· (MW 391.36)
(electrophilic reagent that specifically reacts with amines to yield substituted guanidines1-4)
Alternate Name: (tert-butoxycarbonylamino-trifluoromethanesulfonylimino-methyl)-carbamic acid tert-butyl ester.
Physical Data: mp 114-115 °C.
Solubility: soluble in CHCl3, CH2Cl2, MeOH, DMF, and most organic solvents; insoluble in H2O.
Form Supplied in: nonhygroscopic, white crystalline solid.
Analysis of Reagent Purity: NMR, HPLC, and elemental analysis.
Preparative Methods: A solution of N,N´-diBoc-guanidine (29 mmol) and NEt3 (36 mmol) in anhydrous CH2Cl2 (100 mL) was cooled to -78 °C under N2. Triflic anhydride (35 mmol) was added dropwise over a period of 20 min, and the resulting mixture was allowed to warm to -20 °C for 4 h. A 2 M aq NaHSO4 solution was added at -20 °C such that the reaction temperature does not rise above -10 °C, and the resulting layers were stirred vigorously for 5 min. The organic layer was washed with 2 M NaHSO4, H2O, and brine and then dried (MgSO4).1,2
Purification: flash column chromatography (20% hexanes in CH2Cl2).
Handling, Storage, and Precautions: indefinitely stable at rt.
Synthesis of Substituted Guanidines
N,N´-Bis(tert-butoxycarbonyl)-N´´-trifluromethanesulfonyl guanidine (1) serves as an efficient electrophilic species for the guanidinylation of a variety of amines under mild conditions to give high yields (75-100%) of substituted, protected guanidines (1).1,2 Its use is limited, however, to the guanidinylation of primary and secondary amines. Aromatic amines react somewhat slower and hindered secondary amines such as diisopropylamine do not react at all. The reaction proceeds most efficiently in nonpolar solvents such as CH2Cl2 and CHCl3 although reactions have been successfully carried out in polar solvents such as DMF and MeOH. In a typical reaction, reagent 1 is added as a solid to a slight excess of amine followed by 1 equiv of NEt3.3,4 This transformation is not moisture sensitive. After completion of the reaction determined by TLC, the excess starting amines, NEt3 and triflic amide are removed by aqueous work up. Kinetic studies of several guanidinylating reagents showed compound 1 and N,N´-diBoc-thiourea with the Mukaiyama reagent (2-chloro-1-methylpyridinium iodide)5 gave very rapid product formation.1 Between these two reagents, the thiourea seems to be superior for sterically hindered amines, but experimental setup and product isolation are much less demanding for reagent 1. The reaction using N,N´-diBoc-1H-pyrazole-1-carboxamidine6,7 proceeded much slower and N,N´-diBoc-isothiourea8 did not react at all. (All reactions were carried out using the recommended solvent.) The N,N´-diCbz1,2 and N,N´-diAlloc derivatives of reagent 1 have also been prepared starting from guanidine hydrochloride. These compounds work similar to reagent 1 and their use is advantageous when different protecting groups are required.
Modification of Amino Acids and Peptides in Solution
Orthogonally protected amino acids and peptides react in the same manner as described above; however, a different protocol is used for the guanidinylation of N-a-ornithine and lysine derivatives that are insoluble in CH2Cl2 (2).1 It is necessary to first convert these compounds into soluble derivatives by silylation with methyl(trimethylsilyl)trifluoroacetamide in refluxing CH2Cl2 under N2. A slight excess of reagent 1 is then added at room temperature followed by NEt3. Yields of greater than 90% are typical.
Modification of Peptides on Solid Support
As with 4-nitro-1H-pyrazole-N,N´-diBoc-1-carboxamidine,9 reagent 1 can guanidinylate ornithine and lysine residues of a peptide on solid support using a similar protocol as described in the first section (3).2 Once the desired peptide is constructed on the resin of choice and the amino-protecting group is removed, the free amino function is guanidinylated by treatment with a solution of reagent 1 and NEt3 overnight. This reaction can be accomplished for a peptide with multiple amine-containing residues and even when the amine-containing amino acid of the peptide is proximal to a sterically demanding resin.
Preparation of Guanidinoglycosides
Reagent 1 is also used to convert aminoglycosides such as tobramycin to the corresponding guanidinoglycosides (4).10 This transformation is carried out in a mixture of 1,4-dioxane and H2O with a three fold excess of reagent 1 and NEt3 to each amino group. The reaction is carried out at room temperature and takes approximately 3 d for complete conversion. The reaction can be terminated before complete conversion and the partially guanidinylated derivatives can be isolated using flash column chromatography. Other syntheses employ reagents such as 3,5-dimethylpyrazoylformamidinium nitrate11 and 1H-pyrazole-1-carboxamidine hydrochloride12,13 at elevated temperatures in DMF, but all show limited success presumably because of limited solubility of the aminoglycosides in DMF.
2-methyl-2-thiopseudourea sulfate [867-44-7];
o-methylisourea sulfate [52328-05-9];
1H-pyrazole-1-carboxamidine hydrochloride [4023-02-3].
- 1. Feichtinger, K.; Zapf, C.; Sings, H. L.; Goodman, M., J. Org. Chem. 1998, 63, 3804.
- 2. Feichtinger, K.; Sings, H. L.; Baker, T. J.; Matthews, K.; Goodman, M., J. Org. Chem. 1998, 63, 8432.
- 3. Baker, T. J.; Goodman, M., Synthesis Special Issue, 1999, 1423.
- 4. Baker, T. J.; Tomioka, M.; Goodman, M., Organic Syntheses 2001, 78, 91-98.
- 5. Yong, Y. F.; Kowalski, J. A.; Lipton, M. A. J., Org. Chem. 1997, 62, 1540.
- 6. Bernatowicz, M. S.; Wu, Y.; Matsueda, G. R., Tetrahedron Lett. 1993, 34, 3389.
- 7. Drake, B.; Patek, M.; Lebl, M., Synthesis 1994, 579.
- 8. Bergeron, R. J.; McManis, J. S., J. Org. Chem. 1987, 52, 1700.
- 9. Yong, Y. F.; Kowalski, J. A.; Thoen, J. C.; Lipton, M. A., Tetrahedron Lett. 1999, 40, 53.
- 10. Baker, T. J.; Luedtke, N. W.; Tor, Y.; Goodman, M., J. Org. Chem. 2000, 65, 9054.
- 11. Wessel, H. P.; Banner, D.; Gubernator, K.; Hilpert, K.; Müller, K.; Tschopp, T., Angew. Chem. Int. Ed. Engl. 1997, 36, 751.
- 12. Cotner, E. S.; Smith, P. J., J. Org. Chem. 1998, 63, 1737.
- 13. Hauser, S. L.; Cotner, E. S.; Smith, P. J., Tetrahedron Lett. 1999, 40, 2865.
Professor Murray Goodman
University of California, San Diego, La Jolla, CA, USA
Copyright © 1995-2000 by John Wiley & Sons, Ltd. All rights reserved.