D. J. JOM 1984, 270, 121. (c) Demonceau, A.; Noels, A. F.; Anciaux, A. J.; Hubert, A. J.; Teyssie, P. BSB 1984, 93, 949.
16. Graziano, M. L.; Iesce, M. R. S 1985, 762.
17. (a) De Meijere, A.; Kozhushkov, S. I.; Spaeth, T.; Zefirov, N. S. JOC 1993, 58, 502. (b) Lukin, K. A.; Kozhushkov, S. I.; Andrievskii, A. A.; Ugrak, B. I.; Zefirov, N. S. Mendeleev Commun. 1992, 51.
18. Protopopova, M. N.; Shapiro, E. A. RCR 1989, 58, 1145.
19. Danilkina, L. P.; D'yakonov, I. A., JOU 1966, 2, 1.
20. Protopopova, M. N.; Doyle, M. P.; Mueller, P.; Ene, D. JACS 1992, 114, 2755.
21. Dodd, J. H.; Schwender, C. F.; Gray-Nunez, Y. JHC 1990, 27, 1453.
22. Dave, V.; Warnhoff, E. W. JOC 1983, 48, 2590.
23. Korobitsyna, I. K.; Studzinskiii, O. P. JOU 1969, 5, 1246.
24. Hooz, J.; Linke, S. JACS 1968, 90, 6891.
25. (a) Fieser, M.; Fieser, L. F. FF 1974, 4, 229. (b) Brown, H. C.; Salunkhe, A. M.; SL 1991, 684.
26. Fieser, M.; Fieser, L. F. FF 1975, 5, 295.
27. Demonceau, A.; Noels, A. F.; Anciaux, A. J.; Hubert, A. J.; Teyssie, P. BSB 1984, 93, 945.
28. Baghery, V.; Doyle, M. P.; Taunton, J.; Claxton, E. E. JOC 1988, 53, 6158.
29. Noels, A. F.; Demonceau, A.; Petiniot, N.; Hubert, A. J.; Teyssie, P. T 1982, 38, 2733.
30. Hoffman, K-L.; Maas, G.; Regitz, M. JOC 1987, 52, 3851.
31. Anciaux, A. J.; Demonceau, A.; Noels, A. F.; Hubert, A. J.; Warin, R.; Teyssie, P. JOC 1981, 46, 873.
32. (a) Doyle, M. P.; Tamblyn, W. H.; Bagheri, V. JOC 1981, 46, 5094. (b) Yoshimoto, M.; Ishihara, S.; Nakayama, E.; Soma, N. TL 1972, 2923.

Vladimir V. Popik

St. Petersburg State University, Russia

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