Ethyl Azidoformate1

[817-87-8]  · C3H5N3O2  · Ethyl Azidoformate  · (MW 115.09)

(electron-deficient azide; can undergo cycloadditions with alkenes to yield triazolines;1 generates ethoxycarbonylnitrenes on thermolysis and photolysis1)

Physical Data: bp 40 °C/30.5 mmHg.

Solubility: sol ether, methylene chloride.

Preparative Methods: as reported by Lwowski and Mattingly.27

Handling, Storage, and Precautions: is potentially explosive and care should be taken when distilling or heating solutions of this compound. It has been stored in the cold, protected from light, for up to 3 months without any apparent deterioration. However, ethyl azidoformate is eventually hydrolyzed in the presence of moisture, leading to the formation of HN3. Such long-stored samples can explode on handling (due to the HN3) and it is therefore recommended that ethyl azidoformate be used immediately after preparation. The vapors of this compound are also toxic. The original literature should be consulted before preparation and use of this compound.27 This reagent should only be handled in a fume hood.


Ethyl azidoformate is usually prepared by the reaction of Ethyl Chloroformate with Sodium Azide. It is principally used for two broad classes of reactions: (a) the cycloaddition of the azide moiety to an unsaturated functionality, and (b) as a source of ethoxycarbonylnitrene. This reagent has limited synthetic utility primarily because of its thermal instability. Ethyl azidoformate and other azidoformates begin to decompose above 60 °C.1b The related methyl azidoformate also displays similar reactivity and will also be discussed wherever relevant.

Cycloaddition Reactions.

The cycloaddition reactions of azides to alkenes are generally believed to be concerted. Ethyl azidoformate is considered an electron-poor azide and reacts readily with electron-rich alkenes. The product of these reactions are D2-triazolines. The triazolines derived from electron-poor azides are usually not stable and can lose nitrogen readily to give the aziridines and/or imines even at room temperature.1c However, many triazolines have been isolated in good yields. If the desired products are the triazolines themselves, the cycloaddition reactions are synthetically useful only if they proceed readily well below the decomposition temperature of the parent azide. At higher temperatures, ethyl azidoformate decomposes to give the corresponding nitrene which can react in a variety of pathways. Also, at higher temperatures, triazoline decomposition occurs readily. Strained and/or electron-rich alkenes undergo cycloaddition readily at room temperature or below. Norbornene,2 substituted norbornenes,3 and other strained bicyclic systems give triazolines in high yields (eqs 1 and 2). The presence of functional groups such as primary amines on the alkene are known to interfere with the cycloaddition reaction.4

Cycloadditions with norbornenes usually proceed from the exo face, even in the case of a 7-substituted azanorbornene (eq 3),5 although exceptions have been reported.6 Unsymmetrical norbornenes exhibit poor regioselectivity (eq 2). The products of triazoline fragmentation under thermal conditions are not always predictable and both aziridines and imines can result, although there are occasional examples of good product selectivity. Other rearrangement products have also been observed (eq 4).7 However, photolysis of triazolines generally gives the aziridines in good yields, which are free of other side-products (eq 5).3 In many cases this thermolysis/photolysis route to aziridines is superior to the direct photolysis of ethyl azidoformate in the presence of an alkene. If aziridines are the desired products, the poor regioselectivity in the cycloaddition step is not a drawback since both regioisomeric triazolines lead to the same aziridine.

Cycloadditions of ethyl azidoformate with electron-rich alkenes are also expected to proceed readily, although few examples are known. The cycloadducts from the reaction of ethyl azidoformate with optically active enamines were subject to photolysis.8a a-Amino ketones were isolated in moderate yields, presumably derived from the ring opening of the initially formed aziridine (eq 6). Reaction of enol silanes with ethyl azidoformate has also been reported to give N-substituted a-amino ketones.8b However, under these conditions it is possible that the reaction may proceed through a nitrene intermediate.

Cycloaddition of ethyl azidoformate to unactivated, unstrained alkenes usually requires elevated temperatures (70-120 °C). Under such conditions, nitrenes may be generated, leading to products derived from the fragmentation of triazolines. For example, reaction of ethyl azidoformate with tetramethylethylene (solvent) at 72 °C gave four products (eq 7).9 The authors estimate that at least 60% of the aziridine was produced via the nitrene pathway.

Cycloadditions of ethyl azidoformate with alkynes and other triple bonds have also been attempted. The reaction with N,N-diaminopropyne, a ynamine, and Ethoxyacetylene has been reported to proceed at room temperature to give triazoles, although no yields were given.10 Reaction of ethyl azidoformate with tetramethylallene at 130 °C gave a 38% yield of the triazoline along with the oxazoline.11 The latter is probably derived from a nitrene intermediate. The reaction of ethyl azidoformate with stabilized phosphorus ylides has also been reported to give the corresponding triazoles in excellent yields.12

Generation and Reactions of Nitrenes.

Photolysis of ethyl azidoformate gives rise to ethoxycarbonylnitrene. Curtius rearrangement of azidoformates to give isocyanates under photolytic conditions (the photo-Curtius rearrangement) is a minor pathway. Depending on the conditions of photolysis, the nitrenes generated can react from either the singlet or the triplet state and the reactivity of the two species can be different. Nitrenes undergo two major reactions, insertion into single bonds and addition across double bonds. In many cases, both reactions occur, limiting the utility. Other side products can also be formed. The synthetic application of intermolecular C-H insertion of nitrenes is severely limited because of the poor selectivity of the nitrenes for different types of C-H bonds.13 Even intramolecular insertions of substituted azidoformates usually give a mixture of the possible insertion products and have hence found only rare application in synthesis.14 Insertion of nitrenes into aromatic and heteroaromatic rings has found some preparative value. Irradiation of ethyl azidoformate in benzene with UV light gives good yields of the azepine (eq 8),15 in contrast to the thermal process which gives a 40% yield.16

The addition of nitrenes to double bonds under photolytic conditions has found wider use. Singlet nitrenes add across alkenes stereospecifically. This reaction is applicable to many types of alkenes. Thus methoxycarbonylnitrene reacts with a strained alkene, Methylenecyclopropane, to give the azaspiropentane (eq 9).17 Reaction of ethoxycarbonylnitrene with an unactivated alkene, 3-Sulfolene, gives the aziridine which on thermal decomposition yields a divinyl carbamate (eq 10).18 Ethoxycarbonylnitrene has also been added to activated alkenes such as dihydropyrans19 and optically active silyl ketene acetals.20 In the latter case, the isolated products were N-carbonylethoxy a-amino esters, presumably formed by ring opening of the initial aziridine. Modest levels of asymmetric induction were obtained. In many cases the photolysis can be done below room temperature to minimize undesirable side reactions.

Ethoxycarbonylnitrene can also be generated from ethyl azidoformate by thermolysis, producing singlet nitrenes. Reaction of ethoxycarbonylnitrene with an electron-deficient alkene gives the aziridine in good yield (eq 11).21

The reaction of ethoxycarbonylnitrene with Diphenylacetylene gives the corresponding oxazole in 33% yield (eq 12).22 The mechanism of this reaction may proceed via a 1,3-dipole as shown or by a stepwise mechanism involving initial attack of the nitrene to produce a 1H-azirine. Aliphatic nitriles react in a similar manner under photolytic conditions to give the corresponding 5-ethoxyoxadiazoles.23 The reaction of ethyl azidoformate with 1,1-dimethylallene under photolytic conditions has been reported to occur regioselectively at the more substituted double bond to give the the oxazoline.11

Photochemical addition of ethoxycarbonylnitrene to isocyanides leads to the corresponding carbodiimides in moderate yields, which on hydrolysis give ureas.24 Addition of ethoxycarbonylnitrene to cobalt cyclopentadiene complexes has also been reported to give pyrroles, albeit in low yields.25

Other reagents such as p-Nitrobenzenesulfonyloxyurethane and N-ethoxycarbonyl-N,O-bis(trimethylsilyl)hydroxylamine26 have also been used as a source of ethoxycarbonylnitrene. The article on the urethane reagent should be consulted for further applications of ethoxycarbonylnitrene in organic syntheses.

Related Reagents.

t-Butyl Azidoformate; p-Nitrobenzenesulfonyloxyurethane.

1. (a) Scriven, E. F. V.; Turnbull, K. CRV 1988, 88, 297. (b) Lwowski, W. In Azides and Nitrenes; Scriven, E. F. V., Ed.; Academic: Orlando, 1984; pp 205. For a review on triazolines, see (c) Kadaba, P. K.; Stanovnik, B.; Tisler, M. In Advances in Heterocyclic Chemistry; Katritzky, A. R., Ed.; Academic: Orlando, 1984; Vol. 37, pp 219.
2. Tanida, H.; Tsuji, T.; Irie, T. JOC 1966, 31, 3941. Also see (b) Oehlschlager, A. C.; McDaniel, R. S.; Thakore, A.; Tillman, P.; Zalkow, L. H. CJC 1969, 47, 4367.
3. Nativi, C.; Reymond, J.-L.; Vogel, P. HCA 1989, 72, 882.
4. Oakland, J. S.; Scheinmann, F. JCS(P1) 1973, 800.
5. Sasaki, T.; Manabe, T.; Nishida, S. JOC 1980, 45, 479.
6. Kozlowska-Gramsz, E.; Hahn, W. E. Pol. J. Chem. 1985, 59, 493.
7. Crandall, J. K.; Crawley, L. C.; Komin, J. B. JOC 1975, 40, 2045.
8. (a) Fioravanti, S.; Loreto, M. A.; Pellacani, L.; Tardella, P. A. TA 1990, 1, 931. (b) Lociuro, S.; Pellacani, L.; Tardella, P. A. TL 1983, 24, 593.
9. Nicholas, P. P. JOC 1975, 40, 3396.
10. Ykman, P.; L'abbe, G.; Smets, G. CI(L) 1972, 886.
11. Bleiholder, R. F.; Shechter, H. JACS 1968, 90, 2131.
12. L'abbe, G.; Bestmann, H. J. TL 1969, 63.
13. (a) Breslow, D. S.; Prosser, T. J.; Marcantonio, A. F.; Genge, C. A. JACS 1967, 89, 2384. (b) Lwowski, W.; Maricich, T. J. JACS 1965, 87, 3630.
14. For recent examples, see (a) Berner, H.; Vyplel, H.; Schulz, G.; Stuchlik, P. T 1984, 40, 919. (b) Wright, J. J. K.; Albarella, J. A.; Lee, P. JOC 1982, 47, 523. For a review, see (c) Meth-Cohn, O. ACR 1987, 20, 18.
15. Hafner, K.; Konig, C. AG(E) 1963, 2, 96.
16. (a) Cotter, R. J.; Beach, W. F. JOC 1964, 29, 751. (b) Hafner, K.; Zinser, D.; Moritz, K.-L. TL 1964, 1733.
17. Aue, D. H.; Lorens, R. B.; Helwig, G. S. TL 1973, 4795.
18. (a) Meyers, A. I.; Takaya, T. TL 1971, 2609. For a similar approach toward the syntheses of N-substituted 1,4-dihydropyridines, see (b) Stout, D. M.; Takaya, T.; Meyers, A. I. JOC 1975, 40, 563.
19. (a) Kozlowska-Gramsz, E.; Descotes, G. CJC 1982, 60, 558. (b) Kozlowska-Gramsz, E.; Descotes, G. TL 1981, 22, 563. (c) Brown, I.; Edwards, O. E. CJC 1965, 43, 1266.
20. Loreto, M. A.; Pellacani, L.; Tardella, P. A. TL 1989, 30, 2975.
21. Hassner, A.; Anderson, D. J.; Reuss, R. H. TL 1977, 2463.
22. Huisgen, R.; Blaschke, H. TL 1964, 1409.
23. (a) Huisgen, R.; Blaschke, H. LA 1965, 686, 145. (b) Lwowski, W.; Hartenstein, A.; deVita, C.; Smick, R. L. TL 1964, 2497.
24. Kozlowska-Gramsz, E.; Descotes, G. TL 1982, 23, 1585.
25. Hong, P.; Yamazaki, H. JOM 1989, 373, 133.
26. Chang, Y. H.; Chiu, F.-T.; Zon, G. JOC 1981, 46, 342.
27. Lwowski, W.; Mattingly, Jr., T. W. JACS 1965, 87, 1947.

William H. Pearson & P. Sivaramakrishnan Ramamoorthy

University of Michigan, Ann Arbor, MI, USA

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