194
H.-O. Kim et al.
LETTER
In summary, we have developed an efficient and mild syn-
thetic method for the preparation of disubstituted
guanidines 1 by the reaction of N-substituted pyrazole
carboxamidine or N-substituted pseudothiourea with
amines. The N-substituted guanylating reagents were syn-
thesized by the treatment of primary or secondary alco-
hols with bis-Boc pyrazole carboxoamidine 2a or bis-Boc
pseudothiourea 2b under Mitsunobu conditions in moder-
ate to excellent chemical yields. Further synthetic applica-
tion of this method to the solid phase synthesis will be
reported in due course.
NBoc
NP
NBoc
X
R'
2a or 2b
BocN
PHN
N
PHN
Boc
R'
OH
R'
4k: P=Cbz, R'=Bn, X=pyrazole
4l: P=Boc, R'=H, X=SMe
5a
5b
Equation 1
Boc
2b
OH
N
SMe
BocN
Me
BocN
Me
NBoc
4m
Acknowledgement
Equation 2
The authors are grateful to Professor Michael Kahn and Dr. Mark
Blaskovich for the helpful discussion. We thank Dr. Thomas Vaisar
and Tom Little for obtaining the mass spectra and preparation of 2a.
From the monosubstituted guanylating agents 4d and 4e,
we synthesized disubstituted guanidine 1a and 1b by reac-
tion with glycine or proline esters in 84% and 36% yields
respectively (Eq. 3). Again, the moderate yield of 1b is
likely due to the steric encumbrance of the secondary ami-
no group of the proline. When 4j was treated with Gly-
OMe, only cyclic guanidine 6 was isolated in 74% yield
presumably via the disubstituted guanidine (Eq. 4).
References and Notes
(1) a) Ogbu, C. O.; Boatman, D.; Eguchi, M.; Cao, B.; Nakanishi,
H.; Kahn, M.; Tulinsky, A.; Padmanabhan, K. Abstracts of
Papers, 214th National Meeting of the American Chemical
Society, Las Vegas, NV; American Chemical Society: Wa-
shington, DC, September 1997; MED 60. b) Peptide Secon-
dary Structure Mimetics. Tetrahedron Symposia-in-print no.
50, Kahn, M. Ed., 1993, 49, 3444. c) Kahn, M. Synlett 1993,
821. d) Kim, H. -O.; Lum, C.; Lee, M. S. Tetrahedron Lett.
1997, 38, 4935. e) Kim, H. -O.; Kahn, M. Tetrahedron Lett.
1997, 38, 6483.
NBoc
NBoc
amino ester
(3)
N
X
N
R
Boc
THF
Boc
(2) a) During the preparation of this manuscript, a paper descri-
bing the solid phase synthesis of disubstituted guanidines ap-
peared. Dodd, D. S.; Wallace, O. B. Tetrahedron Lett. 1998,
39, 5701. b) Blaskovich, M.; Kahn, M. unpublished results
(3) Dodd, D. S.; Kozikowski, A. P. Tetrahedron Lett. 1994, 35,
977
(4) Bernatowicz, M. S.; Wu, Y.; Matsueda, G. R. Tetrahedron
Lett. 1993, 21, 3389.
(5) Ko, S. Y.; Lerpiniere, J.; Christofi, A. M. Synlett 1995, 815.
(6) Monache, G. D.; Botta, B; Monache, F. D.; Espinal, R.; De
Bonnevaux, S. C.; De Luca, C.; Botta, M.; Corelli, F.; Carmi-
gnani, M. J. Med. Chem. 1993, 36, 2956.
(7) Typical Reaction for the Preparation of 4. To a stirred solution
of benzyl alcohol (10 mL, 0.1 mmol) with 1,3-bis-Boc-2-me-
thyl-2-thiopseudourea (2b) (30 mg, 0.1 mmol), triphenylphos-
phine (40 mg, 0.15 mmol) in THF (1 mL) was added
diethylazodicarboxylate (25 mL, 0.15 mmol) at rt. After com-
pletion of reaction by TLC, the solution was concentrated to
purify by preparative TLC (hexane:EtOAc =95:5) to provide
4a as an oil (33 mg, 87%). NMR (500 MHz, CDCl3) d 1.39
and 1.55 (two s, 18H), 2.28 (s, 3H), 4.78 (s, 2H), 7.35 (m, 5H):
MS AP+ m/z 181.0 (100), 225.0 (25), 281.0 (5), 381(2,
M+H+).
(8) Typical Reaction for the Preparation of 1. The mixture of 4n
(50 mg, 0.10 mmol) with benzylamine (34mL, 0.3 mmol) in
THF (1 mL) was heated at 60 oC for 2h. The solution was con-
centrated and purified by flash chromatography (hexa-
ne:EtOAc = 95:5 to 80:20) to provide 1c as an oil (30 mg,
53%). NMR (500 MHz, CDCl3) d 1.30 (t, J=7.5Hz , 3H), 1.49
and 1.56 (two s, 18H), 1.55 - 2.1 (set of m, 5H), 2.25 (m, 1H),
, 2.36 (d, J=15Hz, 1H), 3.00 (d, J=13Hz, 1H), 4.02 (m, 1H),
4.20 (q, J=7.5Hz, 2H), 4.46 (s, 2H), 5.81 (d, J=15Hz, 1H),
5.95 (d, J=12Hz, 1H), 7.2 - 7.4 (set of m, 5H), 7.55 (dd, J=12,
15Hz, 1H): MS ES+ m/z 542.4 (100, M+H+).
1a: R= Gly-OMe, 84%
1b: R= Pro-OBn, 36%
4d: X= SMe
4e: X= pyrazole
Equation 3
NBoc
Me NBoc
Gly-OMe
THF
BocN
Me
N
4j
MeOOC
N
NH
COOMe
Boc
O
MeOOC
6: 74%
Equation 4
Finally, we applied this synthetic method to the prepara-
tion of disubstituted guanidine 1c8 under the same reac-
tion conditions from the cyclohexanol derivative 7 (Eq.
5).
NBoc
NBoc
OH
BocN
X
BocN
N
H
2a or 2b
benzylamine
PPh3,
DEAD
THF
COOEt
COOEt
COOEt
4n: X=SMe, 35%
4o: X=pyrazole, 36%
1c : 53% from 4n
48 % from 4o
7
Equation 5
Synlett 1999, No. 2, 193–194 ISSN 0936-5214 © Thieme Stuttgart · New York