Facile synthesis of new imidazoles from direct reaction of 2,3-diamino-1,4-naphthoquinone with aldehydes

Article abstract of DOI:10.1002/jhet.582

Figure represented. New imidazoles were easily prepared from 2,3-diamino-1,4-naphthoquinone and stoichiometric quantities of the appropriate aldehydes in dimethyl sulfoxide as a solvent. The reaction proceeded for few hours. The procedure can be generaliz

Full text of DOI:10.1002/jhet.582

July 2011
Facile Synthesis of New Imidazoles from Direct Reaction of
2,3-Diamino-1,4-naphthoquinone with Aldehydes
787
Ashraf A. Aly,a,b* Alaa A. Hassan,a Alan B. Brown,c Kamal M. El-Shaieb,a
and Tarek M. I. Bedaira
aDepartment of Chemistry, Faculty of Science, El-Minia University, 61519-El-Minia, Egypt
bDepartment of Chemistry, College of Science, Al-Jouf University, Sakaka, Al-Jouf, KSA
cChemistry Department, Florida Institute of Technology, 150 W University Blvd, Melbourne,
Florida 32901
*E-mail: ashrafaly63@yahoo.com
Received April 6, 2010
DOI 10.1002/jhet.582
Published online 7 April 2011 in Wiley Online Library (wileyonlinelibrary.com).
New imidazoles were easily prepared from 2,3-diamino-1,4-naphthoquinone and stoichiometric quan-
tities of the appropriate aldehydes in dimethyl sulfoxide as a solvent. The reaction proceeded for few
hours. The procedure can be generalized to different classes of aldehydes. 2-Methyl-1H-naphtho[2,3-
d]imidazole-4,9-dione was also obtained in good yield during refluxing of 2,3-diaminonaphthoquinone
in acetic acid. The structure of the newly synthesized imidazoles was extensively investigated using
NMR experiments.
J. Heterocyclic Chem., 48, 787 (2011).
tivity [8,9] and have attracted the attention of synthetic
chemists for over a century. [10] Imidazoles are subu-
nits of highly significant biomolecules, including biotin,
the essential amino acid histidine, histamine, the pilo-
carpine alkaloids [9], and other alkaloids, which have
been shown to exhibit interesting biological activities,
such as antimicrobial, anticryptococcal, inhibition of ni-
tric oxide synthase, and cytotoxic activities. [11] Imid-
azole derivatives can be further substituted on the
nitrogen atom so that the electron density of the chro-
mophore can be changed. This functionalization will
remove the possibility of tautomerism and introduces a
new potentially useful chemical variable for the optimi-
zation of nonlinear optical (NLO) activity of the
INTRODUCTION
Heterocyclic compounds containing the quinone
group represent an important class of biologically
active molecules [1]. Some benzimidazole-4,7-dione
derivatives have been found to exhibit cytotoxic activ-
ity against human lymphoblastic leukemia, non-Hodg-
kin lymphoma, and other cancer cell lines [2,3]. The
compounds also showed antifungal activities [4] and
inhibited protozoal purine nucleoside phosphorylase.
[5] It was recently reported that some benzimidazole-
dione derivatives strongly inhibited the proliferation of
vascular smooth muscle cells [6] and human umbilical
vein endothelial cells. [7] Imidazoles are common scaf-
folds in many compounds of significant biological ac-
C
V
2011 HeteroCorporation

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A. A. Aly, A. A. Hassan, A. B. Brown, K. M. El-Shaieb, and T. M. I. Bedair
Vol 48
Scheme 1. Synthesis of mono- and bisimidazoles from 2,3-diamino-1,4-naphthoquinone (1).
chromophore (e.g., introduction of groups with suitable
electronic properties). For the practical application of
second-order NLO materials, not only a high hyperpo-
larizability but also good thermal stability is required.
In this respect, promising candidates are (benz)imida-
zole derivatives. [11,12] Due to their optoelectronic
properties, aryl-imidazophenanthrolines play important
roles in materials science and medicinal chemistry
RESULTS AND DISCUSSION
Gentle heating of 2,3-diamino-1,4-naphthoquinone (1)
and various aromatic aldehydes 2a-f at 70ꢀC in the min-
imum amount of DMSO produced the corresponding
imidazoles 3a-f in 74–94% yields (Scheme 1). The yield
of 3f is slightly lower than those of the other products.
The role of DMSO is presumably to cosolubilize start-
ing compounds of markedly different polarities, and per-
haps also to oxidize an intermediate [9]. In similar fash-
ion, reaction of 1 with terephthalaldehyde (4) and iso-
phthalaldehyde (6) gave the bisimidazoles 5 and 7,
respectively. The yield of compound 7 is lower than
that of 5, and the reaction required twice as long (10 h)
as production of 5 (5 h).
MM2 calculations [20] indicate that the cross-linked
compound 7 has a minimum energy of 39.07 Kcal
molꢁ1, whereas the linear bisimidazole 5 has a mini-
mum energy 38.78 Kcal molꢁ1. Consistent with the
thought that rate and yield inversely reflect steric hin-
drance, reaction of 1 with phthalaldehyde (8) did not
give the corresponding bisimidazole 9, even upon pro-
longed heating. Heating of 1 in glacial acetic acid at
reflux afforded 2-methyl-1H-naphtho[2,3-d]imidazole-
4,9-dione (3g; Scheme 1).
[13–15].
2-Phenyl-1H-naphtho[2,3-d]imidazole-4,9-
dione was formed as a side product in the reaction of
2,3-diamino-1,4-naphthoquinone (1) with diethyl benzy-
lidenemalonate [16]. Recently, Ashraf et al. reported
the synthesis of biologically active heterocycles such
as (Z)-methyl 2-[(Z)-2-(4-arylimino)-4-oxo-3-phenyl-
1,3-thiazolidin-5-ylidene]acetates. One derivative of
1,3-thiazolidine showed moderate antiproliferative
in vitro activity against hepatocellular carcinoma Hep-G2,
whereas another 1,3-thiazolidine exhibited effective
antioxidant activity compared to ascorbic acid [17].
Additionally, 4-oxo-3-(propan-2-ylideneamino)-thiazoli-
dine-5-ylidene)acetates have shown antitumor and anti-
oxidant activities [18]. We have recently reported the
synthesis of an imidazolone bearing a paracyclophanyl
moiety from the reaction of paracyclophanyl nitrone
with phenyl isocyanate [19]. To the best of our knowl-
edge, direct preparation of imidazoles derived by 2,3-
diaminonaphthoquinone and the corresponding alde-
hydes has been not reported.
The IR spectrum of each product showed an NH
absorption between 3450–3350 cmꢁ1, two C¼¼O absorp-
tions between 1690–1680 cmꢁ1, and a C¼¼N absorption
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2011
Facile Synthesis of New Imidazoles from Direct Reaction of 2,3-Diamino-
1,4-naphthoquinone with Aldehydes
789
Scheme 2. Condensation mechanism of 1 with aldehydes 2a-f.
CONCLUSION
The reaction of aldehydes with 2,3-diamino-1,4-naph-
thoquinone (1) in DMSO constitutes a facile synthesis
of imidazoles, and reaction of dialdehydes with 1 per-
mits synthesis of symmetrical bisimidazolonaphthoqui-
nones. Compound 3g, formally derived from 1 and acet-
aldehyde, is instead prepared by heating 1 in acetic
acid.
between 1630–1610 cmꢁ1. Each assigned molecular for-
mula is supported by a molecular ion in the mass spec-
trum, and by elemental analysis. NMR signals were
assigned with the aid of COSY, HSQC, and HMBC
EXPERIMENTAL
1
experiments. [21] In the H-NMR of each naphthimida-
zoledione subunit, the imidazole NH gives a broad sin-
Melting points were determined on using open capillaries on
a Gallenkamp melting point apparatus and are uncorrected.
The IR spectra were recorded with Shimadzu 408 instrument
using potassium bromide pellets. NMR spectra were recorded
on a Bruker AV-400 spectrometer (400 MHz for 1H and 100
MHz for 13C). Chemical shifts are expressed as d (ppm) with
DMSO-d6 as a solvent, b ¼ broad, s ¼ singlet, and m ¼ mul-
tiplet. Coupling constants (J) are expressed in Hz. The mass
spectra (70 eV, electron impact mode) were recorded on Var-
ian MAT 312 instruments. Elemental analyses were carried out
at the Microanalytical Center, Cairo University, Egypt. TLC
was performed on analytical Merck 9385 Silica aluminum
sheets (Kieselgel 60) with PF254 indicator. TLC’s were viewed
kmax ¼ 254 nm UV.
glet at dH ¼ 14.5–14.1. The naphthimidazoledione subu-
1
nits appear to have two-fold symmetry; the H signals
are approximate AA‘XX’ patterns at dH ¼ 8.12–8.08
(H-5,8) and 7.87–7.82 (H-6,7). Such symmetry is only
possible if the NH proton exchanges between the two
nitrogens; consistent with this idea, the three 13C lines
observed for each naphthoquinone part structure are
broadened. The aryl groups on C-2 give characteristic
NMR signals. For example, the p-anisyl group of 3b has
a signal for the methoxyl group, at dH ¼ 3.84, to which
the other carbons and protons in the p-anisyl unit corre-
late in stepwise fashion. The imino carbon C-2, which
resonates at dC ¼ 152.5, gives HMBC correlation with
H-20 at dH ¼ 8.18. Similarly, the p-chloro compound 3c
shows HMBC correlation between its imino carbon (dC
¼ 151.3) and H-20 (dH ¼ 8.25). The piperonal derivative
3d gives a two-proton singlet at dH ¼ 6.13 for the meth-
ylene protons, and a three-spin aromatic system for the
benzodioxole unit.
Starting materials. 2,3-Diamino-1,4-naphthoquinone (1)
was prepared according to literature [16].
General procedure: Reactions of 2,3-diaminonaphtha-
lene-1,4-dione (1) with aldehydes 1a-f; synthesis of 2-(sub-
stituted)-1H-naphtho[2,3-d]imidazole-4,9-diones. Equimolar
amounts of 2,3-diaminonaphthalene-1,4-dione (1, 0.188 g, 1
mmol) and the appropriate aldehyde (1 mmol) in DMSO (5–
10 mL) was heated at 70ꢀC for 4–12 h. The reaction was fol-
lowed by TLC analysis The reaction mixture was cooled and
the precipitate obtained was filtered, washed with cold ethanol,
and recrystallized from appropriate solvents.
1
In compound 3f, the H-NMR revealed eight proton
signals for the ethano-bridges, between dH ¼ 2.80–3.32.
The seven paracyclophane aromatic protons appeared
between dH ¼ 6.35–7.08. Compound 3g gave a methyl
singlet at dH ¼ 2.45, in addition to the usual signals for
the naphthimidazoledione substructure.
2-Phenyl-1H-naphtho[2,3-d]imidazole-4,9-dione (3a). Yield
0.233 g (85%), m.p. ¼ 340–341ꢀC (339–342ꢀC) [16].
2-(40-Methoxyphenyl)-1H-naphtho[2,3-d]imidazole-4,9-dione
(3b). Orange crystals (acetonitrile), 0.274 g (90%), mp 320–
322ꢀC (dec). IR: 3400 (NH), 2110 (ArACH), 2920 (AliACH),
1690, 1685 (CO), 1630 (C¼¼N), 1610, 1580 (Ar and C¼¼C)
The NMR spectra of compounds 5 and 7 indicated
their symmetry: each structure showed a single set of
naphthimidazoledione signals, with integrals requiring
two naphthimidazolediones and a single central phenyl-
ene unit. The p-phenylene protons of 5 appeared as a
singlet at dH ¼ 7.85, whereas the m-phenylene group of
7 showed three types of protons as expected. The signal
at dC ¼ 151.91 is assigned as C-2 (C¼¼N) not C-10,
based on its HMBC correlations with H-60 and H-20 (dH
¼ 9.10 and 8.32, respectively), both of which are three
bonds away.
1
cmꢁ1. H-NMR: 14.14 (bs, 1H; NH), 8.18 (d, J ¼ 8.7, 2H; H-
20), 8.08 (m, 2H; H-5,8). 7.83 (m, 2H; H-6,7), 7.09 (d, J ¼
13
8.7, 2H; H-30), 3.84 (s, 3H; OCH3). C-NMR: 161.1 (C-40),
152.5 (C-2), 133.7 (C-6,7), 132.7 (C-4a,8a), 128.5 (C-20),
126.2 (C-5,8), 121.0 (C-10), 114.4 (C-30), 55.3 (CH3). C-3a,9a
and C-4,9 were not observed. MS: m/z: 304 (Mþ, 100), 289
(22), 275 (14), 261 (17), 233 (6), 171 (8), 134 (26), 130 (13),
104 (10), 88 (6), 76 (16). Anal. Calcd. for C18H12N2O3
(304.30): C, 71.05; H, 3.97; N, 9.21. Found: C, 70.90; H,
4.03; N, 9.15.
2-(40-Chlorophenyl)-1H-naphtho[2,3-d]imidazole-4,9-dione
(3c). Violet crystals (ethanol), 0.246 g (80%), mp 300–302ꢀC.
IR: 3450 (NH), 3115 (ArACH), 2950 (AliACH), 1690, 1684
The mechanism of the reaction can be described as
due to condensation reaction between 1 and 2, with par-
tial oxidation, to form intermediate 10. Elimination of
water from 10 would produce imidazoles 3 (Scheme 2).
Dehydration might also occur before oxidation.
(CO), 1628 (C¼¼N), 1594, 1580 (Ar and C¼¼C) cmꢁ1
.
1H-
NMR: 14.46 (bs, 1H; NH), 8.25 (d, J ¼ 7.9, 2H; H-20), 8.12
(m, 2H; H-5,8), 7.87 (m, 2H; H-6,7), 7.64 (d, J ¼ 7.9, 2H; H-
13
30). C-NMR: 151.3 (C-2), 135.3 (C-40), 133.9 (C-6,7), 132.8
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DOI 10.1002/jhet

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A. A. Aly, A. A. Hassan, A. B. Brown, K. M. El-Shaieb, and T. M. I. Bedair
Vol 48
(C-4a,8a), 129.1 (C-30), 128.6 (C-20), 127.5 (C-10), 126.3 (C-
5,8). C-3a,9a and C-4,9 were not observed. MS (FAB): m/z:
CH3). 13C-NMR: 152.6 (C-2), 133.7 (C-6,7), 132.5 (C-4a,8a),
126.1 (C-5,8), 14.0 (CH3). C-3a,9a and C-4,9 were not
observed. MS: m/z: 212 (Mþ, 100), 198 (16), 184 (24), 171
(32), 155 (10), 143 (6), 130 (22), 115 (16), 103 (22), 97 (7),
88 (10), 76 (22), 69 (10), 55 (14), 44 (54). Anal. Calcd.
C12H8N2O2 (212.20): C, 67.92; H, 3.80; N, 13.20. Found: C,
67.80; H, 3.84; N, 13.10.
Reactions of 2,3-diaminonaphthalene-1,4-dione (1) with
dialdehydes 4 and 6. A mixture of 2,3-diamino-1,4-naphtho-
quinone (1, 0.376 g, 2 mmol) and bisaldehyde (0.134 mg, 1
mmol) in DMSO (5–10 mL) was heated at 70ꢀC for 5 h (for
compound 5) and 10 h (for compound 7). The reaction was
followed by TLC analysis. The reaction mixture was cooled
and the precipitate obtained was filtered and recrystallized
from DMF to give pure products 5 or 7.
309 (M
þ
1, 30), 308 (Mþ, 100). Anal. Calcd. for
C17H9ClN2O2 (308.72): C, 66.14; H, 2.94; Cl, 11.48; N, 9.07.
Found: C, 66.00; H, 2.86; Cl, 11.38; N. 9.07.
2-(Benzo[d][1,3]dioxol-5-yl)-1H-naphtho[2,3-d]imidazole-4,9-
dione (3d). Violet crystals (ethanol), 0.299 g (94%), mp 230ꢀC
(dec). IR: 3450 (NH), 3090 (ArACH), 3080 (AliACH), 1685,
1680 (CO), 1625 (C¼¼N), 1592, 1580 (Ar and C¼¼C) cmꢁ1.
1H-NMR: 14.16 (bs, 1H; NH), 8.09 (m, 2H; H-5,8), 7.84 (m,
2H; H-6,7), 7.80 (dd, J ¼ 8.6, 1H; H-60), 7.75 (d, J, 1H; H-
20), 7.09 (d, J ¼ 8.6, 1H; H-50), 6.13 (s, 2H; CH2). 13C-NMR:
147.8 (C-30,40), 133.8 (C-6,7), 132. (C-4a,8a), 126.2 (C-5,8),
123. (C-10), 121.7 (C-60), 108.8 (C-50), 106.6 (C-20), 101.7
(CH2). C-4a,8a and C-10 were observed via HMBC correla-
tions; C-2, C-3a,9a, and C-4,9 were not observed. MS: m/z:
318 (Mþ, 100), 290 (4), 261 (4), 232 (5), 204 (14), 171 (19),
159 (16), 148 (20), 130 (12), 104 (20), 88 (16), 76 (13), 50
(14), 40 (10). Anal. Calcd. for C18H10N2O4 (318.28): C, 67.92;
H, 3.17; N, 8.80. Found: C, 67.80; H, 3.10; N. 8.72.
2,20-(1,4-Phenylene)bis(1H-naphtho[2,3-d]imidazole-4,9-dione)
(5). Orange crystals, (0.451 g, 96%), mp 350–352ꢀC (dec). IR:
3450 (NH), 3100–3060 (ArACH), 2980–2860 (AliACH),
1686, 1680 (CO), 1610 (C¼¼N), 1592, 1570 (Ar and C¼¼C)
1
cmꢁ1. H-NMR: 14.40 (s, 2H; NH), 8.10 (m, 4H; H-5,8), 7.85
2-(Furan-2-yl)-1H-naphtho[2,3-d]imidazole-4,9-dione (3e). Brick
red crystals (methanol), 0.307 g, (76%), mp 340–342ꢀC (dec).
IR: 3420 (NH), 3080 (ArACH), 3065 (AliACH), 1690, 1685
(s, 4H; H-20), 7.82 (m, 4H; H-6,7). 13C-NMR: 186.8 (C-4,9),
161.2 (C-2), 152.1 (C-10), 133.7 (C-6,7), 132.9 (C-4a, 8a),
128.3 (C-20), 126.4 (C-5,8). C-3a,9a were not observed. MS:
m/z: 470 (Mþ, 100), 442 (14), 300 (30), 235 (6), 207 (10),
171 (10), 130 (14), 115 (18), 91 (19). Anal. Calcd. for
C28H14N4O4 (470.44): C, 71.49; H, 3.00; N, 11.91 Found: C,
71.30; H, 3.00; N. 11.80.
(CO), 1615 (C¼¼N), 1590, 1560 (Ar and C¼¼C) cmꢁ1
.
1H-
NMR: 14.5 (bs, 1H; NH), 8.10 (m, 2H; H-5,8), 7.98 (m, 1H;
H-50), 7.86 (m, 2H; H-6,7), 7.36 (m, 1H; H-30), 6.75 (m, 1H;
H-40). MS (FAB): m/z: 264 (Mþ, 100). Anal. Calcd. for
C15H8N2O3 (264.24): C, 68.18; H, 3.05; N, 10.60. Found: C,
68.00; H, 3.00; N. 10.50.
2,20-(1,3-Phenylene)bis(1H-naphtho[2,3-d]imidazole-4,9-dione)
(7). Obtained as orange crystals, 0.385 g (82%), mp 350–
352ꢀC (dec). IR: 3400 (NH), 3106–3070 (ArACH), 2970–2830
(AliACH), 1685, 1680 (CO), 1613 (C¼¼N), 1590, 1574 (Ar
2-(40-[2.2]Paracyclophanyl)-1H-naphtho[2,3-d]imidazole-4,9-
dione (3f). Orange crystals (ethanol), 0.195 g (74%), mp
330ꢀC. IR: 3350 (NH), 3075 (ArACH), 3060 (AliACH), 1684,
1
and C¼¼C) cmꢁ1. H-NMR: 14.58 (b, 1H; NH), 9.10 (bs, 1H;
H-60), 8.32 (dd, J ¼ 7.8, 1.3, 2H; H-20), 8.09 (m, 4H; H-5,8),
7.83 (m, 4H; H-6,7), 7.69 (t, J ¼ 7.8, 1H; H-30). 13C-NMR:
151.9 (C-2), 133.8 (C-6,7), 132.8 (C-4a,8a), 129.6 (C-30),
128.3 (C-20), 126.3 (C-5,8), 125.5 (C-60). C-10, C-3a,9a, and
C-4,9 were not observed. MS (FAB): m/z: 470 (Mþ, 100).
Anal. Calcd. for C28H14N4O4 (470.44): C, 71.49; H, 3.00; N,
11.91. Found: C, 71.34; H, 3.06; N. 11.84.
1680 (CO), 1620 (C¼¼N), 1590, 1584 (Ar and C¼¼C) cmꢁ1
.
1H-NMR: 8.34–8.40 (m, 2H; H-5,8); 8.13–8.18 (m, 2H; H-
6,7), 7.03–7.08 (m, 1H, 80-H; PC-H), 6.85 (d, 1H; 50-H, PC-
H), 6.73 (dd, 1H; 160-H, PC-H), 6.60 (m, 2H; 70-, 150-H, PC-
H), 6.52 (dd, 1H; 130-H, PC-H), 6.35 (dd, 1H; 120-H, PC-H),
3.32 (ddd, 1H; 2-Hs, ethano bridge), 3.22–3.24 (m, 1H; 9-Ha,
ethano bridge), 3.13 (ddd, 1H; 100-Hs, ethano bridge), 3.10–
3.14 (ddd, 1H; 1-Hs, ethano bridge), 3.20 (ddd, 1H; 10-Ha,
ethano bridge), 2.92 (ddd, 1H; 90-Hs, ethano bridge), 2.85
(ddd, 1H; 1-Ha, ethano bridge), 2.80 (ddd, 1H; 20-Ha, ethano
bridge). NH was not observed. 13C-NMR: 179.2 (CO), 178.7
(CO), 153.4 (C¼¼N), 138.6, 137.6, 138.2, 135.3, 134.2, 134.1,
133.6, 133.4, 133.1, 132.9, 132.8, 132.7, 132.5, 131.3, 129.0,
128.7, 127.6, 127.4, 126.5 (PCAC, ArAC), 124.0 (PC-C-5)
36.3 (CH2-1), 35.3 (CH2-9), 35.0 (CH2-1), 33.8 (CH2-2). MS:
m/z: 404 (40), 300 (100), 273 (14), 242 (18), 228 (4), 105
(24), 77 (10). Anal. Calcd. for C27H20N2O2 (404.46): C, 80.18;
H, 4.98; N, 6.93. Found: C, 80.00; H, 5.00; N. 6.90.
Acknowledgment. The Bruker AV-400 NMR spectrometer was
purchased with assistance from the National Science Foundation
(CHE 03-42251).
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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Facile Synthesis of New Imidazoles from Direct Reaction of 2,3-Diamino-
1,4-naphthoquinone with Aldehydes
791
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet