A highly efficient method for the synthesis of guanidinium derivatives

Article abstract of DOI:10.1016/S0040-4039(01)02165-7

A high yielding synthesis of guanidiniums with the use of the ethyl carbamate protecting group is presented. This strategy eliminates many steric hindrance and electronic problems. The deprotection of the products by Me₃SiBr is also demonstrated.

Full text of DOI:10.1016/S0040-4039(01)02165-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 565–567
A highly efficient method for the synthesis of guanidinium
derivatives
Joseph C. Manimala and Eric V. Anslyn*
Department of Chemistry and Biochemistry, The University of Texas at Austin, Austin, TX 78712, USA
Received 10 November 2001; accepted 13 November 2001
Abstract—A high yielding synthesis of guanidiniums with the use of the ethyl carbamate protecting group is presented. This
strategy eliminates many steric hindrance and electronic problems. The deprotection of the products by Me3SiBr is also
demonstrated. © 2002 Published by Elsevier Science Ltd.
Guanidiniums are very weakly acidic molecules (pKa
around 12.5) with the capacity to form intermolecular
contacts mediated by H-bonding interactions.1 The
guanidinium moiety is common in natural products2
and is often used in molecular recognition.3 They also
play important biological roles.4 Various methods exist
for the synthesis of guanidiniums from different start-
ing materials and reagents.5 One of the well-known
methods is the conversion of thioureas into guanidini-
Scheme 1. (a) CH2Cl2, R2NH2; (b) EDCl, CH2Cl2, Et3N; (c)
ums in the presence of a coupling reagent.6 The conver-
sion of thioureas into guanidiniums is usually
accomplished with an electron withdrawing protecting
group on the thiourea. These protecting groups, such as
t-Boc,7 Fmoc,6 and benzoyl,8 are not only capable of
facile deprotection, but also activate the thiourea for
the coupling reaction. Most thioureas that contain
these activating groups can be only coupled with pri-
mary amines. Furthermore, the efficiency of guanyla-
tion depends on the group attached to the primary
amine. Thioureas mostly react with primary amines
attached to primary carbons due to the bulkiness of the
protecting groups. The efficiency of guanylation also
depends upon whether the group that is attached to the
amine is electron withdrawing or electron donating.
Amines attached to electron withdrawing groups tend
to give lower yields in guanylation.
R3NH2; (d) deprotection.
such as EDCl,9 Sanger’s reagent,10 Mukaiyama’s
reagent,11 and HgCl2.12 Deprotection of 3 then gives the
guanidinium 4.
We were interested in the use of ethyl thiocyanato
formate since it is commercially available and the corre-
sponding thiourea is readily prepared as shown in Eq.
(1).13 While we were working on the synthetic strategies
of ethyl carbamate protected guanidines using various
coupling reagents and their subsequent deprotection,
Hamilton and co-workers published the aforemen-
tioned synthesis with various amines using EDCl as the
coupling reagent.14 Here, we would like to report our
findings on the synthesis of ethyl carbamate protected
guanidines using EDCl, Mukaiyama’s reagent, and
Sanger’s reagent. We also looked at the electronic and
steric effects of different amines on the guanylation as
well as their deprotection using trimethyl silyl bromide
(Me3SiBr).
The general sequence of synthesizing guanidiniums via
a thiourea is illustrated in Scheme 1. At first, potassium
thiocyanate is allowed to react with an electrophile to
give the protected thiocyanate. Addition of an amine to
the protected thiocyanate results in the formation of
thiourea 2. An amine can then be coupled to the
thiourea to form guanidinium 3 with coupling reagents
(1)
* Corresponding author.
0040-4039/02/$ - see front matter © 2002 Published by Elsevier Science Ltd.
PII: S0040-4039(01)02165-7

566
J. C. Manimala, E. V. Anslyn / Tetrahedron Letters 43 (2002) 565–567
use of ammonium hydroxide under mild heating, that is
known to deprotect ethyl carbamate group from the
guanidine of guanosine21 also failed.
We envisioned that the much smaller ethyl carbamate-
protecting group could alleviate steric hindrance prob-
lems created by bigger carbamate groups such as Boc,
Fmoc, and Cbz. To investigate the electronic and steric
limitations of the coupling in the presence of this
protecting group, we decided to couple different amines
to the carbamate protected benzyl thiourea.
The coupling of amines (A–I) to thiourea succeeds with
EDCl coupling conditions without any major, undesir-
able side products in 48 h.15 This same reaction was
also attempted with Mukaiyama’s and Sanger’s reagent
in place of EDCl under different reaction conditions.
The use of Mukaiyama’s reagent did not give any
products. On the other hand, Sanger’s reagent gave
lower yields along with side products. The guanidines
obtained via EDCl coupling were easily purified
through flash chromatography. The yields of these
guanidines are reported in Table 1.
(2)
In conclusion, we report a highly efficient synthesis of
guanidinium derivatives using ethyl carbamate protect-
ing group and EDCl coupling followed by the deprotec-
tion with Me3SiBr.
From Table 1 it is evident that all the amines gave
comparably similar and good yields. It was concluded
that ethyl carbamate protecting groups are very
efficient in the synthesis of guanidinium derivatives
especially for coupling an amine that is attached to a
secondary or tertiary carbon, and even aryl amines.
However, it was previously shown that secondary
amines could not be used in this coupling process.14
Acknowledgements
We gratefully acknowledge the National Institute of
Health and Welch Foundation for support.
The removal of the ethyl carbamate group was carried
out using Me3SiBr under reflux in DMF followed by
protonation with methanol to give complete deprotec-
tion, as seen in Eq. (2), without cleaving the functional
groups.16 The product was easily purified by an acid
work-up. The efforts to deprotect this group in the
presence of reagents such as hydrazine monohydrate,17
HBr,18 Red-Al,19 and NaOH,20 that are known to
cleave this group from amines, were unsuccessful. The
References
1. Burgess, K.; Chen, J. In Solid-Phase Organic Synthesis;
Burgess, K., Ed.; John Wiley & Sons: New York, 2000;
Chapter 1.
2. Greenhill, J. V.; Lue, L. In Progress in Medicinal Chem-
istry; Ellis, G. P.; Luscombe, D. K., Eds.; Elsevier Sci-
ence: New York, 1993; Vol. 30, Chapter 5.
3. Schneider, S. E.; O’Neil, S.; Anslyn, E. V. J. Am. Chem.
Soc. 2000, 122, 542.
4. Hannon, C. L.; Anslyn, E. V. Bioorganic Chemistry Fron-
tiers; Springer: Berlin, 1993; Vol. 3, pp. 193–255.
5. Dodd, D. S.; Kozikowski, A. P. Tetrahedron Lett. 1994,
35, 977.
Table 1.
6. (a) Poss, M. A.; Iwanowicz, E.; Reid, J. A.; Lin, J.; Gu,
Z. Tetrahedron Lett. 1992, 33, 5933; (b) Schneider, S. E.;
Bishop, P. A.; Salazar, M. A.; Bishop, O. A.; Anslyn, E.
V. Tetrahedron 1998, 54, 15063.
7. Chandrakumar, N. S. Synth. Commun. 1996, 26, 2613.
8. Su, W. Synth. Commun. 1996, 26, 407.
9. Albert, J. S.; Pecauh, M. W.; Hamilton, A. D. Bioorg.
Med. Chem. 1997, 5, 1455.
10. Lammin, S. G.; Pedgrift, B. L.; Ratcliffe, A. J. Tetra-
hedron Lett. 1996, 37, 6815.
11. Yong, Y. F.; Kowalski, J. A.; Lipton, M. A. J. Org.
Amine
% Yield of
guanidine 3
Amine
% Yield of
guanidine 3
Chem. 1997, 62, 1540.
12. Levallet, C.; Lerpiniere, J.; Ko, S. Y. Tetrahedron 1997,
53, 5291.
13. Representative procedure for the preparation of ethyl
carbamate protected thiourea: Synthesis of benzyl
thiourea 1. Benzylamine (2.3 g, 21.6 mmol) was added to
ethyl isothiocyanatoformate (1.8 g, 13.7 mmol) dissolved
in 10 ml of DCM. A gas evolution was noticed and a
A
B
C
D
E
80
83
88
85
78
F
G
H
I
80
87
85
83

J. C. Manimala, E. V. Anslyn / Tetrahedron Letters 43 (2002) 565–567
567
yellow solid was formed immediately. The product was
purified through flash chromatography (silica gel; eluant,
DCM/hexanes (2:3)); 1H NMR (300 MHz, CDCl3): l
9.86 (br, 1H), 8.05 (br, 1H), 7.21 (m, 5H), 4.77 (br, 2H),
4.12 (q, 2H), 1.19 (t, 3H); 13C{H} NMR (125 MHz,
CDCl3): l 179.3, 152.7, 136.2, 128.7, 127.7, 127.6, 62.6;
HRMS (CI+) calcd for C11H14N2O2S ([M+H]+): 239.0854;
found: 239.0846.
16. Representative procedure for deprotecting the ethyl car-
bamate group: synthesis of N,N-dibenzyl-guanidine 4A.
Protected guanidinium 3A (100 mg, 0.42 mmol) and
trimethyl silyl bromide (0.32 g, 2.1 mmol) were dissolved
in DMF and the solution was refluxed overnight. The
DMF was distilled off and the residue was resuspended
into 2 M HCl and was washed with ether. The solution
was then made basic by adding NaOH and the guanidine
was extracted with DCM. The DCM was rotary evapo-
rated to give an white solid; 1H NMR (300 MHz,
CDCl3): l 7.30 (m, 13H), 4.31 (s, 4H); 13C{H} NMR
(125 MHz, CDCl3): l 158.6, 139.2, 128.4, 127.1, 127.0;
HRMS (CI+) calcd for C15H17N3 ([M+H]+): 240.1500;
found: 240.1497.
14. Linton, B. R.; Carr, A. J.; Orner, B. P.; Hamilton, A. D.
J. Org. Chem. 2000, 65, 1566.
15. Representative procedure for the preparation of pro-
tected guanidinium: synthesis of N,N-dibenzyl-guanidine
carbamic acid ethyl ester 3A. The thiourea 1 (0.5 g, 2.1
mmol) was dissolved in DMF and Et3N (3 ml, 41.5
mmol) and EDCl (0.5 g, 2.6 mmol) were added to it.
After 30 min, benzylamine (0.23 g, 2.1 mmol) was added.
The reaction was run for 38 h. The product was isolated
through flash chromatography to give an off-white solid
(DCM/hexanes (2:3)); 1H NMR (300 MHz, CDCl3): l
7.19 (m, 10H), 4.41 (br, 4H), 4.10 (q, 2H), 1.26 (t, 3H);
13C{H} NMR (125 MHz, CDCl3): l 164.1, 159.9, 136.9,
128.5, 127.3, 126.9, 60.4; HRMS (CI+) calcd for
C19H21N3O2 ([M+H]+): 312.1712; found: 312.1713.
17. Koren, B.; Stanovnik, B.; Tisler, M. Heterocycles 1987,
26, 689.
18. Wani, M. C.; Campbell, H. F.; Brine, G. A.; Kepler, J.
A.; Wall, M. E. J. Am. Chem. Soc. 1972, 94, 3631.
19. Lenz, G. R. J. Org. Chem. 1988, 53, 4447.
20. Sudarsanan, V.; Nagarajan, K.; Gokhale, N. G. Indian J.
Chem., Sect. B 1982, 21, 1087.
21. Groziak, M. P.; Townsend, L. B. J. Org. Chem. 1986, 51,
1277.