Copper-catalyzed guanidinylation of aryl iodides: The formation of N,N′-disubstituted guanidines

Article abstract of DOI:10.1021/ol1002175

Chemical Equation Presented A copper-catalyzed cross-coupling reaction of guanidine nitrate with aryl iodides was used for the formation of N,N′-disubstituted guanidines to be used as potential therapeutics for strokes. A relatively inexpensive commercially available guanidine salt and a series of aryl iodides together with copper iodide and N,N-diethylsalicylamide as an efficient catalyst/1 igand system provided a simple diarylation procedure.

Full text of DOI:10.1021/ol1002175

ORGANIC
LETTERS
2010
Vol. 12, No. 6
1316-1319
Copper-Catalyzed Guanidinylation of
Aryl Iodides: The Formation of
N,N′-Disubstituted Guanidines
Michelle Cortes-Salva,† Be-Lan Nguyen,† Javier Cuevas,‡ Keith R. Pennypacker,‡
and Jon C. Antilla*,†
Department of Chemistry, UniVersity of South Florida, 4202 East Fowler AVenue CHE
205A, Tampa, Florida 33620, and Department of Molecular Pharmacology and
Physiology, College of Medicine, UniVersity of South Florida, 12901 Bruce B. Downs
BlVd., Box 8, Tampa, Florida 33612
jantilla@cas.usf.edu
Received January 27, 2010
ABSTRACT
A copper-catalyzed cross-coupling reaction of guanidine nitrate with aryl iodides was used for the formation of N,N′-disubstituted guanidines
to be used as potential therapeutics for strokes. A relatively inexpensive commercially available guanidine salt and a series of aryl iodides
together with copper iodide and N,N-diethylsalicylamide as an efficient catalyst/ligand system provided a simple diarylation procedure.
Numerous guanidine-containing compounds have important
biological activity and are, therefore, of pharmaceutical interest.1
In a specific example of diaryl guanidine biological activity,
Ajmo and collaborators showed that the σ-1/σ-2 ligand N,N′-
di-o-tolyl guanidine (DTG) could be used as a potent neuro-
protective agent following a stroke, decreasing the size of the
resulting infarct by ∼80%.2 Activation of σ receptors has been
found to modulate numerous ionic channels present in cortical
neurons that are responsible for neural firing, Ca2+ signaling,
K+ regulation, and neurotransmitter release.3,4 Several of these
channels are regulated by σ receptors, such as ASIC1a, and
have been associated with neuronal injury following ischemic
stroke.5 The success of the pan-selective σ agonist DTG as
a therapeutic agent for the treatment of stroke has prompted
attempts to improve the efficacy and/or potency of this
compound. Substitutions to the parent compound are thought
to increase the membrane permeability, receptor binding
affinity, and specificity of the agonist. Synthesis of guanidines
(3) (a) Albers, G. W.; Amarenco, P.; Easton, J. D.; Sacco, R. L. Seventh
ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest
2004, 126, 483. (b) Astrup, J.; Syrrion, L.; Branston, N. M.; Lassen, N. A.
Stroke 1997, 8, 51. (c) For pharmacology review, see: Su, T- P.; Maurice,
† Department of Chemistry.
‡ Department of Molecular Pharmacology and Physiology.
(1) (a) De Deyn, P. P.; Marescau, B.; Quereshi, I. A.; Mori, A. In
Guanidino Compounds in Biology and Medicine; John Libbey and Co.:
London, 1997; Vol. 2. (b) Rodriguez, F.; Rozas, I.; Kaiser, M.; Brun, R.;
Nguyen, B.; Wilson, W. D.; Garcia, R. N.; Dardonville, C. J. Med. Chem.
2008, 51, 909. (c) Keller, M.; Pop, N.; Beck-Sickingger, A.; Bernhardt,
G.; Buschauer, A. J. Med. Chem. 2008, 51, 8168. (d) Gee, K. R.; Durant,
G.; Holmes, D.; Magar, S. S.; Weber, E.; Wong, S. T.; Keana, J. F. W.
Bioconjugate Chem. 1993, 4, 226. (e) Evindar, G; Batey, R. A. Org. Lett.
2003, 5, 133. (f) Powell, D.; Batey, R. A. Org. Lett. 2002, 4, 2913.
(2) Ajmo, C. T., Jr.; Vernon, D. O.; Collier, L.; Pennypacker, K. R.;
Cuevas, J. Curr. NeuroVasc. Res. 2006, 3, 89.
T. Pharmacol. Ther 2009, 124, 195
.
(4) (a) Zhang, H.; Cuevas, J. J. Neurophysiol. 2002, 87, 2867. (b) Zhang,
H.; Cuevas, J. J. Pharmacol. Exp. Ther. 2005, 313, 1387. (c) Waldmann,
R.; Champigny, G.; Bassilana, F.; Heurteaux, C.; Lazdunski, M. Nature
1997, 386, 173. (d) Katnik, C.; Guerrero, W. R.; Pennypacker, K. R.;
Herrera, Y.; Cuevas, J J. Pharmacol. Exp. Ther. 2006, 319 (3), 1355
.
(5) (a) Herrera, Y.; Katnik, C.; Rodriguez, J. R.; Hall, A. A.; Willing,
A.; Pennypacker, K. Cuevas. J. J. Pharmacol. Exp. Ther. 2008, 327, 492.
(b) Xiong, Z. G.; Zhu, X. M.; Chu, X. P.; Minami, M.; Hey, J. Cell 2004,
118, 687.
10.1021/ol1002175  2010 American Chemical Society
Published on Web 02/19/2010

with arene substitution can represent a technical challenge
in many instances. Traditional methods have included the
addition of cyanogen bromide to aniline6 or the addition of
amines to functionalized thioureas.7 However, cyanogen
bromide is quite hazardous, limiting its attractiveness as a
starting material. Methods utilizing substituted thioureas are
not direct, requiring the separate preparation of each precur-
sor. Therefore we sought to develop a direct catalytic
guanidinylation of aryl halides for access to N,N′-diaryl
guanidines we desired for biological testing.
Table 1. Optimization of Reaction Conditions for the
Copper-Catalyzed Cross-Coupling of Guanidine Nitrate with
2-Iodotoluene
Copper-mediated Ullmann8 (C-C, C-N, or C-O bond
formation) and Goldberg9 (C-N bond formation with
amides) reactions have been used for decades in a variety
of applications, including industrial processes. A limitation
of this chemistry is the use of stoichiometric amounts of
copper. However, a more important consideration is probably
the limits on reactivity. Palladium-catalyzed cross-coupling
reactions are widely used alternatives for similar bond-
forming reactions. However, despite the great success of
these methods, alternative procedures utilizing an inexpensive
metal like copper are highly desirable.10 Recently, catalysts
employing copper in conjunction with suitable ligands have
played an important role in opening new possibilities for the
development of efficient catalytic C-N bond-forming pro-
cesses.11 Buchwald and Kwong reported that N,N-diethyl-
salicylamide and its analogues were excellent ligands for
copper in the cross-coupling of amines with aryl bromides,
even in a solvent-free environment.12
Since the double arylation of guanidines is not commonly
found in the literature, the development of a mild, cost-
effective, and straightforward copper-catalyzed method using
commercially available guanidine nitrate and aryl halides
would be potentially beneficial. Perhaps the closest meth-
odology in the literature for the direct arylation of guanidines
was the work of Deng and co-workers that focused on the
copper-catalyzed formation of substituted benzimidazoles.13
Importantly, the creation of structural analogues to DTG
could provide for new biological testing, as related to
ischemic stroke, of the arylated guanidine analogues.14
We initiated our studies by exploring conditions that
enabled copper-catalyzed cross-coupling using 1 mmol of
each substrate at 0.2 M, 10 mol % of CuI, 6 equiv of base,
entrya
solvent
toluene
ether
DME
DCM
1,4-dioxane
THF
ethanol
DMF
DMSO
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
temp, °C
yield, %d e
,
1
2
3
4
5
6
7
8
110
25
80
40
110
95
80
80
80
20
40
60
80
100
80
80
17
0
0
0
24
0
0
10
0
0
7
9
10
11
12
13
14
15b
16c
89
92
88
82
32
a The reaction used 1 mmol of guanidine nitrate and 1 mmol of
2-iodotoluene. b CuBr was used in place of CuI. c Anhydrous CuCl was
used. d Isoated yields. e 0.2 M in substrate.
and 20 mol % of N,N-diethylsalicylamide as a ligand. It
should be noted that the yield was determined with the aryl
halide as the limiting reagent, as an excess of guanidine was
required for the double arylation. When 2 equiv or more of
the aryl halide (correct stoichiometry for double arylation)
was used, a mixture of di- and triarylation products, with
lower overall yield, was found. After screening various
solvents, double amination was found to proceed efficiently
in acetonitrile, allowing for a 92% yield (Table 1, entry 13).
Other coordinating solvents such as diethyl ether and THF,
along with protic solvents such as ethanol, resulted in
conditions where low yields were obtained (entries 2, 6, and
7). Toluene, dioxane, and DMF were suitable solvents at
higher temperatures, but a diminished yield of the product
was found (entries 1, 5, and 8). The optimal temperature for
reaction in acetonitrile was determined to be 80 °C, with
lower or higher temperatures allowing for decreased yield
(entries 10-12, 14). Other copper salts such as CuBr and
CuCl (anhydrous) were metal sources capable of catalyzing
the reaction, but inferior results compared to that of the CuI
salt were found (entries 15 and 16).
(6) Weber, E.; Sonder, M.; Quarum, M.; McLean, S.; Pou, S.; Keana,
J. F. W. Proc. Natl. Acad. Sci. U.S.A. 1986, 83, 8784.
(7) (a) Bergfeld, M. et al. U.S. Patent 4,898,978, 1990. (b) For a review
on guanidine methods, see: Katritzy, A.; Rogovoy, B. V. ArkiVoc 2005, iV,
49. (c) Powell, D. A.; Ramsden, P. D.; Batey, R. A. J. Org. Chem. 2003,
68, 2300. (d) Powell, D. A.; Batey, R. A. Chem. Commun. 2001, 2362.
(8) (a) Ullmann, F. Ber. Dtsch. Chem. Ges. 1903, 36, 2382. (b) Ma, D.;
Zhang, Y.; Yao, J.; Wu, S.; Tao, F. J. Am. Chem. Soc. 1998, 120, 12459.
(c) Fagan, P. J.; Hauptman, E.; Shapiro, R.; Casalnuovo, A. J. Am. Chem.
Soc. 2000, 122, 5043. (d) Lang, F.; Zewge, D.; Houpis, I.; Volante, R. P.
Tetrahedron Lett. 2001, 42, 3251.
(9) Goldberg, I. Ber. Dtsch. Ges. 1906, 39, 1691.
(10) (a) Tundel, R. E.; Anderson, K. W.; Buchwald, S. L. J. Org. Chem.
2006, 71, 430. (b) Quach, T. D.; Batey, R. A. Org. Lett. 2003, 5, 4397.
(11) (a) Shafir, A.; Buchwald, S. L. J. Am. Chem. Soc. 2006, 128, 8742.
(b) Antilla, J. C.; Baskin, J. M.; Barder, T.; Buchwald, S. L. J. Org. Chem.
2004, 69, 5578. (c) Klapars, A.; Antilla, J. C.; Huang, X.; Buchwald, S. L.
J. Am. Chem. Soc. 2001, 123, 7723.
(14) Cortes-Salva, M.; Behensky, A.; Ajmo, C.; Pennypacker, K.;
Cuevas, J.; Antilla, J. Design, synthesis and eValuation of guanidine analogs
as potential drugs for stroke therapeutics; Presented at the 237th American
Chemical Society National Meeting, March, 2009, Salt Lake City, UT; no.
1216243.
(12) (a) Kwong, F. Y.; Klapars, A.; Buchwald, S. L. Org. Lett. 2002, 4,
581. (b) Kwong, F. Y.; Buchwald, S. L. Org. Lett. 2003, 5, 793.
(13) Deng, X.; McAllister, H.; Mani, N. S. J. Org. Chem. 2009, 74,
5742.
Org. Lett., Vol. 12, No. 6, 2010
1317

A variety of ligands such as L2-L10,11,13 used in previous
studies with copper, were tested against N,N′-diethylsalicy-
lamide (L1)12 (Table 2, entries 1-9). As an example,
cyclohexane-1,2-diamine (L4)11b,c was a ligand for copper
and promotion of the double guanidinylation, albeit with
inferior results (entry 3). To our surprise, our first ligand of
choice, N,N-diethylsalicylamide L1 (entry 10), was the most
suitable, allowing for the highest reactivity (92% yield).
Various bases such as K2CO3, Cs2CO3, and KOt-Bu (entries
11-13) were used with no improvement in reactivity.
Product formation was not significantly observed when
control experiments without ligand or base were performed
(not shown). When the reaction concentration was increased
from 0.2 to 0.4 M, a decrease in yield was noted (entry 16).
catalytic system, we conducted reactions where we could
probe the electronics and sterics of the aryl halide.
Table 3. Aryl Iodide Substrate Scope for the Guanidinylation of
Guanidine Nitrates
Table 2. Ligand and Base Effects on Reactivity
a All reactions were performed with 1 mmol of 1 and 1 mmol of 2 at
0.2 M; isolated yields are shown. b 15 mol % of CuI was used. c Reaction
was performed with 1 mmol of 1 and 0.5 mmol of 2. d 1,4-Dioxane was
used as the solvent. e Toluene was used as the solvent.
entrya
ligand
base
yield, %b
1
2
3
4
5
6
7
8
L2
L3
L4
L5
L6
L7
L8
L9
L10
L1
L1
L1
L1
L1
L1
L1
L1
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K2CO3
CS2CO3
KOt-Bu
K3PO4
K3PO4
K3PO4
K3PO4
15
0
45
0
10
0
19
8
It was shown that 2-iodotoluene and iodobenzene were
excellent substrates, with the former providing N,N′-di-o-
tolylguanidine (DTG) in a very high yield (Table 3, entry 1
and 2). Substrate scope was extended using 3-iodotoluene
and 4-iodotoluene to obtain the meta and para disubstituted
guanidines, giving a moderate yield (entries 4 and 5). The
trend of reactivity of the guanidinylation for the methyl-
substituted aryl iodides was ortho > meta > para. We further
explored substrates with a more electron-donating effect, such
as o-methoxy, which produced a decrease in yield, giving
only 47% (entry 9). Extending aromaticity with 2-napthalene
substitution (entry 2) provided a substrate that was converted
to product in a 50% yield. This was an indication that the
cross-coupling was less efficient because of steric hindrance
in comparison to iodobenzene (entry 2). Additionally,
heteroaryl iodides, such as 3-iodothiophene are good sub-
strates for the guanidinylation reaction (entry 18). It was
observed that halogen-substituted aryl iodides contributed a
stronger electron-withdrawing effect that still allowed for
reactivity with the cross-coupling reaction (entries 13-17).
Halogen substitution in the para position showed an increase
in yield in accordance with increasing electronegativity
(entries 11-13). Disubstituted aryl iodides promoted reactiv-
9
15
92
0
10
11
12
13
14c
15d
16e
17f
0
14
58
64
76
5
a All reactions used 1 mmol of guanidine nitrate and 1 mmol of
2-iodotoluene with a 0.2 M concentration. b Isolated yields. c Guanidine
carbonate was used. d Guanidine sulfate was used. e The reaction was 0.4
M in substrate. f The reaction performed without solvent (neat).
The optimized reaction conditions, 10 mol % CuI, 20 mol
% L1, 6 equiv of K3PO4, 1 mmol of guanidine nitrate (1a)
and 1 mmol of 2-iodotoluene (2), MeCN as the solvent at
0.2 M, and 80 °C under an argon atmosphere for 24 h, were
used for the double guanidinylation. Table 3 shows the
summary of results for the evaluation of various substituted
aryl iodides. In order to demonstrate advantages of this
1318
Org. Lett., Vol. 12, No. 6, 2010

ity higher than that of those with monosubstitution in the
two cases examined (entries 16 and 17).
Acknowledgment. We thank the James and Ester King
Biomedical Research (Florida Department of Health) (K.R.P.,
J.C., J.C.A.), and the Biomolecular Identification Targeting
Therapeutics Research Grant and Fellowship (USF BITT)
for financial support.
In conclusion, a copper-catalyzed cross-coupling reaction
of guanidines with aryl iodides to form disubstituted
guanidines with moderate yields was discovered. By using
mild and inexpensive reagents, we have successfully devel-
oped an expedient preparation of molecular entities based
on a medicinally interesting parent compound, DTG. These
analogues may show higher affinity than DTG for the σ
receptor and consequently may be superior therapeutic agents
for the treatment of ischemic stroke.14
Supporting Information Available: Experimental pro-
cedures, characterization, and spectra. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL1002175
Org. Lett., Vol. 12, No. 6, 2010
1319