Iodine Azide1

IN3

[14696-82-3]  · IN3  · Iodine Azide  · (MW 168.93)

(additions to multiple bonds;1-4 regioselective and stereoselective introduction of the azide function1-3 and other nitrogen functions including amines; synthesis of aziridines5 and azirines6)

Physical Data: dark crystals;7 explosive when neat.

Solubility: sol most organic solvents.

Form Supplied in: not available commercially; prepared in situ in solution.

Preparative Methods: the first reported preparation7 from AgN3 and I2 is not recommended. IN3 can be prepared in situ from Sodium Azide and Iodine Monochloride preferably in MeCN,2 DMF, ether, or CH2Cl2.2,3 It can also be prepared from TlN3 and ICl3c in MeCN or CH2Cl2,3 or from N-Iodosuccinimide and Hydrazoic Acid in CH2Cl2.3 The following is a typical procedure for addition to alkenes:2 to a slurry of 15.0 g (0.25 mol) of NaN3 in 100 mL of MeCN at -10 to 0 °C is added, over 10-20 min, 18.3 g (0.113 mol) of ICl neat or in MeCN. After 10-20 min of further stirring, 0.1 mol of alkene is added neat or in MeCN and the mixture is warmed to 20 °C and stirred for 8-24 h. The red-brown slurry is poured into 250 mL of water and extracted three times with 85 mL portions of ether. The combined ether fractions are washed with 5% aq sodium thiosulfate until colorless (see precautions), then with water, and dried. Removal of the solvent in vacuo is followed by chromatography (neutral alumina) to afford the iodo azide adduct in 80-90% yield.

Handling, Storage, and Precautions: solutions of IN3 in MeCN can be stored in the refrigerator for 1 d. Explosions have been reported on evaporation of solutions of IN3 to dryness. Therefore, after reaction with multiple bonds, the mixture should be washed with sodium bisulfite until colorless to destroy excess IN3 reagent. Violent reaction can also occur on addition of IN3 to alkenes containing low-valent S-functions. An explosion shield should be used when handling this reagent. Operations should be conducted in a fume hood.

Additions to Alkenes.

Addition of IN3 to alkenes (see also Bromine Azide) usually proceeds via a three-membered ring iodonium species, resulting from attack of I+ on the double bond. The reaction is highly stereoselective (anti) and regioselective. Thus cis- and trans-2-butene give stereospecifically the threo and erythro adducts, respectively. The azide-carbon bond usually forms at the more substituted carbon or the one better able to support a positive charge in the transition state. trans-1-Phenylpropene gives, stereo- and regiospecifically, erythro-1-azido-2-iodo-1-phenylpropane (eq 1). Anti elimination of HI from the adduct leads to a vinyl azide.4a However, steric hindrance can influence the position of attack by azide ion. Thus t-butylethylene affords the terminal azide (eq 2).2b

The structure of the adduct with phenylcyclohexene has been questioned8a but it has been proven to be the one expected (eq 3).8b,c With 2-cholestene the trans diaxial adduct, 2b-azido-3a-iodocholestane, results from the a-iodonium species,1,2 but products from b-attack on other steroid alkenes are also known.9a In rare cases, syn addition has been reported,9 for instance to strained cyclobutenes.9b,c

Addition of IN3 to conjugated ketones can lead to a mixture of regiosomers, sometimes depending on the presence of oxygen or on the method of generation of the reagent.3,4 In such cases the addition can proceed via a radical mechanism,3,11 in which the azide radical rather than I+ is the attacking species and different regioisomers can result.3 For instance, cyclopentenone affords 2-iodo-2-cyclopentenone, while cyclohexenone gives a mixture of products.3e

Enantioselective addition of IN3 to conjugated amides derived from sultams or oxazolidones as chiral auxiliaries has been reported.10 Although diastereoselection only averages 34% (eq 4), crystallization raises this to 94%.

Enol ethers, as expected, give a-azido-b-iodo ethers,12a but benzofuran and some indoles give a mixture of cis- and trans-2,3-diazido products.12b Allenes can give mono- or bis-adducts.13 When the monoadduct is an allyl azide, then [3,3] rearrangements are observed (eq 5). When the monoadduct is a vinyl azide, addition of a second molecule of IN3 is faster than the first addition and a bis-adduct results. The cyclopropane group in norcarane is opened by IN3 to give a mixture of products.14

Synthesis of Aziridines.

IN3 addition to alkenes followed by Lithium Aluminum Hydride (or Diborane) reduction is a convenient method (Hassner aziridine synthesis) for the preparation of aziridines.6 This method has been applied to the synthesis of monoaziridine derivatives of terpenes such as squalene, farnesol, and geraniol (eq 6).15

With anti-oriented iodo and azide functions, LAH leads to a large amount of IN3 elimination.6 Many other reagents can be used for the reduction of IN3 adducts to aziridines,6,16 including Hydrazine-Raney Nickel, Me2NH.BH3, and phosphines or phosphites; the last reagents lead to N-phosphorylated aziridines.16a When alkyl- or aryldichloroborane is used, it provides stereospecific entry into N-substituted aziridines (eq 7).16d

Selective reduction of the adducts has also been achieved, as in the formation of b-amino acids from acrylic esters.17 Rearrangements during IN3 additions have been observed in rearrangement-prone systems such as methylenenorbornene, benzonorbornadiene, the pinenes, and tritylethylene.18 In a- and b-pinene, rearrangement is accompanied by trapping with MeCN followed by N3- to afford tetrazoles.19

Synthesis of Vinyl Azides and Azirines.

Various bases, especially Potassium t-Butoxide, cause stereospecific elimination of HI from the adducts and the resulting vinyl azides serve as useful intermediates for the synthesis of azirines (eq 8),6,20 ketones,21 and cyanoketenes,22 and for the amination of aromatic compounds.23

Miscellaneous Reactions.

Addition of IN3 to methylphenylacetylene leads to 2-azido-1-iodo-1-phenylpropene.24 IN3 also adds to isocyanides to produce iodotetrazoles.2 Dimethyl thioacetals react with IN3 to afford an a-azido thioether which can undergo Schmidt rearrangement in the presence of Trifluoroacetic Acid.25


1. Hassner, A. ACR 1971, 4, 9
2. (a) Hassner, A.; Levy, L. A. JACS 1965, 87, 4203. (b) Fowler, F. W.; Hassner, A.; Levy, L. A. JACS 1967, 89, 2077. (c) Hassner, A.; Fowler, F. W. JOC 1968, 33, 2686.
3. (a) L'abbé, G.; Hassner, A. JOC 1971, 36, 258. (b) Cambie, R. C.; Rutledge, P. S.; Smith-Palmer, T.; Woodgate, P. D. JCS(P1) 1977, 2250. (c) Cambie, R. C.; Jurlina, J. L.; Rutledge, P. S.; Woodgate, P. D. JCS(P1) 1982, 315. (d) Cambie, R. C.; Jurlina, J. L.; Rutledge, P. S.; Swedlund, B. E.; Woodgate, P. D. JCS(P1) 1982, 327. (e) Ponsold, K.; Wuderwald, M. ZC 1979, 19, 25. (f) McIntosh, J. M.; CJC 1971, 49, 3045.
4. (a) L'abbé, G.; Hassner, A. AG(E) 1971, 10, 98. (b) Hassner, A. MOC 1990, 10/2, 1243. (c) Hassner, A.; Isbister, R. J.; Friederang, A. TL 1969, 2939.
5. Hassner, A.; Matthews, G. J.; Fowler, F. W. JACS 1969, 91, 5046.
6. Hassner, A.; Fowler, F. W. JACS 1968, 90, 2869.
7. (a) Hantzsch, A. CB 1900, 33, 522. (b) Dehnike, K. AG(E) 1976, 15, 553.
8. (a) Sivasubramanian, S.; Aravind, S.; Kumarasingh, L. T.; Arumugam, N. JOC 1986, 51, 1985. (b) Hassner, A.; Dehaen, W. JOC 1990, 55, 2243. (c) Crotti, P.; Chini, M.; Uccello-Barretta, G.; Macchia, F. JOC 1989, 54, 4525.
9. (a) Carlon, F. E.; Draper, R. W. JCS(P1) 1983, 2793. (b) Mehta, G.; Dutta, P. K.; Pandey, P. N. TL 1975, 445. (c) Sasaki, K.; Kanematsu, K.; Kondo, A. T 1975, 31, 2215. (d) Cambie, R. C.; Hayward, R. C.; Rutledge, P. S.; Smith-Palmer, T.; Swedlund, B. E.; Woodgate, P. D. JCS(P1) 1979, 180.
10. Lee, P-C.; Wu, C-C.; Cheng, M-C.; Wang, Y.; Wu, M-J. J. Chin. Chem. Soc. 1992, 39, 87.
11. Hassner, A.; Boerwinkle, F. JACS 1968, 90, 216.
12. (a) Ghosez, L.; Sainte, F.; Rivera, M; Bernard-Henriet, C.; Gouverneur, V. RTC 1986, 105, 456. (b) Tamura, Y.; Chun, M. W.; Ohno, K.; Kwon, S.; Ikeda, M. CPB 1978, 26, 2874. (c) Tamura, Y.; Chun, M. W.; Kwon, S.; Bayomi, S. M.; Okada, T.; Ikeda, M. CPB 1978, 26, 3515.
13. Hassner, A.; Keogh, J. JOC 1986, 51, 2767.
14. Cambie, R. C.; Dixon, G.; Rutledge, P. S.; Woodgate, P. D. JCS(P1) 1982, 961.
15. (a) Parish, E. J.; Nes, W. D. SC 1988, 18, 221. (b) Avruch, L.; Oehlschlager, A. C. S 1973, 622.
16. (a) Hassner, A.; Galle, J. E. JACS 1970, 92, 3733. (b) Sehgal, R. K.; Almassian, B.; Rosenbaum, D. P.; Zadrozny, R.; Sengupta, S. K. JMC 1987, 30, 1626. (c) Campbell, M. M.; Abbas, N.; Sainsbury, M. T 1985, 41, 5637. (d) Levy, A. B.; Brown, H. C. JACS 1973, 95, 4067.
17. Wasserman, H. H.; Brunner, R. K.; Buynak, J. D.; Carter, C. G.; Oku, T.; Robinson, R. P. JACS 1985, 107, 519.
18. (a) Hassner, A.; Teeter, J. S. JOC 1970, 35, 3397. (b) Hassner, A.; Teeter, J. S. JOC 1971, 36, 2176.
19. Ranganathan, S.; Ranganathan, D.; Mehrotra, A. K. TL 1973, 2265.
20. (a) Hassner, A.; Fowler, F. W. TL 1967, 1545. (b) Padwa, A.; Blacklock, T.; Tremper, A. OS 1977, 57, 83.
21. (a) Belinka, B. A., Jr.; Hassner, A. JOC 1979, 44, 4712. (b) Hassner, A.; Belinka, B. A., Jr. JACS 1980, 102, 6185.
22. Moore, H. W.; Decker, O. H. W. CRV 1986, 86, 821.
23. Hassner, A.; Munger, P.; Belinka, B. A., Jr. TL 1982, 23, 699.
24. Hassner, A.; Isbister, R. J.; Friederang, A. TL 1969, 2939.
25. Trost, B. M.; Vaultier, M.; Santiago, M. L. JACS 1980, 102, 7929.

Alfred Hassner

Bar-Ilan University, Ramat-Gan, Israel



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