Azidoacetyl Chloride1

[30426-58-5]  · C2H2ClN3O  · Azidoacetyl Chloride  · (MW 119.52)

(a-amino carbonyl equivalent suitable for the synthesis of amino azetidinones, has been widely used in the synthesis of b-lactam antibiotics;1-3 can also be used to acylate a variety of nucleophiles to give amino acid derivatives4,5)

Alternate Name: AAC.

Physical Data: bp 50 °C/20 mmHg.

Solubility: sol most chlorinated and nonchlorinated organic solvents.

Preparative Methods: prepared by azide displacement of halide from the corresponding haloacetic acid, followed by treatment with Thionyl Chloride.6,7

Handling, Storage, and Precautions: a-azido carbonyls have been identified as explosives and, as such, should be treated with extreme caution.7,8 Use in a fume hood.

b-Lactams.

The formation of azetidinones from the addition of acid chlorides or bromides to imines was reported by Staudinger in the early 1900s,9 but this reaction attracted relatively little attention until it became associated with the synthesis of b-lactam antibiotics. The use of azidoacetyl chloride (AAC) to make amino azetidinones, first demonstrated in 1966 by Bose et al. (eq 1),10 was rapidly adopted by a number of industrial groups as one step in the synthesis of commercially important b-lactams (eq 2).11,12 The rapid development of bacterial resistance created a demand for new antibiotics and since these initial reports AAC has been shown to react with imidates,13 imines,14,15 acyclic16,17 and cyclic thioimidates, and related systems to give naturally occurring, synthetic, bicyclic, and monocyclic b-lactams. The experimental procedure is very simple, involving treatment of the acid chloride and imine with Triethylamine at or below rt, and appears to have changed little from that originally reported.10 Because of the danger associated with the preparation of AAC, other derivatives of azidoacetic acid suitable for [2 + 2] cycloadditions have also been prepared.18,19

The relative stereochemistry about the C-3-C-4 bond of the azetidinone appears to depend both on the imine and the experimental procedure used. Predominantly or exclusively trans adducts are observed from additions to thioformimidates,20 thiazolines, or thiazines (eq 3),21,22 and the active configuration of the b-lactam must be obtained via epimerization.21,22 On the other hand, aldimines give cis-azetidinones as the major products.14,23

The mechanism of the reaction could involve either a simple [2 + 2] cycloaddition or an imine acylation followed by ring closure.3,15,24 This is not well understood, and the mechanism may vary with individual examples.


1. Ghosez, L.; Marchand-Brynaert, J. COS 1991, 5, 85.
2. Holden, K. G. In Chemistry and Biology of b-Lactam Antibiotics; Morin, R. B.; Gorman, M., Eds; Academic Press: New York, 1982; Vol. 2, p 99.
3. Georg, G. I.; Ravikumar, V. T. The Organic Chemistry of b-Lactams; VCH: New York, 1993; p 296.
4. DeWald, H. A.; Lobbestael, S.; Butler, D. E. JMC 1977, 20, 1562.
5. Mulliez. M. BSF(2) 1985, 1211.
6. Hoppe, D.; Kloft, M. LA 1980, 1512.
7. Ojima, I.; Zhao, M.; Yamato, T.; Nakahashi, K.; Yamashita, M.; Abe, R. JOC 1991, 56, 5263.
8. Bretherick, L. Handbook of Reactive Chemical Hazards, 3rd ed.; Butterworth: London, 1985; pp 231, 1456.
9. Staudinger, H. LA 1907, 356, 51.
10. Bose, A. K.; Anganeyulu, B. CI(L) 1966, 903.
11. Ratcliffe, R. W.; Christensen, B. G. TL 1973, 4649.
12. Edwards, J. A.; Guzman, A.; Johnson, R.; Beeby, P. J.; Fried, J. H. TL 1974, 2031.
13. Just, G.; Tsantrizos, Y. S.; Ugolini, A. CJC 1981, 59, 2981.
14. Ogasa, T.; Saito, H.; Hashimoto, Y.; Sato, K.; Hirata, T. CPB 1989, 37, 315.
15. Doyle, T. W.; Belleau, B.; Luh, B.-Y.; Ferrari, C. F.; Cunningham, M. P. CJC 1977, 55, 468.
16. Anderson, D. W.; Campbell, M. M.; Malik, M.; Prashad, M.; Wightman, R. H. TL 1990, 31, 1759.
17. Hoppe, D.; Schmincke, H.; Kleemann, H.-W. T 1989, 45, 687.
18. Finkelstein, J.; Holden, K. G.; Sneed, R.; Perchonock, C. D. TL 1977, 1855.
19. Manhas, M. S.; Bose, A. K.; Khajavi, M. S. S 1981, 209.
20. Bachi, M. D.; Vaya, J. JOC 1979, 44, 4393.
21. Firestone, R. A.; Maciejewicz, N. S.; Ratcliffe, R. W.; Christensen, B. G. JOC 1974, 39, 437.
22. Watanabe, T.; Kawano, Y.; Tanaka, T.; Hashimoto, T.; Miyadera, T. CPB 1980, 28, 62.
23. Just, G.; Liak, T.-J. CJC 1978, 56, 211.
24. Bose, A. K.; Chiang, Y. H.; Manhas, M. S. TL 1972, 4091.

Arun Ghosh, Marvin J. Miller, Stewart K. Richardson, & Gordon C. Savela

University of Notre Dame, IN, USA



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