Microwave-assisted synthesis of N,N′-diaryl cyanoguanidines

Article abstract of DOI:10.1021/ol050728q

(Chemical Equation Presented) A mild, efficient, and high-yielding method for the synthesis of N,N′-diaryl cyanoguanidines from their corresponding thioureas under microwave-assisted conditions is described. A series of cyanoguanidines were synthesized containing both electron-donating and electron-withdrawing substituents. The reactions were facilitated by the use of polar solvents along with moderate temperatures.

Full text of DOI:10.1021/ol050728q

ORGANIC
LETTERS
2005
Vol. 7, No. 12
2429-2431
Microwave-Assisted Synthesis of
N,N -Diaryl Cyanoguanidines
′
Sean K. Hamilton, Doug E. Wilkinson, Gregory S. Hamilton, and Yong-Qian Wu*
Department of Research, Guilford Pharmaceuticals, Inc., Baltimore, Maryland 21224
wuy@guilfordpharm.com
Received April 5, 2005
ABSTRACT
A mild, efficient, and high-yielding method for the synthesis of N,N′-diaryl cyanoguanidines from their corresponding thioureas under microwave-
assisted conditions is described. A series of cyanoguanidines were synthesized containing both electron-donating and electron-withdrawing
substituents. The reactions were facilitated by the use of polar solvents along with moderate temperatures.
The cyanoguanidine functionality is commonly referred to
as a bioisostere of the urea and thiourea moieties. They share
several physicochemical properties such as pKa. The cyano-
guanidine moiety can be found in several biologically active
agents such as cimetidine (1), a histamine-H2 antagonist,1
and pinacidil (2), an antihypertensive (Figure 1).2 Addition-
ally, aryl cyanoguanidines are currently being investigated
as potassium channel activators and inhibitors of insulin
release.3 As a result, there is enormous interest in developing
novel approaches toward their synthesis. The most widely
employed strategy for the synthesis of cyanoguanidines
involves the treatment of diphenyl N-cyanocarbonimidate
with an alkyl or arylamine, followed by conversion of the
corresponding N-cyano-alkyl or N-cyano-aryl isourea with
a basic amine, generally, in a sealed flask at high tempera-
tures (Scheme 1). While other methods are known in the
literature4 such as those that take advantage of carbodiimide
or S-alkylisothiouronium salts as intermediates, they often
require harsh conditions and long reaction times and suffer
from poor yields. Furthermore, there is a paucity of effective
methods for the synthesis of N,N-diaryl cyanoguanidines. In
our attempt to synthesize this type of compounds, most
Figure 1. Cimetidine (1) and pinacidil (2).
published methodologies were unsuccessful, even in cases
where the amines were activated using trimethyl-
aluminum.5
(4) (a) Iwanowicz, E. J.; Watterson, S. H.; Liu, C.; Gu, H. H.; Mitt, T.;
Leftheris, K.; Barrish, J. C.; Fleener, C. A.; Rouleau, K.; Sherbina, N. Z.;
Hollenbaugh, D. L. Bioorg. Med. Chem. Lett. 2002, 20, 2931.
(b) Yoshiizumi, K.; Ikeda, S.; Goto, K.; Morita, T.; Nishimura, N.;
Sukamoto, T.; Yoshino, K. Chem. Pharm. Bull. (Tokyo) 1996, 44, 2042.
(c) Atwal, S. K.; Ahmed, S. D.; O’Reilly, B. C. Tetrahedron Lett. 1989,
30, 7313.
(1) Roberts, S. M.; Price, B. J. Medicinal Chemistry, The Role of Organic
Chemistry in Drug Research; Academic Press: New York, 1985; p 93.
(2) McBurney, A.; Farrow, P. R.; Ward, J. W. J. Pharm. Sci. 1987, 12,
940.
(3) Tagmose, T. M.; Schou, S. C.; Mogensen, J. P.; Nielsen, F. E.;
Arkhammar, P. O. G.; Wahl, P.; Hansen, B. S.; Worsaae, A.; Boonen, H.
C. M.; Antoine, M. H. J. Med. Chem. 2004, 47, 3202.
(5) Atwal, S. K.; Ferrara, F. N.; Ahmed, S. Z. Tetrahedron Lett. 1994,
35, 8085.
10.1021/ol050728q CCC: $30.25
© 2005 American Chemical Society
Published on Web 05/17/2005

Scheme 1. General Synthesis of Cyanoguanidinesa
Scheme 2. Synthesis of N,N′-Diaryl Cyanoguanidines
a When R2 is an alkyl group, a sealed tube is not necessary.
Recently, Novak et al.6 reported the synthesis of
N,N′-diphenyl cyanoguanidine in moderate yield. This
method required conversion of N,N′-diphenyl thiourea to
N,N′-diphenyl cyanoguanidine via the thioether under ex-
tensive heating in the presence of a strong base as a catalyst.
However, there are two major limitations to this approach.
First, it precluded the use of compounds with base-
sensitive moieties. Second, we found that this method was
incapable of synthesizing N,N′-diaryl cyanoguanidines bear-
ing electron-withdrawing groups. Conventional heating of
the reaction for an extended period of time caused decom-
position of the thioether to the aniline before it reacted with
the nucleophile.
subjected to microwave heating (typically <20 min), efficient
conversion of thioethers 6 to cyanoguanidines 7 were
observed without any decomposed products.
Microwave synthesis has received a great deal of attention
in recent years. Several publications7 have shown that
microwave irradiation can circumvent the need for prolonged
heating and generally accelerate the rate of chemical reac-
tions, often with increased yields. This increase in reaction
rate is due in large part to the vast amount of microwave
energy being absorbed by the system as compared with the
required energy necessary to attain the requisite activation
energy.8
Table 1. Effects of Solvent and Temperature on the Yield of
7a
T °C
2-propanol
CH3CN
CH2Cl2
23
40
80
77
90
95
90
60
67
78
80
5
7
100
Herein, we wish to report a clean, mild, efficient, and high-
yielding procedure under microwave conditions for the
synthesis of N,N′-diaryl cyanoguanidines, including those
bearing strong electron-withdrawing substituents, which,
to the best of our knowledge, are not known in the literature.
The synthesis of the cyanoguanidines is outlined in
Scheme 2. Phenyl isothiocyanate 3 was treated with several
aromatic amines 4 in methylene chloride to provide thioureas
5. Upon treatment with methyl iodide and potassium carbon-
ate in acetone, 5 was smoothly converted to thioethers 6 in
>95% yield. Heating of compounds 6 in 2-propanol with
sodium hydrogen cyanamide in the presence of a catalytic
amount of the strong base 1,4-diazabicyclo[2.2.2]octane in
many cases produced no product or poor yields of 7 were
obtained. Further analysis of the reaction mixtures revealed
decomposition of 6 to substituted anilines and other unidenti-
fied products. However, when the reaction mixtures were
To explore the full scope and versatility of this method,
various conditions were investigated, including solvent and
temperature variations, and different substituents on the
phenyl rings. Highlighted in Table 1 for compound 7a, for
example, is the influence of solvent and temperature on the
reaction yield. It was found that 2-propanol provided the best
yield at 80 °C, although other polar solvents such as
acetonitrile gave moderate yields. Negligible product forma-
tion was observed in methylene chloride and other nonpolar
solvents.
These results are consistent with what is known in the
literature reports, namely, that solvent polarity plays a pivotal
role in nucleophilic reactions. In addition, polar solvents tend
to couple with microwave energy efficiently, thus resulting
in a rapid rise in temperature of the reaction mixture and
accelerated reaction rates.
(6) Novak, L.; Hanania, M.; Kovacs, P.; Kovacs, C. E.; Kolonits, P.;
Szantay, C. Synth. Commun. 1999, 29, 1757.
(7) Xu, G.; Wang, Y. G. Org. Lett. 2004, 6, 985.
(8) Hayes, B. L. MicrowaVe Synthesis, Chemistry at the Speed of Light;
CEM Publishing: Matthews, North Carolina, 2002; Chapter 1, p 16.
It is noteworthy that when microwave conditions were
utilized, a cleaner reaction accompanied with higher yields
was observed in the absence of base catalyst.
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Org. Lett., Vol. 7, No. 12, 2005

Under our reaction conditions, electron-donating substituents
readily provided cyanoguanidines in high yields (Table 2,
entry 5). Surprisingly, electron-withdrawing-substituted cy-
anoguanidines were obtained in high yields as well, as
highlighted by nitro-containing 7c and 7h, which were
obtained in 86 and 90% yield, respectively. It is worth noting
that Atwal et al.5 had reported 0% yield in their efforts to
synthesize a similar compound. This result is significant since
there is no literature precedent for the synthesis of N,N′-
diaryl cyanoguanidines bearing electron-withdrawing groups.
Furthermore, the reaction is not limited to arylamines but
can be used with heterocyclic amines such as pyridine (Table
2, entry 6) and thiozole (Table 2, entry 7) as well.
Table 2. Microwave Synthesis of Cyanoguanidinesa,9
In conclusion, we have described a straightforward and
high-yielding method for the synthesis of N,N′-diaryl cyano-
guanidines from their corresponding thioethers under mild
conditions using microwave irradiation. This method is
independent of electronic factors and compatible with a
variety of substituent groups.
Supporting Information Available: Experimental pro-
cedures and spectral data for compounds 7a-h. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL050728Q
(9) Typical Procedure for the Preparation of Cyanoguanidine. (7a
as an example) Thioether 6a (0.5 g, 2 mmol) was dissolved in 2-propanol
(5 mL), treated with NaHNCN (0.16 g, 2.5 mmol), and heated in a
microwave (20 min, powermax, 80 °C). The solvent was evaporated, and
the residue was partitioned between EtOAc and H2O. The organic layer
was dried with MgSO4 and filtered, and the solvent was evaporated. Column
chromatography of the residue provided 7a in 95% yield. 1H NMR (300
MHz, DMSO) δ: 7.01-7.04 (m, 2H); 7.21 (bs, 8H); 9.37 (s, 2H), mp )
198-200 °C. MS (ESI): 235.1 (MH-). Analytical data are in agreement
with literature values.
a Reactions were irradiated for 20 min in 2-propanol at 80 °C with CEM
Discovery. b Isolated yields.
As shown in Table 2, a study of the electronic effect with
various substituents on the phenyl rings was conducted.
Org. Lett., Vol. 7, No. 12, 2005
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