A simple solid-phase synthesis of disubstituted guanidines using Rink amide resin as an amine component

Article abstract of DOI:10.1016/S0040-4039(01)00162-9

A practical solid-phase synthesis that simply uses Rink amide resin as an amine component in reacting with aromatic isothiocyanates and aliphatic amines to generate disubstituted guanidines is described. No special linker or guanylation reagents are involved in this method. The product is obtained in a 'traceless-linker' fashion and in high yield and purity when an electron-deficient isothiocyanate is employed.

Full text of DOI:10.1016/S0040-4039(01)00162-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 2273–2275
A simple solid-phase synthesis of disubstituted guanidines using
Rink amide resin as an amine component
Min Li,* Lawrence J. Wilson and David E. Portlock
Procter & Gamble Pharmaceuticals, Health Care Research Center, 8700 Mason-Montgomery Road, Mason, OH 45040, USA
Received 7 December 2000; accepted 22 January 2001
Abstract—A practical solid-phase synthesis that simply uses Rink amide resin as an amine component in reacting with aromatic
isothiocyanates and aliphatic amines to generate disubstituted guanidines is described. No special linker or guanylation reagents
are involved in this method. The product is obtained in a ‘traceless-linker’ fashion and in high yield and purity when an
electron-deficient isothiocyanate is employed. © 2001 Elsevier Science Ltd. All rights reserved.
Substituted guanidines are well known to be important
pharmacophores in many therapeutic areas, e.g. anti-
During a study of the solid-phase synthesis of substituted
guanidines and guanidine derivatives, we found that
7
hypertensive, cardiotonic, H antagonist/agonist and
Rink amide resin can be simply used as an amine
component in reactions with isothiocyanates and amines
to generate disubstituted guanidines in a traceless-linker
fashion. The general procedure (Scheme 1) includes two
major steps: isothiocyanate addition and guanylation.
The commercial Rink amide resin (1) was deprotected
with 25% piperidine/DMF, and then treated with an iso-
thiocyanate (5 equiv.) in CH Cl to give the resin bound
2
1
anti-tumor activity. Interest in making substituted
guanidines on solid support has been rapidly growing
2
in recent years. Many of the known methods either
3
involve special linkers and reagents, or leave the gener-
ated guanidine with a linker trace, usually as an acid or
4
amide. As an on-going effort in the solid-phase synthe-
5
sis of small drug-like organic molecules, we earlier
2
2
reported a traceless-linker approach to substituted
guanidines by utilizing a novel acyl isothiocyanate
linker. Herein, we wish to report a simple, clean, high
yielding and linker-free method for the synthesis of
disubstituted guanidines by using Rink amide resin as
an amine component.
thiourea (2). The thiourea 2 was subjected to guanylation
with an amine (5 equiv.) at 50°C in CHCl in the presence
3
6
of DIC (5 equiv.) and DIPEA (5 equiv.) to give the resin
bound guanidine (3). The disubstituted guanidine (4) was
then cleaved under mild Rink resin cleavage conditions
(25% TFA/CH Cl at room temperature).
2
2
R2
NH
S
1
) 25% piperidine/DMF
) R1
CH2Cl2, r.t., 8 h
R3
R1
NH-Fmoc
N
H
N
H
DIC, DIPEA, CHCl3
2
N C S
o
(1)
50 C, 2 days
(2)
(Rink amide
polystyrene resin)
R2
R3
R2
R3
N
N
N
2
5% TFA/CH2Cl2
R1
R1
r.t., 1 h
HN
N
H
N
H
(3)
(4)
Scheme 1. Solid-phase synthesis of disubstituted guanidines using Rink amide resin.
Keywords: disubstituted guanidines; solid-phase synthesis; Rink amide resin.
*
0
Corresponding author. E-mail: lim2@pg.com; lwilson3@prius.jnj.com; portlockde@pg.com
040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00162-9

2
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M. Li et al. / Tetrahedron Letters 42 (2001) 2273–2275
The addition of the amino group from Rink resin to an
isothiocyanate is very efficient for both aromatic and
aliphatic isothiocyanates. However, the structural effect
becomes more significant in the guanylation step. Simi-
lar to what was found previously, under these guanyla-
tion conditions, aromatic isothiocyanates and aliphatic
synthesis, isothiocyanate addition and guanylation, the
method generates disubstituted guanidines in good yield
and purity from aromatic isothiocyanates and aliphatic
amines. It is important to note that aliphatic isothio-
cyanates and anilines did not work well under this
particular synthetic system. With this limitation in
mind, the method is suitable for the combinatorial
synthesis of compounds of this type.
7
amines are the most suitable substrates. The thiourea
formed from an aromatic isothiocyanate with an elec-
tron-withdrawing group is more favorable to the
guanylation. It is also understandable that with this
particular amine component from the Rink amide
linker, the guanylation could be more difficult for those
thioureas formed from less electrophilic isothio-
cyanates. Therefore, unreacted thiourea intermediate
was the primary by-product in these cases. Typical
yields and purities for disubstituted guanidines made
via this method by utilizing the Argonaut Quest 210 are
listed in Table 1. With suitable substrates, especially
aromatic isothiocyanate with an electron-withdrawing
group, the synthesis is very efficient in providing high
yield and purity for disubstituted guanidines.
Acknowledgements
We wish to thank Dr. Jack Chen for helpful discussion.
References
1. (a) Durant, G. J.; Ganellin, C. R.; Hills, D. W.; Miles, P.
D.; Parsons, M. E.; Pepper, E. S.; White, G. R. J. Med.
Chem. 1985, 28, 1414; (b) Corelli, F.; Dei, D.; Monoche,
G. D.; Botta, B.; Delucca, C.; Carmiganni, M.; Volpe, A.
R.; Botta, M. Bioorg. Med. Chem. Lett. 1996, 6, 653; (c)
Ohnota, H.; Koizumi, T.; Tsutsumi, N.; Kobayashi, M.;
Inoue, S.; Sato, F. J. Pharmcol. Exp. Ther. 1994, 269, 489;
(d) Smets, L. A.; et al. Cancer Chemother. Pharmacol.
1988, 21, 9.
In conclusion, we have developed a simple and conve-
nient solid-phase synthetic method to prepare disubsti-
tuted guanidines. No special linker or reagents are
involved in this method. By utilizing Rink amide resin
as an amine input and following a short two-step
8
Table 1. Typical yields and purities of disubstituted guanidines synthesized by this method

M. Li et al. / Tetrahedron Letters 42 (2001) 2273–2275
2275
2
. (a) Burgess, K.; Chen, J. Solid-phase Synthesis of Guanidi-
nes; Burgess, K., Ed. Solid-phase organic synthesis. John
Wiley: New York, 2000; pp. 1–23; (b) Chen, J.; Pat-
tarawarapan, M.; Zhang, A. J.; Burgess, K. J. Comb.
Chem. 2000, 2, 276; (c) Dahmen, S.; Brase, S. Org. Lett.
ml) was added isothiocyanate (5 equiv.), and the mixture
was agitated at room temperature for 8 h. The resin was
filtered and washed in the same way as above. The resin
was then treated with amine (5 equiv.), DIC (5 equiv.) and
DIPEA (5 equiv.) in CHCl3 (4 ml) at 50°C for 2 days,
filtered, washed in the same way as above. The resin was
cleaved with 25% TFA/CH Cl (4 ml) at room tempera-
2000, 2, 3563; (d) Schneider, S. E.; Bishop, P. A.; Salazar,
M. A.; Bishop, O. A.; Anslvn, E. V. Tetrahedron 1998, 54,
2
2
15063; (e) Dodd, D. S.; Wallace, O. B. Tetrahedron Lett.
ture for 1 h, filtered, and washed with CH Cl and MeOH.
2 2
1
998, 39, 5701.
The filtrate was evaporated to dryness by SpeedVac
(Savant Instruments, Inc.) to give the desired product in
yield and purity, as shown in Table 1. Analytical data for
3
. (a) Patek, M.; Smrcina, M.; Nakanishi, E.; Izawa, H. J.
Comb. Chem. 2000, 2, 370; (b) Yong, Y. F.; Kowalski, J.
A.; Thoen, J. C.; Lipton, M. A. Tetrahedron Lett. 1999,
representative compounds:
1
40, 53; (c) Josey, J. A.; Tarlton, C. A.; Payne, C. E.
4f: H NMR (300 MHz, CD OD) l 8.09–7.52 (m, 7H),
3
13
Tetrahedron Lett. 1998, 39, 5899.
3.75 (m, 4H), 1.88 (bs, 6H); C NMR (300 MHz,
4
. (a) Kearney, P. C.; Fernandez, M.; Flygare, J. A. Tetra-
hedron Lett. 1998, 39, 2663; (b) Drewry, D. H.; Gerritz, S.
W.; Linn, J. A. Tetrahedron Lett. 1997, 38, 3377.
. Wilson, L. J.; Li, M.; Portlock, D. E. Tetrahedron Lett.
CD OD) l 157.8, 136.7, 133.3, 131.5, 130.4, 130.2, 128.8,
3
128.3, 127.4, 126.7, 123.4, 49.3, 27.0, 25.3; HRMS (FAB)
+
m/z for C H N (M+Na) calcd: 276.1476, found:
16
19
3
5
6
276.1467.
1
1
998, 39, 5135.
. Wilson, L. J.; Klopfenstein, S. R.; Li, M. Tetrahedron Lett.
999, 40, 3999.
4g: H NMR (300 MHz, CD OD) l 8.25 (d, 2H, J=9.0
3
Hz), 7.43 (d, 2H, J=9.0 Hz), 7.21 (m, 4H), 4.72 (s, 2H),
13
1
3.77 (t, 2H, J=6.0 Hz), 3.03 (t, 2H, J=6.0 Hz); C NMR
7
8
. Li, M.; Wilson, L. J. Tetrahedron Lett. 2001, 42, 1455.
. General procedure for the synthesis of disubstituted
guanidines on the Argonaut Quest 210 (each step was
repeated once except the cleavage step): The commercial
Rink amide polystyrene resin (0.3 g; 0.7 mmol/g;
Advanced ChemTech) was treated with 25% piperidine/
DMF (4 ml) at room temperature for 1 h, filtered and
(300 MHz, CD OD) l 156.8, 146.6, 145.1, 136.1, 132.8,
3
129.7, 129.2, 128.5, 127.8, 126.8, 124.2, 49.7, 46.7, 29.7;
+
HRMS (FAB) m/z for C H N O (M+H) calcd:
16
16
4
2
297.1352, found: 297.1359.
1
4k: H NMR (300 MHz, CD OD) l 7.58–7.29 (m, 9H),
3
4.40 (s, 2H), 3.86 (m, 1H), 3.62 (m, 2H), 3.14 (m, 2H), 2.29
13
(m, 2H), 1.95 (m, 2H); C NMR (300 MHz, CD OD) l
3
washed successively with DMF (three times), CH Cl2
156.7, 135.6, 134.5, 132.8, 131.8, 131.5, 130.8, 130.6, 128.3,
2
(
three times), MeOH (three times) and CH Cl2 (three
62.0, 52.7, 37.4, 30.6; HRMS (FAB) m/z for C H ClN
(M+H) calcd: 343.1690, found: 343.1679.
2
19 23
4
+
times). To a slurry of the deprotected resin in CH Cl (4
2
2
.
.