Synthesis of novel modified guanidines: Reaction of dicyandiamide with amino Acids, Amides, and Amines in aqueous medium

Article abstract of DOI:10.1002/jhet.1762

Figure presented Reaction of dicyandiamide with series of amino acids afforded guanidinyl pyrazolones 2-19, respectively. Although reaction of dicyandiamide with urea, acetamide, bezamide, allantion, p-aminobenzoic acid, sulphanilic acid, and adenine gave

Full text of DOI:10.1002/jhet.1762

1
322
Synthesis of Novel Modified Guanidines: Reaction of Dicyandiamide with
Vol 51
Amino Acids, Amides, and Amines in Aqueous Medium
a
b
Ahmed M. Soliman, Shaaban K. Mohamed, *
a
a
Mahmoud. Abd El Aleem. Ali. Ali. El-Remaily, * and H. Abdel-Ghany
a
Department of Chemistry, Faculty of Science, Sohag University, Egypt
b
School of Chemistry and Environmental Science, Manchester Metropolitan University, Manchester, UK
*
E-mail: msremaily@yahoo.com
Received March 17, 2012
DOI 10.1002/jhet.1762
Published online 17 March 2014 in Wiley Online Library (wileyonlinelibrary.com).
NH NH NH2
Ar
ArNH2
NH NH
O
R
NH
OH
O
NH
2
N
NC
R
NH
NH
NH NH2
R
NH2
N
H
H N
2
O
R
NH NH NH2
NH NH
O
Reaction of dicyandiamide with series of amino acids afforded guanidinyl pyrazolones 2–19, respectively.
Although reaction of dicyandiamide with urea, acetamide, bezamide, allantion, p-aminobenzoic acid, sulphanilic
acid, and adenine gave biguanides 20–26, respectively. All compounds have been characterized on the basis of
1
IR and H-NMR.
J. Heterocyclic Chem., 51, 1322 (2014).
INTRODUCTION
and guanidine-containing compounds has received intensive
studies since mid of last century. Polymerisation, solvation,
and high hydrophilicity [11–13] of guanidinium compounds
are the main obstacles in synthesis of such compounds. Also,
many of biguanide compounds have been reported in patients
with obscure synthetic methods. Moreover, the whole world
now gets more alert towards the global environmental chem-
ical pollutions. Organic reactions under aqueous conditions
have increasingly attracted chemists’ interests, particularly
from the viewpoint of green chemistry [14–20]. These values
and facts prompted us to explore a simple, straightforward,
and environment-friendly method of preparation of different
classes of guanidine-like compounds in a good yield by using
aqueous medium reaction conditions.
Diabetes mellitus is one of the most prevalent chronic
diseases worldwide [1]. During the last 20 years, the total
number of people with diabetes has risen from 30 to 230
million according to the International Diabetes Federation
[
2]. Biguanidines and cyclic guanidines are one of most
active diabetic inhibitors. Metformin (sold as Glucophage)
is the first line medicine used by clinicians to treat diabetic
and prediabetic patients [3,4].
NH
NH
NH
NH
NH
CH3
CH3
H N
NH
N
NH
NH
CH3
2
Cl
CH3
Metformin
Proguanil
RESULTS AND DISCUSSION
Such guanidine-like compounds showed not only a
crucial antidiabetic drugs, but also it showed a diverse of
chemical, biochemical, and pharmacological properties.
Recent achievements in the synthesis of guanidine-containing
molecules make them of great importance to the design and
development of novel drugs acting as anti-inflammatory
agents, antithrombotic, and chemotherapeutic agents [5].
Guanidines showed a wide range of biological activities.
For example, it not only lowers blood glucose [6] and inhibits
dihydrofolate reductase of opportunistic microorganisms [7]
but also acts as an anti-inflammatory [8] and fire redardant
On the reaction of dicyandiamide (DCD) with amino
acids L-tryptophan, L-histidine, L-phenylalanine, L-proline,
thioproline, b-alanine, D-alanine, DL-aspartic acid, isoleucine,
L-threonine, L-valine, L-glutamic acid, DL-serine, L-asparagine,
L-glutamine, L-arginine, L-lysine, and L-citrulline in aqueous
sulphuric acid medium afforded the guanidinyl pyrazolones
2–19, respectively (Scheme 1). All compounds 2–19 were also
prepared via another condition by using aqueous hydrochloric
acid medium [21] instead of aqueous sulphuric acid [22].
The reaction mechanism of formation of compounds 2–19
was preceded via a nucleophilic addition of the amino group
to the cyano group, then elimination of water molecule.
[9] (e.g., Proguanil). It is also used to develop novel drugs
acting at central nervous system [10]. Synthesis of biguanidines
©
2014 HeteroCorporation

September 2014
Synthesis of Novel Modified Guanidines
1323
Scheme 1
COOH
HO
COOH
NH
OH
O
H
N
H C
H C
NH
2
NH
NH
N
N
H
N
10% H2SO4
NH
H N
NH
or
1
1
N
H
HCl
1
0% H SO
or
2
4
H N
2
N
H
O
CH
HCl
2
H
N
H C
COOH
NH
COOH
H C
NH
H C
NH
NH
NH2
N
NH
NH
O
NH
2
N
O
H N
1
0% H2SO4
or
HCl
12
N
H
HOOC
10% H SO
N
H
COOH
NH
2
4
H
N
3
or
HCl
HOOC
NH
NH
N
O
1
0% H2SO4
or
H N
COOH
NH
NH
N
13
HCl
NH
2
NH2
NH
HO
HO
COOH
NH
NH
1
0% H SO
or
2
4
O
4
O
N
NH
HCl
1
0% H2SO4
or
H N
NH
14
NH
NH
HCl
COOH
O
NH
N
NC
N
H
O
HN
NH2
O
H
N
H N
COOH
N
1
NH
1
0% H SO
NH
2
4
2
H N
5
NH
0% H2SO4
N
NH
or
NH
NC
O
HCl
H N
1
15
or
NH
NH2
S
S
O
HCl
1
COOH
NH
COOH
N
H
N
O
H N
O
HN
H
N
N
H N
NH
NH
1
0% H SO
H
2
N
NH
2
4
N
6
10% H2SO4
or
O
H N
or
HCl
NH
16
HCl
COOH
H
N
HN
NH
COOH
NH
H N
NH
H
N
NH
N
NH
2
H N
NH
NH
2
O
NH
HN
NH
10% H2SO4
N
1
0% H SO
2
4
7
or
17
or
O
HCl
HCl
COOH
H
N
H
3
C
H N
COOH
NH
NH
NH
NH
H
3
C
NH
O
N
NH
O
NH
2
N
10% H2SO4
or
H N
18
1
0% H SO
NH
NH
2
4
H N
2
HCl
or
COOH
8
NH
HCl
HOOC
HN
O
H
N
NH
COOH
H
N
O
NH
NH
H N
HOOC
N
NH
NH
2
10% H2SO4
or
O
NH
H N
N
19
1
0% H SO
O
2
H N
2
4
HCl
or
9
HCl
CH
3
COOH
CH
3
H
N
H
3
C
3
H C
NH
2
NH
NH
N
1
0% H SO
or
O
2
4
2
H N
10
HCl
Treatment of DCD with urea, acetamide, bezamide, and
Dicyandiamide was subjected to react with p-amino-
allantion gave N-carbamoy-limidodicarbonimidic diamide
benzoic acid, sulphanilic acid, and adenine gave 4-(carba-
mimidoylcarbamimidamido)benzoic acid (24), 4-(car
bamimidoylcarbamimidamido)benzenesulfonic acid (25),
and N-9H-purin-6-ylimidodicarbonimidic diamide (26), re-
spectively (Scheme 2).
(
20), N-(carbamimidoylcarbamimidoyl)acetamide (21),
N-(carbamimidoylcarbamimidoyl)benzamide (22), and
N-[(2,5-dioxoimidazolidin-4-yl)carbamoyl]imidodicar-
bonimidic diamide (23), respectively (Scheme 2).
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1
324
A. M. Soliman, S. K. Mohamed, M. A. E. A. A. A. El-Remaily, and H. Abdel-Ghany
Vol 51
Scheme 2
adenine (50mmol) was dissolved on heating in 50 mL of 10%
sulfuric acid, and DCD (75 mmol) was added. The reaction
mixture was heated for 20min, and then, 10 mL of 50% sodium
hydroxide solution was added. After heating for additional
15min, the reaction mixture was cooled; the solid collected by
filtration and washed with water. The prepared compounds were
sufficiently pure and were used without further purification.
Recrystalised samples have been prepared for analyses.
O
O
NH
NH
H N
NH2
2
H N
NH
2
NH
NH2
1
mol : 1mol
or
mol : 1mol
2
0
2
1
0% H2SO4
O
O
NH
Method B.
A mixture of L-tryptophan, L-histidine,
NH
H C
NH2
3
H C
NH
O
L-phenylalanine, L-proline, thioproline, b-alanine, D-alanine,
DL-aspartic acid, isoleucine, L-threonine, L-valine, L-glutamic
acid, DL-serine, L-asparagine, L-glutamine, L-arginine, L-lysine
and L-citrulline (1 mol), DCD (1 mol), concentrated hydrochloric
acid (2 mol), and water (15 cc) was heated under reflux for 3 h.
The reaction mixture was allowed to cool down. Samples of
products have been recrystallised from an appropriate solvent
for all analysis purposes.
3
NH
NH2
1
0% H2SO4
O
2
1
NH
NH
NH
NH
NH
NH2
2
2
1
0% H2SO4
H
NH
O
N
NC
O
H
N
O
Synthesis of 1-[4-(1H-indol-3-ylmethyl)-5-oxo-4,5-dihydro-
NH NH
2
O
O
NH
N
H
NH
NH
NH
ꢀ
O
1H-imidazol-2-yl]guanidine 2.
Yield 67%, mp 310 C; IR
1
N
H
NH
NH
À1
NH
NH2
(potassium bromide): cm
3392, 3274, 3212, 3120 (4NH,
NH ), 1679 (C═O); H-NMR: d 10.30 (s, 1H, NH), 9.20
1
0% H2SO4
1
2
3
2
COOH
(
(
s, 2H, 2NH), 7.92(s, 1H, NH), 7.88–7.20 (m, 4H, arom), 6.77
s, 1H, CH), 6.10 (t, 1H, CH), 5.50 (br, 4H, 2NH ), 2.46
); MS m/z (%): M 270 (20.00), 204 (33.10), 185
NH
NH
2
H
N
HOOC
NH
NH
NH2
+
(d, 2H, CH
2
1
0% H2SO4
or
(11.00), 159 (09.70), 130 (100), 77 (22.30). Anal. Calcd for
C H N O (270.29): C, 57.77; H, 5.22; N, 31.09. Found: C,
13 14 6
24
HCl
5
7.98; H, 5.02; N, 30.94.
SO
H
Synthesis of 1-[5-oxo-4-(1H-pyrrol-3-ylmethyl)-4,5-dihydro-
NH
NH
ꢀ
H
N
1H-imidazol-2-yl]guanidine 3.
Yield 81%, mp 263–265 C;
HO S
NH
25
À1
3
NH
NH2
IR (potassium bromide): cm 3408, 3374, 3245, 3183 (4NH,
1
0% H2SO4
1
or
HCl
NH
NH), 7.80 (s, 1H, NH), 7.70–7.15 (m, 3H, Pyrrol), 6.80 (t, 1H,
CH), 5.50 (br, 2H, NH ), 2.65 (d, 2H, CH ); Anal. Calcd for
C H N O (220.23): C, 49.08; H, 5.49; N, 38.16. Found: C,
2
), 1705 (C═O); H-NMR: d 10.00(s, 1H, NH), 9.25 (s, 2H,
2
NH
NH
NH
N
2
2
N
HN
NH
N
NH2
9
12 6
N
N
N
H
49.35; H, 5.34; N, 38.01.
1
0% H2SO4
or
N
N
H
Synthesis of 1-(4-benzyl-5-oxo-4,5-dihydro-1H-imidazol-2-yl)
ꢀ
guanidine 4. Yield 72%, mp 305 C; IR (potassium bromide):
HCl
26
À1
cm
2
3420, 3366, 3226, 3183 (3NH, NH ), 1666 (C═O);
1
H-NMR: d 10.12 (s, 1H, NH), 9.25 (s, 2H, 2NH), 7.24–6.86
(
(
m, 5H, arom), 6.56 (t, 1H, CH), 5.64 (br, 2H, NH ), 2.68
d, 2H, CH ); Anal. Calcd for C11H N O (231.26): C, 57.13;
2 13 5
The reaction mechanism of compounds 20–26 was
preceded via a nucleophilic addition of the amino group
to the cyano group.
2
H, 5.67; N, 30.28. Found: C, 57.31; H, 5.33; N, 30.10.
Synthesis of 1-(1-oxo-5,6,7,7a-tetrahydro-1H-pyrrolo[1,2-c]
ꢀ
imidazol-3-yl)guanidine 5.
(
Yield 88%, mp >340 C; IR
À1
potassium bromide): cm
3381, 3222, 3173 (2NH, NH2),
EXPERIMENTAL
1
1
667 (C═O); H-NMR: d 10.08(s, 1H, NH), 9.12 (s, 1H, NH),
), 3.17 (t, 2H, CH ), 2.67
(m, 2H, CH ), 1.59 (m, 2H, CH ); Anal. Calcd for C H N O
All melting points are uncorrected and were recorded on
Melt-Temp II melting point apparatus. IR spectra were
measured as KBr pellets on a Shimadzu DR-8001 spectro-
meter. 1H and 13C-NMR spectra were recorded on a Varian
Gemini at 400 MHz using TMS as an internal reference and
DMSO-d6 as a solvent. Mass spectra were performed on a
Shimadzu GCMS-QP 1000 mass spectrometer at 70 eV. The
elemental analyses were carried out on a Perkin-Elmer 240C
Microanalyzer. All compounds were checked for their purity
on TLC plates.
6.66 (s, 1H, CH), 5.37 (br, 2H, NH
2
2
2
2
7 11 5
(181.20): C, 46.40; H, 6.12; N, 38.65. Found: C, 46.61; H,
5.98; N, 38.34.
Synthesis of 1-(7-oxo-7,7a-dihydro-1H-imidazo[1,5-c][1,3]
ꢀ
thia-zol-5-yl)guanidine 6.
(potassium bromide): cm
1670 (C═O); H-NMR: d 10.05 (s, 1H, NH), 9.24 (s, 1H, NH),
6.34 (t, 1H,CH), 5.85 (br, 2H, NH ), 4.96 (s, 2H, CH ), 3.54
(d, 2H, CH ); Anal. Calcd for C OS (199.23): C, 36.17;
Yield 74%, mp 320 C; IR
3388, 3227, 3181 (2NH, NH2),
À1
1
2
2
2
6 9 5
H N
General procedure for preparation of compounds 2–26.
Method A. L-Tryptophan, L-histidine, L-phenylalanine, L-proline,
thioproline, b-alanine, D-alanine, DL-aspartic acid, isoleucine,
L-threonine, L-valine, L-glutamic acid, DL-serine, L-asparagine,
L-glutamine, L-arginine, L-lysine, L-citrulline, urea, acetamide,
bezamide, allantion, p-aminobenzoic acid, sulphanilic acid, and
H, 4.55; N, 35.15; S, 16.09. Found: C, 36.19; H, 4.61; N,
34.99, S, 15.97.
Synthesis of 1-(4-oxo-1,4,5,6-tetrahydropyrimidin-2-yl)guanidine 7.
ꢀ
À1
Yield 76%, mp 229 C; IR (potassium bromide): cm 3384, 3220,
1
3189 (3NH, NH
2
), 1681 (C═O); H-NMR: d 9.27 (s, 1H, NH), 8.45
), 3.44 (t, 2H, CH ), 2.65 (t, 2H,
(s, 2H, 2NH), 5.65 (br, 2H, NH
2
2
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

September 2014
Synthesis of Novel Modified Guanidines
1325
CH ); Anal. Calcd for C H N O (155.16): C, 38.70; H, 5.85; N, 45.14.
Found: C, 38.78; H, 5.77; N, 45.02.
Synthesis of 3-(2-carbamimidamido-4-oxo-4,5-dihydro-1H-
2
5 9 5
ꢀ
imidazol-5-yl)propanamide 16.
Yield 82%, mp >320 C; IR
À1
Synthesis of 1-(5-methyl-4-oxo-4,5-dihydro-1H-imidazol-2-yl)
(potassium bromide): cm 3381, 3212, 3133 (3NH, 2NH
2
),
ꢀ
1
guanidine 8. Yield 80%, mp 330 C; IR (potassium bromide):
1682 (2C═O); H-NMR: d 9.21 (s, 1H, NH), 8.04 (s, 2H,
2NH), 6.01 (br, 2H, NH ), 5.11 (t, 1H, CH), 4.88 (br, 2H,
NH ), 2.49 (t, 2H, CH ), 2.07 (m, 2H, CH ); Anal. Calcd for
À1
1
cm 3380, 3222, 3189 (3NH, NH
2
), 1675 (C═O); H-NMR:
2
d 9.11 (s, 1H, NH), 8.84 (s, 2H, 2NH), 5.65 (br, 2H, NH ), 5.12
2
2
2
2
(
q, 1H, CH), 1.98 (d, 3H, CH ); Anal. Calcd for C H N O
C H N O (212.21): C, 39.62; H, 5.70; N, 36.60. Found: C,
7 12 6 2
3
5
9
5
(
155.16): C, 38.70; H, 5.85; N, 45.14. Found: C, 38.78; H, 5.77;
39.69; H, 5.74; N, 36.51.
N, 45.02.
Synthesis of 1-[3-(2-carbamimidamido-4-oxo-4,5-dihydro-
Synthesis of (2-carbamimidamido-4-oxo-4,5-dihydro-1H-
1H-imidazol-5-yl)propyl]guanidine 17.
Yield 68%, mp
ꢀ
ꢀ
À1
imidazol-5-yl)acetic acid 9.
potassium bromide): cm
Yield 83%, mp 262–265 C; IR
270 C; IR (potassium bromide): cm 3381, 3226, 3141 (5NH,
À1
1
(
3
9
(
3424–2808 (OH), 33801, 3210,
2NH
(s, 3H, 3NH), 5.87 (br, 2H, NH
(t, 1H, CH), 3.38 (t, 2H, CH ), 2.16 (q, 2H, CH
CH ); Anal. Calcd for C H N O (240.26): C, 39.99; H, 6.71;
2
), 1662 (C═O); H-NMR: d 9.45 (s, 2H, 2NH), 8.37
), 5.29 (br, 2H, NH ), 5.01
), 1.88 (m, 2H,
1
175 (3NH, NH
2
), 1667 (2C═O); H-NMR: d 10.17(s, H, OH),
2
2
.57 (s, 1H, NH), 8.33 (s, 2H, 2NH), 5.67 (br, 2H, NH
2
), 5.17
2
2
t, 1H, CH), 2.85 (d, 2H, CH ); Anal. Calcd for C H N O
2 6 9 5 3
2
8 16 8
(
199.17): C, 36.18; H, 4.55; N, 35.16. Found: C, 36.24; H,
N, 46.64. Found: C, 40.02; H, 6.74; N, 46.59.
4
.59; N, 35.11.
Synthesis of 1-[5-(4-aminobutyl)-4-oxo-4,5-dihydro-1H-
ꢀ
Synthesis of 1-(5-sec-butyl-4-oxo-4,5-dihydro-1H-imidazol-2-
imidazol-2-yl]guanidine 18.
Yield 78%, mp 225 C; IR
ꢀ
À1
yl)guanidine 10. Yield 87%, mp 285 (dec) C; IR (potassium
(potassium bromide): cm 3388, 3223, 3171 (3NH, 2NH
2
),
À1
1
bromide): cm 3365, 3218, 3165 (3NH, NH ), 1698 (C═O);
1661 (C═O); H-NMR: d 9.13 (s, 1H, NH), 8.16 (s, 2H, 2NH),
2
1
H-NMR: d 9.12 (s, 1H, NH), 8.24 (s, 2H, 2NH), 5.61 (br, 2H,
5.94 (br, 2H, NH ), 5.30 (br, 2H, NH ), 4.97 (t, 1H, CH), 3.23
2
2
NH
.10 (d, 3H, CH
O (197.24): C, 48.72; H, 7.67; N, 35.51. Found: C,
2
), 5.13 (d, 1H, CH), 2.23 (m, 1H, CH), 1.49 (m, 2H, CH
2
),
(t, 2H, CH
2
), 2.48 (q, 2H, CH
2
2
), 1.81 (m, 2H, CH ), 1.42
1
C
3
), 0.97 (t, 3H, CH ); Anal. Calcd for
3
(m, 2H, CH ); Anal. Calcd for C H N O (212.25): C, 45.27;
H, 7.60; N, 39.59. Found: C, 45.30; H, 7.63; N, 39.50.
2 8 16 6
8
H
15
N
5
4
8.85; H, 7.70; N, 35.44.
Synthesis of 1-[5-(1-hydroxyethyl)-4-oxo-4,5-dihydro-1H-
Synthesis of 1-[3-(2-carbamimidamido-4-oxo-4,5-dihydro-
ꢀ
1H-imidazol-5-yl)propyl]urea 19. Yield 74%, mp 325 C; IR
ꢀ
À1
imidazol-2-yl]guanidine 11. Yield 74%, mp 310 (dec) C; IR
(potassium bromide): cm 3383, 3220, 3177 (4NH, 2NH
2
),
À1
1
1
(
(
(
potassium bromide): cm
3NH, NH ), 1674 (C═O); H-NMR: d 10.11 (s, 1H, OH), 9.32
s, 1H, NH), 8.12 (s, 2H, 2NH), 5.61 (br, 2H, NH ), 5.22 (d,
3403 (OH), 3366, 3238, 3167
1666 (2C═O); H-NMR: d 9.19 (s, 1H, NH), 8.10 (s, 2H,
2NH), 6.38 (s, 1H, NH), 5.89 (br, 2H, NH ), 5.58 (br, 2H,
2
2
NH ), 4.94 (t, 1H, CH), 3.13 (t, 2H, CH ), 2.19 (q, 2H, CH ),
2
2
2
2
1
H, CH), 4.86 (m, 1H, CH), 1.48 (d, 3H, CH
3
); Anal. Calcd for
1.55 (m, 2H, CH
2
); Anal. Calcd for C
8
H
15
N
7
O
2
(241.25): C,
C
6
H
11
N
5
O
2
(185.18): C, 38.91; H, 5.99; N, 37.82. Found: C,
39.83; H, 6.27; N, 40.64. Found: C, 39.88; H, 6.30; N, 40.59.
3
8.98; H, 6.03; N, 37.74.
Synthesis of 1-(5-isopropyl-4-oxo-4,5-dihydro-1H-imidazol-
Synthesis of N-carbamoylimidodicarbonimidic diamide 20.
ꢀ
À1
Yield 83%, mp 230 C; IR (potassium bromide): cm 3379,
ꢀ
1
2
-yl)guanidine 12.
Yield 74%, mp 310 (dec) C; IR
3262, 3186 (4NH, NH ), 1674 (C═O); H-NMR: d 9.10
2
À1
(
potassium bromide): cm
3388, 3216, 3164 (3NH, NH
2
),
(s, 2H, 2NH), 8.02 (s, 2H, 2NH), 6.32 (br, 2H, NH
2
), 3.75
1
1
5
687 (C═O); H-NMR: d 9.11 (s, 1H, NH), 8.23 (s, 2H, 2NH),
.55 (br, 2H, NH ), 5.03 (d, 1H, CH), 2.11 (m, 1H, CH), 1.04
(br, 2H, NH ); Anal. Calcd for C O (144.13): C, 25.00;
2
3 8 6
H N
2
H, 5.59; N, 58.31. Found: C, 25.11; H, 5.67; N, 58.23.
(
d, 6H, 2CH ); Anal. Calcd for C H N O (183.21): C, 45.89;
Synthesis of N-(carbamimidoylcarbamimidoyl)acetamide 21.
3
7 13 5
ꢀ
À1
H, 7.15; N, 38.23. Found: C, 45.93; H, 7.17; N, 38.19.
Yield 79%, mp 250 (dec) C; IR (potassium bromide): cm 3381,
1
Synthesis of 3-(2-carbamimidamido-4-oxo-4,5-dihydro-1H-
3260, 3188 (4NH, 2NH
NH), 7.65 (s, 3H, 3NH), 6.85 (br, 2H, NH
Anal. Calcd for C O (143.15): C, 33.56; H, 6.34; N, 48.92.
2
), 1677 (C═O); H-NMR: d 10.07 (s, 1H,
ꢀ
imidazol-5-yl)propanoic acid 13. Yield 70%, mp 245 (dec) C;
IR (potassium bromide): cm 3419–2814 (2OH), 3385, 3219,
3
2
5
2
), 2.08 (s, 3H, CH );
3
À1
4 9 5
H N
1
171 (4NH, NH ), 1664 (2C═O); H-NMR: d 10.23(s, 2H,
Found: C, 33.63; H, 6.41; N, 48.81.
2
OH), 9.23 (s, 2H, NH), 8.24 (s, 2H, NH), 5.61 (br, 2H, NH2),
Synthesis of N-(carbamimidoylcarbamimidoyl)benzamide 22.
ꢀ
À1
.36 (t, 1H, CH), 2.46 (t, 2H, CH
2
), 2.12 (q, 2H, CH
2
); Anal.
Yield 75%, mp 145 C; IR (potassium bromide): cm 3371, 3215,
1
Calcd for C
7
H
11
N
5
O
3
(213.19): C, 39.44; H, 5.20; N, 32.85.
2
3173, 3104 (4NH, NH ); H-NMR: d 11.47 (s, 1H, NH), 8.12
Found: C, 39.51; H, 5.27; N, 32.79.
(s, 3H, 3NH), 7.69–7.25 (m, 5H, arom), 6.22 (br, 2H, NH2);
Synthesis of 1-[5-(hydroxymethyl)-4-oxo-4,5-dihydro-1H-
Anal. Calcd for C H N O (205.22): C, 52.68; H, 5.40; N,
34.13. Found: C, 52.74; H, 5.49; N, 34.04.
9
11 5
ꢀ
imidazol-2-yl]guanidine 14.
Yield 79%, mp 295 (dec) C; IR
À1
(
potassium bromide): cm 3401 (OH), 3341, 3210, 3155 (3NH,
Synthesis of N-[(2,5-dioxoimidazolidin-4-yl)carbamoyl]
1
ꢀ
NH
2
), 1687 (C═O); H-NMR: d 11.03 (s, 1H, OH), 9.22 (s, 1H,
imidodicarbonimidic diamide 23. Yield 81%, mp 270 C; IR
À1
NH), 8.11 (s, 2H, 2NH), 5.60 (br, 2H, NH ), 5.18 (t, 1H, CH),
(potassium bromide): cm
3382, 3265, 3189, 3112 (7NH,
NH ); H-NMR: d 11.67 (s, 1H, NH), 9.43 (s, 1H, NH), 9.27
2
1
4
.17 (d, 2H, CH ); Anal. Calcd for C H N O (171.16): C, 35.09;
2
5
9
5
2
2
H, 5.30; N, 40.92. Found: C, 35.14; H, 5.33; N, 40.86.
(s, 1H, NH), 9.14 (s, 1H, NH), 8.14 (s, 3H, 3NH), 6.32 (s, 1H,
Synthesis of 2-(2-carbamimidamido-4-oxo-4,5-dihydro-1H-
2 6 10 8 3
CH), 5.48 (br, 2H, NH ); Anal. Calcd for C H N O (242.20):
C, 29.76; H, 4.16; N, 46.27. Found: C, 29.81; H, 4.20; N, 46.18.
ꢀ
imidazol-5-yl)acetamide 15.
Yield 88%, mp 263 C; IR
À1
(
1
5
potassium bromide): cm 3323, 3202, 3105 (3NH, 2NH2),
Synthesis of 4-(carbamimidoylcarbamimidamido)benzoic acid 24.
1
ꢀ
À1
691 (2C═O); H-NMR: d 9.25 (s, 1H, NH), 8.17 (s, 2H, NH),
.66 (br, 2H, NH ), 5.19 (t, 1H, CH), 4.10 (br, 2H, NH ), 2.97
); Anal. Calcd for C (198.18): C, 36.36;
H, 5.09; N, 42.41. Found: C, 36.41; H, 5.11; N, 42.38.
Yield 72%, mp 280 (dec) C; IR (potassium bromide): cm
3416–2840 (OH), 3388, 3140 (4NH, NH ), 1685 (C═O);
H-NMR: d 10.55 (s, 1H, OH), 9.47 (s, 2H, 2NH), 8.23 (s, 2H,
2NH), 7.53–6.43 (br, 4H, arom), 4.47 (br, 2H, NH ); Anal.
2
2
2
1
(
d, 2H, CH
2
6 10 6 2
H N O
2
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1
326
A. M. Soliman, S. K. Mohamed, M. A. E. A. A. A. El-Remaily, and H. Abdel-Ghany
Vol 51
Calcd for C H N O (222.22): C, 48.64; H, 5.44; N, 31.51.
Found: C, 48.72; H, 5.51; N, 31.42.
9
12
5
2
P. D.; Meglasson, M. D.; Robinson, D. D.; Stevens, F. C.; Tucker,
J. A.; Vidmar, T. J.; Yu, J. H. J Med Chem, 2001, 44(8), 1231.
[7] J Enzyme Inhib Med Chem, October, 2009, 4, 1.
Synthesis of 4-(carbamimidoylcarbamimidamido)benzenesulfonic
ꢀ
À1
[8] Sutherl, C. J.; Laundy, M.; Price, N. November 2008, or http://
acid 25. Yield 72%, mp >320 C; IR (potassium bromide): cm
3
1
477 (OH), 3395, 3162 (4NH, NH
2
); H-NMR: d 10.34 (s, 1H, OH),
www.malariajournal.com/content/7/1/240.
[9] United States Patent 3,518,818 (1974).
9.24 (s, 2H, NH), 8.07 (s, 2H, 2NH), 7.57–7.12 (br, 4H, arom), 5.14
[
[
10] Expert Opin Ther Pat 2009, 10, 1417.
11] Wolfenden Andersson, R. L.; Cullis, P. M.; Southgate, C. C.
(
br, 2H, NH ); Anal. Calcd for C H N O S (257.27): C, 37.35; H,
2
8 11 5 3
4.31; N, 27.22; S, 12.46. Found: C, 37.44; H, 4.39; N, 27.11; S, 12.20.
B. Biochemistry 1981, 20, 849.
Synthesis of N-9H-purin-6-ylimidodicarbonimidic diamide 26.
[
[
12] Springs, B.; Haake, P. Bioorg Chem 1977, 6, 181.
13] Boudon, S.; Wipff, G.; Maigret, B. J Phys Chem 1990, 94, 6056.
ꢀ
À1
Yield 69%, mp 350 C; IR (potassium bromide): cm 3408, 3388,
1
3
2
5
140 (5NH, NH ); H-NMR: d 10.07 (s, 1H, NH), 9.22 (s, 2H,
NH), 8.12 (s, 2H, 2NH), 7.88 (s, 1H, CH), 6.74 (s, 1H, CH),
.04 (br, 2H, NH ); Anal. Calcd for C H N (219.21): C, 38.35;
2 7 9 9
2
[14] Valizadeh, H.; Fakhari, A. J Heterocyclic Chem 2009, 46, 1392.
[15] Li, C. J.; Chan, T. H. Organic Reactions in Aqueous Media;
Wiley: New York, 1997.
[
[
16] Soliman, A. M. J Heterocyclic Chem 2002, 39, 1.
17] Soliman, A. M.; Mohamed, S. K.; El-Remaily, M. A. A.;
H, 4.14; N, 57.51. Found: C, 38.47; H, 4.19; N, 57.44.
Abdel-Ghany, H. Eur J Med Chem 2012, 47, 138.
18] Soliman, A. M.; El-Remaily, M. A. A.; Sultan Adel, A.;
Abdel-Ghany, H. Synth Commun 2011 (in press).
19] Mohamed, S. K.; Soliman, A. M.; El-Remaily, M. A. A.;
Abdel-Ghany, H. J Heterocyclic Chem 2012 (in press).
[20] Mohamed, S. K.; Soliman, A. M.; El-Remaily, M. A. A.;
Abdel-Ghany, H. J. Heterocyclic Chem. 2012 (in press).
[21] King, F. E.; Acheson, R. M.; Spensley, P. C. J Chem Soc
1948, 1366.
[
REFERENCES AND NOTES
[
[
[
[
[
[
[
1] BBC News Channel Wednesday, 2 January 2008, 16:39 GMT.
2] New York Times, 5 February 2010.
3] Saczewski, F.; Balewski, L. Expert Opin Ther Pat 2009, 10, 1417.
4] Bailey, C. J.; Day, C. Practical Diabetes Int 2004, 21, 115.
5] Kalender, A. Cell Metab 2010, 11(5), 341.
6] Vaillancourt, V. A.; Larsen, S. D.; Tanis, S. P.; Burr, J. E.;
[22] Dolzhenko, A. V.; Dolzhenko, A. V.; Chui, W. K. J Heterocyclic
Chem 2008, 45, 173–176.
Connell, M. A.; Cudahy, M. M.; Evans, B. R.; Fisher, P. V.; May,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet