Azidation Polymer1

(used for nucleophilic substitution of azide for halide or sulfonate;1-6 for introduction of the azide function1-6)

Physical Data: polymeric resin in form of beads.2

Solubility: insol organic solvents, water.

Form Supplied in: available as azide exchange resin, containing ~3.8 mequiv azide ions per gram of resin.

Preparative Methods: the azidation polymer is prepared2 from Amberlite IR-400 Cl-ion exchange resin (a quaternary ammonium chloride), which is prewashed first with 1.5 times its volume of warm DMF, twice with MeOH, and finally with water. Then the resin is converted into the azide form by washing with twice its volume of 20% aq sodium azide, followed by three washings with deionized water until the eluents give no precipitate with AgNO3 (eq 1). To remove adhered water (which may lead to alcohol product), the resin is washed three times each with 30% MeOH, 60% MeOH, MeOH, 50% MeOH-ether, and ether (or another organic solvent to be used in the nucleophilic substitution reaction). The resin is dried at rt in vacuum and contains ~2.55 mmol azide ions per gram of polymer.

Handling, Storage, and Precautions: the polymer can be stored for several months, preferably either wet with water or wet with the last washing solvent. It is stable to the hammer test and has a friction parameter of 14.4 kg. It should not be treated with acids because toxic HN3 is formed. Caution: when CH2Cl2 is used as a solvent for the displacement reaction and the reaction is allowed to proceed for several days, explosive CH2(N3)2 may be formed.2 Handle reagent in a fume hood.

Synthesis of Alkyl Azides.

A typical procedure for nucleophilic displacement of alkyl halides or tosylates with azide ions:1 to 4.9 g of azidation polymer (12.5 mmol of azide ions) was added 4 mL of CH2Cl2 (see above) or another solvent and 0.265 g (1.06 mmol) of p-bromobenzyl bromide. The reaction is followed for disappearance of starting benzyl bromide and after 2 h of mild shaking of the slurry in an horizontal cuvette the polymer is filtered and washed with CH2Cl2. Mechanical stirring of the slurry of azidation polymer and substrate is not recommended because shearing of the polymer beads occurs. Evaporation of the combined solvents gave pure (by 1H NMR) p-bromobenzyl azide as an oil in 93% yield.

The use of azidation polymer permits displacement of alkyl halides or tosylates by azide ions at room temperature in any organic solvent, usually within hours, as the reaction is followed to the disappearance of starting alkyl halide.1 After filtration of the polymeric reagent, a solution of pure alkyl azide is obtained. Further purification is usually not necessary. Iodides are displaced faster than bromides, which react faster than tosylates; alkyl chlorides react slowest.1 In polar solvents (MeCN, DMF) the displacement is faster than in less polar solvents (CHCl3, ether) and secondary halides react slower than primary ones.1 The more dilute the slurry, the slower the reaction. Even bromoform is converted at rt slowly (22 days for 50% conversion) to highly explosive triazidomethane.2

In MeCN, quantitative conversion of n-Bu-X to n-Bu-N3 takes place at rt by means of the azidation polymer in the following approximate times:1 n-Bu-I (1 h), n-Bu-Br (3 h), n-Bu-OTs (24 h), n-Bu-Cl (>7 d), Br-(CH2)4-Br (24 h).

Benzyl chloroformate is converted to benzyl azidoformate at rt.1 Allyl azides can be prepared readily from allyl bromides using the reagent. For instance, 5-bromo-1,3-pentadiene is converted in 95% yield to 5-azido-1,3-pentadiene.3

o-Azido-4-methoxyacetophenone is obtained from the respective phenacyl bromide.4 Anhydrothymidine after N-alkyl-ation with ethyl triflate followed by reaction with the azidation reagent at 0 °C for 16 h gave the 4-azido- and 2-azidothymidine derivatives (eq 3).5 1,2-cis-Diols have been converted to 1,2-cis-azido alcohol benzoates via the trans-chlorohydrin benzoate.6

1. Hassner, A.; Stern, M. AG(E) 1986, 25, 478.
2. Hassner, A.; Stern, M.; Gottlieb, H. E.; Frolow, F. JOC 1990, 55, 2304.
3. Molina, P.; Alajarin, M.; Lopez-Leonardo, C.; Alcantara, J. T 1993, 49, 5153.
4. Molina, P.; Fresneda, P. M.; Almendros, P. H 1993, 36, 2255.
5. Goulaouic, C.; Adams, D. R.; Chiaroni, A.; Riche, C.; Grierson, D. S. JOC 1993, 58, 3030.
6. Lakshman, M. K.; Sayer, J. M.; Jerina, D. M. JOC 1992, 57, 3438.

Alfred Hassner

Bar-Ilan University, Ramat-Gan, Israel

Copyright 1995-2000 by John Wiley & Sons, Ltd. All rights reserved.