t-Butyl Azidoformate

[1070-19-5]  · C5H9N3O2  · t-Butyl Azidoformate  · (MW 143.15)

(electron-deficient azide; can undergo cycloadditions with alkenes to yield triazolines;1 used for the introduction of a t-Boc group on alcohols and amines)

Physical Data: bp 57-61 °C/40 mmHg; n24 1.4224-1.4230.

Solubility: freely sol common organic solvents.

Analysis of Reagent Purity: 1H NMR.

Preparative Methods: see Insalaco and Tarbell.10

Handling, Storage, and Precautions: as with all azides of low molecular weight, t-butyl azidoformate is sensitive to both heat and shock. It is usually purified by distillation under reduced pressure and detonation under these conditions has been reported.2 All operations involving this reagent should be carried out with great caution in a fume hood and behind a safety shield. The vapors of this reagent are toxic and inhalation is known to cause giddiness, nausea, and severe headache. It is recommended that the reagent be used immediately after preparation. The original literature should be thoroughly consulted before preparation and use of this reagent.

Introduction.

t-Butyl azidoformate is prepared by the reaction of t-butylcarbonic diethylphosphoric anhydride and potassium azide.10 Other preparations involve the reaction of t-butyl carbazate with nitrous acid,3 and the reaction of t-Butyl Chloroformate with tetramethylguanidinium azide.4 t-Butyl azidoformate has been used in three broad classes of reactions: for the generation and reactions of the corresponding nitrenes, for the cycloaddition of the azide moiety to alkenes and other unsaturated groups, and for the t-butyloxycarbonylation of a wide variety of functional groups.

t-Butoxycarbonylnitrenes.

The nitrenes can be generated from t-butyl azidoformate both by thermolysis and photolysis. The synthetic utility of these nitrenes is limited because they often react by a variety of pathways to give a mixture of products. One of the few useful reactions involves heating t-butyl azidoformate in DMSO to give the corresponding sulfoximides via the nitrene (eq 1).5

Cycloaddition Reactions.

t-Butyl azidoformate has been used only sparingly in cycloadditions to alkenes. Azidoformates usually begin to decompose above 60 °C and only cycloadditions that proceed readily below this temperature are synthetically useful. This requirement has limited the cycloaddition partners to strained and/or electron-rich alkenes. The D2-triazolines formed may be isolated or subjected to irradiation directly to give the aziridines. Cycloadditions to strained alkenes often proceed in high yields but with poor regioselectivity. However, if aziridines are the desired products, the poor regioselectivity in the cycloaddition is not a drawback since both regioisomeric triazolines lead to the same aziridine. Heating the substituted 7-oxabicyclo[2.2.1]hept-2-ene with t-butyl azidoformate in the dark followed by irradiation of the crude mixture of regioisomeric triazolines gives the aziridine in 63% yield (eq 2).6

t-Butoxycarbonylation.

t-Butyl azidoformate has been used for the t-butoxycarbonylation of a variety of functional groups such as alcohols, phenols, and amines.7 Eq 3 illustrates the use of this reagent for the t-butoxycarbonylation of an amine.7a The mild conditions of the reaction coupled with the importance of the t-Boc functionality as a protecting group has made the reagent popular and it has found widespread use in peptide chemistry.8 The t-butoxycarbonylation of pyrroles and indoles has also been accomplished using this reagent.9 However, in recent years, other commercially available compounds have replaced t-butyl azidoformate as the reagent of choice for such reactions in view of the potentially explosive properties of the latter.

Related Reagents.

1-(t-Butoxycarbonyl)imidazole; 1-N-(t-Butoxycarbonyl)-1H-benzotriazole 3-N-Oxide; 2-(t-Butoxycarbonyloxyimino)-2-phenylacetonitrile; N-(t-Butoxycarbonyloxy)phthalimide; 1-t-Butoxycarbonyl-1,2,4-triazole; Di-t-butyl Dicarbonate.


1. (a) Lwowski, W. In Azides and Nitrenes; Scriven, E. F. V., Ed.; Academic: Orlando, 1984; p 205. For a review on triazolines, see (b) Kadaba, P. K.; Stanovnik, B.; Tisler, M. Adv. Heterocycl. Chem. 1984, 37, 217.
2. Feyen, P. AG(E) 1977, 16, 115.
3. Carpino, L. A.; Carpino, B. A.; Crowley, P. J.; Giza, C. A.; Terry, P. H. OSC 1973, 5, 157.
4. Sakai, K.; Anselme, J.-P. JOC 1971, 36, 2387.
5. Kirby, G. W.; McGuigan, H.; MacKinnon, J. W. M.; McLean, D.; Sharma, R. P. JCS(P1) 1985, 1437.
6. (a) Vogel, P.; Allemann, S. S 1991, 923. For other examples, see (b) Nativi, C.; Reymond, J.-L.; Vogel, P. HCA 1989, 72, 882. (c) Reymond, J.-L.; Vogel, P. TL 1988, 29, 3695. (d) Christl, M.; Leininger, H. TL 1979, 1553.
7. (a) Lofthouse, G. L.; Suschitzky, H.; Wakefield, B. J.; Whittaker, R. A. JCS(P1) 1979, 1634. Also see (b) Jacob, III, P.; Callery, P. S.; Shulgin, A. T.; Castagnoli, Jr., N. JOC 1976, 41, 3627.
8. (a) Chakravarty, P. K.; Olsen, R. K. JOC 1978, 43, 1270. (b) Fridkin, M.; Goren, H. J. CJC 1971, 49, 1578. (c) Polzhofer, K. P. TL 1969, 2305.
9. Hasan, I.; Marinelli, E. R.; Lin, L.-C. C.; Fowler, F. W.; Levy, A. B. JOC 1981, 46, 157.
10. Insalaco, M. A.; Tarbell, D. S. OSC 1988, 6, 207.

William H. Pearson & P. Sivaramakrishnan Ramamoorthy

The University of Michigan, Ann Arbor, MI, USA



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