N-Iodosuccinimide

[516-12-1]  · C4H4INO2  · N-Iodosuccinimide  · (MW 224.99)

(electrophilic iodination of arenes, alkenes, and alkynes; activation of glycosyl donors)

Alternate Names: NIS; 1-iodo-2,5-pyrrolidinedione.

Physical Data: mp 193-199 °C (dec).

Solubility: sol dioxane, THF, MeCN; insol ether, CCl4.

Form Supplied in: white powder; widely available, but quite expensive.

Preparative Method: reaction of N-silversuccinimide with I2 in anhydrous dioxane, removal of AgI by fitration, and addition of CCl4 to promote crystallization.1

Purification: recrystallization from dioxane-CCl4 at -20 °C.

Handling, Storage, and Precautions: stored at 0 °C under nitrogen, and protected from light and moisture to avoid decomposition; an irritating solid and precautions should be taken to avoid inhalation of the powder.

Introduction.

N-Iodosuccinimide is an efficient reagent for the electrophilic iodination of organic compounds for which the reactivity of I2 is often insufficient. A variety of functional groups are electrophilically iodinated using NIS with similar effectiveness to the corresponding brominations using N-Bromosuccinimide (NBS).2 Electrophilic attack on soft nucleophiles (e.g. as in dithiane deprotection) is achieved in the presence of other sensitive groups with optimum selectivity by iodination using NIS under mild conditions (see also 1,3-Diiodo-5,5-dimethylhydantoin).3 For other iodinations a more powerful source of iodonium ion can be generated by the combination of NIS with protic acids including AcOH, TsOH, and TfOH.4

Reaction with Organometallic Derivatives.

Similarly, the lesser reactivity of NIS compared with NBS allows it to be used for the synthesis of vinyl iodides by iodination of vinylaluminum intermediates in the presence of reactive alkenic groups.5 NIS has also been found to be an excellent reagent for the oxidative cyclization of dipeptide dianions to b-lactams (eq 1).6

Iodination of Alkenic Compounds.

Iodolactonization and related reactions with alkenes can be achieved using NIS in aprotic solvents. In addition, iodoesters may also be prepared by the reaction of alkenes with NIS in the presence of carboxylic acids (eq 2),7 and allylic trichloroacetimidates may be cyclized to 5-iododihydro-1,3-oxazines (eq 3).8

In combination with protic acid, NIS has been used for the preparation of a-iodo enones and b,b-dihalo enones (eqs 4 and 5; HTIB = [Hydroxy(tosyloxy)iodo]benzene).9 More reactive alkenes such as enol acetates react with NIS to afford a-iodo ketones.10 The reaction of enol ethers with NIS in the presence of an alcohol, affording iodoacetals, allows the synthesis of acetals by dehalogenation or mixed ketene acetals by elimination.11

Activation of Glycosyl Donors.12

NIS is a useful reagent for the coupling of glycals to alcohols (eq 6)13 or other carbohydrates,14 affording 2-iodoglycosides which are readily dehalogenated to 2-deoxysugars, or can serve as precursors to 2-aminosugars via the epoxide intermediate.15 Selective activation of glycosyl thioethers for coupling with carboxylic acids and heterocyclic compounds is achieved under mild conditions by reaction with NIS and Trifluoromethanesulfonic Acid (eq 7).16 In addition, the combination of NIS and TfOH is also the reagent of choice for the activation of 4-pentenylglycosides.17

Oxidation Reactions.

Hypoiodite intermediates may be generated from the reaction of simple alcohols with NIS. When conducted under photochemical irradiation, the products of Barton-type or fragmentation reactions of alkoxyl radical intermediates may be obtained.18 Aldehydes are oxidized to methyl esters via hemiacetal intermediates by reaction with NIS in methanol at rt.19 However, such conditions are not effective for the oxidation of simple alcohols. The combination of NIS and Tetra-n-butylammonium Iodide in dichloromethane has been developed for the oxidation of a variety of alcohols to the corresponding carbonyl compounds (eq 8).20 This reagent system is most widely used for the oxidation of lactols to lactones, in which near-quantitative yields are generally obtained under mild conditions (eq 9).21


1. Benson, W. R.; McBee, E. T.; Rand, L. OSC 1973, 5, 663.
2. NIS is generally not effective in the range of radical halogenations possible for NBS. See also: Taneja, S. C.; Dhar, K. L.; Atal, C. K. JOC 1978, 43, 997.
3. Burri, K. F.; Cardone, R. A.; Chen, W. Y.; Rosen, P. JACS 1978, 100, 7069.
4. Olah, G. A.; Wang, Q.; Sandford, G.; Prakash, G. K. S. JOC 1993, 58, 3194.
5. Marshall, J. A.; Lebreton, J.; DeHoff, B. S.; Jenson, T. M. TL 1987, 28, 723.
6. Kawabata, T.; Minami, T.; Hiyama, T. JOC 1992, 57, 1864.
7. (a) Adinolfi, M.; Parrilli, M.; Barone, G.; Laonigro, G.; Mangoni, L. TL 1976, 3661. (b) Haaima, G.; Weavers, R. T. TL 1988, 29, 1085.
8. Bongini, A.; Cardillo, G.; Orena, M.; Sandri, S.; Tomasini, C. JOC 1986, 51, 4905.
9. (a) Iwaoka, T.; Murohashi, T.; Katagiri, N.; Sato, M.; Kaneko, C. JCS(P1) 1992, 1393. (b) Angara, G. J.; Bovonsombat, P.; McNelis, E. TL 1992, 33, 2285.
10. Djerassi, C.; Grossman, J.; Thomas, G. H. JACS 1955, 77, 3826.
11. Middleton, D. S.; Simpkins, N. S. SC 1989, 19, 21.
12. (a) Theim, J.; Karl, H.; Schwentner, J. S 1978, 696. (b) Theim, J. In Trends in Synthetic Carbohydrate Chemistry, Horton, D.; Hawkins, L. D.; McGarvey, G. J.; Eds.; ACS: Washington, 1989; Vol. 386, Chapter 8.
13. Sebesta, D. P.; Roush, W. R. JOC 1992, 57, 4799.
14. Horton, D.; Priebe, W.; Sznaidman, M. Carbohydr. Res. 1990, 205, 71.
15. Friesen, R. W.; Danishefsky, S. J. T 1990, 46, 103.
16. (a) Veeneman, G. H.; van Leeuwen, S. H.; van Boom, J. H. TL 1990, 31, 1331. (b) Knapp, S.; Shieh, W.-C. TL 1991, 32, 3627. (c) Konradsson, P.; Udodong, U. E.; Fraser-Reid, B. TL 1990, 31, 4313.
17. (a) Konradsson, P.; Mootoo, D. R.; McDevitt, R. E.; Fraser-Reid, B. CC 1990, 270. (b) Ratcliffe, A. J.; Konradsson, P.; Fraser-Reid, B. JACS 1990, 112, 5665.
18. (a) McDonald, C. E.; Beebe, T. R.; Beard, M.; McMillen, D.; Selski, D. TL 1989, 30, 4791. (b) McDonald, C. E.; Holcomb, H.; Leathers, T.; Ampadu-Nyarko, F.; Frommer, J., Jr. TL 1990, 31, 6283.
19. McDonald, C.; Holcomb, H.; Kennedy, K.; Kirkpatrick, E.; Leathers, T.; Vanemon, P. JOC 1989, 54, 1213.
20. Hanessian, S.; Wong, D. H.; Therien, M. S 1981, 394.
21. Hamada, Y.; Kawai, A.; Matsui, T.; Hara, O.; Shioiri, T. T 1990, 46, 4823.

Scott C. Virgil

Massachusetts Institute of Technology, Cambridge, MA, USA



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