Hydrazoic Acid1

HN3

[7782-79-8]  · HN3  · Hydrazoic Acid  · (MW 43.04)

(adds electrophilically to alkenes, alkynes, and related conjugated systems;1c converts carboxylic acids to amines (Schmidt reaction)1 and alcohols to azides;11a cleaves epoxides;17 aminates arenes;19 affords sulfoximines from sulfoxides;21c reacts with a variety of other functional groups1a)

Solubility: sol halogenated hydrocarbons, Et2O, C6H6.

Preparative Methods: treatment of Sodium Azide with Sulfuric Acid or Polyphosphoric Acid;1a,2,3 hydrolysis of Azidotrimethylsilane.4

Handling, Storage, and Precautions: highly toxic; extremely explosive; use in a fume hood.

Addition to Unsaturated Systems.

Being a moderately weak acid (pKa = 4.69 at 25 °C5), HN3 has not been found to undergo electrophilic addition to alkenes except for phenyl-substituted cyclopropenes (eq 1)6 and electron-rich alkenes, such as vinyl ethers (eqs 2 and 3).3 With Lewis acid catalysis, it undergoes addition to styrenes and 1,1-dialkylalkenes (eq 4).3,7

Protic acid catalyzed additions of HN3 to alkenes have also been effected using Trifluoroacetic Acid, Trichloroacetic Acid, or Phosphoric Acid.8 However, azides readily undergo decomposition in the presence of Lewis acids and strong protic acids.8b,9 Moreover, the necessity of generating and handling the highly toxic and explosive HN3 limits the attractiveness of these methods. Recently it has been reported that silica gel and alumina mediate the addition of HN3 to styrenes, 1,3-dienes (eq 5), and 1,1-dialkylalkenes (eq 6) in the presence of an acid catalyst to give good to excellent yields of alkyl azides.4 Under these conditions, HN3 can be conveniently prepared in situ by hydrolysis of Azidotrimethylsilane over silica gel or alumina.

HN3 adds to enones and related conjugated systems (eq 7);1c,10 however, addition does not occur to a number of enones having a phenyl substituent at the b-position.10

Alkynes commonly undergo 1,3-dipolar addition of HN3 to afford triazoles; however, addition leads to azides in exceptional cases.1c

Schmidt Reaction.

Acid-catalyzed reaction of HN3 with carboxylic acids gives an amine with one less carbon atom.1 Typically the procedure involves generating HN3 in situ with NaN3 and excess H2SO4 in the presence of the substrate. Although preformed HN3 may be used, the presence of an acid catalyst is still required. The reaction is quite general, and the yields are often high for a variety of carboxylic acids, including aliphatic, aromatic, and sterically hindered systems (eq 8). Conditions can be controlled so that dicarboxylic acids yield either mono- or diamines as products.

Ketones and aldehydes similarly react with HN3 in the presence of H2SO4. Whereas reaction with aldehydes typically gives nitriles, ketones afford amides (eq 9). With 2 or more equiv of HN3, tetrazole products may be formed (eq 10), while imino esters are obtained in the presence of alcohols (eq 11). The different products arise through capture of a common intermediate.

Reaction with Alcohols.

Benzylic alcohols react with HN3 in the presence of an acid catalyst to give the corresponding benzylic azides.11 Typically HN3 is generated in situ through treatment of NaN3 with excess H2SO4, and the acid further catalyzes the substitution reaction. Moderate to good yields of triarylmethyl azides are formed from the corresponding triarylcarbinols, but diarylcarbinols such as 9-hydroxyfluorene give poorer yields due to further reaction of the azide with the acid catalyst. This problem can be circumvented by using the weaker acid Trichloroacetic Acid as catalyst (eq 12).8b,12 Tertiary alcohols are converted to tertiary azides by HN3 in the presence of H2SO4 as catalyst (eq 13).13

Acidic conditions in the substitution process can be avoided by subjecting primary and secondary alcohols to Mitsonobu conditions in the presence of HN3.14 Azides, with inverted stereochemistry at the carbon center, are formed in high yields (eq 14). A procedure has been developed in which alcohols are converted to azides via the Mitsonobu reaction and are then reduced to amines without prior isolation of the azide.15 This process allows for a one-pot conversion of alcohols to amines.

In a related reaction, tertiary alkyl halides react with HN3 in the presence of H2SO4 to give products derived from the corresponding tertiary azide.1a

Cleavage of Epoxides.

HN3, generated in situ through reaction of Me3SiN3 with MeOH, cleaves epoxides in cases in which attempted nucleophilic ring opening with azide ion fails (eq 15).16

In the presence of the Lewis acid Triethylaluminum, epoxides are efficiently cleaved under mild conditions in a regio- and stereospecific manner (eq 16).17 This method is successful for cases in which nucleophilic methods fail or give mixtures of products.

Reaction with Arenes.

Photolysis of HN3 in the presence of toluene results in formation of trace amounts of toluidine.18 Higher yields (65%) of amination products are obtained through reaction of HN3 with toluene in the presence of Aluminum Chloride.18,19 Reaction apparently occurs through a conventional electrophilic aromatic substitution mechanism, as revealed by the ratio of o-, m-, and p-substituted products formed. The use of H2SO4 as catalyst results in lower yields. Chlorobenzene can be similarly aminated in 19% yield.

Subjection of aryl-substituted alkanes to the oxidant 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) in the presence of HN3 results in regioselective oxidative nucleophilic substitution reactions to form benzylic azides (eq 17),20 which can be readily reduced to benzylic amines.

Aryl nitroso compounds react with HN3 under mild conditions to give aryl azides in high yields.1c

Formation of Sulfoximines.

The reaction of sulfoxides with HN3 gives sulfoximines in good yields (eq 18).21 Treatment of a series of appropriately substituted diaryl sulfoxides with HN3 (generated in situ) gives 1,2,4-benzothiadiazine 1-oxides in moderate to high yields via cyclization of the initially formed sulfoximines (eq 19).22 Interestingly, reaction of dialkyl sulfides with excess HN3 in the presence of H2SO4 also gives sulfoximines.21c,23

Reaction with Other Functional Groups.

The reactions of HN3 with various functional groups have been the subject of several reviews.1a,24 Several examples are shown in eqs 20-23. The ready reaction of HN3 with -C&tbond;N bonds affords convenient syntheses of a variety of substituted tetrazoles.

When subjected to HN3 in the presence of pyridine, acid chlorides are converted to acyl azides, which can then be converted to isocyanates in good yield.25

Cyclic imidates are converted in high yields to azido-substituted amides via reaction with HN3 generated in situ (eq 24).26 The method is mild, requiring no acid catalyst, and tolerates the presence of other functional groups.

A method for the overall conversion of ketones to amines has been reported.27 When the acetal or methyl ether derived from a ketone is subjected to HN3 in the presence of catalytic amounts of Trifluoroacetic Acid, a-alkoxy azides are formed, which are readily reduced to the amines with Lithium Aluminum Hydride in a one-pot procedure in good overall yields (eq 25).

Related Reagents.

Sodium Azide; Azidotrimethylsilane.


1. (a) Wolff, H. OR 1946, 3, 307. (b) Beckwith, A. L. J. In The Chemistry of Amides; Zabicky, J., Ed.; Interscience: New York, 1970; Chapter 2. (c) Biffin, M. E. C.; Miller, J.; Paul, D. B. In The Chemistry of the Azido Group; Patai, S., Ed.; Wiley: London, 1971; Chapter 2. (d) Shioiri, T. COS 1991, 6, 817.
2. Audrieth, L. F.; Gibbs, C. F. Inorg. Synth. 1939, 1, 77.
3. Hassner, A.; Fibiger, R.; Andisik, D. JOC 1984, 49, 4237.
4. Breton, G. W.; Daus, K. A.; Kropp, P. J. JOC 1992, 57, 6646.
5. McDonald, J. R.; Rabalais, J. W.; McGlynn, S. P. JCP 1970, 52, 1332.
6. Galle, J. E.; Hassner, A. JACS 1972, 94, 3930.
7. Pancrazi, A.; Khuong-Huu, Q. T 1974, 30, 2337.
8. (a) Balderman, D.; Kalir, A. S 1978, 24. (b) Ege, S. N.; Sherk, K. W. JACS 1953, 75, 354. (c) Schaad, R. E. U. S. Patent 2 557 924, 1951 (CA 1952, 46, 1028h).
9. Arcus, C. L.; Marks, R. E.; Vetterlein, R. CI(L) 1960, 1193.
10. Boyer, J. H. JACS 1951, 73, 5248.
11. (a) Arcus, C. L.; Mesley, R. J. JCS 1953, 178. (b) Saunders, W. H., Jr.; Ware, J. C. JACS 1958, 80, 3328.
12. Arcus, C. L.; Marks, R. E.; Coombs, M. M. JCS 1957, 4064.
13. Logothetis, A. L. JACS 1965, 87, 749.
14. Kanda, Y.; Fukuyama, T. JACS 1993, 115, 8451.
15. Fabiano, E.; Golding, B. T.; Sadeghi, M. M. S 1987, 190.
16. Saito, S.; Bunya, N.; Inaba, M.; Moriwake, T.; Torii, S. TL 1985, 26, 5309.
17. Mereyala, H. B.; Frei, B. HCA 1986, 69, 415.
18. Keller, R. N.; Smith, P. A. S. JACS 1944, 66, 1122.
19. Kovacic, P.; Russell, R. L.; Bennett, R. P. JACS 1964, 86, 1588.
20. Guy, A.; Lemor, A.; Doussot, J.; Lemaire, M. S 1988, 900.
21. (a) Johnson, C. R.; Rogers, P. E. JOC 1973, 38, 1793. (b) Misani, F.; Fair, T. W.; Reiner, L. JACS 1951, 73, 459. (c) Whitehead, J. K.; Bentley, H. R. JCS 1952, 1572.
22. Cohnen, E.; Mahnke, J. CB 1972, 105, 757.
23. Hayashi, K. CPB 1960, 8, 177.
24. (a) Lieber, E.; Pillai, C. N.; Hites, R. D. CJC 1957, 35, 832. (b) Braun, J. V.; Keller, W. CB 1932, 65, 1677. (c) Benson, F. R. CRV 1947, 41, 1.
25. (a) van Reijendam, J. W.; Baardman, F. S 1973, 413. (b) See also Yajima, H.; Kawatani, H. CPB 1968, 16, 182.
26. Saito, S.; Tamai, H.; Usui, Y.; Inaba, M.; Moriwake, T. CL 1984, 1243.
27. Kyba, E. P.; John, A. M. TL 1977, 2737.

Gary W. Breton & Paul J. Kropp

University of North Carolina, Chapel Hill, NC, USA



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