An aminoimidazole and its utility in heterocyclic synthesis

Article abstract of DOI:10.1002/hc.10178

Aminoacetonitrile (1) reacted with acetamidinium chloride to give 4-aminoimidazole (4), which reacted with DMFDMA to yield imidazole derivative 7 and with benzylidinemalononitrile and ethoxymethylene malononitrile to give imidazo[1,5-a]pyrimidine derivatives 12 and 15. Compound 1 reacted with β-crotononitrile to yield pyridine derivative 20. Imidazo[1,2-a]pyridine derivative 23 could be obtained via the reaction of 20 with DMFDMA.

Full text of DOI:10.1002/hc.10178

Heteroatom Chemistry
Volume 14, Number 6, 2003
A
n Aminoimidazole and Its Utility
in Heterocyclic Synthesis
1
2
Yehya M. Elkholy and Ayman W. Erian
1
Department of Chemistry, Faculty of Science, Helwan University, Cairo, Ain-Helwan, Egypt
Department of Chemistry, Faculty of Science, Cairo University, Giza, Egypt
2
Received 14 February 2003
Novel cephalosporins with incorporated aminoi-
midazole rings display both Gram-positive and
Gram-negative antibacterial activity as well as good
ABSTRACT: Aminoacetonitrile (1) reacted with ac-
etamidinium chloride to give 4-aminoimidazole (4),
which reacted with DMFDMA to yield imidazole
derivative 7 and with benzylidinemalononitrile and
ethoxymethylene malononitrile to give imidazo[1,5-
a]pyrimidine derivatives 12 and 15. Compound 1 re-
acted with ꢀ-crotononitrile to yield pyridine deriva-
tive 20. Imidazo[1,2-a]pyridine derivative 23 could
be obtained via the reaction of 20 with DMFDMA.
ꢀ
-lactamase stability [13]. In addition, aminoimida-
zole can serve as an important starting material in
the preparation of azomycin, a naturally occurring
antibiotic [14–17].
We try to develop convenient syntheses of bio-
logically active heterocycles [18–20].
ꢀ
C
2003 Wiley Periodicals, Inc. Heteroatom Chem 14:503–
08, 2003; Published online in Wiley InterScience
5
RESULTS AND DISCUSSION
(
www.interscience.wiley.com). DOI 10.1002/hc.10178
Treatment of aminoacetonitrile (1) with acetami-
dinium chloride (2) in an ethanol/AcOH mixture af-
forded N-cyanomethyl-acetamidine (3). Compound
INTRODUCTION
3
could be cyclized on refluxing AcOH to give the
The aminoimidazole ring structure is of particular
interest especially within the realms of medicinal
chemistry. Several classes of marine natural prod-
ucts possessing this structure were recently discov-
ered and identified [1–7]. Many of these compounds
display biological activities including antibacterial,
anti-inflammatory, anticancer, and antiviral activ-
ity. Synthetic aminoimidazole derivatives, including
target 4-aminoimidazole (4) (Scheme 1).
It reacted readily with a variety of electrophiles
to give unique heterocyclic compounds. Thus, it cou-
pled with phenyldiazonium salt to give the diazo
amino compound 5 as a major and the N-pheny-
limidazole (6) as a minor product [21], which prove
that the amino group is the most nucleophilic center
in the molecule. After reacting the amino group with
dimethylformamide dimethylacetal (DMFDMA) to
give 7, all the coupling trials failed. Treatment with
aniline 7 gave 9 (Scheme 2).
aminohistamine, have been shown to have H
-receptor agonist and antagonist activity [8–12].
Other unrelated aminoimidazole derivatives are se-
lective 5-HT receptor antagonists, which are po-
1
- and
H
2
3
Furthermore, 4 reacted with benzylidene-
tentially useful in the treatment of chemotherapy-
induced emesis [12].
malononitrile (10) to yield imidazo[1,5-a]pyrimidine
derivative 12. This product is assumed to be formed
via addition of the amino group in 4 to the double
bond in 10 to yield a Michael adduct 11, which then
cyclizes and autoxidizes to 12. Similar autoxidation
has been previously reported [22,23]. Compound
Correspondence to: Yehya M. Elkholy; e-mail: y elkholy@
yahoo.com.
ꢀ
c 2003 Wiley Periodicals, Inc.
5
03

5
04 Elkholy and Erian
SCHEME 1
1
2 could also be obtained via reaction of 4 with
ment of 4 with ethoxymethylene malononitrile 14
(Scheme 3).
Attempts to prepare the 1:1 condensation 4-
aminopyrrole derivative 18 via the reaction of
benzaldehyde and subsequent addition of malonon-
itrile to the so-formed Schiff’s base derivative 13.
Similarly, compound 15 could be obtained on treat-
+
-
N
N
N
Ph N N Cl
+
H C
NH2
H C
N
H
N=N-NHPh H C
NH2
3
N
H
3
3
N
Ph
5
4
6
major
minor
DMFDMA
N
H C
N=
N
3
N
H
PhNH2
NMe2
H C
N
3
N
H
7
-
+
Ph.NH
PhN NCl
9
-
N
H C
N=
3
N
NMe2
N=NPh
8
SCHEME 2

An Aminoimidazole and Its Utility in Heterocyclic Synthesis 505
N
CN
CN
N
H C
NH
Ph
3
N
H
10
H C
3
N
N
4
Ph
NC
H N
Ph
2
NC
CN
PhCHO
12
11
CN
CH2
CN
CN
CN
N
EtO
H C
N=CHPh
3
N
H
14
13
N
H C
3
N
N
H N
2
CN
15
SCHEME 3
aminoacetonitrile (1) with ꢀ-aminocrotononitrile
16) failed; the reaction gave the 1:2 condensate
data were obtained from the microanalytical data
unit at Cairo University.
(
product 20 instead. The reaction is believed to pro-
ceed via the acyclic 1:2 condensation intermediate
Acetamidinoacetonitrile (3)
1
9 (Scheme 4).
Compound 20 could be further cyclized to 2-
aminoimidazo[1,2-a]pyridine derivative 21 by boil-
ing in basic medium.
Imidazo[1,2-a]pyridine derivative 23 could be
obtained via reaction of 20 with DMFDMA. The reac-
tion proceeds via the intermediate enamine deriva-
tive 22 (Scheme 5).
A solution of aminoacetonitrile (1) (0.01 mol) and
acetamidinium chloride (2) (0.01 mol) was stirred
overnight in ethanol/AcOH for 2 h. The solvent was
removed and the solid product, so formed, was col-
lected by filtration and crystallized from ethanol.
◦
Yield: 68%; m.p. 116 C. IR (KBr): ν = 3350 (NH );
2
1
2210 (CN). H NMR: δ = 2.40 (s, 3H, CH ); 3.81 (s,
3
2
H, CH
2
), 5.61 (s, 2H, NH
2
). C
4
H
7
N (97.14): calcd
3
C 49.45, H 7.28, N 43.27; found C 49.72, H 7.51, N
3.50.
EXPERIMENTAL
4
All melting points are uncorrected. IR spectra were
recorded (KBr disc) on a Pye Unicam SP-1000 spec-
5
-Amino-2-methyl-1H-imidazole (4)
1
13
trophotometer. H NMR and C NMR spectra were
2
recorded on a Varian EM-390 spectrometer in [ H
6
]
A solution of 3 (0.01 mol) in acetic acid was refluxed
for 2 h. The solvent was removed and the residue
cooled to deposit a solid, which was crystallized from
DMSO as solvent and TMS as internal reference;
chemical shifts δ are reported in ppm. Mass spec-
tra were measured on a Shimadzu GCMS-QP 1000
Ex mass spectrometer at 70 eV. Microanalytical
◦
ethanol. Yield: 70%; m.p. 165 C. IR (KBr): ν = 3400–
1
3350 (NH, NH
2
). H NMR: δ = 2.04 (s, 3H, CH
3
); 6.36

5
06 Elkholy and Erian
CH CN
2
NH2
H N
1
+
CN
H C
3
H C
CN
3
16
17
16
-
NH HSO4
4
NC
-NH3
NH2
H
H C
N
H
3
H C
N-CH CN
3
2
CN
18
NC
CH CN
2
CH3
NH
H C
N
3
19
n
NC
CH3
20
SCHEME 4
s, 1H, imidazole-H), 7.29 (br s, 2H, NH
(
2
), 10.91 (br
Diazotization of 4
1
3
s, 1H, NH). C NMR: (300 MHz, DMSO): δ = 154.92
(C-2), 129.24 (C-4), 119.37 (C-5), 29.14 (CH
3
). C
4
H
7
N
3
Phenyldiazonium chloride (0.01 mol) was added to
a cold mixture of 4 (0.01 mol) and sodium acetate
trihydrate (5 g) in EtOH (30 ml). The mixture was
(97.14): calcd C 49.45, H 7.28, N 43.27; found C 49.61,
H 7.43, N 43.51.
NH2
H C
N
N
Dioxane
TEA /
3
20
NC
CH3
DMFDMA
21
NC
N
NC
NMe2
H C
3
NH
- NHMe2
H C
N
N
3
NC
NC
CH3
CH3
23
22
SCHEME 5

An Aminoimidazole and Its Utility in Heterocyclic Synthesis 507
stirred for 30 min, water was then added, and the
precipitate formed was filtered off and recrystallized
from ethanol.
3 h. The solvent was removed and the solid product,
so formed, was collected by filtration and recystal-
◦
lized from ethanol. Yield: 66%; m.p. 243 C. IR (KBr):
1
ν = 3350, 3220 (NH
s, 3H, CH
H, NH ); 7.63–7.81 (m, 5H, phenyl-H). C14
2
), 2210 (CN). H NMR: δ = 2.04
(
2
3
); 6.24 (s, 1H, imidazole-H), 6.24 (br s,
2-Methyl-5-phenyldiazoamino-1H-imidazole (5)
2
H
11
N
5
◦
1
Yield: 80%; m.p. 181 C. IR (KBr): ν = 3350 (NH). H
NMR: δ = 2.04 (s, 3H, CH ), 6.36 (s, 1H, imidazole-
H), 7.81–7.93 (m, 5H, phenyl-H); 10.91 (s, 1H, NH),
1.95 (s, 1H, NH). C10 (201.26): calcd C 59.67,
H 5.52, N 34.8; found C 59.72, H 5.74, N 34.62.
(249.31): calcd C 67.37, H 4.41, N 28.07; found C
67.51, H 4.42, N 28.31.
3
1
H
11
N
5
Method B (Via 5-Benzylideneamino-2-methyl-
imidazole (13)). A mixture of 4 (0.01 mol) and ben-
zaldehyde (0.02 ml) was refluxed in ethanol and in
the presence of triethylamine (3 ml) for 3 h. The
solid product, so formed, was collected by filtra-
tion and recrystallizd from ethanol Yield: 61%; m.p.
5-Amino-2-methyl-1-phenylimidazole (6)
◦
Yield: 20%; m.p. 201 C. IR (KBr): ν = 3440, 3350
1
◦
1
(
NH
2
). H NMR: δ = 2.03 (s, 3H, CH
3
); 6.36 (s, 1H,
), 7.34–7.65 (m, 5H,
198 C. IR (KBr): ν = 3350 (NH). H NMR: δ = 2.10
(s, 3H, CH ), 6.24 (s, 1H, imidazole-H), 6.5 (s, 1H,
N CH) 7.4–7.6 (m, 5H, phenyl-H), 10.91 (s, 1H,
(185.25): calcd C 71.3, H 5.9, N 22.68;
imidazole-H), 7.29 (br s, 2H, NH
phenyl-H). C10 (173.34): calcd C 69.33, H 6.41,
N 24.26; found C 69.51, H 6.52, N 24.53.
2
3
H
11
N
3
NH). C11
H
11
N
3
found C 71.50, H 6.11, N 22.75.
A solution of 13 (0.01 mol) in ethanol (20 ml) and
in the presence of triethylamine (5 ml) was refluxed
with malononitrile (0.01 mol) for 3 h. The solid prod-
uct, so formed, was collected by filtration and recrys-
tallized from ethanol.
5
-(N,N-Dimethylaminomethylidineamino-2-
methyl-1H-imidazole (7)
A mixture of compound 4 (0.01 mol) and DMFDMA
(0.01 mol) was refluxed in dioxane (20 ml) for 3 h.
The reaction mixture was partially concentrated. The
solid obtained was collected by filtration and re-
4
-Amino-6-methylimidazo[1,5-a]pyrimidine-3-
◦
crystallized from ethanol. Yield: 68%; m.p. 213 C.
carbonitrile (15)
1
IR (KBr): ν = 3210 (NH). H NMR: δ = 2.03 (s, 3H,
CH
3
); 2.51 (s, 6H, NMe
2
); 3.5 (s, 1H, N CH ); 6.58
A mixture of 4 (0.01 mol) and ethoxymethylene-
malononitrile (14) (0.01 mol) in ethanol (20 ml) in
the presence of triethylamine (3 ml) was refluxed for
3 h. The solid product, so formed, was collected by
filtration and recrystallized from ethanol. Yield: 68%;
(
(
5
s, 1H, imidazole-H); 10.92 (s, 1H, NH). C
152.23): calcd C 55.23, H 7.96, N 36.81; found C
5.51, H 8.10, N 36.94.
7
H
12
N
4
◦
1
m.p. 234 C. IR (KBr): ν = 3350 (NH
2
), 2210 (CN). H
5-Anilinomethylidineamino-2-methyl-1H-
NMR: δ = 2.04 (s, 3H, CH ), 6.52 (s, 1H, imidazole-
3
imidazole (9)
H), 6.81 (s, 1H, pyrimidine-H); 7.29 (br s, 2H, NH
(173.2): calcd C 55.47, H 4.08, N 40.4; found
C 55.61, H 4.20, N 40.63.
2
).
A mixture of 7 (0.01 mol) and aniline (0.01 mol)
was refluxed in ethanol (20 ml) for 3 h, and then
left to cool at room temperature. The solid prod-
uct, so formed, was collected by filtration and re-
C
8
H
7
N
5
1
-Cyanomethyl-2,4-dimethyl-1,6-dihydro-6-
◦
crystallized from ethanol. Yield: 66%; m.p. 193 C.
iminopyridine-3-carbonitrile (20)
1
IR (KBr): ν = 3250 (NH). H NMR: δ = 2.05 (s, 3H,
CH
3
); 3.40 (s, 1H, N CH ); 6.82 (s, 1H, imidazole-
A mixture of 1 (0.01 mol) and ꢀ-aminocrotononitrile
(16) (0.02 mol) in ethanol (20 ml) was refluxed in the
presence of sodium hydroxide (5 g) for 3 h. The solid
product, so formed, was collected by filtration and
H), 7.63–7.82 (m, 5H, phenyl-H); 9.05 (br s, 1H,
NH); 10.91 (s, 1H, NH). C11 (200.27): calcd
H
12
N
4
C 65.97, H 6.05, N 27.98; found C 66.10, H 6.31,
N 28.23.
◦
recrystallized from ethanol. Yield: 63%; m.p. 135 C.
1
IR (KBr): ν = 3350 (NH), 2210, 2218 (2CN). H NMR:
δ = 2.10 (s, 3H, 4-methyl), 2.41 (s, 3H, 2-methyl), 4.20
4
-Amino-6-methyl-2-phenylimidazo[1,5-
(s, 2H, CH CN), 6.8 (s, 1H, pyridine-H), 10.81 (s,
2
a]pyrimidine-3-carbonitrile (12)
1
3
1
H, NH). C NMR (300 MHz, DMSO): δ = 165.95
Method A. A mixture of 4 (0.01 mol) and ben-
zylidenemalononitrile (10) (0.01 mol) was refluxed
in ethanol in the presence of triethylamine (3 ml) for
(C-6), 144.31 (C-5), 139.25 (C-3), 125.98 (C-2), 124.28
(C-4), 121.73 (CN), 116.64 (CN), 33.48 (CH
(CH ), 20.52 (CH
2
), 21.01
+
3
3
). MS (EI, 70 eV): m/z = 186 [M ].

5
08 Elkholy and Erian
C
10
H
10
N
4
(186.23): calcd C 64.51, H 5.37, N 30.10;
[4] Morales, J. J.; Rodriguez, A. D. J Nat Prod 1991, 54,
29.
5] Alvi, K. A.; Crews, P.; Laughhead, D. G. J Nat Prod
991, 54, 1684.
6] Bedoya Zurita, M.; Ahond, A.; Poupat, C.; Potier, P.
Tetrahedron 1989, 45, 6713.
7] Walker, R. P.; Faulkner, D. J.; Van Engen, D.; Clardy,
J. J Am Chem Soc 1981, 103, 6772.
8] Nagai, W.; Kirk, K. L.; Cohen, L. A. J Org Chem 1973,
6
found C 64.82, H 5.2, N 30.15.
[
[
[
[
[
1
2
-Amino-5,7-dimethylimidazo[1,2-a]pyridine-6-
carbonitrile (21)
A solution of 20 (0.01 mol) in dioxane (20 ml) in the
presence of triethylamine (3 ml) was refluxed for 3 h.
The solvent was removed and the residue cooled to
deposit a solid, which was crystallized from ethanol.
3
8, 1971.
9] Dismukes, K.; Rogers, M.; Daily, J. W. J Neurochem
1976, 26, 785.
[10] Lipinski, C. A.; La Mattina, J. L.; Hohnke, L. A. J Med
Chem 1985, 28, 1628.
◦
Yield: 71%; m.p. 228 C. IR (KBr): ν = 3400, 3220
1
(NH
2
), 2210 (CN). H NMR: δ = 2.10 (s, 3H, CH
3
),
[
11] Impicciatore, M.; Morini, G.; Chiavarini, M.; Plazzi,
2
(
(
.41 (s, 3H, CH
s, 1H, pyridine-H), 7.29 (br s, 2H, NH2). C10
186.25): calcd C 64.5, H 5.3, N 30.10; found C 64.63,
3
), 6.52 (s, 1H, imidazole-H), 6.80
P. V.; Bordi, F.; Vitali, F. Agents Actions 1986, 18,
H
10
N
4
1
34.
[12] Haaksma, E. E. J.; Donne-Op den Kelder, G. M.;
Timmerman, H.; Weinstein, H. Agents Actions Suppl
H 5.5, N 30.34.
1
991, 313; Ann Drug Data Rep 1993, 15, 513.
[
13] Jung, F.; Boucherot, D.; Delvare, C.; Olivier, A.; Davies,
G. M.; Betts, M. J.; Brown, R.; Stevenson, R.; Joseph,
M.; Kingston, J. F.; Pittam, J. D. J Antibiot 1993, 46,
5
,7-Dimethylimidazo[1,2-a]pyridine-3,6-
dicarbonitrile (23)
9
92.
14] Gomez, E.; Avendano, C.; Mckillopa, A. Tetrahedron
986, 42, 2625.
[
[
A mixture of 20 (0.01 mol) and DMFDMA (0.01 mol)
was refluxed in dioxan (20 ml) for 3 h. The solid
product, so formed, was collected by filtration and
1
15] James, P. C.; Minzohong; Simona, C. J Chem Re-
search (S) 2001, 195.
◦
recystallized from ethanol. Yield: 63%; m.p. 210 C.
[16] Jenkins, T. C.; Naylor, M. A.; O’Neill, P.; Threadgill,
M. D.; Cole, S.; Stratford, I. J.; Adams, G. E.; Fielden,
E.; Suto, M. J.; Stier, M. A. J Med Chem 1990, 33,
1
IR (KBr): ν = 2210, 2218 (2 CN). H NMR: δ = 2.10
(s, 3H, CH
3
), 2.42 (s, 3H, CH ), 6.54 (s, 1H, imidazole-
3
2
603.
17] Adams, G. E.; Stratford, I. J. Biochem Pharm 1986,
5, 71.
H), 6.84 (s, 1H, pyridine-H). C11
C 67.32, H 4.12, N 28.56; found C 67.51, H 4.5, N
8.71.
H
8
N (196.23): calcd
4
[
3
2
[18] Elkholy, Y. M.; Abu-Shanab, F. A.; Erian, A. W. Phos-
phorus Sulfur Silicon 2000, 167, 151.
[19] Abu-Shanab, F. A.; Elkholy, Y. M.; Elnagdi, M. H. Syn-
thetic Commun 2002, 32, 22.
REFERENCES
[
20] Elassar, A. A.; Elkholy, Y. M.; Elnagdi, M. H. Phar-
mazie 1996, 51, 10.
[
[
[
1] Alvi, K. A.; Peters, B. M.; Hunter, L. M.; Crews, P.
Tetrahedron 1993, 49, 329.
2] Tsuda, M.; Shigemori, H.; Ishibashi, M.; Kobayashi,
J. Tetrahedron Lett 1992, 33, 2597.
3] Keifer, P. A.; Schwartz, R. E.; Koker, M. E. S.; Hughes,
R. G.; Rittschof, D.; Rinehart, K. L. J Org Chem 1991,
[21] Elnagdi, M. H.; Erian, A. W. Arch Pharm (Weinheim)
1991, 324, 853.
[22] Elnagdi, M. H.; Abdelrazek, F. M.; Ibrahim, N. S.;
Erian, A. W. Tetrahedron 1989, 45, 3597.
[23] Elgemeie, G. E. H.; Sherif, S. M.; Abdelall, F. A. E. M.;
Elnagdi, M. H. Z Naturforsch 1986, 41b, 781.
5
6, 2965.