Tri-n-butyltin Azide1


[17846-68-3]  · C12H27N3Sn  · Tri-n-butyltin Azide  · (MW 332.13)

(nucleophilic azide equivalent; useful for the preparation of tetrazoles and triazoles via 1,3-dipolar cycloaddition reactions;2 cleaves oxiranes to give 1,2-azido alcohols;3 reacts with anhydrides and acid chlorides to give isocyanates4)

Alternate Name: azidotributylstannane.

Physical Data: bp 118-120 °C/0.18 mmHg.4,5

Solubility: sol most nonprotic organic solvents (i.e. toluene, hexane, acetonitrile, THF, etc.).

Preparative Method: prepared in 91% yield by the reaction of Tri-n-butylchlorostannane with aqueous Sodium Azide at 0 °C.4,5

Purification: distillation.4,5

Handling, Storage, and Precautions: organotin derivatives are known to be toxic.6 Avoid inhalation and contact with skin. Organotin azides are claimed to be thermally very stable.2a However, extreme caution should be exercised when heating an azide solution due to the possibility of explosion. Use in a fume hood.

Preparation of Tetrazoles.

The reaction of tributyltin azide with nitriles serves as one of the most convenient and versatile methods for the preparation of tetrazoles.2a The reaction proceeds via a 1,3-dipolar cycloaddition to give directly a 5-tributyltin-substituted tetrazole (eq 1). The Sn-N bond is readily cleaved by treatment with Hydrochloric Acid to give the free tetrazole and Bu3SnCl. In general, reactions are carried out under inert atmosphere either neat or in solvents such as acetonitrile, 1,2-dimethoxyethane, THF, benzene, toluene, and xylene. Reaction temperature and duration are largely dependent on steric and electronic factors associated with the nitrile substrate.2a

Tributyltin azide has been used in the synthesis of many complex molecules of pharmaceutical interest where a tetrazole is desired as a carboxylic acid bioisostere. Examples that illustrate the use of this reagent include application to the synthesis of an HMG-CoA reductase inhibitor (eq 2),7 NMDA antagonist (eq 3),8 leukotriene receptor antagonist (eq 4),9 and a peptide inhibitor of vitamin K dependent carboxylation (eq 5).10

Additionally, tributyltin azide has been used in the preparation of a key biphenyltetrazole intermediate employed in the synthesis of angiotensin II receptor antagonists (eq 6).11,12 It was found that treatment of the tin adduct with Sodium Hydroxide followed by trityl chloride led directly to the highly crystalline trityl-protected tetrazole.12 This modification facilitates isolation of the tetrazole that is generally made difficult by the presence of organic soluble tin residues.

In a similar manner to that described for nitriles, tributyltin azide reacts with isothiocyanates to yield thiotetrazoles upon acidic workup (eq 7).2d,e A comparison of tributyltin azide with other methods for tetrazole synthesis has been published.12

Preparation of 1,2,3-Triazoles.

Tributyltin azide reacts with mono- and disubstituted alkynes via a 1,3-dipolar cycloaddition reaction to yield tributyltin-substituted 1,2,3-triazoles (eqs 8 and 9).2b,c As with tetrazoles, the Sn-N bond is readily cleaved by treatment with HCl to give the triazole N-H derivative.

Preparation of Isocyanates, Carbamates, and Ureas.

Tributyltin azide reacts with acid chlorides under mild conditions to give isocyanates.4 In a one-pot procedure, the isocyanate can be treated with an amine or alcohol to yield a urea (eq 10) or carbamate (eq 11), respectively. Anhydrides can be used in place of acid chlorides. This method serves as an alternative to using Azidotrimethylsilane.13

Preparation of 1,2-Azido Alcohols.

In contrast to trimethylsilyl azide, tributyltin azide is very reactive toward nucleophilic ring cleavage of oxiranes leading to 1,2-azido alcohols.3 Reactions are typically carried out neat at 60 °C. The rate of reaction is highly dependent on the structure of the oxirane. Simple, nonsterically hindered oxiranes react rapidly (eq 12), while those with neighboring alkoxy groups (eq 13) or ester functions (eq 14) require longer reaction times. This difference in reactivity is attributed to modulation of the Lewis acidity of the tin species by the neighboring oxygen functionality.

One limitation of this method is the difficulty of removing organotin residues from the reaction products. This has partially been addressed by studying a catalytic system using 10 mol % tributyltin azide and trimethylsilyl azide.3a Additionally, the use of dibutyltin diazide in place of tributyltin azide in nucleophilic cleavage of oxiranes has been reported to circumvent some of the problems associated with product isolation, as well as displaying enhanced reactivity.3b

1. Pereyre, M.; Quintard, J.-P.; Rahm, A. Tin in Organic Synthesis; Butterworths: London, 1987; p 310.
2. (a) Sisido, K.; Nabika, K.; Isida, T.; Kozima, S. JOM 1971, 33, 337. (b) Kozima, S.; Itano, T.; Mihara, N.; Sisido, K.; Isida, T. JOM 1972, 44, 117. (c) Hitomi, T.; Kozima, S. JOM 1977, 127, 273. (d) Dunn, P.; Oldfield, D. AJC 1971, 24, 645. (e) Deeth, R. J.; Molloy, K. C.; Mahon, M. F.; Whittaker, S. JOM 1992, 430, 25.
3. (a) Saito, S.; Yamashita, S.; Nishikawa, T.; Yokoyama, Y.; Inaba, M.; Moriwake, T. TL 1989, 30, 4153. (b) Saito, S.; Nishikawa, T.; Yokoyama, Y.; Moriwake, T. TL 1990, 31, 221. (c) Guy, A.; Dubuffet, T.; Doussot, J.; Godefroy-Falguieres, A. SL 1991, 403.
4. Kricheldorf, H. R.; Leppert, E. S 1976, 329.
5. Luijten, J. G. A.; Janssen, M. J.; van der Kerk, G. J. M. RTC 1962, 81, 202.
6. Pereyre, M.; Quintard, J.-P.; Rahm, A. Tin in Organic Synthesis; Butterworths: London, 1987; pp 6-7, and references cited therein.
7. Balasubramanian, N.; Brown, P. J.; Catt, J. D.; Han, W. T.; Parker, R. A.; Sit, S. Y.; Wright, J. J. JMC 1989, 32, 2038.
8. Ornstein, P. L.; Schoepp, D. D.; Arnold, M. B.; Augenstein, N. K.; Lodge, D.; Millar, J. D.; Chambers, J.; Campbell, J.; Paschal, J. W.; Zimmerman, D. M.; Leander, J. D. JMC 1992, 35, 3547.
9. Dillard, R. D.; Carr, F. P.; McCullough, D.; Haisch, K. D.; Rinkema, L. E.; Fleisch, J. H. JMC 1987, 30, 911.
10. Dubois, J.; Bory, S.; Gaudry, M.; Marquet, A. JMC 1984, 27, 1230.
11. Carini, D. J.; Duncia, J. V.; Aldrich, P. E.; Chiu, A. T.; Johnson, A. L.; Pierce, M. E.; Price, W. A.; Santella, J. B., III; Wells, G. J.; Wexler, R. R.; Wong, P. C.; Yoo, S.-E.; Timmermans, P. B. M. W. M. JMC 1991, 34, 2525.
12. Duncia, J. V.; Pierce, M. E.; Santella, J. B., III JOC 1991, 56, 2395.
13. Kricheldorf, H. R. S 1972, 551.

Alan D. Palkowitz, K. Jeff Thrasher, & Kenneth L. Hauser

Lilly Research Laboratories, Indianapolis, IN, USA

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