2-Chloro-1,3-dimethylimidazolidium Hexafluorophosphate

[101385-69-7]  · C5H10N2Cl·PF6  · (278.57)

(reagent used for the coupling and esterification of sterically hindered amino acids1)

Physical Data: mp 227-229 °C.

Solubility: soluble in DMF; partially soluble in H2O, MeOH, EtOAc, CH2Cl2, and CHCl3.

Form Supplied in: colorless solid; available from Aldrich, Fluka, and Watanabe Chemical Industries.

Analysis of Reagent Purity: IR (KBr), 1650, 1555, 1420, 1345, 1310, 840 cm-1. 1H NMR (270 MHz, DMSO-d6) d 3.07 (s, 6H), 3.64 (s, 4H).

Handling, Storage, and Precautions: can be stored refrigerated for at least 5 years without loss of reactivity. 2-Chloro-1,3-dimethylimidazolidium hexafluorophosphate (CIP) is an irritant and should be used in a fumehood, when possible.


2-Chloro-1,3-dimethylimidazolidium hexafluorophosphate (CIP), in the presence of an additive, is best suited for the coupling of sterically hindered a,a-dialkylamino acids, N-methylamino acids, and peptide fragments. The coupling reaction proceeds under slightly basic conditions, with diisopropylethylamine generally being used as an organic base. A catalytic amount of the additive is sufficient for the coupling reaction to proceed, and a suitable additive can be selected for each reaction type. 1-Hydroxy-7-azabenzotriazole (HOAt, 1)2 or N-dimethylaminopyridine (DMAP, 2)3 is generally best suited for use as an additive. An optically active a-amino acid can be activated by CIP to yield the coupling product with negligible racemization.

Coupling of a,a-Dialkylamino Acid

The efficient coupling of an a,a-dialkylamino acid is particularly difficult when the carboxyl and amino components are both a,a-dialkylamino acids.4 In the presence of 0.25 equiv of HOAt as an additive, CIP mediates the solution-phase coupling of an a,a-dimethylamino acid (Aib, a-aminoisobutyric acid) to yield Z-Aib-Aib-OMe, in 82% yield (1).5 The reaction proceeds at 25 °C in less than 60 min. The same dipeptide ester was prepared using PyBrop,6 a typical coupling reagent in peptide synthesis, under the same conditions in 17% yield. The amount of D-Val in the Z-Val-Aib-OMe, which was prepared by the CIP/HOAt procedure, was less than 0.5%. In the CIP-mediated Aib coupling, a Z or Fmoc group as an amino protecting group gave much better results than a Boc protecting group, probably due to the facile formation of the N-carboxy anhydride during the activation of the Boc amino acid.7

The CIP-mediated coupling of Aib proceeds through the oxazolone,8 followed by its transformation to a highly active HOAt ester. The active intermediate ester reacts quickly with an amino component to give the condensation product and HOAt. The liberated HOAt functions as a catalyst for the coupling. The coupling procedure was successfully applied to an efficient synthesis of Alamethicin F30, a linear peptide consisting of 19 a-amino acids including eight Aib residues and a C-terminal a,a-aminoalcohol, phenylalaninol (Pheol). The stepwise coupling of Aib residues using CIP/HOAt proceeded nearly quantitatively in CH2Cl2 or DMF at 25 °C within 60 min to yield the necessary fragments without any difficulty.9

More complex and hindered a,a-dialkylamino acids can also be coupled with CIP/HOAt. CIP-mediated activation was applied for the difficult coupling of three adjacent a-methylcysteine residues. The coupling reaction proceeded at 25 °C in a 60% yield (2).10

The procedure was the key step in the convergent syntheses of the polythiazoline alkaloids, mirabazole B (3),11 mirabazole C (4),10 and thiangazole(5).12

Coupling of N-methylamino Acid

An N-methylamino acid is incorporated with difficulty using conventional peptide coupling reagents because of its steric hindrance and marked tendency to racemize.13 CIP/HOAt was found to mediate the solution-phase coupling of the N-methylamino acid at 25 °C in CH2Cl2 in quantitative yield. The most hindered coupling between two N-methylated residues proceeds within 3 h, to give a 97% yield of the product with no detectable racemization: the corresponding D-isomer was produced in less than 0.5% yield (3).14

In the coupling of Z-MeVal-OH with MeAla-NHNH-Boc in solution phase, an efficient conventional reagent, BOP-Cl,15 resulted in an 87% yield after an 18 h reaction time providing <0.5% isomerization, whereas the 1,3-dicyclohexylcarbodiimide (DCC)/DMAP procedure resulted in a 72% yield after a 24 h reaction, with 37% isomerization.16

The CIP-mediated activation procedure can be applied to the coupling of N-methylamino acids on solid support.1417 Quantitative-to-moderate coupling yields were obtained by a single coupling reaction (1-3 h) at 25 °C with practically no racemization. The coupling between two N-methylated amino acids proceeded on solid support in 53% yield after a 3 h single coupling reaction (4). The content of the D-isomer was less than 2%. As a reaction solvent, the use of DMF resulted in better yields than CH2Cl2.

Solid phase coupling using CIP/HOAt was successfully applied to a convergent synthesis of Dolastatin 15, a cytostatic depsipeptide isolated from a marine mollusk. A tetrapeptide fragment was obtained by cleavage of 6, which was prepared by the successive CIP-mediated coupling of N-methylamino acids on a 2-chlorotrityl polystyrene resin. The overall yield based on starting resin was 50%.14

Fragment Coupling

The reaction efficiency of fragment coupling is generally low, compared with the coupling of a single amino acid. A greater fragment size results in a lower coupling efficiency. Fragment coupling is also prone to racemization via the oxazolone, which is formed during the activation of the C-terminus, i.e. during the activation of the N-acylamino acid.18 These difficulties can be avoided by taking advantage of the high reactivity of a coupling reagent combined with a judicious choice of coupling position.

CIP/HOAt was employed for the coupling of an N-terminal 11-residue fragment with a Gly residue at its C-terminus, and a C-terminal nine-residue fragment to yield protected Alamethicin F-30. The coupling reaction proceeded at 25 °C within 60 min to yield 66% of the homogeneous product after purification.19 The same coupling procedure was used in the final coupling reaction in the synthesis of Dolastatin 15 (7). The coupling reaction at the Pro residue proceeded at 25 °C within 2 h to yield Dolastatin 15 in 89% yield.14

CIP/HOAt can also be applied to the coupling of fragments with an optically active a-amino acid at the C-terminus. In the synthesis of Trichovirin I4A (8) using CIP/HOAt, coupling efficiency and the rate of racemization were found to be greatly dependent on the coupling site. Fragment coupling between the Ala and Val residues proceeded within 60 min at 25 °C in 81% yield with no detectable racemization, whereas fragment coupling between the more hindered Val and Aib residues resulted in a lower yield (69%) of the epimerized product.19


Head-to-tail cyclization represents a type of intramolecular fragment coupling and an efficient coupling reagent required for this transformation. A low reaction rate, as the result of an improper choice of the coupling reagent or the coupling site, facilitates extensive side reactions such as dimerization, oligomerization, and racemization.

CIP/HOAt was employed for the intramolecular cyclization to yield the key intermediate 9 in the synthesis of MEN11420, a glycosylated bicyclic peptide which has potent tachykinin antagonistic activity. CIP-mediated cyclization at the site between Dap(Boc) and Phe proceeded in DMF within 15 min to yield the cyclized monomeric product containing 6% of the D-Phe isomer. In contrast, cyclization at the more hindered site between the glycosylated-Asn and Leu proceeded in the presence of an excess amount of CIP (9 equiv) within 15 min to yield the monomeric product contaminated with 33% of the D-Leu isomer.20


CIP can be used for the esterification of a carboxylic acid to a hindered alcohol, such as a hindered secondary alcohol and a resin-bound alcohol. The CIP-mediated esterification of an Fmoc amino acid to a 4-alkoxybenzylalcohol resin was conducted at 25 °C within 60 min using 3 equiv of the Fmoc amino acid and 6 equiv of CIP in pyridine/CH2Cl2 (1:1). The reaction proceeded faster, with the same or lower level of racemization than the anchoring reaction using DIPCDI or PyBrop. For example, Fmoc-Lys(Boc)-OH was anchored to the alcohol resin in 74% yield accompanied by an 0.8% formation of the corresponding D-isomer, whereas a 57% yield using DIPCDI and a 33% yield using PyBrop was obtained.21

The esterification of Boc-Pro-OH with a secondary alcohol was achieved, after a 10 h reaction at 25 °C, using CIP in the presence of an additive (5).14 The additive, DMAP, gave better results than HOAt, giving the desired product in 92% yield.

CIP can also be used for the introduction of a sterically hindered 2-azidomethylbenzoyl (AZMB) group into the 3-hydroxy function of nucleosides (6). The esterification reaction proceeded within 2 h at 25 °C to yield the desired product in 66% isolated yield.22 An excess amount of CIP (2.5 equiv) was necessary for a smooth reaction because of the steric hindrance involved.

Related Reagents.

3-(Diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one (DEPBT);23 ethyl 1-hydroxy-1H-1,2,3-triazole-4-carboxylate (HOCt);24 5-(1H-benzotriazol-1-yloxy)-3,4-dihydro-1-methyl 2H-pyrrolium hexachloroantimonate (BDMP);25 2-bromo-3-ethyl-4-methyl thiazolium tetrafluoroborate (BEMT).26

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2. Carpino, L. A., J. Am. Chem. Soc. 1993, 115, 4397.
3. Hassner, A.; Krepski, L. R.; Alexanian, V., Tetrahedron 1978, 34, 2069.
4. Spencer, J. R.; Antonenko, V. V.; Delaet, N. G. J.; Goodman, M., Int. J. Peptide Protein Res. 1992, 40, 282.
5. Akaji, K.; Kuriyama, N.; Kiso, Y., Tetrahedron Lett. 1994, 35, 3315.
6. Frerot, E.; Coste, J.; Pantaloni, A.; Dufour, M. N.; Jouin, P., Tetrahedron 1991, 47, 259.
7. Frerot, E.; Coste, J.; Poncet, J.; Jouin, P.; Castro, B., Tetrahedron Lett. 1992, 33, 2815.
8. (a) Perlow, D. S.; Erb, J. M.; Gould, N. P.; Tung R. D.; Freidinger, R. M.; Williams, P. D.; Veber, D. F., J. Org. Chem. 1992, 57, 4394. (b) Paquet, A.; Chen, F. M.; Benoiton, N. L., Can. J. Chem. 1984, 62, 1335.
9. Akaji, K.; Tamai, Y.; Kiso, Y., Tetrahedron Lett. 1995, 36, 9341.
10. Akaji, K.; Kuriyama, N.; Kiso, Y., J. Org. Chem. 1996, 61, 3350.
11. Kuriyama, N.; Akaji, K.; Kiso, Y., Tetrahedron 1997, 53, 8323.
12. Akaji, K.; Kiso, Y., Tetrahedron 1999, 55, 10685.
13. Coste, J.; Frerot, E.; Jouin, P., J. Org. Chem. 1994, 59, 2437.
14. Akaji, K.; Hayashi, Y.; Kiso, Y; Kuriyama, N., J. Org. Chem. 1999, 64, 405.
15. Diago-Meseguer, J.; Palomo-Coll, A. L.; Fernandez-Lizarbe, J. R.; Zugaza-Bilbao, A., Synthesis 1980, 547.
16. Ward, D. E.; Lazny, R.; Pedras, M. S., Tetrahedron Lett. 1997, 38, 339.
17. Raman, P.; Stokes, S. S.; Angell, Y. M.; Flentke, G. R.; Rich, D. H., J. Org. Chem. 1998, 63, 5734.
18. (a) Carpino, L. A.; Ionescu, D.; El-Faham, A., J. Org. Chem. 1996, 61, 2460. (b) Carpino, L. A.; El-Faham, A., Tetrahedron 1999, 55, 6813.
19. Akaji, K.; Tamai, Y.; Kiso, Y., Tetrahedron 1997, 53, 567.
20. Akaji, K.; Aimoto, S., Tetrahedron 2001, 57, 1749.
21. Akaji, K.; Kuriyama, N.; Kimura, T.; Fujiwara, Y.; Kiso, Y., Tetrahedron Lett. 1992, 33, 3177.
22. Wada, T.; Ohkubo, A.; Mochizuki, A.; Sekine, M., Tetrahedron Lett. 2001, 42, 1069.
23. Li, H.; Jiang, X.; Ye, Y.; Fan, C.; Pomoff, T.; Goodman, M., Org. Lett. 1999, 1, 91.
24. Robertson, N.; Jiang, L.; Ramage, R., Tetrahedron 1999, 55, 2713.
25. Li, P.; Xu, J.-C., Tetrahedron 2000, 56, 4437.
26. Li, P.; Xu, J.-C., J. Org. Chem. 2000, 65, 2951.

Kenichi Akaji

Osaka University, Osaka, Japan

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