Imidazolium Derived Reagents

Matthias Junkers

N-Acylimidazoles were recognized in the early 1950s as reactive intermediates suitable for the acylation of amino compounds. The search for better coupling reagents than DCC led to the development of CDI (1,1’-carbonyldiimidazole) and related carbonylimidazoles.1 For practical considerations it should be noted that moisture must be carefully excluded during work with CDI. Also, CDI excess should be avoided. Apart from peptide synthesis, carbonyldiimazoles find use as an efficient replacement for highly toxic phosgene in the preparation of carbamates and ureas from alcohols and amines.2,3

Kiso developed modified imidazolium reagents like CIP (2-Chloro- 1,3-dimethylimidazolidinium hexafluorophosphate) as new peptide coupling reagents and later as new esterification reagents to avoid the toxic HMPA by-product of the BOP reagent (benzotriazol-1- yloxytris(dimethylamino)phosphonium hexafluorophosphate).4 CIP was successfully applied to the coupling of a,a-dialkylated amino acids and proved to be especially efficient in combination with HOAt (1-hydroxy-7-azabenzotriazole).5

Materials
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1.
Staab HA. 1962. New Methods of Preparative Organic Chmistry IV. Syntheses Using Heterocyclic Amides (Azolides). Angew. Chem. Int. Ed. Engl.. 1(7):351-367. http://dx.doi.org/10.1002/anie.196203511
2.
Staab HA. 1957. Reaktionsfähige Heterocyclische Diamide Der Kohlensäure. Justus Liebigs Ann. Chem.. 609(1):75-83. http://dx.doi.org/10.1002/jlac.19576090108
3.
Staab HA. 1957. Reaktionsfähige Heterocyclische Diamide Der Kohlensäure. Justus Liebigs Ann. Chem.. 609(1):75-83. http://dx.doi.org/10.1002/jlac.19576090108
4.
Akaji K, Kuriyama N, Kimura T, Fujiwara Y, Kiso Y. 1992. Anchoring of Fmoc amino acid to 4-alkoxybenzyl alcohol resin using a new esterification reagent. Tetrahedron Letters. 33(22):3177-3180. http://dx.doi.org/10.1016/s0040-4039(00)79845-5
5.
Albericio F, Bailén MA, Chinchilla R, Dodsworth DJ, Nájera C. 2001. 2-Mercaptopyridine-1-oxide-based peptide coupling reagents. Tetrahedron. 57(47):9607-9613. http://dx.doi.org/10.1016/s0040-4020(01)00985-1

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