New cellulose-supported reagent: A sustainable approach to guanidines

Article abstract of DOI:10.1021/ol047926m

(Chemical Equation Presented) A new cellulose-supported reagent for the synthesis of guanidine in aqueous medium is reported starting from commercially available functionalized cellulose beads. Primary and secondary amines, anilines, and amino acids were transformed to the corresponding guanidines in high yields and under very mild conditions.

Full text of DOI:10.1021/ol047926m

ORGANIC
LETTERS
2
004
Vol. 6, No. 26
925-4927
New Cellulose-Supported Reagent: A
Sustainable Approach to Guanidines
4
Andrea Porcheddu,* Giampaolo Giacomelli, Alessandra Chighine, and
Simonetta Masala
Dipartimento di Chimica, UniVersit a` degli Studi di Sassari, Via Vienna 2,
I-07100 Sassari, Italy
anpo@uniss.it
Received October 8, 2004
ABSTRACT
A new cellulose-supported reagent for the synthesis of guanidine in aqueous medium is reported starting from commercially available
functionalized cellulose beads. Primary and secondary amines, anilines, and amino acids were transformed to the corresponding guanidines
in high yields and under very mild conditions.
The guanidine group is a decisive feature in many biologi-
cally active compounds. A growing number of biologically
As a consequence, guanidine synthesis has been intensively
investigated using traditional solution-phase chemistry. Typi-
cally, the synthesis of guanidine-containing compounds
involves treatment of an amine with an electrophilic amidine
species. The most commonly used reagents include (Scheme
1
and pharmaceutically relevant compounds incorporate guani-
dine functionality. Compounds containing the guanidine core
have been isolated from many species, such as algae,
2
4
5
sponges, and other marine and freshwater microorganisms.
1) cyanamide (1), O-methylisourea hydrogen sulfate (2),
Moreover synthetic guanidines have found wide applications
in the engineering of advanced synthetic molecular recogni-
tion devices, sensors, organic materials, and phase-transfer
Scheme 1. Guanidinylating Reagents
3
catalysts.
(1) The references cited are only a very few examples of biologically
active guanidines. (a) Guanidines: Historical, Biological, Biochemical and
Clinical Aspects of the Naturally Occurring Guanidino Compounds; Mori,
A., Cohen, B. D., Lowenthal, A., Eds.; Plenum Press: New York, 1985.
(b) Guanidines 2: Further Explorations of the Biological and Clinical
Significance of Guanidino Compounds; Mori, A., Cohen, B. D., Koide, H.,
Eds.; Plenum Press: New York, 1987. (c) Greenhil, J. V.; Lue. P. In
Progress in Medicinal Chemistry; Ellis, G. P., Luscombe, D. K., Eds.;
Elsevier Science: New York, 1993; Vol. 30, Chapter 5. For reviews of
guanidine natural products, see: (d) Durant, G. J. Chem. Soc. ReV. 1985,
1
4, 375-398. (e) Berlinck, R. G. S. Nat. Prod. Rep. 1996, 13, 377-409.
6
derivatives of pyrazole-1-carboxamidine (3), S-methyl-
(
f) Berlinck, R. G. S. Nat. Prod. Rep. 1999, 16, 339-365. (g) Heys, L.;
7
isothiouronium salts (4), and protected thiourea derivatives
(5), the last mainly used in conjunction with either mercury
salts or the Mukaiyama reagent. Moreover, using reagent
Moore, C. G.; Murphy, P. J. Chem. Soc. ReV. 2000, 29, 57-67. (h) Berlink,
R. G. S Nat. Prod. Rep. 2002, 19, 617-649 and references therein.
(2) See refs 1e and 1f and reference therein.
8
9
(3) (a) Echavarren, A.; Galan, A.; Lehn, J. M.; de Mendoza, J. J. Am.
Chem. Soc. 1989, 11, 4994-4995. (b) Pedersen, C. J. J. Am. Chem. Soc.
967, 89, 7017-7036. (c) Simoni, D.; Invidiata, F. P.; Manfredini, S.;
Ferroni, R.; Lampronti, I.; Roberti, M.; Pollini, G. P. Tetrahedron Lett.
997, 38, 2749-2752.
1
(4) (a) Davis, T. L. Org. Synth. 1927, 7, 46-48. (b) Schow, S.
Cyanamide. In Encyclopedia of Reagents for Organic Synthesis; Paquette,
L. A., Ed.; Wiley: Sussex, U.K., 1995; pp 1408-1410.
1
1
0.1021/ol047926m CCC: $27.50
© 2004 American Chemical Society
Published on Web 11/19/2004

5
, formed N-protected guanidines require an additional
guanidinylating agents work well in polar media, polystyrene-
based supports were considered unsuitable for this pourpose.
Thus, we have examined the applicability of beaded
10
deprotection step that is associated with workup drawbacks.
A direct synthetic approach should have the advantage of
a quick assembly of the guanidines without using protecting
groups. However, owing to the polarity of the guanidine
group and hence excellent water solubility of organic
materials that bear the guanidine moiety, workup and
separation from byproducts including those derived from the
reagent in Scheme 1 are often cumbersome. Therefore, recent
efforts have been focused on solid-phase-based amidination
techniques.11
1
4
cellulose as the support for this reagent. Cellulose shows
good swelling properties both in polar solvents and water
1
5
and is biodegradable also. Furthermore, the low cost of
the cellulose beads may make it possible to carry out a solid-
phase synthesis on a macro scale also.
Herein, we wish to report a new example of a cellulose-
supported reagent (inspired by compound 3) for the prepara-
tion of an array of guanidines using exclusively EtOH and
The triazene linker developed by Brase offers an elegant
solution to immobilize and modify guanidines on solid
H O as the solvents.
The triazene linker was prepared starting from aniline-
functionalized cellulose 6 with aqueous nitrous acid at 0
°C under classical conditions (Scheme 2). Diazotization
2
12
16
support. In fact the synthesis of a small library of guanidines
1
3
17
on solid support has been described using this linker. In
developing a new strategy for the synthesis of free guanidines,
we pointed out the possibility of developing a new supported
reagent to generate guanidines in solution. As most of the
Scheme 2. Synthesis of Solid-Supported Reagents 8
(5) (a) Callahan, J. F.; Ashton-Shue, D.; Bryan, H. G.; Bryan, W. M.;
Heckman, G. D.; Kinter, L. B.; McDonald, J. E.; Moore, M. L.; Schmidt,
D. B.; Silvestri, J. S.; Stassenh, F. L.; Sulat, L.; Yim, N. C. F.; Huffman,
W. F. J. Med. Chem. 1989, 32, 391-396. (b) Palmer, D. C. O-
Methylisourea. In Encyclopedia of Reagents for Organic Synthesis; Paquette,
L. A., Ed.; Wiley: Sussex, U.K., 1995; pp 3525-3526.
(
6) (a) Bernatowicz, M. S.; Wu, Y. L.; Matsueda, G. R. J. Org. Chem.
1
992, 57, 2497-2502. (b) Bernatowicz, M. S.; Wu, Y.; Matsueda, G. R.
Tetrahedron Lett. 1993, 3389-3392. (c) Drake, B.; Patek, M.; Lebl, M.
Synthesis 1994, 579-582. (d) Bernatowicz, M. S. 1H-Pyrazole-1-carboxa-
midine Hydrochloride. In Encyclopedia of Reagents for Organic Synthesis;
Paquette, L. D., Ed.; Wiley: Sussex, U.K., 1995; pp 4343-4344. (e) Ghosh,
A. K.; Hol, W. G. J.; Fan, E. J. Org. Chem. 2001, 66, 2161-2164. (f)
Powell, D. A.; Philip, D.; Ramsden, P. D.; Batey, R. A. J. Org. Chem.
2
003, 68, 2300-2309 and references therein.
(
7) (a) Bergeron, R. J.; McManis, J. S. J. Org. Chem. 1987, 52, 1700-
1
703. (b) Dumas, D. J. J. Org. Chem. 1988, 53, 4650-4653. (c) Palmer,
D. C. S-Methylisothiourea. In Encyclopedia of Reagents for Organic
Synthesis; Paquette, L. A., Ed.; Wiley: Sussex, U.K., 1996; pp 3523-
3525. (d) Moroni, M.; Kokschy, B.; Osipov, S. N.; Crucianelli, M.; Frigerio,
M.; Bravo, P.; Burger, K. J. Org. Chem. 2001, 66, 130-133.
8) (a) Kim, K. S.; Qian, L. Tetrahedron Lett. 1993, 48, 7677-7680.
b) Jirgensons, A.; Kums, I.; Kauss, V.; Kalvins, I. Synth. Commun. 1997,
in water with HCl/NaNO
bound diazonium salt 7, whereas diazotization with with -
BuONO and boron trifluoride etherate or NOBF
solvents was less successful and resulted in poor yields of
the compound 7.
The attachment of the guanidinylating agent to the
cellulose beads was carried out by shaking at 0 °C a cold
aqueous solution of 1H-pyrazole-1-carboxamidine hydro-
chloride 3 with solid-supported diazonium salt 7 in the
2
leads successfully to the polymer-
(
t
(
2
7, 315-322. (c) Levallet, C.; Lerpiniere, J.; Ko, S. Y. Tetrahedron 1997,
18
4
in organic
5
3, 5291-5304. (d) Cunha, S.; Costa, M. B.; Napolitano, H. B.; Lariucci,
C.; Vencato, I. Tetrahedron 2001, 57, 1671-1675. (e) Zhang, J.; Shi, Y.;
Stein, P.; Atwal, K.; Li, C. Tetrahedron Lett. 2002, 43, 57-59. (f) Yu, Y.;
Ostresh, J. M.; Houghten, R. A. J. Org. Chem. 2002, 67, 3138-3141.
(9) (a) Shibanuma, T.; Shiono, M.; Mukaiyama, T. Chem. Lett. 1977,
5
1
75-578. (b) Yong, Y. F.; Kowalski, J. A.; Lipton, M. A. J. Org. Chem.
997, 62, 1540-1542.
(10) Miel, H.; Rault, S. Tetrahedron Lett. 1997, 38, 7865-7866.
11) (a) Kowalski, J. A.; Lipton, M. A. Tetrahedron Lett. 1996, 37,
(
1
9
5
6
1
1
3
839-5840. (b) Robinson, S.; Roskamp, E. J. Tetrahedron 1997, 53, 6697-
705. (c) Kearney, P. C.; Fernandez, M.; Flygare, J. A. Tetrahedron Lett.
998, 39, 2633-2666. (d) Gelbard, G.; Vielfaure-Joly, F. Tetrahedron Lett.
998, 38, 2743-2746. (e) Lin, P.; Ganesan, A. Tetrahedron Lett. 1998,
9, 9789-9792. (f) Ostrech, J. M.; Schoner, C. C.; Hamashin, V. T.; Nefzi,
3
presence of NaHCO (Scheme 2) for 12 h. As observed
2
0
from elemental analyses, an almost quantitative loading was
achieved using a 4-fold excess of guanidinylating reagents
3
.
A.; Meyer, J.-P.; Houghten, R. A. J. Org. Chem. 1998, 63, 8622-8623.
(g) Yong, Y. F.; Kowalski, J. A.; Thoen, J. C.; Lipton, M. A. Tetrahedron
Lett. 1999, 40, 53-56. (h) Patek, M.; Smrcina, M.; Nakanishi, E.; Izawa,
H. J. Comb. Chem. 2000, 2, 370-377. (i) Jammalamadaka, V.; Berger, J.
G. Synth. Commun. 2000, 30, 2077-2082. (j) Acharya, A. N.; Ostresh, J.
M.; Houghten, R. A. J. Comb. Chem. 2001, 3, 578-589. (k) Sylyok, G. A.
G.; Gibson, C.; Goodman, S. L.; Holzemann, G.; Wiesner, M.; Kessler, H.
J. Med. Chem. 2001, 44, 1938-1950. (l) Ghosh, A. K.; Hol, W. G. J.; Fan,
E. J. Org. Chem. 2001, 66, 2161-2164. (m) Acharya, A. N.; Ostresh, J.
M.; Houghten, R. A. Tetrahedron 2001, 57, 9911-9914. (n) Katritzky, A.
R.; Rogovoy, B. V.; Vvedensky, V.; Kovalenko, K.; Forood, B. J. Comb.
Chem. 2002, 4, 290-294. (o) Corelli, F.; Federico, R.; Cona, A.; Venturini,
G.; Schenone, S.; Botta, M. Med. Chem. ReV. 2002, 11, 309. (p)
Boguszewski, P. A.; Rahman, S. S.; Ganesan, A. J. Comb. Chem. 2004, 6,
(14) (a) De Luca, L.; Giacomelli, G.; Porcheddu, A.; Salaris, M.; Taddei,
M. J. Comb. Chem. 2003, 5, 465-471. (b) Bowman, M. D.; Jeske, R. C.;
Blackwell, H. E. Org. Lett. 2004, 6, 2019-2022.
(15) Chesney, A.; Barwell, P.; Stonehouse, D. F.; Steel, P. G. Green
Chem. 2000, 2, 57-62.
(16) The cellulose employed was a modified bead form containing
aminoaryl-ethyl sulphone groups in flexible chains obtained from Iontosorb,
Czech Republic (Usti nad Labem). The content of amino aryl groups in
Iontosorb AV can be regulated according to the customer’s demands in the
range 0.1-2.8 mmol/g
(17) Covolan, V. L.; Innocentini Mei, L. H.; Rossi, C. L. Polym. AdV.
Technol. 1997, 8, 44-50.
(18) (a) Wannagat, U.; Hohlstein, G. Chem. Ber. 1955, 88, 1839-1846.
(b) Doyle, M. P.; Bryker, W. J. J. Org. Chem. 1979, 44, 1572-1574. (c)
Brase, S.; Kobberling, J.; Enders, D.; Lazny, R., Wang, M.; Brandtner, S.
Tetrahedron Lett. 1999, 40, 2105-2108.
3
2-34 and references therein.
12) (a) Brase, S. Acc. Chem. Res. 2004 (ASAP) and references therein.
b) Gil, C.; Brase, S Curr. Opin. Biol. 2004, 8, 230-237.
13) Dahmen, S.; Brase, S. Org. Lett. 2000, 2, 3563-3565.
(
(
(
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Org. Lett., Vol. 6, No. 26, 2004

During the development of this protocol, the progress of
the reaction was verified by using a colorimetric test. The
diazonium group on cellulose was monitored using the
Scheme 3. Synthesis and Cleavage of Cellulose-Attached
Guanidines
2
1
â-naphthol test. Thereby, a negative test indicates that the
diazonium salt 7 on the solid support was completely
22
converted to 8. The triazene 8 is stable, and its swelling
properties are comparable with those of the starting material.
The color of the beads is slightly yellow-orange.
To investigate the scope and limitations of the new solid-
supported agent, a series of structurally different amines 9
23
were reacted with the solid-phase-bound reagent 8 in EtOH
at pH ) 7-8 to prevent the displacement of pyrazole before
reaction or undesired cleavage. Optimal conversions were
achieved using 5 equiv of amines in refluxing EtOH for 12
2
4
h. Guanidines 10a-j (Scheme 3) were obtained in good
20
to acceptable yields. Most of primary and secondary amines
react efficiently with 8 affording compounds 10a-j. Poor
nucleophiles such as arylamines (entries 6 and 7) provide
25
the corresponding guanidines in good yields. p-Nitroaniline
was the only one that did not react (entry 8). Moderate yields
were obtained with glycine methyl ester (entry 5), whereas
hindered diisopropylamine gave good yields of guanidine
1
0j. Typically, the target molecules were prepared from 2 g
26
of cellulose, which correlated to about 1.0 mmol of product.
1
Finally, chemical identity was established by H NMR and
1
HPLC measurements corroborated by comparing their H
NMR data with the spectra obtained from conventional
solution-phase experiments.
In summary, we have described a new solid supported
reagent for converting a variety of amines to guanidines using
a biodegradable solid support and renewable solvents. The
new reagent can be used on a macro scale, giving access,
after cleavage, to guanidinium salts without further purifica-
tions.
Acknowledgment. The work was financially supported
by the University of Sassari and MIUR (Rome) within the
project PRIN 2003.
(
19) Preparation of Guanidinylating Reagent 8. Aniline cellulose 6
2 g, 1 mmol) was added to a chilled solution of NaNO2 (0.21 g, 3.0 mmol)
in H2O (20 mL). The mixture was shaken at 0 °C while 37% aqueous HCl
2.6 mL, 3.1 mol) was added in portions over 10 min. Then the slurry was
shaken at 0 °C for a further 3 h, filtered, and washed with chilled water (5
20 mL). The resulting cellulose-bound diazonium salt 7 was transferred
(
(
Supporting Information Available: Synthetic procedures
and characterization of new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
×
into water (10 mL) at 0 °C. Then an ice-water solution (15 mL) of 1H-
pyrazole-1-carboxamidine hydrochloride 3 (0.59 g, 4 mmol) and NaHCO3
(0.42 g 5 mmol) was added in portions at 0 °C over 10 min. The reaction
mixture was shaken at 0 °C for 3 h and for 12 h at room temperature. After
filtration, the cellulose was washed with H2O (20 mL) and stirred in EtOH
OL047926M
(20 mL) for 1 h, filtered again, and washed with EtOH (20 mL), H2O (20
mL), and EtOH (20 mL). The cellulose 8 was then swollen in EtOH (15
mL). A few beads of cellulose were dried in high vacum for 1 d to yield
pale brown beads of 8. Functionalization of all cellulose-bound amines was
verified by the â-naphthol test. The efficiency of the transformation
according to nitrogen elemental analysis proved to be over 99%. IR (KBr):
(26) Sample Procedure. The cellulose 8 previously obtained (1 mmol)
was suspended in EtOH (10 mL/g resin), treated with benzylamine (0.53
g, 547 µL, 5 mmol), and heated at reflux for 12 h. The cellulose beads
were filtered, then washed sequentially with EtOH, NMP, 2% NaHSO4
(aqueous), H2O, and EtOH (3 × 15 mL/g of cellulose), and dried in a
vacuum. The corresponding guanidine was cleaved from the polymer by
treatment with 1 N HCl in H2O (15 mL) under mechanical agitation for 3
h. Subsequently, the cellulose was filtered and washed with H2O (2 × 10
mL) and EtOH (15 mL). (In order to increase the recover yields it is better
to repeat the cleavage step three times). The cellulose was then washed
finally with H2O (2 × 15 mL), and the combined filtrates were concentrated
under vacuum to afford benzylguanidine hydrochloride 10d (0.182 g, 98%).
3
8
228, 3097, 1675 (s), 1600, 1518, 1441, 1379, 1340 (s), 1240, 1153 (s),
28.
(20) The loading was determined by comparison of the amount of N
and S determined before and after the reaction with 3. The contents of N
and S in 6 were found to be N 0.75%, S 1.73%. Elementary analysis of S,
N content for the cellulose 8 after the loading of pyrazole-1-carboxamide
3
was found be N 4.30%, S 1.59%.
21) Gaggini, F.; Porcheddu, A.; Reginato, G. Rodriquez, M.; Taddei,
(
M. J. Comb. Chem. 2004, 6, 805-810.
1
(
(
(
22) The triazene 8 can be stored at 0-4 °C for long times.
White crystalline solid, mp 173-174 °C. H NMR (DMSO-d6): δ (ppm)
13
23) Water can be used instead, although longer times are required.
24) After several crossed analyses, we have found that it is possible to
8.15 (brs, 1H), 6.84-7.62 (m, 9H), 4.35 (brs, 2H). C NMR (DMSO-d6):
δ (ppm) 162.8, 141.7, 121.9, 118.0, 114.0, 110.3. (ESI + ve ion): calcd
+
quantify the formation of desired supported guanidine by HPLC analysis
of the pyrazole released in the reaction.
for C8H12N3 150.1 [(M + H) ], found. 150.2. HPLC purity 99%. Anal.
Calcd for C8H12ClN3: C, 51.76; H, 6.51; N, 22.63. Found: C, 51.81; H,
6.44; N, 22.66.
(25) Reaction time for aromatic amine: 24 h.
Org. Lett., Vol. 6, No. 26, 2004
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