Iodine Isocyanate1

INCO

[3607-48-5]  · CINO  · Iodine Isocyanate  · (MW 168.92)

(additions to multiple bonds;1-11 regioselective and stereoselective introduction of the isocyanate, amine, or carbamate function;1-8 formation of aziridines,1-7 2-oxazolidones,1,2 2-amino alcohols,1,2 1,2-diamines,5 and azepines;6 interconversion of alkene stereoisomers9)

Physical Data: usually prepared in situ in solution.1-4

Solubility: sol most organic solvents.

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

Preparative Methods: INCO can be prepared in situ from silver cyanate and I2 in anhydrous ether,2,4 MeCN (faster),2 THF,2 or CH2Cl2 (faster).4d The preformed solution can be stored in the dark at -20 to -30 °C for 48 h,2 and sometimes reacts faster with alkenes.10 The purity of AgNCO is critical; it should be white or pale-gray, prepared fresh or kept in the dark in a desiccator.2 A typical procedure for addition to alkenes is as follows:2 to a stirred slurry of 20 g (0.13 mol) of fresh AgCNO in 200 mL anhydrous ether at 0 °C is added 0.1 mol of alkene followed by 25.4 g (0.1 mol) of I2. The mixture is stirred at rt for 1-5 h (brown color lightens). Filtration of the salts through a filter aid (Celite) and washing with aqueous sodium bisulfite gives a solution of the iodo isocyanate which is converted to the methyl b-iodo carbamate by treatment with 100 mL of MeOH and 2-3 drops of dil LiOMe. Alternatively, the iodo isocyanate can be converted into a stable sodium bisulfite adduct, which can regenerate the isocyanate or lead to an aziridine.

Additions to Alkenes.

Addition of INCO to alkenes (see also Iodine Azide) proceeds via a three-membered cyclic 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.8 The new N-C bond usually forms at the more substituted carbon or the one better able to support a positive charge in the transition state (eq 1),1 although 1-hexene and methylenecyclohexene give a mixture of regioisomers.8

Steric effects play an important role in the attack by cyanate ion; thus t-butylethylene affords the terminal isocyanate. 2-Cholestene gives the diaxial adduct, 2b-isocyanato-3a-iodocholestane (eq 2),2b whereas 5-cholestene does not react.1

Mono addition of INCO to dienes or trienes can be achieved with the less-substituted double bond reacting first (eq 3).8 Electron-poor double bonds, as in conjugated ketones or esters, do not react well with INCO.

Rearrangements have occasionally been observed, as in the case of 3,3-diphenylpropene which gives, in low yield, an iodo carbamate resulting from phenyl migration,11 and also in the case of rearrangement-prone alkenes such as 5-methylene-2-norbornene (eq 4).8 Enol acetates react fast but give an unstable adduct.10

Formation of Amines or Carbamates.

After the INCO adducts are converted with alcohol into the corresponding carbamates, the iodo function can be reduced by Zinc-Acetic Acid-ether (eq 5), except in diaxial adducts which tend to undergo elimination.8 Alternatively, the carbamates can be hydrolyzed to amines and the iodo amine salt can be reduced by Lithium Aluminum Hydride to an amine.4b

Synthesis of Aziridines.

The iodo carbamates resulting from INCO addition to alkenes followed by reaction with alcohol are readily converted into aziridines with base (refluxing Potassium Hydroxide in MeOH) (eq 6).1,2 Alternatively, the INCO adducts can be hydrolyzed by aq HI or HCl to trans-2-iodoalkylamines, which when heated with base afford aziridines.2b,4b

Aziridines can be converted into trans-2-amino alcohol derivatives (by heating with Acetic Acid),2b or into trans-1,2-diamines (by treatment with Sodium Azide followed by hydrogenation).5

Synthesis of 2-Oxazolidones and cis-2-Amino Alcohols.

Pyrolysis of b-iodo carbamates neat at 140-190 °C or in solvents (i-PrOH, TCE, diglyme) leads to the formation of 2-oxazolidones (eq 7).1

Since addition of INCO to cycloalkenes affords trans-2-iodo carbamates and formation of 2-oxazolidones proceeds with inversion of configuration, hydrolysis (KOH in aq MeOH) of the oxazolidones provides a stereospecific entry to cis-2-amino alcohols (eq 7).1

Miscellaneous Reactions.

Addition of a preformed solution of INCO in THF to phenylacetylene yields a monoadduct which provides acetophenone on workup with dil HCl. A general route to 1H-azepines involves INCO addition to 1,4-dihydrobenzenes and conversion of the resulting fused aziridines into azanorcaradienes which rearrange to azepines (eq 8).6

Interconversion of cis- and trans-alkenes can be achieved using this reagent; for example, from a cis-alkene via the 2-oxazolidone and the derived (inverted) 2-amino alcohol. The latter is ring-closed with acid to a trans-aziridine, which on deamination with n-BuONO yields a trans-alkene (eq 9).9


1. Hassner, A.; Lorber, M. E.; Heathcock, C. JOC 1967, 32, 540.
2. (a) Hassner, A.; Heathcock, C. T 1964, 20, 1037. (b) Hassner, A.; Heathcock, C. JOC 1965, 30, 1748. (c) Heathcock, C. H.; Hassner, A. OSC 1988, 6, 795, 967.
3. (a) Birckenbach, L.; Linhard, M. CB 1930, 63B, 2528, 2544. (b) Birckenbach, L.; Linhard, M. CB 1931, 64B, 961, 1076.
4. (a) Drehfahl, G.; Ponsold, K. CB 1960, 93, 519. (b) Drehfahl, G.; Ponsold, K.; Köllner, G. JPR 1964, 23, 136. (c) Wittekind, R. R.; Rosenau, J. D.; Poos, G. I. JOC 1961, 26, 444. (d) Gebelein, C. G. CI(L) 1970, 57.
5. Swift, G.; Swern, D. JOC 1967, 32, 511.
6. Paquette, L. A.; Khula, D. E. TL 1967, 4517.
7. Saito, M.; Kayama, Y.; Watanabe, T.; Fukushima, H.; Hara, T.; Koyano, K.; Takenaka, A.; Sasada, Y. JMC 1980, 23, 1364.
8. Hassner, A.; Hoblitt, R. P.; Heathcock, C.; Kropp, J. E.; Lorber, M. JACS 1970, 92, 1326.
9. Carlson, R. D.; Lee, S. Y. TL 1969, 4001.
10. Rosen, S.; Swern, D. Anal. Chem. 1966, 38, 1392.
11. Hassner, A.; Teeter, J. S. JOC 1971, 36, 2176.

Alfred Hassner

Bar-Ilan University, Ramat-Gan, Israel



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