Reactivities of 2-aminomethylimidazole: An approach for a synthesis of imidazo[1,5-a]imidazole

Article abstract of DOI:10.3987/com-02-9608

A synthesis of 5-oxo-1H-5,6-dihydroimidazo[1,5-a]imidazole which has 5,5-fused heteroaromatic ring system is described.

Full text of DOI:10.3987/com-02-9608

HETEROCYCLES, Vol. 57, No. 12, 2002, pp. 2393 - 2400, Received, 23rd August, 2002
REACTIVITIES OF 2-AMINOMETHYLIMIDAZOLE: AN APPROACH
FOR A SYNTHESIS OF IMIDAZO[1,5-a]IMIDAZOLE
Sujin Park and Yonghan Kang*
Department of Chemistry and Applied Chemistry, Hanyang University, Ansan,
Kyunggi-do, 425-791, Korea
Abstract – A synthesis of 5-oxo-1H-5,6-dihydroimidazo[1,5-a]imidazole which has
5,5-fused heteroaromatic ring system is described.
INTRODUCTION
Though various synthetic nucleosides were synthesized and reported for the past decades, only a few of
them have been treated as antiviral agents in chemotherapy.1-7 In general, the synthetic nucleosides have
been utilized as mimics of the naturally occurring nucleosides, and the relationships between the modified
structures and the biological activities provided the useful information to antiviral drug design.8-11 The
antiviral agent is very effective when it passes quickly and easily through the membrane because the virus is
transcribed and replicated in the nucleus of the host cell. In accordance with this aspect, 5,5-fused
heteroaromatic ring system is considered as an alternative aglycon in nucleoside.
5-Oxo-1H-5,6-dihydroimidazo[1,5-a]imidazole (2) which is smaller than the purine and has a similar
structural relationship with guanine (1) was selected as the target molecule (Figure 1).
O
N
O
H
N
H
N
N
N
N
H
H2N
N
H
1
2
Figure 1. Structural similarity between guanine (1) and 5-oxo-1H-5,6-dihydroimidazo[1,5-a]imidazole (2).
*To whom correspondence should be addressed. Tel: +82-31-400-5495; Fax: +82-31-407-3863; e-mail:
yhmkang@hanyang.ac.kr

From a retro-synthesis of 5-oxo-1H-5,6-dihydroimidazo[1,5-a]imidazole (2), two components were
obtained, i.e., 2-aminomethylimdazole and carbonyl compound which is substituted with two leaving
groups (Figure 2).
O
O
N
H
N
N
HN
2
L
L
N
H
N
H
L = leaving group
2
Figure 2. Retro-synthesis (I) of 5-oxo-1H-5,6-dihydroimidazo[1,5-a]imidazole (2).
2-Aminomethylimidazole (4) was prepared by using imidazole as a starting material in accordance with
the synthetic method in the literaures12-14 as shown in Scheme 1.
Bz
N
N
N
N
a
b
2 HCl
NH2
N
H
N
H
N
N
Bz
Bz
3
4
o
(a) BzCl, MeCN, Et3N, 20 C, 15 h; (b) i-PrOH saturated with HCl(g), MeOH, reflux, 24 h.
Scheme 1
The treatment of a solution of imidazole in anhydrous acetonitrile under ice cooling with excess benozyl
chloride followed by addition of triethylamine provided 1-benzoyl-2-(1,3- dibenzoyl-4-imidazolin-2-yl)-
imidazole (3).12 The compound (3) was converted into 2-aminomethylimidazole dihydrochloride (4)13,14
1
by ring opening reaction and the following 1,5-hydrogen shift in acidic medium. H NMR spectrum of 4
was identical with that reported previously.13
1,1’-Carbonyldiimidazole was selected as the carbonyl transfer reagent to insert between the
2-aminomethyl and N-1 of imidazole ring of 4. After the treatment of 4 with sodium hydrogen carbonate
o
in DMF, the obtained free amine of 4 was reacted with 1,1’-carbonyldiimidazole at 120 C to provide a
colorless needle (5) after purification. 1H NMR spectrum of the isolated product (5) showed the methylene
group at 4.25 ppm, aromatic protons at 6.95 ppm and two protons at 11.93 and 6.50 ppm which
disappeared on the addition of D2O. The compound (5), therefore, was identified as 1,3-bis-
[(1H-imidazol-2-yl)methyl]urea (Scheme 2). It was assumed the result was brought by higher
nucleophilicity of aminomethyl group than that of aromatic ring nitrogen.

N
H
N
H
N
N
Carbonyl diimidazole,
NaHCO3 / DMF
N
NH2
2 HCl
N
H
N
H
N
H
reflux, 1 h
O
5
4
O
H
N
N
N
H
2
Scheme 2
To induce the cyclization, another attempt to bring the carbonyl group at the imidazole nitrogen was
carried out according to retro-synthesis (II) as shown in Figure 3.
O
N
H
N
N
H
NH2
X
N
N
or
N
C
N
H
O
N
H
O
X
2
Figure 3. Retro-synthesis (II) of 5-oxo-1H-5,6-dihydroimidazo[1,5-a]imidazole (2).
It was necessary to protect the 2-aminomethyl group before the construction of the formate group at N-1
of the imidazole (4). Through the reaction of 2-aminomethylimidazole dihydrochloride (4) with benzyl
o
chloride in the presence of triethylamine at 50-60 C, 2-(N,N-dibenzylaminomethyl)imidazole (6) was
separated with 62% yield. As the reaction temperatures being increased, the amount of the tribenzyl
substituted product, 1-benzyl-2-(N,N-dibenzylaminomethyl)imidazole, increased. The anion which was
prepared from the treatment of 6 with sodium hydride in DMF was treated with ethyl chlorformate at
1
room temperature to provide N-ethoxycarbonyl-2-(N,N-dibenzylaminomethyl)imidazole (7). From H
NMR spectrum of 7, ethyl formate group was observed as three protons as a triplet at 1.27 ppm and two
protons as a quartet at 4.29 ppm, respectively. The compound (7) presented a labile reactivity. The ethyl
formate group of 7 was easily detached to return to the starting material (6) in polar protic solvents, and
furthermore, a large amount of 6 was isolated after silica gel column chromatography of 7 by using
dichloromethane-methanol (100:1, v/v) as an eluent. The further reaction of 7 did not proceed since a
suitable solvent for 7 was not found. Prior to undergoing the debenzylation, the breakaway of the ethyl
formate group from 7 was occurred during catalytic hydrogenation (Scheme 3).
In consideration of the previous result, 2-aminomethylimidazole dihydrochloride (4) was reacted with
excess of ethyl chloroformate in presence of triethylamine to provide N-ethoxycarbonyl-2-(N-ethoxy-

carbonylaminomethyl)imidazole (8) which was converted into 2-(N-ethoxycarbonylaminomethyl)-
imidazole (9) in acidic medium [30% ethanol(aq):conc. HCl = 150:1, v/v] (Scheme 4).
N
Bn
N
Bn
N
N
N
a
b
c
2 HCl
NH2
N
H
Bn
Bn
N
H
N
O
OEt
4
6
7
o
(a) BnCl, Et3N, DMF, 50-60 C, 2 h; (b) NaH, ethyl chloroformate, DMF, rt, 2 h;
(c) SiO2 column chromatography or in polar protic solvents.
Scheme 3
For the cyclization of 9 to 5-oxo-1H-5,6-dihydroimidazo[1,5-a]imidazole (2), the compound (9) was
heated with ethylene glycol over 250 oC in the presence of potassium hydroxide to result in the formation
of an intractable mixture. On the other hand, compound (9) was treated with DBU in dry DMF, followed
o
by heating at 120 C for 6 h to give a mixture of several products. Thin-layer chromatographic analysis
indicated that five or more components were present in the mixture. Consequently, relatively pure
5-oxo-1H-5,6-dihydroimidazo[1,5-a]imidazole (2) was obtained by silica gel column chromatography of
the mixture and several recrystallization from methanol. The structure of 2 was confirmed by an
1
1
examination of its H NMR spectrum and elemental analysis. H NMR spectrum of 2 exhibited one
aromatic proton singlet at 7.01 ppm which was not observed from the previous compound (9).
O
H
N
H
N
N
N
a
c
b
H
N
N
4
OEt
OEt
N
H
N
N
H
O
O
O
OEt
8
9
2
(a) Ethyl chloroformate, Et3N, DMF, 100oC, 2 h; (b) 30% EtOH(aq):conc. HCl (150:1, v/v), rt, 16 h;
(c) DBU, DMF, 120 oC, 6 h.
Scheme 4
EXPERIMENTAL
Materials and instruments. All chemicals used were purchased from commercial sources with an
analytical grade. The solvents were purified by distillation and the other reagents were used without
1
further purification. H NMR spectra were measured at 300 MHz using a Varian Unity Plus 300
spectrometer. The chemical shift values are reported as δ downfield from TMS as an internal standard.

Melting points were determined on a Büchi 530 and a Mettler FP62 melting point apparatus and were
uncorrected. UV spectra were performed on a Perkin Elmer Lambda 7, and the samples were prepared as a
concentration of 10-2 molL-1. Elemental analyses were performed by Fisions EA 1108.
1-Benzoyl-2-(1,3-dibenzoyl-4-imidazolin-2-yl)imidazole (3). To a stirred solution of imidazole (6.8 g,
0.1 mol) in dry acetonitrile (200 mL), cooled in an ice-bath, was added benzoyl chloride (42 mL, 0.4 mol)
dropwise followed by triethylamine (56 mL, 0.4 mol). The mixture was allowed to warm to rt and stirred
for 15 h. The precipitation was filtered and washed with water. The solid residue was recrystallized from
methanol to give 3 as a colorless needle (33 g, 74%): mp 202 °C (lit.,12 203 ℃); Rf = 0.41 (silica gel,
1
n-hexane: acetone = 1:1, v/v); H NMR (CDCl3) δ 7.80~7.50 (m, 16H, C5H and Ph × 3), 7.30 (s, 1H,
C2’H), 7.04 (s, 1H, C4H), 6.50 (s, 2H, C4’H and C5’H).
2-Aminomethylimidazole dihydrochloride (4). To a stirred solution of 3 (9 g, 0.02 mol) in dry methanol
(100 mL) was added isopropanol (20 mL) saturated with hydrogen chloride at 0 oC. The reaction mixture
was heated under reflux for 24 h. The mixture was allowed to cool to rt, after which it was evaporated to
dryness. The resulting solid was washed with acetone (50 mL) and recrystallized from methanol to give 4
o
as a colorless powder (2.3 g, 68%): mp 253 ℃ (lit., 256 ℃13 and 240-242 C14); Rf = 0.03 (silica gel,
1
CH2Cl2:MeOH = 9:1, v/v); H NMR (DMSO-d6) δ 11.2 (br, NH2), 7.72 (s, 2H, C4H and C5H), 4.48 (s,
2H, CH2).
1,3-bis-[(1H-imidazol-2-yl)methyl]urea (5). A suspension of 4 (1.7 g, 0.01 mol), NaHCO3 (3.3 g, 0.04
mol), and 1,1’-carbonyldiimidazole (2.28 g, 0.014 mol) in dry DMF (100 mL) was heated at 120 oC for 1
h. The precipitated insoluble material was filtered off and the filtrate was evaporated to dryness in vacuo.
The resulting solid was dissolved in dichloromethane (100 mL). The organic layer was washed with water
(100 mL), dried over Na2SO4, filtered, and evaporated to dryness. The residue was applied to a silica gel
column in dichloromethane. The fraction which was eluted with dichloromethane-methanol (10:1, v/v)
was then recrystallized from methanol to provide 5 as a colorless needle (0.58 g , 53%): mp 212 ℃; Rf =
0.65 (silica gel, CH2Cl2:MeOH = 9:1, v/v); 1H NMR (DMSO-d6) δ 11.93 (s, 1H, N1H), 7.02 and 6.86 (br s,
1H x 2, C4H and C5H), 6.50 (br, 1H, NH), 4.25 (s, 2H, CH2). Anal. Calcd for C9H12N6O: C, 49.08; H,
5.49; N, 38.16. Found: C, 49.43; H, 5.29; N, 37.87.
2-(N,N-Dibenzylaminomethyl)imidazole (6). To a mixture of 4 (1.7 g, 0.01 mol) and triethylamine (5.6
mL, 0.04 mol) in dry DMF (100 mL) was added benzyl chloride (2.5 mL, 0.02 mol) dropwise. The
reaction mixture was heated at 50 ~ 60 °C for 2 h, filtered and filtrate evaporated to dryness in vacuo. The
resulting solid was dissolved in dichloromethane (50 mL). The organic layer was washed with water (50
mL), dried over Na2SO4, filtered, and evaporated to dryness. The residue was recrystallized from n-hexane
to give 6 as a yellow powder (1.72 g, 62%): mp 138 ℃; Rf = 0.48 (silica gel, CH2Cl2:MeOH = 9:1, v/v);

1H NMR (DMSO-d6) δ 11.85 (s, 1H, N1H), 7.43~7.21 (m, 10H, Ph × 2), 6.96 (s, 2H, C4H and C5H), 3.58
(s, 2H, N-CH2), 3.52 (s, 4H, Ph-CH2×2); 13C NMR (DMSO-d6) δ 144.45 (C1 and C2), 138.56 (C6),
128.46 (C-m), 127.97 (C-o), 126.68 (C-p), 56.53 (C-5), 50.03 (C-4); UV (MeOH) λmax 209 nm
(logε4.40). Anal. Calcd for C18H19N3: C, 77.95; H, 6.90; N, 15.15. Found: C, 77.72; H, 7.09; N, 14.98.
N-Ethoxycarbonyl-2-( N,N-dibenzylaminomethyl)imidazole (7). To a stirred solution of 6 (0.4 g, 1.4
mmol) in dry DMF (50 mL), cooled in an ice-bath, was added sodium hydride (0.06 g, 2 mmol, 80 % in
mineral oil) portionswise, and then ethyl chloroformate (0.19 mL, 2 mmol) was added dropwise. The
reaction mixture was allowed to warm to rt and stirred for 2 h. The precipitation was filtered off and
filtrate evaporated to dryness in vacuo. The residue was dissolved in dichloromethane (50 mL). The
organic layer was washed with water (50 mL), dried over Na2SO4, filtered, and evaporated to dryness. The
residue was subjected to flash chromatography using dichloromethane-methanol (100:1, v/v) to give 7 as a
1
yellow powder (0.36 g, 71%): Rf = 0.77 (silica gel, CH2Cl2:MeOH = 9:1, v/v); H NMR (DMSO-d6) δ
7.48 (d, J = 1.7 Hz, 1H, C5H), 7.23~7.20 (m, 10H, Ph × 2), 6.95 (d, J = 1.7 Hz, 1H, C4H), 4.29 (q, J = 7.1
Hz, 2H, O-CH2), 3.98 (s, 2H, N-CH2), 3.69 (s, 4H, Ph-CH2 × 2) 1.27 (t, J = 7.2 Hz, 3H, CH3). This
compound did not give a correct elemental analysis and was used in the next step without further
purification.
N-Ethoxycarbonyl-2-(N-ethoxycarbonylaminomethyl)imidazole (8). To a stirred suspension of 4 (5 g,
0.03 mol) and triethylamine (16.8 mL, 0.12 mol) in dry DMF (250 mL) was ethyl chloroformate (8.7 mL,
o
0.08 mol) dropwise. The reaction mixture was heated at 100 C for 2 h. After cooling to rt, the
precipitation was filtered off and filtrate evaporated to dryness in vacuo. The residue was dissolved in
ethyl acetate (100 mL). The organic layer was washed with water (100 mL), dried over Na2SO4, filtered,
and evaporated to dryness. The residue was subjected to flash chromatography using
dichloromethane-methanol (100:1, v/v) to give 8 as a yellow syrup (5.28 g, 73%): Rf = 0.55 (silica gel,
CH2Cl2:MeOH = 9:1, v/v); 1H NMR (DMSO-d6) δ 7.57 (s, 1H, NH), 7.11 (s, 1H, C5H), 6.87 (s, 1H, C4H),
4.23 (d, J = 5.4 Hz, 2H, N-CH2), 4.03~3.92 (m, 4H, O-CH2), 1.26 (t, J = 7.5 Hz, 3H, CH3), 1.15 (t, J =
7.1 Hz, 3H, CH3); 13C NMR (DMSO-d6) δ 126.42 (C1), 119.62 (C2), 62.54 (C6), 59.76 (C9), 39.95 (C4),
16.24 (C10), 14.70 (C7); UV (MeOH) λmax 215 nm (logε3.92), 333 (2.05), 375 (1.60). This
compound did not give a correct elemental analysis and was used in the next step without further
purification.
2-(N-Ethoxycarbonylaminomethyl)imidazole (9). To a solution of 8 (3.1 g, 0.13 mol) in 30% aqueous
ethanol (150 mL) was added conc. HCl (1 mL). The reaction mixture was stirred at rt for 16 h, neutralized
with saturated aqueous NaHCO3 solution, and evaporated to dryness. The residue was dissolved in ethyl
acetate (100 mL). The organic layer was washed with water (100 mL), dried over Na2SO4, filtered, and
evaporated to dryness. The resulting solid was recrystallized from ethanol to give 9 as a yellow powder

1
(1.5 g, 69%): mp 132 ℃; Rf = 0.13 (silica gel, CH2Cl2:MeOH = 9:1, v/v); H NMR (DMSO-d6) δ 11.73
(br s, 1H, N1H), 7.49 (s, 1H, NH), 6.98 and 6.79 (br s, 1H x 2, C4H and C5H), 4.18 (d, J = 6.0 Hz, 2H,
13
N-CH2), 4.00 (q, J = 7.2 Hz, 2H, O-CH2), 1.16 (t, J = 7.2 Hz, 3H, CH3); C NMR (DMSO-d6) δ 156.16
(C5), 144.96 (C3), 127.02 (C2), 115.97 (C1), 59.77 (C6), 38.67 (C4), 14.68 (C7); UV (MeOH) λmax
210 nm (logε4.05). Anal Calcd for C7H11N3O2: C, 49.70; H, 6.55; N, 24.84. Found: C, 49.32; H, 6.88; N,
24.50.
5-Oxo-1H-5,6-dihydroimidazo[1,5-a]imidazole (2). To a solution of 9 (1.7g, 0.01 mol) in dry DMF (50
mL) was added DBU (3.5 mL, 0.023 mol) dropwise, and the reaction mixture was heated at 120 oC for 6 h.
After cooling to rt, the resulting solution was neutralized with saturated aqueous NaHCO3 solution, and
evaporated to dryness. The residue was subjected to flash silica gel column chromatography. The fraction
which was eluted with dichloromethane-methanol (10:1, v/v) was then recrystallized from methanol to
provide 2 as a yellow powder (0.52 g, 43%): mp 273 ℃(decomp); Rf = 0.15 (silica gel, CH2Cl2:MeOH =
5:1, v/v); 1H NMR (DMSO-d6) δ 7.01 (s, 1H, C7H), 6.71(d, J = 6.0 Hz, 1H, C2H), 7.33(d, J = 6.0 Hz, 1H,
C3H), 11.53 (br s, 1H, N6H), 10.88 (br s, 1H, N1H). Anal. Calcd for C5H5N3O: C, 48.78; H,4.09; N,
34.13. Found: C, 48.49; H, 4.29; N, 33.89.
ACKNOWLEDGEMENT
This work was supported by Hanyang University, Korea, made in the program year of 2000.
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