3804
J . Org. Chem. 1998, 63, 3804-3805
Sch em e 1
Dip r otected Tr iflylgu a n id in es: A New Cla ss
of Gu a n id in yla tion Rea gen ts
Konrad Feichtinger, Christoph Zapf,
Heather L. Sings, and Murray Goodman*
Department of Chemistry and Biochemistry, University of
California, San Diego, La J olla, California 92093-0343
Received March 9, 1998
The guanidino group is an important structural compo-
nent in many biologically active compounds.1 Because of
their strongly basic character, guanidines are fully proto-
nated under physiological conditions. The positive charge
thus imposed on the molecule forms the basis for specific
interactions between ligand and receptor or enzyme and
substrate, mediated by hydrogen bonds and/or electrostatic
interactions. Consequently, synthetic procedures that allow
the preparation of guanidines with high yield and under
mild conditions are of great interest in medicinal chemistry.
Typically, the synthesis of guanidines involves treatment of
an amine with an electrophilic amidine species. The most
commonly used reagents include derivatives of pyrazole-1-
carboxamidine, S-alkylisothioureas, and protected thiourea
derivatives, the latter mostly used in conjunction with
mercury salts or Mukaiyama’s reagent.2-11
Ta ble 1. Gu a n id in yla tion of Am in es w ith Dip r otected
Tr iflyl-gu a n id in es
We now wish to report N,N′-di-Boc-N′′-triflylguanidine 1
and N,N′-di-Cbz-N′′-triflylguanidine 2 as two examples of
diprotected triflylguanidines, a new class of guanidinylation
reagents. Both compounds are stable crystalline substances
that allow the preparation of protected guanidines with
exceptional ease and efficiency. The starting material
guanidine hydrochloride is cheap and readily available in
large quantities.
Reagent 1 is obtained in two steps from guanidine
hydrochloride 3 in 51% overall yield (Scheme 1). Reaction
of 3 with Boc-anhydride under strongly alkaline conditions
produces intermediate 4, which is easily converted to target
compound 1 with triflic anhydride. In a similar sequence
of reactions, the synthesis of reagent 2 commences with the
conversion of guanidine hydrochloride to N,N′-di-Cbz-guani-
dine 5. Contrary to the synthesis of reagent 1, the final
sulfonation step is carried out with sodium hydride as a base
in place of triethylamine. Both 1 and 2 are stable, crystal-
line substances which have been stored at room temperature
for at least three months with no apparent loss of activity;
hence, these compounds should remain stable indefinitely
if refrigerated.
a
Isolated yield after chromatography. b Diisopropylamine showed
no reaction.
To investigate the scope and limitations of our new
reagents, a series of structurally different amines was
subjected to reaction with compounds 1 or 2. The results
are illustrated in Tables 1 and 2. Dichloromethane or
chloroform was employed as a solvent in all examples.
Although guanidinylations have been successfully carried
out in polar solvents such as DMF or methanol (data not
shown), the reactions proceed faster in nonpolar solvents.
In a typical reaction (procedure A), a slight excess of the
amine was added in one portion to a solution of either 1 or
2 and 1 equiv of triethylamine, and the course of the reaction
was followed by TLC. After completion of the reaction,
triethylamine and the byproduct triflic amide were removed
during a simple aqueous workup procedure. Typically, the
crude products obtained in this way were greater than 95%
* To whom correspondence should be addressed.
(1) Berlinck, R. G. S. Fortschr. Chem. Org. Naturst. 1995, 66, 119.
(2) Poss, M. A.; Iwanowicz, E.; Reid, J . A.; Lin, J .; Gu, Z. Tetrahedron
Lett. 1992, 5933.
(3) Bernatowicz, M. S.; Wu, Y.; Matsueda, G. R. Tetrahedron Lett. 1993,
3389.
(4) Kim, K. S.; Qian, L. Tetrahedron Lett. 1993, 34, 7677.
(5) Dodd, D. S.; Kozikowski, A. P. Tetrahedron Lett. 1994, 35, 977.
(6) Drake, B.; Patek, M.; Lebl, M. Synthesis 1994, 579.
(7) Katriztky, A. R.; Parris, R. L.; Allin, S. M.; Steel, P. S. Synth.
Commun. 1995, 25, 1173.
(8) Kent, D. R.; Cody, W. L.; Doherty, A. M. Tetrahedron Lett. 1996, 37,
8711.
1
pure as evidenced by TLC and H NMR. A different protocol
(procedure B) was developed for the guanidinylation of N-R-
protected ornithine derivatives (Table 2, entries 1 and 2)
which are insoluble in dichloromethane. In this case the
amino acids were first converted into soluble derivatives by
silylation with methyl(trimethylsilyl)trifluoracetamide in
refluxing dichloromethane under anhydrous conditions. The
(9) Levallet, C.; Lerpiniere, J .; Ko, S. Y. Tetrahedron 1997, 53, 5291.
(10) Yong, Y. F.; Kowalski, J . A.; Lipton, M. A. J . Org. Chem. 1997, 62,
1540.
(11) Bergeron, R. J .; McManis, J . S. J . Org. Chem. 1987, 52, 1700.
S0022-3263(98)00425-3 CCC: $15.00 © 1998 American Chemical Society
Published on Web 05/27/1998