Synthesis of Azides

Department of Chemistry, University of Coimbra, 3004-535 Coimbra, Portugal 

Here an overview is provided of the more relevant synthetic methods for the preparation of organic azides. 

1 Classic Nucleophilic Substitutions Azides from Halides, Sulfonates, 

Among the varions possibilities for preparing alkyl azides, classic nucleophilic substitutions are of special importance. Alkali metal azides, mainly sodium azide, are commonly 

Organic Azides Syntheses and Applications Edited by Stefan Erase and Klaus Banert 2010 John Wiley Sons, Ltd. ISBN 978-0-470-51998-1 

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Tyagi YK (2000) Studies on the synthesis of azides and heterocyclic triazoles and investigation on biotransformation of polyphenols. Thesis. CCS University, Meerut... 

A major side reaction in the synthesis of azides is the formation of amides. This was detected for the first time in the preparation of Z-Lys(Z)-N3 via the NaN02/HCl procedure where Z-Lys(Z)-NH2 was obtained as a side product. " Sinnilarly, in the case of Z-Cys(Bzl)-N3 the related amide is readily formed.b ] As this side reaction does not occur when the azide is prepared from the acid chloride and sodium azide, it was proposed that the mechanism involves cleavage of the nitrosated hydrazide as shown in Scheme 6.h l... 

In recent reviews of the chemistry of organic azido compounds attention has been focused mainly on the reactions rather than the synthesis of azides ". The last comprehensive account of the introduction of the azido group was published by Boyer and Canter in 1954 and for the purposes of this chapter we have concerned ourselves primarily with developments subsequent to this review. Reference to work cited in the review of Boyer and Canter is made only where it is pertinent to the discussion. Because of the very large number of azide syntheses described in the chemical literature no attempt has been made at an encyclopaedic coverage. Instead, each major synthetic method has been discussed from a mechanistic viewpoint with representative examples being used as illustration. Only reactions in which a carbon-azide bond is formed are considered reactions in which organic azides are implicated as intermediates but are not isolated, e.g. the Schmidt reaction, were deemed to be outside the scope of this chapter. 

B. Synthesis of Azides by Nucleophilic Substitution I. Aliphatic and alicyclic azides... 

Table 5. Synthesis of azides by hydrazoic acid additions to conjugated olehns...

V. SYNTHESIS OF AZIDES FROM DIAZOTIZATION AND RELATED REACTIONS... 

Table 14. Synthesis of azides from aromatic nitroso compounds and hydrazoic acid...

An electro-oxidation procedure developed by Wright for the synthesis of azides from salts of carboxylic acids or nitroalkanes (equations 147, 148) has been briefly referred to by Smith in a recent review . ... 

Reactions of this type were first studied by Curtius and co-workers . For example, diethyl malonate and /(-toluenesulphonyl azide reacted in the presence of cold sodium ethoxide to give the sodium salt of the 5-hydroxytrizizole (296) . Acidification gave the 5-triazolone (297) which isomerized to the diazo compound (298) (overall yield 90%). (The same product could be obtained in 85% yield without base by heating the azide and malonate at 100° and a pressure of 20 mm) . This reaction provided the basis for the so-called diazo-transfer reaction, an extremely useful method of synthesizing diazo compounds, which has been reviewed. The reaction has been formulated as shown in equation (134), and has been extended to the synthesis of azides by a diazo transfer to amine anions/i-Toluenesulphonyl azide reacts with hydrazone... 

A MW-assisted protocol for the synthesis of azides, thiocyanates, and sulfones has been developed (Scheme 12) that has proved to be a useful alternative, as the use of environmentally deterimental volatile chlorinated hydrocarbons is avoided.All the reactions with these readily available halides or tosylates have shown significant increase in reactivity, thus reducing the reaction times with substantial improvement in the yields. Various functional groups such as ester, carboxylic acid, carbonyl, and hydroxyl were unaffected under the mild reaction conditions employed. This method involves simple experimental procedures and product isolation which avoids the use of phase-transfer catalysts, and is expected to contribute to the development of greener strategy for the preparation of various azides, thiocyanates, sulfones, and other useful compounds. 

Scheme 8.31 Synthesis of azides, thiocyanates and sulfones in aqueous medium.

This MW-assisted synthesis of azides, thiocyanates and sulfones proved to be a useful alternative that avoids the use of environmentally detrimental volatile chlorinated hydrocarbons. Various functional groups such as ester, carboxylic acid, carbonyl and hydroxyl were unalTected under the mild reaction conditions employed. ... 

The initial intent to cover the subject exhaustively had to be abandoned because of the overwhelming amount of relevant literature. The following reactions are not covered but are briefly discussed, with references to reviews and seminal papers, in the section on Comparison with Other Methods reactions of carbanions and enolates and their surrogates with nitrogen oxides, nitrite and nitrate esters, and nitroso and nitro compounds reactions of enolates with diazonium salts, including the Japp-Klingemann reaction the diazo transfer reaction except as it interferes with the synthesis of azides the animation of boranes and the Neber rearrangement. 

Kuse M, Doi 1, Kondo N, Kageyama Y, Isobe M. Synthesis of azide-fluoro-dehydrocoelenterazine analog as a photoaffinity-labeling probe and photolysis of azide-fluoro-coelenterazine. Tetrahedron 2005 61 5754-62. 

The possibility of practical synthesis of azides from amines, which emerged about a decade ago [123], recently attracted considerable attention [107,112] and was successfully applied for the syntheses of mono- and disaccharide analogs of Dau bearing the azidopyranose moiety. 

Nitrous acid (a source of dinitrogen trioxide) is a well-known reagent for the synthesis of azides. The mechanism for the conversion of hydrazides is similar to the diazotization of primary amines with nitrous acid ... 

Synthetic approaches to the synthesis of azides directly from alcohols are known and include the use of NaN3/BF3-Et20, HNsAIiCh and NaNs/triphosgene. Conversion of... 

An extensive review on the use of hexadecyltributylphosphonium azide [n-Ci6H33(n-C4H9)3PN3] for the synthesis of unusual azides has been published recently. This highly potent reagent allows extremely rapid nucleophilic substitution reactions and is appropriate for the synthesis of azides from unstable starting materials and compounds with stetic hindrance or with internal strain. 

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